Download OIE International Standards on Antimicrobial Resistance, 2003

OIE International Standards
on
Antimicrobial Resistance,
2003
OIE Headquarters, Paris, 2 to 4 October 2001
OIE publication with the participation of the
OIE Collaborative Centre on Veterinary Medicinal
Products, Fougères
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OIE (World organisation for animal health), 2003
(reprinted in April and November 2004)
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Contents
Contents
Introduction .............................................................................................................................. 1
OIE International Standards on Antimicrobial
Resistance
Terrestrial Animal Health Code
Guidelines for the harmonisation of antimicrobial resistance surveillance
and monitoring programmes .................................................................................................. 5
Guidelines for the monitoring of the quantities of antimicrobials used in
animal husbandry..................................................................................................................... 13
Guidelines for the responsible and prudent use of antimicrobial agents in
veterinary medicine.................................................................................................................. 17
Manual of Diagnostic Tests and Vaccines for Terrestrial
Animals
Laboratory methodologies for bacterial antimicrobial susceptibility testing ................ 29
Proceedings of the OIE International Conference
1. General aspects
J. Acar & B. Röstel
Antimicrobial resistance: an overview ......................................................................... 45
J. Threlfall
Antimicrobial drug resistance from salmonellas in humans and
food animals: the current situation in relation to foodborne
zoonoses in the United Kingdom ................................................................................ 69
S. Benredjeb & A. Hammami
Resistance in salmonellae: the situation in developing countries................................. 71
J.-L. Martel
Resistant bacteria and their impact on therapy in veterinary
medicine ........................................................................................................................... 72
P. Nordmann
New resistance mechanisms – review of the diversity.............................................. 73
OIE International Standards on Antimicrobial Resistance, 2003
III
Contents
M.H. Nicolas-Chanoine & S. Granier
Possibilities of characterising resistance genes for use as an
epidemiological tool ....................................................................................................... 74
O. Fortineau
The perception of veterinary practitioner with regard to the
contribution of the use of antimicrobials in animal husbandry to
the problems of human health associated with resistant bacteria........................... 79
O.G. Pedersen
The pig producer’s position as herd manager following the
cessation of the use of antibiotic growth promoters in Denmark.......................... 80
B. Andrews
Antimicrobial use in animal husbandry and its relationship to
resistant bacteria in human health................................................................................ 85
S. Sirinavin
Perception of society with regard to the contribution of the use
of antimicrobials in animal husbandry to the problems of human
health associated with resistant bacteria: the situation in
developing countries........................................................................................................ 89
L.Y Lefferts
A consumer perspective: to what extent does antimicrobial use
in animal husbandry contribute to resistance associated human
health problems? ............................................................................................................. 90
Y. Cheneau
Activities of the Food and Agriculture Organization in relation
to antimicrobial resistance in humans and animals ................................................... 95
R. Williams
The activities of the World Health Organization in antimicrobial
resistance .......................................................................................................................... 99
A. Bruno
Codex activities in relation to antimicrobial resistance...........................................100
2. Surveillance of antimicrobial consumption
†T. Nicholls, J. Acar, F. Anthony, A. Franklin, R. Gupta, Y. Tamura,
S. Thompson, E.J. Threlfall, D. Vose, M. van Vuuren, D.G. White,
H.C. Wegener & M.L. Costarrica
Antimicrobial resistance: monitoring the quantities of antimicrobials
used in animal husbandry ............................................................................................109
G. Moulin
Surveillance of antimicrobial consumption activities in France ............................118
IV
OIE International Standards on Antimicrobial Resistance, 2003
Contents
D.L. Monnet, F. Bager & L. Larsen
Surveillance of antimicrobial consumption in Denmark........................................122
J.J. Webber
Antimicrobial resistance: monitoring the quantity of antimicrobials
used in animal husbandry ............................................................................................123
T. Mudd
The global usage of antimicrobials for animals health............................................128
3. Risk analysis
D. Vose, J. Acar, F. Anthony, A. Franklin, R. Gupta, †T. Nicholls, Y.
Tamura, S. Thompson, E.J. Threlfall, M. van Vuuren, D.G. White,
H.C. Wegener & M.L. Costarrica
Antimicrobial resistance: risk analysis methodology for the potential
impact on public health of antimicrobial resistant bacteria of animal
origin ............................................................................................................................... 133
M. Wooldridge
Risk assessment techniques – and antibiotic resistance.......................................... 162
L. Tollefson
Impact of resistant campylobacteriosis in humans due to
fluoroquinolone use in chickens................................................................................. 170
M. van Vuuren
Antimicrobial resistance and risk analysis: the view of a developing
country............................................................................................................................ 174
L.A. Cox
Campylobacter risk analysis: a cause-and-effect view ................................................. 177
4. Surveillance of resistance programme
A. Franklin, J. Acar, F. Anthony, R. Gupta, †T. Nicholls, Y. Tamura,
S. Thompson, E.J. Threlfall, D. Vose, M. van Vuuren, D.G. White,
H.C. Wegener & M.L. Costarrica
Antimicrobial resistance: harmonisation of national antimicrobial
resistance monitoring and surveillance programmes in animals and in
animal-derived food......................................................................................................181
P.J. Fedorka-Cray, M.L. Headrick & L. Tollefson
The National Antimicrobial Resistance Monitoring System (NARMS) ..............200
V. Jarlier
Surveillance of resistance – human/animal coordinated approaches in
France ............................................................................................................................205
OIE International Standards on Antimicrobial Resistance, 2003
V
Contents
Y. Tamura
The Japanese Veterinary Antimicrobial Resistance Monitoring System
(JVARM) ........................................................................................................................206
T.T.T. Phuong
Cases of antimicrobial resistance to some pathogens in Vietnam ........................211
S. Kariuki, G. Revathi & C.A. Hart
Antimicrobial resistance surveillance in Kenya: achievements and
challenges .......................................................................................................................216
5. Laboratory methods
D.G. White, J. Acar, F. Anthony, A. Franklin, R. Gupta, †T. Nicholls,
Y. Tamura, S. Thompson, E.J. Threlfall, D. Vose, M. van Vuuren,
H.C. Wegener & M.L. Costarrica
Antimicrobial resistance: standardisation and harmonisation of
laboratory methodologies for the detection and quantification of
antimicrobial resistance................................................................................................223
I. Phillips
Standardisation of antimicrobial susceptibility testing in Europe: the
work of the European Committee for Antimicrobial Susceptibility
Testing (EUCAST) .......................................................................................................239
T.R. Shryock
National Committee for Clinical Laboratory Standards: a perspective
on antimicrobial susceptibility testing methods.......................................................243
I.S.T. Fisher, O.N. Gill, W.J. Reilly, H.R. Smith & E.J. Threlfall
Harmonisation of antimicrobial resistance testing results – the outcome
of the international Enter-net study ..........................................................................245
6. Prudent use and containment of resistance
F. Anthony, J. Acar, A. Franklin, R. Gupta, †T. Nicholls, Y. Tamura,
S. Thompson, E.J. Threlfall, D. Vose, M. van Vuuren & D.G. White
Antimicrobial resistance: responsible and prudent use of antimicrobial
agents in veterinary medicine......................................................................................249
D.L. Smith & J.A. Johnson
Antibiotic use in animals and the emergence of antibiotic resistance in
human commensal microbes and zoonotic pathogens...........................................267
I.M. Gould
Prudent use of antibiotics and containment of antimicrobial resistance:
the role of medical associations, guidelines and interventions ..............................273
VI
OIE International Standards on Antimicrobial Resistance, 2003
Contents
J. Edwards
Prudent use of antibiotics and containment of antimicrobial resistance .............276
B. Jennings
Prudent use and containment of antimicrobial resistance – the work of
the responsible use of medicines in agriculture alliance .........................................279
D.K. Byarugaba
Prudent use and containment of antimicrobial resistance in developing
countries .........................................................................................................................280
Web links ...............................................................................................................................285
OIE International Standards on Antimicrobial Resistance, 2003
VII
Introduction
Introduction
The increasing antimicrobial resistance of important human pathogenic bacteria, and
the spread of such bacteria from the closed environment of hospitals into surrounding
communities, are increasingly perceived as threats to public health. Any use of
antimicrobials, whether in humans, animals, plants or food-processing, may lead to
bacterial resistance. The use of antimicrobials in livestock production is thought to
significantly contribute to the phenomenon, but little is known about the true causes
of antimicrobial resistance. The lack of relevant scientific data means that risk
managers must take precautionary measures, even though the underlying causes of
public health risks associated with resistant bacteria may not have been adequately
identified.
Increasing international travel and international trade in animals and animal products
may spread resistance world-wide.
The OIE (World organisation for animal health) is developing international standards
on antimicrobial resistance to enable Member Countries to protect themselves,
without setting up unjustified sanitary barriers. These standards are consistent with the
OIE’s missions to:
• guarantee the safety of world trade by developing sanitary rules for international
trade in animals and animal products,
• inform governments on the existence and evolution of animal diseases and
zoonoses including their control measures,
• coordinate, at the international level, studies and investigations on surveillance and
control of animal diseases and zoonoses.
The main normative works produced by the OIE are: the Terrestrial Animal Health
Code, the Manual of Diagnostic Tests and Vaccines for Terrestrial Animals, the Aquatic Animal
Health Code and the Manual of Diagnostic Tests and Vaccines for Aquatic Animals.
The OIE normative works are recognised by the World Trade Organization (WTO)
as international sanitary standards. They are developed by elected Specialist
Commissions and Working Groups which bring together internationally renowned
scientists, most of whom are experts within the network of 156 Collaborating Centres
and Reference Laboratories which also contribute to the scientific objectives of the
OIE. Specific recommendations were elaborated in five subject areas1 by the ‘OIE ad
1
1. Risk analysis and antimicrobial resistance, 2. Prudent use and containment of antimicrobial
resistance, 3. Surveillance of antimicrobial consumption in animal husbandry, 4. Resistance surveillance
programmes, 5. Laboratory Methods – Standardisation and Harmonisation
OIE International Standards on Antimicrobial Resistance, 2003
1
Introduction
hoc on Antimicrobial Resistance’ created in 1999. The standards proposed to the OIE
International Committee were adopted in May 2003.
Countries which import animals and animal products can now legaly use these
standards to verify whether or not exporting countries are complying with these new
requirements. The second OIE International Conference on Antimicrobial Resistance,
held from 2 to 4 October 2001 at the OIE Headquarters in Paris, was a milestone in
promoting communication between stakeholders from both human and animal
medical fields. This conference reviewed progress achieved since the first OIE
International Conference of March 1999, and in particular, focussed on understanding
the development of antimicrobial resistance in humans and animals, the problems in
human and veterinary medicine and the actions taken for the containment of
resistance. It also provided a public forum for the presentation of the results of two
years’ work by the OIE and the identification of potential future actions by the OIE.
The present publication offers, in the first section, the OIE International Standards on
Antimicrobial Resistance as adopted by the OIE International Committee in May
2003, and published in the OIE Terrestrial Animal Health Code, 2003 and in the Manual
of Standards for Diagnostic Tests and Vaccines for Terrestrial Animals. The second section
contains the Proceedings of the 2nd OIE International Conference where the reports
of the OIE ad hoc group on Antimicrobial Resistance were discussed publicly.
I would like to express my gratitude to Dr Jean Blancou, Director General of the OIE
(1990-2000) and Dr Jacques Boisseau, Director of the OIE Collaborating Centre for
Veterinary Medicinal Products2, for initiating this important scientific activity of the
OIE. Furthermore, my particular appreciation goes to the OIE ad hoc group on
Antimicrobial Resistance, to its Chairman Prof. Jacques Acar and its secretary
Dr Barbara Röstel from the OIE Collaborating Centre for the very efficient
organisation of this conference.
I also would like to thank all national and international experts, who have contributed
so generously and eloquently to the success of this second OIE International
Conference on Antimicrobial Resistance.
Bernard Vallat
Director General
Dr Jacques Boisseau retired in March 2002. Dr Patrick Dehaumont has been designated as new
Director of the OIE Collaborating Centre
2
2
OIE International Standards on Antimicrobial Resistance, 2003
OIE
International Standards on
Antimicrobial Resistance
OIE International Standards on Antimicrobial Resistance, 2003
3
Terrestrial Animal Health Code
Terrestrial Animal Health Code
Section 3.9.
Antimicrobial resistance
Appendix 3.9.1.
Guidelines for the harmonisation of
antimicrobial resistance surveillance and
monitoring programmes
Article 3.9.1.1.
Objective
This Appendix provides criteria for the:
1.
development of national antimicrobial resistance surveillance and monitoring
programmes
2.
harmonisation of existing national surveillance and monitoring programmes, in
animals and in products of animal origin intended for human consumption.
Article 3.9.1.2.
Purpose of surveillance and monitoring
1.
2.
Surveillance and monitoring of antimicrobial resistance is necessary to:
a)
follow trends in antimicrobial resistance in bacteria;
b)
detect the emergence of new antimicrobial resistance mechanisms;
c)
provide the data necessary for conducting risk analyses with relevance for
human and animal health;
d)
provide a basis for policy recommendations for animal and public health;
e)
provide information
recommendations.
for
prescribing
practices
and
prudent
use
Antimicrobial resistance monitoring and surveillance programmes may include
the following components:
a)
scientifically based surveys (including statistically based programmes);
OIE International Standards on Antimicrobial Resistance, 2003
5
Terrestrial Animal Health Code
b)
routine sampling and testing of animals on the farm, at market or at
slaughter;
c)
an organised sentinel programme, sampling animals, herds, flocks, and
vectors;
d)
analysis of veterinary practice and diagnostic laboratory records.
3.
Countries should conduct active surveillance and monitoring. Passive surveillance
and monitoring may offer additional information.
4.
Targeted surveillance is conducted through an active sampling scheme designed
to meet programme objectives. Passive surveillance is conducted when samples
are submitted to a laboratory for testing from sources outside the programme.
Article 3.9.1.3.
The development of antimicrobial resistance surveillance and
monitoring programmes
1.
General aspects
Surveillance of antimicrobial resistance at regular intervals or ongoing monitoring
of prevalence changes of resistant bacteria of animal, food, environmental and
human origin, constitutes a critical part of a strategy aimed at limiting the spread
of antimicrobial resistance and optimising the choice of antimicrobials used in
therapy.
Monitoring of bacteria from products of animal origin intended for human
consumption collected at different steps of the food chain, including processing,
packing and retailing, should also be considered.
2.
Sampling strategies
a)
General
i)
Sampling should be conducted on a statistical basis. The sampling
strategy should assure:
–
–
ii)
The following criteria are to be considered:
–
–
–
–
–
–
–
6
the sample representativeness of the population of interest;
the robustness of the sampling method.
sample size;
sample source (animal, food, animal feed);
animal species;
category of animal within species (age group, production type);
stratification within category;
health status of the animals (healthy, diseased);
random sample (targeted, systematic);
OIE International Standards on Antimicrobial Resistance, 2003
Terrestrial Animal Health Code
–
b)
sample specimens (faecal, carcass, processed food).
Sample size
The sample size should be:
i)
ii)
large enough to allow detection of existing resistance,
not excessively large to avoid waste of resources.
Details are provided in Table I. Sampling shall follow standard operating
procedures.
Table I
Sample size estimates for prevalence of antimicrobial resistance in a
large population
Expected prevalence
10%
20%
30%
40%
50%
60%
70%
80%
90%
Level of confidence
90% desired precision
95% desired precision
10%
5%
1%
10%
5%
1%
24
43
57
65
68
65
57
43
24
97
173
227
260
270
260
227
173
97
2,429
4,310
5,650
6,451
6,718
6,451
5,650
4,310
2,429
35
61
81
92
96
92
81
61
35
138
246
323
369
384
369
323
246
138
3,445
6,109
8,003
9,135
9,512
9,135
8,003
6,109
3,445
Calculations based on Epi Info v6.04b to c Upgrade, October 1997, Centers for Disease Control
(public domain software available at http://www.cdc.gov/epo/epi/epiinfo.htm).
3.
Sample sources
a)
Animals
Each Member Country should examine its livestock production systems and
decide, after risk analysis, the relative importance of antimicrobial resistance and
its impact on animal and human health.
Categories of livestock that should be considered for sampling include cattle and
calves, slaughter pigs, broiler chickens, layer hens and/or other poultry and
farmed fish.
b)
Food and animal feed
Contaminated food is commonly considered to be the principal route for the
transfer of antimicrobial resistance from animals to humans. Plants and
vegetables of different types may be exposed to manure or sewage from livestock
OIE International Standards on Antimicrobial Resistance, 2003
7
Terrestrial Animal Health Code
and may thereby become contaminated with resistant bacteria of animal origin.
Animal feed, including imported feed, may also be considered in surveillance and
monitoring programmes.
Table II
Examples of sampling sources, sample types and outcome of monitoring
Source
Sample type
Herd of origin
Abattoir
Prevalence of resistance in bacteria
originating from animal populations (of
different production types)
Relationship resistance – antibiotic use
Faecal
Prevalence of resistance in bacterial
populations originating from animals at
slaughter age
Intestine
As above
Carcass
Hygiene, contamination during slaughter
Processing,
packing
Meat
products
Hygiene, contamination during processing
and handling
Retail
Meat
products
Prevalence of resistance in bacteria
originating from food, exposure data for
consumers
Vegetables
Prevalence of resistance in bacteria
originating from vegetables, exposure data
for consumers
Animal feed
Prevalence of resistance in bacteria
originating from animal feed, exposure
data for animals
Various origin
4.
Outcome
Additional information
required/additional
stratification
Per age categories,
production types, etc.
Antibiotic use over time
Sample specimens to be collected
Faecal samples should be collected from livestock, and whole caeca should be
collected from poultry. In cattle and pigs, a faecal sample size at least of 5 g
provides a sufficient sample for isolation of the bacteria of concern.
Sampling of the carcasses at the abattoir provides information on slaughter
practices, slaughter hygiene and the level of faecal contamination of meat during
the slaughter process. Further sampling from the retail chain provides
information on prevalence changes before the food reaches the consumer.
Existing food-processing microbiological monitoring and ‘hazard analysis and
critical control points’ (HACCP) programmes may provide useful samples for
surveillance and monitoring of resistance in the food chain after slaughter.
5.
Bacterial isolates
The following categories of bacteria could be monitored:
a)
8
Animal bacterial pathogens
OIE International Standards on Antimicrobial Resistance, 2003
Terrestrial Animal Health Code
Monitoring of antimicrobial resistance in animal pathogens is important, both to:
i)
detect emerging resistance that may pose a concern for human and
animal health;
ii)
guide veterinarians in their prescribing decisions.
Information on the occurrence of antimicrobial resistance in animal pathogens is
in general derived from routine clinical material sent to veterinary diagnostic
laboratories. These samples, often derived from severe or recurrent clinical cases
including therapy failures, may provide biased information.
Table III
Examples of animal bacterial pathogens that may be included in
resistance surveillance and monitoring
Target
animals
Respiratory pathogens
Enteric
pathogens
Udder
pathogens
Cattle
Pasteurella spp.
Escherichia coli
Staphylococcus
aureus
Streptococcus spp.
Haemophilus somnus
Salmonella spp.
Actinobacillus pleuropneumoniae Escherichia coli
Brachyspira spp.
Salmonella spp.
Pigs
Poultry
Fish
b)
Other
pathogens
Streptococcus suis
Escherichia coli
Vibrio spp.
Aeromonas spp.
Zoonotic bacteria
i)
Salmonella
Salmonella should be sampled from cattle, pigs, broilers and other poultry. For
the purpose of facilitating sampling and reducing the concurrent costs, samples
should preferably be taken at the abattoir. Surveillance and monitoring
programmes may also use bacterial isolates from designated national laboratories
originating from other sources.
Isolation and identification of bacteria and bacterial strains should follow
internationally accepted procedures.
Serovars of epidemiological importance such as S. typhimurium and S. enteritidis
should be included. The selection of other relevant serovars will depend on the
epidemiological situation in each country.
All Salmonella isolates should be serotyped and, when appropriate, phage-typed
according to standard methods used at the nationally designated laboratories.
Validated methods should be used.
OIE International Standards on Antimicrobial Resistance, 2003
9
Terrestrial Animal Health Code
ii)
Campylobacter
Campylobacter jejuni and C. coli can be isolated from the same samples as
commensal bacteria. Isolation and identification of these bacteria should follow
internationally accepted procedures. Campylobacter isolates should be identified to
the species level.
Agar or broth micro-dilution methods are recommended for Campylobacter
susceptibility testing. Internal and external quality control programmes should be
strictly adhered to.
Validated methods with appropriate reference strains are expected to become
available in the near future.
iii) Enterohaemorrhagic Escherichia coli
Enterohaemorrhagic Escherichia coli (EHEC), such as the serotype O157, which
is pathogenic to humans but not to animals, may be included in resistance
surveillance and monitoring programmes.
c)
Commensal bacteria
Escherichia coli and enterococci are common commensal bacteria. These bacteria
are considered to constitute a reservoir of antimicrobial resistance genes, which
may be transferred to pathogenic bacteria causing disease in animals or humans.
It is considered that these bacteria should be isolated from healthy animals,
preferably at the abattoir, and be monitored for antimicrobial resistance.
Validated methods should be used.
6.
Storage of bacterial strains
If possible, isolates should be preserved at least until reporting is completed.
Preferably, isolates should be permanently stored. Bacterial strain collections,
established by storage of all isolates from certain years, will provide the possibility
of conducting retrospective studies.
7.
Antimicrobials to be used in susceptibility testing
Clinically important antimicrobial classes used in human and veterinary medicine
should be monitored. However, the number of tested antimicrobials may have to
be limited according to the financial resources of the country.
8.
Type of data to be recorded and stored
Data on antimicrobial susceptibility should be reported quantitatively.
Appropriate validated methods should be used in accordance with Chapter
I.1.10. of the Terrestrial Manual concerning laboratory methodologies for bacterial
antimicrobial susceptibility testing.
10
OIE International Standards on Antimicrobial Resistance, 2003
Terrestrial Animal Health Code
9.
Recording, storage and interpretation of results
a)
b)
c)
d)
Because of the volume and complexity of the information to be stored and
the need to keep these data available for an undetermined period of time,
careful consideration should be given to database design.
The storage of raw (primary, non-interpreted) data is essential to allow the
evaluation of the data in response to various kinds of questions, including
those arising in the future.
Consideration should be given to the technical requirements of computer
systems when an exchange of data between different systems (comparability
of automatic recording of laboratory data and transfer of these data to
resistance monitoring programmes) is envisaged. Results should be collected
in a suitable national database. They shall be recorded quantitatively:
i)
as distribution of minimum inhibitory concentrations (MICs) in
milligrams per litre;
ii)
or inhibition zone diameters in millimetres.
The information to be recorded should include at least the following
aspects:
i)
ii)
iii)
iv)
v)
vi)
vii)
e)
sampling programme;
sampling date;
animal species/livestock category;
type of sample;
purpose of sampling;
geographical origin of herd, flock or animal;
age of animal.
The reporting of laboratory data should include the following information:
i)
ii)
iii)
iv)
f)
g)
h)
identity of laboratory,
isolation date,
reporting date,
bacterial species, and, where relevant, other typing characteristics, such
as:
v) serovar,
vi) phage-type,
vii) antimicrobial susceptibility result/resistance phenotype.
The proportion of isolates regarded as resistant should be reported,
including the defined breakpoints.
In the clinical setting, breakpoints are used to categorise bacterial strains as
susceptible, intermediate susceptible or resistant. These breakpoints, often
referred to as clinical or pharmacological breakpoints, are elaborated on a
national basis and vary between countries.
The system of reference used should be recorded.
OIE International Standards on Antimicrobial Resistance, 2003
11
Terrestrial Animal Health Code
i)
j)
For surveillance purposes, the microbiological breakpoint, which is based on
the distribution of MICs or inhibition zone diameters of the specific
bacterial species tested, is preferred. When using microbiological
breakpoints, only the bacterial population with acquired resistance that
clearly deviates from the distribution of the normal susceptible population
will be designated as resistant.
If available, the phenotype of the isolates (resistance pattern) should be
recorded.
10. Reference laboratory and annual reports
a)
Countries should designate a national reference centre that assumes the
responsibility to:
i)
coordinate the activities related to the resistance surveillance and
monitoring programmes;
ii)
collect information at a central location within the country;
iii) produce an annual report on the resistance situation of the country.
b)
The national reference centre should have access to the:
i)
raw data;
ii)
complete results of quality assurance and inter-laboratory calibration
activities;
iii) proficiency testing results;
iv) information on the structure of the monitoring system;
v)
12
information on the chosen laboratory methods.
OIE International Standards on Antimicrobial Resistance, 2003
Terrestrial Animal Health Code
Appendix 3.9.2.
Guidelines for the monitoring of the
quantities of antimicrobials used in
animal husbandry
Article 3.9.2.1.
Purpose
The purpose of these guidelines is to describe an approach to the monitoring of
quantities of antimicrobials used in animal husbandry.
These guidelines are intended for use by OIE Member Countries to collect objective
and quantitative information to evaluate usage patterns by animal species,
antimicrobial class, potency and type of use in order to evaluate antimicrobial
exposure.
Article 3.9.2.2.
Objectives
The information provided in these guidelines is essential for risk analyses and
planning, can be helpful in interpreting resistance surveillance data and can assist in
the ability to respond to problems of antimicrobial resistance in a precise and targeted
way. This information may also assist in evaluating the effectiveness of efforts to
ensure prudent use and mitigation strategies (for example, by identifying changes in
prescribing practices for veterinarians) and to indicate where alteration of
antimicrobial prescribing practices might be appropriate, or if changes in prescription
practice have altered the pattern of antimicrobial use.
The continued collection of this basic information will also help give an indication of
trends in the use of animal antimicrobials over time and the role of these trends in the
development of antimicrobial resistance in animals.
For all OIE Member Countries, the minimum basic information collected should be
the annual weight in kilograms of the active ingredient of the antimicrobial(s) used in
food animal production. In addition, the type of use (therapeutic or growth
promotion) and route of administration (parenteral or oral administration) should be
recorded.
Member Countries may wish to consider, for reasons of cost and administrative
efficiency, collecting medical, food animal, agricultural and other antimicrobial use
data in a single programme. A consolidated programme would also facilitate
comparisons of animal use with human use data for relative risk analysis and help to
promote optimal usage of antimicrobials.
Article 3.9.2.3.
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Development and standardisation of monitoring systems
Systems to monitor antimicrobial usage consist of the following elements:
1.
Sources of antimicrobial data
a) Basic sources
Sources of data will vary from country to country. Such sources may include
customs, import and export data, manufacturing and manufacturing sales data.
b) Direct sources
Data from animal drug registration, wholesalers, retailers, pharmacists,
veterinarians, feed stores, feed mills and organised industry associations in these
countries might be efficient and practical sources. A possible mechanism for the
collection of this information is to make the provision of appropriate
information by manufacturers to the regulatory authority one of the requirements
of antimicrobial registration.
c) End-use sources (veterinarians and food animal producers)
This may be appropriate when basic or direct sources cannot be used for the
routine collection of this information and when more accurate and locally
specific information is required.
Periodic collection of this type of information may be sufficient.
It may be important when writing recommendations on antimicrobial resistance
to take into account factors such as seasonality and disease conditions, species
affected, agricultural systems (e.g. extensive range conditions and feedlots), dose
rate, duration and length of treatment with antimicrobials.
Collection, storage and processing of data from end-use sources are likely to be
inefficient and expensive processes unless carefully designed and well managed,
but should have the advantage of producing accurate and targeted information.
2.
Categories of data
a)
Requirements for data on antimicrobial use
The minimal data collected should be the annual weight in kilograms of the
active ingredient of the antimicrobial(s) used in food animal production. This
should be related to the scale of production (see point 3 below).
For active ingredients present in the form of compounds or derivatives, the mass
of active entity of the molecule should be recorded. For antibiotics expressed in
International Units, the calculation required to convert these units to mass of
active entity should be stated.
If a Member Country has the infrastructure for capturing basic animal
antimicrobial use data for a specific antimicrobial, then additional information
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can be considered to cascade from this in a series of subdivisions or levels of
detail. Such a cascade of levels should include the following:
i)
The absolute amount in kilograms of active antimicrobial used per
antimicrobial family per year, or for a specific antimicrobial chemical
entity when this information is required.
ii)
Therapeutic and growth promotion use in kilograms of the specific
active antimicrobial.
iii) Subdivision of antimicrobial use into therapeutic and growth
promotion use by animal species.
iv) Subdivision of the data into the route of administration, specifically infeed, in-water, injectable, oral, intramammary, intra-uterine and topical.
v)
Further subdivision of these figures by season and region by a Member
Country may be useful (Note: This may be especially management
conditions, or where animals are moved from one locality to another during
production).
vi) Further breakdown of data for analysis of antimicrobial use at the
regional, local, herd and individual veterinarian level may be possible
using veterinary practice computer management software as part of
specific targeted surveys or audits. Analysis of this information within
the local or regional context could be useful for individual practitioners
and practices where specific antimicrobial resistance has been identified
and feedback is required.
b)
Classes of antimicrobials
Nomenclature of antimicrobials should comply with international standards
where available.
Decisions need to be made on what classes of antimicrobials should be
considered and what members of various antimicrobial classes should be
included in the data collection programme. These decisions should be based on
currently known mechanisms of antimicrobial activity and resistance of the
particular antimicrobial and its relative potency.
c)
Species and production systems
Countries should keep a register of all animal use of antimicrobials for individual
food animal species (cattle, sheep, goats, pigs, poultry, horses and fish) and for
specific diseases. This will help to identify possible nonauthorised usage.
3.
Other important information
Breakdown of farm livestock into species and production categories, including
total live weights, would be most useful in any risk analysis or for comparison of
animal antimicrobial use with human medical use within and between countries.
OIE International Standards on Antimicrobial Resistance, 2003
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For example, the total number of food animals by category and their weight in
kilograms for food production per year (meat, dairy and draught cattle, and meat,
fibre, poultry and dairy sheep) in the country would be essential basic
information.
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Appendix 3.9.3.
Guidelines for the responsible and prudent use
of antimicrobial agents in veterinary medicine
Article 3.9.3.1.
Purpose
These guidelines provide guidance for the responsible and prudent use of
antimicrobials in veterinary medicine, with the aim of protecting both animal and
human health. The competent authorities responsible for the registration and control
of all groups involved in the production, distribution and use of veterinary
antimicrobials have specific obligations.
Prudent use is principally determined by the outcome of the marketing authorisation
procedure and by the implementation of specifications when antimicrobials are
administered to animals.
Article 3.9.3.2.
Objectives of prudent use
Prudent use includes a set of practical measures and recommendations intended to
prevent and/or reduce the selection of antimicrobial-resistant bacteria in animals to:
1.
maintain the efficacy of antimicrobial agents and to ensure the rational use of
antimicrobials in animals with the purpose of optimising both their efficacy and
safety in animals;
2.
comply with the ethical obligation and economic need to keep animals in good
health;
3.
prevent, or reduce, as far as possible, the transfer of bacteria (with their
resistance determinants) within animal populations;
4.
maintain the efficacy of antimicrobial agents used in livestock;
5.
prevent or reduce the transfer of resistant bacteria or resistance determinants
from animals to humans;
6.
maintain the efficacy of antimicrobial agents used in human medicine and
prolong the usefulness of the antimicrobials;
7.
prevent the contamination of animal-derived food with antimicrobial residues
that exceed the established maximum residue limit (MRL);
8.
protect consumer health by ensuring the safety of food of animal origin.
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Article 3.9.3.3.
Responsibilities of the regulatory authorities
1.
Marketing authorisation
The national regulatory authorities are responsible for granting marketing
authorisation. They have a significant role in specifying the terms of this
authorisation and in providing the appropriate information to the veterinarian.
2.
Submission of data for the granting of the marketing authorisation
The pharmaceutical industry has to submit the data requested for the granting of
the marketing authorisation. The marketing authorisation is granted only if the
criteria of safety, quality and efficacy are met. An assessment of the potential risk
to both the animal and the consumer resulting from the use of antimicrobial
agents in food-producing animals must be carried out. The evaluation should
focus on each individual antimicrobial product and not be generalised to the class
of antimicrobials to which the particular active principle belongs. If dose ranges
or different durations of treatment are suggested, guidance on the usage should
be provided.
3.
Market approval
Regulatory authorities should attempt to expedite the market approval process of
a new antimicrobial in order to address a specific need for the treatment of
disease.
4.
Registration procedures
Countries lacking the necessary resources to implement an efficient registration
procedure for veterinary medicinal products (VMPs), and whose supply
principally depends on imports from foreign countries, must undertake the
following measures:
a)
check the efficacy of administrative controls on the import of these VMPs;
b)
check the validity of the registration procedures of the exporting country;
c)
develop the necessary technical co-operation with experienced authorities to
check the quality of imported VMPs as well as the validity of the
recommended conditions of use.
Regulatory authorities of importing countries should request the pharmaceutical
industry to provide quality certificates prepared by the competent authority of
the exporting country. All countries should make every effort to actively combat
the trade, distribution and use of unlicensed and counterfeit products.
5.
Quality control of antimicrobial agents
Quality controls should be performed:
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6.
a)
in compliance with the provisions of good manufacturing practices;
b)
to ensure that analysis specifications of antimicrobial agents used as active
ingredients comply with the provisions of approved monographs;
c)
to ensure that the quality and concentration (stability) of antimicrobial
agents in the marketed dosage form(s) are maintained until the expiry date,
established under the recommended storage conditions;
d)
to ensure the stability of antimicrobials when mixed with feed or drinking
water;
e)
to ensure that all antimicrobials are manufactured to the appropriate quality
and purity in order to guarantee their safety and efficacy.
Control of therapeutic efficacy
a)
Preclinical trials
i)
Preclinical trials should:
–
–
–
ii)
establish the range of activity of antimicrobial agents on both
pathogens and non-pathogens (commensals);
assess the ability of the antimicrobial agent to select for resistant
bacteria in vitro and in vivo, taking into consideration pre-existing
resistant strains;
establish an appropriate dosage regimen necessary to ensure the
therapeutic efficacy of the antimicrobial agent and limit the
selection of antimicrobial-resistant bacteria.
The activity of antimicrobial agents towards the targeted bacteria
should be established by pharmacodynamics. The following criteria
should be taken into account:
–
–
–
–
mode of action;
minimum inhibitory and bactericidal concentrations;
time- or concentration-dependent activity;
activity at the site of infection.
iii) The dosage regimens allowing maintenance of effective antimicrobial
levels should be established by pharmacokinetics. The following criteria
should be taken into account:
–
–
–
–
–
bio-availability according to the route of administration;
concentration of the antimicrobial at the site of infection and its
distribution in the treated animal;
metabolism that may lead to the inactivation of antimicrobials;
excretion routes;
use of combinations of antimicrobial agents should be justified.
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b)
Clinical trials
Clinical trials should be performed to confirm the validity of the claimed
therapeutic indications and dosage regimens established during the preclinical
phase. The following criteria should be taken into account:
i)
diversity of the clinical cases encountered when performing multicentre trials;
ii)
compliance of protocols with good clinical practice;
iii) eligibility of studied clinical cases, based on appropriate criteria of
clinical and bacteriological diagnoses;
iv) parameters for qualitatively and quantitatively assessing the efficacy of
the treatment.
7.
Assessment of the potential of antimicrobials to select for resistant
bacteria
Other studies may be requested in support of the assessment of the potential of
antimicrobials to select for resistant bacteria. The interpretation of their results
should be undertaken with great caution.
The party applying for market authorisation should, where possible, supply data
derived in target animal species under the intended conditions of use.
Considerations may include:
a)
the concentration of active compound in the gut of the animal (where the
majority of potential food-borne pathogens reside) at the defined dosage
level;
b)
the level of human exposure to food-borne resistant bacteria;
c)
the degree of cross-resistance within the class of antimicrobials and between
classes of antimicrobials;
d)
the pre-existing level of resistance in the pathogens of human health
concern (baseline determination).
Other studies may be requested in support of the assessment of the potential of
antimicrobials to select for resistant bacteria. The interpretation of their results
should be undertaken with great caution.
8.
Establishment of acceptable daily intake, maximum residue level
and withdrawal periods for antimicrobial compounds
a)
20
When setting the acceptable daily intake (ADI) and MRL for an
antimicrobial substance, the safety evaluation should also include the
potential biological effects on the intestinal flora of humans.
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b)
The establishment of an ADI for each antimicrobial agent, and an MRL for
each animal-derived food, should be undertaken.
c)
For each VMP containing antimicrobial agents, withdrawal periods should
be established in order to produce food in compliance with the MRL, taking
into account:
i)
ii)
iii)
iv)
v)
d)
9.
the MRL established for the antimicrobial agent under consideration;
the composition of the product and the pharmaceutical form;
the target animal species;
the dosage regimen and the duration of treatment;
the route of administration.
The applicant should provide methods for regulatory testing of residues in
food.
Protection of the environment
An assessment of the impact of the proposed antimicrobial use on the
environment should be conducted. Efforts should be made to ensure that
environmental contamination with antimicrobials is restricted to a minimum.
10. Establishment of a summary of product characteristics for each
veterinary medicinal product
The summary of product characteristics contains the information necessary for
the appropriate use of VMPs and constitutes the official reference for their
labelling and package insert. This summary always contains the following items:
a)
b)
c)
d)
e)
f)
g)
h)
i)
j)
k)
pharmacological properties,
target animal species,
therapeutic indications,
target bacteria,
dosage and administration route,
withdrawal periods,
incompatibilities,
expiry date,
operator safety,
particular precautions before use,
particular precautions for the proper disposal of un-used products.
Antimicrobials that are considered to be important in treating critical diseases in
humans should only be used in animals when alternatives are either unavailable
or inappropriate.
Consideration should be given to providing such guidance by means of the
product label and data sheet.
The oral route should be used with caution.
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11. Post-marketing antimicrobial surveillance
The information collected through pharmacovigilance programmes, including
lack of efficacy, should form part of the comprehensive strategy to minimise
antimicrobial resistance.
a)
Specific surveillance
Specific surveillance to assess the impact of the use of a specific antimicrobial
may be implemented after the granting of the marketing authorisation The
surveillance programme should evaluate not only resistance development in
target animal pathogens, but also in food-borne pathogens and/or commensals.
Such surveillance will also contribute to general epidemiological surveillance of
antimicrobial resistance.
b)
General epidemiological surveillance
The surveillance of animal bacteria resistant to antimicrobial agents is essential.
The relevant authorities should implement a programme according to the
Terrestrial Code.
12. Distribution of the antimicrobial agents used in veterinary medicine
The relevant authorities should ensure that all the antimicrobial agents used in
animals are:
a)
b)
c)
d)
prescribed by a veterinarian or other suitably trained and authorised person;
delivered by an authorised animal health professional;
supplied only through licensed/authorised distribution systems;
administered to animals by a veterinarian or under the supervision of a
veterinarian or by other authorised persons.
13. Control of advertising
All advertising of antimicrobials should be controlled by a code of advertising
standards, and the relevant authorities must ensure that the advertising of
antimicrobial products:
a)
complies with the marketing authorisation granted, in particular regarding
the content of the summary of product characteristics;
b)
is restricted to authorised professionals, according to national legislation in
each country.
14. Training of antibiotic users
Training of antibiotic users should focus on:
22
a)
information on disease prevention and management strategies,
b)
the ability of antimicrobials to select for resistant bacteria in food-producing
animals,
OIE International Standards on Antimicrobial Resistance, 2003
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c)
the need to observe responsible use recommendations for the use of
antimicrobial agents in animal husbandry in agreement with the provisions
of the marketing authorisations
15. Research
The relevant authorities should encourage public- and industry-funded research.
Article 3.9.3.4.
Responsibilities of the veterinary pharmaceutical industry
1.
Marketing authorisation of VMPs
The veterinary pharmaceutical industry has responsibilities to:
2.
a)
supply all the information requested by the national regulatory authorities;
b)
guarantee the quality of this information in compliance with the provisions
of good manufacturing, laboratory and clinical practices;
c)
implement a pharmacovigilance programme and on request, specific
surveillance for bacterial susceptibility and resistance.
Marketing and export of VMPS
For the marketing and export of VMPs:
3.
a)
only licensed and officially approved VMPs should be sold and supplied,
and then only through licensed/authorised distribution systems;
b)
only VMPs that have been authorised in the (exporting) country in which
the product(s) is approved for sale or the quality of which is certified by a
regulatory authority should be exported;
c)
the national regulatory authority should be provided with the information
necessary to evaluate the amount of antimicrobial agents marketed.
Advertising
The veterinary pharmaceutical industry should:
4.
a)
disseminate information in compliance with the provisions of the granted
authorisation;
b)
ensure that the advertising of antimicrobials directly to the livestock
producer is discouraged.
Training
The veterinary pharmaceutical industry should participate in training programmes
as defined in point 14 of Article 3.9.3.3.
OIE International Standards on Antimicrobial Resistance, 2003
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Terrestrial Animal Health Code
5.
Research
The veterinary pharmaceutical industry should contribute to research as defined
in point 15 of Article 3.9.3.3.
Article 3.9.3.5.
Responsibilities of pharmacists
1.
Pharmacists should only distribute veterinary antimicrobials on prescription. All
products should be appropriately labelled (see point 5 of Article 3.9.3.6.).
2.
The guidelines on the responsible use of antimicrobials should be reinforced by
pharmacists who should keep detailed records of:
a)
b)
c)
d)
e)
f)
3.
date of supply,
name of prescriber,
name of user,
name of product,
batch number,
quantity supplied.
Pharmacists should also be involved in training programmes on the responsible
use of antimicrobials, as defined in point 14 of Article 3.9.3.3.
Article 3.9.3.6.
Responsibilities of veterinarians
The prime concern of the veterinarian is to encourage good farming practice in order
to minimise the need for antimicrobial use in livestock.
Veterinarians should only prescribe antimicrobials for animals under their care.
1.
Use of antimicrobial agents
The responsibilities of veterinarians in this area are to carry out a proper clinical
examination of the animal(s) and then:
a)
only prescribe antimicrobials when necessary;
b)
make an appropriate choice of the antimicrobial based on experience of the
efficacy of treatment.
On certain occasions, a group of animals that may have been exposed to
pathogenic bacteria may need to be treated without recourse to an accurate
diagnosis and antimicrobial susceptibility testing to prevent the development of
clinical disease and for reasons of animal welfare.
2.
Choosing an antimicrobial agent
a)
24
The expected efficacy of the treatment is based on:
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i)
the clinical experience of the veterinarian;
ii)
the activity towards the pathogenic bacteria involved;
iii) the appropriate route of administration;
iv) known pharmacokinetics/tissue distribution to ensure that the selected
therapeutic agent is active at the site of infection;
v)
the epidemiological history of the rearing unit, particularly in relation to
the antimicrobial resistance profiles of the pathogenic bacteria
involved;
vi) Should a first line antibiotic treatment fail or should the disease recur, a
second line treatment should ideally be based on the results of
diagnostic tests.
To minimise the likelihood of antimicrobial resistance developing, it is
recommended that antimicrobials be targeted to bacteria likely to be the cause of
infection.
b)
Combinations of antimicrobials are used for their synergistic effect to
increase therapeutic efficacy or to broaden the spectrum of activity.
Furthermore, the use of combinations of antimicrobials can be protective
against the selection of resistance in cases in which bacteria exhibit a high
mutation rate against a given antimicrobial.
Some combinations of antimicrobials may, in certain cases, lead to an increase in
the selection of resistance.
3.
Appropriate use of the antimicrobial agent chosen
A prescription for antimicrobial agents must indicate precisely the treatment
regime, the dose, the dosage intervals, the duration of the treatment, the
withdrawal period and the amount of drug to be delivered, depending on the
dosage and the number of animals to be treated.
As far as ‘Off label use’ (extra-label use) of veterinary medicinal products is
concerned, although all medicinal products should be prescribed and used in
accordance with the specifications of the marketing authorisation, the prescriber
should have the discretion to adapt these in exceptional circumstances.
4.
Recording
All available information should be consolidated into one form or database. This
information should:
a)
allow monitoring of the quantities of medication used;
b)
contain a list of all medicines supplied to each livestock holding;
OIE International Standards on Antimicrobial Resistance, 2003
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Terrestrial Animal Health Code
5.
c)
contain a list of medicine withdrawal periods and a system for allowing
information to be updated;
d)
contain a record of antimicrobial susceptibilities;
e)
provide comments concerning the response of animals to medication;
f)
allow the investigation of adverse reactions to antimicrobial treatment,
including lack of response due to antimicrobial resistance. Suspected adverse
reactions should be reported to the appropriate regulatory authorities.
Labelling
All medicines supplied by a veterinarian should be adequately labelled with the
following minimum information:
a)
b)
c)
d)
e)
f)
g)
h)
the name of the owner/keeper or person who has control of the animal(s);
the address of the premises where the animal(s) is kept;
the name and address of the prescribing veterinarian;
identification of the animal or group of animals to which the antimicrobial
agent was administered;
the date of supply;
the indication ‘For animal treatment only’;
the warning ‘Keep out of the reach of children’;
the relevant withdrawal period, even if this is nil.
The label should not obscure the expiry date of the preparation, batch number or
other important information supplied by the manufacturer.
6.
Training
Veterinary professional organisations should participate in the training
programmes as defined in point 14 of Article 3.9.3.3.
Article 3.9.3.7.
Responsibilities of livestock producers
1.
Livestock producers with the assistance of a veterinarian, where possible, are
responsible for preventing outbreaks of disease and implementing health and
welfare programmes on their farms.
2.
Livestock producers have to:
26
a)
draw up a health plan with the veterinarian in charge of the animals that
outlines preventative measures (mastitis plan, worming and vaccination
programmes, etc.);
b)
use antimicrobial agents only on prescription, and according to the
provisions of the prescription;
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c)
use antimicrobial agents in the species, for the uses and at the doses on the
approved/registered labels and in accordance with product label instructions
or the advice of a veterinarian familiar with the animals and the production
site;
d)
isolate sick animals, when appropriate, to avoid the transfer of resistant
bacteria;
e)
comply with the storage conditions of antimicrobials in the rearing unit,
according to the provisions of the leaflet and package insert;
f)
address hygienic conditions regarding contacts between
(veterinarians, breeders, owners, children) and the animals treated;
g)
comply with the recommended withdrawal periods to ensure that residue
levels in animal-derived food do not present a risk for the consumer;
h)
dispose of surplus antimicrobials under safe conditions for the environment;
partially-used medicines should only be used within the expiry date, for the
condition for which they were prescribed and, if possible, in consultation
with the prescribing veterinarian;
i)
maintain all the laboratory records of bacteriological and susceptibility tests;
these data should be made available to the veterinarian responsible for
treating the animals;
j)
keep adequate records of all medicines used, including the following:
people
i)
ii)
iii)
iv)
name of the product/active substance and batch number,
name of supplier,
date of administration,
identification of the animal or group of animals to which the
antimicrobial agent was administered,
v) diagnosis/clinical conditions treated,
vi) quantity of the antimicrobial agent administered,
vii) withdrawal periods,
viii) result of laboratory tests,
ix) effectiveness of therapy;
k)
inform the responsible veterinarian of recurrent disease problems.
OIE International Standards on Antimicrobial Resistance, 2003
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Manual of diagnostic tests and vaccines for terrestrial animals
Manual of Diagnostic Tests and Vaccines for
Terrestrial Animals
Chapter I.1.10.
Laboratory methodologies for bacterial antimicrobial
susceptibility testing
Introduction
The spread of multiple antibiotic-resistant pathogenic bacteria has been recognised by
the OIE and the World Health Organization as a serious global animal and human
health problem. The emergence of antimicrobial resistance among many bacterial
pathogens makes antimicrobial susceptibility testing (AST) essential when
antimicrobials are used in therapy. The resistance of a pathogen to an antimicrobial is
highly predictive that the treatment will not be effective and the susceptibility of the
pathogen is an excellent base for the choice of the antibacterial treatment. Thus, AST
is an important component of effective treatment programme. Additionally, AST of
recovered bacterial pathogens is a component of prudent antimicrobial use guidelines in
animal husbandry world-wide and the veterinarian should have these data
available (1).
AST is also the basis of the epidemiological surveillance of bacterial pathogens in
animals and humans. Such epidemiological surveillance provides a base to choose
properly empirical treatment (first line therapy) and to detect the emergence and/or the
dissemination of resistant bacterial strains or resistance determinants in different
bacterial species. Standardisation and harmonisation of AST methodologies, used in
epidemiological surveillance of antimicrobial drug resistance, are critical if data are to
be compared among national or international surveillance/monitoring programmes of
OIE Member Countries. It is essential that AST methods provide reproducible
results in day-to-day laboratory use and that the data be comparable with those results
obtained by an acknowledged ‘gold standard’ reference method. In the absence of
standardised methods or reference procedures, susceptibility results from different
laboratories cannot be reliably compared.
This Chapter provides Guidelines for AST methodologies, and includes procedures to
standardise and harmonise interpretation of antimicrobial susceptibility test results.
1.
Test requirements
In order to achieve standardisation of AST methods and comparability of AST results,
the following requirements apply:
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Manual of diagnostic tests and vaccines for terrestrial animals
i)
the use of standardised AST methods and the harmonisation of
susceptibility data (including interpretive criteria) are essential,
ii)
standardised AST methods and similar interpretive criteria should be
accepted and used by all participating laboratories,
iii) all AST methods should generate reproducible data,
iv) all data should be reported quantitatively,
v)
establishment of national or regional designated laboratories is essential for
the coordination of AST methodologies, interpretations and quality
controls,
vi) microbiological laboratories should conduct their work within an internal
quality assurance system,
vii) laboratories should become accredited, where applicable, and participate in
external proficiency testing programmes,
viii) specific bacterial reference/quality control strains are essential for
determining intra- and inter-laboratory quality control, quality assurance and
proficiency testing.
2.
Antimicrobial susceptibility testing methodologies
The following requirements should be respected:
i)
bacteria subjected to AST must be isolated in pure culture from the
submitted sample,
ii)
the isolation procedure for that particular bacterium should be standardised
so that the subject bacteria are consistently and correctly identified to the
genus and/or species level,
iii) when possible, bacterial isolates should be stored for future analysis (either
lyophilisation or cryogenic preservation at –70°C to –80°C),
iv) once the bacterium has been isolated in pure culture, the inoculum must be
standardised to obtain accurate susceptibility results.
The following factors influencing AST methods should be standardised:
i)
the composition of the agar and broth media used (pH, cations, thymidine
or thymine, use of supplemented media),
ii)
the content of antimicrobial in the carrier (disk, strip, tablet),
iii) composition of solvents and diluents for preparation of antimicrobial stock
solutions,
iv) growth and incubation conditions (time, temperature, atmosphere e.g. CO2),
v)
30
agar depth,
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Manual of diagnostic tests and vaccines for terrestrial animals
vi) the subsequent interpretive criteria.
For these reasons, special emphasis has to be placed on reference procedures and
standardised methods, as sufficient reproducibility can be attained only through the
use of standardised methodology.
3.
Selection of antimicrobial susceptibility testing methodology
The selection of an AST methodology may be based on the following factors:
i)
ii)
iii)
iv)
v)
vi)
vii)
viii)
4.
ease of performance,
flexibility,
adaptability to automated or semi-automated systems,
cost,
reproducibility,
reliability,
accuracy,
national preference.
Test methods
The following three methods are the only ones that consistently provide reproducible
and repeatable results:
i) disk diffusion,
ii) broth dilution,
iii) agar dilution.
a) Disk diffusion method
Disk diffusion refers to the diffusion of an antimicrobial agent of a specified
concentration from disks, tablets or strips, into the solid culture media, which has
been seeded with a standardised bacterial inoculum. Disk diffusion is based on
the determination of an inhibition zone proportional to the bacterial
susceptibility to the antimicrobial present in the disk.
The diffusion of the antimicrobial agent into the seeded culture media results in a
gradient of the antimicrobial. When the concentration of the antimicrobial
becomes so diluted that it can no longer inhibit the growth of the test bacterium,
the zone of inhibition is demarcated. In theory, the edge of this zone of
inhibition correlates with the minimum inhibitory concentration (MIC) for that
particular bacterium/antimicrobial combination. In other words, the zone of
inhibition correlates inversely with the MIC of the test bacterium. Generally, the
larger the zone of inhibition, the lower the concentration of antimicrobial
required to inhibit the growth of the organisms. However, this depends on the
concentration of antibiotic in the disk and its diffusibility.
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Note: Disk diffusion tests based solely on the presence or absence of a zone of
inhibition without regard to the size of the zone of inhibition are not acceptable
AST methodology.
• Considerations for the use of the disk diffusion methodology
Disk diffusion is straightforward to perform, reproducible, and does not require
expensive equipment. Its main advantages are:
i)
ii)
low cost,
ease in modifying test antimicrobial disks when required.
Manual measurement of zones of inhibition may be time-consuming. Automated
zone-reading devices are available that can be integrated with laboratory
reporting and data-handling systems. A maximum of 12 disks can be placed on
one 150 mm agar plate. A maximum of five disks can be placed on a 100 mm
plate. Regardless of the number of disks placed on the agar surface, the disks
should be distributed evenly so that they are no closer than 24 mm from centre
to centre.
b) Broth and agar dilution methods
The aim of the broth and agar dilution methods is to determine the lowest
concentration of the assayed antimicrobial that inhibits the growth of the
bacterium being tested (MIC, usually expressed in mcg/ml or mg/litre).
However, the MIC does not always represent an absolute value. The ‘true’ MIC is
a point between the lowest test concentration that inhibits the growth of the
bacterium and the next lower test concentration.
Antimicrobial ranges should:
i)
encompass both the interpretive criteria (susceptible, intermediate and
resistant) and quality control reference organisms.
ii) take into consideration the antimicrobial concentrations that are achievable
in vivo for a specific bacteria/antibiotic combination.
Antimicrobial susceptibility dilution methods appear to be more reproducible
and quantitative than agar disk diffusion. However, antibiotics are usually tested
in doubling dilutions, which can produce inexact MIC data.
Any laboratory that intends to use a dilution method and set up its own reagents
and antibiotic dilutions should have the ability to obtain, prepare and maintain
appropriate stock solutions of reagent-grade antimicrobials and to generate
working dilutions on a regular basis. It is then essential that such laboratories use
quality control organisms (see below) to assure accuracy and standardisation of
their procedures.
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• Broth dilution
Broth dilution is a technique in which a standardised suspension of bacteria is
tested against varying concentrations of an antimicrobial agent (usually doubling
dilutions) in a standardised liquid medium. The broth dilution method can be
performed either in tubes containing a minimum volume of 2 ml (macrodilution)
or in smaller volumes using microtitration plates (microdilution). Numerous
microtitre plates containing prediluted antibiotics within the wells are
commercially available. The use of identical lots of microdilution plates may
eliminate potential errors that may arise due to the preparation and dilution of
the antimicrobials. The use of these plates with a standardised protocol, including
appropriate quality control reference strains, may facilitate harmonisation where
sufficient financial resources are available.
Due to the fact that most broth microdilution antimicrobial test panels are
prepared commercially, they can be considered to be less flexible than agar
dilution or disk diffusion in adjusting to the changing needs of the
surveillance/monitoring programme.
Because the purchase of the equipment and antimicrobial panels may be costly,
this methodology may not be the choice for laboratories with limited budgets.
• Agar dilution
Agar dilution involves the incorporation of an antimicrobial agent into an agar
medium in a geometrical progression of concentrations, followed by the
application of a defined bacterial inoculum to the agar surface of the plate. These
results are often considered as the gold standard for the determination of an MIC
for the test bacterium/antimicrobial combination.
The advantages of agar dilution methods include:
i)
a greater control of the purity of the test bacterium,
ii)
the ability to test multiple bacteria on the same set of agar plates at the same
time,
iii) the potential to improve the identification of MIC endpoints and extend the
antibiotic concentration range,
iv) can be adapted to semi-automation. Commercially produced inoculum
replicators are available and these can transfer between 32 and 37 different
bacterial inocula to each agar plate.
Agar dilution methods also have certain disadvantages, for example:
i)
they are very laborious and require substantial economic and technical
resources,
ii)
once prepared they have to used within a week,
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iii) the endpoints are by no means always easy to read nor is the purity of the
inoculum easy to verify.
Agar dilution is often recommended as a standardised AST method for fastidious
organisms, such as anaerobes, Helicobacter and Campylobacter species. However, at
least in veterinary medicine, broth microdilution also works very well for
organisms such as Hemophilus, Campylobacter and Brachyspira amongst others.
c) Concentration gradient strips methodology
Additionally, bacterial antimicrobial MICs can be obtained from commercially
available gradient strips that diffuse a pre-formed antibiotic concentration.
However, the use of gradient strips can be very expensive and MIC discrepancies
can be found when compared with agar dilution results (2).
Regardless of the AST method used, the procedures should be standardised to ensure
accurate and reproducible results, and appropriate quality control reference organisms
need to be tested every time AST is performed in order to ensure accuracy of the data.
The appropriate AST choice will ultimately depend on the growth characteristics of
the bacterium in question. In special circumstances, novel test methods and assays
may be more appropriate for detection of particular resistance phenotypes. For
example, chromogenic cephalosporin-based tests (e.g. nitrocefin) or equivalent
methods may provide more reliable and rapid results for beta-lactamase determination
in certain bacteria.
Similarly, extended-spectrum beta-lactamase activity in certain bacteria can also be
detected by using standard disk diffusion susceptibility test methods using specific
cephalosporins (cefotaxime and ceftazidime) in combination with a beta-lactamase
inhibitor (clavulanic acid) and measuring the resulting zones of inhibition.
Additionally, chloramphenicol resistance attributed to production of chloramphenicol
acetyl transferase can be detected in some bacteria via rapid tube or filter paper tests
within 1–2 hours (4).
5. Antimicrobial susceptibility breakpoints and zone of inhibition
criteria
The objective of in vitro AST is to predict the way in which a bacterial pathogen may
respond to the antimicrobial agent in vivo. The results generated by bacterial in vitro
antimicrobial susceptibility tests, regardless of whether disk diffusion or dilution
methods are used, are generally reported as resistant, susceptible or intermediate to the
action of a particular antimicrobial.
Antimicrobial susceptibility breakpoints are established by national standards
organisations, professional societies or regulatory agencies. The relevant documents
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should be consulted. However, there can be notable differences in breakpoints among
different countries for the same antimicrobial agent.
As mentioned previously, antimicrobial susceptibility testing results should be
recorded quantitatively:
i)
as distribution of MICs in milligrams per litre,
ii)
or as inhibition zone diameters in millimetres.
The following two primary factors enable a bacterium to be interpreted as susceptible
or resistant to an antimicrobial agent:
i)
the development and establishment of quality control ranges, using diffusion
when possible and dilution testing, for quality control microorganisms.
This is essential for validating the specific AST method used. The quality control
ranges for the quality control microorganisms should be established prior to
determining breakpoints for susceptibility or resistance.
ii)
the determination of the appropriate interpretive criteria.
This involves the generation of three distinct pieces of data:
•
population distribution of MICs of relevant microorganisms,
•
pharmacokinetic parameters of the antimicrobial agent,
•
results of clinical trials and experience.
The interpretation of the data involves creating a scattergram from the bacterial
population distribution (representative bacterial isolates), by plotting the zone of
inhibition against the MIC for each bacterial pathogen. The selection of breakpoints is
then based on multiple factors, including regression line analysis, bacterial population
distributions, error rate bounding, pharmacokinetics, and ultimately, clinical
verification.
The development of a concept known as ‘microbiological breakpoints’, which is based
on the population distributions of the specific bacterial species tested, may be more
appropriate for some antimicrobial surveillance programmes. In this case, bacterial
isolates that deviate from the normal susceptible population would be designated as
resistant, and shifts in susceptibility to the specific antimicrobial/bacterium
combination could be monitored (5).
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6.
Antimicrobial susceptibility testing guidelines
A number of guidelines are currently available for antimicrobial susceptibility testing
and subsequent interpretive criteria throughout the world. Amongst others, these
include standards and guidelines published by:
–
–
–
–
–
–
–
National Committee for Clinical Laboratory Standards (NCCLS),
British Society for Antimicrobial Chemotherapy (BSAC),
Comité de l’Antibiogramme de la Société française de Microbiologie (CASFM),
Swedish Reference Group for Antibiotics (SIR),
Deutsches Institut für Normung (DIN),
Japanese Society for Chemotherapy (JSC),
Werkgroep richtlijnen gevoeligheidsbepalingen (WRG system, the Netherlands).
At this time, only the NCCLS has developed protocols for susceptibility testing of
bacteria of animal origin and determination of interpretive criteria (4). However,
protocols and guidelines are available from a number of standards organisations and
professional societies for susceptibility testing for similar bacterial species that cause
infections in humans. It is possible that such guidelines can be adopted for
susceptibility testing for bacteria of animal origin, but each country must evaluate its
own AST standards and guidelines. Additionally, efforts focusing on harmonisation of
susceptibility breakpoints on an international scale are progressing. These efforts have
primarily focused on the adoption of the standards and guidelines of the NCCLS,
which provide laboratories with standardised methods and quality control values
enabling comparisons of AST methods and generated data. For those OIE Member
Countries that have not standardised AST methods, the adoption of NCCLS
guidelines and standards would be an appropriate initial step.
As a first step towards comparability of monitoring and surveillance data, Member
Countries should be encouraged to strive for harmonised and standardised
programme design (6). Data from countries using different methods and study design
may otherwise not be directly comparable (3, 6). Notwithstanding this, data collected
over time in a given country may at least allow the detection of emergence of
antimicrobial resistance or trends in prevalence of resistance in that particular country.
However, if results achieved with different AST methods are to be presented side by
side, then comparability of results must be demonstrated and consensus on
interpretation achieved.
Note: This will be best accomplished by the use of accurate and reliable standardised
AST methods in conjunction with monitoring of AST performance with defined
quality control bacterial strains among participating laboratories.
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7.
Comparability of results
To determine the comparability of results originating from different surveillance
systems, results should be reported quantitatively including information on the
methods, quality control organisms and antimicrobial concentration ranges tested and
interpretive criteria used.
8.
Quality control and quality assurance
Adequate quality control/quality assurance systems should be established in AST
performing laboratories.
The following components should be monitored:
i)
precision of the AST procedure,
ii)
accuracy of the AST procedure,
iii) performance of the appropriate reagents,
iv) the laboratory personnel.
The following requirements should be respected:
i)
Strict adherence to standardised techniques in conjunction with quality control of
media and reagents.
ii)
Record keeping of:
•
lot numbers of all appropriate materials and reagents,
•
expiration dates of all appropriate materials and reagents.
iii) The appropriate quality control reference bacteria should also be tested to ensure
standardisation regardless of the AST method used.
iv) Reference bacterial strains should be catalogued and characterised with stable
defined antimicrobial susceptibility phenotypes. These quality control strains
should also encompass resistant and susceptible ranges of the antimicrobials to
be assayed.
v)
Laboratories involved in AST should use the appropriate quality control
reference strains.
vi) Reference strains should be kept as stock cultures from which working cultures
are derived and should be obtained from national or international culture
collections. Reference bacterial strains should be stored at designated centralised
or regional laboratories.
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vii) The preferred method for analysing the overall performance of each laboratory is
to test the appropriate quality control bacterial strains on each day that
susceptibility tests are performed.
Because this may not always be practical or economic, the frequency of such quality
control tests may be reduced if the laboratory can demonstrate that the susceptibility
testing procedures are reproducible. If a laboratory can document the reproducibility
of the susceptibility testing methods used, testing may be performed on a weekly
basis. If quality control errors emerge, the laboratory has a responsibility to determine
the cause(s) and repeat the tests. If the laboratory cannot determine the source of
error(s), then quality control testing should be re-initiated on a daily basis.
viii) Recognised quality control strains should be tested each time a new batch of
medium or plate lot is used and on a regular basis in parallel with the bacterial
strains to be assayed.
ix) Appropriate biosecurity issues should be addressed in obtaining and dispersing
quality control reference strains to participating laboratories. The use of such
strains will allow for comparison of antimicrobial susceptibility data (run on).
9.
External proficiency testing
To ensure that reported susceptibility data is accurate, OIE Member Countries should
initiate external proficiency testing (e.g. third party testing). External proficiency
testing can be carried out on a national basis. Laboratories in Member Countries are
encouraged to participate in international inter-laboratory comparisons. All important
bacterial species should be included.
Countries should appoint or establish designated national laboratories that are
responsible to:
i)
monitor the quality assurance programmes of laboratories participating in
surveillance and monitoring of antimicrobial resistance,
ii)
supply to those laboratories a set of reference strains.
References
1. Anthony F., Acar J., Franklin A., Gupta R., Nicholls T., Tamura Y., Thompson S.,
Threllfall E.J., Vose D., van Vuuren M. & White D.G. (2001). – Antimicrobial resistance:
responsible and prudent use of antimicrobial agents in veterinary medicine. Rev. sci. tech. Off. int.
Epiz., 20, 829-839.
2. Brown D.F. & Brown L. (1991). – Evaluation of the E-test, a novel method of
quantifying antimicrobial activity. J. Antimicrob. Chemother., 26, 185-190.
3. Leegard T.M., Caugant D.A., Froholm L.O. & Hoib E.A. (2000). – Apparent differences
in antimicrobial susceptibility as a consequence of national guidelines. Clin. Microbiol. Inf. Dis., 6,
290-293.
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4. National Committee for Clinical Laboratory Standards (NCCLS) (2002). – Document
M31-A2. Performance standards for antimicrobial disk and dilution susceptibility tests for
bacteria isolated from animals, approved standard, 2nd Edition. NCCLS, Wayne, Pennsylvania,
80 pp.
5. Ringertz S., Olsson-Liljequist B., Kahlmeter G. & Kronvall G. (1997). – Antimicrobial
susceptibility testing in Sweden II. Species-related zone diameter breakpoints to avoid
interpretive errors and guard against unrecognised evolution of resistance. Scand. J. Infect. Dis.,
105 (Suppl.), 8-12.
6. Threlfall E.J., Fisher I.S.T., Ward L., Tschape H. & Gerner-Smidt P. (1999). –
Harmonisation of antibiotic susceptibility testing for Salmonella: results of a study by 18
national reference laboratories within the European Union-funded Enter-Net group. Microb.
Drug Resist., 5, 195–199.
__________
OIE International Standards on Antimicrobial Resistance, 2003
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Proceedings of the
OIE International Conference
OIE International Standards on Antimicrobial Resistance, 2003
41
1.
General aspects
OIE International Standards on Antimicrobial Resistance, 2003
43
1. General aspects
Antimicrobial resistance: an overview
J. Acar (1) & B. Röstel (2)
(1)
Université Pierre et Marie Curie, Service de Microbiologie Médicale, Fondation Hôpital Saint-Joseph, 185 rue
Raymond Losserand, 75674 Paris Cedex 14, France
(2)
Centre collaborateur de l’OIE (Organization mondiale pour la santé animale) pour les médicaments vétérinaires,
Agence française de sécurité sanitaire des aliments (AFSSA) Fougères, Agence nationale du médicament vétérinaire
(ANMV), B.P. 90203, 35302 Fougères Cedex, France
This report, prepared by the OIE Ad hoc Group of experts on antimicrobial resistance, has not yet received the
approval of the International Committee of the OIE
Summary
Increased antimicrobial resistance in bacteria that are important pathogens of humans, and spread of
resistance from the closed environment of hospitals into open communities are increasingly perceived as
a threat to public health. Any antimicrobial use, whether in humans, animals, plants or food
processing technology, could lead to bacterial resistance. Use of antimicrobials in livestock production is
suspected to significantly contribute to this phenomenon in species of bacteria which are common to
humans and animals. Further research is required into the specific use conditions that govern the
selection and dissemination of resistant bacteria. International travel and trade in animals and food
increase the risk of antimicrobial resistance world-wide. Countries are considering import restrictions
for products deemed a risk to public health. The World Organisation for Animal Health, a World
Trade Organization reference organisation for the Agreement on the Application of Sanitary and
Phytosanitary Measures, develops international standards on antimicrobial resistance which, as is the
case for national measures, must be based on risk analysis. The scientific background and problems of
resistance in human medicine are reviewed. Current knowledge, missing information and actions to be
taken are identified.
Keywords
Agreement on the Application of Sanitary and Phytosanitary Measures –
Antimicrobial resistance – Containment of resistance – Food – International
standards – National measures – Public health – Resistance mechanisms – Risk
analysis – World organisation for animal health.
Introduction
The existence of antimicrobial resistance, the increase in resistance to a number of
antibiotics of bacteria that are important human pathogens, and the spread of
resistance from the rather closed environment of hospitals into open communities, are
increasingly perceived as a threat to public health.
The appearance of new resistance mechanisms, the development of multi-drug
resistance or combinations of resistance, and the facility with which genetic material
encoding resistance may, in certain cases, spread horizontally between different
species of bacteria, all increase the feeling of defencelessness against diseases that were
thought to have been controlled when antibiotics were first developed.
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Reports referring to apocalyptic visions of the plague depopulating nations and
women dying of puerperal fever, are prone to increase public fears rather than helping
to appropriately address important matters of public health. Unfortunately, these kind
of publications, such as ‘World leading killers planning their escape’ are rather
common and are not only communicated by the kind of media aiming at increasing
their sales figures.
Any use of antibiotics, may it be for human, animal, plant or food-processing
technology, has the potential to lead, at some point in time, to bacterial resistance.
Although many publications are beginning to appear, little is known about the
different conditions of use under which antibiotics preferably select, or select to a
lesser extent, for resistant bacteria. Resistance, once developed, is not bound to
borders of different ecological environments or countries. Limited scientific research
on resistance (abandoned for several decades and only recently re-established, pushed
by growing concerns) and the consequent lack of scientific data leave society and
decision makers in the uncomfortable situation of requesting and deciding upon
corrective actions when the underlying causes may not have been appropriately
identified.
This situation, coupled with the slowing, and in certain sectors disappearing, discovery
and development of new antibiotics with new mechanisms of action, creates an
atmosphere of anxiety calling for immediate action, whether efficient or not.
Globalisation, new trade environments and transfer of resistant bacteria through
international travel, and trade of animals and food, raise the risk of the spread of
resistance world-wide. It also bears the risk of countries closing borders for trade on
the basis of inappropriately evaluated risks or perceived risks.
Antimicrobial resistance – a responsibility of the OIE
Why has the World Organisation for Animal Health taken action on
antibiotic resistance?
Countries must protect animal and human health. This also includes protecting against
risks arising from bacteria resistant to antimicrobial treatment.
At the same time, members of the World Trade Organization (WTO) must respect
their obligations under the WTO Agreement on the Application of Sanitary and
Phytosanitary Measures (SPS), which are to base any sanitary measure on risk
assessment and scientific evidence and to restrict measures to the extent necessary to
achieve the chosen level of protection. In cases where several potential measures exist,
the least trade restrictive measure must be chosen.
The OIE (World animal health organisation) is the organisation recognised by the
WTO for the elaboration of international standards, guidelines and recommendations
on matters of animal health and zoonoses relevant for the trade of animals and animal
products.
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Antibiotic resistance, as it relates to zoonotic bacteria and to resistance determinants
(which may be transferred between animals and from animals to humans), and the
measures to be taken in view of their control are the responsibility and field of
competence of the OIE. The OIE is the appropriate organisation to prepare
international recommendations on the detection and control of antimicrobial
resistance as they relate to zoonotic bacteria and resistance determinants as they
originate from animal bacteria. These standards, when finalised and adopted by the
OIE International Committee, will serve as a WTO reference standard, should trade
disputes arise.
What action has been taken by the World Organisation for Animal
Health?
A report on existing activities and capacities for the detection and control of antibiotic
resistance was made in 1998 to fifty countries of Europe at the OIE Regional
Commission for Europe. This report emphasised that additional efforts should be
made to develop official antimicrobial resistance surveillance/monitoring
programmes, to improve their harmonisation and the harmonisation of laboratory
methodologies, which in turn will improve the reliability and comparability of
generated resistance data. The report also pointed out that risk analysis was not
commonly used when the implementation of sanitary measures was considered by
countries.
Based on this report, the OIE Regional Commission for Europe recommended to the
OIE International Committee that an international Ad hoc Group of experts be
formed to address, using a comprehensive and multidisciplinary approach, human and
animal health risks related to antimicrobial resistance originating from the use of
antimicrobials in veterinary medicine. The OIE International Committee endorsed
this recommendation in May 1999 and the OIE Director General appointed the Ad
hoc Group of experts on antimicrobial resistance.
The OIE Ad hoc Group of experts decided to engage in a three pillar strategy:
– immediate measures to contain and reduce antimicrobial resistance (prudent and
responsible use of antimicrobials)
– development of tools to assess and manage the risks to animal and human health
(risk analysis methodology), and harmonisation of surveillance systems and laboratory
methodologies
– improve knowledge on antimicrobial resistance world-wide (information
gathering).
The achievements of the Ad hoc Group of the World Organisation for
Animal Health
As a result of the work of the OIE Ad hoc Group, countries are now gaining access
to a set of comprehensive methodologies, assuring that the identification of, and
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1. General aspects
decision upon appropriate intervention measures are conducted in an objective,
science-based, transparent and defensible way.
The specific considerations that were given to the different conditions (geographical,
use of antimicrobials, resistance situation) and to the technical capabilities and
capacities of countries around the world, open the way for an equal application of
these methodologies both to developing and developed countries. The OIE Ad hoc
Group emphasises that where animal or human health problems exist throughout the
world, without respect to national borders, all countries have an equal need to protect
their animal and human populations and their national trade interests.
The tools underlying two of the three pillars of the recommendation of the OIE Ad
hoc Group (monitoring the quantities of antimicrobials used in animal husbandry and
the immediate measures to contain antimicrobial resistance through the prudent and
responsible use of antibiotics) and the tools to assess and manage risks to animals and
humans (risk analysis methodology, harmonisation of surveillance systems and
laboratory methodologies) became available for implementation by country
governments and competent authorities.
The five respective guidelines, prepared by the OIE Ad hoc Group with the
participation of the Food and Agriculture Organization (FAO) and the World Health
Organization (WHO) compose the body of this document.
The third pillar (to improve knowledge on antimicrobial resistance world-wide) will be
constructed as the implementation of the tools constituting the first two pillars
proceeds and results are obtained.
Future directions of the World Organisation for Animal Health
The 69th General Session of the OIE International Committee of May 2001 adopted
Resolution No. XXV requesting the OIE Specialist Commissions to develop
international standards in the area of antimicrobial resistance. The Specialist
Commissions will use the recommendations of the OIE Ad hoc Group to develop
these standards. The draft standards proposed by the Specialist Commissions will be
circulated for comments to the OIE Member Countries. Revised draft standards will
be circulated a second time to the OIE Member Countries and after a second revision,
as appropriate, be submitted for adoption to the 70th General Session of the OIE
International Committee in May 2002. The standards will be published in the
International Animal Health Code and the Manual of Standards for Diagnostic Tests and
Vaccines.
The OIE is taking steps to encourage Member Countries to make use of the new
methodologies in order to establish an objective, science-based view on the subject
and consequently contain antimicrobial resistance in animal bacteria. The OIE will
undertake the necessary steps to provide assistance, as appropriate, to its Member
Countries, on aspects related to the implementation of this standard.
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The OIE Standards Commission decided during its spring meeting in January 2001 to
introduce standards for antimicrobial sensitivity testing into the OIE Manual of
Standards for Diagnostic Tests and Vaccines. The Standards Commission also
recommended the designation of OIE Reference Laboratories for the detection and
quantification of antimicrobial resistance in animal bacteria. These laboratories will,
among others, assist OIE Member Countries in setting up microbiological
laboratories, where appropriate, and in placing the work of these laboratories under
quality assurance.
At the 14th Conference of the OIE Regional Commission for Africa, held on 23-26
January 2001, Member Countries decided to actively engage in the promotion of the
prudent use of antimicrobials in animals and to undertake efforts to establish national
programmes for the management of antimicrobial resistance. The Regional
Commission for Africa also recommended that OIE Reference Laboratories assist
OIE Member Countries in implementing quality assurance schemes in national
microbiological laboratories and in participating in external proficiency testing
programmes.
The OIE will continue to insist that sanitary measures are based on risk assessment of
sound scientific data, and conducted according to appropriate recommended
methodologies.
Some scientific facts
The scientific background
What is antimicrobial resistance?
Antimicrobial resistance is the capacity of bacteria to survive exposure to a defined
concentration of an antimicrobial substance. Antimicrobial resistance has multiple
definitions according to the scientific discipline and the goals involved:
– clinical definition: the bacteria survive an adequate treatment with an antibiotic
– pharmacological definition: the bacteria survive a range of concentrations
expressing the various amounts of an antibiotic present in the different compartments
of the body when the antibiotic is administered at the recommended dose
– microbiological and molecular definition: the bacteria have a mechanism which
governs a higher minimum inhibitory concentration (MIC) than the original or wild
bacteria
– epidemiological definition: any group of bacterial strains which can be
distinguished from the normal (Gauss) distribution of MICs to an antibiotic.
Bacterial resistance to a particular antibiotic can be a natural property of the bacteria
or a secondarily acquired mechanism. Surviving the effect of an antibiotic is a normal
reaction of a bacterial cell. When successful, such a reaction gives origin to a clone of
bacterial cells able to confront the antibiotic. However, according to the mechanism
of resistance, the bacterial clone may confront different amounts of antibiotic, ranging
from a small amount, close to the amount formerly able to inhibit the growth (MIC)
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1. General aspects
of the bacterial cell, to a very large quantity of antibiotics (e.g. hydrolysing exoenzyme
produced by the bacteria).
It is a very well known fact that bacteria can resist any antibiotic, and this is a global
phenomenon which affects all countries. However, characteristics of the resistance
phenomenon relate to the affected bacterial species, the set of antibiotics involved, the
distribution of the resistant strains in particular settings in which antibiotics are used
(hospital, community, animal husbandry, etc.). The resistant strains are classified
according to their identification (genus, species) and to their antibiotic resistance
phenotype (sometimes referred to as antibiotype or resistance pattern).
The antibiotic resistance phenotype is established by the comparison of the list of
antibiotics active on the reference (original, wild) strain of the bacterial species (which
may have a natural resistance to some antibiotics) with the list of antibiotics to which
the strain tested is resistant. This represents acquired resistance, which is the opposite
of natural resistance. It is recommended to group the antibiotics under classes and
subclasses according to the mechanism of resistance. This is called cross-resistance
(e.g. a β-lactamase Tem type in Escherichia coli governs a cross-resistance to all
aminopenicillins, all ureidopenicillins and a few first generation cephalosporins. The
cross-resistance for six compounds is expressed by ampicillin resistance).
When the sequence of resistance markers concerns different classes of antibiotics, this
is referred to as co-resistance.
Bacterial resistance to an antibiotic can be considered according to three aspects
described below.
The mechanism by which the bacteria is able to resist
It is important to note that a bacterial cell often possesses more than one mechanism
to resist to an antibiotic. Co-operation between several resistance mechanisms often
generates high level resistance. A summary of resistance mechanisms, the affected
antibiotics and the resulting level of resistance, is presented in Table I.
The genetic mechanism governing the proteins involved in the resistance and
the origin of resistance
Two genetic mechanisms are involved, namely: mutation in an existing gene
(chromosome or plasmid), and the de novo acquisition of a gene governing resistance.
The location of the altered or the new genes is important (chromosomes, integrons,
transposons or plasmids). The most important consequence of the location of the
resistance genes concerns the spread of the resistance:
– a chromosomal mutation affects a bacterial cell. The clone issued from this cell
will multiply and spread. This mode of spread is often called vertical transmission of
resistance
– a resistance gene located on a transposon or a plasmid can be transmitted
horizontally, independently from the spread of the resistant clone. Moreover, the
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horizontal transmission may occur between different bacterial species. Concomitantly
or independently to the expansion of the resistant bacteria, plasmid (gene) epidemics
can occur. Many of them have been reported affecting six to eight species of Gramnegative bacteria.
Plasmids or transposons are the main systems (genetic material) transferring resistance
from bacteria (donor) to bacteria (recipient). They usually carry more than one marker
of resistance. Large plasmids may transfer several different mechanisms of resistance
against a number of different antibiotics. Their concurrent appearance in the same
bacteria explains that one antibiotic may continue to co-select for the whole set of
resistance mechanisms (multi-drug resistance).
The medical (or therapeutic) aspect
Bacterial resistance is recognised in medicine when an antibiotic treatment fails to cure
a patient and the bacterial pathogen persists unharmed by the antibiotic prescribed.
This is the point in time when human medicine becomes concerned. It is important to
note that when a particular resistance emerges in a human bacterial pathogen (except
the rapid selection of a chromosomal mutant bacteria), it can be assumed that many
bacteria (commensal, environmental and animal) have also acquired the same
resistance mechanism. A delay, sometimes very long, elapsed between the emergence
of the resistance mechanism and its medical visibility.
Table I
Resistance mechanisms, the affected antibiotics and the resulting level of
resistance
Mechanism
Affected antibiotics
Level of resistance
Efflux
Tetracyclines
Macrolides
Quinolones
Others in different systems
Low
Penetration
β-lactams
Chloramphenicol
Trimethroprim
Tetracyclines
Low
Target alteration
β-lactams
Aminoglycosides
Macrolides
Quinolones
Rifampicin
Glycopeptides
Sulphonamides
Trimethropim
Variable
By-pass
Enzyme detoxification
β-lactams
Aminoglycisides
Macrolides
Chloramphenicol
Lincosamide
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High
High
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Why and how does resistance develop?
Resistance develops as an answer to the selection pressure exerted by an antibiotic, or
by another compound (e.g. antiseptic), provided that they share at least one similar
mechanism of resistance. Two conditions should be met. The selecting substance
(selector) must be in prolonged contact with the bacterial population. The selector
should be at a concentration which allows the bacteria to survive. This is generally
referred to as a sub-inhibitory concentration. However, it should be noted that the
lower limit of a sub-inhibitory concentration still acting as a selector has been poorly
explored.
An apparent contradiction exists between the statement that there is a positive
correlation between high consumption/usage of antibiotics in a country and resistant
bacteria, and the fact that low doses of antibiotics in an individual ecosystem (patient,
animal or environment) are more selective for resistance. This stems from the fact that
two different systems are compared, which are not directly related. One system is the
total human or animal population in a country, the other system is the bacterial
populations in a patient or group of patients. High consumption of antibiotics is a
surrogate measure of the amount of antibiotics distributed among humans, animals
and the environment. The important criteria is not the high concentration of an
antibiotic in an individual patient or animal, but the extent of distribution of the
antibiotics in the ecosystem. The larger the distribution of antibiotics, the greater the
chance that in some place a large population of bacteria will be in contact with the
correct selecting concentration of the antibiotic.
The different events in bacterial life which can lead to the development of resistance
are shown in Table II.
Table II
Events leading to the development of resistance
Events
Result
Chromosomal mutations (one or more)
Induction
Derepression (pre-existing mechanism not
expressed or barely expressed)
Mutation (plamid)
Altered target
Altered cell wall
Efflux system
Modifying enzyme
Modifying enzyme
Inducible trait:
constitutive
Modifying enzyme
Efflux
By-passing target
Acquisition of genes
Plasmids, transposons, phages
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Spread
Clonal (not
transferable)
Clonal and
transferable
Transferable
Needs donor
strains and
recipient strain
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In the first case, the resistance trait is generated from a mutation which occurs in the
particular clone in contact with the selector.
In the second case, the acquisition of a resistance gene requires the transfer of such a
gene from a donor strain to the recipient strain. In that case, two populations of
bacteria are required in the presence of the antibiotic, with one resistant (donor) and
one susceptible (recipient).
It should be noted that in infectious diseases, there is usually one bacterial population
at the site of infection. Resistance due to mutation can be acquired by the patient
during treatment (rifampin, fluoroquinolones). Only emergence of resistance due to
mutation can be easily and rapidly observed in the patient, whereas resistance due to
acquisition of genes is only recognised after a delay of months or even years.
The primary origin of genes governing mechanism of resistance and able to circulate
between bacteria of the same or different species remains partly unknown. However,
it is accepted that these genes may originate from the antibiotic-producing organism,
which uses the mechanism to survive its own antibiotic production (e.g. enzyme
modifying aminoglycoside). This is an event that occurs in nature and is independent
of the man-made production and use of antibiotics.
There is also evidence that transferable resistance genes can originate from a ‘pick up’
mechanism which mobilises a gene from the chromosome of a naturally resistant
bacteria (e.g. plasmid located cephalosporinase).
Although no strict separation can be made between chromosomal resistance and
transferable resistance, it is useful to keep the distinction as an epidemiological tool. It
can be of importance to recognise that the spread of quinolone resistant strains is
clonal (resistance to quinolone is a chromosomal mutation) compared to that of
ceftriaxon resistant Salmonella. In that case, plasmid-mediated spread is combined with
clonal spread, and can be linked to different Salmonella species or other
Enterobacteriacae.
Where does resistance develop?
Very few studies have demonstrated the favourable niche for resistance development.
The selector must be mixed with the bacterial population at the right concentration
and time needed for the selection and the multiplication of the resistant population. In
a unique bacterial population, emerging resistance is necessarily selected through
mutations in the pre-existing genes of the bacterial cells. When the niche comprises
mixed populations of different bacteria (resistant and susceptible), the emerging
resistance may be due either to mutation or to a de novo acquisition of genes from a
resistant bacterial cell. An antibiotic entering a niche with several bacterial species will
kill the susceptible bacteria while the resistant species will multiply by mere vital
advantage. Resistant clones from the susceptible population may be selected provided
that:
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a) the antibiotic concentration has declined, allowing the survival of a portion of the
susceptible population
b) a mutant bacterial cell exists in the bacterial population (the frequency of
mutation varies greatly between antibiotics)
c) a transfer of genes (plasmids or transposons) has taken place between the preexisting resistant bacterial cells and the surviving susceptible bacterial cells.
The most studied location of emergence of resistance is the digestive system of
humans and animals. The enormous number of bacteria and species and the
obligatory presence of most antibiotics in the gut (oral administration and bile
elimination) explain the importance of this essential niche for resistance emergence.
Clearly, mutant bacterial cells are theoretically selectable in any site where bacteria and
antibiotic are in contact (e.g. abscess, empyema, urine, etc.).
However, resistance by chromosomal mutation is not the most frequent system of
resistance and does not affect a large number of antibiotics. The only antibiotics
affected are those for which a high frequency of mutation (> 10–8) exists (rifampin,
fusidic acid, quinolones and phosphomycin).
In these cases, mutations are readily selected. Resistant clones are often observed
during treatment or shortly afterwards. Such emergence of resistant strains is
spectacular and easily observed by medical doctors or veterinarians.
In fact, mutations are a small part of the resistance problem. The principal problem is
related to the selection and the stabilisation of mechanisms governed by foreign genes
acquired by the originally susceptible bacterial cells.
As mentioned earlier, the intense circulation of bacteria can either be gene circulation
or bacterial cell circulation. The emergence of multiple-resistant pathogens (with
plasmids, transposons or integrons) takes a long time, during which numerous bacteria
(commensal, environmental) are involved; during this period the phenomenon is not
clinically visible. In this case, emergence of the resistant pathogen occurs far from the
prescriber of the antibiotic and a long time after the original selection.
The second important locations where resistant strains are built and selected are those
related to the environment (water, soil, animal litter, sewage, hospital fomites, etc.).
Several antibiotics can be present together in a niche. Those antibiotics will select for
resistance separately, but also in a co-operative manner, if bacteria exist which are
already resistant to them. The multiple resistant strains are favoured, since they can
more easily survive the exposure to multiple antibiotics. Those multiple resistant
strains are also more likely to acquire a new resistance.
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What problems are faced?
Infectious diseases and resistance in human medicine
The difficulties faced in depicting the current situation of antimicrobial resistance are
related to the limited, or in many cases lacking, systematic official disease
investigations and reporting in this area. Hard data, such as laboratory confirmed
cases, are limited even in developed countries where sophisticated disease
investigation and reporting systems exist. Total disease burden, morbidity, mortality
and economic impact descriptions are based on estimations, which may inherit errors
and uncertainties depending on the validity of the underlying assumptions. The few
countries that have, in recent years, started official resistance surveillance are
beginning to obtain in vitro bacterial susceptibility data. However, systematic reporting
of data on clinical outcomes is limited. Therefore, in many instances, in vitro data may
have to be interpreted without being able to relate back to clinical outcomes.
The reasons for this situation may be related initially to the inherent costs of disease
investigation and reporting, but also to political unawareness and the potential
negative impact of disease statistics on public opinion.
According to the WHO, the emergence and spread of antimicrobial resistance in
human pathogens is considered a global problem which increasingly affects the
successful treatment of infectious diseases in humans.
The WHO has identified six diseases (tuberculosis, malaria, pneumonia, human
immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS),
diarrhoea and measles) which cause 90% of infectious disease deaths world-wide. A
proportion of these diseases is caused by bacteria and a relatively larger proportion by
parasite and virus infections.
To provide an overview on the resistance situation in medicine, these infections will
be briefly reviewed.
Tuberculosis
Tuberculosis, a disease once thought to be controlled, is currently responsible for the
deaths of 1.5 million people a year (a further 0.5 million die from a combination of
tuberculosis and HIV/AIDS). Nearly two billion people (one-third of the population
of the world) have latent tuberculosis infection. This constitutes a huge potential
reservoir for the disease. Tuberculosis is one of the biggest infectious killers of
adolescents and adults, and a leading cause of death among women. In addition,
infection with HIV weakens the immune system and can activate latent tuberculosis.
Infection with HIV is also believed to multiply the risk of contracting tuberculosis.
Approximately one-third of all AIDS deaths are currently caused by tuberculosis.
Because a patient may have both AIDS and tuberculosis, the reservoir for tuberculosis
has increased and threatens more people in the community.
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Moreover, tuberculosis is becoming increasingly resistant to anti-tuberculosis drugs.
Researchers assess the approximate number of multi-drug resistant tuberculosis cases
at between 1% and 2% of current global tuberculosis figures. However, in some parts
of the world, the rates of multi-drug resistant tuberculosis are much higher. China
(Henan and Zhejiang), India (Tamil Nadu), Iran, Mozambique and Russia (Tomsk)
each reported high levels of multi-drug resistant tuberculosis (over 3%) in new cases.
Israel, Italy, Mexico (Baja California, Oaxaca and Sinaloa) reported multi-drug
resistant tuberculosis in over 6% of both new and previously treated cases.
Malaria
Malaria kills over one million people a year, most of them young children. Most
malaria deaths occur in sub-Saharan Africa, where malaria accounts for one in five of
all childhood deaths. Women are especially vulnerable during pregnancy, suffering
miscarriages or giving birth to premature, low-weight babies, and are more likely to die
from the disease. An estimated 300 to 400 million people world-wide are infected by
this mosquito-borne parasite each year.
The development of resistance in the malaria parasite shows similarities to bacterial
resistance.
Acquired immune deficiency syndrome and sexually transmitted infections
At the end of 1999, an estimated 33.6 million individuals were living with HIV worldwide. There is still no cure on the horizon. In some countries, up to one in four of the
adult population is now living with HIV/AIDS. The worst affected region is subSaharan Africa.
A small but growing number of patients are showing primary resistance to zidovudine
(AZT), as opposed to ‘secondary’ resistance where viruses grow increasingly
insensitive to antivirals over the course of the illness. This is also true for protease
inhibitors which became available only ten years ago.
Gonorrhoea and sexually transmitted infections (STIs) are important co-factors in the
transmission and spread of HIV. This is because HIV bonds to white blood cells
collecting at inflamed sites around the uro-genital tract. Studies show that those coinfected with gonorrhoea and HIV shed HIV at nine times the rate of individuals
affected with HIV alone.
Of the STIs, including chancroid and chlamydial infections, gonorrhoea is the most
resilient, with a resistance rate that continues to outstrip new treatment strategies.
Gonorrhoea resistance was first reported in American servicemen during the Vietnam
war and is now entrenched around the globe, with multi-drug resistant strains
appearing in 60% of those infected each year. In most of South-East Asia, resistance
to penicillin has been reported in nearly all strains at an overall rate of 98%. Recent,
more expensive drugs, notably ciprofloxacin, are likewise showing an increasing failure
rate. Owing to resistance, chronic gonorrhoea has become a driving force in the HIV
epidemic.
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Pneumonia
Acute respiratory infections (ARIs) are responsible for 3.5 million deaths each year.
Pneumonia, the most dangerous ARI, kills more children than any other infectious
disease. Most of these deaths (99%) occur in developing countries, while in
industrialised countries childhood deaths from pneumonia are rare. Pneumonia often
affects children with low birth weight or those whose immune systems are weakened
by malnutrition or other diseases. Without treatment, pneumonia kills quickly.
The major causes of pneumonia are the influenza virus and Streptococcus pneumoniae.
The development of resistance to penicillin G by S. pneumoniae is now recognised
world-wide. However, the prevalence of resistant strains ranges from 5% to 70% of
the investigated laboratory samples. Most of these strains are also resistant to several
other antibiotics (macrolides, tetracyclines, trimethoprim), dangerously restricting the
choice of first-line therapy.
Measles
Measles is the most contagious disease known to mankind. It is a major childhood
killer in developing countries, accounting for approximately 900,000 deaths a year.
The measles virus may ultimately be responsible for more child deaths than any other
single microbe, due to complications from pneumonia, diarrhoea and malnutrition.
Hospital acquired infections
Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Gram-negative
rods (VRE) and enterococci and fermentative Gram-negative Entero-bacteriaceae are
the most frequent multi-drug resistant bacteria isolated in hospitals both in developed
and developing countries, and are responsible for the most difficult-to-treat hospital
infections.
Diarrhoeal diseases
Diarrhoeal diseases claim nearly two million lives a year among children under five.
These diseases are so widespread in developing countries that parents often fail to
recognise the danger signs. Children die simply because their bodies are
undernourished through lack of food and then are weakened through rapid loss of
fluids. Diarrhoeal diseases impose a heavy burden on developing countries,
accounting for 1.5 billion cases of illness a year in children under five. The burden is
highest in deprived areas where there is poor sanitation, inadequate hygiene and
unsafe drinking water. In certain developing countries, epidemics of diarrhoeal
diseases such as cholera and dysentery affect both adults and children.
Other diarrhoeal diseases include typhoid fever, rotavirus infection, salmonellosis and
campylobacteriosis.
Multi-drug resistance is also occurring in microbes that cause diarrhoeal diseases. One
such agent, Shigella dysenteriae, is a highly virulent microbe that is resistant to almost
every available drug. The results of this growing crisis were illustrated most notably in
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the wake of the 1994 civil war in Rwanda when the bacterium spread through
vulnerable refugee populations already traumatised by war and loss. Left untreated,
death can follow within days of infection. Ten years ago, a shigella epidemic could
easily be controlled with co-trimoxazole, a drug available in generic form at low cost.
Today, nearly all shigella are non-responsive to the drug, while resistance to
ciprofloxacin (the only remaining viable medication) appears to be imminent.
The bacteria that cause cholera and typhoid are also revealing the ease with which they
acquire resistance. For the treatment of cholera, fluid replacement is paramount, but
antibiotics (especially tetracycline) play an important public health role in limiting the
spread of epidemics. Salmonella serotype Typhi, like shigella, is adept at accumulating
cassettes of resistance genes, producing strains that withstand first-line, second-line
and now, third-line drugs. Until 1972, chloramphenicol was the treatment of choice
for typhoid fever throughout much of the subcontinent of India. By 1992, two-thirds
of reported cases were chloramphenicol-resistant, thereby necessitating treatment with
expensive quinolones that are themselves losing effectiveness. Without proper
treatment, typhoid is a serious and frequently relapsing disease that kills up to 10% of
those infected.
Food-borne infections
Food- and water-borne pathogens generally cause diarrhoeal diseases. Six major
bacterial groups (Salmonella, Campylobacter, E. coli, Yersinia, Clostridia and Listeria) are
responsible for these infections. In severe cases, systemic forms of disease may
develop.
Due to the considerable potential for food and water for human consumption to be
contaminated by animal and environmental bacteria, scientists have started to focus
attention on this area. Although available scientific data is limited, food and foodborne diseases are considered by many to play a specific role in antimicrobial
resistance in humans.
When considering antimicrobial resistance in this context, a number of elements
should be taken into account, of which a few are mentioned below.
If food- or water-borne bacteria cause disease in humans (e.g. Salmonella and
Campylobacter), they may directly cause human illnesses, independent of whether they
are resistant or susceptible to antibiotics. These food- and water-borne illnesses will, in
most cases, result in diarrhoeal diseases. The majority of these diseases are selflimiting, do not require antibiotic treatment and are most appropriately treated by
symptomatic treatment. If the illness is caused by a resistant bacteria and does require
an antibiotic treatment, the treatment may be prolonged or recourse may have to be
taken to another, potentially more expensive, antibiotic. In cases where a bacteria is
resistant to all available antibiotics, the infection may become untreatable by
antibiotics and eventually a patient may die due to the consequences of a noncontrollable infection.
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If food- or water-borne bacteria are non-disease causing in humans (enterococci), they
may indirectly lead to human illness in those specific cases where the animal or
environmental bacteria has become resistant to antibiotics and where the potential
exists for a transfer of the resistance genes of these bacteria to human pathogenic
bacteria. As a consequence, a completely different human illness, which may not be
food- or water-related, may become more difficult or impossible to treat. The
evaluation of the impact of the potential transfer of resistance genes from nonpathogenic animal or environmental bacteria to pathogenic human bacteria is a much
more complex and difficult undertaking, which currently still resides in the domain of
research. Molecular and epidemiological methods are required to demonstrate the
identical composition of the resistant gene in both the animal/environment and the
human pathogenic bacteria and to trace the transfer of genes from the
animal/environment to the human bacterial populations or vice versa. The tracing of
the direction of transfer is particularly difficult in those cases where the incriminated
antibiotic has been used both in humans and animals or plants.
To evaluate the impact and the importance for human health of the non-human use
of antimicrobials in animals and plants, data should be systematically collected on the
contamination of food and water with resistant bacteria, food-borne infections, the
percentage of infections due to resistant bacteria and the clinical outcome of these
resistant infections.
Food-borne disease surveillance and resistance
Although food-borne disease surveillance was launched twenty years ago in some
countries (WHO Surveillance Programme for Control of Food-borne Infections and
Intoxications in Europe), food-borne disease surveillance appears to be lacking in
many countries around the world and requires significant improvement. Where this
kind of surveillance does exist, systematic, official collection of information on
antimicrobial resistant bacteria in food and water and on human infections due to
antimicrobial resistant animal or environmental bacteria appears to be scarce.
Some references to food- and water-borne disease reporting are given below, which
may to some extent illustrate the complexity in the evaluation of the role of
antimicrobial resistance in food-borne disease, and the role of food- and watertransferred resistance of animal or environmental origin in the human resistance
problem.
The 7th report of the WHO Surveillance Programme for Control of Food-borne
Infections and Intoxications in Europe states that ‘the variety and extent of foodborne diseases are such that no country is able to provide accurate data on their
incidence and prevalence and surveillance programmes, where they exist, mostly
collect information on only a low number of incidences. It is therefore not possible to
give an estimate of the real magnitude of the problem. In some cases, the aetiology is
multifactorial in nature and disease becomes manifest only after a long period of
exposure. Consequently, many of the health problems resulting from food
contaminants do not figure in statistics on food-borne diseases.’
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Indicating that there is direct evidence that antimicrobial use in animals selects for
antimicrobial resistant non-typhoid Salmonella serotypes (referencing resistant
S. Typhimurium DT 104), and for fluoroquinolone resistant Campylobacter jejuni
isolated from humans, poultry and poultry meat, the report indicates however that
there ‘is limited information on the prevalence and spread of resistance in zoonotic
bacteria. Monitoring programmes in some countries are in the early stage of
development, some of these are in parallel with the strengthening of resistance
monitoring in hospitals and community settings. Monitoring of antimicrobial
resistance of bacteria from food animals and food of animal origin – whether national
or international – is still in its infancy.’
With regard to food-borne illness in the United States of America (USA), summarised
quantitative data is readily available and data for 1997 are given below.
In the USA, food-borne diseases are estimated to cause 76 million illnesses, 325,000
hospitalisations and 1,800 deaths. Among all illnesses attributable to food-borne
transmissions, 30% are caused by bacteria, 3% by parasites and 67% by viruses. Six
pathogens account for over 90% of the estimated food-related deaths; Salmonella
(31%), Listeria (28%), Toxoplasma (21%), Norwalk-like viruses (7%), Campylobacter (5%)
and E. coli O157:H7 (3%).
In 1997, active surveillance by US FoodNet reported 8,576 laboratory-confirmed
cases of food-borne illnesses, of which 3,974 were identified as campylobacteriosis,
2,205 as salmonellosis, 1,273 as shigellosis, 468 as cryptosporidiosis, 340 as E. coli
O157:H7, 139 as yersinellosis, 77 as listeriosis, 51 as Vibrio infections and 49 as
cyclosporiasis. Overall, 1,270 (15%) of 8,576 patients with laboratory-confirmed
infections were hospitalised; the proportion of cases in which people were hospitalised
was highest for listeriosis (88%), followed by E. coli O157:H7 infections (29%), and
salmonellosis (21%). Thirty-six patients with laboratory-confirmed infections died:
fifteen with Listeria, thirteen with Salmonella, four with E. coli O157:H7, two with
Cryptosporidium, one with Campylobacter, and one with Shigella. In 1997, the catchment
area included 16.1 million people, 6.0% of the population of the USA.
Unfortunately, no information is currently available in these publications on the
percentage of infections due to resistant micro-organisms.
Scientific opinion
Current knowledge
Antimicrobial resistance is a natural phenomenon. It is the natural response of a
bacterium to defend itself against the effects of an antibiotic. The development of
antimicrobial resistance is an ecological phenomenon. Any antibiotic use, whether in
humans, animals or plants/environment may lead to resistance. In principle, the same
molecules and classes of antimicrobials are used in humans, animals and plants.
Humans, animals and the environment represent a reservoir in which resistance can
develop. As most bacteria can, at least transitionally, contaminate or colonise all
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possible hosts (humans, animals, plants, environment), there is an exchange between
the different hosts and between the hosts and the environment.
There is a problem of antimicrobial resistance in human medicine, increasingly
perceived around the world as a threat to public health. The major problems have
been described; these generally relate to parasites, viruses and human pathogenic
bacterial infections and the use of antimicrobials in human medicine. One of the six
major human diseases, diarrhoea, is in part related to zoonotic bacteria. The WHO
indicates that cholera, typhoid, shigella and rotavirus infections, coupled with
undernourishment, poor sanitation, inadequate hygiene and unsafe drinking water, are
the principal causes of the heavy diarrhoeal disease burden in developing countries. In
the USA, three pathogens, Salmonella, Listeria and Toxoplasma, are considered
responsible for more than 75% of deaths caused by known pathogens. Of these three,
Salmonella is a zoonotic bacterial pathogen.
Concern has increasingly been expressed that, additionally to the resistance existing
and emerging in human medicine, the use of antimicrobials in animals and plants will
lead to resistance, thereby adding to the existing resistance burden in humans.
Two potential mechanisms of resistance transfer from animals or plants/environment
to humans are currently under consideration, as follows:
a) the transfer of pathogenic bacteria
b) the transfer of non-pathogenic bacteria or the transfer of their genes encoding
resistance.
Infection with resistant zoonotic bacteria may directly lead to human illness. However,
the contribution of these bacteria to the overall resistance burden in humans should
be carefully evaluated. In view of the very limited existing resistance data in this area,
this evaluation might prove to be difficult.
Regarding the transfer of non-pathogenic bacteria, the great fear is that resistance
mechanisms encoded in mobile, transferable genetic material may be transferred to
already multi-drug resistant human pathogenic bacteria, causing a life-threatening
infection, which could be impossible to treat. As a less dramatic scenario, it is thought
that the transfer of resistance genes could add to multiple resistance in human
pathogens. As the treatment of multiple resistant infections is more difficult and more
expensive, such infections would result in an increase in public health costs.
Studies have been published on resistance gene transfer between bacteria. The impact
of the potential transfer of resistance genes is a current area of research. Although a
very small number of countries performs surveillance of resistance in enterococci
(these commensal bacteria are considered as the appropriate indicator bacteria, as they
easily develop or pick up transferable resistance), there is no scientific consensus on
how surveillance findings should be interpreted.
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Missing information
Where official collection of human infectious disease information exists, information
on percentages of resistant infections and clinical outcome data is limited. Food-borne
disease surveillance, although present in a number of countries, varies considerably
between countries and requires intensification and harmonisation. In other countries,
food-borne disease surveillance does not exist. As for zoonotic pathogens, official
surveillance of antimicrobial resistance in animal bacteria and food has started only
recently in a very small number of countries and in a limited number of bacteria.
Recognising the important efforts made by a number of countries, supported by
international organisations such as the WHO and the OIE, additional effort must be
made by countries world-wide for the collection of the appropriate data. Countries
should attempt to establish their priorities in view of the identified public health
problems, the inherent costs and the available resources.
Continued research to increase knowledge of antimicrobial resistance is vital, as is the
integration of scientific knowledge in the decision-making processes to the greatest
extent possible.
Future research
All further research in the subject will be valuable and will add to the knowledge and
our understanding of the emergence and the appropriate measures for the
containment of antimicrobial resistance.
A number of subject areas which urgently require further investigation are presented
below:
a) The role of different modes of use of antibiotics in animals and humans. This is
critical in the emergence and increased number of resistant strains among pathogens,
commensals and environmental bacteria. A number of issues should be considered,
namely: dose and duration of treatment, route of administration, pharmacokinetic,
pharmacodynamic, number of patients/animals treated, stability in the environment
(sewage, litter, land and animal housing), bacterial species and animal species.
b) The innumerable pathways which enable bacteria and genes to spread between
animals and humans. From the living animals to the contaminated food on the table
of the consumer, there are many opportunities for contamination and transmission.
This calls into question the idea that contamination necessarily originates from the
animal reservoir and calls for very careful studies to clarify this question. Such studies
are particularly difficult to design and conduct in cases where resistance genes, rather
than the bacterial strains, are to be tracked down.
c) The colonisation of humans by animal or environmental bacteria. Gram-positive
bacteria seem to spread differently to Gram-negative bacteria. The factors in the host
specificity of bacteria are to a great extent unknown.
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d) The factors to be taken into account when trying to measure human health
problems through a risk analysis study, specifically when it is applied to resistance
traits (transfer of resistance genes).
e) The information needed to assess and follow the resistance problems. This
depends on surveillance systems and records of the antibiotic consumption in humans
and animals. Most countries have not yet established any surveillance system.
Moreover, the methods of comparison and interpretation of the results are not yet
operational.
f) The factors which may explain an increase or a decrease in the prevalence of
resistant bacteria. These were recently investigated to determine the strength of their
link to the use of a particular antibiotic. Multiple resistance poses a difficult question,
since antibiotics other than those immediately concerned can be responsible for coand cross-selection. Many other questions are raised in accordance with the concern
for decreasing or containing antibacterial resistance. Environmental ecosystems,
animals and humans are very intimately linked through a bacterial circulation that we
are only recently beginning to understand.
Specific studies, basic and applied, coupled with bacterial surveillance systems and
more responsible use of antibiotics should generate feedback and deliver clues for
new understanding. It must be understood that not all antibiotics behave in the same
way, even those belonging to the same class. Such scientific knowledge will be
essential in making public health and political decisions and in adapting and updating
guidelines for a better protection of the consumer and the global community.
Actions to be taken
Immediate actions
The OIE Ad hoc Group of experts invites countries to inform themselves about the
problem of antimicrobial resistance.
As an immediate action, the OIE experts urge countries to implement the prudent
and responsible use of antimicrobial agents in veterinary medicine, as laid down in
their recommendations which are included in Antimicrobial resistance: responsible and
prudent use of antimicrobial agents in veterinary medicine, later in this volume.
Concurrent with the implementation of the prudent use of antimicrobials, countries
are invited to establish the surveillance of importation, distribution and use of
antimicrobials in animals. Countries should undertake all necessary efforts to impede
the importation, distribution and use of counterfeit antimicrobial products. The
recommendations of the OIE Ad hoc Group of experts are included in Antimicrobial
resistance: monitoring the quantities of antimicrobials used in animal husbandry, later in this
volume.
Furthermore, countries should attempt, as a preliminary evaluation, to obtain an
overview of the most important public health and antimicrobial resistance problems in
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their country. To this end, communication between the animal production and the
medical field should be established.
Countries should prioritise further medium-term actions, including time frames for
their implementation, according to the most important problems identified.
Requirements for the future
The OIE Ad hoc Group encourages the OIE Member Countries to take ownership of
the new methodologies and to make use of them in order to establish an objective,
science-based view on the resistance situation in their countries. The OIE urges
countries to carry out a risk analysis process when establishing sanitary measures
relative to antimicrobial resistance. The respective information and recommendations
of the OIE Ad hoc Group of experts are included in Antimicrobial resistance: risk analysis
methodology for the potential impact on public health of antimicrobial resistant bacteria of animal
origin, later in this volume.
OIE Member Countries should assure the use of standardised laboratory methods for
the detection and identification of antimicrobial resistance. To generate reliable
resistance data, microbiological laboratories should implement quality assurance
schemes and participate in external proficiency testing programmes. Proficiency
testing programmes would preferably be conducted on a regional or sub-regional
level. The recommendations of the OIE Ad hoc Group of experts are included in
Antimicrobial resistance: standardisation and harmonisation of laboratory methodologies for the
detection and quantification of antimicrobial resistance, later in this volume.
After a prioritisation of the most important public health and antimicrobial resistance
problems, countries should establish antimicrobial resistance surveillance programmes
in human pathogenic bacteria, where necessary, and in animal bacteria and food, as
appropriate. The recommendations of the OIE Ad hoc Group on how to address the
matter are included in Antimicrobial resistance: harmonisation of national antimicrobial
resistance monitoring and surveillance programmes in animals and in animal-derived food, later in
this volume.
Considering the importance of the issue and to foster consistency in decisions taken,
the OIE will continue to co-ordinate its work with other international organisations,
such as the FAO and WHO, and will also continue to be available for co-operation
with other international or regional organisations, as appropriate.
Antibiorésistance : une synthèse
J. Acar & B. Röstel
Résumé
L’augmentation de l’antibiorésistance des bactéries pathogènes pour l’homme et la propagation de cette
résistance, de l’environnement confiné des hôpitaux à la collectivité apparaissent, de plus en plus,
comme une menace pour la santé publique. Tout traitement antimicrobien appliqué aux humains,
aux animaux, aux végétaux ou dans les techniques de transformation des aliments peut entraîner une
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OIE International Standards on Antimicrobial Resistance, 2003
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résistance bactérienne. L’utilisation d’antibiotiques dans les élevages pourrait être en grande partie
responsable de ce phénomène dans les espèces bactériennes communes à l’homme et aux animaux. Il
est important d’explorer les conditions d’utilisation spécifiques qui président à la sélection et à la
dissémination des bactéries résistantes. Le commerce et les échanges internationaux d’animaux et de
denrées alimentaires élargissent au monde les risques de la résistance bactérienne. Certains pays
envisagent des restrictions à l’importation pour les produits jugés à risque pour la santé publique.
L’Organisation mondiale pour la santé animale, en tant qu’organisme de référence reconnu par
l’Organisation mondiale du commerce aux termes de l’Accord sur l’application des mesures sanitaires
et phytosanitaires, élabore des normes internationales sur l’antibiorésistance qui devront s’appuyer sur
l’analyse du risque, au même titre que les mesures nationales. Les auteurs examinent les aspects
scientifiques de la résistance ainsi que les problèmes qu’elle pose à la médecine humaine. Ils font
également le point sur l’état actuel des connaissances, sur les lacunes existantes et sur les mesures qu’il
conviendrait de prendre.
Mots-clés
Accord sur l’application des mesures sanitaires et phytosanitaires – Analyse du risque
– Antibiorésistance – Denrées alimentaires – Maîtrise de la résistance – Mécanismes
de la résistance – Mesures nationales – Normes internationales – Organisation
mondiale pour la santé aniamale – Santé publique.
Resistencia a los antimicrobianos: síntesis
J. Acar & B. Röstel
Resumen
El aumento de la resistencia a los antimicrobianos en bacterias que causan importantes afecciones
humanas y la salida de esas resistencias del reducto hospitalario al entorno abierto engendran una
creciente sensación de amenaza para la salud pública. Cualquier producto antimicrobiano que se
utilice en personas, animales, plantas o procesos de transformación de alimentos puede dar lugar a
resistencias bacterianas. Hay motivos para pensar que el uso de antimicrobianos en la producción
pecuaria contribuye sensiblemente al fenómeno entre especies bacterianas comunes al hombre y a los
animales. Será importante investigar acerca de las condiciones específicas de uso que intervienen en la
selección y la diseminación de bacterias resistentes. El comercio y movimiento internacional de
animales y productos alimentarios confieren una dimensión planetaria a los riesgos de resistencia
bacteriana, y no pocos países están estudiando restricciones a la importación de productos considerados
peligrosos para la salud pública. La Organización mundial de sanidad animal, en cuanto organismo
de referencia reconocido por la Organización Mundial del Comercio para el Acuerdo sobre la
aplicación de medidas sanitarias y fitosanitarias, elabora normas internacionales sobre la resistencia a
los productos antimicrobianos, cuya aplicación, como ocurre con las medidas de ámbito nacional, debe
basarse en el análisis de riesgos. Los autores pasan revista a los antecedentes y problemas científicos de
las resistencias en el ámbito de la medicina humana y determinan el estado actual de los
conocimientos, las lagunas existentes y las acciones que convendría emprender.
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1. General aspects
Palabras clave
Acuerdo sobre la aplicación de medidas sanitarias y fitosanitarias – Alimentos –
Análisis de riesgos – Contención de las resistencias – Mecanismos de la resistencia –
Medidas nacionales – Normas internacionales – Organización mundial de sanidad
animal – Resistencia a los productos antimicrobianos – Salud pública.
Appendix A
World Organisation for Animal Health Ad hoc Group of experts on
antimicrobial resistance
Members
Jacques Acar (Chair), Emeritus Professor of Microbiology, Université Pierre et Marie
Curie, Paris, France. E-mail: [email protected]
Sharon Thompson (Vice-Chair), Joint Institute for Food Safety Research, Department
for Health and Human Services Liaison, 1400 Independence Avenue, SW, Mail Stop
2256, Washington, DC 20250-2256, United States of America. E-mail:
[email protected]
Francis Anthony, Topic Leader Guideline No. 2, Fresh Acre Veterinary Surgery,
Flaggoners Green, Bromyard, Herefordshire, HR7 4QR, United Kingdom. E-mail:
[email protected]
Anders Franklin, Topic Leader Guideline No. 5, Department of Antibiotics, SVA, SE
751 89 Uppsala, Sweden. E-mail: [email protected]
David Vose, Topic Leader Guideline No. 1, David Vose Consulting, Le Bourg, 24400
Les Lèches, France. E-mail: [email protected]
†Terry Nicholls, Topic Leader Guideline No. 3, Animal Health Science and
Emergency Management Branch, National Offices of Animal and Plant Health and
Food Safety, Department of Agriculture, Fisheries and Forestry, P.O. Box 858,
Canberra ACT 2601, Australia.
R. Gupta, College of Veterinary Sciences, Veterinary Bacteriology, Department of
Microbiology, G.B. Pant University of Agriculture and Technology, Pantnagar 263
145 Uttar Pradesh, India.
Yutaka Tamura, National Veterinary Assay Laboratory, Ministry of Agriculture,
Forestry and Fisheries, 1-51-1 Tokura, Kokubunji, Tokyo 185-8511, Japan. E-mail:
[email protected]
E. John Threlfall, Laboratory of Enteric Pathogens, PHLS Central Public Health
Laboratory, 61 Collindale Avenue, London NW9 5HT, United Kingdom. E-mail:
[email protected]
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OIE International Standards on Antimicrobial Resistance, 2003
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Moritz van Vuuren, Department of Veterinary Tropical Diseases, Faculty of
Veterinary Science, University of Pretoria, Private Bag X04, Onderstepoort 0110,
South Africa. E-mail: [email protected]
David G. White, Topic Leader Guideline No. 4, Centre for Veterinary Medicine, Food
and Drug Administration, Office of Research, HFV-530, 8401 Muirkirk Rd, Laurel,
MD 20708, United States of America. E-mail: [email protected]
Observers
Maria Lourdes Costarrica, FAO, Food Quality and Standards Service, Via delle Terme
di Caracalla, 00100 Rome, Italy. E-mail: [email protected]
H.C. Wegener, WHO, Division of Emerging and Transmissible Diseases, Animal and
Food-related Public Health Risks, 20 avenue Appia, 1211 Geneva, Switzerland.
OIE
Barbara Röstel, OIE Collaborating Centre for Veterinary Medicinal Products,
ANMV-AFSSA Fougères, B.P. 90203, 35302 Fougères Cedex, France. E-mail:
[email protected]
Jacques Boisseau, Director of OIE Collaborating Centre for Veterinary Medicinal
Products, ANMV-AFSSA Fougères, B.P. 90203, 35302 Fougères Cedex, France.
E-mail: [email protected]
Jim Pearson, Head, Scientific and Technical Department, World Organisation for
Animal Health, 12 rue de Prony, 75017 Paris, France. E-mail: [email protected]
Appendix B
World Organisation for Animal Health Guidelines on antimicrobial
resistance
The following documents constitute the work and the recommendations of the OIE
Ad hoc Group of experts on antimicrobial resistance. International experts with
recognised expertise in the field composed this group. The group was set up to
respect and assure a representation of the different regions of the world. It brought
together internationally recognised scientific expertise in medical and veterinary
medical sciences, microbiology, laboratory sciences and risk analysis.
– Risk analysis methodology for the potential impact on public health of
antimicrobial resistant bacteria of animal origin
– Responsible and prudent use of antimicrobial agents in veterinary medicine
– Monitoring the quantities of antimicrobials used in animal husbandry
– Standardisation and harmonisation of laboratory methodologies for the detection
and quantification of antimicrobial resistance
– Harmonisation of national antimicrobial resistance monitoring and surveillance
programmes in animals and in animal-derived food
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1. General aspects
Appendix C
Background literature
Boisseau J. & Röstel B. (1999). – The role of international trade in animals, animal
products and feed in the spread of transferable antibiotic resistance and possible
methods for control of the spread of infectious agent resistance factors. In
Comprehensive reports on technical items presented to the International Committee
or to Regional Commissions. OIE (World organisation for animal health), Paris, 197234.
Centers for Disease Control and Prevention (1998). – Incidence of foodborne
illnessess – FoodNet, 1997. MMWR, 47 (37), 782-786.
Mead P.S., Slutsker L., Dietz V., McCaig L.F., Bresee J.S., Shapiro C., Griffin P.M. &
Tauxe R.V. (1999). – Food-related illness and death in the United States. Emerg. infect.
Dis., 5 (6), 840-842.
OIE (World organisation for animal health) (1998). – Report of the 18th Conference
of the OIE Regional Commission for Europe, 22-25 September, Prague, 11-18, 53-54.
OIE (World organisation for animal health) (1999). – Recommendations of the
Regional Commissions. In Final report of the 67th General Session of the OIE
International Committee, 17-21 May, Paris. OIE, Paris, 35.
OIE (World organisation for animal health) (2001). – International animal health
code: mammals, birds and bees, 10th Edition. OIE, Paris, 473 pp.
OIE (World organisation for animal health) (2001). – Manual of standards for
diagnostic tests and vaccines: Lists A and B diseases of mammals, birds and bees, 4th
Edition, 2000. OIE, Paris, 957 pp.
OIE (World organisation for animal health) (2001). – Report of the 14th Conference
of the OIE Regional Commission for Africa, 23-26 January, Arusha, Tanzania. OIE,
Paris, 38-40.
OIE (World organisation for animal health) (2001). – Resolution XXV. Antimicrobial
resistance. In Final report of the 69th General Session of the OIE International
Committee, 27 May-1 June, Paris. OIE, Paris, 117-118.
OIE (World organisation for animal health) (2001). – Standards Commission meeting,
31 January-2 February, 2001 report. In Final report of the 69th General Session of the
OIE International Committee, 27 May-1 June, Paris, 50.
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Antimicrobial drug resistance from salmonellas in
humans and food animals: the current situation in
relation to foodborne zoonoses in the United
Kingdom
E.J. Threlfall
Antibiotic Resistance/Molecular Epidemiology Laboratory, Division of Gastrointestinal Infections, Central Public
Health Laboratory, 61 Colindale Avenue, London NW9 5HT, United Kingdom
There are two distinct epidemiologies for non-typhoidal salmonellosis. In developing
countries infections caused by salmonella organisms are characterised by a high
incidence of septicaemia with a consequent high mortality. The strains involved are
multiple drug-resistant, often with resistance to up to ten antimicrobials. Nosocomial
infection is a common means of transmission and food animals do not seem to be an
important reservoir of such strains. In contrast, in developed countries the normal
presentation is gastro-enteritis and the principal reservoirs of infection for humans are
food animals. In such strains resistance is for the most part acquired in the food
animal host before transmission to humans through the food chain.
In 1999 the incidence of multiple drug resistance (to four or more antimicrobials) in
non-typhoidal salmonellas from humans has fallen in isolations of Salmonella enterica
serotypes typhimurium, virchow and hadar in comparison to 1996. This fall has been most
noticeable in S. typhimurium, where 59% of isolates were multiresistant compared to
81% in 1996. The main reason for this has been a 75% decline in isolations of
multiple-resistant (MR) S. typhimurium definitive phage type DT104 since 1996.
Nevertheless, MR S. typhimurium DT104 remains second to S. enteritidis phage type 4 as
the most common strain in cases of human salmonellosis in England and Wales.
Multiple resistance has also remained high in S. hadar, with 49% of isolates resistant to
four drugs or more compared to 56% in 1996. Decreased susceptibility to
ciprofloxacin has increased in incidence in S. enteritidis, S. virchow and S. hadar; in
S. hadar 70% of isolates exhibited decreased susceptibility to this antimicrobial. Use of
LightCycler technology has proved invaluable in tracing outbreaks of MR
S. typhimurium DT104 with decreased susceptibility to ciprofloxacin through the food
chain.
The overall decline in resistance has been also evident in isolations from food animals
and in 2000 less than 60% of isolations of S. typhimurium from food animals were
resistant to chloramphenicol (a marker for MR DT104) compared to 80% in 1996.
Although there has been an overall decline in resistance since 1996 outbreaks caused by
multiple-resistant strains of S. typhimurium have continued to cause serious problems in
2000. Of particular note have been outbreaks of MR S. typhimurium DT104, S.
typhimurium DT204b and S. typhimurium phage type U302. Although for the most part the
OIE International Standards on Antimicrobial Resistance, 2003
69
1. General aspects
vehicles of infection have not been food animal products, food animals have been
implicated as the primary reservoirs of infection.
It is hoped that Codes of Practice recently introduced by some pharmaceutical
companies, governments, professional organisations and others for the use of specific
antimicrobials in animal husbandry, coupled with international agreements on
guidelines for resistance monitoring, will now result in a reduction in the incidence of
resistance to antimicrobials, such as the fluoroquinolones in salmonella organisms,
causing infections in humans.
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Resistance in salmonellae: the situation in developing
countries
S. Benredjeb & A. Hammami
Laboratoire ‘Résistance aux antibiotiques’, Faculté de Médecine, Tunis, Tunisia
The increasing rate of multidrug resistant (MDR) Salmonellae has become a serious
public health problem. Salmonella serotype typhi is endemic in developing countries and
strains resistant to chloramphenicol, ampicillin and trimethoprim have been reported
since 1989 in the Indian subcontinent, Southeast Asia and Africa. In North Africa, the
majority of isolates are susceptible to antibiotics of choice for typhoid fever, which
include chloramphenicol, ampicillin, cotrimoxazole and fluoroquinolones. Concerning
non typhoidal Salmonellae (NTS), an increasing rate of antimicrobial resistance was
observed. The majority of human infections is caused by only few serovars. Currently,
serotype enteritidis is the most prevalent in developed countries. In North Africa a
change was observed from a greater prevalence of serotype wien over the 1980s to a
greater prevalence of serotype enteritidis over the 1990s. The distribution of the other
serotypes varies between countries but since 1989 S. mbandaka has gained some
importance in the epidemiology of salmonellosis in Algeria and Tunisia. MDR was
detected in several Salmonellae serotypes particularly serotypes wien, typhimurium,
mbandaka with a pattern of resistance to most betalactams, aminoglycosides and
cotrimoxazole. They have been reported as producing extended spectrum
betalactamases and were responsible for protracted outbreaks of severe paediatric
infections. In Tunisia, the susceptibilities to antibiotics of 151 strains of NTS isolated
from clinical specimens in 1999-2000 showed high rates of resistance to tetracycline
(62.2%), ampicillin (36.4%), cotrimoxazole (30.5%), cephalotin (30.5%), cefotaxime
and ceftazidime (28.5%). Most of the MDR Salmonellae belonging to serotypes
mbandaka and livingstone were related to nosocomial outbreaks.
The increasingly high prevalence of MDR Salmonellae in developing countries in
relation with complex socio-economic and behavioural factors contribute to the
world-wide spread of resistance.
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1. General aspects
Resistant bacteria and their impact on therapy in
veterinary medicine
J.-L. Martel
Head of Bacteriology and Antimicrobial Resistance Unit AFSSA Lyons 31, avenue Tony Garnier F.69364 Lyons
Cedex 07, France
Since the introduction of antimicrobial agents in medicine, the therapeutic efficacy of
the currently available drugs has been increasingly compromised by the development
of bacterial resistance in both human and veterinary medicine.
As examples in the veterinary field, we will quote some results from the French
monitoring network (named ‘RESABO’). Three key factors with regard to the
emergence of antimicrobial resistance have to be taken into account:
a) the occurrence of resistance genes (present in bacteria before the antibiotic era
and cannot be avoided)
b) the close contact between bacteria in a polymicrobial environment
c) the selective pressure imposed by the use of antimicrobials.
This latter aspect is the one which can effectively be influenced by all parties involved
in medicine, and particularly by veterinarians who prescribe and use antimicrobial
agents. But it is essential not to forget the second aspect and to establish an integrated
hygiene management, including not only husbandry, but also food-processing, food
storage and consumer handling.
The two main objectives of veterinary medicine are to maintain healthy food animals
and to prevent hazards to public health. The control and prevention of bacterial
infections are achieved by either therapeutic, metaphylactic or prophylactic application of
antimicrobials. Substances of mainly the same classes as used in human medicine are
available for the treatment of food producing animals. According to the number of
animals present and the type of production, these treatments may be individual and
given by oral and parenteral route or, when large groups of animals have to be treated,
are applied via water or feed. For these purposes, particular galenic forms such as
‘long acting products’, ‘premixes’, intramammary infusions are developed and imply
specific pharmacokinetic data.
In veterinary medicine, as in human, antibiotics are vital drugs to treat specific
bacterial infections. They are crucial for insuring a safe food supply through healthier
food producing animals. Thus, veterinarians must have access to a variety of
antibiotics for selecting the most effective drug and for alternating compounds to
keep resistance at low levels.
The prudent use of antimicrobial agents requires the development of and respect for
good veterinary practices.
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New resistance mechanisms – review of the diversity
P. Nordmann
Head Dept. Microbiology, Hospital Bicêtre, South Paris Medical School, University Paris XI, France
Novel mechanisms of antibiotic resistance continue to be recognised as consequences
of mutations in house-keeping structural or regulatory genes and of acquisition of
foreign genetic elements. These resistance mechanisms, which may become major
public health threats, have been reported in nosocomial and community-acquired
bacterial isolates. Among Gram-positive nosocomial isolates, the molecular
mechanisms involved in vancomycin-intermediate and vancomycin-resistant
Staphylococcus aureus and in glycopeptide resistance in Enterococcus sp. and their
relationships with peptidoglycan biosynthesis genes are not known with certainty.
Among Gram-negative nosocomial isolates, the list of expanded spectrum
β-lactamases is still growing. Novel clavulanic-acid inhibited extended-spectrum
β-lactamases (Cla-ESBL) have been mostly reported in Enterobacteriaceae and in
Pseudomonas aeruginosa, whose genes are, in some cases, part of expression structures
named integrons. Plasmid-mediated Cla-ESBLs with an expanded spectrum to
carbapenems have been identified in Klebsiella pneumoniae and in P. aeruginosa. Acquired
metallo-enzymes (IMP and VIM series) with significant carbapenemase activity are
increasingly recognised world-wide, especially in P. aeruginosa. Carbapenem resistance
in Acinetobacter baumannii may be the result of expanded-spectrum oxacillinases.
Upregulation of naturally-occurring efflux systems is now established as a source of
acquired resistance to most antibiotic classes including aminoglycosides in P. aeruginosa
and in Enterobacteriaceae.
Among community acquired pathogens, mutations in target genes of fluoroquinolones
have been reported for quinolone resistance in Streptococcus pneumoniae, S. pyogenes,
S. mitis and S. oralis. In S. pneumoniae, cephalosporin-resistant and penicillin-susceptible
strains have been reported. Plasmid-mediated cephalosporinases that are derivatives of
chromosomally-encoded Ambler class C enzymes are reported increasingly in
enterobacterial species including those involved in community-acquired infections.
Finally, multiple-antibiotic resistance Salmonella sp., strains have been identified worldwide as a consequence of antibiotic resistance genes located in integrons.
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1. General aspects
Possibilities of characterising resistance genes for use
as an epidemiological tool
M.-H. Nicolas-Chanoine (1) & S. Granier (1, 2)
(1)
Service de Microbiologie-Hygiène, Hôpital Ambroise Paré (AP-HP), UFR Médicale Paris-Ile-de-France-Ouest,
Boulogne-Billancourt, France
(2)
Laboratoire de Microbiologie Médicale, Fondation Hôpital Saint-Joseph, Paris, France
Introduction
Epidemiological markers are markers able to discriminate between epidemiologically
unrelated isolates of a given species and able to recognise the close-relatedness of
isolates derived from the same outbreak or chain of transmission (1).
Properties of an epidemiological marker
In fact, any marker can be used as an epidemiological marker if and only if it displays
the four principal criteria required to type isolates, namely, typeability, stability,
reproducibility and discriminatory power.
The marker must be present in all isolates of the species, meaning a typeability of
100%. This marker must remain persistent, meaning a stability of 100%. The marker
must also be found to be identical to itself following independent and separate
analyses, meaning a reproducibility of 100%. The discriminatory power of a marker
corresponds to the average probability that this marker will assign a different type to
two unrelated strains randomly sampled in the microbial population of a given species.
This power is calculated by using the formula of the Simpson index of diversity:
1S
D = 1 – ⎯⎯⎯⎯⎯⎯ Σ nj (nj -1) ≥ 0.95
N (N – 1) j=1
where D is the index of discriminatory power, N the number of unrelated strains
tested, S the number of different types and nj the number of strains belonging to the
jth type, assuming that strains will be classified into mutually exclusive types.
To be used as an epidemiological marker, the marker must display a D factor superior
or equal to 0.95.
Can resistance encoding genes be effectively used as
epidemiological markers?
Resistance genes are carried on plasmids or chromosomes.
If we refer to the first two criteria, typeability and stability, plasmidic genes cannot be
used as an epidemiological marker of isolates as all isolates of a given species do not
possess resistance coding plasmids, and furthermore, plasmids can also be lost.
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OIE International Standards on Antimicrobial Resistance, 2003
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Concerning the chromosomal genes involved in resistance, there are those which code
natural resistance, for example, β-lactamase genes. On the other hand, genes coding
antibiotic targets can be the object of genetic events (mutations, insertions and
deletions) resulting in acquired resistance. Moreover, a certain allelic diversity exists
for all of these genes.
The question is: ‘are all of these genetic events involved in resistance, together with
allelic diversity, variable enough to reach an index of discriminatory power superior or
equal to 0.95?’
Such a question was addressed by Sreevatsan et al. about Mycobacterium tuberculosis (2).
Different genes involved in antibiotic resistance in a large number of isolates were
analysed: katG for isoniazide resistance, rpoB for rifampin resistance, gyrA for
quinolone resistance and pzaA for pyrazinamide resistance. As indicated in Table I,
they found very few sites with silent variations; two for katG, two for rpoB, six for
gyrA and zero for pzaA.
Table I
Variability of genes coding antibiotic target in Mycobacterium tuberculosis
Gene
Resistance
katG
rpoB
gyrA
pzaA
INH
Rifampin
Quinolones
Pyrazinamide
Number of strains
analysed
Number of sites with
silent variations
360
305
629
30
2
2
6
0
By combining the katG and gyrA sequences of a large number of strains, it was only
possible to classify all the strains into three groups.
Thus, resistance genes cannot be used as an epidemiological marker for M. tuberculosis.
We have recently analysed, in my laboratory, the β-lactamase genes of Klebsiella oxytoca.
It was previously demonstrated that the β-lactamase genes of this species are divided
into two groups, blaOXY-1 and blaOXY-2, which have 87% sequence identity (3). We have
demonstrated that the blaOXY gene is able to divide the Klebsiella oxytoca taxon into two
genetic groups which are also recognizable by other markers, such as sequence
signatures in the 16S rDNA and rpoB genes and characteristic bands in the profiles
generated by the ERIC-1R PCR method (4).
We sequenced the blaOXY gene of 15 unrelated isolates obtained from 9 centres from
1996 to 2000. Table II which represents the percentage of sequence identity of the
blaOXY gene of the fifteen isolates, compared two by two, shows that we found only
three pairs of isolates having a blaOXY gene with an identical sequence, whereas the
genes of the other isolates were different; 87% representing the sequence identity
OIE International Standards on Antimicrobial Resistance, 2003
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1. General aspects
between the oxy-1 and oxy-2 gene groups and 99% representing the sequence identity
within each group.
Table II
blaOXY gene comparison of fifteen K. oxytoca clinical isolates
SG SG SG
74 49 56
SG
176
SG
337
SG
344
SG
254
SL
781
SL
911
SG
62
SG
69
SG SG SG
77 81 9
99
99
87
99
99
87
87
99
87
99
99
87
99
99
87
87
99
87
99
99
9
87
99
99
87
87
99
87
99
99
99
99
87
99
99
87
87
99
87
99
99
99
(percentage)
SG15 99
SG74S
SG49
SG56
SG176
SG337
SG344
SG254
SL781
SL911
SG62
SG69
SG77
SG81
87
87
99
99
87
99
99
87
99
87
87
99
87
87
87
87
99
87
87
99
100
99
87
99
99
87
87
87
87
99
87
99
99
99
87
99
100
87
99
99
87
87
99
87
99
99
99
99
99
99
87
99
99
87
87
99
87
99
99
100
99
99
We calculated the index of diversity and found that it was equal to 0.97, suggesting
that blaOXY genes can be used as a marker for isolate typing. By using the ERIC-1R
PCR typing system, we confirmed (data not shown) that the isolates found to be
different from each other by blaOXY gene sequence, were also found to be different by
this method. However, we also found that the pairs of isolates with an identical
sequence of blaOXY gene, were different according to the ERIC-1R profiles. Thus, the
ERIC-1R PCR method is more discriminatory than blaOXY gene sequence for typing
K. oxytoca isolates.
The second study that we carried out on Klebsielle oxytoca concerned nine isolates
obtained from one hospital over a 4-year period. We found that five out of the nine
isolates had an identical blaOXY-2 gene sequence with 3 identical mutations leading, for
one of them, to an amino-acid substitution in comparison with the reference blaOXY-2
gene (3).
The presence of a single strain over a 4-year period suggested by the blaOXY gene
sequence, was confirmed by the ERIC-IR PCR typing system as indicated in Figure 1
(an identical profile A for five isolates).
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Interestingly, we note that the blaOXY gene of this strain has shown no mutation over a
four-year period.
Faced with these molecular data, we had to look at the clinical epidemiological data.
The first patient concerned by the strain was hospitalised in the gastro-intestinal
surgery in August 1996, the second in intensive care unit in March 1998, the third in
vascular surgery in December 1998, the fourth consulted in gastrology in March 1999
and the fifth was in fact the fourth patient who was hospitalised in May 1999 in the
gastro-intestinal surgery.
Additional studies showed that the four patients had one point in common, namely
repeated hospitalisations in this hospital with at least one hospital stay in the gastrointestinal surgery ward. Thus, the discovery of the same blaOXY gene sequence in five
K. oxytoca isolates led us to carry out an epidemiological study whose results strongly
suggested the presence of a K. oxytoca strain in the digestive surgery ward.
A A B A A M A C D E
Fig. 1
ERIC- 1R PCR of nine clinical isolates of Klebsiella oxytoca
These displayed five different profiles (A B C D E), M corresponding to weight
marker
Conclusion
The two examples presented here, strongly suggest that resistance chromosomal genes
could be used as an epidemiological marker of isolates for certain species. To confirm
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this suggestion, the analysis of resistance gene sequences of each species must be
carried out.
References
1. Struelens M.J., Bauernfeind A., Van Belkum A., Blanc D., Cookson B.D., Dijkshoorn L.,
El Solh N., Etienne J., Garaizar J., Gerner-Smidt P., Legakis N., De Lencastre H., NicolasChanoine M.H., Pitt T.L., Römling U., Rosdahl V. & Witte W. (1996). – Consensus guidelines
for appropriate use and evaluation of microbial epidemiologic typing systems. Clin. microbiol.
Infect., 2, 2-11.
2. Sreevatsan S., Pan X., Stockbauer K.E., Connell N.D., Kreiswirth B.N., Whittam T.S. &
Musser J.M. (1997). – Restricted structural gene polymorphism in the Mycobacterium tuberculosis
complex indicates evolutionarily recent global dissemination. Proc. Natl. Acad. Sci. USA, 94,
9869-9874.
3. Fournier B., Roy P.H., Lagrange P.H. & Philippon A. (1996). – Chromosomal betalactamase genes of Klebsiella oxytoca are divided into two main groups, blaOXY-1 and blaOXY-2.
Antimicrob. Agents Chemother., 40, 454-459.
4. Granier S.A., Plaisance L., Leflon-Guibout V., Lagier E., Morand S., Goldstein F.W. &
Nicolas-Chanoine M.-H. (2003). – Recognition of two genetic groups in Klebsiella oxytoca taxon
on the basis of the chromosomal beta-lactamase and housekeeping gene sequences as well as
ERIC-1R
PCR
typing.
Int.
J.
Syst.
Evol.
Microbiol.,
53,
661-668.
http://dx.doi.org./10.1099/ijs.0.02408-0
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Perception of the veterinary practitioner with regard
to the contribution of the use of antimicrobials in
animal husbandry to the problems of human health
associated with resistant bacteria
O. Fortineau
Groupement Technique Vétérinaire, 5 rue Moufle, 75011 Paris, France
Cross-resistance to avoparcin and vancomycin has highlighted the link between animal
health and public health. Whilst restrictions on the use of antibiotics as feed additives
in the European Union aim to minimise the risks due to antibioresistance, new
questions are now being raised regarding the therapeutic use of antibiotics.
The phenomenon of antibioresistance is directly linked to the use of antibiotics. Some
bacteria are currently developing resistance, which sometimes limits the actions of the
veterinary surgeon.
But the main question is linked to the transfer of such resistance acquired in animals
to bacteria that may affect humans.
Several routes are possible, but the main risk is linked to the ingestion by man of
animal intestinal bacteria, such as Coli bacteria, Salmonella, Enterococci and Campylobacter.
The strict observance of hygiene rules in force at every level of the food-production
chain effectively limits the risk of transferring such bacteria to man. These hygiene
rules must, however, be constantly observed, even by the final consumers, who too
often forget to wash their hands before eating.
However, veterinary surgeons are well aware of the risks linked to their prescription of
antibiotics: following the initiatives of the Federation of Veterinarians of Europe, and
those of many national organisations, the number of seminars and publications on
antibiotic resistance is increasing and more best practice manuals on the use of
antibiotics are being published.
Veterinary surgeons are working at improving antibiotic usage in animal production:
this is in line with public health, animal health and production cost objectives.
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The pig producer’s position as herd manager
following the cessation of the use of antibiotic growth
promoters in Denmark
O.G. Pedersen
Copa Cogeca, 23-25 rue de la Science, 1040 Bruxelles, Belgique
The National Committee for Pig Production, representing the European farmers on behalf of COPA COGECA
The Danish background
In Denmark, we produce approximately 23.5 million pigs, 134 million broilers, and we
have a population of 1.9 million cattle and 3.7 million hens (over six months). The
Danish farmers voluntarily decided to stop using antibiotics as growth promoters
from 1 January 2000. In addition, we have a very restrictive system with registration of
the use of all veterinary medication at herd level. The basis for the ban on antibiotic
growth promoters in Denmark was a double-sided debate. This was partly political
and partly due to affirmation by the medical scientists and the veterinary institutes of
the risk of the development of resistance and thereby reduced possibility for treating
patients in the hospitals.
Chain of events in Denmark
Antibiotic growth promoters (AGPs) have not been used in animal production in
Denmark since 1 January 2000.
Figure 1 illustrates the development in antibiotic consumption over the last seven
years. The curves are affected by the following events:
1995: National ban on avoparcin
1998: National ban on virginiamycine. Voluntary agreement on stopping the use of
antibiotic growth promoters for calves, broilers and for pigs weighing more than 35 kg
(sows and finishers)
Control and penalty systems were introduced
National tax on AGPs
1999: EU ban: tylosine, bacitracine, spiramycine, virginiamycine, olaquindox and
carbadox
2000: Voluntary agreement not to use AGPs for pig weighing less than 35 kg
(weaners). At the same time control and penalty systems were introduced.
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Active substance (tonnes)
250
200
150
100
50
0
1994
1996
1997
1998
1999
2000
Year
Therapy/medication
Growth promoters
Total
Fig. 1
The development of antibiotic consumption in Denmark
Finishers, broilers and calves
As mentioned, a voluntary agreement on stopping the use of antibiotic growth
promoters for finishers, broilers and calves was made in 1998.
‘The National Committee for Pig Production collected information on the experiences
of 62 Danish finisher herds in the period after they stopped using APGs. The majority
(63%) of the herds did not experience problems in the form of reduced daily gain or
increased frequency of treatments for diarrhoea when AGPs were removed from the
feed. 26% of the herds experienced a temporary decrease in the daily gain, while 11%
experienced permanent problems, probably as a consequence of the removal of AGPs
from the feed. Thus, the removal of AGPs from finisher feed has been fairly
unproblematic in the herds participating in this study. Several herds changed the
composition of the feed in connection with the ban of antibiotic growth promoters,
e.g. reduced crude protein content and increased barley/texture.’
The results from the study are confirmed by the results from the national productivity
surveillance in Denmark (cf. Table I). Daily gain and mortality showed no significant
changes in the 1998 statement compared with the previous year. It was, however,
observed that the increase in daily gain (from 1997/1998 to 1998/1999) was not quite
as high as in the previous years, and mortality was marginally higher.
We can hereby conclude that antibiotic growth promoters have been removed from
the finisher feed without any significant effects on productivity and health. The annual
increase in daily gain in 2000/2001 returned to the same level as before antibiotic
growth promoters were removed.
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The removal of antibiotic growth promoters from feed for calves on 1 January 1998,
also took place without significant problems. It should be noted that the use of
antibiotic growth promoters before the removal was very low in feed for calves. In
broilers, the voluntary stop resulted in an increased feed consumption (from 1.78 kg
feed/kg live broiler to approx. 1.82 units) and a lower gain (the average weight after
42 days dropped from 1,960 g to 1,930 g). Since then, the average weight has
increased and is now more than 2,000 g. The moderately negative effect of removing
antibiotic growth promoters from the feed for broilers is in particular due to the very
high demands to hygiene because of the Salmonella programme the aim of which is
zero prevalence.
Table I
National productivity surveillance – finishers
In each column, approximately 1,400 herds are represented
Daily gain (g)
Mortality (%)
April 1995April 1996
April 1996April 1997
April 1997April 1998
April 1998April 1999
April 1999April 2000
April 2000April 2001
744
3.0
762 (+18 g)
3.2
778 (+16 g)
3.2
786 (+8 g)
3.4
798 (+12 g)
3.6
817 (+19 g)
3.5
Weaners
The great challenge was the removal of antibiotic growth promoters from weaner
feed, which commenced on 1 January 2000, in the form of a voluntary agreement.
This means that the three products still approved are not used in Denmark.
A large proportion of the pigs (approx. 50%) had already been fed without AGPs
from mid-1999 without severe problems. In Table II the results in the weaner period
from the national productivity surveillance in Denmark are shown. The statement for
1999/2000, which was the first period without using AGPs for weaners, shows a
decrease in daily gain (20 g) and a corresponding increase in the pigs’ age at 30 kg
compared with the 1998/1999 statement. Post-weaning mortality also increased
(0.7%-units). The latest statement (2000/2001) shows that the negative effect on the
weaners’ productivity continues and that it is difficult to reach the level of productivity
attained when antibiotic growth promoters were used.
We therefore conclude that the removal of AGPs from weaner feed has had
significantly negative consequences in the form of reduced gain and higher mortality.
It has also exacerbated a number of fundamental problems in many of the herds, such
as post-weaning diarrhoea and chronic infections (Lawsonia intracellularis).
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Table II
National average for production efficiency control – weaners
Daily gain (g)
Mortality (%)
Age at 30 kg
April 1995April 1996
April 1996April 1997
April 1997April 1998
April 1998April 1999
April 1999April 2000
April 2000April 2001
422
2.7
82.6
420
2.8
82.6
419
2.9
82.8
427
2.9
82.9
407 (-20 g)
3.6 (+ 0.7)
85.3 (+ 2.4)
411
3.5
85.5
Management factors
In order to minimise the use of antibiotics, it is important to focus on housing
conditions and management in the individual herd. Optimising production systems
and management factors in the herds includes:
– the use of health promoting housing systems with sectioned batch operation and
all in-all out production
– the avoidance of overstocking. The reduced growth without AGPs has resulted
in an accumulation of weaners in many herds. Overcrowding, increased batch sizes
and lack of hospital pens have probably contributed to the negative consequences
after removal of AGPs
– increased focus on the immediate environment of the pigs in the pen. It is
recommended that the pigs are protected against draughts, low temperatures and
humidity. Pens fitted with a covered area (two-climate pens) and use of
bedding/additional heating are very suitable in that regard
– increased focus on weaning weight. For instance, the avoidance of unnecessary
transfer of pigs later than 48 hours after birth, since this will reduce the weight at
weaning.
Nutrition
In terms of improving the gastro-intestinal health of weaners through the feeding
practices, there is particular focus in Denmark on:
– feeding strategy. Restricted feeding in the first 14 days post-weaning can improve
the pigs’ health significantly compared with ad libitum feeding. Mortality may also be
reduced.
– use of additives. The content of copper (Cu) in Danish diets for weaners is close
to the allowed maximum content of 175 mg/kg. High doses of zinc (Zn) (2,500
mg/kg) reduce the occurrence of diarrhoea, but the content of Zn in Danish diets is
no more than 250 mg/kg. More than 100 commercial feed additives for weaners and
finishers have been tested during the last five years in Denmark. For weaners, a group
of organic acid products has shown on average to improve the production results at
the same level as when AGPs were used.
– use of protective diets. These are typically characterised by low protein content,
with a high animal protein component (fish meal, whey powder, skimmed milk
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powder), high content of barley, and with the addition of an organic acid product.
This type of diet often reduces the incidence of diarrhoea.
Optimised production in problem herds
The National Committee for Pig Production has performed a number of studies in
herds with poor health and a high consumption of medication and low gain in the
weaner period. The aim was to improve the health status and production results in the
weaner unit by optimising the production conditions in general. In the test groups
improvements were made in the following: management procedures, hygiene, pen
design, composition of the feed, feeding strategy, etc. The results in the test groups
were compared with those from herds whose production conditions had not been
improved. The preliminary results show that the optimised system reduced the
number of treatments for diarrhoea in most herds. However, it appears to be difficult
to improve production results. The optimised system was also able to reduce mortality
significantly in two of the herds compared with the control treatment (normal
practice). However in two other herds, mortality was unacceptably high in both
groups (control and optimised) due to aggressive E. coli and Lawsonia intracellularis
infections.
Conclusion
Overall, we can conclude that the removal of antibiotic growth promoters from the
feed in Denmark has only significantly increased mortality and reduced weight gain in
weaner production and also increased feed consumption in broilers. Studies in weaner
herds with problems show that optimisation of production conditions and feed
significantly improves health. However, it is difficult to improve the production
results of the weaners.
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Antimicrobial use in animal husbandry and its
relationship to resistant bacteria in human health
B. Andrews
International Federation for Animal Health, Fort Lee, NJ 07024, United States of America
Thank you for this opportunity to address the 2nd Annual OIE International
Conference on Antimicrobial Resistance. Representing the International Federation
for Animal Health (IFAH) and its member organisations, I am honored by your
invitation to offer my comments on society’s perception of this important issue.
What I hope to provide is a brief framework for what has shaped society’s, and more
specifically the consumer’s perceptions, regarding the use of antibiotics in livestock
production, and its relationship to resistant bacteria in humans.
There was a time when consumer groups carefully assessed and conducted extensive
tests to confirm their position. More recently, they seem to have become primarily
lobbying organisations that spend much of their money on campaigns. So how have
we moved from the US National Academy of Sciences’ (NAS) serious review of the
resistance issue in 1956, to today’s anti-industry, anti-technology PR spin-machines
which cleverly reduce one of the most heavily researched and complex scientific
discussions of our time, into a handful of sound bytes aimed at scaring the public and
ending modern livestock production? I am not referring to the many science-based
and dedicated organisations involved in the serious debate over microbial resistance,
many of whom are at this conference. I am confident we are equally committed to
protecting human health, and it is through our continued collaboration that we will
resolve these concerns. I am referring to the more militant consumerists, nonintensive farming and organic farming lobby, and the animal rights activists whose
sole agenda is to end the use of animals for food production. When their attempts to
gain attention through animal rights issues failed in the 1960s and 1970s, they seized
upon the food safety issue and have found the key to the consumer’s conscience – the
dinner table.
One thing seems clear as we follow the course of events – less science and more
supposition have increasingly become the foundation for government and regulatory
decisions – the result of increased political pressure by these special interest groups.
Respected scientific bodies throughout the world have been unable to substantiate any
definite link between antimicrobial use in animals and treatment failure in humans.
Yet, the highly politicised Swann Committee report was the foundation for the current
ban on a number of products in the EU, and most recently the FDA has moved to
withdraw its approval for fluoroquinolones in poultry.
By the late 1970s, antagonists of animal agriculture had turned up the volume and
enlisted the power of the popular press. What has resulted is a consuming public
drawn to the issue through gloom and doom messages and emotive rhetoric regarding
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the future of our food supply. They have perpetuated a ‘conventional wisdom’ with
the consumer, based upon misinformation, half-truths, and in some instances patently
false messages.
IFAH the AHI (Animal Health Industry) and numerous other producer and trade
organisations have developed consumer education materials and invested in media
relations in an attempt to balance the debate. But as we have all learned, good news is
no news in today’s consumer press, and our efforts seldom see the front page. A
review of recent literature provides a common thread of consumer perceptions that to
date, the scientific community has been unable to thwart. The scientifically defensible
facts relative to these myths will be addressed by many of the distinguished speakers at
this conference. What I would like to provide is a general framework to establish the
existing gap between society’s perception, and the science.
Consumers are being told that livestock and poultry producers abuse antibiotics, using
more of these products than are being used in human medicine.
This statement begs several responses. First, the actual amount used should be put in
context with the much larger population of animals relative to humans that may need
treatment. Also the amount of antibiotics used in animal feed is minor. For instance,
products are used at various inclusion levels from as low as 0.5ppm up to 500ppm
per tonne of feed, dependent upon use for prevention or treatment. Second, and
possibly more significant, is the fact that these products are highly regulated and used
under the supervision of a veterinarian. Prudent use guidelines as well as producer
Quality Assurance programmes have been established for proper storage, handling,
administration and record-keeping, and these guidelines have been adopted by both
national, regional and global animal health organisations.
Consumers are being told that the sub-therapeutic use of antibiotics in animal
agriculture is eroding physicians’ ability to treat infectious disease in humans, resulting
in a related perception that banning the use of these products will fix the problem of
treatment failure in humans.
The fact is, the only irrefutable scientific evidence available demonstrates that bacterial
resistance to antibiotics in humans has been brought about by the over-prescribing
and misuse of these products in human medicine.
A recent WHO paper on the use of antimicrobials outside human medicine states,
‘there is no doubt that most of the rising antimicrobial resistance problem in human
medicine is due to the overuse and misuse of antimicrobials by doctors and other
health personnel.’ Improved doctor and patient education on the proper use of
antibiotics will be the cornerstone for combating the resistance problems that are
emerging today.
Another fact that seems to escape the attention of the industry detractors is that the
vast majority of antibiotics currently administered through the feed or in the water
have little or no significance in human medicine, making the development of
resistance to these products largely irrelevant to the treatment of disease in humans.
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Consumers are being told that antibiotics are routinely added to the feed and water of
healthy animals for non-therapeutic purposes such as growth promotion.
Non-therapeutic is a term coined by the Union of Concerned Scientists in its recent
‘hogging it’ report. We can only assume it is intended to create disdain if not fear in
the consumer, by implying these products serve no purpose other than to sustain the
greed of the producer. I would suggest that even the use of the term sub-therapeutic is
unfortunate, since low doses clearly have a beneficial effect in the control of subclinical disease. Livestock and poultry producers throughout the world have learned
the necessity of maintaining an animal’s health and robust growth for both
humanitarian and economic reasons. Only healthy animals can produce healthy meat,
milk and eggs. And maintaining this superior health status is, currently at least, our
only means of insuring we continue to meet the world’s growing demand for a safe,
abundant and affordable supply of animal protein. This requires our unceasing efforts
to insure the availability of existing, effective products, while continuing our research
into new antimicrobial agents for animal treatment.
In 2000, the world produced 283.7 million head of beef cattle and veal calves: 44.7
billion chickens and turkeys and 1.2 billion pigs. Without the prudent use of
antibiotics, we would need millions more of these food producing animals to
compensate for losses to disease. The cost of animal protein would skyrocket, not to
mention the impact on our environment.
These seem to be the foundation for the myths that abound in society regarding
antibiotics and their use in animal agriculture. Words are changed and put in different
contexts, but the message is the same – using antibiotics in animal production is bad.
However, in reality, how wide-spread are these perceptions and what level of
significance do they hold for the consumer?
As an industry, have we succumbed to the gloom and doom as well, believing that the
vast majority of society shares these concerns?
In Europe, consumers have become afraid of their food for reasons other than
antibiotic resistance, such as dioxin contamination and BSE. Research from the
International Food Information Council demonstrates that when asked what
consumers were most concerned about when it comes to food safety, antibiotics were
not mentioned. They are more concerned about package security, how food is being
handled and prepared, diseases and pathogen contamination, chemicals and pesticides
and altered or engineered foods. This suggests we may be a little too close to the issue
to objectively assess what impact anyone’s message will have on society, whether or
not it is based upon sound science or sensationalised sound bytes.
There is good news to report. In 1996 the National Information Program on
Antibiotics, a Canadian coalition of patient, physician and pharmacist organisations,
began running advertisements in medical journals, handing out posters and literature
to convince doctors to be more prudent in prescribing antibiotics. Since then,
Canadian doctors have indeed been writing fewer prescriptions for them and the
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results have been impressive. Two of the so-called drug-resistant superbugs are on the
retreat in Canadian communities. The number of Streptococcus pneumoniae resistant to
penicillin reached 14% in 1998. Today, for the first time in a decade, it has dropped to
10%. And 40% of Haemophilus influenzae were strains resistant to amoxicillin in 1996.
That figure has since dropped to about 25%.
At the heart of this issue lies the undeniable truth that food has a profound meaning
to people everywhere in the world. It carries significant religious meaning in many
countries. Society’s perception of how their food is being produced will never be
shaped solely by the scientific assessments we present, but by a careful balancing of
messages, both emotional and measurable. As a professional observer of human
nature, George Bernard Shaw once noted, ‘there is no love sincerer than the love of
food.’
Mr Chairman, distinguished guests, IFAH and its member organisations are
committed to continuing the discussion and review of this critical issue, and feel
confident a solution lies – not in emotive rhetoric and fear-mongering in the popular
media – but through collaborative efforts towards science-based understanding and
risk management.
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Perception of society with regard to the contribution
of the use of antimicrobials in animal husbandry to
the problems of human health associated with
resistant bacteria: the situation in developing
countries
S. Sirinavin
Division of Infectious Disease, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol
University, Bangkok, Thailand
Antimicrobial resistance is a major health problem in developing countries. It is an
important cause of increasing morbidity, mortality, and cost of treatment of infectious
diseases in human beings. The most important mechanism is selection pressure from
the use of antimicrobial agents. Humans, animals and microbes share the same world,
and microbes do not discriminate between humans and animals. In addition, effective
antimicrobial agents which are useful for treating infection in humans and animals are
limited. High levels of environmental contamination due to antimicrobial use in
animal husbandry is a very important cause of drug resistance, as well as over-thecounter use of the drugs in human beings.
In Thailand, overuse of antimicrobial drugs, for both animals and humans, is the
starting point. The concept that the use of antimicrobials can lead to resistant
microbes is difficult for Thai people to appreciate, since the effects of drug usage are
not directly visible. The drugs used appear to be not only useful but also harmless.
Antimicrobial drugs can be obtained from drugstores without prescription, either for
human or animal use. Antimicrobial drugs are widely used in animal husbandry
without adequate guidance or control. Concern from regulatory and relevant
authorities is still minimal, especially about the use of antimicrobial drugs in animals.
The rapidly growing problem of antimicrobial resistance has been of special concern
in academic institutes in Thailand for more than a decade without resulting in effective
intervention. Recently the concern seems to have reached the national level. The
National Antimicrobial Resistant Surveillance Center for monitoring resistance
problems in human beings and the Center for Antimicrobial Resistance Monitoring in
Food-Producing Animals were developed a few years ago. Since non-typhoidal
salmonellosis is an important endemic disease in Thailand for both humans and
animals, a National Committee on Controlling Non-Typhoidal Salmonellosis has been
developed. This is an important activity for generating concern about antimicrobial
resistance problems in animals and humans and for persuading people to work and to
think together in order to reduce them.
It is hoped that improved control of antimicrobial use in animal husbandry and in
humans will follow, resulting in a reduction in resistance problems.
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A consumer perspective: to what extent does
antimicrobial use in animal husbandry contribute to
resistance associated human health problems?
L.Y. Lefferts
Consumers International, 526 Mountain Field Trail, Nellysford, VA 22958, United States of America
Most consumers recognise that antimicrobials are vitally important tools in human
and animal medicine. They share the concerns of the public health community about
the increase in bacteria resistant to antimicrobials. What is the basis for this concern?
Infectious disease is the world’s biggest killer of children and young adults – more
than 13 million deaths each year, according to the World Health Organization
(WHO). Over the next hour alone, 1,500 people will die from an infectious disease –
over half of them children under five. Infectious disease has major economic and
human costs in both developing and developed countries. And without antimicrobials,
many infectious diseases would be untreatable.
Multi-resistance in bacteria is widespread and a major problem for the treatment of
bacterial diseases. Infections that were once easily cured by antimicrobials are more
difficult to treat, and sometimes require lengthy hospitalisation, or cause death. For
example, in one retrospective study of 52 Salmonella outbreaks in the USA, it was
found that the case mortality rate was higher for patients infected with resistant
Salmonella (4.2%) than for those with non-resistant infections (0.2%) (5). Antimicrobial
resistance kills almost two people in the US every hour, according to the Alliance for
Prudent Use of Antibiotics, a non-profit educational, research, and networking
organisation headquartered in the US with chapters in over 25 countries.
Few new antimicrobials are being developed, and resistance is showing up in some of
the new compounds already. The emergence of resistance in five patients to Linezolid,
the first structurally different antibiotic introduced in almost three decades, was
recently reported (3). On average, research and development of anti-infective drugs
takes ten to twenty years.
Consumers believe that antimicrobial use in animal husbandry does contribute to the
resistance problem to an extent that could and should be better addressed in many
countries. What is the basis for this belief?
Resistance to antimicrobials naturally evolves but is greatly amplified by overuse and
misuse of antimicrobials. While uses in humans probably are more important than
uses in animals, and there is no consensus on how much animal husbandry
contributes, it is clear that antimicrobial use in food-producing animals contributes
significantly to the problem.
A recent study by the Union of Concerned Scientists estimated that 84% of
antimicrobial use in the USA is in animals (6). The study challenged the conventional
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wisdom that use in animals is closer to about 40% of total antimicrobial use in the
USA. It also estimated that non-therapeutic livestock use accounts for 70% of total
antimicrobial use in the USA (including drugs important in human medicine such as
tetracycline, penicillin and erythromycin).
A number of resistant pathogens have been found in food animals and foods. For
example, scientists at the Swiss Federal Research Institute in Zurich found bacteria in
salami resistant to five common antibiotics: chloramphenicol, erythromicin,
streptomycin, streptothricin, and kanamycin. A preliminary survey of factory-packaged
beef and poultry conducted by the US Food and Drug Administration (FDA) in local
supermarkets also found antibiotic-resistant bacteria. Enterococci were found in 67%
of chicken samples, 34% of the turkey samples and 66% of the beef samples, and
tested for resistance to 29 different types of antibiotics, including six commonly used
in animal feed. Strains of enterococci taken from either chicken or turkey were
resistant to more drugs than those taken from beef. There have also been reports of
antibiotic-resistant bacteria in unpasteurised milk, fresh and frozen seafood, cheese
and parsley (9).
Resistant pathogens can be transferred indirectly to consumers through the
environment or through workers. For example, a child in Nebraska became infected
by Rocephin-resistant Salmonella bacteria that had originated from cattle on his farm
(2). Animal wastes can contain antimicrobials and antimicrobial-resistant bacteria. As
much as 75% of an antimicrobial may pass undigested through the animal into waste.
That waste may be spread onto crops, or be stored in lagoons, often unlined lagoons,
where it can leach into groundwater or get into surface waters (1, 8). Farm workers
may become infected with resistant germs and pass them on to family members or
others in their community.
Evidence linking use of antimicrobials in animals with illness in humans is mounting.
For example: an outbreak of antibiotic-resistant Salmonella in humans was linked to
beef cattle that had been fed chlorotetracycline for non-therapeutic purposes (growth
promotion) (4); and a multi drug-resistant Salmonella typhimurium outbreak in Denmark
affecting 25 and killing 2 was traced to meat from infected pigs (7). The emergence of
vancomycin-resistant Enterococcus faecium (VRE) in food can be traced to the
widespread use of avoparcin (the animal equivalent of the human antibiotic
vancomycin) in livestock (10).
Moreover, with livestock production increasing, both in developed and developing
countries – particularly intensive (‘factory farm’) production – reliance on
antimicrobials is likewise expanding – often without adequate guidelines or
requirements for prescriptions. With the trends toward globalisation and the relaxing
of trade barriers, inadequate standards and enforcement in one nation means all
consumers are vulnerable.
What do consumers think should be done, in the context of antimicrobials used in
food-producing animals?
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Given the relationship between use of antimicrobials and the development of
resistance, consumers support the recommendations from the World Health
Organization concerning the phase-out of non-therapeutic use of antimicrobials that
are or may become important in human medicine (and structurally related chemicals).
They believe that antimicrobials that are or may become important in human medicine
(and structurally related chemicals, and those which select for cross-linked resistance)
should never be used nontherapeutically.
In some instances, consumers may favor restricting certain therapeutic uses in
animals, such as fluoroquinolones, to protect the efficacy of vital human drugs,
particularly where the drug is administered on a flock-wide or herd-wide basis rather
than to individual sick animals.
All antimicrobial usage in animals should be subject to veterinary prescription.
Many consumers oppose the use of intensive animal production practices that rely
heavily on antimicrobials, preferring improved hygiene, animal housing, feed, and
other animal management practices that reduce the need to use antimicrobials.
Consumers want labeling that indicates whether or not foods have been produced
from animals raised using nontherapeutic antimicrobials.
Improved data on the therapeutic and non-therapeutic use of antimicrobials in
agriculture is needed, as well as improved surveillance of food-borne illness associated
with antimicrobial-resistant bacteria and monitoring of foods for antimicrobialresistant bacteria.
Consumers believe that the burden of proof of demonstrating that agricultural use of
antimicrobials does not contribute to resistance in human therapeutic drugs should be
borne by proponents of such use; unless that burden can be met, those uses should be
promptly phased out, following a precautionary approach. For example, they support
the WHO recommendation that antimicrobials used for growth promotion should be
removed from the market in the absence of a risk assessment demonstrating their
safety.
Consumer organisations are working at numerous national and international fora on
these critical public health issues:
The Trans-Atlantic Consumer Dialogue (a forum of some 20 consumer groups in the
USA and 45 in Europe, see www.tacd.org) in 1999 issued a number of
recommendations to the governments of the USA and the EU, including the
institution of a total ban on the non-medical use of antibiotics in animals and food.
Just this year in April, they updated their recommendations to call for a ban on the use
of fluoroquinolone antibiotics in poultry unless the drug is administered by injection.
Consumers International, the world-wide federation of consumer organisations,
representing more than 270 organisations in over 120 countries
(www.consumersinternational.org), has actively participated in debates on this issue at
committees of the Codex Alimentarius Commission.
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The most recent World Congress of Consumers International held in Durban, South
Africa issued a statement calling on governments and international institutions to,
amongst other things, prohibit the use of antibiotics as feed additives.
Consumer-nominated experts have been invited to attend WHO and FAO meetings
and consultations on the issue of antimicrobial resistance.
Bureau Européen des Unions de Consommateurs (BEUC), Europe’s largest consumer
organisation,
has
a
position
on
antimicrobials
(see
www.beuc.org/public/xfiles2000/x2000/x007e.pdf).
Six Nordic consumer organisations united in their fight to urge their governments to
develop restrictions on the use of antibiotics in agriculture.
Educational
materials
such
as
the
on-line
guide
at
www.iatp.org/EatWell/orgResults.cfm helps consumers identify and understand the
different labels used for meat raised without antibiotics in the US, and provides
information on producers, restaurants, supermarkets, co-ops, and community
supported agriculture networks that sell antibiotic-free meats in the US.
More than 50 scientists and 40 health and consumer groups in the US petitioned the
US Food and Drug Administration to ban the use of certain antibiotics in animal feed
if they are also used in (or are related to those used in) human medicine.
A coalition of consumer, environmental, health, and agriculture groups in the US
sponsored KeepAntibioticsWorking.com, an educational and outreach initiative
dedicated to ending the overuse of antibiotics in animal agriculture.
These activities provide ample evidence of the concern and viewpoint of consumers
on the issue of using antimicrobials in animal husbandry. While there are great
benefits to the prudent use of antimicrobials in both human and animal medicine, the
risks posed by certain uses and misuses are unacceptable to consumers.
References
1. Chee-Sanford J.C., Aminov R..I., Krapac I.J., Garrigues-Jeanjean N. & Mackie R.I.
(2001). – Occurrence and diversity of tetracycline resistance genes in lagoons and groundwater
underlying two swine production facilities. App. Env. Microbio., 67 (4), 1494-1502.
2. Fey P.D., Safranek T.J., Rupp M.E., Dunne E.F., Ribot E., Iwen P.C., Bradford P.A.,
Angulo F.J. & Hinrichs S.H. (2000). – Celtriaxone-resistant salmonella infection acquired by a
child from cattle. N. Engl. J. Med., 342 (17), 1242-1249.
3. Gonzales R.D., Schreckenberger P.C., Graham M.B., Kelkar S., DenBesten K. &
Quinn J.P. (2001). – Infections due to vancomycin-resistant Enterococcus faecium resistant to
linezolid. Lancet Apr., 357 (9263), 1179.
4. Holmberg S.D., Osterholm M.T., Senger K.A. & Cohen M.L. (1984). – Drug-resistant
Salmonella from animals fed antimicrobials. N. Engl. J. Med., 311 (10), 617-622.
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5. Holmberg S.D., Wells J.G. & Cohen M.L. (1984). – Animal-to-man transmission of
antimicrobial-resistant Salmonella. Investigations of U.S. outbreaks, 1971-1983. Science, 225,
833-835.
6. Mellon M., Benbrook C. & Benbrook K.L. (2001). – Hogging it! Estimates of
antimicrobial abuse in livestock. Union Concerned Scientists.
7. Molbak K., Baggesen D.L., Aarestrup F.M., Ebbesen J.M., Engberg J., Frydendahl K.,
Gerner-Smidt P., Petersen A.M. & Wegener H.C. (1999). – An outbreak of multidrug-resistant,
quinolone-resistant Salmonella enterica serotype typhimurium DT104. N. Engl. J. Med., 341 (19),
1420-1425.
8.
Raloff J. (1999). – Waterways carry antibiotic resistance. Science News, 155, 356.
9.
Raloff J. (2001). – Antibiotic resistance is coming to dinner. Science News, 159, 325.
10. Wegener H.C., Aarestrup F.M., Jensen L.B., Hammerum A.M. & Bager F. (1999). – Use
of antimicrobial growth promoters in food animals and Enterococcus faecium resistance to
therapeutic antimicrobial drugs in Europe. Emerg. infect. Dis., 5 (3), 329-335.
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Activities of the Food and Agriculture Organization in
relation to antimicrobial resistance in humans and
animals
Y. Cheneau
Animal Health Service, Food and Agriculture Organization of the United Nations, Rome, Italy
Following the accidental discovery in the early 1950s that the administration of
antibiotics to animals increased their growth rates, the practice of adding such agents
to the diet of animals has become a common practice throughout the world. This
appears to be the case in the developed world where intensive systems of livestock
production are common practice. In addition to the use of antimicrobial agents as
growth promoters in feed and water, the therapeutic and sub-therapeutic use of these
agents are thought to contribute to the development of resistance in bacteria. A
bacterial strain is said to be resistant when a genetic modification allows it to tolerate a
significant increase in antibiotic concentration. The problem with antibiotics in feed
was recognised by the Government of the United Kingdom when in 1971, the Swann
Committee report on the use of antibiotics in animal feed was accepted. The most
important recommendation of this committee was that the only antibiotics that could
be added to animal feed without a prescription from a veterinarian were those that
had little or no application as therapeutic agents in man or animals and did not
produce cross resistance against those that were used as therapeutic agents. Thirty
years after the acceptance of the Swann Report, the problem of antibiotic resistance is
still with us. Screaming headlines in journals and newspapers world-wide recently,
seem to echo the continuing concerns of the general public on problems associated
with antibiotic resistance in bacteria.
Resistant bacteria could be transmitted from food animals to humans primarily via
food. The need for containment of the development of resistant bacteria has therefore
gained the attention of agencies responsible for food and the general well being of
mankind, such as FAO (Food and Agriculture Organization of the United Nations),
WHO (World Health Organization) and OIE (World organisation for animal health).
Animal products are often contaminated with antimicrobial residues administered
through feed or water. Residues, which may give rise to the evolution of resistant
bacteria, can also occur through accidental cross contamination in feed mills. Feed
contamination with undeclared antimicrobials is now a global problem calling for
attention. To assess the magnitude of the problem accurately, utilisation patterns of
antimicrobials should be quantified. It is in the context of problems posed world-wide
by resistant bacteria to public health that the FAO, together with other agencies that
share similar concerns, came together to form committees specifically to address this
problem. This paper attempts to present the role of FAO through its various scientific
committees and joint committees, in dealing with the problem of antimicrobial
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resistance. Recommendations and proposals are also presented on the way forward in
the global efforts to contain antimicrobial resistance.
Statement of the problem
Compounds used as growth promoters are normally put in feed or water at low
concentrations. This on going and often low level dosing for growth promotion and
for prophylaxis inevitably results in the development of resistant bacteria in or near
livestock. It heightens the fear of new resistant strains ‘jumping’ between species.
Vancomycin-resistant Enterococcus faecium (VRE) is a typical example of a resistant
bacterium appearing in animals that might have ‘jumped’ into the vulnerable segments
of the human population. In 1997, the WHO recommended that antibiotics or their
derivatives normally prescribed for humans be prohibited as growth promoters in
animals. Secondly, it was recommended that antimicrobials should never be used as a
substitute for high quality animal hygiene and management. In 1998, the European
Union banned the use of antimicrobials prescribed for the treatment of human
infections as growth promoters in animals. In Germany and Denmark, preliminary
research appears to offer support to the adoption of this policy. The ban on avoparcin
as a growth promoter in poultry and pigs, has led to the decrease in the prevalence of
VRE in poultry, pigs and the population at large in these two countries. According to
recent data (FEDESA [European Federation of Animal Health], 2001) an estimated
13,216 tonnes of antibiotics were used in the EU member states and Switzerland in
1999. Out of this amount, 8,585 tonnes (65%) were utilised for human health
purposes, while animals used 4,688 tonnes (35%). Of the antibiotics that were used in
animals, 3,902 tonnes (29% of total usage) were administered for prophylactic or
therapeutic reasons, while 786 tonnes (or 6% of the total) were given to farm animals
in their feed or water as growth promoters. It has been estimated that the amount of
antibiotics used as growth promoters has fallen by 50% since 1997, when the WHO
and later the EU recommended the ban of antibiotics used in human therapy as
growth promoters.
Position of the Food and Agriculture Organization
a) The use of veterinary antimicrobial in food producing animals is likely to result in
small quantities of residues of the product, or its metabolites, being present in foods
of animal origin. It is now possible to detect such residues at extremely low
concentrations based on Maximum Residue Limits (MRL) set by the FAO/WHO
Codex Alimentarius (Committee on Residues of Veterinary Drugs in Foods). Several
existing FAO/WHO Codex Alimentarius standards, guidelines and recommendations
that include provisions relating to the quality and safety of animal feeds and foods of
animal origin, consider the utilisation of antimicrobials in animal foodstuffs. These
include:
– List of Codex Maximum Residue Levels (MRL,s) for Veterinary Drugs (Vol. 3)
– Recommended International Code of Practice for the control of the use of
veterinary drugs (CAC/RCP38-1993, Vol. 3).
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This code sets out guidelines on the prescriptions, application, distribution and
control of drugs used for treating animals and improving animal production. It
includes Good Practices in the Use of Veterinary Drugs (GPVD), including premixes
for the manufacture of medicated feedstuffs.
The question of microbial resistance is also being discussed within the Codex
Committee on Residues of Veterinary Drugs in Foods (CCRVDF) and the Codex
Committee on Food Hygiene (CCFH). The CCRVDF receives scientific advice from
the FAO/WHO Joint Expert Committee on Food Additives which considers the
impact of antimicrobial residues on the gut. The CCFH considers antimicrobial
resistant bacteria in relation to food hygiene. This committee is already involved in
risk assessment associated with microbiological contamination of food and is
therefore, well placed to take a risk analysis approach to the question of antimicrobial
resistance.
b) FAO endorses WHO recommendation to phase out and finally abolish the use
of antimicrobials as growth promoters if similar products are also licensed in human
medicine.
c) FAO advised countries to adopt immediate measures and to follow the available
guidelines for the containment of antimicrobial resistance from antimicrobial use in
livestock.
d) FAO encourages countries to contain the spread of antimicrobial resistance by
implementing a combination of measures such as:
– establishing, implementing and verifying compliance of policies and legislation
for the use of antimicrobials as feed addictives
– monitoring the patterns of bacterial resistance and the use (qualitative and
quantitative) of antimicrobials in animal production
– continuous education, training and awareness of veterinarians, government
inspectors, feed producers and farmers on the appropriate utilisation of antimicrobials
and the consequences of abuse.
Proposed action for the livestock and animal feed industry in
all countries
Given the direct links between biosecurity, feed safety and safety of foods of animal
origin with regards to the prevention of antimicrobial resistance, it is essential that
adequate attention be given to feed production and manufacture. Feed production
must therefore be subject, in the same way as food production, to quality assurance.
Industry is ultimately responsible for the quality and safety of the food and feed that it
produces. National authorities should provide guidance to industry, including codes of
practice and standards that they must respect. Governments must also establish the
necessary controls to ensure that industry consistently meets mandatory quality and
safety standards. It is the responsibility of industry and national governments to
ensure safety of feed and food. It is important to realise however, that the large
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volume of international trade in foods of animal origin, as well as in feedstuffs, adds
an important international dimension to the control of animal feedstuffs. International
organisations also have an important role to play in providing information and
training that could be used at national level to improve the knowledge on
antimicrobial additives to feedstuffs.
Recommendations
a) The FAO together with the WHO and the OIE and other interested bodies,
must develop a global strategy to contain the deteriorating situation with regards to
the emergence of resistant bacterial strains. Creating awareness in the general public,
especially livestock farmers, on the wiser use of antimicrobial agents is imperative to
halt the spread of antimicrobial resistance. The strengthening of legal frameworks on
the prescription of drugs and control of growth promoters in feed will all help to curb
this potential menace.
b) Evidence is gradually emerging that resistant strains of members of the
Enterobacteriaceae in the gut flora of domestic animals reach man by the food chain.
This calls for the highest degree of hygiene and the implementation, from the farm
(stable) to the table, of HACCP (Hazard Analysis and Critical Control Point)
standards.
c) It is also suggested that a co-ordinated effort be made to survey the incidence of
antimicrobial resistance in domestic animal populations world-wide. A distribution
map of global microbial resistance to be made from this surveillance, could form the
basis of early warning and reaction e.g. enforcement or re-evaluation of regulations in
affected countries.
References
1. Anon. (1973). – Control of harmful residues in food for human and animal consumption:
the public health aspect of antibiotics in feedstuffs. Report of a working group – WHO
Regional Office for Europe.
2. Anon. (2000). – Overcoming antimicrobial resistance: world health report on infectious
diseases.
3. Anon. (2001). – Antibiotic use in farm animals. Report of the European Federation of
Animal Health (FEDESA).
4. Anon. (2001). – Evaluation of certain veterinary drug residues in food. 55th Report of
the Joint FAO/WHO Expert Committee on Food Additives.
5. Kidd A.R.M. (1994). – The potential risk of antimicrobial residues on human gastrointestinal microflora.
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The activities of the World Health Organization in
antimicrobial resistance
R. Williams
Communicable Disease Surveillance and Response, World Health Organization, Geneva, Switzerland
The aim of this presentation is to summarise through examples, the four main areas of
WHO’s activities in antimicrobial resistance in humans and animals.
– Raising awareness: targeted particularly towards Ministries of Health in Member
States; professional societies and non-governmental organisations (NGOs);
professionals working in infectious disease control programmes; the media and the
public. Examples include: Resolutions of the World Health Assembly; expert
consultations and reports; participation and presentation at meetings; fact sheets,
documents and publications available through the web (www.who.int/emc/amr.html);
and information exchange with other WHO programmes through working groups etc.
– Providing strategic and technical guidance on interventions to contain resistance:
examples include: WHO Global Principles for the Containment of Antimicrobial
Resistance in Animals Intended for Food and the WHO Global Strategy for
Containment of Antimicrobial Resistance.
– Assisting countries to establish surveillance through providing guidelines for
surveillance, laboratory manuals, software tools, etc.; laboratory training courses, and
the provision of external quality assurance schemes.
– Promoting partnership and information sharing: examples include: the WHO
Collaborating Centre network which provides key support for national and
international capacity strengthening activities and quality assurance; partnerships with
NGOs and professional societies in projects to test interventions to contain
resistance; web-based databases such as AR Infobank and Global Salm Surv.
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Codex activities in relation to antimicrobial
resistance 1
A. Bruno
Secretariat, Codex Alimentarius Commission, Joint FAO/WHO Food Standards Programme, Vialle delle Terme di
Caracalla, 00100 Rome, Italy
The relationship of the use of antimicrobials in food-producing animals and the
emergence of resistant bacteria in the food chain is a concern and has been the subject
of numerous national and international consultations. The extent to which
antimicrobial use in food animals (including aquaculture), horticulture or humans
contributes to antimicrobial-resistant bacteria in humans varies between the different
bacteria and different regions.
Within Codex, there are a number of bodies that currently are considering the public
health implications of using antimicrobial agents in food-producing animals: the
Codex Committee on Residues of Veterinary Drugs in Foods (CCRVDF) and the
Joint FAO/WHO Expert Committee on Food Additives (JECFA), the Codex
Committee on Food Hygiene (CCFH), the ad hoc Intergovernmental Task Force on
Animal Feeding (TFAF) and others. Approaches to understanding the public health
significance of antimicrobial resistance have tended to focus on the professional
disciplines reflected by the traditional membership of these groups: safety of residues
in CCRVDF and JECFA, microbiological risk profiles in CCFH, and feeding practices
and the manufacture of animal feeds in TFAF (Task Force on Animal Feeding).
Codex Committee on Residues of Veterinary Drugs in Foods
The CCRVDF is responsible for the establishment of maximum levels for residues of
veterinary drugs in foods, including drugs used for therapeutic, prophylactic or
diagnostic purposes or for modification of physiological functions or behaviour.
CCRVDF obtains its scientific advice from JECFA. The CCRVDF was established
following the recommendation of a Joint FAO/WHO Expert Consultation on
Residues of Veterinary Drugs in Foods 2, (29 October-5 November 1984).
The consultation also discussed the problem of sub-therapeutic use of antibiotics in
animals and the concern as to the effects on public health. In this context, it clearly
recognised that the threat to man due to the sub-therapeutic uses of antibacterials in
animals and the development of resistant organisms in animals should not be
confused with the threat associated with the ingestion of veterinary drugs residues.
However, because of the importance of the problem and the lack of uniformity in
1 Paper based on ‘Discussion Paper on Antimicrobial Resistance and the Use of Antimicrobial in Animal Production’
(CX/RVDF 01/10) prepared for 13th Session of Codex Committee on Residues of Veterinary Drugs in Foods,
4-7 December 2001, Charleston, South Carolina (USA)
2 Residues of Veterinary Drugs in Foods – Report of a Joint FAO/WHO Expert Consultation. FAO Food and
Nutrition Paper N. 32, Rome, 1985
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regulating such uses, the Consultation pointed out that the issue, although unrelated to
the drug residues issue may require further action by FAO/WHO and other
international organisations with possible further implication for the Codex.
The CCRVDF at its First Session (27-31 October 1986) considered the framework of
the Committee. At that time, several delegations expressed concern at the
consequences of adding antibiotics to feedstuffs in low doses to increase feed
efficiency. The CCRVDF agreed that it should deal only with problems related to the
residues of veterinary drugs in foods and not to the possibility of transferring resistant
strains to human beings; and that the latter was a matter of food hygiene which should
be referred to the appropriate Codex Committee 3.
The issue of antimicrobial resistance was again considered by the CCRVDF at its 11th
Session (15-18 September 1998) as a result of the discussion on the reports on WHO
consultation on ‘Use of Antimicrobials in Livestock Production’ and the Joint
FAO/WHO Consultation on ‘The Non-Human Medical Use of Antimicrobials’. As
the delegations expressed different opinions on how CCRVDF should address issues
related to antimicrobial resistance and safety of food of animal origin, the Committee
agreed to prepare for its next Session, a paper which takes into account Codex
discussion and/or decision on these issues and relevant reports of other international
organisations. As per recommendation of the 12th CCRVDF, the paper 4 was further
revised for consideration by the 13th CCRVDF, to be held on 4-7 December 2001.
This discussion paper entitled ‘Antimicrobial Resistance and the Use of
Antimicrobials in Animal Production’ 5 provides an overview of issues and activities
concerning antimicrobial resistance relevant to the work of the CCRVDF and
proposes a draft ‘Code of Practice to Minimise and Contain Antimicrobial Resistance’,
which uses as its starting point the OIE (World organisation for animal health)
Guidelines for the Responsible and Prudent Use of Antimicrobial Agents in
Veterinary Medicine.
The paper highlights the importance of the CCRVDF working closely with other
relevant international standard-setting and regulatory bodies and in close coordination
with the CCFH and the Codex Committee on Pesticide Residues (CCPR), in
accordance with their respective terms of reference. It recognises that the CCRVDF is
composed of people having responsibilities in veterinary medicinal product
management in general and in veterinary medicinal product registration in particular,
and that the CCRVDF has experience with the issue of antimicrobial resistance in
establishing MRLs (Maximum Residue Limits) for antimicrobial residues and is
currently basing its work on the risk analysis approach, including the setting of
science-based risk assessment policy. The paper recommends that the CCRVDF be
ALINORM 87/31, paragraph 130,131
CX/RVDF 00/4, July 2001
5 CX/RVDF 01/10 ‘Discussion Paper on Antimicrobial Resistance and the Use of Antimicrobials in Animal
Production’, July 2001
3
4
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1. General aspects
involved in reducing the prevalence of bacteria resistant to antimicrobials in animalderived food and that it should be responsible for:
a) developing a risk assessment policy regarding animal bacteria resistant to
antimicrobials
b) identifying the priority risk assessments to be carried out by an appropriate
expert group in conjunction with CCFH
c) considering the outcome of these risk assessments for proposing
recommendations likely to help Codex member states in their risk management
responsibilities.
Codex Committee on food hygiene
The CCFH is responsible for the elaboration of provisions on food hygiene applicable
to all foods, and has established principles for the establishment and application of
microbiological criteria for foods and principles and guidelines for the conduct of
microbiological risk assessment.
The CCFH, due to its recognised expertise in food hygiene in general and in food
microbiology in particular, has the specific duty to propose any measures likely to
improve the microbiological quality of animal-derived food and to decrease the
burden of bacteria, sensitive or resistant to antimicrobials. The CCFH should also
prioritise pathogens or pathogen-commodity combinations, including antimicrobialresistant pathogens, for microbiological risk assessments.
The CCFH addressed the issue of antibiotic resistance in its last three sessions. The
31st CCFH (26-30 October 1998) considered a paper on ‘Antibiotic Resistance
Bacteria in Foods’, which outlined the need to evaluate and address the risks
associated with the development of drug resistance in bacteria following the use of
antibiotics. As there were different opinions expressed at the meeting, the Committee
agreed to prepare a discussion paper to clarify the issues involved and their relevance
to the work of the Committee, for further consideration at the 32nd session
(29 November-4 December 1999). As recommended by the Executive Committee at
its 47th session in June 2000, the paper 6 was further revised in the form of a risk
profile to determine which subjects fall within the terms of reference of the CCFH.
The revised paper 7 presented at the 33rd CCFH (23-28 October 2000) highlighted
that:
a) antimicrobial resistance contributes to the public health risk of pathogenic
bacteria in food because they result in an increase in the morbidity, mortality and costs
associated with the infection; and
b) antimicrobial-resistant bacteria represent a public health risk via food due to the
potential dissemination of resistant genes.
6
7
CX/FH 99/12
CX/FH 00/11 ‘Risk Profile on Antimicrobial-Resistant Bacteria in Food’
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It recognises that the presence of antimicrobial-resistant bacteria in food is related to
the use of antimicrobials, including growth promoting antimicrobials in food
production and in humans, as well as the transmission of bacteria in the various steps
of the food chain and environmental spread. It also identifies a number of strategies
available to control antimicrobial-resistant bacteria in foods including hygienic
measures, prudent use and other efforts to reduce overuse and misuse of
antimicrobials.
The paper recommended that the health risk associated with antimicrobial-resistant
bacteria in the food chain be further addressed in the various committees involved;
that the CCFH commission a risk assessment for selected specific scenarios and that
quinolone-resistant Salmonella and Campylobacter in poultry should be the top priority.
Moreover, it recommended that the principles of ‘reservation for human medicine’ of
certain antimicrobial substances need international validation.
Recognising the importance of the issue of antimicrobial resistant bacteria in food, the
CCFH agreed to forward the document to the Codex Executive Committee to assist
the coordination of work between the Committees concerned with the work of other
international organisations (e.g. the OIE). In its 34th Session (8-13 October 2001) the
CCFH will deliberate on the Executive Committee’s recommendations (see below).
The CCFH will explore the possibility of discontinuing or tabling the work until the
recommendations made by the Executive Committee are implemented or, continue
the work to develop guidelines for incorporation into other Codex documents such as
General Principles of Food Hygiene or the Guidelines for Risk Assessment.
Ad-Hoc Intergovernmental Task Force on Animal Feeding
The ad-hoc Task Force on Animal Feeding was established by the 23rd Session of the
Codex Commission with the mandate to:
a) complete and extend the work done by the relevant Committee on the Draft
Code of Practice for Good Animal Feeding
b) address other aspects which are important for food safety, such as problems
related to toxic substances, pathogens, microbial resistance, new technologies, storage,
control measures, traceability, etc.
At its First Session (13-15 June 2000), the Task Force was informed of the current
activities of other Codex Committees including the CCFH, the CCRVDF, the CCPR
regarding antimicrobial resistance in foods. The Task Force also addressed the issue of
antibiotics used for growth promotion purposes. Opinions varied between those
delegations that supported a statement in the Code that would prohibit such uses and
those delegations that were of the opinion that antibiotics should not be used in the
absence of a public health safety risk assessment. Attention was drawn to the report of
the Representative of WHO on the outcome of the WHO Consultation on ‘Global
Principles for the Containment of Antimicrobial Resistance’. It was agreed that further
discussion of this issue should be undertaken in the light of the report and
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recommendations of the Consultation, as well as the reports and guidance of other
groups such as the OIE, CCFH and CCRVDF.
Codex Committee on Pesticide Residues
In its 33rd Session 8 the CCPR considered the issue of the development of antibiotic
resistance in humans following the request to add gentamycin and oxytetracycline on
the priority list of substances to be evaluated. The request was supported by the fact
that these substances complied with the criteria for inclusion on the priority list as
they are very effective and important for the control of bacterial diseases of certain
commodities; and also, by the fact that, according to GAP, residue levels are very low
when these substances are used.
Codex Committee on Fish and Fishery Products
The issue of the development of resistance is taken into account in the draft Code of
Practice for Fish and Fishery Products, Section 16 ‘Aquaculture Production’ 9, not yet
been finalised by the CCFFP, as follows:
‘Uncontrolled and unlimited use of medicinal products may lead to the accumulation
of undesirable residues in the fish treated and in the environment, and that the
continuous use of antibacterial, antiprotozoan or anthelmintic products may favour
the development of resistance. It is the responsibility of the veterinarian or other
authorised persons to draw up programmes of preventive medicine for the fish farmer
and to stress the importance of sound management and good husbandry in order to
reduce the likelihood of fish diseases. Every effort should be made to use only those
drugs known to be effective in treating the specific disease.’ 10
Executive Committee
The Executive Committee examined the issues of coordination of work on
Antibiotics Used on Agricultural Commodities and on Antimicrobial Resistant
Bacteria in Food at its 48th Session 11 at the request of the Committee on Pesticide
Residues 12 and the Committee on Food Hygiene 13. In relation to the matter raised by
CCPR, the Executive Committee was of the opinion that the use of antimicrobials on
agricultural commodities should be subject to evaluation within a risk analysis
framework; the question was whether the normal process used for the evaluation of
pesticides was the appropriate one. In the second case, the Executive Committee
agreed that consideration should be given to antimicrobial resistant micro-organisms
in food within a risk analysis framework on a case-by-case basis as microorganism/food combinations were being assessed.
ALINORM 01/24, para.222
CX/FFP 00/4
10 CX/FFP 00/4, Section 16.9.1
11 ALINORM 01/4, paras 36-37
12 ALINORM 01/24A, para.122
13 ALINORM 01/13A, paras 132-142
8
9
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1. General aspects
The Executive Committee agreed however, that the issues raised by these Committees
required a more general, multidisciplinary and multi-agency response and
recommended that FAO and WHO should give consideration to convening, as soon
as possible, a multidisciplinary expert consultation in cooperation with the OIE, and if
required, the IPPC, to advise the Commission on possible directions to be taken,
including the establishment of a new task force if necessary.
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2. Surveillance
of antimicrobial consumption
OIE International Standards on Antimicrobial Resistance, 2003
107
2. Surveillance of antimicrobial consumption
Antimicrobial resistance: monitoring the quantities of
antimicrobials used in animal husbandry
†T. Nicholls (1), J. Acar (2), F. Anthony (3), A. Franklin (4), R. Gupta (5), Y. Tamura (6),
S. Thompson (7), E.J. Threlfall (8), D. Vose (9), M. van Vuuren (10), D.G. White (11),
H.C. Wegener (12) & M.L. Costarrica (13)
(1)
National Offices of Animal and Plant Health and Food Safety, Animal Health Science and Emergency
Management Branch, Department of Agriculture, Fisheries and Forestry, P.O. Box 858, Canberra, ACT 2601,
Australia
(2)
Université Pierre et Marie Curie, Service de Microbiologie Médicale, Fondation Hôpital Saint-Joseph, 185 rue
Raymond Losserand, 75674 Paris Cedex 14, France
(3)
Fresh Acre Veterinary Surgery, Flaggoners Green, Bromyard, Herefordshire HR7 4QR, United Kingdom
(4)
The National Veterinary Institute (SVA), Department of Antibiotics, SE 751 89 Uppsala, Sweden
(5)
College of Veterinary Sciences, Veterinary Bacteriology, Department of Microbiology, G.B. Pant University of
Agriculture and Technology, Pantnagar, 263 145 Uttar Pradesh, India
(6)
National Veterinary Assay Laboratory, Ministry of Agriculture, Forestry and Fisheries, 1-51-1 Tolura,
Kokubunji, Tokyo 185-8511, Japan
(7)
Joint Institute for Food Safety Research, Department for Health and Human Services Liaison, 1400
Independence Avenue, SW, Mail Stop 2256, Washington, DC 20250-2256, United States of America
(8)
Public Health Laboratory Service (PHLS), Central Public Health Laboratory, Laboratory of Enteric Pathogens,
61 Collindale Avenue, London NW9 5HT, United Kingdom
(9)
David Vose Consulting, Le Bourg, 24400 Les Lèches, France
(10) University of Pretoria, Faculty of Veterinary Science, Department of Veterinary Tropical Diseases, Private Bag
X04, Onderstepoort 0110, South Africa
(11) Centre for Veterinary Medicine, Food and Drug Administration, Office of Research, HFV-530, 8401 Muirkirk
Road, Laurel, Maryland 20708, United States of America
(12) World Health Organization, Detached National Expert, Division of Emerging and Transmissible Diseases,
Animal and Food-related Public Health Risks, 20 avenue Appia, 1211 Geneva, Switzerland
(13) Food and Agriculture Organization, Food Quality and Standards Service, Senior Officer, via delle Terme di
Caracalla, 00100 Rome, Italy
This report, prepared by the OIE Ad hoc Group of experts on antimicrobial resistance, has not yet received the
approval of the International Committee of the OIE
Summary
This guideline, developed by the OIE (World organisation for animal health) for the monitoring of
the quantities of antimicrobials used in animal husbandry, provides the methodology required to assess
the amounts of antimicrobials used, to supply data to be used for risk analysis and to improve
guidance on the appropriate use of antimicrobials. Information may be gathered from a number of
sources, such as the competent authorities, industry and users. The usefulness of different types of
information is discussed and recommendations are given on how to collect detailed information, each
year, on the antimicrobial quantities used per class and active substance. Information should also be
collected on the route of administration (oral and parenteral) and the animal species.
OIE International Standards on Antimicrobial Resistance, 2003
109
2. Surveillance of antimicrobial consumption
Keywords
Animal health – Antimicrobial resistance – Containment of resistance – Human
medicine – Monitoring of antimicrobial use – Public health – Risk analysis –
Standards – Veterinary medicine – World Organisation for Animal Health.
Introduction
There is world-wide concern about antimicrobial resistance in bacteria and about the
use of antimicrobials in food-producing animals which may contribute to
antimicrobial resistance problems in human and veterinary medicine. Data on
antimicrobial use in food animals is essential to identify such problems at the national
level and in subsequent risk analysis, planning and execution of programmes where
this concern is further defined and addressed.
The purpose of this document is to describe an approach for the monitoring of
quantities of antimicrobials used in animal husbandry. The objectives of such a
monitoring system will be defined, as will indications for the use of the data. The
sources and the types of data to be collected will be identified. Attention will be given
to the collection of information that most accurately describes the use of
antimicrobials in animals, and potential difficulties in the collection of that data.
Monitoring programmes will also be useful for local authorities dealing with specific,
individual or regional antimicrobial resistance problems. The reporting of data and
future directions to facilitate international harmonisation will be addressed.
The information presented in this chapter is not designed to be prescriptive for OIE
(World organisation for animal health) Member Countries where abilities to monitor
the quantities of antimicrobials used in animal husbandry vary greatly. Rather, this
chapter outlines a systematic approach that Member Countries can consider when
addressing this aspect of antimicrobial resistance management.
Reasons for collecting information on the quantities of
antimicrobials used in animal husbandry
The goal of any programme to monitor the quantities of antimicrobials used in
animals is to have objective and quantitative information to evaluate usage patterns by
animal species, antimicrobial class, potency and type of use in order to evaluate
antimicrobial exposure. These data are essential for risk analyses and planning, can be
helpful in interpreting resistance surveillance data and can assist in the ability to
respond to problems of antimicrobial resistance in a precise and targeted way. The
data may also assist in evaluating the effectiveness of efforts to ensure prudent use
and mitigation strategies (for example, by identifying changes in prescribing practices
for veterinarians) and to indicate where alteration of antimicrobial prescribing
practices might be appropriate, or if changes in prescription practice have altered the
pattern of antimicrobial use.
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2. Surveillance of antimicrobial consumption
The continued collection of this basic data will also help give an indication of trends
in the use of animal antimicrobials over time and the role thereof in the development
of antimicrobial resistance in animals. This information could be compared with
medical, agricultural and other antimicrobial use data as part of any risk analysis
necessary for the holistic and integrated approach of a Member Country to optimise
antimicrobial use.
The level of information collected will depend on the perceived or actual concern of a
Member Country with the issue of antimicrobial resistance, and the ability of that
country to fund the necessary programmes. However, in the consideration of
antimicrobial resistance by a Member Country, there will also be a need for data on
the medical and agricultural use of the chemicals if meaningful evaluations are to be
undertaken.
For all OIE Member Countries, the minimum basic information collected should
include the total amount of active antimicrobial ingredient used per kilogram by class,
or specific formula if there are differences in potency within a class. In addition, the
type of use (therapeutic or growth promotion) and route of administration (parenteral
or oral administration) should be recorded.
Member Countries could explore the possibility of establishing regional or local
databases of antimicrobial usage/resistance patterns, since these may be of more
practical use to the consulting veterinarian. Such use would require a classification of
food animal antimicrobial use. Such classifications need to produce useful data. For
example, a simple classification of in-feed and veterinary use would probably be
misleading in risk analysis because both in-feed use and veterinary use of
antimicrobials can be for the purpose of treatment and growth promotion.
The key to understanding the relationship between antimicrobial use in animals and
the development of resistance in animal bacteria is likely to be related to the reasons
for selection of particular antimicrobials as well as the rate of prescription and the
dose and length of treatment regimens. This information is critical if feedback
pathways to veterinarians prescribing antimicrobials are to be established so usage
patterns can be defined and the development of antimicrobial resistance in animal
bacteria can be analysed and acted on by regulatory and other authorities, where
appropriate.
The total consumption of antimicrobials for human, medical, food animal and other
uses is a key factor in any consideration of this issue. While this guideline will only
consider animal antimicrobial use, Member Countries may wish to consider, for
reasons of cost and administrative efficiency, collecting medical, ood animal,
agricultural and other antimicrobial use data in a single programme. A consolidated
programme would also facilitate comparisons of animal use with human use data for
relative risk analysis.
OIE International Standards on Antimicrobial Resistance, 2003
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2. Surveillance of antimicrobial consumption
Sources of antimicrobial use data
Basic sources
Sources of data will vary from country to country and depend on factors such as
whether a Member Country manufactures antimicrobials, exports and/or imports
antimicrobials, and whether or not there is any accessible and accurate source of this
information from the national regulatory authorities. Such sources may include
customs, import and export data, manufacturing and manufacturing sales data.
Direct sources
Most countries have a legislative infrastructure for the registration, distribution and
control of animal antimicrobial use (see Antimicrobial resistance: responsible and prudent use
of antimicrobial agents in veterinary medicine, earlier in this volume). Data from animal drug
wholesalers, retailers, pharmacists, veterinarians, feed stores, feed mills and organised
industry associations in these countries might be an efficient and practical source of
data on antimicrobial use in animals. A possible mechanism for the collection of this
information is that the provision of appropriate information by manufacturers to the
regulatory authority is a requirement of antimicrobial registration, provided
commercial confidentiality requirements can be met.
End-use sources (veterinarians and food animal producers)
Periodic audits and statistically based surveys of either direct sources or end-use
sources of animal antimicrobials, rather than ongoing data collection programmes,
may be a method of obtaining accurate and detailed information on animal
antimicrobial use. This may be appropriate when basic or direct sources cannot be
used for the routine collection of this information. Targeted surveys or audits could be
used as an adjunct to this information, or when more accurate and locally specific
information is required. In addition to assisting in quantifying the extent of use of
antimicrobials, end-use (particularly of veterinarians and food animal producers)
surveys may be used to identify patterns of antimicrobial, prophylactic, therapeutic
and growth promoter use that may have implications in an epidemiological
investigation of the development of antimicrobial resistance. Factors such as
seasonality and disease conditions, species affected, agricultural systems (e.g. extensive
range conditions and feedlots), dose rate, duration and length of treatment with
antimicrobials relative to the recommendations for the purpose of the antimicrobial,
may be important factors. An issue may be the need to recruit sufficient numbers of
veterinarians and farmers to allow robust analysis. Collection, storage and processing
of data from end-use sources are likely to be inefficient and expensive processes
unless carefully designed and well managed, but should have the advantage of
producing accurate and targeted information.
Recommendation
In consideration of antimicrobial resistance management programmes, the sources of
data available and options for the collection of data for individual OIE Member
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2. Surveillance of antimicrobial consumption
Countries need early and careful analysis as well as careful consideration to ensure the
cost-effective use of resources to fund national programme objectives.
Categories of data
Minimal antibiotic use data requirements and data levels
It is the opinion of the OIE Ad hoc Group on antimicrobial resistance that, in OIE
Member Countries, the minimal data collected should be the annual weight in
kilograms of the active ingredient of the antimicrobial(s) used in food animal
production.
If a Member Country has the infrastructure for capturing basic animal antimicrobial
use data for a specific antimicrobial, then additional information can be considered to
cascade from this in a series of subdivisions or levels of detail. The relevant authorities
within the Member Country should decide on the level of detail required so that the
data collected can contribute to the aspirations of the Member Country to limit the
development of antimicrobial resistance. Such a cascade of levels could include the
following:
a) the absolute amount in kilograms of antimicrobial active used per antimicrobial
family per year, or for a specific antimicrobial chemical entity when this information is
required
b) therapeutic and growth promotion use in kilograms of the specific antimicrobial
active
c) subdivision of antimicrobial use into therapeutic and growth promotion use by
species
d) subdivision of the data into the route of administration, specifically in-feed, inwater, injectable, oral, intramammary, intra-uterine and topical
e) further subdivision of these figures by season and region by a Member Country
may be useful (note: this may be especially helpful in countries with large variations in
environmental/management conditions, or where animals are moved from one
locality to another during production)
f) further breakdown of data for analysis of antimicrobial use at the regional, local,
herd and individual veterinarian level may be possible using veterinary practice
computer management software as part of specific targeted surveys or audits. Analysis
of this information within the local or regional context could be useful for individual
practitioners and practices where specific antimicrobial resistance has been identified
and feedback is required.
Registration and regulation
All OIE Member Countries should have appropriate veterinary chemical registration
standards, either through a national veterinary medicinal product registration
authority, or through requirements that imported products comply with the
registration system of the exporting country or of another country. This is to ensure
that safe, efficacious and quality veterinary products are used in food animals. Many
OIE International Standards on Antimicrobial Resistance, 2003
113
2. Surveillance of antimicrobial consumption
Member Countries also have agriculture and veterinary chemical residue monitoring
and surveillance programmes for measuring chemical residues in food.
These two activities can guide Member Countries regarding the level of detail of
animal antimicrobial use information required. For example, monitoring the amount
of registered antimicrobial residues in food animals at slaughter would be an
elementary data collection activity. If the antimicrobial residue programme or other
information indicated that non-registered antimicrobials were used in food animals,
then provisions could be made to collect animal antimicrobial use information at the
end-user level, using targeted surveys or specially designed monitoring programmes.
However, if these programmes are not in place, a good starting point for Member
Countries may be to utilise customs permit data to quantify imported antimicrobials.
The basic regulatory requirements of Member Countries recommended by this OIE
Ad hoc Group are discussed in more detail in Antimicrobial resistance: responsible
and prudent use of antimicrobial agents in veterinary medicine.
Classes of antimicrobials
Decisions need to be made on what classes of antimicrobials should be considered
and what members of various antimicrobial classes should be included in the data
collection programme. These decisions should be based on currently known
mechanisms of antimicrobial activity of the particular antimicrobial and its relative
potency. For example, individual members of the dichloracetic acid group of
antimicrobials (e.g. chloramphenicol and florfenicol) have different mechanisms of
action. Other preparations, such as the tetracyclines, have different potency levels, for
example, chlortetracycline is not as potent as doxycycline on a mg/kg basis. Ideally,
animal-use data should be collected for each individual member of the antimicrobial
group registered for use. Where common mechanisms of action exist, this data can be
aggregated at a later date, if required.
An internationally accepted method of comparing antimicrobials, taking these factors
into account, would be useful, as would internationally accepted nomenclature for
antimicrobial classes so that future comparison of use data could be facilitated. An
international code for the specific identification of medical and veterinary
antimicrobials is available in the ATCvet Index (2). It is recommended that this code be
used in the identification of specific antimicrobials.
Species, production system, regional and seasonal data
Most countries register animal use antimicrobials for a specific food animal species
(cattle, sheep, goats, pigs, poultry, horses and fish) and often for specific diseases.
Frequently, antimicrobial product registration is for multiple species use, such as for
cattle, sheep and goats, and this may create difficulties in determining use patterns. In
order for a country to effectively analyse animal antimicrobial use patterns, including
off-label use, a good understanding of the circumstances of food animal antimicrobial
use is required. For example, cattle are raised in extensive range conditions, in feedlots
or held in barns during the winter. An understanding of what antimicrobials are used
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2. Surveillance of antimicrobial consumption
in specific animal species and industries in different regions, as well as seasonal
influences on disease prevalence are likely to be important information in the risk
analysis of this issue. Such general information may, for example, identify a potential
problem, such as possible inappropriate animal antimicrobial use. Further
investigation could lead to confirmation and suggest corrective action, such as
feedback of information to veterinarians and producers.
Other important information
If an OIE Member Country is considering animal antimicrobial use in food animals, a
breakdown of the animal industries may be useful in any risk analysis or for
comparison of animal antimicrobial use with human medical use within and between
countries. For example, the total number of animals (meat, dairy and draught cattle,
and meat, fibre and dairy sheep) in the country would be essential basic information.
In addition, the total number of animals raised and their weight in kilograms for food
production per year would be essential information in the assessment of animal
antimicrobial use figures.
Breakdown of the type of production enterprises (for example, extensive versus
intensive) would also be useful if accurate industry enterprise antimicrobial use data
was not available to give an indication of how animal antimicrobials were being used.
Future directions
Since the crude amount of antimicrobial (in kilograms) used yearly only indirectly
represents antimicrobial exposure, and hence the selective pressure on bacterial
populations, more sophisticated measures are needed. Such concepts have been
developed in human medicine. Medical monitoring of antibiotic use in community
and hospital medicine has led to the evolution of the concept of the defined daily dose
(DDD) expressed as the DDDs/1,000 population/day. This approach takes into
account the activity and potency of individual antimicrobials and the basic unit of
comparison
between
individual
antimicrobials
becomes
the
DDD/1,000/population/day applied to the particular environment. However, a direct
comparison between medical and animal use of antimicrobials is difficult and perhaps
pointless other than for medical and veterinary authorities to have a rational baseline
measure of national antibiotic use for ongoing comparison over a period of years. The
management of medical and veterinary antimicrobial registration and use in most OIE
Member Countries are separate and independent exercises. In the future, the
management of animal antibiotic use may be dependent on risk analysis findings of
the contribution of animal antibiotic use to medical antimicrobial resistance problems.
Developing a DDD approach for antimicrobials in food animals would be difficult
because of the wide range of animal weights (e.g. compare the weight of newly
hatched chickens and new-born calves or meat chickens and cattle at slaughter). The
reports of the Danish Zoonosis Centre (DANMAPs) use the concept of milligram of
antimicrobial used per kilogram of meat produced (1). This concept could be useful in
the monitoring and analysis of animal use of antibiotics overall, and within particular
OIE International Standards on Antimicrobial Resistance, 2003
115
2. Surveillance of antimicrobial consumption
species, although it does not address dose rate and length of treatment regimens in
specific animal husbandry circumstances.
However, by using milligram of antimicrobial active used per kg of meat produced as
a measure of antimicrobial use in food animals it may be possible to undertake a
comparison for specific antimicrobials, thus enabling evaluation of the relative
selection pressure of, for example, two antibiotics with different activity and potency
such as tetracycline and fluoroquinolones. This approach does not take into account
the different pharmacological activity of different antibiotics and potency may need to
be standardised in some way. Such a system would be a better measure, over time, of
the total selection pressure applied to the particular environment under study, and
would provide a more accurate measure of the relative importance of the different
potential of antimicrobials for generating bacterial resistance. It would also be of
value, for example, in measuring the consequence of changes in use patterns, such as
the replacement of tetracycline use with fluoroquinolones, or in analyses where
lifetime exposures of animals to antimicrobials were important.
The development of concepts on the action of antimicrobials reflecting their relative
activity through the consideration of potency, in conjunction with the kilograms of
food animal product produced using these antimicrobials, is important. It would
provide useful baseline information and assist in assessing the possible contribution of
the animal use of antimicrobials in the production of antimicrobial resistance of
medical and veterinary concern.
Conclusions
Data on the use of antimicrobials in animals is essential for risk analysis and the design
and planning of antimicrobial resistance monitoring and surveillance programmes, as
well as for the ongoing management of antimicrobial resistance on the individual
farm, district, regional, national and international levels.
Antibiorésistance : contrôle des quantités d’antibiotiques
utilisées en production animale
†T. Nicholls, J. Acar, F. Anthony, A. Franklin, R. Gupta, Y. Tamura, S. Thompson,
E.J. Threlfall, D. Vose, M. van Vuuren, D.G. White, H.C. Wegener & M.L. Costarrica
Résumé
Cette ligne directrice, préparée par l’Organisation mondiale pour la santé animale et applicable au
contrôle des quantités d’antibiotiques utilisées en production animale, fixe la méthodologie requise
pour évaluer les quantités de produits antimicrobiens utilisés, pour fournir les informations nécessaires
à l’analyse du risque et pour améliorer les instructions relatives à l’utilisation appropriée des
antibiotiques. Les informations peuvent émaner de plusieurs sources, telles que les autorités
compétentes, les professionnels du secteur et les utilisateurs. L’utilité des différents types d’information
fait l’objet de la discussion et des recommandations sont données sur la manière de recueillir une
information détaillée, chaque année, sur les quantités d’antibiotiques utilisés, par catégorie et par
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OIE International Standards on Antimicrobial Resistance, 2003
2. Surveillance of antimicrobial consumption
substance active. Il convient également de recueillir des informations relatives aux modes
d’administration (orale ou parentérale) et aux espèces animales concernées.
Mots-clés
Analyse du risque – Antibiorésistance – Gestion de l’utilisation des antibiotiques –
Maîtrise de la résistance – Médecine humaine – Médecine vétérinaire – Normes –
Organisation mondiale pour la santé anbimale – Santé animale – Santé publique.
Resistencia a los antimicrobianos: seguimiento del volumen
de antimicrobianos utilizados en producción animal
†T. Nicholls, J. Acar, F. Anthony, A. Franklin, R. Gupta, Y. Tamura, S. Thompson,
E.J. Threlfall, D. Vose, M. van Vuuren, D.G. White, H.C. Wegener & M.L. Costarrica
Resumen
Esta directriz, elaborada por la Organización mundial de sanidad animal para facilitar el
seguimiento de los volúmenes de antimicrobianos utilizados en producción animal, define la
metodología indicada para evaluar ese parámetro, obtener datos útiles para el análisis de riesgos y
orientar mejor al usuario sobre el empleo adecuado de los antimicrobianos. La información puede
proceder simultáneamente de varias fuentes, como las autoridades competentes, los industriales del
ramo y los usuarios. Los autores valoran la utilidad de distintos tipos de información y recomiendan
métodos para recabar anualmente datos exactos sobre los volúmenes de productos antimicrobianos
utilizados (desglosados por clase y principio activo). Conviene también obtener información sobre la vía
de administración (oral o parenteral) y la especie animal de que se trate.
Palabras clave
Análisis de riesgos – Contención de las resistencias – Gestión del uso de
antimicrobianos – Medicina humana – Medicina veterinaria – Normativa –
Organización mundial de sanidad animal – Resistencia a los productos
antimicrobianos – Salud pública – Sanidad animal.
References
1. Danish Zoonosis Centre (2001). – DANMAP 2000. Danish Veterinary Laboratory,
Ministry
of
Agriculture
and
Fisheries,
Copenhagen,
56
pp.
Website:
http://www.svs.dk/uk/organization/lgo_zoo.htm (document accessed on 9 August 2001).
2. Nordic Council on Medicines (NCM) (2001). – Anatomical Therapeutic Chemical (ATC)
vet Index. NCM, Uppsala. Website: http://www.nln.se/default.asp (document accessed on
9 August 2001).
__________
OIE International Standards on Antimicrobial Resistance, 2003
117
2. Surveillance of antimicrobial consumption
Surveillance of antimicrobial consumption activities
in France
G. Moulin
National Agency for Veterinary Products (AFSSA – French Food Safety Agency), La Haute Marche, Javené
B.P. 90203, 35302 Fougères, France
Introduction
In France, different studies have been carried out regarding the surveillance of
antimicrobial consumption under the sponsorship of the Ministry of Agriculture: a
sales survey of antimicrobials in Veterinary Medicinal Products (VMP), a survey of
prescriptions by veterinarians, and an anti-microbial consumption survey in farms.
This paper presents the results of the first survey carried out in France and relates to
VMP sales in France in 1999.
The survey was set up in collaboration with the French association of veterinary
pharmaceutical companies (Syndicat de l’industrie du médicament vétérinaire et réactif
– SIMV).
The survey was only set up for veterinary medicinal products. Additives, growth
promoters and coccidiostats were not followed, as they are out of scope of the
activities of the National Agency for Veterinary Medicinal Products.
Protocol
The methodology used is quite simple and based on a very simple questionnaire sent
by the agency and completed by the marketing authorisation holder.
In March 2000, a letter was sent from the agency to the marketing authorisation
holder asking for the return of the enclosed questionnaire for 30 June 2000 for every
VMP containing antibiotics.
For each medicinal product, the number of sold units should have been given for the
period between 1 January 1999 and 31 December 1999.
The sales figures for each product were cross-referenced with the data (quantitative
and qualitative composition, pharmaceutical form, purpose, target animals) that is
available in the National Agency of Veterinary Medicinal Products database.
Then, calculations were done to obtain sold quantities in active substance per unit of
mass. These figures were then sorted by active constituent and by antibiotics class.
Results
Sales data were collected for 1938 of medicinal products containing antibiotics.
In France, 1,364 tonnes of antibiotics were sold in 1999.
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OIE International Standards on Antimicrobial Resistance, 2003
2. Surveillance of antimicrobial consumption
Sales distribution by antibiotics class
The distribution by antibiotics class appears in Figure 1:
700
600
Tonnes
500
400
300
200
100
Am
in
og
lyc
os
Be
id
tal
es
ac
tam
Ce
in
ph
es
alo
sp
Fl
or
uo
in
ro
es
qu
in
ol
on
es
Fu
ra
ne
s
M
ac
ro
lid
es
O
th
er
s
Ph
en
ico
Po
lym ls
yx
in
es
Q
ui
no
lo
Su
ne
lfo
s
na
m
id
Te
es
tra
cy
cli
Tr
ne
im
s
eth
op
rim
0
Antibiotic class
Fig. 1
Veterinary use of antibiotics in France 1999 (tonnes)
Four antibiotic classes (Tetracycline, Sulfonamide, Betalactam, Aminoglycoside)
represent 83% of sold antibiotics.
Tetracycline represents nearly half the total.
It can be observed that compounds belonging to newer antibiotic classes represent
relatively low volumes (Fluoroquinolone: 0.24%, Cephalosporine: 0.53%).
Distribution of antibiotic sales by animal categories
It is difficult to give figures for each animal species as the same VMP can be indicated
for use in several species.
Nevertheless, it is possible to have some information regarding the distribution
between companion animals and food producing animals.
In volume, sales of antibiotics for cats and dogs represent between 1.3% and 7.7% of
the total.
Food producing animal use represents the main part of antibiotic sales.
There are several reasons why the distribution between food and companion animals
is different.
For example, furans are not permitted for use in food animal species and can only be
used in companion animals.
OIE International Standards on Antimicrobial Resistance, 2003
119
2. Surveillance of antimicrobial consumption
In addition, for antibiotics such as cephalosporins, differences can be related to,
among other parameters, the cost of the VMP.
Antibiotic sales distribution by administration route
The oral route accounts for 85% of anti-microbial sales, the parenteral route for 13%
and other routes for 6.4%.
Comparison with data from other countries of the European Union
Percentage
The distribution by antibiotic class is very similar to that observed in other countries.
60
50
40
30
20
10
0
France
United-Kingdom
Denmark
Country
Aminoglycosides
Betalactams/Cephalosporines
Fluoroquinolones
Macrolides
Trimethoprim/Sulphonamides
Tetracyclines
Others
Fig. 2
Percentage sales of antibiotics by country in 1999
Discussion
Data interpretation should be done with caution and one must take into account
different factors such as, the number of animals, their weights, the dosage and the
treatment duration.
For example, the difference in antibiotic volumes used between food producing
animals and companion animals is certainly related to the following factors: number of
animals, weight, preferred route of administration, health status.
Such surveys have some limitation. In particular, it is not possible to obtain sales data
by species due to the fact that the same VMP can be authorised and used in different
species.
However, this kind of survey remains very interesting for historical comparisons and
as a tool for risk analysis.
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Conclusion
This was the first time that VMP sales in France had been studied. Antibiotic sales
monitoring should be continued in order to follow the evolution of antibiotic use over
time.
These data could serve as a basis for the interpretation of the evolution of antibiotic
resistant bacteria.
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Surveillance of antimicrobial consumption in
Denmark
D.L. Monnet (1), F. Bager (2) & L. Larsen (3)
(1)
Statens Serum Institut, Department of microbiological research and development, Artillerivej 5, 2300
Copenhagen, Denmark
(2)
Danish Zoonosis Centre, Danish Veterinary Laboratory, Bülowsvej 27, 1790 Copenhagen, Denmark
(3)
Danish Medicines Agency for the Danish Integrated Antimicrobial Resistance Monitoring and Research
Programme (DANMAP), Axel Heides Gade 1, 2300 Koberhavn’s, Denmark
In Denmark, all antimicrobials used in humans and for therapy in food animals are
prescription-only medicines and must be distributed through pharmacies. All
medicines must be registered by the Danish Medicines Agency (DMA).
The DMA has the legal responsibility for monitoring the consumption of all medicinal
products in humans. Since 1994, such data are available through monthly electronic
reporting by all pharmacies. For each sale, packages are recorded by their specific
code, together with information to identify the patient and the prescriber, the date and
place of the sale, and possible subsidisation of cost. However, information on the
indications for the prescription is not yet available. Data on antimicrobial
consumption and the results of specific analyses, e.g. on the effect of changes in
subsidisation, are reported at least yearly, as the number of WHO defined daily doses
per 1,000 population per day in the DMA newsletter, on its website
(www.laegemiddelstyrelsen.dk) and in the DANMAP report (www.svs.dk,
‘Zoonosecentret’). Summarised data on antimicrobial consumption in humans in
Denmark are now updated monthly and made available to registered users on a
dedicated website.
Since 1996, data on the consumption of antimicrobials for therapy of food animals
have been available through the yearly reporting by the pharmaceutical industry to the
DMA on quantities sold in Denmark. Data on the use of antimicrobials for growth
promotion were obtained through compulsory reporting to the Danish Plant
Directorate by companies authorised to produce premixes containing antimicrobials.
Such data are now starting to be collected through a new monitoring programme
called VETSTAT. Pharmacies report on prescriptions by veterinarians, including the
identity of the farm, the animal species and age group, the identity of the prescriber
and the reason for prescribing, in addition to the name and quantity of the drug.
Medicines sold or used by veterinarians must be reported directly to VETSTAT with
the same information. Finally, feed mills report all sales of animal feed containing
medicines or coccidiostats. Data on the consumption of antimicrobials in food
animals in kilograms are presented yearly in the DANMAP report, together with a
comparison with consumption in humans. Monthly data should soon be available
through VETSTAT.
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2. Surveillance of antimicrobial consumption
Antimicrobial resistance: monitoring the quantity of
antimicrobials used in animal husbandry
J.J. Webber 1
Agriculture Fisheries and Forestry, G.P.O. Box 858, Canberra ACT 2601, Australia
Introduction
There is world-wide concern about the potential of antimicrobial use in food animals
to contribute to antimicrobial resistance problems in human and veterinary medicine.
Data on antimicrobial use in food animals are essential in identifying such problems at
the national level and in subsequent risk analysis, planning and execution of
programmes to further define and address this concern.
Reasons for collecting information on the quantities of
antimicrobials used in animal husbandry
The goal of any programme to monitor the quantities of antimicrobials used in
animals is quantitative information on usage patterns by animal species and
antimicrobial class, including potency and type of use that can be used to evaluate
antimicrobial exposure. The level of information collected will depend on the member
country’s overall concern, perceived or actual, with the issue of antimicrobial
resistance, and its ability to fund the necessary programmes. These data can be used
for:
– risk analysis and planning
– interpreting surveillance data on resistance
– a precise and targeted response to problems of antimicrobial resistance
– evaluating the effectiveness of prudent use guidelines for antimicrobials and
strategies for mitigating resistance
– tracking trends in animal antimicrobial use over time.
The total consumption of antimicrobials for human medical, food animal and other
uses is a key factor in any consideration of antimicrobial resistance. This guideline
addresses antimicrobial use only in animals. However, for reasons of cost and
administrative efficiency, member countries may wish to consider the collection of
data on medical, food animal, agricultural and other antimicrobial use in the one
programme.
1 Adapted from the OIE Guideline prepared by the OIE Ad hoc Group of Experts on antimicrobial resistance and
authored by T. Nicholls, J. Acar, F. Anthony, R. Gupta, Y. Tamura, S. Thompson, E. Threlfall, D. Vose, M. van
Vuuren, D. White, H. Wegener & M. Costarrica.
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2. Surveillance of antimicrobial consumption
Sources of antimicrobial use data
The sources of data available and options for their collection require careful
consideration by individual OIE member countries to ensure that resources are used
in a cost effective manner to meet the objectives of national programmes.
Basic sources of data
Basic sources of data will vary from country to country and depend on factors such as
whether a member country manufactures antimicrobials, exports, and/or imports
antimicrobials, and whether or not there is an accessible and accurate bank of
information held by the national regulatory authorities. Sources may include customs,
import and export data, manufacturing and sales data.
Direct sources of data
Animal drug wholesalers, retailers, pharmacists, veterinarians, feed stores, feed mills
and organised industry associations in member countries might be efficient and
practical sources of data on antimicrobial use in animals. A possible mechanism for
the collection of information is that the provision of appropriate information by
manufacturers to the regulatory authority is a requirement of antimicrobial
registration, provided commercial confidentiality requirements can be met.
End use surveys (veterinary surgeons and food animal producers)
Periodic audits and statistically based surveys of either direct or end use sources of
animal antimicrobials, rather than ongoing data collection programmes, may be a
method of obtaining more accurate and detailed information on animal antimicrobial
use. In addition to assisting in quantifying the use of antimicrobials, end use surveys,
particularly of veterinarians and food animal producers, may be used to identify:
– patterns of use that may have implications in epidemiological investigation of the
development of antimicrobial resistance
– related aspects of antimicrobial use on farms, such as methods of disposal of
unused product.
Collection, storage and processing of data from end use sources are likely to be
inefficient and expensive unless carefully designed and well managed, but should
produce accurate and targeted information.
Categories of data
Minimal antimicrobial use data requirements and data levels
In OIE member countries, the minimal data collected should be the annual weight in
kilograms of the active ingredient of the antimicrobial(s) used in food animal
production. If a member country has the infrastructure for capturing basic animal
antimicrobial use data for a specific antimicrobial, then additional information can be
considered to cascade from this in a series of subdivisions or levels of detail. The
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2. Surveillance of antimicrobial consumption
relevant authorities within the member country should decide on the level of detail
required. Such a cascade of levels could include:
– The absolute amount in kilograms of antimicrobial active used per antimicrobial
family per year, or for specific antimicrobial chemical entity when this information is
required.
– Therapeutic and growth promotion use in kilograms of the specific antimicrobial
active.
– Subdivision of antimicrobial use into therapeutic and growth promotion use by
species.
– Subdivision of the data into the route of administration, specifically in-feed, inwater, injectable, oral, intramammary, intra-uterine and topical.
– Further subdivision of these figures by season and region by a member country
may be useful in countries with large variations in environmental/management
conditions within its borders, or where animals are moved from one locality to
another during production.
– Further breakdown of data for analysis of antimicrobial use at the regional, local,
herd and individual veterinarian level may be possible using veterinary practice
computer management software as part of specific targeted surveys or audits.
Registration and regulation
All OIE member countries should have appropriate veterinary chemical registration
standards to ensure that safe, efficacious and quality veterinary products are used in
food animals. Many member countries also have agriculture and veterinary chemical
residue monitoring programmes for measuring chemical residues in food. These two
activities can guide members on what level of detail of animal antimicrobial use
information may be required. If the antimicrobial residue programme or other
information indicated that non-registered antimicrobials were used in food animals,
then provisions could be made to collect animal antimicrobial use information at the
end user level using targeted surveys or specially designed monitoring programmes.
Classes of antimicrobials
Ideally, animal use data should be collected for each individual member of the
antimicrobial group registered for use. Where common mechanisms of action exist
data analysis could be enhanced if potency could be standardised in such a way that
relative antimicrobial exposure (i.e. selection pressure) can be considered in risk
analysis. For example chlortetracycline is not as potent as doxycycline on a mg/kg
basis. Future comparison of use data would be facilitated by an internationally
accepted method of comparing antimicrobial consumption and of an internationally
accepted nomenclature for antimicrobial classes.
Species, enterprise, regional and seasonal data
Most countries register animal use antimicrobials for a specific food animal species
and often for specific diseases. Frequently antimicrobial product registration is for
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2. Surveillance of antimicrobial consumption
multiple species use, such as for cattle, sheep and goats, and this may create difficulties
in determining use patterns. In order for a country to effectively analyse animal
antimicrobial use patterns, including off-label use, a good understanding of the
circumstances of food animal antimicrobial use is required e.g. cattle are raised in
extensive range conditions, in feedlots or held in barns over winter. An understanding
of what antimicrobials are used in specific animal species and industries in different
regions, as well as seasonal influences on disease prevalence is likely to be important
information in the risk analysis of this issue.
Other important information
If an OIE member country is considering animal antimicrobial use in food animals, a
breakdown of the animal industries may be useful in any risk analysis or for
comparison of animal antimicrobial use with human medical use within and between
countries. For example, the total number of animals [cattle (meat, dairy, draft), sheep
(meat, fibre and dairy)] in the country would be essential information. In addition, the
weight in kg for food production per year would be essential information in the
assessment of animal antimicrobial use figures.
Breakdown of the type of production enterprises (extensive versus intensive for
example) would also be useful if accurate industry enterprise antimicrobial use data
was not available to give an indication of how animal antimicrobials were being used.
Future directions
Since the crude amount of antimicrobial (in kilograms) used yearly only indirectly
represents antimicrobial exposure, and hence the selective pressure on bacterial
populations, more sophisticated measures are needed. Medical monitoring of
antimicrobial use in community and hospital medicine has led to the evolution of the
concept of the Defined Daily Dose (DDD) 2 expressed as the DDDs/1,000
population/day. This approach takes into account the activity and potency of
individual antimicrobials.
Developing a DDD approach to antimicrobials in food animals would be difficult
because of the wide range of animal weights. The DANMAP 3 reports use the concept
of milligram of antimicrobial used per kilogram of meat produced. This concept could
be useful in the monitoring and analysis of animal use of antimicrobial overall, and
within particular species, although it does not address dose rate and length of
treatment regimens in specific animal husbandry circumstances.
Direct comparison between medical and animal use of antimicrobials is difficult and
perhaps pointless other than for medical and veterinary authorities to have a rational
WHO Collaborating Centre for Drug Statistics Methodology. http://www.whocc.no/atcddd/
DANMAP 2001. Use of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food
animals and food and humans in Denmark. ISSN 1600-2032. http://www.vetinst.dk/high_uk.asp?page_id=179
2
3
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2. Surveillance of antimicrobial consumption
baseline measure of national antimicrobial use for ongoing comparison over a period
of years.
Conclusions
Data on the use of antimicrobials in animals is essential for risk analysis and the design
and planning of antimicrobial resistance monitoring and surveillance programmes, as
well as for the ongoing management of antimicrobial resistance on the individual farm
and at district, regional, national and international levels.
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2. Surveillance of antimicrobial consumption
The global usage of antimicrobials for animal health
Dr T. Mudd
IFAH, rue Defacqz 1, 1000 Bruxelles, Belgium
The International Federation for Animal Health (IFAH) is the global organisation
representing the animal health industry. The primary goal of the organisation is the
development of pharmaceuticals and vaccines to ensure animal health and welfare.
IFAH has three primary tasks involving Codex Alimentarius, the Veterinary
International Committee for Harmonisation of Regulations (VICH) and Antimicrobial
Resistance.
IFAH has been supportive of the Codex approach to Risk Assessment and agrees that
this must be an integral part of the veterinary medicines regulatory process. For this
reason, IFAH has participated in the discussions at the level of the Codex Committee
on general principles whereby a standard for international use of the risk analysis
process is the objective.
Over the past twelve years the market for animal health products has evolved from
about US$9 billion to a peak of about US$11.5 billion in the late 1990s. Since that
time there is evidence that total sales have flattened out or even declined. This
suggests that very few new products are coming to the market and it has been
essential to ensure that the existing products maintain their efficacy as long as
possible. For this reason the members of IFAH have a direct interest in ensuring that
resistance to antimicrobials is minimised. By product category biologicals or vaccines
comprise 21%, medicinal feed additives 16% and pharmaceuticals, including
antimicrobials 64%. This pharmaceuticals category is further split to 18% antiinfectives, 27% parasiticides, 3% performance enhancers and 16% other
pharmaceuticals.
Global markets are North America 35%, West Europe 26%, Far East 19%, Latin
America 13%, East Europe 4% and rest of the world 3%. By species, the largest
market now is for companion animals at 34%, next, cattle at 29%, swine 17%, poultry
14% and sheep 6% (2).
There are three major areas of usage of antimicrobials in veterinary medicine:
therapeutic, prophylactic and digestive/performance enhancement, also known as
growth promoters. Regulatory agencies and their independent advisory committees
conduct a risk assessment prior to introduction on the market and whenever new
information becomes available. It is unfortunate that political interference in recent
years has overridden scientific opinion and decisions taken based on the
‘precautionary principle’. IFAH has worked with the WHO in recent years
culminating in the publication of the ‘Global Principles for the Containment of
Antimicrobial Resistance due to Antimicrobial Use in Animals intended for Food’.
This is part of the WHO Global Strategy whose purpose is ‘To minimise the public
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2. Surveillance of antimicrobial consumption
health impact of the use of antimicrobial agents in food-producing animals whilst at
the same time providing for their safe and effective use in veterinary medicine’.
The quantities of antimicrobial usage are frequently expressed in terms of US$. To
obtain some direct comparison with other countries that express quantities as kg
active ingredient (kg a.i.) a conversion factor has been used to express all usage in kg
a.i. Medicinal feed additives such as ionophores for the control of coccidiosis, rather
than as an antimicrobial are not included, unless as stated. In Latin America, as
elsewhere, the livestock populations are a good index of the usage of antimicrobials.
Thus, Brazil is by far the greatest user at 1,200 tonnes of a.i. Next is Mexico at about
400 tonnes followed by Colombia and Peru at about 150 tonnes and 100 tonnes
respectively. Argentina and Venezuela are about 80 tonnes and 50 tonnes respectively,
whereas Chile has a lower rate of use at about 20 tonnes.
In Asia, values for China are at best an estimate but are in the range around 1,500
tonnes followed by Japan at 1,100 tonnes. The latter is probably an overestimate since
the prices of products to the end user are higher than most other countries due to the
distribution chain. The quantities for India and Pakistan are 400 tonnes and 200
tonnes respectively, followed by Malaysia and Bangladesh at 150 tonnes and 100
tonnes. Indonesia has a lower rate of use at about 20 tonnes.
Other countries in the Far East and Australasia include South Korea at 550 tonnes,
Thailand at 420 tonnes, Philippines at 350 tonnes and Taiwan at 180 tonnes. Australia
and New Zealand are about 200 tonnes and 50 tonnes respectively. Vietnam usage is
similar to New Zealand at about 50 tonnes.
Two surveys of usage of antimicrobials in Europe were conducted on behalf of the
animal health industry in 1997 and 1999. These data are shown in Table I.
Table I
European usage of antimicrobials 1997/1999
Year
Total tonnes a.i
Human use
Veterinary therapy
Growth promoter
1997
12,752
1999
13,152
7,659
60%
8,525
65%
3,494
27.5%
3,827
29%
1,599
12.5%
800
6%
Growth promoter usage has halved in the period but there is a disturbing trend for
increased use for veterinary therapy. The data from Denmark (3) show substantial
increase of use of therapeutics associated with increased disease in weaner pigs
following the withdrawal of growth promoters.
A recent survey in the US by the Animal Health Institute estimates a use for disease
prevention and treatment at 8,080t and for performance enhancement 1,200 tonnes.
Together these account for about one-third the total use of antimicrobials in the US
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2. Surveillance of antimicrobial consumption
when human use is considered. Animal usage in Canada is approximately 10% of that
in the USA.
In conclusion, the usage of antimicrobials for animal populations appears to be
around one-third the quantities used for humans. In general, these antimicrobials tend
to be those which are not widely used in man. Many, such as the tetracyclines, were
developed over fifty years ago and their potency is considerably less per unit of a.i.
compared with the modern antimicrobials used in man. This needs to be considered
when comparing quantities on a kg or tonne a.i.
The regulatory process for veterinary products includes risk assessment and
precautionary measures. A comment from the University of Harvard (1) is relevant in
this respect ‘Countries that do not invest in scientific enquiry are likely to misuse the
precautionary principle to unduly control or restrain technological change’.
IFAH worked with the World Veterinary Association and the International Federation
of Agricultural Producers in the late 1990s to produce a set of global principles for the
prudent use of antimicrobials in animals. It is encouraging that since then these have
been adopted by many regional and national agencies. Increasing populations,
particularly in developing countries, have a desperate need for adequate supplies of
healthy affordable food that can only be supplied from healthy animals.
References
1.
Anon. (2000). – World chemical news. University of Harvard.
2.
Anon. (2001). – IFAH Annual Report 2000. Wood Mackenzie.
3. DANMAP (2001). – Use of antimicrobial agents and occurrence of antimicrobial
resistance in bacteria from food animals, foods and humans in Denmark. DANMAP,
Cpenhagen, 68 pp.
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3.
Risk analysis
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3. Risk analysis
Antimicrobial resistance: risk analysis methodology
for the potential impact on public health of
antimicrobial resistant bacteria of animal origin
D. Vose (1), J. Acar (2), F. Anthony (3), A. Franklin (4), R. Gupta (5), †T. Nicholls (6),
Y. Tamura (7), S. Thompson (8), E.J. Threlfall (9), M. van Vuuren (10), D.G. White (11),
H.C. Wegener (12) & M.L. Costarrica (13)
(1)
David Vose Consulting, Le Bourg, 24400 Les Lèches, France
(2)
Université Pierre et Marie Curie, Service de Microbiologie Médicale, Fondation Hôpital Saint-Joseph, 185 rue
Raymond Losserand, 75674 Paris Cedex 14, France
(3)
Fresh Acre Veterinary Surgery, Flaggoners Green, Bromyard, Herefordshire HR7 4QR, United Kingdom
(4)
The National Veterinary Institute (SVA), Department of Antibiotics, SE 751 89 Uppsala, Sweden
(5)
College of Veterinary Sciences, Veterinary Bacteriology, Department of Microbiology, G.B. Pant University of
Agriculture and Technology, Pantnagar 263 145 Uttar Pradesh, India
(6)
National Offices of Animal and Plant Health and Food Safety, Animal Health Science and Emergency
Management Branch, Department of Agriculture, Fisheries and Forestry, P.O. Box 858, Canberra ACT 2601, Australia
(7)
National Veterinary Assay Laboratory, Ministry of Agriculture, Forestry and Fisheries, 1-51-1 Tolura,
Kokubunji, Tokyo 185-8511, Japan
(8)
Joint Institute for Food Safety Research, Department for Health and Human Services Liaison, 1400
Independence Avenue, SW, Mail Stop 2256, Washington, DC 20250-2256, United States of America
(9)
Public Health Laboratory Service (PHLS), Central Public Health Laboratory, Laboratory of Enteric Pathogens,
61 Collindale Avenue, London NW9 5HT, United Kingdom
(10) University of Pretoria, Faculty of Veterinary Science, Department of Veterinary Tropical Diseases, Private Bag
X04, Onderstepoort 0110, South Africa
(11) Centre for Veterinary Medicine, Food and Drug Administration, Office of Research, HFV-530, 8401 Muirkirk
Road, Laurel, Maryland 20708, United States of America
(12) World Health Organization, Detached National Expert, Division of Emerging and Transmissible Diseases,
Animal and Food-related Public Health Risks, 20 avenue Appia, 1211 Geneva, Switzerland
(13) Food and Agriculture Organization, Food Quality and Standards Service, Senior Officer, via delle Terme di
Caracalla, 00100 Rome, Italy
This report, prepared by the OIE Ad hoc Group of experts on antimicrobial resistance, has not yet received the
approval of the International Committee of the OIE
Summary
The Ad hoc Group of experts on antimicrobial resistance, appointed by the OIE (World
organisation for animal health), has developed an objective, transparent and defensible risk analysis
process, providing a valid basis for risk management decisions in respect to antimicrobial resistance.
The components of risk analysis and of different possible approaches in risk assessment (qualitative,
semi-quantitative and quantitative) are defined. The Ad hoc Group recommended the following: an
independent risk assessment based on scientific data; an iterative risk analysis process; a qualitative
risk assessment systematically undertaken before considering a quantitative approach; the
establishment of a risk assessment policy; and the availability of technical assistance for developing
countries.
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3. Risk analysis
Keywords
Antimicrobial resistance – Containment of resistance – Food – Human medicine –
International standards – Public health – Risk analysis – Risk assessment – Risk
management – Veterinary medicine.
Introduction
This document presents the concept of risk analysis, comprising the components of
hazard identification, risk assessment, risk management and risk communication, as
applicable to antimicrobial resistance. The inter-relationship of these components is
described and the respective distinct responsibilities of risk assessors and risk
managers are identified. An example of a risk analysis methodology is given both in
relation to animal health and to human health.
Background
Use of antimicrobials in animals for therapeutic, preventative and growth promotion
purposes can reduce the therapeutic value of antimicrobials used in animal and human
medicine because of losses in susceptibility of pathogenic bacteria. This risk may be
represented by the loss of therapeutic value of one or several antimicrobial drugs and
includes the emergence of multi-resistant bacteria.
The principal aim of risk analysis of antimicrobial resistance in bacteria from animals
is to provide Member Countries of the OIE (World organisation for animal health)
with an objective and defensible method of assessing and managing the human and
animal health risks associated with the development of resistance due to the use of
antimicrobial drugs in animals, including appropriate communication measures. The
procedure should be transparent and clearly separate responsibilities in risk assessment
and risk management. Risk assessment should be based on the available scientific data.
Transparency is essential because data are often uncertain or incomplete, and without
full documentation, the distinction between facts and value judgements may not be
clear. Risk management should also be a structured approach so that all stakeholders
(for example, agricultural and pharmaceutical industries, healthcare providers and
consumer groups) are provided with clear reasons for the imposition of risk
management controls (for example, on the animal use of the antimicrobial in question,
more stringent slaughtering or processing requirements, or import restrictions on
products from animals that have been treated with antimicrobials).
A policy framework for the authority regulating antimicrobials should be established
to provide risk managers and risk assessors with a consistent set of legal, regulatory
and political rules within which risk analyses must be conducted.
This Guideline explains the recommendations of the OIE Ad hoc Group on
antimicrobial resistance for guidelines and principles for conducting transparent,
objective and defensible risk analyses to control the impact of using antimicrobials in
animals, and provides recommended definitions of terms used in risk analysis.
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Two principal sets of terminology are currently in use in risk analysis relating to this
topic, namely: the United States (US) National Academy of Science (NAS) system on
which the Codex Alimentarius Commission (Codex) approach is based, developed for
food safety issues, and the Covello-Merkhofer system on which the OIE International
Animal Health Code risk analysis is based. Beyond their apparent differences, both
systems are very similar and largely contain the same components. The way these
components are ordered in each of these two systems has evolved because of the type
of risks that are being addressed. The terminology presented in this document follows
the Covello-Merkhofer system. Comparison between the two systems and definitions
of terms are given in Appendix C.
The risk analysis process
Risk analysis is defined in the OIE Code as ‘The process composed of hazard
identification, risk assessment, risk management and risk communication’. It is a term
frequently used to describe the complete process of properly addressing a risk issue. It
encompasses assessing and managing the risk together with all the appropriate
communication between risk assessors, stakeholders and risk managers. A typical risk
analysis proceeds as detailed below.
a) A policy framework will previously have been established by risk managers that
describes the types of risk that need to be addressed, implying, among other things,
the ranking of these risks among the other risk issues. In consultation with technical
experts and risk assessors, a strategy for the assessment of the risk is then formulated.
The policy framework also provides an explanation of the type of risk management
options that can be considered under the legislative and regulatory framework of the
country. Finally, the policy framework should explain the risk decision-making
process, including methods of evaluating and quantifying risks and the level of risk
deemed to be acceptable.
b) A risk issue and plausible risk management actions that could be taken to reduce
or eliminate the risk are identified by management.
c) In consultation with technical experts, risk assessors and other stakeholders, a
strategy for a preliminary assessment of the risk is formulated, including precisely how
the risk is to be evaluated.
d) Risk assessors execute a preliminary qualitative assessment (scoping study) and
advise management on the feasibility of assessing quantitatively the risk and on the
identified risk management strategies. This report is made public.
e) Managers will determine from this scoping study whether the risk is sufficiently
severe to warrant further action, including whether resources (which could be very
limited) can be dedicated to the issue. If the risk is considered sufficiently important,
and if feasible, risk managers may then instruct risk assessors to fully assess the risk
(qualitatively, and/or quantitatively) and the reduced level of risk that would exist after
each identified risk reduction option. Refining of the risk reduction options and risk
assessment may go through several iterations.
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3. Risk analysis
f) The risk assessment may be presented for review at various stages until the final
risk assessment report has been produced, which is then made public. This aspect of
risk communication is particularly helpful in ensuring transparency of the risk analysis
as a whole and the efficient collection of data.
g) Risk managers use the results of the risk assessment in order to determine, in line
with previously defined policy, the appropriate actions to take in order to manage the
risk in question in the most efficient manner.
h) The risk management decision by a regulatory authority is made public with the
greatest possible clarity.
i) The risk managers have to implement their decision and to organise the followup of these regulatory and other measures in order to evaluate the impact of these
decisions with regard to the expected results.
j) The data acquired by the follow-up must be assessed in order to allow a possible
amendment of the risk analysis policy, of the assessment strategy, of the outcome of
the scientific assessment, and of the regulatory and other actions that have been taken.
The following sections elaborate on these stages, categorised into four parts according
to the Covello-Merkhofer system. References refer to where in the above bullet points
each stage appears:
– hazard identification (b)
– risk assessment (c, d, e, f)
– risk management (b, g, i, j)
– risk communication (c, d, f, h).
Hazard identification
Hazard identification is defined under the OIE system as ‘The process of identifying
the pathogenic agents that could potentially be introduced in the Commodity
considered for importation’. It is the identification of ‘risk agents’ (hazards) and the
conditions under which they might potentially produce adverse consequences. In
terms of risk issues related to antimicrobial-resistant bacteria, the risk agent is most
generally represented by the resistance determinant that emerges as a result of the use
of a specific antimicrobial in animals. This definition then reflects the development of
resistance in a species of bacterium that is pathogenic, as well as the development of a
resistance determinant that may be passed to other bacteria that are pathogenic. The
conditions under which the risk agent might potentially produce adverse
consequences include any feasible scenarios via which humans or animals become
exposed to pathogens which contain that resistance determinant, fall ill and where the
human or animal would be treated with an antimicrobial that is no longer effective
because of the resistance.
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Risk management
Risk management policy
Risk management policy is a new term defined as ‘The regulatory policy framework
for monitoring, measuring, assessing and managing risks involved in the use of
antimicrobials in food producing animals’. A critical precursor to the risk analysis
process is the development and public explanation of such a policy framework. This
framework, aimed at providing the guidelines for conducting an appropriate risk
assessment, has to be developed by the risk managers with the technical support of
the scientific experts in charge of the risk assessment.
The policy framework explains the philosophy behind monitoring and controlling
risks involved in the use of antimicrobials in food producing animals. It must explain
methods for involving risk assessment in the approval of new drug use, the various
restrictions of use that might be applied to control and reduce any adverse impact and
the procedure for retracting approval of use of the drug. It must also explain how the
human or animal impact due to resistance will be measured, what level of impact will
be considered unacceptable and how this information is used in the registration of
new drugs.
The policy framework may also address the additional importance of certain
antimicrobial drugs needed to treat infectious diseases in human medicine for which
there are no effective alternative therapies. Furthermore, it should explain the range of
risk reduction actions that management can select within legislative and regulatory
restrictions.
The framework should explain the impact of uncertainty on the risk management
decision. It should also address what actions will be taken in the event of identifying
an unquantifiable risk due to antimicrobial use.
The establishment of a population of resistant bacteria as a result of the use of an
antimicrobial in animals means that the human or animal health impact may continue
long after the animal use of an antimicrobial has ceased. The policy framework should
therefore address how to measure a long-term impact, and may include some cut-off
period or discount factor that recognises the reduced value of a therapeutic drug as
new drugs become available.
However, the policy framework should not necessarily restrict risk management from
considering potential risk management options that may be outside the current
domain of the regulatory authority. Clear explanation of these conditions allows the
pharmaceutical and agricultural industries and the veterinary and healthcare
professional bodies to plan and test current and future antimicrobial products in a
predictable environment and modify their use to achieve clear objectives.
Clearly stating the policy framework ensures transparency during the risk management
phase of a risk analysis. People react to risk in very different and often emotional
ways: a clear policy on how to measure risk and what is deemed acceptable implicitly
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recognises that a zero risk policy is unachievable and greatly reduces any suspicion of
false argument.
Risk management components
Risk management is conducted by risk managers who have a comprehensive
understanding of policy, and an appropriate level of technical background to
communicate effectively with the risk assessors. The OIE defines risk management as
consisting of the steps described below.
Risk evaluation
The process of comparing the risk estimated in the risk assessment with the
appropriate level of protection of the Member Country.
Option evaluation
The process of identifying, evaluating the efficiency and feasibility of, and selecting
measures in order to reduce the risk associated with an importation in line with the
appropriate level of protection of the Member Country. The efficacy is the degree to
which an option reduces the likelihood and/or magnitude of adverse biological and
economic consequences. Evaluating the efficacy of the options selected is an iterative
process that involves their incorporation into the risk assessment followed by
comparison of the resulting level of risk with that considered acceptable. The
evaluation for feasibility normally focuses on technical, operational and economic
factors affecting the implementation of the risk management options.
Implementation
The process of following through with the risk management decision and ensuring
that the risk management measures are in place.
Monitoring and review
The ongoing process by which the risk management measures are continually audited
to ensure that they are achieving the results intended.
Risk decision when data are insufficient or inadequate
In the event that insufficient or inadequate data are available to reasonably assess the
importance of a potential risk issue, and it is considered that the risk is potentially of
such severity that one cannot wait for sufficient data before taking action, it is
reasonable for the risk managers to take a temporary risk avoidance action that
minimises any exposure to the risk. There are five extremely important considerations
when faced with this situation, as follows:
a) a risk assessment must first be attempted, and all reasonable efforts made to
acquire the necessary data, within the allowable timeframe, before taking the
temporary risk avoidance action
b) the risk avoidance action must be chosen to provide the required level of
protection in the manner least restrictive to trade
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c) the risk avoidance action should be commensurate with the potential severity of
the risk
d) in all cases, particularly in international trade, the risk avoidance action should be
taken in conjunction with a commitment to acquire the necessary data, within a
reasonably short and defined time, to help assess the severity of the risk and the most
appropriate risk reduction strategy
e) the process must remain transparent.
Risk assessment
Risk assessment is defined in the OIE Code as ‘The evaluation of the likelihood and
the biological and economic consequences of entry, establishment, or spread of a
pathogenic agent within the territory of an importing country’. There are a number of
approaches to assessing the magnitude of a risk and the value of potential risk
reduction options. These can be broadly categorised into three types: qualitative, semiquantitative and quantitative risk assessments. Whichever approach is taken, the risk
assessment must be designed to address the specific question posed by the risk
managers.
The risk assessment process is usually sub-divided into four components: risk release
assessment; exposure assessment; consequence assessment; and risk estimation. Their
meanings are described below and examples of factors that may be considered in each
component are listed in Appendices A and B.
Release assessment
Defined in the OIE Code as ‘Description of the biological pathways necessary for the
use of an antimicrobial in animals to release resistant bacteria or resistance
determinants into a particular environment, and estimating the probability of that
complete process occurring either qualitatively or quantitatively’.
Exposure assessment
Defined in the OIE Code as ‘Describing the biological pathways necessary for
exposure of animals and humans to the hazards released from a given source, and
estimating the probability of the exposure occurring, either qualitatively or
quantitatively’.
Consequence assessment
Defined in the OIE Code as ‘Description of the relationship between specified
exposures to a biological agent and the consequences of those exposures. A causal
process must exist by which exposures produce adverse health or environmental
consequences, which may in turn lead to socio-economic consequences. The
consequence assessment describes the potential consequences of a given exposure and
estimates the probability of them occurring. This estimate may be either qualitative or
quantitative’.
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Risk estimation
Defined in the OIE Code as ‘Integration of the results from the release assessment,
exposure assessment, and consequence assessment to produce overall measures of
risks associated with the hazards identified at the outset. Thus risk estimation takes
into account the whole of the risk pathway from hazard identified to unwanted
outcome’.
The policy framework will provide guidelines to the risk assessors on how to assess
the complete impact of any risk issue and risk reduction strategies. For example,
removing an antimicrobial from veterinary use may mean that another antimicrobial is
used in its place with potentially worse consequences. Unless these secondary impacts,
whether positive or negative, are addressed, the risk management strategy may be suboptimal.
The initial planning stages of a risk assessment can be performed as described below.
a) The risk issue in question is formally expressed to ensure that all participants
agree on the problem to be addressed. The potential mechanisms and pathways via
which the hazard can result in an adverse effect are also described. This system, as
understood by the risk assessment team, can be explained using one or more flow
diagrams. At this point, the diagram is purely conceptual and there is therefore no
need for data. The purpose of such diagrams is to focus thought on what data would
be useful, what possible risk management options exist, and to integrate and review
the level of knowledge about the system in general. It is advisable to involve a broad
participation in the exercise and to circulate widely to stakeholders and relevant
experts.
b) A preliminary data search is conducted to assess what components of the system
might be adequately quantified. Components might include, for example: the
prevalence of resistant bacteria in faeces, water or carcasses; the distribution by animal
species, season and geographical region of use of an antimicrobial; the frequency of
the use of the antimicrobial in human medicine and the health status of those
receiving the antimicrobial. At this stage, it is sufficient to know of the availability of
data. Requests for data that might help quantify the components of the system can
also be made to stakeholders and relevant experts. Strong consideration should also be
given to useful data that may not be immediately available, but that could become
available within a reasonable period, perhaps with some research effort. The
interpretation of what constitutes a reasonable period will reflect the imminence and
severity of the risk issue in question. It may be appropriate to consider completing a
risk assessment rapidly to help decision makers identify the immediate actions to be
taken, recognising that a re-evaluation of the risk issue when more data become
available may lead the decision makers to alter the preliminary actions that were taken.
c) A review of the system, as perceived by the risk assessment team, together with
the data available to quantify the components of that system can provide important
guidance. It can illustrate which risk management options can be properly assessed for
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their effectiveness. It can also guide the risk assessor regarding the production of a
quantitative risk assessment, if required, that would be based on data as well as
supplying guidance as to whether such a model could be validated in some way. It is
the combination of feasible risk management options, together with the data that
could be available to assess those options, that should direct the risk assessment team
towards the form of their assessment. If the system is not sufficiently well understood,
or insufficient data are available to meaningfully quantify the model, it may only be
possible to produce a qualitative risk analysis. However, quantification of certain
aspects of the system may also be possible, which could enable the evaluation of a
restricted number of risk management options. The risk assessment model can be
kept as simple as possible to support the range of risk management decisions being
considered. The model structure may not include a complete pathway analysis of the
risk scenario if there are limited risk reduction strategies the benefits of which can be
addressed in a far simpler model. Flexibility in the approach to modelling will reduce
the effort required to produce the assessment and limit the number and type of
assumptions that may have to be made in the model. However, the model may not
then be useful in addressing other questions that arise over the same risk issue and
may not help other stakeholders contribute to efficiently managing the risk. It may
also be difficult to demonstrate consistency between models where different model
structures have been used together with quite different assumptions.
A full assessment of the risk to human and animal health from antimicrobial-resistant
bacteria resulting from use of antimicrobials in food-producing animals can be divided
into three parts, as follows:
a) production of the resistant bacteria of interest as a result of antimicrobial use, or
more particularly, production of the resistant determinants if transmission is possible
between bacteria. (If it is the use of the antimicrobial in animals that is being
considered as the hazard, there may be several different species of bacteria to
consider.)
b) consideration of the realistic pathways via which humans can become exposed to
these resistant bacteria or resistance determinants, together with the possible range of
bacterial load ingested at the moment of exposure
c) consideration of the response of the person to the exposure.
Risk assessment of antimicrobial issues can be technically difficult, and it is essential
that the assessment is the work of a team of professionals with broad expertise in risk
analysis modelling, microbiology, veterinary medicine and animal husbandry, human
healthcare and medicine, chemistry and any other relevant disciplines. Published
chemical, microbial and genetic risk assessments can provide useful generic
illustrations for modelling components of the risk assessment.
Qualitative risk assessment
Qualitative risk assessment is defined in the OIE Code as ‘An assessment where the
outputs on the likelihood of the outcome or the magnitude of the consequence are
expressed in qualitative terms such as high, medium, low or negligible’. A qualitative
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risk assessment is always completed first as part of a preliminary evaluation (scoping
study), whether or not one progresses to a semi-quantitative or fully quantitative
assessment. It is the collation of all available information that will enable the
determination of the probability and impact of the risk in question. A qualitative risk
assessment discusses the steps necessary for the risk to occur, which pathways are
feasible and which can be logically discounted. In a risk assessment of a human health
impact due to use of a specific antimicrobial in food producing animals, for example,
factors would include patterns of use of the antimicrobial, rates of resistance
acquisition in exposed bacteria, the ecology of these resistant bacteria, pathways via
which these bacteria may directly or indirectly transfer resistance to pathogens that
infect humans, and the rates at which antimicrobials analogue to the animal
antimicrobial are prescribed for the infected humans.
A qualitative risk assessment would also need to discuss the level of loss of benefit of
the human medicine antimicrobial. All of these factors constitute a risk scenario on
which one can overlay possible risk reduction strategies and discuss the benefits they
might provide. Appendices A and B list factors that may be useful in an assessment.
At this stage, a risk may be determined to be logically insignificant because, for
example, the biological pathway is not possible or the risk is logically less severe than
another for which a full analysis has been completed and determined to be acceptably
small. As more risk assessments are conducted on antimicrobial issues, there may be
broad agreement concerning the likely risks associated with particular hazards. In such
cases, a qualitative assessment may frequently be the sole requirement. Qualitative
assessment does not require mathematical modelling skills and so will often be the
type of assessment used for routine decision-making.
When all easily-obtainable information has been collected, a preliminary report to the
risk managers is necessary to advise of any further information that will be needed to
complete the picture, or perhaps any additional information that will be necessary to
complete a more quantitative analysis. It should also be apparent at this stage whether
data are or can be made available to assess each risk reduction strategy and
communicating this to the risk managers enables them to assess which risk reduction
strategies are worth pursuing in greater depth.
Quantitative risk assessment
Quantitative risk assessment is defined in the OIE Code as ‘An assessment where the
outputs of the risk assessment are expressed numerically’. The purpose of quantitative
risk assessment is to numerically evaluate the probability and impact(s) associated with
a risk issue. Two principal mathematical approaches are feasible: the most common is
to use a Monte Carlo simulation model to describe the risk event (the development of
the hazard into an actual impact), together with its uncertainty (lack of knowledge)
and variability (inherent randomness); the second method is to use the algebra of
probability theory to produce a formulaic model of the risk event. Monte Carlo
simulation is almost always preferred over algebraic methods because it is far simpler
to execute, particularly with modern software. It offers greater modelling flexibility, is
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easy to understand, check and explain, and less prone to human error in model
development. However, Monte Carlo simulation of rare events can become onerous,
in which case a combination of calculating some simpler parts of a risk scenario and
simulating the remainder may sometimes prove more efficient.
A quantitative risk assessment produces a mathematical model that estimates the
effect of possible risk management actions. It may be desired that any possible action
between and including production of the food animal and the final human health
effect be evaluated quantitatively. If so, the quantitative risk assessment model must
simulate all important microbial pathways between the farm and the exposed human
or animal in sufficient detail to evaluate possible changes in the system as a result of a
risk management action. For risk management purposes, it may only be necessary to
evaluate changes in the human or animal health impact as a result of a risk
management action, not the underlying base health risk, although it may be
informative to be able to estimate the base health risk for other purposes.
Thus, a full risk assessment model may need to consider a wide range of pathways.
For example, Enterococcus faecium is a hardy organism that can survive for long periods
outside its original host. Feasible pathways may include, for example, runoff from
manure lagoons or fields sprayed with manure entering waterways used by swimmers,
or the consumption of vegetables that have been grown in fields sprayed with manure.
By contrast, these pathways would not be important for Campylobacter which succumb
rapidly to changes in their environment. Failure to appreciate the range of
pathwayscould lead to a misevaluation of the effect of some risk management action.
For example, irradiation of poultry carcasses may be effective against Campylobacter if
consumption of meat were to be considered the primary exposure pathway. However,
irradiation might prove ineffective for E. faecium if the primary exposure pathway was
from consumption of raw vegetables.
Microbial food safety risk assessments have for some time attempted to model very
similar risk issues to those posed by antimicrobial resistance. A variety of modelling
techniques exists for microbial risk assessments, based around the principles of
stochastic simulation of risk scenarios (14, 18, 19, 22). Spreadsheet models are
generally used together with Monte Carlo simulation add-ins to create simulations of
the entire ‘farm-to-fork’ continuum, finishing with the way in which the consumer is
affected by consumption of the bacteria. Other commercially available dynamic
simulation applications can achieve much the same effect. There are a variety of
formula-based models available from the field of predictive microbiology to estimate
the growth and attenuation of various bacteria when exposed for different amounts of
time to different environments, particularly level of moisture, temperature and pH.
Thus, a quantitative risk assessment combines probability mathematics (11, 17),
usually from the binomial and Poisson processes, with empirical curve-fitting
equations and sometimes theoretically based formulae from predictive microbiology,
to attempt to characterise the exposure events. Microbial food safety models consider
the redistribution, growth and attenuation of bacteria during the various actions in
slaughtering, processing, food handling and cooking. For example, the microbial load
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3. Risk analysis
on contaminated carcasses will be reduced drastically through correct handling,
removal of the most contaminated parts of the carcass, scalding and washing. In
contrast, cross-contamination between carcasses through aerosols, splashing, workers,
etc., may mean that the proportion of contaminated carcasses leaving the slaughter
plant is greater than the proportion of contaminated animals entering the plant. Much
of the modelling principles necessary in antimicrobial resistance risk assessment
parallel those used in microbial food safety risk assessment. At the time of writing
(November 2000), very few antimicrobial resistance risk assessments have been
published (http://www.fda.gov/cvm/fda/mappgs/antitoc.html; 23) but a significant
number of microbial food safety risk assessments have been completed which provide
practical
illustrations
of
the
techniques
employed
(2,
8;
http://www.fsis.usda.gov/ophs/risk/index.htm;
http://www.foodriskclearinghouse.umd.edu/risk_assessments.htm;
http://www.fsis.usda.gov/OPHS/ecolrisk/home.htm;
http://www.nal.usda.gov/fnic/foodborne/risk.htm).
Microbial risk assessments typically use logarithmic scales in estimating the microbial
load because of the range of numbers that can be involved and the multiplying nature
of bacterial growth and attenuation. Subsequent estimations of the probability of
infection, illness or perhaps death from specific exposures are made through doseresponse equations to produce a final estimate of the total human health impact. Risk
assessments that model the complete microbial pathway from the farm to final
ingestion are sometimes called ‘farm-to-fork’ or ‘farm-to-table’ risk assessments,
though these are potentially misleading terms in cases where significant exposure
pathways are associated with ingestion via other means (e.g. consumption of
vegetables, ingestion through soil or water, and human-to-human or animal-to-human
transmission). A full ‘farm-to-fork’ model invariably contains a host of potentially
contestable assumptions because of the inherent complexity of the system being
modelled and the gaps in knowledge of that system. It also relies a great deal on the
validity of a dose-response model, the weaknesses of which are well known (21).
In general, a risk assessment model should only be as complex as necessary to evaluate
the risk management options available to the regulatory authority, therefore a full
‘farm-to-fork’ model may not be necessary. For example, the risk assessment
completed by the United States Food and Drug Administration Center for Veterinary
Medicine (USFDA-CVM) on the human health effect of fluoroquinolone-resistant
Campylobacter (http://www.fda.gov/cvm/fda/mappgs/antitoc.html) considered only
the effect of removal of fluoroquinolone use in poultry. This assessment avoided any
modelling of the ‘farm-to-fork’ pathways. It estimated the number of human cases of
campylobacteriosis that would have been affected by the fluoroquinolone-resistance
from poultry, to provide an estimate of the current risk. The argument was that
removing fluoroquinolone from poultry would have the effect of reducing the human
impact by this amount, which was supported by the low survivability of Campylobacter
outside its host, so resistance would rapidly disappear. The assessment then related
this risk to the level of prevalence of fluoroquinolone-resistant Campylobacter
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contaminated broiler carcasses at the end of the slaughter plant. The argument then
presented was that changes in that prevalence and/or the load on the contaminated
carcasses can be mapped to a corresponding change in the human health impact. The
structure of models like this can be used very effectively in other countries, using data
appropriate to that country, where similar assumptions would apply.
All parameters in a quantitative risk assessment model must be quantified. The most
transparent approach, least likely to attract criticism, is to use published data from
peer-reviewed papers. However, such data will frequently not be available and
reasonable surrogates may be used in their place, together with supporting arguments
for the surrogacy. Expert opinion may also be used, but it is more transparent if any
data from which the expert has based his or her opinion can be used in its place (12).
Unpublished data from reliable sources may also be used. Regardless of the source, all
data used in the risk assessment must be critically reviewed.
A quantitative risk assessment must explicitly model the uncertainty associated with
the model parameters using techniques like the bootstrap (5, 6), Bayesian inference (9,
20) and classical statistics (1, 10, 13). Bayesian inference is particularly useful at
explicitly stating the contribution arising from observations, interpretation of those
observations and any subjective estimation. Bayesian inference also allows the analyst
to combine information from different sources, such as two different random surveys
of a population for contamination with different test sensitivities and specificities.
The results of the risk assessment are presented as a report to the risk managers,
explaining the methods used, characterising the risk in appropriate terms according to
policy, together with the benefits of any risk reduction strategies that could be
assessed. All quantified terms should be reported with their uncertainties in an easily
understandable form. The relative frequency distribution provides an excellent visual
representation of the level of uncertainty, whilst cumulative distribution plots allow
the risk manager to evaluate the risk at any desired level of confidence. Sensitivity
analyses should be performed to determine the key uncertainty parameters of the
model and illustrated using techniques such as spider plots and tornado charts. Key
assumptions must also be explicitly described, together with a balanced argument of
the reasoning for the assumptions and a discussion of the inaccuracy of the
predictions of the model should those assumptions be false. This model uncertainty
must be keenly analysed, and possible methods of validating assumptions must be
considered, perhaps through scientific experiments or comparison with the experience
of other nations. Inclusion and discussion of all types of uncertainty in the risk
assessment report allow the risk managers to apply the appropriate level of
conservatism in valuing the risk and any risk reduction options. It should be
emphasised that failure to properly address uncertainty in the risk assessment report
equates to an implicit value judgement of the risk that is not the remit of the risk
assessor.
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Semi-quantitative risk assessment
Semi-quantitative risk assessment is a new term defined as ‘An assessment where
estimates of the likelihood of the outcome and the magnitude of the consequences are
expressed in semi-quantitative terms via some scoring mechanism’. It will frequently
not be possible to perform a complete quantitative risk assessment on each item in a
portfolio of risk issues facing risk managers because of lack of appropriate data. In
such circumstances, it would nonetheless be useful to have a method for comparing
the magnitude of risks and the benefits of risk reduction strategies for those risks.
Semi-quantitative risk assessment, when properly executed, is a transparent approach
that supports the efficient management of a portfolio of risk issues without requiring
complete quantification of the risks or excessive risk avoidance. Semi-quantitative risk
assessment techniques are commonly used for risk analysis in commercial projects,
but are currently not widely accepted in international risk issues because of the
difficulty in retaining transparency and because the process is open to abuse without
proper guidelines.
The principle of semi-quantitative risk assessment (22) is initially to estimate the
probability and size of the potential consequences into broad, but well-defined
categories, then convert these estimates using a scoring system to produce a severity
score for the risk. Various risk management options can be evaluated according to the
degree to which they would reduce the severity score of the risk. The technique has a
number of advantages, as follows:
– the risks can be compared in a systematic fashion
– a severity threshold can be set for unacceptable risk
– an efficient and consistent policy framework can be developed which minimises
the total severity scores for all risks given the resources available.
Risk communication
As defined in the OIE Code, ‘Risk communication is the interactive exchange of
information on risk among risk assessors, risk managers and other interested parties’.
There are many aspects to risk communication. Failure to pay proper attention to risk
communication may easily result in failure of the risk analysis process. Both risk
managers and risk assessors should be well versed in the concepts of risk analysis. The
risk assessors should have a clear understanding of policy. Similarly, the risk managers
should be fully conversant with the taxonomy and terminology of risk assessment and
appreciate the level of effort and variety of disciplines involved in producing a reliable
risk assessment. The goals of risk communication are the following:
– to promote awareness and understanding of the specific issues under
consideration during the risk analysis process, by all participants
– to promote consistency and transparency in arriving at and implementing risk
management decisions
– to provide a sound basis for understanding the risk management decisions
proposed or implemented
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– to improve the overall effectiveness and efficiency of the risk analysis process
– to strengthen working relationships and mutual respect among all participants
– to promote the appropriate involvement of all stakeholders in the risk
communication process
– to exchange information on the knowledge, attitudes, values, practices and
perceptions of stakeholders concerning the risks in question.
The joint Food and Agriculture Organization (FAO)/World Health Organization
(WHO) Expert Consultation on the application of risk communication to food
standards and safety measures, held in 1998 in Rome, provides an in-depth discussion
on the subject (7).
Communication between assessors and managers
Management must provide clear instructions for the risk issue that is to be analysed,
together with the preferred method(s) of characterisation (e.g. person days of illness
per year). Assessors must ensure that the managers have reasonable expectations of
the assessment and may also advise of other potential information the assessment may
provide that would help the management with their decision-making. There should be
communication between the risk assessors and risk managers throughout the
assessment process to ensure that the assessment is completed in a timely fashion and
that the required resources are made available.
Communication between assessors and stakeholders
It is extremely helpful to widely publicise the intended method of assessment,
including model structure and assumptions at the earliest possible opportunity,
together with an expression of flexibility in the eventuality of any new information or
ideas. This allows stakeholders to provide input, improves transparency of the process
and improves support for the assessment and any resultant risk management decision.
Communication between managers and stakeholders
Risk managers will usually need to advise stakeholders of the intention to perform a
risk analysis at the beginning of the project. At this stage, communication with
stakeholders is an important opportunity to gather political and scientific support for
the risk assessment, as well as a data gathering exercise. When the risk assessment has
been completed, it is advisable to make the report publicly available with a reasonable
comment period to ensure that there are no large errors in the assessment or
additional data available. The World Wide Web is an excellent means for maximising
the availability of the assessment and may include downloadable, self-contained
versions of the risk assessment. Publishing comments received, together with any
responses from the risk assessment and risk management teams, underlines the
transparency of the process. These can be included in the final risk analysis document
that explains the results of the risk assessment together with the risk management
decision that has been made.
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3. Risk analysis
Recommendations
To effectively manage antimicrobial resistance risk issues, the OIE Ad hoc Group
recommends that:
– risk analysis should be conducted in an objective and defensible manner
– the risk analysis process should be transparent and consistent
– risk analysis should be conducted as an iterative and continuous process
– risk management and risk assessment functions should be kept separate to ensure
the independence of decision-making and evaluation of the risk
– risk management should be conducted in reference to a policy framework setting
out the domain of the regulator and the range of risk reduction actions that may be
considered
– the risk assessment should be based on sound science and conducted according
to a strategy established by the risk managers in co-operation with the risk assessors
– risk assessment requires a multidisciplinary team and should be conducted in
broad consultation with available scientific expertise
– qualitative risk assessment should always be undertaken, and provides
information on whether progression to full quantitative risk assessment is feasible
and/or necessary
– risk assessment of antimicrobial resistance issues requires very specific, technical
skills that may not be available to developing countries. The OIE and its Member
Countries should work towards helping these countries to develop or access these
skills, to ensure that risk assessment itself does not become a barrier to trade
– communication between managers, assessors and stakeholders is essential. Effort
should be made to establish such communication early in the process, to allow
opportunity for responses, and should be continued throughout the risk analysis
process.
Antibiorésistance : méthodologie d’analyse du risque
appliquée à l’impact potentiel sur la santé publique des
bactéries d’origine animale résistantes aux antibiotiques
D. Vose, J. Acar, F. Anthony, A. Franklin, R. Gupta, †T. Nicholls, Y. Tamura,
S. Thompson, E.J. Threlfall, M. van Vuuren, D.G. White, H.C. Wegener &
M.L. Costarrica
Résumé
Le Groupe ad hoc d’experts sur l’antibiorésistance créé par l’Organisation mondiale pour la santé
animale a élaboré une procédure d’analyse du risque à la fois objective, transparente et justifiée, offrant
une base valable pour les décisions de gestion du risque relatives à l’antibiorésistance. Les auteurs
définissent les éléments constitutifs de l’analyse du risque et les différentes approches possibles de
l’évaluation du risque (qualitative, semi-quantitative et quantitative). Les recommandations du
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3. Risk analysis
Groupe ad hoc portent sur les points suivants: évaluation du risque indépendante basée sur des
données scientifiques; processus itératif d’analyse du risque; réalisation systématique d’une évaluation
qualitative du risque avant toute approche quantitative; élaboration d’une politique d’évaluation du
risque; enfin, prestation d’une assistance technique pour les pays en développement.
Mots-clés
Analyse du risque – Antibiorésistance – Denrées alimentaires – Évaluation du risque –
Gestion du risque – Maîtrise de la résistance – Médecine humaine – Médecine
vétérinaire – Normes internationales – Santé publique.
Resistencia a los antimicrobianos: metodología de análisis de
riesgos para determinar la eventual incidencia en la salud
pública de bacterias de origen animal resistentes a los
antimicrobianos
D. Vose, J. Acar, F. Anthony, A. Franklin, R. Gupta, †T. Nicholls, Y. Tamura,
S. Thompson, E.J. Threlfall, M. van Vuuren, D.G. White, H.C. Wegener &
M.L. Costarrica
Resumen
El Grupo Ad hoc de expertos sobre la resistencia de las bacterias a los productos antimicrobianos,
creado por la Organización mundial de sanidad animal, ha elaborado un proceso de análisis de
riesgos objetivo, transparente y defendible, brindando con ello una sólida base para tomar decisiones de
gestión de riesgos ligados a la resistencia a los antimicrobianos. Los autores exponen los elementos que
configuran el análisis de riesgos y los distintos planteamientos que se pueden aplicar (cualitativo,
semicuantitativo y cuantitativo). El Grupo Ad hoc recomendó los siguientes procedimientos: una
evaluación de riesgos independiente y basada en datos científicos; un proceso iterativo de análisis de
riesgos; una evaluación cualitativa sistemática previa a la eventual aplicación de un método
cuantitativo; la definición de una política de evaluación de riesgos; y la prestación de asistencia técnica
a los países en desarrollo.
Palabras clave
Alimentos – Análisis de riesgos – Contención de las resistencias – Evaluación de
riesgos – Gestión de riesgos – Medicina humana – Medicina veterinaria – Normas
internacionales – Resistencia a los productos antimicrobianos – Salud pública.
Appendix A
Risk assessment of human health impact due to the use of
antimicrobials in animals
The following lists, although not exhaustive, describe factors that may need
consideration in a risk assessment of human health impact.
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3. Risk analysis
Definition of the risk
The infection of humans with bacteria that have acquired resistance to the use of a
specific antimicrobial in animals, and resulting in the loss of benefit of antimicrobial
therapy used to manage the human infection.
Hazard identification
Two types of hazard exist, as follows:
– bacteria that have acquired resistance due to the use of a particular antimicrobial
in animals
– resistance determinants selected as a result of the use of a particular antimicrobial
in animals.
The identification of the hazard must include considerations on the class or subclass
of antimicrobial.
Release assessment
Release assessment consists of describing the biological pathways necessary for the
use of a specific antimicrobial in animals to lead to the release of resistant bacteria or
resistant determinants into a particular environment, and estimating the probability of
that complete process occurring either qualitatively or quantitatively. The release
assessment describes the probability of the release of each of the potential hazards
under each specified set of conditions with respect to amounts and timing, and how
these might change as a result of various actions, events or measures. Examples of the
kind of inputs that may be required in the release assessment are as follows:
– species of animal treated with the antimicrobial in question
– number of animals treated, geographical distribution of those animals
– variation in methods of administration of the antimicrobial
– bacteria developing resistance as a result of the antimicrobial use
– mechanism of direct or indirect transfer of resistance
– capacity of resistance transfer (chromosomes, plasmids)
– cross-resistance and/or co-resistance with other antimicrobials
– surveillance of animals, animal products and waste products for the existence of
resistant bacteria.
Exposure assessment
Exposure assessment consists of describing the biological pathways necessary for
exposure of humans to the resistant bacteria or resistance determinants released from
a given antimicrobial use in animals, and estimating the probability of the exposures
occurring, either qualitatively or quantitatively. The probability of exposure to the
identified hazards is estimated for specified exposure conditions with respect to
amounts, timing, frequency, duration of exposure, routes of exposure and the number,
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3. Risk analysis
species and other characteristics of the human populations exposed. Examples of the
kind of inputs that may be required in the exposure assessment are as follows:
– human demographics and consumption patterns, including traditions and cultural
practices
– prevalence of food and/or the animal environment contaminated with resistant
bacteria
– prevalence of animal feed contaminated with resistant bacteria
– microbial load in contaminated food at the point of consumption
– survival capacity and redistribution of resistant bacteria during the agrofood
process (including slaughtering, processing, storage, transportation and retailing)
– disposal practices for waste products and the opportunity for human exposure to
resistant bacteria or resistance determinants in those waste products
– point of consumption of food derived from the food-producing animal
(professional catering, home cooking)
– variation in consumption and food-handling methods of sub-populations
– capacity of resistant bacteria to settle in human intestinal flora
– human-to-human transmission of the bacteria under consideration
– capacity of resistant bacteria to transfer resistance to human commensals
– exposure to resistance determinants from other sources
– amount of antimicrobials used in response to human illness
– dose, route of administration (oral, injection) and duration of human treatment
– pharmacokinetics (metabolism, bioavailability, access to intestinal flora).
Consequence assessment
Consequence assessment consists of describing the relationship between specified
exposures to resistant bacteria or resistance determinants and the consequences of
those exposures. A causal process must be believed to exist by which exposures
produce adverse health or environmental consequences, which may in turn lead to
socio-economic consequences. The consequence assessment describes the potential
consequences of a given exposure and estimates the probability of them occurring.
This estimate may be either qualitative or quantitative. Examples of consequences
include the following:
– dose-response relationships
– variation in susceptibility of sub-populations
– variation and frequency of human health effects resulting from loss of efficacy of
antimicrobials
– changes in human medicine practices resulting from reduced confidence in
antimicrobials
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3. Risk analysis
– changes in food consumption patterns due to loss of confidence in the safety of
food products and any associated secondary risks
– associated costs
– interference with a classical first line antibiotherapy in humans
– perceived future of the drug (time reference).
Risk estimation
Risk estimation consists of integrating the results from the release assessment,
exposure assessment and consequence assessment to produce overall measures of
risks associated with the hazards identified at the outset. Thus, risk estimation takes
into account the whole of the risk pathway from the hazard identified to the unwanted
outcome. For a quantitative assessment, the final outputs may include the following:
– number of people falling ill
– increased severity or duration of disease
– number of person/days of illness per year
– deaths (total per year; probability per year or lifetime for a random member of
the population or a member of a specific more exposed sub-population)
– importance of the pathology caused by the bacteria
– absence of alternate antibiotherapy
– level of resistance observed in humans
– some arbitrary scale of impact to allow weighted summation of different risk
impacts (e.g. illness and hospitalisation).
Risk management options to evaluate
The following risk management measures could be implemented:
– decision not to grant a licence for use of a new antimicrobial
– review of licence authorisation and label indications
– revoking of licence
– restrict use of antimicrobial (e.g. in particular industries, therapeutic only)
– review of prudent use guidelines
– establish monitoring of veterinary use of antimicrobials
– revision of treatment guidelines.
Appendix B
Risk assessment of impact on animal health due to the use of
antimicrobials in animals
The following lists, though not exhaustive, describe factors that may need
consideration in a risk assessment of animal health impact.
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3. Risk analysis
Definition of the risk
The infection of animals with bacteria that have gained resistance from the use of a
specific antimicrobial in animals, and resulting in the loss of benefit of antimicrobial
therapy used to manage the animal infection.
Hazard identification
Possible hazards are as follows:
– bacteria that have acquired resistance due to the use of a particular antimicrobial
in animals
– resistance determinants selected as a result of the use of a particular antimicrobial
in animals.
The identification of the hazard must include consideration of the class or subclass of
antimicrobial.
Release assessment
Examples of the type of inputs that may be required in the release assessment are as
follows:
– species of animal treated with the antimicrobial in question
– number of animals treated, geographical distribution of those animals
– variation in methods of administration of the antimicrobial
– bacteria developing resistance as a result of the antimicrobial use
– mechanism of direct or indirect transfer of resistance
– capacity of resistance transfer (chromosomes, plasmids)
– cross-resistance and/or co-resistance with other antimicrobials
– surveillance of animals, animal products and waste products for the existence of
resistant bacteria.
Exposure assessment
The following are examples of the type of inputs that may be required in the exposure
assessment:
– prevalence of resistant bacteria in ill animals
– prevalence of food and/or the animal environment contaminated with resistant
bacteria
– animal-to-animal transmission of the bacteria under consideration
– number/percentage of animals treated with the particular antimicrobial
– dissemination of resistant bacteria from animals (animal husbandry method,
movement of animals)
– prevalence of animal feed contaminated with resistant bacteria
– amount of antimicrobial used in animals
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3. Risk analysis
– treatment (dose, route of administration, duration)
– microbial load in contaminated food at point of consumption
– survival capacity of resistant bacteria (competition of mixed populations, survival
in the environment, contamination cycles including potentially the following elements:
animals, humans, animal feed, environment, food, non-food producing animals,
wildlife)
– dissemination of resistant bacteria and resistance determinants
– disposal practices for waste products and the opportunity for human exposure to
resistant bacteria or resistance determinants in those waste products
– capacity of resistant bacteria to become established in animal intestinal flora
– exposure to resistance determinants from other sources
– dose, route of administration (oral, injection) and duration of human treatment
– pharmacokinetics (metabolism, bioavailability, access to intestinal flora).
Consequence assessment
Examples of consequences include the following:
– dose-response relationships
– variation in susceptibility of sub-populations
– variation and frequency of animal health effects resulting from loss of efficacy of
antimicrobials
– changes in veterinary medicine practices resulting from reduced confidence in
antimicrobials
– associated costs
– perceived future of the drug (time reference).
Risk estimation
For a quantitative assessment, the final outputs may include the following:
– number of therapeutic failures due to resistant bacteria
– animal suffering (level and increase)
– economic cost (treatment with antibiotics, veterinary services, husbandry,
reduced income, loss of market)
– deaths (total per year; probability per year or lifetime for a random member of
the population or a member of a specific more exposed sub-population)
– level of resistance observed in animals.
Risk management options to evaluate
The following risk management measures could be implemented:
– decision not to grant a licence for use of a new antimicrobial
– review of licence authorisation and label indications
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3. Risk analysis
–
–
–
–
–
revoking of licence for antimicrobials already used
restrict use of antimicrobial (e.g. in particular industries, therapeutic only)
review of prudent use guidelines
establish monitoring of veterinary use of antimicrobials
revision of treatment guidelines.
Appendix C
Comparison of systems and terms used by the Codex Alimentarius and
the World Organisation for Animal Health
The terms used in this document comply with the OIE terminology, as defined in
Section 1.4. of the Code (16) based on the Covello-Merkhofer system (4). The Codex
Alimentarius (3) uses a different, but equally valid system, designed by the US NAS
(15). The issue of antimicrobial resistance arising from the use of antimicrobials in
food-producing animals bridges the domain of OIE for animal husbandry and that of
the FAO for food safety. It is therefore useful to compare these two systems and
define terms used in this paper, to help integrate the two approaches.
Two risk analysis terminology systems: description
Table I summarises the components of risk analysis in the OIE and Codex models.
Table I
The components of risk analysis: a comparison of the systems used by the
Codex Alimentarius and the OIE (World organisation for animal health)
Codex Alimentarius
Risk assessment
Risk management
Risk communication
Components of risk analysis system
OIE
Hazard identification
Risk assessment
Risk management
Risk communication
Table II summarises the components of risk assessment in the OIE and Codex
models.
In a system based on the NAS model (called the ‘Codex system’ here), there are only
three components of risk analysis, whereas in the system based on the CovelloMerkhofer model (called the ‘OIE system’ here), four components are present. Both
systems include risk assessment, risk management and risk communication as
components of risk analysis. However, the OIE system also includes hazard
identification as a component of risk analysis, whereas the Codex system includes
hazard identification as a sub-component of risk assessment. The terms risk
management and risk communication are equivalent under both systems.
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3. Risk analysis
Table II
The components of risk assessment: a comparison of the United States
Academy of Science model (used by Codex Alimentarius) and the CovelloMerkhofer model (used by the OIE [World Organisation for Animal Health])
Codex Alimentarius
Components of risk assessment model
OIE
Hazard identification
Hazard characterisation
Exposure assessment
Risk characterisation
Risk release assessment
Exposure assessment
Consequence assessment
Risk estimate
The NAS system was initially developed to assess the risks to health from exposure to
chemicals. Codex has adapted this system for food safety purposes. The CovelloMerkhofer system was initially developed to assess a wide range of risks from any
potential hazard. The specific wording of the explanations in Table III reflects those
differences.
Table III
Definition of risk analysis terms: a comparison of the systems used by the Codex Alimentarius
and the OIE (World organisation for animal health)
Term
OIE definition or equivalent
Codex Alimentarius definition or
equivalent
Acceptable risk
Risk level judged by Member Countries to be
compatible with the protection of animal and public
health within their country
No equivalent defined
Consequence
assessment
Definition of the relationship between specified
Codex equivalent: dose-response
exposures to a biological agent and the consequences of assessment
those exposures. A causal process must exist by which
exposures produce adverse health or environmental
consequences, which may in turn lead to socioeconomic consequences. The consequence assessment
describes the potential consequences of a given
exposure and estimates the probability of these
consequences occurring. This estimate may be either
qualitative or quantitative
OIE equivalent: consequence assessment
The determination of the relationship
between the magnitude of exposure
(dose) to a chemical, biological or
physical agent and the severity and/or
frequency of associated adverse health
effects (response) – see ‘hazard
characterization’
Describing the biological pathways necessary for
The qualitative and/or quantitative
exposure of animals and humans to the hazards
evaluation of the likely intake in
released from a given source, and estimating the
biological, chemical and physical agents
probability of the exposure occurring, either
via food as well as exposures from
qualitatively or quantitatively
other sources if relevant
…/…
Dose-response
assessment
Exposure
assessment
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Term
OIE definition or equivalent
Codex Alimentarius definition or
equivalent
Hazard
In the context of the Code, any pathogenic agent that
could produce adverse consequences on the
importation of a commodity
A biological, chemical or physical agent
in, or condition of, food with the
potential to cause an adverse health
effect
Hazard
characterisation
Embodied in the ‘consequence assessment’ in the OIE The qualitative and/or quantitative
system
evaluation of the nature of the adverse
health effects associated with biological,
chemical and physical agents that may
be present in food. For chemical
agents, a dose-response assessment
should be performed if the data are
obtainable
Hazard
The process of identifying the pathogenic agents which The identification of biological, chelical
identification
could potentially be introduced to the commodity
and physical agents capable of causing
considered for importation
adverse health affects and which may
be present in aparticular food or group
of foods
Implementation The process of following through with the risk
No equivalent defined
management decision and ensuring that the risk
management measures are in place
Monitoring and The ongoing process by which the risk management
No equivalent defined
review
measures are continually audited to ensure that they are
achieving the results intended
Option
The process of identifying, evaluating the efficiency and No equivalent defined
evaluation
feasibility of, and selecting measures in order to reduce
the risk associated with an importation in line with the
appropriate level of protection of the Member Country.
The efficacity is the degree to which an option reduces
the likelihood and/or magnitude of adverse biological
and economic consequences. Evaluating the efficacy of
the options selected is an iterative process that involves
their incorporation into the risk assessment and then
comparing the resulting level of risk with that
considered acceptable. The evaluation for feasibility
normally focuses on technical, operational and
economic factors affecting the implementation of the
risk management options
Qualitative risk An assessment in which the outputs on the likelihood No equivalent defined
assessment
of the outcome or the magnitude of the consequence
are expressed in qualitative termes such as high,
medium, low or negligible
Quantitative
An assessment in which the outputs of the risk
No equivalent defined
risk assessment assessment are expressed numerically
Release
Description of the biological pathways necessary for the No equivalent defined
assessment
use of an antimicrobial in animals to release resistant
bacteria or resistance determinants into a particular
environment, and estimation of the probability of that
complete process occurring, either qualitatively or
quantitatively
Risk
The likelihood of the occurrence and the likely
A function of the probability of an
magnitude of the consequences of an adverse event to adverse health effect and the severity of
animal or human health in the importing countryduring that effect, consequential to a hazard(s)
a specified time period
in food
…/…
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3. Risk analysis
Term
OIE definition or equivalent
Codex Alimentarius definition or
equivalent
Risk analysis
The process composed of hazard identification, risk
assessment, risk management and risk communication
A process consisting of three
components: risk assessment, risk
management and risk communication
Risk assessment The evaluation of the likelihood and the biological and
economic consequences of entry, establishment, or
spread of a pathogenic agent within the territory of an
importing country
Risk
characterisation
OIE equivalent: risk estimation
Risk
communication
Risk communication is the interactive exchange of
information on risk among risk assessors, risk managers
and others interested parties
Integration of the results from the release assessment,
exposure assessment and consequence assessment to
produce overall measures of risks associated with the
hazards identified at the outset. Thus, risk estimation
takes into account the entire risk pathway from the
hazrd identified to the unwanted outcome
The process of comparing the risk estimate in the risk
assessment with the appropriate level of protection of
the Member Country
Risk estimation
Risk evaluation
Risk
management
Sensitivity
analysis
Transparency
Uncertainty
Variability
158
The process of identifying, selecting and implementing
measures that can be applied to reduce the level of risk
The process of examining the impact of the variation in
individual model inputs on the model outputs in a
quantitative risk assessment
Comprehensive documentation of all data, information,
assumptions, methods, results, discussion and
conclusions used in the risk analysis. Conclusions
should be supported by an objective and logical
discussion and the document should be fully referenced
The lack of of precise knowledge of the input values
which is due to measurement error or the lack of
knowledge of the steps required, and the pathways
from hazrd to risk, when building the scenario being
assessed
A real-world complexity in which the value of an input
is not the same for each case due to natural diversity in
a given population
A scientifically based process consisting
of the following steps: (i) hazard
identification, (ii) hazard
characterisation, (iii) exposure
assessment and (iv) risk characterisation
The qualitative and/or quantitative
estimation, including attendant
uncertainties, of the probability of
occurrence and severity of known
population based on hazard
identification, hazard characterisation
and exposure assessment
Codex equivalent: risk characterisation
Embodied in ‘risk management’ in the
Codex system
The process, distinct from risk
assessment, of weighing policy
alternatives, in consultation with all
interested parties, considering risk
assessment and other factors relevant
for the health protection of consumers
and for the promotion of fair trade
practices, and if needed, selecting
appropriate prevention and control
options
No equivalent defined
No equivalent defined
No equivalent defined
No equivalent defined
OIE International Standards on Antimicrobial Resistance, 2003
3. Risk analysis
The first difference centres around the place of hazard identification in the models.
The initial report of the NAS model (15), describes hazard identification as a major
undertaking. The definition relates specifically to chemicals, and even in this case,
NAS indicates that it includes weighing the available evidence relevant to cause and
effect, as well as evidence relating to the magnitude of effect for the specified
chemical. It is essentially a qualitative process of considerable magnitude. Given the
number of potential pathogen hazards present in animals and animal products, the
OIE risk analysis system, with a separate hazard identification step, is more adapted to
pathogenic risk management.
The second difference is the presence in the OIE system of a step called release
assessment, absent in the Codex system. Covello and Merkhofer argue that this is
necessary for describing the probability of a given system (e.g. an industrial complex, a
meat processing plant or another risk source) to release risk agents into the
environment of interest. They believe this to be an essential step in obtaining an
accurate understanding of risk. From a practical standpoint, this is an essential explicit
step either to assess the risks due to a particular hazard from a specific source or
process, or to undertake a cost-benefit analysis of putting in place release reduction
safeguards for that source or process.
‘Release’ comes before the possibility of exposure in actual exposure events. Thus, the
Covello-Merkofer system follows release assessment by assessing the probability of
exposure for each potential exposure route of interest. The third difference between
the models is that the NAS system places exposure assessment after the dose response
(hazard characterisation) step. The precise definitions are also slightly different.
The fourth difference is in the place and meaning of consequences in the two models.
Exposure can then lead to consequences – unwanted consequences when considering
a hazard. Thus, the Covello-Merkhofer system places consequence assessment after
exposure assessment, and defines it broadly (any consequences that can occur can be
considered, and their probability assessed). However, the NAS system looks only at
the consequences of variation in dose of the chemical being considered (i.e. a doseresponse assessment, also called hazard characterisation).
Table IV
Definition of new terms introduced in this document
Term
Definition
Risk management policy The regulatory policy framework for the monitoring, measuring, assessing
and managing of risks involved in the use of antimicrobials in foodproducing animals
Semi-quantitative risk
An assessment where estimates of the likelihood of the outcome and the
assesment
magnitude of the consequences are expressed in semi-quantitative terms via a
scoring mechanism
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3. Risk analysis
References
1. Casella G. & Berger R.L. (1990). – Statistical inference. Brooks/Cole Publishing
Company, Pacific Grove, California, 650 pp.
2. Cassin M.H., Lammerding A.M., Todd E.C.D., Ross W. & McColl R.S. (1998). –
Quantitative risk assessment for Escherichia coli O157:H7 in ground beef hamburgers. Int. J.
Food Microbiol., 41 (1), 21-41.
3. Codex Alimentarius Commission (Codex) (1999). – Principles and guidelines for the
conduct of microbiological risk assessment, CAC/GL-30. Food and Agriculture Organization,
Rome, 6 pp. Website: ftp://ftp.fao.org/codex/standard/volume1b/en/GL_030e.pdf
(document accessed on 13 September 2001).
4. Covello V.T. & Merkhofer M.W. (1993). – Risk assessment methods: approaches for
assessing health and environmental risks. Plenum Press, New York and London, 334 pp.
5. Davison A.C. & Hinkley D.V. (1997). – Bootstrap methods and their applications.
Cambridge University Press, Cambridge, 582 pp.
6. Efron B. & Tibshirani R.J. (1993). – An introduction to the bootstrap. Chapman & Hall,
New York, 436 pp.
7. Food and Agriculture Organization (FAO) (1998). – The application of risk
communication to food standards and safety matters. Food and Nutrition Paper No. 70.
Report of a Joint FAO/World Health Organization Expert Consultation. FAO, Rome, 46 pp.
8. Food and Agriculture Organization (FAO) (2000). – Joint FAO/WHO Expert
Consultation on risk assessment of microbiological hazards in foods. Food and Nutrition
Paper No. 71. FAO, Rome, 54 pp.
9. Gelman A., Carlin J.B., Stern H.S. & Rubin D.B. (1995). – Bayesian data analysis.
Chapman & Hall, London, 526 pp.
10. Groebner D.E. & Shannon P.F. (1993). – Business statistics: a decision-making approach.
Macmillan, New York, 1,119 pp.
11. Jeffreys H. (1961). – Theory of probability, 3rd Ed. Oxford University Press, Oxford,
470 pp.
12. Kaplan S. (1999). – Beyond the domain of direct observation: how to specify a
probability distribution that represents the state of knowledge about uncertain inputs. Risk
Analysis, 19, 131-134.
13. Levin R.I. & Rubin D.S. (1994). – Statistics for management. Prentice Hall, New Jersey,
1,024 pp.
14. Morgan M.G. & Henrion M. (1990). – Uncertainty: a guide to dealing with uncertainty in
quantitative risk and policy analysis. Cambridge University Press, New York, 332 pp.
15. National Academy of Sciences National Research Council (NAS-NRC) (1983). – Risk
assessment in the Federal Government: managing the process. NAS-NRC Committee on the
Institutional Means for the Assessment of Risks to Public Health. National Academy Press,
Washington, DC, 191 pp.
160
OIE International Standards on Antimicrobial Resistance, 2003
3. Risk analysis
16. OIE (World organisation for animal health) (1999). – International animal health code:
mammals, birds and bees, 8th Ed. OIE, Paris, 468 pp.
17. Olkin I., Glaser L.J. & Derman C. (1980). – Probability models and applications.
Macmillan, New York.
18. Ripley B.D. (1987). – Stochastic simulation. Wiley, New York, 252 pp.
19. Rubinstein R. (1981). – Simulation and Monte Carlo methods. Wiley, New York, 278 pp.
20. Sivia D.S. (1996). – Data analysis: a Bayesian tutorial. Oxford University Press, Oxford,
189 pp.
21. Teunis P.S.N. & Havelaar A.H. (2000). – The beta Poisson dose-response model is not a
single-hit model. Risk Analysis, 2 (4), 513-520.
22. Vose D. (2000). – Risk analysis: a quantitative guide. Wiley, Chichester, 418 pp.
23. Wooldridge M. (1999). – Risk assessment report: qualitative risk assessment for antibiotic
resistance. Case study: Salmonella Typhimurium and quinolone/fluoroquinolone class of
antimicrobials. Annex IV. In Antibiotic resistance in the European Union associated with the
therapeutic use of veterinary medicines: report and qualitative risk assessment by the
Committee for Veterinary Medicinal Products, 14 July 1999. European Agency for the
Evaluation of Medicinal Products, London, 41 pp.
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3. Risk analysis
Risk assessment techniques – and antibiotic
resistance
Dr M. Wooldridge
Central Veterinary Laboratory, New Raw, Addle Stone, Surrey KT15 3NB, United Kingdom
Introduction
Risk assessment is one of the components of risk analysis, the others being hazard
identification, risk management, and risk communication (OIE Animal Health Code,
2001). Whatever the issue of concern, including that of antibiotic resistance, the
purpose of a risk assessment is to supply information to the risk managers,
policymakers, and other stakeholders. That information may include estimates of risk,
identification of crucial data deficiencies allowing targeted further data collection, and
new insights into the processes occurring.
Risk assessments may be qualitative, quantitative, and occasionally semi-quantitative.
Whilst quantitative risk assessments use numerical data to estimate probabilities in
numerical terms, qualitative assessments estimate probabilities by making logical
deductions, in words, from the information available. Semi-quantitative assessments,
when used, generally involve a system of categorisation, although there is controversy
about their usefulness. Quantitative assessments may be deterministic, or stochastic.
Deterministic assessments use single numbers as model inputs and therefore give
single numbers as the outputs, or risk estimates. However, stochastic assessments use
distributions to describe uncertainty in the model inputs, and as a result the model
outputs, or risk estimates, are also in the form of distributions. These can be described
statistically (mean, mode, median and other percentiles), and illustrated graphically.
This method therefore gives much more information to the policymaker about the
uncertainty in the risk estimate.
Risk assessment methodology applied to antibiotic resistance
Basic elements of a risk assessment
Briefly, risk assessment methodology, whether qualitative or quantitative, requires:
– the selection of one or more ‘risk questions’
– the construction of a ‘risk pathway’ of necessary steps from the initiating event to
the outcome of interest (that is, the risk to be estimated)
– the collection of data and information to enable the probability of each step in
the risk pathway, and thus also the final outcome, to be estimated.
Looking specifically at the problem of antibiotic resistance, we now consider what is
meant by a ‘risk question’, how the way in which this is framed is crucial to the
construction of the ‘risk pathway’, and the effect on the outcome or risk estimate,
using three different examples.
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The effect of the ‘risk question’ on the assessment method and resultant
output
The simplest type of risk question
A ‘risk question’ usually concerns the probability of occurrence of a specified event. A
simple example would be:
‘What is the probability that a randomly selected piece of uncooked meat on sale in
country K is contaminated with pathogen D carrying resistance to antibiotic A?’
In this example, there is no requirement to identify the original source of the
pathogen. There is no requirement to identify the further effects, or consequences, of
contamination. It is therefore a simple ‘one step’ risk pathway with the initiating event
(contamination of the meat) and the outcome of interest (contamination of the meat)
being identical. Thus, the question can be answered most simply by a single piece of
data – that is data obtained from a statistical survey of contamination of retail meat.
Such a survey gives the prevalence of contamination directly, and as it is statistically
based, the probability of contamination of a random piece of meat can be estimated
directly from the prevalence. Indeed, those answering such a question might not be
aware that they are conducting a quantitative risk assessment, so routine is this type of
question.
Adverse human health effects – the introduction of ‘cases’ into the risk
question
However, in general, the reason for wanting this information is to determine the
adverse effects of such meat on human health. We are interested in human ‘cases’.
Therefore, suppose we define a case as:
‘A human who has suffered an adverse health effect due to resistance to an antibiotic
of group A present in pathogen D’.
Efficient surveillance of the human population will then give the total number of such
cases occurring in a given region and time-span, and from this the probability of a
random person becoming a case can be estimated. However, there may be many
sources of pathogen D and its associated resistance. Surveillance alone cannot give
information on the source of this resistance unless pathogen D varies specifically due
to its source (for example by strain), and also that there are no other possible sources
of that strain of pathogen D. This may sometimes be the case, but it is certainly not
always so.
So the second example, a much more complex risk question often asked, is of the
form:
‘What is the probability of an adverse health effect occurring in a randomly selected
person due to the development of antibiotic resistance in pathogen D due in turn to
the use of antibiotic A in species S?’
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This risk question is a very complex risk question, with at least one, and possibly more
multi-step risk pathways. The most direct pathway is a farm-to-fork pathway with
additional steps, ingestion, infection, treatment of antibiotic resistance, and failure of
that treatment leading to adverse effects. This pathway is illustrated diagrammatically
in Figure 1.
Antibiotic A
Species S
Pathogen D
Slaughter
Food chain
Effect
on D
Effect
on D
Processing
Retail
Effect
on D
Effect
on D
Prepare
and cook
Effect
on D
Proportion
of D develops
resistance
Adverse
health effect
Cross-contamination? Multiplication? Death?
More D? Less D?
Resistance causes
failure to work
Antibiotic (A or
related) used
Pathogen D
colonises or
infects human
Human
eats
Proportion
still resistant
Fig. 1.
Simplified risk pathway illustration for the second example risk question,
showing the steps necessary for resistance developed in pathogen D due to the
administration of antibiotic A to species S to result in adverse human health
effects
However, additional risk pathways include for example the pathway via environmental
contamination, and the pathway via exchange between pathogens of genetic material
coding for resistance – and there are others. The totality of this risk assessment is
therefore a very complex exercise, and exceptionally data-hungry.
Taking simply the pathway illustrated above, the typical kinds of data necessary are
outlined in Table I.
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Table I
Examples of the types of data necessary to undertake the risk assessment
indicated in the second risk question example
Probability of
Probable amount of
D is random animal of species S
Use of antibiotic A in species S
D in animal, given infected
D at each stage of food chain, given
present in defined unit of meat
Development of resistance in D when A used
Meat consumed per helping
D remaining viable through each stage of food
D required for illness (i.e. dosechain, and therefore present in defined unit of meat response)
Random human eating S-meat
Colonisation/infection with D
Illness
Antibiotic treatment with A (or related)
Failure A (or related) to work
To summarise, in this example it is necessary to estimate the probability and probable
amount of antibiotic A-resistant pathogen D in species S, due to the use of antibiotic
A. It is then necessary to trace that pathogen D through the food chain pathway,
estimating the probability of the resistant pathogen remaining viable, multiplying or
dying, whilst passing through each of those steps, and the total amount present at
each step and thus at ingestion, which is dependant upon those effects. Given
knowledge of the dose-response effect in humans, this then allows an estimate of the
probability that treatment with antibiotic A is required, and will fail. Thus, in theory,
an overall estimate of the probability of an adverse human health effect in a random
person due to the use of antibiotic A in species S can be ascertained. In practice, the
complexity of this pathway is such that currently there are likely to be many areas of
data uncertainty and many complete data gaps. It is therefore more likely that the
method will currently be useful, and used, specifically to gain insights into the risk
pathway, to identify those data gaps which are crucial to the estimation, and to
estimate levels of uncertainty in available data.
The question is often asked as to whether this method can be simplified, and the
answer is yes, under certain circumstances it can be. For example, if there is only one
possible source of antibiotic A-resistant pathogen D in meat of species S, then a
knowledge of the probability and probable amount of pathogen present at the point
of ingestion will give the required estimate. Sometimes, if the pathogen strain or type
is very specific to one species of livestock, this may be appropriate, and the
assessment may begin part-way along the food chain, for example with retail
prevalence data. However, adopting this approach means that no insights into the
process at earlier stages are possible, and it can give no information on the effect of
control strategies at, for example the farm or early in the processing stages. The
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decision to adopt this approach must therefore be considered carefully in the light of
all the policy makers’ requirements from the risk assessment process.
Which is the problem of interest? – the importance of the correct risk
question
A third possible risk question format is shown in the following example:
‘Given an adverse health effect due to resistance to antibiotic A in pathogen D
occurring in a particular person, what is the probability that it is due to the use of
antibiotic A in species S?’
Although at first glance this may appear to be similar to the previous risk question, it
is in fact very different. Here, a specific person has actually suffered an adverse health
effect. The probability of an adverse health effect therefore does not need to be
estimated – it is known, and it is one – a certainty. And the question also specifies that
this adverse health effect is known to be due to resistance to antibiotic A in pathogen
D. Therefore the probability of antibiotic A-resistant pathogen D being present is also
one. The person is not a random member of the total population, but is known to be
a member of the sub-population ‘cases’.
The question therefore asks not what is the probability that the person will be
adversely affected; rather it concerns the source of the development of antibiotic
resistance in the affecting organism. To illustrate this risk question more fully, we
therefore need to consider what possible sources there are; there may be many. As
well as the possible source being treatment with antibiotic A of pathogen D-affected
species S (the source in which the risk question is interested, which we will call source
1), other obvious examples of possible source include; treatment of pathogen Daffected species Y with antibiotic A (and species Y may often be humans); previous
treatment of any species with a related antibiotic causing cross-resistance to develop in
D; or innate resistance mechanisms to antibiotic A present in pathogen D, requiring
no prior treatment of any species for development. Other sources may also be
possible. Each potential source has a risk pathway, with varying complexities. Each
source will result in a certain number of cases due specifically to that source for a
given region and time-frame, and the addition of these cases-by-source will give the
total number, that is 100%, of cases in that region and time-frame. Fig. 2 illustrates
these sources by proportion, and their risk pathways, simplified.
The risk assessor presented with this third risk question needs therefore to be able to
estimate the proportion of the sub-population of cases caused by the method
specified in the risk question; that is, the probability that the effect has come via the
specified pathway 1, and this depends directly upon proportion 1. Therefore the
assessor needs to estimate proportion 1. The question then becomes ‘how is this
proportion estimated?’ In theory this is easily solved. The method used to answer risk
question 2 will give an estimate of the probable number of cases from a particular
specified source, for example source 1, above. Surveillance data will give the total
number of cases from all sources. The estimate from source 1 can then be converted
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to a proportion of total cases, and this then gives a direct estimate of the probability
of source 1 as the causal source for the case under consideration. In practice, of
course, the estimate of the number of cases due to source 1 is as complex as the
estimate for the second risk question example.
Proportions 1+2+3+4+5 =100% of cases
Species S
with D
Antibiotic A
Proportion 2
Proportion of
D develops
resistance
Human subpopulation
cases
Proportion 2
Complex pathways
contact ?
Environment ? Food
handling?
Antibiotic A
(or related)
Proportion 5
Complex pathways
(as for example 2)
Proportion of
D develops
resistance
Humans
with D
Any other
source
D from any
source
Proportion
3
Antibiotic A
(or related)
previous dose
Proportion
5
D with
innate
resistance
Fig. 2
Simplified risk pathway illustration for the third example risk question,
showing the possible sources of resistance, by proportion, to antibiotic A
present in pathogen D in the sub-population ‘cases’
Cause for confusion – the difference the risk question makes
It should now be apparent that the risk estimates for the second and third risk
question examples will be very different, and this is illustrated in the following simple
numerical example. Suppose that a survey has shown that 0.1% of the whole
population suffers adverse health effects due to resistance to antibiotic A present in
pathogen D. This sub-population of ‘cases’ is a very small proportion of the total
population. The probability of any randomly selected person being within this subpopulation – i.e. a case – is low. Suppose also that there are, say, five different sources
for antibiotic A-resistant pathogen D being present in humans, and that each source is
equally likely. Then the percentage of cases by source is 20% for each source. This is
illustrated in Figure 3.
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„ whole population
„ cases: adverse health
effects - any route
„ small sub-group
e.g. say: 0.1% „ low proportion
of population
„ low probability
„ cases: adverse
health effects
„ proportions by route
„ total =100%
„ proportion 1
e.g. say: 20%
of subgroup
Fig. 3
The whole population showing the sub-population ‘cases’ as a percentage, and
the subpopulation ‘cases’ showing the adverse health effects proportionally by
source of antibiotic resistance: a comparison.
This means that, for a specified case, the probability that the effect was due to a
particular source is 20%, or P=0.2 (a 1 in 20 chance). However, as the cases comprise
only 0.1% of the population, then 20% of the cases is equivalent to only 0.02% of the
total population. So the probability that a particular source will result in the adverse
effect in a random person in the total population is 0.02%, or P= 0.0002 (a 1 in
20,000 chance). Clearly these results are very different, and this is summarised in
Table II.
Table II
A comparison of the difference in outputs, or risk estimates, which might
typically be expected from the second and third risk question examples,
illustrating the necessity of ensuring precision in the risk question asked, so
that it will give the type of information required
Question 2
‘What is the probability of an adverse health effect occuring in a randomly selected
person due to the development of antibiotic resistance in pathogen D due in turn to
the use of antibiotic A in species S?’
P2 = 0.0002
(1 in 20,000
chance)
Question 3
‘Given an adverse health effect due to antibiotic resistance in pathogen D occuring in P3 = 0.2
a particular person, what is the probability that it is due to the use of antibiotic A in
(1 in 20 chance)
species S?’
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Summary
All risk assessments are designed to answer ‘risk questions’, and there may be many
possible different ‘risk questions’ surrounding a particular issue. One essential element
of technique is to select appropriate risk questions, and this is usually done in
conjunction with the risk manager and other stakeholders. Inappropriate risk
questions lead to inappropriate answers. Worse still, they may lead to misunderstood
or misinterpreted answers, which in turn may lead to very poor risk management
decisions. One illustrated example of a possible risk question in the field of antibiotic
resistance is:
‘What is the probability of an adverse health effect occurring in a randomly selected
person due to the development of antibiotic resistance in pathogen D due in turn to
the use of antibiotic A in species S?’
The estimated probability for the above question may well be very low. An apparently
similar, but in fact very different risk question is:
‘Given an adverse health effect due to antibiotic resistance in pathogen D occurring in
a particular person, what is the probability that it is due to the use of antibiotic A in
species S?’
The estimated probability for this second question may be very high, particularly if the
only significant source of pathogen P is species S. This difference in estimated
probability may well be the cause of misunderstanding if the differences in the
meaning of the information elicited by the two questions are not appreciated.
In the first question, the intention is to estimate the probability of any random person
suffering the unwanted effect, from a particular source. Thus, one is looking forward
in time from the source action to an event, which may or may not occur. In the
second question, the event has occurred – and one is then looking back from this to
the action, which may have caused it. The estimated probabilities associated with the
two questions are therefore likely to be very different.
When undertaking risk assessments, a crucial part of the technique is therefore to
decide which ‘risk questions’ are the most appropriate to ask, which are actually being
asked, and to ensure that risk assessors and risk managers agree with the risk question,
and all parties including other stakeholders understand what the estimate obtained
actually does mean.
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3. Risk analysis
Impact of resistant campylobacteriosis in humans
due to fluoroquinolone use in chickens
L. Tollefson
United States Food and Drug Administration/Center for Veterinary Medicine, Office of research, HFV-530, 8401
Muirkirk Rd, Laurel, MD 20708, United States of America
Introduction and background
In 1999 the Food and Drug Administration (FDA) Center for Veterinary Medicine
published a framework document that proposed a process for evaluating and
managing the human health impact of the microbial effects of antimicrobial animal
drugs intended for use in food-producing animals. Stakeholders, particularly the
animal pharmaceutical companies and food animal veterinarians, stated that the
magnitude of the risk of using antimicrobials in food-producing animals needed to be
determined prior to implementing regulatory changes that would impact the industry.
In response to these comments, the Center for Veterinary Medicine agreed to conduct
a quantitative risk assessment to determine the human health impact in the United
States of America (USA) of acquiring fluoroquinolone-resistant Campylobacter infection
from exposure to chicken.
Process
The Center for Veterinary Medicine contracted with a risk analyst to develop a risk
assessment model to relate the prevalence of fluoroquinolone-resistant Campylobacter
infections in humans associated with the consumption of chicken to the prevalence of
fluoroquinolone resistant Campylobacter in chickens. The FDA is particularly concerned
about resistant Campylobacter because this organism is one of the most common causes
of bacterial foodborne illness in the USA (2, 4). Chicken is known to be a common
source, although not the only source, of campylobacteriosis in humans in the United
States of America and fluoroquinolones are important drugs in human medical
therapy that are often used empirically to treat human enteric infections (3, 4). The
risk assessment addressed that portion of the risk that was quantifiable, which is that
related to consumption of chicken. The unquantifiable portion, that portion due to
spread of the pathogen from chicken to other foods through contamination during
food preparation or from secondary spread to other animals, although an important
factor in the etiology of resistant Campylobacter infections, was not considered in the
risk assessment.
The Campylobacter risk assessment is a model for the direct transfer of resistance, which
describes the situation where the resistant bacteria are transferred from animals to
humans as a food contaminant. The etiology can be simplistically described by the
following scenario:
a) Poultry contract a disease, e.g. colibacillosis, and all birds in a house are treated
with a fluoroquinolone drug.
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b) Selective pressure from fluoroquinolone use leads to proliferation of
fluoroquinolone-resistant Campylobacter in the poultry gut.
c) Humans are infected by the fluoroquinolone-resistant Campylobacter organisms by
consuming poultry.
d) Treatment of humans with resistant illness with fluoroquinolones may be less
effective.
The approach to the risk assessment was straightforward with some initial broad
assumptions. The model assumes that the presence of fluoroquinolone-resistant
Campylobacter on chicken carcasses results from the use of fluoroquinolones in
chickens. This does not mean that every chicken carrying resistant Campylobacter had to
have been treated with a fluoroquinolone. Resistant organisms could have been
acquired from a contaminated environment due to fluoroquinolone drug use in a
previous group of birds, through contact with other chickens during transportation to
the slaughter plant and antemortem processing, through contamination in the
slaughter plant by other infected chicken carcasses, or through contamination of other
foods in the home by the raw chicken meat. The model also assumes that susceptible
and resistant Campylobacter have the same virulence characteristics and that susceptible
and resistant Campylobacter have the same survival characteristics from slaughter to the
point of human exposure. Finally, the model assumes that the presence of resistant
Campylobacter on the chicken carcasses was due to antimicrobial drug use. Because of
data supporting the linkage between antimicrobial drug use and antimicrobial
resistance in animals in studies and in surveillance, this assumption is considered to be
scientifically sound.
The risk analysis methodology used for the Campylobacter risk assessment is based on
that described by the OIE (World organisation for animal health) Ad Hoc Group on
Antimicrobial Resistance (8). The risk analysis methodology described in the OIE
document is tailored to address antimicrobial resistance in animals and includes hazard
identification, risk assessment, risk management, and risk communication. Although it
differs somewhat organisationally, the OIE approach includes similar steps in the risk
assessment process as the risk analysis paradigm described by the National Academy
of Sciences/National Research Council (NAS/NRC) that was developed for the
assessment of carcinogenic risks (1).
Data
The number of Campylobacter culture confirmed human cases in the US population was
used to estimate the total burden of campylobacteriosis. These data are collected from
state public health laboratories that participate in FoodNet, the Centers for Disease
Control and Prevention’s (CDC) Foodborne Disease Active Surveillance Network.
FoodNet monitors the incidence of foodborne disease in humans and conducts
studies to identify the sources and consequences of infection. Using the data on
human Campylobacter cases reported in FoodNet, the risk assessment calculated
1.4 million cases of campylobacteriosis for 1999 (7).
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The model also estimates the number of fluoroquinolone-resistant Campylobacter cases
attributable to chickens. Data from a Campylobacter case-control study conducted by
CDC assisted in the removal of proportions of resistance attributed to other sources.
Two other major sources of fluoroquinolone-resistant Campylobacter in humans are
foreign travel and human use of fluoroquinolone antimicrobials. We therefore
excluded from the estimate cases who had traveled to countries outside the USA in
the last seven days, those patients who were prescribed a fluoroquinolone prior to
stool culture, and those patients who were unsure of the timing of their treatment in
relation to stool culture. For 1999 the mean number of the domestically-acquired
fluoroquinolone-resistant Campylobacter cases attributable to chickens was
approximately 154,000 (7).
The model also estimated the number of the cases with fluoroquinolone-resistant
campylobacteriosis due to chickens who actually received a fluoroquinolone drug for
therapy. For 1999 the estimated mean number of people infected with
fluoroquinolone-resistant Campylobacter from consuming or handling chicken and who
subsequently received a fluoroquinolone as therapy was approximately 9,300 (7).
These people likely received less effective or ineffective therapy for their infections,
resulting in adverse health effects. The adverse health effects also have a negative
impact on productivity in terms of lost workdays and increased cost of medical care.
However, the risk assessment was limited to resistance development due to use of
fluoroquinolones in chickens only and the impact is a mean estimate. The actual risk
to humans from fluoroquinolone-resistant Campylobacter infections from all foodborne
sources is likely to be higher.
To estimate the quantity of chicken with fluoroquinolone-resistant Campylobacter
consumed, several sources of data were used. The estimate is based on the per capita
consumption of meat, the size of the population of the USA, the prevalence of
Campylobacter among carcasses and the prevalence of resistance among contaminated
carcasses. To estimate the quantity of chicken consumed, data were obtained from the
US Department of Agriculture Economic Research Service with product sent for
rendering, diverted for pet food, exports, water added during processing and imports
subtracted (6). The proportion of chicken with Campylobacter and the proportion of
Campylobacter that were fluoroquinolone-resistant were determined from samples that
the Department of Agriculture had analysed (contaminated with Campylobacter) and
susceptibility tested by the National Antimicrobial Resistance Monitoring System for
fluoroquinolone resistance (5).
Discussion
One of the advantages of the model used for this risk assessment is its simplicity.
Since we used data on actual human cases of campylobacteriosis, it wasn’t necessary to
determine infectious dose and then estimate the potential number of human cases
based on an average infectious dose. That process is cumbersome and requires
complex assumptions with little data available to substantiate the assumptions.
Instead, we limited the risk assessment to the human cases of disease. Also, we used
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prevalence of fluoroquinolone-resistant Campylobacter on chicken carcasses at the
slaughter plant, a point very close to the consumer, rather than resistance levels on the
farm. The farm is remote to what the consumer is actually exposed to through food;
testing retail chicken would be an even closer exposure source for consumers.
References
1. Committee on the Institutional Means for Assessment of Risks to Public Health,
Commission on Life Sciences, and National Research Council (1983). – Risk assessment in the
Federal Government: managing the process. National Academy Press, Washington, DC.
2. Mead P.S., Slutsker L., Dietz V., McCraig L.F., Bresee J.S., Shapiro C., Griffin P.M. &
Tauxe R.V. (1999). – Food-related illness and death in the Unites States. Emerg. infect. Dis., 5
(5), 607-625.
3. Sande M., Kapusnik-Uner J. & Mandell G. (1996). – Antimicrobial agents general
considerations, section XI, chemotherapy of microbial diseases. In The pharmacological basis
of therapeutics, 9th Edition (J. Hardman, L. Limbird, P. Molinoff, et al., eds). Goodman &
Gilman’s, The McGraw-Hill Companies, New York., 1,039.
4. Tauxe R.V. (1992). – Epidemiology of Campylobacter jejuni infections in the United States
and other industrial nations. In Campylobacter jejuni: current and future trends (I. Nachamkin,
M.J. Blaser & L.S. Tompkins, eds). American Society for Microbiology, Washington, DC, 9-12.
5. United States Department of Agriculture – Agricultural Research Service. – National
antimicrobial resistance monitoring system: enteric bacteria – 1999 animal Campylobacter isolate
report. Athens, Georgia. (available at http://www.arru.saa.ars.usda.gov/main.htm)
6. United States Department of Agriculture (USDA) (1999). – Economic Research Service
Food Consumption, prices and expenditures, 1970-1997. USDA. (available at:
http://www.econ.ag.gov/)
7. United States Food and Drug Administration (USFDA) (2001). – Human health impact
of fluoroquinolone resistant Campylobacter associated with consumption of chicken. USFDA.
(available at: http://www.fda.gov/cvm/antimicrobial/Risk-assess.htm)
8. Vose D., Acar J., Anthony F., Franklin A., Gupta R., †Nicholls T., Tamura Y.,
Thompson S., Threlfall E.J., van Vuuren M., White D.G., Wegener H.C. & Costarrica M.L.
(2001). – Antimicrobial resistance: risk analysis methodology for the potential impact on public
health of antimicrobial resistant bacteria of animal origin. Rev. sci. tech. Off. int. Epiz., 20 (3), 811827.
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Antimicrobial resistance and risk analysis: the view of
a developing country
M. van Vuuren
Department of Veterinary Tropical Diseases, Faculty of Veterinary Science, University of Pretoria, South Africa
Risk analysis has been used and applied for many years in diverse disciplines such as
engineering and veterinary import control. It is currently also used in assessing the risk
of food additives and drug residues in food, including toxicity studies in animals for
risk assessment of animal products intended for human consumption. However, it
was only after the Agreement on the Application of Sanitary and Phytosanitary (SPS)
Measures became active during 1995 that regulatory officials from many countries
became exposed to concepts such as risk assessment, regionalisation, equivalence and
transparency. Under the SPS Agreement, it is expected that World Trade Organization
Member Countries adopt risk assessment and risk management systems as part of
their obligations to base their SPS protection measures on scientific principles.
More specifically, however, in terms of the role that the use of antimicrobial drugs in
animals might play as a possible threat to public health, strong sentiments were
expressed at the 1999, Paris-based, OIE-sponsored (World organisation for animal
health) meeting on The Use of Antibiotics in Animals, that scientific risk analysis
should be the vehicle with which to approach this issue. To this effect, the
International Committee of the OIE decided in May 1999 to create an ad hoc group
to develop guidance documents for member countries that included inter alia risk
analysis methodology for managing the potential impact on public health of
antimicrobial resistant bacteria of animal origin.
The OIE guidance document on risk analysis (1) is the result of continuing efforts
(similar to that of other standard-setting organisations such as the International Plant
Protection Convention and the Codex Alimentarius Commission in terms of plant
health and food safety standards) to develop internationally acceptable standards in
the field of animal health.
In many developing countries, the application of risk analysis is in its infancy, mainly
as a result of a lack of expertise. These countries are confronted with the problem of
having to develop the capability to perform risk assessment, which implies that they
will have to obtain the services of qualified professionals. To achieve this objective,
the establishment of a risk assessment unit within a country is highly desirable,
especially in view of the fact that risk assessment is a team effort, requiring experts in
several disciplines. Such initiatives will go a long way in satisfying importing countries
that the quality of the exporting country’s surveillance systems, laboratory capabilities
and approach to quarantine measures are acceptable. Such a capability will also enable
developing countries to analyse risk assessment procedures of other countries and to
argue against unreasonable import measures.
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The OIE has employed the Covello-Merkhofer method for import risk assessment
and its ad hoc group on antimicrobial resistance has also applied this model to
develop the risk analysis methodology for the potential impact on public health of
antimicrobial resistant bacteria of animal origin (1). Prior to the publication of the
latter document, an approach to determine the risk involved in the use of
antimicrobial drugs in animals was first described by Wooldridge (2).
Some developing countries apply risk assessment to food safety issues. In South
Africa (and certain neighbouring countries) for example, risk assessments for
pesticides and toxic substances follow the model of the joint Food and Agriculture
Organization/World Health Organization (FAO/WHO) Codex Alimentarius
Commission. The latter is based on maximum residue limits (MRLs) developed by the
Joint FAO/WHO Meeting on Pesticide Residues and the Joint FAO/WHO Expert
Committee for Food Additives (JECFA) and published as a Codex document. Briefly,
companies apply for registration with the National Department of Agriculture. The
dossiers are then forwarded to the Department of Health for risk assessment of the
toxicological data. The main objective is to determine the maximum residue limits.
The Acceptable Daily Intake is established by either JECFA and published by the
Codex Alimentarius, the European Union (EU) or the Food and Drug Administration
of the United States Department of Agriculture. ADIs for substances not published
by any of these organisations are established locally following full risk assessments.
After reviewing the available toxicological profiles of the new active ingredient based
on acute toxicity, sub-chronic and chronic toxicity, ecotoxicity and environmental fate,
and if there is no toxicological reason for concern, the Department of Health
recommends registration thereof to the Department of Agriculture in terms of the
appropriate Act. In the case of pesticides, companies are also required to have the
MRLs determined for local conditions. For veterinary drug and food additive MRLs,
the standards of JECFA, published by Codex are followed. These MRLs are based on
the global food basket model and are accepted by African countries. If standards are
available from both the EU and JECFA, the lowest value is accepted.
Risk analysis for the potential impact on public health of antimicrobial resistant
bacteria of animal origin is a formidable challenge for developing countries. It will
entail inter alia the gathering of information (data) on the quantities of antimicrobial
drugs used, and resistance patterns and trends through a national antimicrobial
resistance surveillance and monitoring programme. In the realm of risk management,
developing countries must encourage the implementation of prudent use principles,
either through the initiative of the national government or relevant professional
organisations. Marketing authorisation for antimicrobial drugs should be based on a
complete evaluation by the appropriate authorities. Equally important is the
responsibility to communicate the risk to all role players including veterinarians,
livestock producers and pharmaceutical distributors. This will essentially entail the
drafting of guidance documents for all on prudent use principles. Ideally, countries
must strive to separate risk assessment from risk management and communication to
ensure the independence of decision-making and evaluation of the risk. The
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responsibility of the risk assessor is to evaluate the data and to make
recommendations on which the risk manager must act. On the other hand, the
framework wherein a risk assessor will function in a country, including aspects such as
threshold levels accepted by the public is determined and delineated by the risk
manager, i.e. politician. These functions in many developing countries are currently
performed by the same person.
In Africa several initiatives have been launched as part of an effort to implement
international standards relating to measures to ensure the protection of public health.
The Southern and Eastern African Drug Registration Application Conference
(SEAVDRAC) is an annual meeting devoted to the harmonisation of the evaluation
and licensing procedures for veterinary medicines. The Southern and Eastern African
Regulatory Committee for Harmonisation (SEARCH) is pursuing similar objectives by
working towards harmonisation of pesticide registration and MRLs.
Although the application of risk analysis in developing countries is absent or
minimally implemented in many instances, the ability to do so in many of these
countries already exists. The extent to which risk assessment is implemented by
developing countries, is limited only by the motivation of management (national
governments) to provide human, physical and financial resources.
References
1. Vose D., Acar J., Anthony F., Franklin A., Gupta R., Nicholls T., Tamura Y., Thompson
S., Threlfal, E.J., Van Vuuren M., White D.G., Wegener H.C. & Costarrica M.L. (2001). –
Antimicrobial resistance: risk analysis methodology for the potential impact on public health of
antimicrobial resistant bacteria of animal origin. Rev. sci. tech. Off. int. Epiz., 20 (3), 811-827.
2. Woolridge M. – Risk assessment applied to antibiotic resistance. In Proc. European
Scientific Conference on the use of antibiotics in animals, 24-26 March, Paris, 18-28.
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Campylobacter risk analysis: a cause-and-effect view
L.A. Cox, Jr.
Cox Associates, Denver, Colorado, United States of America
Campylobacter (CP) is the most commonly diagnosed cause of bacterial gastroenteritis
in the United States. In undercooked chicken and non-poultry meats, raw milk and
water and other undercooked contaminated foods or water, CP may cause
gastroenteritis and infectious diarrhea lasting a week or more (Friedman et al., 2000).
CP-infected patients are sometimes treated with the fluoroquinolone (FQ) antibiotic
ciprofloxacin. It seems plausible that an FQ prescription might have diminished
effectiveness against FQ-resistant CP strains, leading to excess days of illness.
Development of FQ-resistant strains of CP in chickens may be favored by the use of
other FQs, such as enrofloxacin, to combat respiratory disease in chicken broilers.
Thus, a hypothesis in which eating chicken is a leading cause of domestic sporadic CP
cases, and treating chickens with enrofloxacin raises the risk of FQ-resistant CP
illness, seems sensible. We call this ‘hypothesis 1’.
Although plausible, hypothesis 1 does not explain why several recent data sets indicate
that eating chicken (and even touching raw chicken) at home can reduce risk of CP
illness. An alternative, hypothesis 2, instead attributes risk of sporadic domestic CP
cases primarily to commercial cooking of hamburger, chicken, and other meats.
This paper examines evidence for hypothesis 2 from international trend data, a farmto-fork simulation model, and new analysis of case-control data collected by the
Centers for Disease Control and Prevention (CDC). First, a simulation model of
human exposures to CP via chicken is used to predict probable human health impacts
of alternative risk management strategies. It predicts that strategies that reduce
microbial load during processing and at the point of food consumption create the
largest public health benefits.
The case-control data reveal interactions among risk factors. For example, sex and age
affect patterns of commercial food consumption, as well as risk of CP illness. We
introduce causal graph models based on the data to summarise the main causal
relations of interest. These causal models raise policy and methodological problems
about how to attribute risks to specific factors (e.g., chicken consumption or use of
FQs in chickens) when both direct and indirect effects are present.
__________
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Antimicrobial resistance: harmonisation of national
antimicrobial resistance monitoring and surveillance
programmes in animals and in animal-derived food
A. Franklin (1), J. Acar (2), F. Anthony (3), R. Gupta (4), †T. Nicholls (5), Y. Tamura (6),
S. Thompson (7), E.J. Threlfall (8), D. Vose (9), M. van Vuuren (10), D.G. White (11),
H.C. Wegener (12) & M.L. Costarrica (13)
(1)
The National Veterinary Institute (SVA), Department of Antibiotics, SE 751 89 Uppsala, Sweden
(2)
Université Pierre et Marie Curie, Service de Microbiologie Médicale, Fondation Hôpital Saint-Joseph, 185 rue
Raymond Losserand, 75674 Paris Cedex 14, France
(3)
Fresh Acre Veterinary Surgery, Flaggoners Green, Bromyard, Herefordshire HR7 4QR, United Kingdom
(4)
College of Veterinary Sciences, Veterinary Bacteriology, Department of Microbiology, G.B. Pant University of
Agriculture and Technology, Pantnagar 263 145 Uttar Pradesh, India
(5)
National Offices of Animal and Plant Health and Food Safety, Animal Health Science and Emergency
Management Branch, Department of Agriculture, Fisheries and Forestry, P.O. Box 858, Canberra ACT 2601, Australia
(6)
National Veterinary Assay Laboratory, Ministry of Agriculture, Forestry and Fisheries, 1-51-1 Tolura,
Kokubunji, Tokyo 185-8511, Japan
(7)
Joint Institute for Food Safety Research, Department for Health and Human Services Liaison, 1400
Independence Avenue, SW, Mail Stop 2256, Washington, DC 20250-2256, United States of America
(8)
Public Health Laboratory Service (PHLS), Central Public Health Laboratory, Laboratory of Enteric Pathogens,
61 Collindale Avenue, London NW9 5HT, United Kingdom
(9)
David Vose Consulting, Le Bourg, 24400 Les Lèches, France
(10) University of Pretoria, Faculty of Veterinary Science, Department of Veterinary Tropical Diseases, Private Bag
X04, Onderstepoort 0110, South Africa
(11) Centre for Veterinary Medicine, Food and Drug Administration, Office of Research, HFV-530, 8401 Muirkirk
Road, Laurel, Maryland 20708, United States of America
(12) World Health Organization, Detached National Expert, Division of Emerging and Transmissible Diseases,
Animal and Food-related Public Health Risks, 20 avenue Appia, 1211 Geneva, Switzerland
(13) Food and Agriculture Organization, Food Quality and Standards Service, Senior Officer, via delle Terme di
Caracalla, 00100 Rome, Italy
This report, prepared by the OIE Ad hoc Group of experts on antimicrobial resistance, has not yet received the
approval of the International Committee of the OIE
Summary
A guideline on the harmonisation of national antimicrobial resistance monitoring and surveillance
programmes in animals and animal-derived foods has been developed by the Ad hoc Group of experts
on antimicrobial resistance of the OIE (World organisation for animal health). The objective of the
guideline is to allow the generation of comparable data from various national surveillance and
monitoring systems in order to compare the situations in different regions or countries and to
consolidate results at the national, regional and international level. Definitions of surveillance and
monitoring are provided. National systems should be able to detect the emergence of resistance, and to
determine the prevalence of resistant bacteria. The resulting data should be used in the assessment of
risks to public health and should contribute to the establishment of a risk management policy. Specific
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4. Surveillance of resistance programme
factors identified for harmonisation include the animal species, food commodities, sampling plans,
bacterial species, antimicrobials to be tested, laboratory methods, data reporting, database structure
and the structure of reports.
Keywords
Antimicrobial resistance – Containment of resistance – Harmonisation – Human
medicine – International standards – Laboratory methodology – Monitoring – Public
health – Risk analysis – Surveillance – Veterinary medicine – World Organisation for
Animal Health.
Introduction
This document describes the objectives of programmes for the monitoring and
surveillance of antimicrobial resistance in bacteria of animal origin and animal-derived
food products. The programmes will serve as a basis for the detection of national and
global trends in the development of antimicrobial resistance in these bacteria. Animal
species, food products, bacterial species and antimicrobials to be included in the
programmes will be proposed. Sampling strategies, including statistically-based
sampling options, data collection, recording, evaluation, and access to the data are
considered. Comments are made on programme costs that may be of relevance to
Member Countries.
All aspects relating to laboratory methodologies are dealt with in Antimicrobial resistance:
standardisation and harmonisation of laboratory methodologies for the detection and quantification of
antimicrobial resistance, earlier in this volume.
Background
Antimicrobial susceptibility testing of bacteria has basically aided the clinician in the
choice of efficient antimicrobials. Numerous point prevalence studies on antimicrobial
resistance in bacteria of animal origin have been reported. Unfortunately, the
usefulness of data from published studies is often hampered by inadequacies in study
design. The methods and interpretive criteria used vary and comments on drug
statistics are rarely included. The number of investigated isolates is generally low and
confidence limits are rarely presented. The inclusion and exclusion criteria for the
isolates included may be reasonably well described, but not the criteria for sampling.
For example, most studies include results from clinical specimens sent to laboratories
for routine analysis. It should be borne in mind when designing resistance monitoring
and surveillance programmes that results from diagnostic submissions may not reflect
the resistance situation in the animal population, as these types of submissions tend to
include specimens from severe and/or recurrent clinical cases, including therapy
failures. As a first step towards comparability of monitoring and surveillance data,
Member Countries of the OIE (World organisation for animal health) should be
encouraged to strive for harmonised and standardised programme design (2, 15, 17,
20). Data from countries using different methods and study design may otherwise not
be directly comparable (10, 20). Nevertheless, data collected over time in a given
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country may at least allow the detection of emergence of antimicrobial resistance or
trends in prevalence of resistance in that particular country.
A limited number of countries has established national structures for central collection
and evaluation of antimicrobial susceptibility data of bacteria isolated from animals
(1). In most countries which have already initiated official resistance monitoring and
surveillance, these programmes arose from the need to give guidance to practitioners
on appropriate clinical therapy. Recently in some countries, programmes have been
extended to include knowledge about antimicrobial resistance in food-borne
pathogens and commensal bacteria, including evaluating local, regional and national
trends (4, 7, 12, 13, 22). Existing systems may include central co-ordination,
harmonisation of laboratory methodology, establishment of quality assurance schemes
and external proficiency testing by a designated national co-ordinating laboratory.
Definition of monitoring and surveillance
In the International Animal Health Code, the OIE defines surveillance in animal health as
‘the continuous investigation of a given population to detect the occurrence of disease
for control purposes, which may involve testing of a part of the population’.
According to the OIE definition, monitoring ‘constitutes on-going programmes
directed at the detection of changes in the prevalence of disease in a given population
and in its environment’ (16).
In the context of this guideline, ‘disease’ can be substituted by ‘antimicrobial
resistance’.
The chapter of the International Animal Health Code on monitoring and surveillance of
animal health describes options for agent detection and disease prevalence.
Antimicrobial resistance and prevalence can follow some of the OIE monitoring and
surveillance definitions in animal disease guidelines mentioned below:
a) scientifically-based surveys (including statistically-based programmes)
b) routine sampling and testing of animals on the farm, at market or at slaughter
c) an organised sentinel programme, sampling animals, herds, flocks, vectors,
and/or collecting diagnostic results from veterinary practice
d) the storage of biological specimens for retrospective studies
e) analysis of veterinary diagnostic laboratory records.
Passive surveillance is conducted when samples are submitted to a laboratory for
testing by sources outside the programme. Active surveillance is conducted when the
programme develops a sampling scheme based on the objectives of the programme
and actively obtains isolates.
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4. Surveillance of resistance programme
Reasons for resistance monitoring and surveillance
programmes
Resistance monitoring and surveillance programmes are intended to generate data that
can be used as follows:
– in risk analysis to determine risk to human and animal health
– to detect emergence of antimicrobial resistance (e.g. particular phenotypes)
– to determine the prevalence or trend in prevalence of reduced susceptibility to a
certain antimicrobial (or resistance) in a defined population
– to provide a basis for policy recommendations for animal and public health
– to generate data that may guide the design of further studies
– to identify the need for potential interventions
– to assess the impact of interventions
– to provide information for prescribing practices and prudent use
recommendations.
General aspects to be considered in resistance monitoring and
surveillance
When Member Countries are considering their options for the control of
antimicrobial resistance arising from the use of antimicrobials in animals, several
issues should be examined and analysed. In particular, the resistance situation in
humans, including resistance in bacteria of concern to human medicine, and the
capacity of countries to undertake resistance surveillance in bacteria of human origin
should be taken into consideration. Monitoring of bacteria from animal-derived food
collected at different steps of the food chain, including processing, packing and
retailing, should also be considered.
There are large variations among Member Countries both in the extent of the use of
antimicrobials in animals and the public concern over such use. However, for all
countries, the basic mechanisms of exposure of humans to resistant bacteria from
food are the same. Exposure of humans to resistant bacteria can be either direct
through exposure to zoonotic pathogens (Salmonella, Campylobacter), or indirect through
exposure to resistance genes potentially transferable from commensal animal bacteria,
such as Escherichia coli and Enterococcus spp., to human bacteria (9, 18, 21).
Any antimicrobial use will exert selection pressure on exposed bacteria and may result
in development of resistance. This should be taken into account when designing
monitoring and surveillance programmes. This means that information is required on
the antimicrobial substance used, the mode of usage and the quantities used. Although
there is no linear relationship between the amount of a certain antimicrobial used and
the development of resistance, increased use of an antimicrobial often results in
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decreased susceptibility among exposed bacteria. An antimicrobial selective pressure
may affect the resistance phenotype of bacteria in different ways, as follows:
a) cross-resistance and co-selection of resistance genes may explain how one
antimicrobial selects for another antimicrobial
b) multiple resistance confers resistance to several antimicrobials
c) virulence and lack of hygiene may account for the survival and spread of resistant
bacteria, even in the absence of an antimicrobial selection pressure (14).
Thus, the rate of development of resistance in bacteria will, amongst others, depend
on the character(s) of the resistance gene(s), such as transferability, time of exposure
of the micro-organism to the antimicrobial, and not least on the characteristics of the
exposed bacterial populations (11).
Surveillance of antimicrobial resistance at regular intervals or ongoing monitoring of
prevalence changes of resistance bacteria of animal, food, environmental and human
origin, constitutes a critical part of a strategy aiming at limiting the spread of
antimicrobial resistance and optimising choice of antimicrobials used in therapy. As
the situation will vary over time and between countries and regions, data need to be
collected at the appropriate regional and national level. Monitoring and surveillance
programmes may serve as early warning systems in the sense that even minor shifts in
susceptibility may be identified at an early stage. Interventions may then be taken to
limit the further shifts in susceptibility or spread of resistance.
Despite differences among Member Countries, it is essential that countries consider
the collection of certain standardised information and the harmonisation of their
surveillance and monitoring programmes to enable the international comparison of
data. As bacteria do not respect country boundaries, the ability to evaluate the
situation at a global level will enable a better assessment of the potential risks posed by
resistant bacteria on human and animal health. The risk for human health from
resistant bacteria or resistance genes of animal origin should, as far as possible, be
quantified and put into perspective with other human health risks. As
recommendations prepared by the OIE will be of global relevance, careful
consideration must be given to realistic needs and public and animal health issues of
OIE Member Countries in all regions of the world.
Specific factors to be considered for the harmonisation of
resistance monitoring and surveillance programmes
To achieve comparability of results between national monitoring and antimicrobial
surveillance programmes, the following factors should be considered by Member
Countries in the design of such programmes:
a) animal species/categories (including age) to be sampled
b) for food sampling, the relative merits of sampling at the abattoir and retail outlet
should be considered. In addition to food of domestic origin, food of foreign origin
may also be considered, possibly at the port of entry of the products
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4. Surveillance of resistance programme
c) sampling strategy to be employed, for example: active or passive collection of
samples; random, stratified or systematically collected samples; statistically based
sampling or opportunistic sampling
d) samples to be collected (faeces, carcass, raw and/or processed food)
e) bacterial species to be isolated
f) antimicrobials to be used in susceptibility testing
g) standardised susceptibility testing (under laboratory methodologies)
h) quality control – quality assurance (under laboratory methodologies)
i) type of quantitative data to be reported (under laboratory methodologies)
j) database design for appropriate data extraction
k) analysis and interpretation of data
l) reporting (consideration of transparency of reporting and interests of
stakeholders).
A detailed consideration of specific factors is presented below.
Animals
Each Member Country should examine its livestock production systems and decide,
after risk analysis, the relative importance of antimicrobial resistance for animal and
human health. Categories of livestock that should be considered for sampling include
cattle and calves, slaughter pigs, broiler chickens, layer hens and/or other poultry and
farmed fish. The results of this examination coupled with knowledge of antimicrobial
use in animals, where available (see Antimicrobial resistance: monitoring the quantities of
antimicrobials used in animal husbandry, earlier in this volume), regional and seasonal
factors, as well as the international trading status of the Member Country (e.g. net
importer or exporter of livestock products), may influence the design of resistance
monitoring and surveillance programmes.
Food
When considering the transfer of antimicrobial resistance from animals to humans,
contaminated food is commonly considered to be the principal route. Antimicrobial
resistance can be transferred either by pathogenic bacteria or by transfer of resistance
genes carried by commensal bacteria.
Raw food of animal origin may be contaminated with resistant enteric pathogens such
as Salmonella spp., Campylobacter jejuni and Campylobacter coli or resistant commensal
bacteria such as E. coli and Enterococcus spp. Little is known about the prevalence of
resistant bacteria in food of animal origin, but it is important that food bacterial
isolates (including isolates from food of plant origin) are included in national
monitoring and surveillance programmes for antimicrobial resistance (3, 20). Plants
and vegetables of different types may be exposed to manure or sewage from livestock
and may thereby become contaminated with resistant bacteria of animal origin.
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4. Surveillance of resistance programme
Animal feed, including imported feed, may also be considered in monitoring in
surveillance programmes.
Sampling strategies
General
As described in Chapter 1.3.5. of the OIE International Animal Health Code on
surveillance and monitoring of animal health (16), Member Countries will have to
consider whether to utilise passively collected data from existing sources of
information, such as data from veterinary diagnostic laboratories (appreciating the
limitations of the data) and/or design new monitoring or surveillance programmes for
specific needs, or perhaps modify existing programmes. After deciding on the
objectives of the required programme, for example monitoring antimicrobial
resistance prevalence changes in bacterial populations of the national pig herd, specific
programme design decisions must be taken.
The OIE recommends that Member Countries, very early in their consideration of the
issue, examine their capacity to undertake such work with regards to financial and
human resources. Some Member Countries may need to develop basic scientific
antimicrobial resistance expertise in the animal health area before embarking on a
resistance monitoring and/or surveillance programme. Other countries may have
already implemented comprehensive monitoring and surveillance programmes and
may only have to consider the issues related to harmonisation as discussed in this
paper.
Statistically based sampling strategies for food-borne pathogens and
commensal bacteria
Sampling strategies are usually based on two basic features: sample representativeness
of the population of interest and the robustness of the sample collected.
Sampling strategies should be based on addressing the defined objectives of the
programme.
Samples are typically targeted at representing a specific group or population of interest
and may be collected randomly, systematically or stratified within the population of
concern. An appropriate sampling strategy provides sample estimates that are accurate
for the population of interest. If appropriate sampling strategies have been defined,
calculating a statistically based sample size allows programme monitors to determine
the precision of the prevalence estimates that will be obtained from the collected
sample. Sample size considerations are important, as an inadequate sample size may
fail to detect existing resistance and an excessively large sample size is a waste of
resources.
The source of sample specimens should be determined by the objectives of the
monitoring programme. If the objective is to monitor the potential human health
impact of antimicrobial resistant bacteria from food of animal origin, then faecal
samples from an appropriate sample source, such as the abattoir, may be the most
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4. Surveillance of resistance programme
convenient and least costly option for sample collection (2, 4, 13, 15). This would
reflect the prevalence of resistance at the first step of the food chain. Sampling of the
carcasses at the abattoir would provide information on slaughter practices, slaughter
hygiene and the level of faecal contamination of meat during the slaughter process.
Further sampling from the retail chain would provide an indication of prevalence
changes before the food reaches the consumer (4, 19). However, for studies on the
relationship between use of antimicrobials and prevalence of resistance in animal
bacterial populations, samples taken from animals with known health status and
antimicrobial exposure might be more suitable (Table I).
Programmes need to be statistically-based, using random sampling techniques, and
need to be stratified for relevant factors. An example of a table and formula to assist
Member Countries in programme design considerations is included in Appendix A.
The sampling should be stratified by geographic region and run continuously over the
year to account for regional and seasonal variations. Depending on, amongst others,
the financial resources of a country, sampling may be extended over longer time
periods or modified in other ways.
Table I
Examples of sampling sources, samples types and outcome of monitoring
Source
Herd of
origin
Abattoir
Processing,
packing
Retail
Various
origin
Sample
type
Outcome
Additional
information
required/additional
statification
Faecal
Prevalence in bacteria originating from animal Per age categories,
populations (of different age categories and
production types, etc.
production types)
Relationship resistance – antibiotic use
Antibiotic use over time
Faecal
Prevalence in bacterial populations originating
from animals at age of slaughter
Intestine
As above
Carcass
Hygiene, contamination during slaughter
Meat
Hygiene, contamination during processing and
products
handling
Meat
Prevalence of resistance in bacteria originating
products
from food, exposure data for consumers
Vegetables Prevalence of resistance in bacteria originating
from vegetables, exposure data for consumers
Animal feed Prevalence of resistance in bacteria originating
from animal feed, exposure data for animals
As different practices for rearing an animal species might entail different antimicrobial
exposure, the category of animal included should be strictly defined. If several
categories of the same animal species are included, the sampling should again be
stratified for these categories. A single animal should be sampled per herd or flock on
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4. Surveillance of resistance programme
each occasion. It is the prevalence of resistance and trends in the bacterial
populations, rather than the specific prevalence on the herd or flock level, that is of
interest in antimicrobial resistance monitoring and surveillance programmes (2, 4).
Bacterial isolates collected in this way will represent a stratified random sample of the
bacterial population of each animal species surveyed.
Determining the number of isolates to be tested in order to obtain a statistically robust
estimate involves gathering information on the expected prevalence of resistance in
the population. The level of precision desired in the prevalence estimate and the
degree of confidence that the prevalence estimate would fall within this range are parts
of the design parameters of the monitoring or surveillance programme.
The total number of samples required to achieve the targeted number of resistant
isolates, with the desired confidence in the estimated prevalence level of resistance,
should be based on the statistical considerations mentioned above. Additionally, the
known frequency with which bacteria may be isolated from animals or food must be
taken into account. Furthermore, the actual number of isolates to be tested may need
to be adjusted, due to laboratory and other pragmatic resource considerations.
However, in the interpretation of data, the concomitant limitations arising from these
adjustments must be recognised and taken into consideration. If results of the
monitoring programme indicated a prevalence other than that estimated, the
programme testing regime would need to be adjusted, or more detailed surveillance
and investigation would be required.
Sample specimens to be collected (faeces, carcass and retail food)
As a rule, faecal samples are collected from livestock and whole caeca are collected
from poultry. From cattle and pigs, a faecal sample size of 5 g to 50 g will provide a
sufficient sample for isolation of the bacteria of concern. A large sample size will
result in a higher number of isolates of the target bacterial species compared to a
smaller sample size. The same sample can be used for isolation of both zoonotic and
commensal bacteria.
Existing food-processing microbiological monitoring and ‘hazard analysis and critical
control points’ (HACCP) programmes may provide useful samples for monitoring
and surveillance of resistance in the food chain after slaughter. However, experience
in the collection of this type of sample is currently rare.
Bacteria
Three major categories of organisms would be monitored, as follows:
a) animal bacterial pathogens
b) zoonotic bacteria
c) commensal bacteria.
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If possible, isolates should be preserved at least until reporting is completed. A
collection for retrospective studies may be set up by further storing of all isolates from
certain years. Isolates should preferably be stored cryogenically.
Animal bacterial pathogens
Monitoring of resistance in animal pathogens is important, both to detect emerging
resistance that may pose a concern for human and animal health and to guide
veterinarians in their prescribing decisions. Furthermore, this information will be of
value in providing guidance for the prudent use of antimicrobials in veterinary
medicine. Animal pathogens have the capacity to rapidly spread between animals and
may, in consequence, be repeatedly exposed to antimicrobials. Emergence of new
resistance mechanisms and loss of susceptibility in animal bacterial pathogen
populations will be detected at its earliest stage by surveillance and monitoring
programmes for resistance in these bacterial populations. Furthermore, this type of
information is readily available in many countries. Information on the occurrence of
antimicrobial resistance in animal pathogens is in general derived from routine clinical
material sent to veterinary diagnostic laboratories.
These samples are often derived from severe or recurrent clinical cases, including
therapy failures. However, because these isolates are likely to represent biased
samples, this type of susceptibility data may not show the true prevalence of resistance
within the given animal population and the appropriate caution must be exercised in
the interpretation of the data. A means of mitigating this bias would be to consider
collection of samples from primary clinical cases not previously treated with
antibiotics, or isolation of potentially pathogenic bacteria from healthy animals.
Examples of animal pathogenic bacteria
The range of priority animal bacterial pathogens to be monitored should be
determined, taking into account the national animal health situation.
Examples of bacterial pathogens which may be considered for inclusion in resistance
surveillance or monitoring programmes are presented in Table II.
Table II
Examples of animal bacterial pathogens which may be included in the
resistance surveillance and monitoring
Target
animals
Respiratory pathogens
Enteric
pathogens
Udder pathogens
Cattle
Pasteurella spp.
Haemophilus somnus
Actinocacillus pleuropneumoniae
Escherichia coli
Salmonella spp.
Escherichia coli
Brachyspira
Salmonella spp.
Staphylococcus aureus
Streptococcus spp.
Pigs
Poultry
Fish
190
Other
pathogens
Streptococcus suis
Escherichia spp.
Vibrio spp.
Aeromonas spp.
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4. Surveillance of resistance programme
All bacteria should be identified according to internationally recognised standard
procedures. Antimicrobial susceptibility testing should be performed with validated
methods under internal and external quality assurance (see Antimicrobial resistance:
standardisation and harmonisation of laboratory methodologies for the detection and quantification of
antimicrobial resistance).
Zoonotic bacteria
Salmonella
Sampling should preferably represent the primary production of cattle, pigs, broilers
and other poultry. For the purpose of facilitating sampling and reducing the
concurrent costs, samples are preferably taken at the abattoir. However, monitoring
and surveillance programmes may also be able to use bacterial isolates from
designated national laboratories originating from other sources. A collection of an
optimal number of Salmonella isolates should be attempted within the practical and
economic constraints of the country. Isolation and identification of bacteria and
bacterial strains should follow internationally accepted procedures. Serovars of
epidemiological importance such as S. Typhimurium and S. Enteritidis should be
included. The selection of other relevant serovars will depend on the epidemiological
situation in each country. All Salmonella isolates should be serotyped and when
appropriate, phage-typed according to standard methods used at the nationally
designated laboratories. Validated methods should be used for antimicrobial
susceptibility testing of Salmonella (see Antimicrobial resistance: standardisation and
harmonisation of laboratory methodologies for the detection and quantification of antimicrobial
resistance).
Campylobacter
Campylobacter jejuni and C. coli can be isolated from the same samples as commensal
bacteria. Isolation and identification of these bacteria should follow internationally
accepted procedures. Campylobacter isolates should be identified, but also if possible,
typed and characterised. However, this is likely to depend on the technical abilities and
resources available in the Member Country.
Agar or broth micro-dilution methods are recommended for susceptibility testing of
Campylobacter. Internal and external quality control programmes should be strictly
adhered to (see Antimicrobial resistance: standardisation and harmonisation of laboratory
methodologies for the detection and quantification of antimicrobial resistance). It should be noted
that there are no validated methods for susceptibility testing of Campylobacter and no
internationally accepted reference strains available for quality control. However, work
is currently in progress on validation of methods for susceptibility testing of
Campylobacter.
Enterohaemorrhagic Escherichia coli
Enterohaemorrhagic E. coli, such as the serotype O 157 which is pathogenic to
humans but not to animals, may be included in resistance monitoring and surveillance
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4. Surveillance of resistance programme
programmes, provided that adequate laboratory security measures are in place. To
date, experience from studies of bovine isolates of E. coli O 157 indicates that the
prevalence of resistance is similar to that of commensal E. coli (7).
Commensal/indicator bacteria
Escherichia coli and enterococci are commensal bacteria common to all animals. These
bacteria are considered to constitute a reservoir of resistance genes, which may be
transferred to pathogenic bacteria causing disease in animals or humans. It is
considered that these bacteria should be isolated from healthy animals, preferably at
the abattoir, and be monitored for antimicrobial resistance.
Escherichia coli and enterococci should be isolated using solid media without
antimicrobials. Various enterococcal species may be considered for inclusion in
monitoring programmes, but it seems reasonable always to include Enterococcus faecium
(4, 14). For antimicrobial resistance traits of special interest, and where prevalence is
expected to be very low, more sensitive isolation procedures may be required. In such
cases, enrichment in broth containing a selective concentration of the antimicrobial of
interest can be used in addition to solid media (8). Identification should follow
standard methods used at nationally designated laboratories (2, 5).
For susceptibility testing of commensal bacteria, validated methods should be used
(see Antimicrobial resistance: standardisation and harmonisation of laboratory methodologies for the
detection and quantification of antimicrobial resistance).
Antimicrobials to be used in susceptibility testing
All clinically important antimicrobial classes used in human and veterinary medicine
should be monitored. However, the number of tested antimicrobials may have to be
limited according to the financial resources of the country in question. A suggested
selection of antimicrobials that may be considered for inclusion in national monitoring
programmes is presented in Appendix B. The proposed list includes almost all major
classes of antimicrobials used to treat both animal and human bacterial infections. In
susceptibility testing, some of the proposed antimicrobials are also commonly used as
representatives for other antimicrobials belonging to the same class. In general,
bacteria that are for example, resistant to erythromycin or tetracycline, are also
resistant to most other macrolides or tetracyclines, respectively.
Standardised susceptibility testing
See Antimicrobial resistance: standardisation and harmonisation of laboratory methodologies for the
detection and quantification of antimicrobial resistance.
Quality control – quality assurance
See Antimicrobial resistance: standardisation and harmonisation of laboratory methodologies for the
detection and quantification of antimicrobial resistance.
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4. Surveillance of resistance programme
Type of quantitative data to be reported
See Antimicrobial resistance: standardisation and harmonisation of laboratory methodologies for the
detection and quantification of antimicrobial resistance.
Database design and recording of results
Member Countries should give careful consideration to database design for
antimicrobial monitoring and surveillance programmes. This is because of the volume
and complexity of the information and the probable need for access over a long
period of time. The storage of raw (primary, non interpreted) data is essential in order
to allow for the evaluation of the data in response to various kinds of questions,
including those arising in the future. However, it is strongly recommended that the
strains are stored for an even longer period for future analysis.
Consideration may need to be given to technical requirements of computer systems
when an exchange of data between those different systems (comparability of
automatic recording of laboratory data and transfer of these data to resistance
monitoring programmes) should be envisaged.
Results should be entered into a suitable national database and recorded quantitatively,
for example as distribution of minimum inhibitory concentrations (MICs) in
milligrams per litre or inhibition zone diameters in millimetres (2, 4, 12, 15, 20, 21).
The information should include at least the following aspects:
a) sampling programme
b) sampling date
c) animal species/livestock category
d) type of sample
e) purpose of sampling
f) geographic origin of herd, flock or animal
g) age of animal.
The reporting of laboratory data should, where relevant, include the following
information:
a) identity of laboratory
b) isolation date
c) reporting date
d) bacterial species
e) serovar
f) phage-type
g) antimicrobial susceptibility result/resistance phenotype.
The proportion of isolates regarded as resistant should be reported, with defined
breakpoints. In the clinical setting, breakpoints are used to categorise bacterial strains
OIE International Standards on Antimicrobial Resistance, 2003
193
4. Surveillance of resistance programme
as susceptible, intermediate susceptible or resistant (6). These breakpoints, often
referred to as clinical or pharmacological breakpoints, are elaborated on a national
basis and vary between countries (10, 17, 20). The system of reference used should be
recorded. For surveillance purposes, another type of breakpoint, the microbiological
breakpoint, based only on the distribution of MICs or inhibition zone diameters of
the specific bacterial species tested is preferred. When using microbiological
breakpoints, only the bacterial population with acquired resistance that clearly deviates
from the distribution of the normal susceptible population will be designated as
resistant (17). Furthermore, the recording of the phenotype (resistance pattern) of
isolates is also very important.
Reporting and analysis of results
Countries should give consideration to the designation of a national centre, which
should assume the responsibilities to co-ordinate the activities related to the resistance
surveillance and monitoring programmes, to collect information at a central location
within the country and to produce an annual report on the resistance situation of the
country.
Participating laboratories should report results periodically to the national centre. The
national centre should have access to the raw data and the complete results of quality
assurance and inter-laboratory calibration activities and proficiency testing results (see
Antimicrobial resistance: standardisation and harmonisation of laboratory methodologies for the
detection and quantification of antimicrobial resistance).
The annual report should include information on the structure of the monitoring
system and on the chosen laboratory methods. It is of critical importance that
quantitative results are reported in a harmonised way, as MICs or inhibition zone
diameters in the form of histograms or as tables on frequency distributions.
Additional information of value includes statistics on the number of animals
produced, antibiotic use data and antimicrobials authorised for use. If possible, trends
in prevalence of resistance should be related to antimicrobial usage data and also to
the disease situation in each country.
For the purpose of a risk assessment addressing a particular question, it may be
necessary to generate specific information which would be relevant to the model that
has been developed for these purposes. In such cases, special reports might be
produced in co-operation with the persons responsible for conducting a specific risk
assessment.
If countries should envisage the sharing of raw data, the questions of ownership of
the data, access to raw data, interpretation of data and publication of reports should
be addressed.
Conclusions and recommendations
In many countries, antimicrobial resistance monitoring and surveillance in animal
husbandry have recently become a targeted area. Monitoring or surveillance of
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OIE International Standards on Antimicrobial Resistance, 2003
4. Surveillance of resistance programme
antimicrobial resistance in bacteria from food is conducted only by a few countries.
Monitoring of resistance in commensal bacteria of human origin is conducted by even
fewer countries. Acknowledging the different resources available in different
countries, co-ordination with other programmes, such as residue monitoring
programmes, should be considered.
The extensive experience of the OIE in animal disease monitoring and surveillance
may form an important foundation for Member Countries in the consideration of
approaches to the monitoring of antimicrobial resistance. However, as this is a new
area for most OIE Member Countries, each country should evaluate the overall issue
of antimicrobial resistance in animals and animal-derived food and carefully assess its
needs. The practical issues of existing technical expertise, economic and resource
requirements are important factors to be considered.
Antibiorésistance : harmonisation des programmes nationaux
de suivi et de surveillance de l’antibiorésistance chez les
animaux et dans les aliments d’origine animale
A. Franklin, J. Acar, F. Anthony, R. Gupta, †T. Nicholls, Y. Tamura, S. Thompson,
E.J. Threlfall, D. Vose, M. van Vuuren, D.G. White, H.C. Wegener & M.L. Costarrica
Résumé
Le Groupe ad hoc d’experts sur l’antibiorésistance créé par l’Organisation mondiale pour la santé
animale a élaboré une ligne directrice sur l’harmonisation des programmes nationaux de suivi et de
surveillance de l’antibiorésistance chez les animaux et dans les aliments d’origine animale. Cette ligne
directrice a pour objet de permettre l’obtention de données comparables dans les systèmes nationaux de
suivi et de surveillance afin de pouvoir comparer les situations dans différents pays et régions et
d’obtenir ensuite des résultats agrégés aux niveaux national, régional et international. Les auteurs
donnent une définition de la surveillance et du suivi. Les systèmes nationaux devraient être en mesure
de déceler l’apparition d’une résistance et de déterminer la prévalence de bactéries résistantes. Les
données obtenues devraient être utilisées lors de l’évaluation des risques pour la santé publique et
contribuer à la mise en œuvre d’une politique de gestion du risque. Plusieurs facteurs spécifiques ont été
identifiés pour les besoins d’une telle harmonisation: l’espèce animale, les produits alimentaires, les
programmes d’échantillonnage, les espèces bactériennes, les antibiotiques soumis aux tests, les méthodes
de laboratoire, la communication des données, ainsi que la structure des bases de données et des
rapports.
Mots-clés
Analyse du risque – Antibiorésistance – Harmonisation – Maîtrise de la résistance –
Médecine humaine – Médecine vétérinaire – Méthodologie de laboratoire – Normes
internationales – Oragnisation mondiale pour la santé aniamale – Santé publique –
Suivi – Surveillance.
OIE International Standards on Antimicrobial Resistance, 2003
195
4. Surveillance of resistance programme
Resistencia a los antimicrobianos: armonización de
programas nacionales de seguimiento y vigilancia de la
resistencia a los antimicrobianos en animales y alimentos de
origen animal
A. Franklin, J. Acar, F. Anthony, R. Gupta, †T. Nicholls, Y. Tamura, S. Thompson,
E.J. Threlfall, D. Vose, M. van Vuuren, D.G. White, H.C. Wegener & M.L. Costarrica
Resumen
El Grupo Ad hoc de expertos sobre la resistencia de las bacterias a los productos antimicrobianos de
la Organización mundial de sanidad animal ha elaborado una directriz sobre la armonización de
programas nacionales de seguimiento y vigilancia de la resistencia a los antimicrobianos en animales y
alimentos de origen animal, pensada para que puedan obtenerse datos comparables a partir de
distintos sistemas nacionales de vigilancia, lo que a su vez serviría para comparar la situación en
diferentes países o regiones y elaborar datos agregados a escala nacional, regional e internacional. Los
autores ofrecen la definición de ‘vigilancia’ y ‘seguimiento’. Los sistemas nacionales deben ser capaces
de detectar la aparición de resistencias y determinar la prevalencia de bacterias resistentes. Esa
información debe servir después para evaluar los riesgos para la salud pública y ayudar a definir
programas de gestión de riesgos. A juicio de los autores, los principales elementos que conviene
armonizar son: las especies animales, los productos alimentarios, los programas de muestreo, las
especies bacterianas, los antimicrobianos analizados, los métodos de laboratorio, la forma de presentar
los datos y la estructura de bases de datos e informes.
Palabras clave
Análisis de riesgos – Armonización – Contención de las resistencias – Medicina
humana – Medicina veterinaria – Métodos de laboratorio – Normas internacionales –
Organización mundial de sanidad animal – Resistencia a los productos
antimicrobianos – Salud pública – Seguimiento – Vigilancia.
Appendix A
Sample size estimates for prevalence of antimicrobial resistance in a large population
Expected prevalence
10%
20%
30%
40%
50%
60%
70%
80%
90%
Level of confidence
90% desired precision
95% desired precision
10%
5%
1%
10%
5%
1%
24
43
57
65
68
65
57
43
24
97
173
227
260
270
260
227
173
97
2,429
4,310
5,650
6,451
6,718
6,451
5,650
4,310
2,429
35
61
81
92
96
92
81
61
35
138
246
323
369
384
369
323
246
138
3,445
6,109
8,003
9,135
9,512
9,135
8,003
6,109
3,445
Calculations based upon Epi Info v6.04b to c Upgrade, October 1997, Centers for Disease Control
(public domain software available at http://www.cdc.gov/epo/epi/epiinfo.htm)
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OIE International Standards on Antimicrobial Resistance, 2003
4. Surveillance of resistance programme
Appendix B
Proposed list of antimicrobials which, as a first step may be included in
antimicrobial resistance surveillance and monitoring programmes
Antimicrobial
Salmonella/
Escherichia Campylobacter Enterococcus
coli
Animal
pathogens,
Grampoitive
Animal
pathogens,
Gramnegative
Beta-lactams
Penicilin G
Ampicillin
Oxacillin
Amoxi/Clav
Cephalosporins
Ceftiofur
Ceftriaxone
Cephalothin
Macrolides
Erythromycin
Lincosamides
Clindamycin
Streptogramins
Virginiamycin
Quinupristin/Dalfopristin
Tetracyclines
Tetracycline
Aminoglycosides
Streptomycin
Neomycin
Kanamycin
Gentamicin
Apramicin
Amikacin
Amphenicols
Chloramphenicol
Florfenicol
Potentiated
sulphonamides
Trimethroprim/Tmp-Sul
Sulphonamides
Quinolones
Nalidixic Acid
Enrofloxacin/
Ciprofloxacin
Glycopteptides
Vancomycin
+
+
+
+
+
+ (Staph)
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
OIE International Standards on Antimicrobial Resistance, 2003
(+)
+
+
+
+
197
4. Surveillance of resistance programme
References
1. Boisseau J. & Röstel B. (1998). – The role of international trade in animals, animal
products and feed in the spread of transferable antibiotic resistance and possible methods for
control of the spread of infectious agent resistance factors. In Comprehensive reports on
technical items presented to the International Committee or to Regional Commissions. OIE
(World organisation for animal health), Paris, 197-234.
2. Caprioli A., Busani L., Martel J.L. & Helmuth R. (2000). – Monitoring of antibiotic
resistance in bacteria of animal origin: epidemiological and microbiological methodologies. Int.
J. antimicrob. Agents, 14 (4), 295-301.
3. Corpet E.E. (1988). – Antibiotic resistance from food (letter). N. Engl. J. Med., 318,
1206-1207.
4. Danish Zoonosis Centre (2000). – DANMAP 99. Consumption of antimicrobial agents
and occurrence of antimicrobial resistance in bacteria from food animals, food and humans in
Denmark. Danish Veterinary Laboratory, Ministry of Agriculture and Fisheries, Copenhagen,
52 pp. Website: http://www.SVS.dk (document accessed on 22 August 2001).
5. Devriese L.A., Pot B. & Collins M.D. (1993). – Phenotypic identification of the genus
Enterococcus and differentiation of phylogenetically distinct enterococcal species and species
groups. J. appl. Bacteriol., 75, 399-408.
6. European Committee for Antimicrobial Susceptibility Testing (EUCAST) of the
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) (2000). –
EUCAST Definitive Document E.Def 1.2, May 2000: terminology relating to methods for the
determination of susceptibility of bacteria to antimicrobial agents. Clin. Microbiol. Infect., 6,
503-508.
7. Food and Drug Administration (FDA)/United States Department of Agriculture
(USDA)/Centers for Disease Control (CDC) (1998). – National antimicrobial susceptibility
monitoring program – veterinary isolates. Website: www.cdc.gov./ncidod/dbmd/narms
(document accessed on 4 September 2001).
8. Ieven M., Vercauteren E., van Descheemaker P., Laer F. & Goosens H. (1999). –
Comparison of direct plating and broth enrichment culture for the detection of intestinal
colonization by glycopeptide-resistant enterococci among hospitalized patients. J. clin.
Microbiol., 37, 1436-1440.
9. Joint Expert Technical Advisory Committee on Antibiotic Resistance (JETACAR)
(1999). – The use of antibiotics in food producing animals: antibiotic resistant bacteria in
animals and humans. Report of the Joint Expert Advisory Committee on Antibiotic
Resistance. Commonwealth Department of Health and Aged Care and Department of
Agriculture,
Fisheries
and
Forestry,
Canberra,
238
pp.
http://www.affa.gov.au/docs/quarantine/fopolicy/jetacar.htm (document accessed on
22 August 2001).
10. Leegaard T.M., Caugant, D.A., Froholm L.O. & Hoiby E.A. (2000). – Apparent
differences in antimicrobial susceptibility as a consequence of national guidelines. Clin.
Microbiol. Infect., 6, 290-293.
198
OIE International Standards on Antimicrobial Resistance, 2003
4. Surveillance of resistance programme
11. Levy S.B. (1997). – Antibiotic resistance: an ecological imbalance. In Antibiotic resistance.
Origins, evolution, selection and spread (D.J. Chadwick & J. Goode, eds). John Wiley & Sons,
Chichester, 1-14.
12. Martel J.-L., Tardy F., Brisabois A., Lailler R., Coudert M. & Chaslus-Dancla E. (2000). –
The French antibiotic resistance monitoring programs. Int. J. antimicrob. Agents, 14 (4), 275-283.
13. Moreno M.A., Dominguez L., Teshager T., Herrero I.A. & Porrero M.C. (2000). –
Antibiotic resistance monitoring: the Spanish programme. Int. J. antimicrob. Agents, 14 (4),
285-290.
14. Mundy L.M., Sahm D.F. & Gilmore M. (2000). – Relationships between enterococcal
virulence and antimicrobial resistance. Clin. Microbiol. Rev., 13, 513-522.
15. OIE (World organisation for animal health) (1999). – Report of Working Group 3:
resistance monitoring and surveillance. In European Scientific Conference. The use of
antibiotics in animals. Ensuring the protection of public health, 24-26 March, Paris. OIE, Paris,
96-135.
Website:
http://www.anmv.afssa.fr/ccoie/documents/cdrom1999/Antibiotics/index.htm (document
accessed on 22 August 2001).
16. OIE (World organisation for animal health) (2000). – International animal health code:
mammals, birds and bees, 9th Ed. OIE, Paris, 473 pp.
17. Ringertz S., Olsson-Liljequist B., Kahlmeter G. & Kronvall G. (1997). – Antimicrobial
susceptibility testing in Sweden II. Species-related zone diameter breakpoints to avoid
interpretive errors and guard against unrecognised evolution of resistance. Scand. J. infect. Dis.
Suppl., 105, 8-12.
18. Scientific Steering Committee of the European Commission (1999). – Opinion of the
Scientific Steering Committee on antimicrobial resistance. European Commission, DirectorateGeneral
XXIV,
Brussels,
121
pp.
Website:
http://europa.eu.int/comm/food/fs/sc/ssc/out50_en.pdf (document accessed on 22 August
2001).
19. Teuber M. & Perreten V. (2000). – Role of milk and meat products as vehicles for
antibiotic-resistant bacteria. Acta vet. scand. Suppl., 93, 75-87.
20. Threlfall E.J., Fisher I.S.T., Ward L.R., Tschäpe H. & Gerner-Smidt P. (1999). –
Harmonization of antibiotic susceptibility testing for Salmonella: results of a study by 18
national reference laboratories within the European Union-funded Enter-Net group. Microb.
Drug Resist., 5, 195-200.
21. World Health Organization (WHO) (1997). – The medical impact of the use of
antibiotics in food animals. Report of a WHO meeting, 13-17 October, Berlin. WHO, Geneva,
281 pp.
22. Wray C., McLaren I.M. & Beedel Y.E. (1993). – Bacterial resistance monitoring of
salmonellas isolated from animals, national experience of surveillance schemes in the United
Kingdom. Vet. Microbiol., 35, 313-319.
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199
4. Surveillance of resistance programme
The National Antimicrobial Resistance Monitoring
System (NARMS)
P.J. Fedorka-Cray (1), M.L. Headrick (2) & L. Tollefson (2)
(1)
PhD, USDA-ARS-Antimicrobial Resistance Research Unit, Athens, GA, United States of America
(2)
FDA Center for Veterinary Medicine, Rockville, MD, United States of America
Antibiotic resistance in foodborne pathogens is an increasingly important health issue.
There is a programme in place in the United States of America (USA) to monitor
changes in susceptibility of enteric bacteria to antimicrobial drugs used in animals and
humans. That programme is the National Antimicrobial Resistance Monitoring
System – Enteric Bacteria (NARMS).
Background
Resistant bacteria are not as susceptible to antibiotics or other antimicrobial drugs as
non-resistant bacteria. The use of antibiotics may eliminate susceptible bacteria,
leaving resistant bacteria behind. If resistant bacteria spread, a person or animal with
this infection may not be able to be treated with the usual antibiotics, or an increased
dose may be required. As a result they may be sick for a longer time than if they had
an infection caused by bacteria that were easily treatable with antibiotics.
The increase in bacterial resistance to antimicrobial drugs is a natural phenomenon, an
outcome of evolution. Any population of organisms, including bacteria, naturally
includes variants with unusual traits. In this case, some bacteria have the ability to
fend off the action of an antimicrobial. The use of antimicrobial drugs in humans and
animals over the past fifty years has inadvertently accelerated the development of
resistance by increasing the selection pressure exerted on these organisms. Once
antimicrobial pressure has been introduced into an environment, resistance may be
spread to other microbes.
Food animals such as cattle, pigs, turkeys, or chickens may receive antimicrobial drugs
for growth promotion and control or treatment of infectious diseases. Food animals
can carry organisms that can make people sick, but may not necessarily make the
animal sick. For example, Salmonella, Campylobacter, and E. coli O157 are common
bacteria found in the intestines of various food animals. These bacteria may not cause
disease in the animal, however, all three bacteria may cause foodborne illness in
humans. These organisms may develop resistance when exposed to antimicrobial
drugs given to the animal. These resistant organisms can contaminate food products
at slaughter and then infect humans who eat the food, particularly if the food is
undercooked or cross-contaminated after cooking.
Evidence of increasing resistance to antimicrobial drug treatment in bacteria that
infect humans has raised questions about the role that antimicrobial drug use in food
animals plays in the emergence of antimicrobial drug resistant bacteria. The link
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OIE International Standards on Antimicrobial Resistance, 2003
4. Surveillance of resistance programme
between antimicrobial resistance in foodborne pathogenic bacteria and use of
antimicrobials in food animals has been reported in a number of studies. For
foodborne pathogens, particularly those such as Salmonella that are rarely transferred
from person to person in the United States of America, food (such as meat or eggs)
from food animals is considered a likely source of human exposure to resistant
organisms.
The National Antimicrobial Resistance Monitoring System
The United States of America now has a programme in place that allows the Food and
Drug Administration (FDA) to monitor resistance to antimicrobial drugs used in
humans and food animals. The programme is called the National Antimicrobial
Resistance Monitoring System – Enteric Bacteria (NARMS). It combines the activities
of FDA, the Centers for Disease Control and Prevention (CDC), and the U.S.
Department of Agriculture (USDA) to create a nationwide monitoring system.
NARMS was started (and has been expanded) because of the human health concerns
related to the use of antimicrobial drugs in food animals. As a part of NARMS,
isolates of foodborne bacteria such as E. coli, Salmonella, Enterococci, and Campylobacter
from humans and food animals are collected and tested to determine changes in
bacterial susceptibility to antimicrobial drugs. Each year, samples are taken and tested
to determine whether there have been changes over time in the resistance (or
susceptibility) of certain enteric bacteria to a collection of antimicrobial drugs. The
antimicrobial drugs tested are selected based on their importance in human and animal
medicine. The food animal specimens are gathered from healthy farm animals, animal
clinical specimens, from carcasses of food animals at slaughter, ground product at
processing plants, and from retail meats.
The human-origin isolates are sent to the CDC in Atlanta, Georgia, by state and/or
local health departments in all fifty states.
Animal-origin isolates are collected from sites across the U.S. and submitted for
susceptibility testing conducted by the Agricultural Research Service (ARS) of USDA
in Athens, Georgia. Animal isolates are received from a number of sources including
federally inspected slaughter and processing facilities, the USDA National Animal
Health Monitoring System, studies on farms, sentinel sites, which are Veterinary
Diagnostic Laboratories, and the USDA National Veterinary Services Laboratories.
The NARMS programme was begun in 1996 with Salmonella as the sentinel organism.
Other enteric bacteria were added as the programme was expanded. NARMS results
for Salmonella are available since 1997. Links to the summary data are posted on the
FDA Center for Veterinary Medicine (CVM) web site (see below). These data can
provide useful information about patterns of emerging resistance, which in turn can
help guide treatment decisions. NARMS data are an asset to outbreak investigations.
Antimicrobial resistance patterns are useful in identifying the source and magnitude of
resistance. Antimicrobial resistance data from humans and animals are important for
the development of public health recommendations for the use of drugs in humans
and food animals.
OIE International Standards on Antimicrobial Resistance, 2003
201
4. Surveillance of resistance programme
The NARMS programme was expanded in 2001 and 2002 to include a Retail Arm of
NARMS. This aspect of NARMS began with a pilot study that included the
susceptibility testing of enteric bacteria isolated from retail meat samples collected
from grocery stores in Iowa. The success of this pilot project led to the
implementation of the collection of retail meat samples in multiple states in
collaboration with the CDC and FoodNet sites. A study that includes susceptibility
testing of enteric bacteria isolated from animal feed ingredients is also being
conducted. The FDA CVM Office of Research Laboratory in Laurel, Maryland, is
conducting the susceptibility testing of these isolates.
CDC, USDA, and FDA test Salmonella, E. coli, Campylobacter, Enterococci, and other
bacterial isolates for susceptibility to designated panels of selected antimicrobial drugs.
The results of these tests are compared with data from previous years to look for
changes in resistance patterns of the organisms to these drugs. Public health officials,
animal producers, drug manufacturers, physicians, and veterinarians can use the
information from NARMS to control and prevent harm from the use of antimicrobial
drugs in food animals.
The National Antimicrobial Resistance Monitoring System
methods
Human arm
Participating state or local public health laboratories systematically select every 20th
non-typhi Salmonella isolate, Shigella, and E. coli O157:H7 submitted to their laboratory
and send the isolates, at the end of each month, to CDC. All Salmonella typhi, Listeria
monocytogenes, and non-cholerae Vibrio isolates received by the participating laboratories
are forwarded to CDC.
Additionally, health department partners that also participate in the FoodNet
Program, submit one Campylobacter isolate each week to the CDC Foodborne and
Diarrheal Diseases Laboratory for susceptibility testing. States that participate in this
programme continue to increase as more health department partners join the
FoodNet Program. In 2003, FoodNet is expanding to ten sites. The FoodNet Web
Site at: http://www.cdc.gov/foodnet/ contains a listing of the current participants.
The antimicrobial susceptibility testing results are sent from the CDC laboratory to
NARMS epidemiologists at CDC, where data are entered and analysed.
Animal arm
The USDA, ARS, Antimicrobial Resistance Research Unit (ARRU) laboratory in
Athens, Georgia, receives Salmonella, Campylobacter, E. coli and Enterococci isolates from
animals for antimicrobial susceptibility testing. Isolates are received at the Athens
laboratory from the sources described in ‘How We Monitor.’ Poultry carcass rinses are
sent to ARRU from the Food Safety Inspection Service (FSIS) laboratories for
culture, isolation, and susceptibility testing of Campylobacter, E. coli, and Enterococci
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OIE International Standards on Antimicrobial Resistance, 2003
4. Surveillance of resistance programme
organisms. Salmonella isolates are received from FSIS, the Animal and Plant Inspection
Service, the National Veterinary Services Laboratories (NVSL), and sentinel site
laboratories. Salmonella serotyping is conducted at the NVSL. E. coli and Enterococci
isolates are also isolated from on-farm faecal samples as part of the NAHMS or other
on-farm epidemiologic investigations.
Retail arm
The Iowa Retail Meat Pilot Survey included collection and antimicrobial susceptibility
testing of bacterial isolates from retail meats purchased from Iowa retail grocery
stores. A total of 870 samples of ground beef, ground turkey, pork chops, and chicken
breasts were collected from 300 randomly selected sites. These samples were cultured
for Salmonella, Campylobacter, E. coli, and Enterococci. The collection phase of the Iowa
Retail Meat Pilot Survey was completed in June 2002. A FoodNet Retail Meat
Surveillance study began in January 2002. Samples of ground beef, ground turkey,
pork chops and chicken breasts are being collected from grocery stores in
participating FoodNet States. Enteric bacterial isolates from these samples are being
sent from the FoodNet laboratories to FDA/CVM Office of Research for
antimicrobial drug susceptibility testing of Salmonella, Campylobacter, E. coli, and
Enterococci. An animal feed ingredient survey collected samples of meat meal, meat and
bone meal, fish meal, blood meal, and poultry meal at rendering plants in the USA
during 2002. These samples are tested for Salmonella, E. coli, Campylobacter and
Enterococci. Additional components, including a study of plant-origin animal feed
ingredients such as soybean or cottonseed meal in 2003, are being added.
The NARMS programme is designed with comparable methodology between the
human, animal, and retail arms. For all isolates, susceptibility testing currently involves
the determination of the minimum inhibition concentration (MIC) for a panel of
selected antimicrobial agents. These antimicrobial drugs are evaluated each year for
their continued importance in human and animal medicine. The antimicrobial drugs
tested can be modified to meet monitoring needs. Susceptibility testing of
Campylobacter is performed to determine the MICs for eight antimicrobial agents:
azithromycin, chloramphenicol, ciprofloxacin, clindamycin, erythromycin, gentamicin,
nalidixic acid and tetracycline. National Committee for Clinical Laboratory Standards
(NCCLS) guidelines are followed, when possible, throughout the testing procedure.
Using NARMS as a template, FDA CVM and Mexico are working on a cooperative
project known as ‘ResistVet’ to monitor trends in antimicrobial resistance in humans,
animals, and retail meats at four sites in Mexico. A pilot project was begun in 2001
and a three-year cooperative agreement was signed in 2002. To further support
antimicrobial resistance monitoring in Mexico, FDA CVM collaborated with the
World Health Organization to conduct a training course in 2001 on the surveillance of
Salmonella and antimicrobial resistance in foodborne pathogens. The training took
place at a participating ResistVet site in Mexico.
FDA’s goal is to protect the public health by ensuring that significant human
antimicrobial therapies are not lost due to use of antimicrobial drugs in food-
OIE International Standards on Antimicrobial Resistance, 2003
203
4. Surveillance of resistance programme
producing animals, while providing for the safe use of antimicrobial drugs in foodproducing animals. Information from NARMS will allow evaluation of trends in the
susceptibility of the organisms causing disease to the drugs used to treat them. For
more information on antimicrobial resistance issues, visit CVM’s web site at
www.fda.gov/cvm. NARMS reports are published annually. To review the NARMS
Annual Reports and other NARMS information use the following Internet addresses:
FDA/CVM NARMS site:
– http://www.fda.gov/cvm/index/narms/narms_pg.html
– CDC NARMS site: http://www.cdc.gov/narms/
– USDA/ARS web site: http://www.arru.saa.ars.usda.gov/narms.html
For additional information on the NARMS programme, contact Dr Marcia Headrick,
FDA CVM NARMS Coordinator, at [email protected] or (706) 546-3689.
References for this article and the NARMS programme are also available from
Dr Headrick.
__________
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OIE International Standards on Antimicrobial Resistance, 2003
4. Surveillance of resistance programme
Surveillance of resistance – human/animal
coordinated approaches in France
V. Jarlier
Hôpital Pitié Salpêtrière, laboratoire central de bactériologie, 91 bd de l’Hôpital, 75634 Paris Cedex 13, France
L’Observatoire National de l’Epidémiologie de la résistance Bacterienne aux
Antibiotiques (ONERBA) (Scientific Committee: P. Allouch, G. Antoniotti, O. BajoletLaudinat, O. Bellon, J.D. Cavallo, H. Chardon, E. Chaslus-Dancla, H. Dabernat, F.
Grobost, V. Jarlier [coordinator], N. Marty, M.H. Nicolas-Chanoine, Y. Péan, B.
Perichon, J. Robert, M. Roussel-Delvallez, F. Tardy, E. Varon, Ph. Weber.) was created
in 1997 as a non profit organisation, with the following missions:
a) to gather and to analyse available information on bacterial resistance in France
and to provide this to health authorities and professionals
b) to advise on conditions of data collection
c) to set up studies designed to obtain data in areas not yet covered and
d) to participate in training programmes.
ONERBA links fourteen networks organised by medical and veterinary labs that have
been monitoring antibiotic resistance in France for several years, independently of the
pharmaceutical industry. In order to reach its objectives, such a ‘network of networks’
requires methodological support and recommendations concerning the following:
a) principles, aims and presentation of the different types of information
b) definitions and terms
c) data management (e.g. duplicate isolates) and data stratification
d) quality controls.
Efforts have been made to adopt a common body of definitions and terms used for
humans and animals. A guide containing recommendations on the methodology and
implementation of bacterial resistance monitoring in laboratories has been edited by
ONERBA. Moreover it has been decided to include in drug susceptibility tests
antibiotics allowing, as markers, comparisons between bacteria of animal and human
origin, such as: ampicillin, amoxicillin-clavulanate, gentamicin, cotrimoxazole,
tetracycline for Enterobacteriaceae, and penicillin G, oxacillin, kanamycin, gentamicin,
erythromycin, tetracycline for Staphylococcus. The resistance data from private medical
laboratories, hospital laboratories and veterinary laboratories are being presented
under standardised formats on a website (www.onerba.org).
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205
4. Surveillance of resistance programme
The Japanese Veterinary Antimicrobial Resistance
Monitoring System (JVARM)
Y. Tamura
National Veterinary Assay Laboratory, Ministry of Agriculture, Forestry and Fisheries, 1-15-1, Tokura, Kokubunji,
Tokyo 185-8511, Japan
With the rapid development of intensive systems for rearing food-producing animals,
bacterial infection has caused serious economic losses in animal husbandry. As a
result, antimicrobials have been widely used for the control of infection. Some reports
indicate that many bacteria of animal origin have become resistant to these
antimicrobials. An increasing incidence of antimicrobial-resistant bacteria could pose
serious problems not only to animal hygiene, but also to public health. However, until
recently there was a lack of nationwide information available on the antimicrobial
resistance of bacteria of animal origin in Japan. Consequently, the Japanese Veterinary
Antimicrobial Resistance Monitoring System (JVARM) was established in 1999 to
replace the former monitoring system that specialised in animal hygiene.
Background
In 1969, the Swann Committee (4) reviewed the agricultural use of antimicrobials.
Among their recommendations was that regular and much wider surveillance should
be made of the bacteria of animals, animal products and man, including their
antimicrobial resistance. Recently, the relationship between the use of antimicrobials
in food-producing animals and the emergence of resistant bacteria in the food chain
has become of great concern and has been the subject of numerous international
meetings (2, 6, 7). In Japan, basic legislation on food, agriculture and rural areas was
established in 1999 to stabilise and improve people’s lifestyle and to develop the
national economy. This legislation aimed to improve the management of food in order
to ensure food safety and improve food quality.
Objectives
The objectives of JVARM are to monitor the occurrence of antimicrobial resistance in
bacteria in food-producing animals and monitor the consumption of antimicrobials
for animal use. Moreover, other objectives are to identify the efficacy of antimicrobials
in food-producing animals, to promote prudent use of such antimicrobials, and to
ascertain the public health problem.
Outline of the Japanese veterinary antimicrobial resistance
monitoring system
The JVARM (summarised in Fig. 1) is composed of three parts: monitoring the
quantities of antimicrobials used in animals; resistance monitoring in zoonotic and
indicator bacteria isolated from healthy animals; and resistance monitoring in animal
pathogens isolated from diseased animals. In Japan, the Ministry of Agriculture,
Forestry and Fisheries (MAFF) is responsible for the field of animal husbandry, but
206
OIE International Standards on Antimicrobial Resistance, 2003
4. Surveillance of resistance programme
not food hygiene. Thus, test bacteria are isolated on the farm from food-producing
animals, but not in food products.
Ph am aceu tical
com panies
JV A R M
C o n su m p tio n
of
An tim icrob ials
R esistance in
zo ono tic and
indicato r
b acteria
R esistan ce in
an im al
patho g ens
H ealth y an im als
D iseased an im als
Fig. 1
Outline of the Japanese veterinary antimicrobial resistance monitoring system.
Monitoring of antimicrobial consumption
The monitoring of antimicrobial consumption is shown in Figure 2. Pharmaceutical
companies that produce and import antimicrobials for animals are required to submit
data to the National Veterinary Assay Laboratory (NVAL) annually in accordance
with pharmaceutical legislation. The NVAL subsequently collects, analyses and
evaluates such data and MAFF headquarters publishes this data in a yearly report
entitled the ‘Amount of medicines and quasi-drugs for animal use’.
The annual weight in kilograms of the active ingredients of approved antimicrobials
used in animals is collected. This includes only therapeutic antimicrobials for animal
use and the data are subdivided by animal species. However, this only provides an
estimate of the consumption for each target species, because one antimicrobial is
frequently used for multiple animal species.
P h a r m a c e u t ic a l C o .
1
2
...…
F o rm at
( M ic r o s o f t E x c e l)
M AFF
P u b lic a t io n ( y e a r l y )
5
3
4
R ep o rt
N a t io n a l V e t e r in a r y A s s a y L a b o r a t o r y
C o lle c t io n , A n a l y s is , E v a lu a t io n
Fig. 2
Monitoring of antimicrobial consumption
OIE International Standards on Antimicrobial Resistance, 2003
207
4. Surveillance of resistance programme
Bacteria for resistance testing are collected continuously and include: zoonotic bacteria
and indicator bacteria isolated from healthy animals; and pathogenic bacteria isolated
from diseased animals. Zoonotic bacteria include: Salmonella species, and Campylobacter
jejuni or C. coli; indicator bacteria include Escherichia coli including O157 and Enterococcus
faecium or E. fecalis, including Vancomycin-Resistant Enteroccoci. Animal pathogens
included at present are Salmonella species, Staphylococcus aureus, Actinobacillus
pleuropneumoniae, Actinobacillus pyogenes, Pasteurella multocida, Streptococcus species and
Klebsiella species. The zoonotic and indicator bacteria are isolated from faecal samples
collected from cattle, pigs, broilers and layers. Six samples from animals are collected
in each prefecture every year with a limit of one sample per farm. Two strains per
sample are collected for antimicrobial susceptibility testing. Animal pathogens are
isolated from samples submitted for diagnosis. Minimum Inhibitory Concentrations
(MICs) of test bacteria are determined for antimicrobials mainly by the agar dilution
method as described by the National Committee for Clinical Laboratory Standards (3).
The Japanese veterinary antimicrobial resistance monitoring
implementation system
The JVARM implementation system is shown in Figure 3. A total of one hundred and
ninety-five Livestock Hygiene Services Centers (LHSC), which belong to prefecture
offices, participate in JVARM. The LHSC function as participating laboratories of
JVARM, and are responsible for the isolation and identification of target bacteria, as
well as MIC measurement. They send results and resistant bacteria to NVAL, which
functions as the reference laboratory of JVARM, and is responsible for preservation
of resistant bacteria, collection and analysing all data and reporting to MAFF
headquarters. In addition, NVAL conducts research into the molecular epidemiology
and resistance mechanisms of the bacteria.
MAFF
Administrative action
Report
National Veterinary Assay Laboratory
Announcement
Preservation of resistant bacteria
Distribution of reference strains
Molecular epidemiology, resistance mechanisms
Collection, analysis and evaluation of prefecture data
Livestock Hygiene Services Center
Sampling
Isolation/Identification
MIC measurement
Food-producing Animal
Cattle, Swine, Broiler, Layer
Fig. 3
Monitoring of antimicrobial resistant bacteria
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OIE International Standards on Antimicrobial Resistance, 2003
4. Surveillance of resistance programme
Quality assurance/quality control systems
Quality control procedures are implemented in participating laboratories that perform
antimicrobial susceptibility testing to help monitor the precision and accuracy of the
test procedure, the performance of the appropriate reagents and the personnel
involved. Strict adherence to standardised techniques is necessary for the collection of
reliable and reproducible data from participating laboratories. Quality control
reference bacteria are also tested in each participating laboratory to ensure
standardisation. Moreover, NVAL holds a national training course on antimicrobial
resistance every year to provide training in standardised laboratory methods for the
isolation, identification and antimicrobial susceptibility testing of target bacteria.
Recently, proficiency testing of participating laboratories has been initiated for the
major bacterial species included in JVARM. The participating laboratories test these
strains using the same conditions as the antimicrobial susceptibility test. Proficiency
testing is one of the foundations of quality assurance for participating laboratories in
JVARM and ensures that reported MIC data are accurate without question.
Announcement of data
Since a problem with antimicrobial resistance directly influences animal and human
health, it is of paramount importance to distribute information on antimicrobial
resistance as soon as possible. We have officially taken three steps to publicise such
information; initially through the MAFF weekly newspaper called ‘Animal Hygiene
News’, then by publication in scientific journals and via the NVAL website (URL
http://www.nval.go.jp/taisei/taisei.html).
Although JVARM was started in 1999 and conforms to the OIE report on
antimicrobial resistance (1, 5), further steps could be taken to ensure animal and
public health in Japan. In particular, several countries have initiated national
monitoring systems that include both animal and public health, but at present there is
neither a global monitoring system in Japan nor coordination between these areas.
Joint efforts are now needed to establish a national antimicrobial monitoring system
that includes both animal and public health to solve the emerging problem of
antimicrobial resistance.
References
1. Franklin A., Acar J., Anthony F., Gupta R., Nicholls T., Tamura Y., Thompson S.,
Threlfall E.J., Vose D., van Vuuren M., White D.G., Wegener H.C. & Costarrica M.L. (2001).
– Antimicrobial resistance: harmonisation of national antimicrobial resistance monitoring and
surveillance programmes in animals and in animal-derived food. Rev. sci. tech. Off. int. Epiz., 20
(3), 859-870.
2. OIE (World organisation for animal health) (1999). – The use of antibiotics in animals
ensuring the protection of public health. In Proceeding of European Scientific Conference 2426 March, Paris.
3. Shryock T.R., Apley M., Jones R.N., Lein D.H., Thornsberry C., Walker R.D., Watts J.L.,
White D.G. & Wu C.C. (2002). – Performance standards for antimicrobial disk and dilution
susceptibility tests for bacteria isolated from animals. Approved standard, 2nd Ed.. NCCLS
M31-A2.
OIE International Standards on Antimicrobial Resistance, 2003
209
4. Surveillance of resistance programme
4. Swann M.M. (1969). – Report of the joint committee on the use of antibiotics in animal
husbandry and veterinary medicine. HM Stationary Office.
5. White D.G., Acar J., Anthony F., Franklin A., Gupta R., Nicholls T., Tamura Y.,
Thompson S., Threlfall E.J., Vose D., van Vuuren M., Wegener H.C. & Costarrica M.L. (2001).
– Antimicrobial resistance: standardisation and harmonisation of laboratory methodologies for
the detection and quantification of antimicrobial resistance. Rev. sci. tech. Off. int. Epiz., 20 (3),
849-858.
6. World Health Organization (WHO) (1997). – The medical impact of the use of
antimicrobials in food animals. Report of WHO meeting, 13-17 October, Berlin.
7. World Health Organization (WHO) (1998). – Use of quinolones in food animals and
potential impact of human health. Report of WHO meeting, 2-5 June, Geneva.
__________
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OIE International Standards on Antimicrobial Resistance, 2003
4. Surveillance of resistance programme
Cases of antimicrobial resistance to some pathogens
in Vietnam
T.T.T. Phuong 1
SVSV Project supported by European Community, Ho Chi Minh City, Vietnam
Introduction
Reports from all over the world, indicating a steady increase in antimicrobial resistance
of micro-organisms pathogenic for both humans and animals, are causing concern
within the human and veterinary medical professions. Finding answers to this
important problem presents challenges. In Vietnam, little research has been carried
out so far in this field, but the fact that this country is also confronted with the
problem of antimicrobial resistance is demonstrated by the few reported cases that are
presented in this paper. They should be a stern warning to us and a good reason to
step up our national pharmaco-vigilance.
The use of antibiotics in animal production in Vietnam
Market statistics of veterinary drugs in recent years indicate widespread use of
antibiotics in Vietnam. Their share of the total veterinary drug sales is around 50%.
There is a great variety of different antibiotics produced in and imported into
Vietnam. Drugs often contain a cocktail of different antibiotics and little is known
about their therapeutic effect. They are used for therapeutic treatment and also as
animal feed additives with two functions: sub-therapeutic prophylaxis and as a growth
promoter.
Results from some investigations on antimicrobial resistance
Sensitivity to antibiotics of some pathogenic bacteria in animal health
Example 1
Sensitivity of mastitis causing bacteria to antimicrobial drugs
In 1998, the University of Agriculture and Forestry in Ho Chi Minh City carried out
an investigation (2) on the sensitivity to several antibiotic substances of bacteria
(Staphylococcus aureus, Streptococcus agalactiae and E. coli). The samples were derived from
cows with subclinical mastitis (Table I).
1
Representative Office of Department of Animal Health, Ho Chi Minh City, Vietnam
OIE International Standards on Antimicrobial Resistance, 2003
211
4. Surveillance of resistance programme
Example 2
Sensitivity to antimicrobial drugs of pathogenic bacteria isolated from
pigs
A sensitivity investigation on a total of 675 samples from pigs was carried out in
1998-2000 by the University of Agriculture and Forestry in Ho Chi Minh City (3)
(Table II).
Example 3
Sensitivity to antimicrobial drugs of pathogenic bacteria isolated from
poultry
The University of Agriculture and Forestry in Ho Chi Minh City also carried out in
1998-2000 a sensitivity investigation on a total of 237 samples from poultry (3). The
effectiveness of antimicrobial substances against pathogenic bacteria in poultry also
varies widely and is generally low (Table III).
Table I
Sensitivity (as a percentage of the relevant milk samples) of Staphylococci,
Streptococci and E. coli to different antimicrobial substances
Antibiotic
Cephalexin
Gentamycin
Chloramphenicol
Norfloxacin
Bactrim
Staphylococci (n = 50)
Streptococci (n = 67)
E. coli (n = 28)
70
68
56
56
56
35.82
32
50
29
75
50
33
10
21
Penicillin, Ampicillin, Amoxicillin, Neomycin, Kanamycin, Streptomycin,
Erythromycin, Tetracyclin, Colistin were less than 40% effective against Staphylococci,
Streptococci, E. coli.
Table II
Sensitivity (as a percentage of the relevant samples from pigs) of different
pathogenic bacteria to different antimicrobial substances
Antibiotic
Staphylococcus spp Streptococcus spp
n = 38
n = 99
n = 320
E. coli
Enterobacter spp
n = 14
Cephalexin
Gentamycin
Norfloxacin
Bactrim
47.1
32.5
45
32.5
49.5
0
17.7
23.9
23.6
46.4
48.8
19.7
9
63.6
90.9
54.5
Flumequin
Chloramphenicol
0
32.5
0
36.3
9.4
19.7
45.5
90.9
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OIE International Standards on Antimicrobial Resistance, 2003
4. Surveillance of resistance programme
Ampicillin, Amoxycillin, Penicillin, Neomycin, Kanamycin, Colistin, Streptomycin,
Erythromycin, Tetracyclin were from 0% to 36.4% effective against Staphylococcus spp,
Streptococcus spp, E. coli, Enterobacter spp.
Table III
Sensitivity (as a percentage of the relevant samples from poultry) of different
pathogenic bacteria to different antimicrobial substances
Antibiotic
Gentamycin
Neomycin
Kanamycin
Norfloxacin
Bactrim
Chloramphenicol
Colistin
Tetramycin
E. coli (n = 105)
Salmonella spp (n = 35)
43.8
9.5
7.6
20
13.3
18.1
25.7
2.9
78.8
63.6
51.5
69.7
48.5
57.6
48.5
45.5
The effectiveness of Ampicillin, Amoxycillin, Penicillin, Cephalexin, Flumequin,
Streptomycin, Erythromycin against pathogenic bacteria was below 40%.
Sensitivity to antibiotics of some pathogenic bacteria in human health
Over the last few years in Vietnam, a number of clinical and basic laboratory studies
have been jointly carried out by the Center of Tropical Diseases (CTD) in Ho Chi
Minh City and the University of Oxford supported by the Wellcome Trust. They
focused on diseases that have a considerable impact on the health of the community,
such as malaria, pneumonic disease and typhoid fever.
Antimicrobial resistance has been detected in a variety of pathogenic bacteria in some
provinces of Southern Vietnam. According to the CTD experts’ 1997 report (4, 7),
more than 90% of Salmonella typhi bacteria were multi-drug resistant and the sensitivity
to fluoroquinolons in some areas had decreased to only 50%.
As in many other countries, penicillin-resistant Streptococcus pneumoniae (PRP) is also a
significant problem in Vietnam. 50% of Streptococcus pneumonia (thirty-four strains)
isolated from blood and cerebrospinal fluid (CSF) exhibited a low level of resistance
to penicillin, 50% were tetracycline-resistant and 26% carried by healthy children were
highly resistant (5).
15% of Corynebacterium diptheriae were found to be resistant to erythromycin, and some
strains were multi-drug resistant (4).
10% of Mycobacterium tuberculosis isolates were tested as resistant to two or more
antituberculosis drugs (4).
OIE International Standards on Antimicrobial Resistance, 2003
213
4. Surveillance of resistance programme
The resistance to several antimicrobial substances of sixty-two strains of Staphylococcus
aureus isolated from blood cultures at the CTD (6) found that Staphylococcus aureus was
highly resistant to penicillin (97%) and quite resistant to erythromycin.
Residues of antibiotics in animal products
Research results obtained from some provinces in South Vietnam, by the Veterinary
Faculty of the University of Agriculture and Forestry in Ho Chi Minh City between
March 1999 and April 2000, showed that 19.54% of the 87 samples taken from
chicken meat, pork and beef contained residues of antibiotics (1). The following
quantities of different antimicrobial substances were measured in seventeen samples:
Erythromycin: 2.12 mg/kg
Streptomycin:
0.14 mg/kg
Gentamycin:
0.75 mg/kg
Kanamycin:
5.17 mg/kg
Chloramphenicol: 3.04 mg/kg (chicken meat), 3.04 – 111.5 mg/kg (pork)
Sulfamethazol: 119.47 mg/kg (chicken meat), 35.07 – 119.47 mg/kg (pork)
Current difficulties in regulating the use of veterinary drugs
Since 1993, the legal framework for regulating the production, trade and application of
veterinary medicinal products in Vietnam has been the Veterinary Ordinance on
Veterinary Services. The Government of Vietnam is determined to improve the
quality and the control of veterinary medicinal products, including implications for the
safety of food of animal origin. However, this process is taking time and the public
veterinary services face many difficulties.
In this context it should be mentioned that the situation in Vietnam with regard to
medicinal products for application in humans is not much better than in the veterinary
sector. Anybody can buy, for instance, antimicrobial drugs from pharmacies without
prescription. Quality control during production, distribution and storage is deficient,
and improper application widespread. Therefore, it would be prudent if national
efforts were harmonised in regulating medicinal products for both the medical and
veterinary sectors.
Hopefully the pharmaceutical industry will come up with new drugs potent against
drug-resistant microbes. This will inevitably take time and will predictably be
expensive. Therefore, it is of paramount importance to make prudent use of the
existing antimicrobial products to avoid the development of antimicrobial resistance.
References
1. Do C.D. & Nguyen T.T.G. (2000). – Bacterial infection and residues of antibiotics in
animal products. In Summary of Science Researching Conference of Univeristy of Agriculture
and Forestry. Univeristy of Agriculture and Forestry, Ho Chi Minh City, 4-9.
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OIE International Standards on Antimicrobial Resistance, 2003
4. Surveillance of resistance programme
2. Nguyen V.P. et al. (2000). – Isolating pathogen bacteria in milk samples from cows with
latent mastitis. In Summary 3rd Science Conference of Husbandry and Veterinary Faculty.
University of Agriculture and Forestry, Ho Chi Minh City, 113-116.
3. Nguyen V.P. et al. (2000). – Isolating pathogen bacteria from pig and poultry specimens
at the Veterinary Clinic. In Summary 3rd Science Conference of Husbandry and Veterinary
Faculty. University of Agriculture and Forestry, Ho Chi Minh City, 124-127.
4. Parry C.M. (1997). – Antimicrobial resistance: the challenge of the 21th Century. In
Symposium on antimicrobial resistance in Southern Viet Nam. Center of Tropical Diseases,
Ho Chi Minh City, 5-6.
5. Parry C.M. et al. (1997). – Penicilline resistance in Streptococcus pneumonia isolated from
aldults and children in HCMC. In Symposium on antimicrobial resistance in Southern Viet
Nam. Center of Tropical Diseases, Ho Chi Minh City, 9-10.
6. To S.D. et al. (1997). – Antibiotic resistance of Staphylococcus aureus at CTD 1993-1997. In
Symposium on antimicrobial resistance in Southern Viet Nam. Center of Tropical Diseases,
Ho Chi Minh City, 7-8.
7. Tran T.H. (1997). – Treatment options for typhoid fever due to multidrug-resistant
Salmonella typhi. In Symposium on antimicrobial resistance in Southern Viet Nam. Center of
Tropical Diseases, Ho Chi Minh City, 1-4.
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215
4. Surveillance of resistance programme
Antimicrobial resistance surveillance in Kenya:
achievements and challenges
S. Kariuki (1), G. Revathi (2) & C.A. Hart (3)
(1)
Centre for Microbiology Research, KEMRI, P.O. Box 43640, Nairobi, Kenya
(2)
Department of Medical Microbiology, Kenyatta National Hospital, P.O. Box 20723, Nairobi, Kenya
(3)
Department of Medical Microbiology and Genito-Urinary Medicine, University of Liverpool, Liverpool, L69
3GA, United Kingdom
General introduction
Although progress has been achieved in the therapeutic management of many
infectious diseases, the issue of antimicrobial resistance continues to be a major threat
to this achievement. Low resource countries in particular are at greatest risk of drugresistant infections, as paucity of resources makes the purchasing of newer and more
effective treatment agents difficult. Thus, it would be important to carefully manage
available therapeutic choices in order to ensure their continued use in the treatment of
infections. Emerging antimicrobial resistance is an enormous health problem and
more so in low resource countries, where the bulk of communicable diseases are
found and the resources to combat them are meagre. Left unchecked, this problem
will adversely affect our ability to treat and control infectious diseases. In Kenya, the
problem of antimicrobial resistance has been recognised for a number of years, and
this led to the first ever workshop on surveillance of antimicrobial resistance and
rational use of antimicrobial agents held in 1997, with a follow up meeting in 1999.
Background
Several issues concerning antimicrobial resistance were raised during these meetings.
Many laboratories at the Provincial and District level used obsolete methods such as
the modified Stokes in susceptibility testing. There was therefore need to adopt the
widely recommended Kirby-Bauer method and recommendations by the National
Committee for Clinical Laboratory Standards (NCCLS), which should be supported
by regular updates on NCCLS protocols (NCCLS, 2000). In addition, interlaboratory
communication was poor and laboratory-to-clinician rapport was sub-optimal, thus
contributing to the lack of utilisation of available laboratory capabilities.
Participants also raised other issues concerning the practicalities of carrying out
susceptibility testing. Among these concerns were inadequate numbers of suitably
trained personnel and the lack of a credible internal and external quality assurance
programme. Many laboratories, particularly at District level, lacked access to basic
media, antibiotic discs, petri dishes and other materials essential for susceptibility
testing of common bacterial pathogens. In addition, equipment such as autoclaves,
incubators and microscopes were either lacking or broken down. As the collection of
specimens was done by laboratory technical personnel this needed to be well
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OIE International Standards on Antimicrobial Resistance, 2003
4. Surveillance of resistance programme
supervised to ensure that specimens getting to the laboratory for examination were of
high quality.
Several matters touching on communication were also debated. There was a
consensus that information on antibiotic susceptibility testing needed to be shared
between laboratories and epidemiologists; microbiologists, clinicians, pharmacists and
laboratories in various hospitals; clinicians, microbiologists and policy makers. To
make this recommendation viable hospitals and laboratories were requested to find a
forum for exchanging information on antibiotic susceptibility testing and surveillance.
In addition continuing medical education for microbiologists, laboratory technologists
and technicians would ensure that they are equipped with new and updated
information on antimicrobial susceptibility testing, surveillance and control measures.
In order to improve susceptibility testing, a number of immediate measures were
suggested. Firstly, there was a need to define a national focal point and to develop a
situation analysis. Secondly, there was urgent need to ensure quality laboratory training
and participation in external quality assurance programmes provided by the World
Health Organization (WHO). On data collection, analysis and dissemination, sentinel
laboratories should be encouraged to publish data locally in newsletters that should be
circulated to interested groups.
Other recommendations included the establishment of a full-time programme coordinator, to be based at the reference laboratory, who would offer support to all
sentinel sites in internal and external Quality Assurance (QA) programmes. In
addition, antibiotic susceptibility testing protocols, media and reagents, and data
storage, processing and reporting should be standardised to give reliable data.
Achievements in antimicrobial susceptibility testing and
monitoring
Due to limitations in funding, only a few selected laboratories (based on available
manpower, materials and data entry and computational hardware) could begin the
susceptibility testing and surveillance programme. Among them were the Centre for
Microbiology Research, part of the Kenya Medical Research Institute (Reference
laboratory), the Kenyatta referral hospital, two other public hospitals and three private
hospitals. Presently, laboratories in these sites participate in the external Quality
Assurance programme coordinated through a World Health Organization/Centers for
Disease Control and Prevention (WHO/CDC) programme, twice annually. There is
also regular informal consultation between the laboratories, particularly in sharing
antimicrobial susceptibility testing and surveillance data, and updates on pathogens of
importance that would be included in the surveillance programme. In addition,
internal quality assurance for each laboratory has been set up ensuring that all use
NCCLS recommended standards for antimicrobial susceptibility testing, including
using American Type Culture Collection (ATCC) Quality Control strains (NCCLS,
2000).
OIE International Standards on Antimicrobial Resistance, 2003
217
4. Surveillance of resistance programme
Some data are obtained through the Antimicrobial Susceptibility Testing and
Surveillance Programme.
The surveillance programme was aimed at monitoring antimicrobial resistance in some
commonly isolated pathogens, including, Klebsiella, Staphylococci, Shigella and Salmonella
spp.
Cefotaxime-hydrolysing Klebsiella spp
All twenty-two K. pneumoniae isolates (1999-2000) obtained from outbreaks in neonatal
wards were uniformly resistant to ampicillin, cephradine, cefuroxime, cefotaxime,
carbenicillin, ceftazidime and tetracycline. However, they were susceptible to coamoxyclav, ceftazidime, aztreonam, streptomycin, co-trimoxazole, gentamicin and
nalidixic acid. Isolates had minimal inhibitory concentrations (MICs) of 24 and 1
µg/ml for cefotaxime and ceftazidime, respectively. The presence of clavulanic acid
decreased the MIC of cefotaxime 750-fold to 0.032 µg/ml, indicating that resistance
was a result of the production of extended-spectrum β-lactamases (Kariuki et al.,
2001).
Table I
Multidrug-resistant Shigella spp. (1999-2000)
Antimicrobial
agent
Ampicilin
Co-amoxyclav
Piperacilin
Cephradine
Cefuroxime
Ceftazidime
Imipenen
Gentamicin
Cotrimoxazole
Chloramphenicol
Sonnei (n = 32)
84
5
100
8
6
0
0
0
80
30
Percentage of resistance
Flexneri (n = 34) Dysenteriae (n = 6)
76
0
64
12
6
0
0
0
80
10
100
0
100
0
0
0
0
0
100
0
Emergence of multidrug resistant Salmonella typhi, Kenya
Between 1998 and 2000, we studied 87 S. typhi isolated from blood cultures of adults
admitted to various hospitals in Nairobi. Only 15.3% were fully sensitive while the rest
(84.7%) were resistant to all five commonly available drugs – ampicillin,
chloramphenicol, tetracycline (MICs > 256 µg/ml), streptomycin (MIC > 1,024
µg/ml) and cotrimoxazole (MIC > 32µg/ml). For resistant S. typhi MICs for nalidixic
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4. Surveillance of resistance programme
acid and ciprofloxacin were respectively 5- and 10-fold higher than for sensitive
strains (Kariuki et al., 2000).
Multidrug-resistant non-typhi Salmonella from bacteraemic cases
Non-typhi Salmonella from HIV-seropositive patients has recently been one of the
major opportunistic pathogens to be isolated from blood. Our surveillance data
indicates that up to 64% of these isolates are multi-resistant to two or more of the
commonly used antimicrobials (Kariuki et al., 2000).
Table II
MIC using the E-Test of eleven antimicrobial agents for 151 non-typhi
Salmonella isolates from medical wards at two hospitals in Nairobi (1997-2000)
Antimicrobial
agent
Ampicillin
Co-amoxyclav
Cefuromixime
Ceftazidime
Co-trimozadole
Chloramphenicol
Ciprofloxacin
Gentamicin
Nalidixic acid
Streptomycin
Tetracycline
Range
Minimum inhibitory concentration (µg/ml)
MIC90
% resistant
Mode
MIC50
0.75->256
0.5-32
2-128
0.125-16
0.032->32
1.5->256
0.006-0.25
0.19-64
1->256
3->1,024
0.75-192
>256
0.75
3
0.25
>32
>256
0.023
0.75
3
32
1
>256
6
8
0.5
>32
32
0.023
1
3
>1,024
16
>256
16
12
2
>32
>256
0.125
8
>256
>1,024
64
65
8
18
1
60
40
0
9
11
90
48
Limitations to achieving a nation-wide antimicrobial
susceptibility testing and surveillance programme
As there is no formal funding for the programme, distribution of materials from the
external quality assurance programme is limited to the selected sentinel sites. Indeed
several other laboratories interested in participating are locked out due to paucity of
funding. Even for the participating laboratories there is a need for training support for
their staff in order to undertake quality antimicrobial susceptibility testing and
surveillance.
References
1. Kariuki S., Corkill J.E., Revathi G., Musoke R. & Hart C.A. (2001). – Molecular
characterization of a novel plasmid-encoded cefotaximase (CTX-M-12) found in clinical
Klebsiella pneumoniae isolates from Kenya. Antimicrob. Agents Chemother., 45, 2141-2143.
OIE International Standards on Antimicrobial Resistance, 2003
219
4. Surveillance of resistance programme
2. Kariuki S., Gilks, Revathi G. & Hart C.A. (2000). – Genotypic analysis of multidrugresistant Salmonella enterica serovar Typhi, Kenya. Emerg. infect. Dis., 6 (6), 649-651.
3. Kariuki S., Oundo J.O., Muyodi J., Lowe B., Threlfall E.J. & Hart C.A. (2000). – Genotypes
of multidrug-resistant Salmonella enterica serotype typhimurium from two regions of Kenya.
FEMS Immun. Med. Microbiol., 29, 9-13.
4. National Committee for Clinical Laboratory Standards (NCCLS) (2000). – Methods for
dilution antimicrobial susceptibility tests for bacteria that grow aerobically. In Approved
standard, 5th Ed. NCCLS document M7-A5, Wayne, Pa.
5. National Committee for Clinical Laboratory Standards (NCCLS) (2000). – Performance
standards for antimicrobial disk susceptibility tests. In Approved standard, 7th Ed. NCCLS
document M2-A7, Wayne, Pa.
__________
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Laboratory methods
OIE International Standards on Antimicrobial Resistance, 2003
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5. Laboratory method
Antimicrobial resistance: standardisation and
harmonisation of laboratory methodologies for the
detection and quantification of antimicrobial
resistance
D.G. White (1), J. Acar (2), F. Anthony (3), A. Franklin (4), R. Gupta (5), †T. Nicholls (6),
Y. Tamura (7), S. Thompson (8), E.J. Threlfall (9), D. Vose (10), M. van Vuuren (11),
H.C. Wegener (12) & M.L. Costarrica (13)
(1)
Centre for Veterinary Medicine, Food and Drug Administration, Office of Research, HFV-530, 8401 Muirkirk
Road, Laurel, Maryland 20708, United States of America
(2)
Université Pierre et Marie Curie, Service de Microbiologie Médicale, Fondation Hôpital Saint-Joseph, 185 rue
Raymond Losserand, 75674 Paris Cedex 14, France
(3)
Fresh Acre Veterinary Surgery, Flaggoners Green, Bromyard, Herefordshire HR7 4QR, United Kingdom
(4)
The National Veterinary Institute (SVA), Department of Antibiotics, SE 751 89 Uppsala, Sweden
(5)
College of Veterinary Sciences, Veterinary Bacteriology, Department of Microbiology, G.B. Pant University of
Agriculture and Technology, Pantnagar 263 145 Uttar Pradesh, India
(6)
National Offices of Animal and Plant Health and Food Safety, Animal Health Science and Emergency
Management Branch, Department of Agriculture, Fisheries and Forestry, P.O. Box 858, Canberra ACT 2601, Australia
(7)
National Veterinary Assay Laboratory, Ministry of Agriculture, Forestry and Fisheries, 1-51-1 Tolura,
Kokubunji, Tokyo 185-8511, Japan
(8)
Joint Institute for Food Safety Research, Department for Health and Human Services Liaison, 1400
Independence Avenue, SW, Mail Stop 2256, Washington, DC 20250-2256, United States of America
(9)
Public Health Laboratory Service, Central Public Health Laboratory, Laboratory of Enteric Pathogens, 61
Collindale Avenue, London NW9 5HT, United Kingdom
(10)
David Vose Consulting, Le Bourg, 24400 Les Lèches, France
(11) University of Pretoria, Faculty of Veterinary Science, Department of Veterinary Tropical Diseases, Private Bag
X04, Onderstepoort 0110, South Africa
(12) World Health Organization, Detached National Expert, Division of Emerging and Transmissible Diseases,
Animal and Food-related Public Health Risks, 20 avenue Appia, 1211 Geneva, Switzerland
(13) Food and Agriculture Organization, Food Quality and Standards Service, Senior Officer, via delle Terme di
Caracalla, 00100 Rome, Italy
This report, prepared by the OIE Ad hoc Group of experts on antimicrobial resistance, has not yet received the
approval of the International Committee of the OIE
Summary
The Ad hoc Group of experts on antimicrobial resistance of the OIE (World organisation for animal
health) has developed a guideline on the standardisation and harmonisation of laboratory
methodologies used for the detection and quantification of antimicrobial resistance. The existing
methods (disk diffusion [including concentration gradient strips], agar dilution and broth dilution) are
reviewed, including a comparison of their advantages and disadvantages. The definitions of resistance
characteristics of bacteria (susceptible, intermediate and resistant) are addressed and the criteria for the
establishment of breakpoints are discussed. Due consideration has to be given to these aspects in the
OIE International Standards on Antimicrobial Resistance, 2003
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5. Laboratory method
interpretation and comparison of resistance monitoring or surveillance data. The use of validated
laboratory methods and the establishment of quality assurance (internal and external) for
microbiological laboratory work and the reporting of quantitative test results is recommended.
Equivalence of different methods and laboratory test results is also recommended to be established by
external proficiency testing, which should be achieved by the means of a reference laboratory system.
This approach allows the comparison of test results obtained using different methods generated by
laboratories in different countries.
Keywords
Antimicrobial resistance – Breakpoints – Containment of resistance – Harmonisation
– International standards – Laboratory methodology – Public health – Risk analysis –
Standardisation – Threshold – World Organisation for Animal Health.
Introduction
The objective of this document is to review currently used antimicrobial susceptibility
testing methodologies and protocols and to encourage the Member Countries of the
OIE (World organisation for animal health) to initiate standardisation and
harmonisation of bacterial antimicrobial susceptibility testing and results. The
similarities, differences, advantages and disadvantages of accepted standardised
antimicrobial susceptibility testing methods are described. Additionally, the
requirements of each antimicrobial susceptibility testing method are discussed
(equipment, training, resources and quality assurance). The need for internal quality
control and external proficiency testing is emphasised. Standardisation and
harmonisation of antimicrobial susceptibility testing methodologies are critical if data
is to be compared among the international surveillance/monitoring programmes of
OIE Member Countries.
Background
There is increasing international concern regarding both the potential transfer of
antimicrobial resistant bacteria between animals and humans and of resistance genes
from animal strains of bacteria to human bacterial pathogens. Concern about
antimicrobial resistance in relation to animal health is also growing. In response to
these concerns, antimicrobial resistance testing initiatives, together with surveillance
and monitoring programmes focusing on zoonotic bacterial pathogens and enteric
commensals in animals have been initiated in numerous countries throughout the
world (3, 5, 21). Data generated from these surveillance and monitoring programmes
will eventually play a key role in the development of national, and perhaps
international polices for the containment of antimicrobial resistant bacterial pathogens
from animals and their immediate environments. The need to compare susceptibility
testing data between laboratories in different countries necessitates a re-examination
of the standardisation and harmonisation of the antimicrobial susceptibility testing
(AST) methods currently in use world-wide (12).
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5. Laboratory method
Historically, veterinarians and medical practitioners selected effective antimicrobials
based on past clinical experiences. However, with an observed increase in bacterial
resistance to regularly used antimicrobials, it has become gradually more difficult for
clinicians to empirically select an appropriate antimicrobial agent (13, 24). As a result,
laboratory in vitro AST of the relevant bacterial pathogens from properly collected
specimens is currently standard procedure (13, 17, 25).
Antimicrobial susceptibility testing was initiated in many countries world-wide soon
after the introduction of antimicrobials for treatment of bacterial diseases (12). Rapid
bacterial identification systems and subsequent improvements in AST in both human
and veterinary clinical laboratories were primarily driven by the need to identify the
appropriate antimicrobials for successful clinical use. Additionally, the need for
laboratory reproducibility of AST methods arose to ensure that data generated was
technically accurate and consistent. This required that AST laboratories adopt quality
control measures to guarantee the reporting of reliable and reproducible susceptibility
data (9, 17). Although protocols for bacterial identification, AST and data analysis
developed very rapidly, standardisation and validation of these three procedures is
relatively recent compared to the progress achieved in analytical chemistry.
Historically, most laboratories have employed disk diffusion methods for AST.
Reported results can be quantitative if zone diameters are recorded, but they are
generally reported qualitatively as either susceptible, intermediate, or resistant (9, 14,
17, 25). In the past few years, many laboratories have adopted either broth
microdilution or agar dilution methods (9, 11). Results from these assays may be
quantitative, in that they provide the minimal concentration of an antimicrobial
required to inhibit the growth of the test organism (minimum inhibitory concentration
[MIC]), as well as providing a qualitative description (susceptible, intermediate and
resistant). Some laboratories have not been as successful in adopting these methods,
primarily due to training and financial limitations. Additionally, the need to develop
and implement quality assurance programmes for bacterial identification and AST is a
fairly new concept which may take time to implement. However, some initiatives have
been introduced and are currently underway in an attempt to standardise and/or
harmonise AST.
In veterinary and human medicine, antimicrobial resistance data is being shared
between a number of laboratories through the creation of antimicrobial resistance
surveillance networks. Some of these networks are linked internationally. This has
resulted in the standardisation and harmonisation of AST methods between
participating laboratories. Participating laboratories adhere to strict standards of AST
and quality control monitoring to ensure accuracy and comparability of the data.
Examples of international and national surveillance systems employing standardised
methods include the European Antimicrobial Resistance Surveillance System
(EARSS), the Alexander Project for Respiratory Pathogens, Antibiotic Resistance in
Bacteria of Animal Origin (ARBAO), SENTRY, the Surveillance Network (TSN), the
Danish Integrated Antimicrobial Resistance Monitoring and Research Program
(DANMAP), the World Health Organization Network on Antimicrobial Resistance
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5. Laboratory method
Monitoring (WHONET), Enter-Net and the National Antimicrobial Resistance
Monitoring System (NARMS) (3, 15, 16, 21, 22). The success of these surveillance and
monitoring programmes suggests that standardisation and harmonisation of AST
methods are both conceivable and progressing globally.
Although in the past few years there has been a move to standardise AST methods
within countries, the move to harmonise methods and susceptibility data among
countries has not been initiated on a global scale for bacteria originating from animals.
One significant obstacle is the fact that there is no international monitoring system for
AST that utilises a single methodology with identical quality control organisms. To
obtain comparable antimicrobial susceptibility data from different laboratories in the
same country, or in different countries, laboratory methodologies need to be
standardised and harmonised. This can be best accomplished if the antimicrobial
susceptibility data collected is quantitative (i.e. MIC, zone diameters), rather than
qualitative for comparison purposes. Data to be used for epidemiological surveillance
purposes must be reported quantitatively in order to both detect shifts in
antimicrobial susceptibility in bacterial strains and be comparable with other
surveillance programmes.
Quantitative in vitro bacterial antimicrobial susceptibility testing is essential for the
purpose of monitoring shifts in susceptibility to antimicrobial agents. However, to
achieve its aim, testing must be performed according to standardised testing methods.
Comparison of the frequency of antimicrobial resistance in bacterial pathogens among
the many countries that have surveillance systems in place is difficult for many
reasons. Antimicrobial susceptibility testing currently serves two purposes, firstly to
provide meaningful results to the clinician and secondly to monitor shifts in
susceptibility of targeted bacterial populations (12). Historically, laboratories have
been restricted in reporting bacterial AST data as ‘susceptible, intermediate or
resistant’. Bacterial antimicrobial susceptibilities reported this way are primarily for the
immediate needs of physicians or veterinarians as guidelines for appropriate
antimicrobial therapies. Taking into account the different AST protocols and
interpretive criteria among the numerous testing methods and guidelines available, it is
evident that this type of reporting excludes any possibility for the comparison of
susceptibility data. Unfortunately, there is no world-wide consensus on interpretive
criteria for susceptibility testing. Additionally, the emphasis of many surveillance
programmes is to monitor shifts in antimicrobial susceptibilities in target bacterial
pathogens. Since there are no standardised dilution schemes available world-wide, it
becomes difficult to compare susceptibility profiles of bacterial pathogens from
different countries.
Standardisation and harmonisation of AST methods are needed for meaningful
comparisons of quality and accurate susceptibility data between individual OIE
Member Countries involved in both national and international surveillance
programmes. This will be best accomplished by the use of accurate and reliable
standardised AST methods in conjunction with monitoring of AST performance with
defined quality control bacterial strains among participating laboratories. If results
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5. Laboratory method
achieved with different AST methods are to be presented side by side, then
comparability of results must be demonstrated and consensus on interpretation
achieved. It is essential that AST methods provide reproducible results in day-to-day
laboratory use and that the generated data be comparable to those results obtained by
an acknowledged ‘gold standard’ reference method. In the absence of standardised
methods or reference procedures, susceptibility results from different laboratories
cannot be adequately compared with assurance.
Antimicrobial susceptibility testing methodologies
It is essential that the bacteria subjected to AST be isolated in pure culture from the
submitted sample. The isolation procedure for that particular bacterium should be
standardised so that the subject bacteria are consistently and correctly identified to the
genus and/or species level. When possible, bacterial isolates should be stored for
future analysis via either lyophilisation or cryogenic preservation at –70°C to –80°C.
Once the bacterium has been isolated in pure culture, the inoculum must be
standardised to obtain accurate susceptibility results, since variations may substantially
affect both the qualitative and quantitative endpoint determinations. Other factors
influencing AST methods that require standardisation and harmonisation include the
composition of the agar and broth media used (pH, cations, thymidine or thymine, use
of supplemented media), content of antimicrobial agent in the carrier (disk, strip,
tablet), growth and incubation conditions (time, temperature, oxygen), agar depth, and
the subsequent interpretive criteria (17, 18, 24). For these reasons, special emphasis
needs to be placed on reference procedures and standardised methods, as sufficient
reproducibility can be attained only through standardisation.
The decisions regarding which antimicrobials to test can be difficult given the vast
numbers of antimicrobials available. Testing all antimicrobial agents is neither
necessary (since numerous antimicrobials have similar, if not identical, in vitro
activities), nor practical (given the economic restraints faced by laboratories). This is
further discussed in Antimicrobial resistance: harmonisation of national antimicrobial resistance
monitoring and surveillance programmes in animals and in animal-derived food, later in this
volume).
A wide variety of bacterial AST methodologies are being used by microbiological
laboratories around the world. The selection of an AST methodology may be based
on numerous factors, such as ease of performance, flexibility, adaptability to
automated or semi-automated systems, cost, reproducibility, reliability, accuracy and
national preference. However, only three primary methods have been shown to be
reproducible and repeatable. These are disk diffusion (including concentration
gradient strips), broth dilution and agar dilution.
Disk diffusion refers to the diffusion of an antimicrobial agent of a specified
concentration from disks, tablets or strips, into solid culture media seeded with a
standardised bacterial inoculum. The diffusion of the antimicrobial agent into the
seeded culture media results in an antimicrobial gradient. When the concentration of
the antimicrobial becomes so dilute that it can no longer inhibit the growth of the test
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5. Laboratory method
bacterium, a zone of inhibition is formed. The edge of this zone of inhibition
correlates with the MIC for that particular bacterium/antimicrobial combination. In
other words, the zone of inhibition correlates inversely with the MIC of the test
bacterium. The larger the zone of inhibition, the lower the concentration of
antimicrobial required to inhibit the growth of the organisms. However, the MIC
cannot always be easily determined using disk diffusion methods, due to the variation
of the tested antimicrobial agent concentration at the edge of the zone of inhibition
for each drug-bacterium combination (9, 13). It should be emphasised that disk
diffusion tests based solely on the presence or absence of a zone of inhibition without
regard to the size of the zone of inhibition are not acceptable. Disk diffusion is
technically straightforward to perform, reproducible, and does not require expensive
equipment. The main advantages of the disk diffusion method are the low cost and
the ease in modifying test formats when needed. Although disk diffusion is the
simplest and most cost- effective method for AST, many aspects of this method
require standardisation, as mentioned previously. Additionally, manual measurement
of zones of inhibition may be time-consuming, making this method impractical for
some laboratories (2). However, automated zone reading devices are available which
can be integrated with laboratory reporting and data handling systems (2, 13). It is
important to remember that no more than twelve disks should be placed on one
150 mm agar plate, and no more than five disks on a 100 mm plate (18). Regardless of
the number of disks placed on the agar surface, the disks should be distributed evenly
so that they are no closer than 24 mm from centre to centre (18). Additionally,
bacterial antimicrobial MICs can be obtained from commercially available gradient
strips which diffuse a pre-formed antibiotic concentration (4). However, the use of
strips containing antimicrobials at predefined concentrations can be very expensive
and MIC discrepancies can be found when compared with agar dilution results (4).
The aim of the broth and agar dilution methods is to determine the lowest
concentration of the assayed antimicrobial that inhibits the growth of the bacterium
being tested (MIC, usually expressed in mg/ml or mg/l). However, the MIC does not
always represent an absolute value. The ‘true’ MIC is a point between the lowest test
concentration that inhibits the growth of the bacterium and the next lower test
concentration (18). Antimicrobial ranges should be utilised that encompass both the
interpretive criteria (susceptible, intermediate and resistant) and quality control
reference organisms. Additionally, laboratory results should take into consideration
the antimicrobial concentrations that are achievable in vivo for a specific
bacteria/antibiotic combination. Antimicrobial susceptibility dilution methods appear
to be more reproducible and quantitative than agar disk diffusion, although antibiotics
are usually tested in doubling dilutions which can produce inexact MIC data (11). Any
laboratory that intends to use a dilution method and set up its own reagents and
antibiotic dilutions must have the ability to obtain, prepare and maintain appropriate
stock solutions of reagent grade antimicrobials and to generate working dilutions on a
regular basis. It is then essential that such laboratories utilise quality control organisms
to assure accuracy and standardisation of their procedures.
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Broth dilution is a technique in which a standardised suspension of bacteria is tested
against varying concentrations of an antimicrobial agent (usually doubling dilutions) in
a standardised liquid medium. The broth dilution method can be performed either in
tubes containing a minimum volume of 2 ml (macrodilution) or in smaller volumes
using microtitration plates (microdilution) (18). Numerous microtitre plates containing
prediluted antibiotics within the wells are commercially available. The use of these
plates with a standardised protocol, including appropriate quality control reference
strains, is the most likely choice to achieve standardisation of AST world-wide.
Additionally, the use of identical lots of microdilution plates may eliminate potential
errors that may arise due to preparation and dilution of the antimicrobials in
participating laboratories (18). However, due to the fact that most broth microdilution
test panels are prepared commercially, they can be considered less flexible than agar
dilution or disk diffusion in adjusting to the changing needs of the
surveillance/monitoring programme. Additionally, purchasing the equipment and
antimicrobial panels can be quite costly and may not be a choice for laboratories with
limited budgets.
Agar dilution involves the incorporation of an antimicrobial agent into an agar
medium in a geometrical progression of concentrations, followed by the application of
a defined bacterial inoculum to the agar surface of the plate. This results in the
accurate determination of a MIC for the test bacterium/antimicrobial combination.
Agar dilution methods offer several advantages; these include a greater control of the
purity of the test bacterium and the ability to test multiple bacteria on the same set of
agar plates and at the same time. Another attractive benefit of this technique is the
potential to improve the identification of MIC endpoints and extend the antibiotic
concentration range as far as necessary. Additionally, it is the only recommended
standardised antimicrobial susceptibility testing method for many fastidious
organisms, such as anaerobes, Helicobacter and Campylobacter species (14). Agar dilution
can also be adapted to semi-automation. Commercially available inoculum-replicators
are available and these can transfer between thirty-two and thirty-seven different
bacterial inocula to each agar plate (18). Agar dilution is referred to as the ‘gold
standard’ of AST; however, the technique requires extensive training of personnel and
may be more expensive and labour-intensive than other testing methods.
Routine AST methods are best standardised for aerobic and facultative bacteria and
antimicrobial agents that are intended for systemic use. These methods have not been
standardised and in some cases are not recommended for uncommon or fastidious
bacteria, due to potential inaccurate results. Regardless of the AST method used, the
procedures must be standardised to ensure accurate and reproducible results.
Additionally, appropriate quality control reference organisms need to be tested every
time AST is performed, to ensure accuracy of the data. Clearly, the appropriate AST
choice will ultimately depend on the growth characteristics of the bacterium in
question, for example, disk diffusion should not be used to test anaerobes,
Campylobacter, or other bacteria with considerable strain-to-strain variability in growth
rates (14, 25). Given the many biological and technical variables that may influence
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5. Laboratory method
AST, standardisation is essential for the correct interpretation of generated results.
Lastly, if one of these standardised AST methods is to be adopted by a laboratory of
an OIE Member Country where it has not been previously used, programmes should
be developed to educate and train the appropriate technical staff.
In special circumstances, novel test methods and assays may be more appropriate for
detection of particular resistance phenotypes than the standardised AST methods
described above. For example, chromogenic cephalosporin-based tests (e.g. nitrocefin)
or equivalent methods may provide more reliable and rapid results for beta-lactamase
determination in certain bacteria compared to traditional AST methods (18).
Extended-spectrum beta-lactamase (ESBL) activity in certain bacteria can also be
detected by using standard disk diffusion susceptibility test methods utilising specific
cephalosporins (cefotaxime and ceftazidime) in combination with a beta-lactamase
inhibitor (clavulanic acid) and measuring the resulting zones of inhibition (20).
Additionally, chloramphenicol resistance attributed to production of chloramphenicol
acetyl transferase (CAT) can be detected in some bacteria via rapid tube or filter paper
tests within 1 h to 2 h (18).
Interpretation of antimicrobial susceptibility testing results
The objective of in vitro AST is to predict the way in which a bacterial pathogen may
respond to the antimicrobial agent in vivo. The results generated by bacterial in vitro
antimicrobial susceptibility tests, regardless of whether disk diffusion or dilution
methods are used, are generally reported as resistant, susceptible or intermediate to the
action of a particular antimicrobial. Resistant implies that the bacterium would not
respond to treatment with that particular antimicrobial agent at the usually achievable
systemic concentrations and/or possesses a specific resistance mechanism. Susceptible
implies that the antimicrobial agent should be successful in treating the bacterial
infection with the recommended dosage. Intermediate indicates that the antimicrobial
agent may be successful in treating the bacterial infection if high levels of the agent
can be achieved at the site of infection. The term intermediate also indicates a buffer
zone, which prevents bacterial strains exhibiting borderline susceptibility from being
misconstrued as resistant. Similarly, it can serve to indicate that treatment failure may
occur, even though the strains exhibit MICs which are below the theoretical treatment
levels for a particular antimicrobial. These designations are obtained by determining in
vitro breakpoints, those MICs or zones of inhibition at which a bacterium is
considered to be susceptible, intermediate or resistant, based on both obtainable
serum concentrations of the antimicrobial agent administered at therapeutic doses and
through clinical trials (17, 24). A susceptible breakpoint implies that the recommended
dosage of the antimicrobial agent will attain serum or tissue concentrations adequate
to inhibit the growth of the bacterium in vivo. Intermediate breakpoints represent
‘buffer zones’, in which unforeseen laboratory technical problems inadvertently
categorise a susceptible bacterium as resistant, or vice versa. Resistant breakpoints
represent those antimicrobial concentrations that cannot be achieved in the host using
normal dosing regimes.
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5. Laboratory method
Two primary factors enable a bacterium to be interpreted as susceptible or resistant to
an antimicrobial agent. The first factor is the development and establishment of
quality control (QC) ranges, using diffusion when possible and dilution testing, for
QC micro-organisms. This is essential for validating the specific AST method used.
The QC ranges for the QC micro-organisms must be established prior to the
development of the second factor, which is the determination of the appropriate
interpretive criteria. The determination of the interpretive criteria involves the
generation of three distinct pieces of data, population distribution of relevant microorganisms, pharmacokinetic parameters of the antimicrobial agent, and results of
clinical trials and experience (1, 24). Interpretation of the data involves creating a
scattergram from the bacterial population distribution (300-600 representative
bacterial isolates), by plotting the zone of inhibition against the MIC for each bacterial
pathogen and calculating a linear regression line (19). The selection of breakpoints is
then based on multiple factors, including regression line analysis, bacterial population
distributions, error rate bounding, pharmacokinetics, and ultimately, clinical
verification (1, 18, 24).
Antimicrobial susceptibility breakpoints derived by professional societies or regulatory
agencies in various countries are often very similar. However, there can be notable
breakpoint differences among different countries for the same antimicrobial agent.
These differences may be due to many factors, such as variation in technical AST
factors (inoculum density, test media and test method), and the fact that different
countries use different dosages or administration intervals for some antimicrobials.
Some countries are also more conservative in setting interpretive criteria for specific
antimicrobials. Additionally, it is important to remember that interpretive criteria
developed for human clinical medicine are not always relevant for veterinary use, as
pharmacokinetics, pharmacodynamics, and relevant infectious agents may differ
significantly (18). The development of a concept known as ‘microbiological
breakpoints’, which is based on the population distributions of the specific bacterial
species tested, may be more appropriate for some antimicrobial surveillance
programmes. In this case, bacterial isolates that deviate from the normal susceptible
population would be designated as resistant, and shifts in susceptibility to the specific
antimicrobial/bacterium combination could be monitored.
Standardisation and harmonisation of antimicrobial
susceptibility testing methodologies
The most effective approach for the local, national and international surveillance of
antimicrobial resistance would be for all participating OIE Member Country
laboratories to use a common AST method, including similar quality control reference
organisms and ranges. However, since there are several variations in methodologies,
techniques and interpretive criteria currently being used, this will not be an easy task.
A number of guidelines are currently available for antimicrobial susceptibility testing
and subsequent interpretive criteria throughout the world. These include standards
and guidelines published by the National Committee for Clinical Laboratory Standards
OIE International Standards on Antimicrobial Resistance, 2003
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5. Laboratory method
(NCCLS), the Japan Society for Chemotherapy (JSC), the Swedish Reference Group
for Antibiotics (SIR), Deutsches Institut für Normung (DIN), Comité de l’Antibiogramme de la
Société française de Microbiologie (CASFM), Werkgroep richtlijnen gevoeligheidsbepalingen (WRG
system, the Netherlands), the British Society for Antimicrobial Chemotherapy (BSAC)
and others (6, 7, 8, 10, 18, 26). Because of the variations in diffusion and dilution AST
methods and the differing interpretive criteria among the many countries (i.e. choice
of agar medium, inoculum size, growth conditions and susceptibility breakpoints),
comparison of susceptibility data from one system to another is difficult. Additionally,
as mentioned earlier, the majority of the interpretive criteria was developed by AST of
bacteria and antimicrobials relevant to human medical pharmacokinetics and there are
few breakpoints for many veterinary antimicrobials that may be included in
surveillance and monitoring programmes. These data may also not be directly
applicable to veterinary medicine in terms of standardisation of testing of animal
bacterial isolates.
It appears that only the NCCLS has developed protocols for susceptibility testing of
bacteria of animal origin and determination of interpretive criteria (18, 19). However,
protocols and guidelines are available for susceptibility testing for similar bacterial
species which cause infections in humans. It is possible that such guidelines can be
adopted for susceptibility testing for bacteria of animal origin, but each country must
evaluate its own AST standards and guidelines. Additionally, efforts focusing on
harmonisation of susceptibility breakpoints on an international scale are progressing.
These efforts have primarily focused on the adoption of the standards and guidelines
of the NCCLS, which provide laboratories with standardised methods and quality
control values enabling comparisons of AST methods and generated data. For those
OIE Member Countries that have not standardised AST methods, the adoption of
NCCLS guidelines and standards would be an appropriate initial step.
To determine the comparability of results originating from different surveillance
systems from OIE Member Countries, antimicrobial susceptibility test results must be
reported quantitatively, including information on the methods, quality control
organisms and ranges tested. Also essential is agreement upon which micro-organisms
are to be susceptibility tested (e.g. Campylobacter species, for which no susceptibility
testing methods have currently been published and the choice of antimicrobials to be
tested is under discussion). Minimum inhibitory concentration values or zone
diameters should be the desired outcome of AST testing to be able to determine shifts
in antimicrobial susceptibility among the target bacterial pathogens. This can be
achieved by either broth or agar dilution methods, or by statistical transformation of
the zone of inhibition diameters obtained by disk diffusion methods to MICs (1).
Quantitative data can then be transformed into contingency tables or histograms for
comparative purposes and analysis. Regardless of the AST method used, laboratories
engaged in antimicrobial susceptibility testing must give high priority to both
producing and reporting technically accurate data. Additionally, susceptibility data
should be stored electronically in databases, when possible, with additional descriptive
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information regarding the origin of bacterial strains tested and other appropriate
details.
Quality control and quality assurance of antimicrobial
susceptibility testing
The implementation of quality control in laboratories that perform AST aims to help
to monitor the precision and accuracy of the AST procedure, the performance of the
appropriate reagents, and the personnel involved (18). Strict adherence to standardised
techniques in conjunction with quality control of media and reagents is necessary for
the collection of reliable and reproducible antimicrobial susceptibility data from OIE
Member Country laboratories. Records should be kept regarding lot numbers and
expiration dates of all appropriate materials and reagents used in AST. The
appropriate quality control reference bacteria must also be tested to ensure
standardisation regardless of the AST method used. Reference bacterial strains to be
used for quality control should be catalogued and characterised with stable defined
antimicrobial susceptibility phenotypes (18). These quality control strains should also
encompass resistant and susceptible ranges of the antimicrobials to be assayed.
Laboratories involved in AST need to use identical or similar quality control reference
strains. Reference strains should be kept as stock cultures from which working
cultures are derived and should be obtained from national or international culture
collections (e.g. American type culture collection [ATCC]). If possible, the preferred
method for analysing the overall performance of each laboratory is to test the
appropriate quality control bacterial strains on each day that susceptibility tests are
performed (18). Because this may not always be practical or economic, the frequency
of such quality control tests may be reduced if the laboratory can demonstrate that the
susceptibility testing procedures are reproducible. If a laboratory can document the
reproducibility of the susceptibility testing methods used, testing may be performed
on a weekly basis (18). If quality control errors emerge, the laboratory has a
responsibility to determine the cause(s) and repeat the tests. If the laboratory cannot
determine the source of error(s), then quality control testing should be re-initiated on
a daily basis (18).
Recognised quality control strains should be tested each time a new batch of medium
or plate lot is used and on a regular basis in parallel with the bacterial strains to be
assayed. Reference bacterial strains should be stored at designated centralised or
regional laboratories. Appropriate biosecurity issues should be addressed in obtaining
and dispersing quality control reference strains to participating laboratories. The use
of such strains will allow for comparison of antimicrobial susceptibility data among
the many surveillance systems in place among OIE Member Countries. OIE Member
Country laboratories should ultimately base quality control testing on factors and
circumstances specific to their needs and within reason. However, without the
appropriate quality control testing, susceptibility data derived from antimicrobial
surveillance and monitoring systems will be of limited value.
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External proficiency testing (e.g. third party testing) of participating laboratories
should be initiated for major bacterial species included in national surveillance systems
and should be mandatory. Designated national laboratories should be appointed or
established to monitor quality assurance of the participating surveillance laboratories.
The responsibilities of the reference laboratory may include the development of a set
of reference bacterial strains with varying antimicrobial susceptibilities to be sent to
the participating laboratories to ensure the accuracy and precision of the AST
methods and results. The participating laboratories will test these strains under their
normal AST conditions. Proficiency testing on a regular basis would become one of
the foundations of quality assurance for participating laboratories in a surveillance
programme and ensure that reported susceptibility data is accurate (21).
Future directions in antimicrobial resistance detection
The most recent and perhaps the state-of-the-art approach for detection of certain
bacterial antimicrobial resistance phenotypes is via identification and characterisation
of the known genes that encode specific resistance mechanisms. Methods that employ
the use of genetic probes, nucleic acid amplification techniques (e.g. polymerase chain
reaction [PCR]), and deoxyribonucleic acid (DNA) sequencing offer the promise of
increased sensitivity, specificity and speed in the detection of specific known
resistance genes (14, 17). These genotypic methods are important supplements to
traditional phenotypic methods, e.g. for the verification of methicillin resistance in
staphylococci, vancomycin resistance in enterococci, and detection of fluoroquinolone
resistance mutations (14, 17, 23). Additionally, recent technological advances may
facilitate the ability to probe bacterial species for large numbers of antimicrobial
resistance genes rapidly and at low cost, thereby providing additional relevant data for
surveillance and monitoring programmes.
Recommendations
To standardise AST methods and achieve comparability of antimicrobial susceptibility
test results between OIE Member Countries, the following recommendations are
presented:
– standardised antimicrobial susceptibility testing methods and harmonisation of
susceptibility data (including interpretive criteria) are essential for national and
international surveillance comparisons in OIE Member Countries
– standardised AST methods and similar interpretive criteria must be accepted and
used by all participating laboratories in surveillance and monitoring programmes
– it is essential that all data, regardless of the AST method, be reproducible and
reported quantitatively if comparisons are to be drawn on a world-wide scale between
surveillance programmes
– establishment of national or regional designated laboratories is essential for coordination of AST methodologies, interpretations and quality controls
– microbiological laboratories must conduct their work under internal quality
assurance
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– it is desirable for laboratories to become accredited, where applicable, and to
participate in external proficiency testing programmes
– specific bacterial reference/quality control strains, with varying susceptibility
ranges (susceptible, intermediate and resistant), are essential for determining intra- and
inter-laboratory quality assurance and proficiency testing
– interpretive criteria should be determined, developed and internationally agreed
upon for commonly encountered bacteria, especially zoonotic pathogens such as
Salmonella and Campylobacter
– co-ordination, where appropriate, with other international organisations (Food
and Agriculture Organization, World Health Organization) and/or regional
organisations (e.g. European Committee on Antimicrobial Susceptibility Testing,
NCCLS) may be important in providing support for standardisation and
harmonisation of AST methodologies and data among OIE Member Countries.
Antibiorésistance : standardisation et harmonisation
des méthodes de laboratoire pour la détection et la
quantification de l’antibiorésistance
D.G. White, J. Acar, F. Anthony, A. Franklin, R. Gupta, †T. Nicholls, Y. Tamura,
S. Thompson, E.J. Threlfall, D. Vose, M. van Vuuren, H.C. Wegener &
M.L. Costarrica
Résumé
Le Groupe ad hoc d’experts sur l’antibiorésistance créé par l’Organisation mondiale pour la santé
animale a élaboré une ligne directrice sur la standardisation et l’harmonisation des méthodologies de
laboratoire appliquées à la détection et à la quantification de l’antibiorésistance. Les auteurs analysent
les méthodes existantes (diffusion sur disque [avec les bandes de gradients de concentration], dilution
en gélose et dilution en bouillon de culture) et comparent leurs avantages et inconvénients respectifs. Ils
définissent les caractéristiques correspondant au classement des bactéries du point de vue de leur
résistance (sensibles, intermédiaires et résistantes) et discutent les critères relatifs à la détermination des
valeurs critiques. Tous ces aspects doivent être pris en compte lors de l’interprétation et de la
comparaison des données de suivi ou de surveillance de la résistance. Il est recommandé de recourir à
des méthodes de laboratoire validées, d’établir des programmes d’assurance qualité (interne et externe)
pour les travaux microbiologiques en laboratoire et de communiquer les résultats des épreuves
quantitatives. Il est également conseillé de faire établir l’équivalence entre les différentes méthodes et
résultats de tests de laboratoire par des évaluations externes des performances qui devraient être
conduites par un réseau de laboratoires de référence. Cette approche permettrait de comparer les
résultats des tests obtenus par différentes méthodes dans des laboratoires de divers pays.
Mots-clés
Analyse du risque – Antibiorésistance – Harmonisation – Maîtrise de la résistance –
Méthodologie de laboratoire – Normes internationales – Organisation mondiale pour
la santé animale – Santé publique – Standardisation – Valeur critique.
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Resistencia a los antimicrobianos: normalización y
armonización de los métodos de laboratorio para
detectar y cuantificar la resistencia a los
antimicrobianos
D.G. White, J. Acar, F. Anthony, A. Franklin, R. Gupta, †T. Nicholls, Y. Tamura,
S. Thompson, E.J. Threlfall, D. Vose, M. van Vuuren, H.C. Wegener &
M.L. Costarrica
Resumen
El Grupo Ad hoc de expertos sobre la resistencia de las bacterias a los productos antimicrobianos,
creado por la Organización mundial de sanidad animal, ha elaborado una directriz sobre la
normalización y armonización de los métodos de laboratorio para detectar y cuantificar la resistencia a
los productos antimicrobianos. Los autores pasan revista a las técnicas existentes (difusión en disco
[incluidas las tiras de gradiente de concentración], dilución en agar y dilución en caldo) y comparan
sus respectivas ventajas e inconvenientes. También definen las categorías de bacterias en función de su
resistencia (susceptibles, intermedias y resistentes) y examinan los criterios para determinar los valores
críticos, aspectos que conviene tener en cuenta a la hora de interpretar y comparar datos procedentes del
seguimiento o la vigilancia de las resistencias. Los autores recomiendan utilizar métodos de laboratorio
validados y someter a procesos (internos y externos) de garantía de calidad tanto el trabajo
microbiológico como los informes sobre resultados de pruebas cuantitativas. Recomiendan asimismo
que se establezcan equivalencias entre distintos métodos y resultados de laboratorio mediante pruebas
externas de eficiencia, proceso en el que ha de intervenir un sistema de laboratorios de referencia. Esta
fórmula serviría para comparar los resultados obtenidos mediante métodos diversos y por laboratorios
de países distintos.
Palabras clave
Análisis de riesgos – Armonización – Contención de las resistencias – Métodos de
laboratorio – Normalización – Normas internacionales – Organización mundial de
sanidad animal – Resistencia a los productos antimicrobianos – Salud pública –
Valores críticos.
References
1. Acar J. & Goldstein F.W. (1995). – Disk susceptibility test (V. Lorian, ed.). In Antibiotics
in laboratory medicine, 4th Ed. Williams and Wilkins, Baltimore, 1-51.
2. Andrews J.M., Boswell F.J. & Wise R. (2000). – Evaluation of the Oxoid Aura image
system for measuring zones of inhibition with the disk diffusion technique. J. antimicrob.
Chemother., 46, 535-540.
3. Bager F. (2000). – DANMAP: monitoring antimicrobial resistance in Denmark. Int. J.
antimicrob. Agents, 14, 271-274.
4. Brown D.F. & Brown L. (1991). – Evaluation of the E-test, a novel method of
quantifying antimicrobial activity. J. antimicrob. Chemother., 27, 185-190.
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5. Laboratory method
5. Caprioli A., Busani L., Martel J.L. & Helmuth R. (2000). – Monitoring of antibiotic
resistance in bacteria of animal origin: epidemiological and microbiological methodologies. Int.
J. antimicrob. Agents, 14, 295-301.
6. Cars O. (ed.) (1997). – Antimicrobial susceptibility testing in Sweden. Scand. J. infect. Dis.,
105 (Suppl.), 5-31.
7. Comité de l’Antibiogramme de la Société française de Microbiologie (CA-SFM) (1993). –
Définition des catégories thérapeutiques et méthode de détermination de la concentration
minimale inhibitrice en milieu solide pour les bactéries aérobies à croissance rapide. Bull. Soc. fr.
Microbiol., 8, 156-166.
8. Courvalin P. & Soussy C.J. (eds) (1996). – Report of the Comité de l’Antibiogramme de
la Société française de Microbiologie. Clin. Microbiol. Infect., 2 (Suppl. 1), S3-S34.
9. Craig W. (1993). – Qualitative susceptibility tests versus quantitative MIC tests. Diagn.
Microbiol. infect. Dis., 16, 231-236.
10. Deutsch Industrie Norm-Medizinsche Mikrobiologie (1994). – Methoden zur Empfindlichkeitsprunfung von bakteriellen Krankheitserregen (ausser Mykobakterien) gegen
Chemotherapeutika, Geschaftsstelle des NAMeds im DIN. Dtsch Ind. norm-med. Mikrobiol., 58,
940.
11. Gould I.M. (2000). – Towards a common susceptibility testing method? J. antimicrob.
Chemother., 45, 757-762.
12. Greenwood D. (2000). – Detection of antibiotic resistance in vitro. Int. J. antimicrob. Agents,
14, 303-306.
13. Hubert S., Nguyen P.D. & Walker R.D. (1998). – Evaluation of a computerized
antimicrobial susceptibility system with bacteria isolated from animals. J. vet. diagn. Invest., 10,
164-168.
14. Jorgensen J.H. & Ferraro M.J. (2000). – Antimicrobial susceptibility testing: special needs
for fastidious organisms and difficult-to-detect resistance mechanisms. Clin. infect. Dis., 30,
799-808.
15. Livermore D.M. & Wale M.C.J. (1998). – Surveillance of antimicrobial resistance. Br. med.
J., 317, 614-615.
16. Marano N.N., Rossiter S., Stamey K., Joyce K., Barrett T.J., Tollefson L.K. & Angulo F.J.
(2000). – The national antimicrobial resistance monitoring system (NARMS) for enteric
bacteria, 1996-1999: surveillance for action. J. Am. vet. med. Assoc., 217, 1829-1830.
17. Murray P.R., Baron E.J., Pfaller M.A., Tenover F.C. & Yolken R.H. (1999). –
Antimicrobial agents and susceptibility testing. In Manual of clinical microbiology, 7th Ed.
American Society for Microbiology, Washington, DC, 1469-1592.
18. National Committee for Clinical Laboratory Standards (NCCLS) (1999). – Document
M31-A. Performance standards for antimicrobial disk and dilution susceptibility tests for
bacteria isolated from animals, approved standard. NCCLS, Villanova, 57 pp.
19. National Committee for Clinical Laboratory Standards (NCCLS) (1999). – Document
M37-A. Development of in vitro susceptibility testing criteria and quality control parameters for
veterinary antimicrobial agents, approved guideline. NCCLS, Villanova, 17 pp.
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20. National Committee for Clinical Laboratory Standards (NCCLS) (2001). – Document
M100-S11. Performance standards for antimicrobial susceptibility testing, 9th informational
supplement. NCCLS, Wayne, 122 pp.
21. Threlfall E.J., Fisher I.S.T., Ward L.R., Tschäpe H. & Gerner-Smidt P. (1999). –
Harmonization of antibiotic susceptibility testing for Salmonella: results of a study by 18
national reference laboratories within the European Union-funded Enter-Net group. Microb.
Drug Resist., 5, 195-200.
22. Trevino S. (2000). – Antibiotic resistance monitoring: a laboratory perspective. Military
Med., 165, 40-42.
23. Walker R.A., Lawson A.J., Lindsay E.A., Ward L.R., Wright P.A., Bolton F.J.,
Wareing D.R.A., Corkish J.D., Davies R.H. & Threlfall E.J. (2000). – Decreased susceptibility
to ciprofloxacin in outbreak-associated multiresistant Salmonella Typhimurium DT104. Vet.
Rec., 147, 395-396.
24. Walker R.D. (2000). – Antimicrobial susceptibility testing and interpretation of results. In
Antimicrobial therapy in veterinary medicine, 3rd Ed. Iowa State University Press, Ames,
12-26.
25. Woods G.L. (1995). – In vitro testing of antimicrobial agents. In Antibacterial therapy: in
vitro testing, pharmacodynamics, pharmacology, new agents. Infectious Disease Clinics of
North America, Vol. 9. W.B. Saunders, Philadelphia, 463-495.
26. Working Party on Antibiotic Sensitivity Testing of the British Society for Antimicrobial
Chemotherapy (1991). – A guide to sensitivity testing. J. antimicrob. Chemother., 27 (Suppl. D),
1-50.
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Standardisation of antimicrobial susceptibility testing
in Europe: the work of the European Committee for
Antimicrobial Susceptibility Testing (EUCAST)
I. Phillips
Department of Infection, KCL, st Thomas’Hospital Campus, London SE1 7EH, United Kingdom
The European Committee for Antimicrobial Susceptibility Testing (EUCAST) is a
standing committee of the European Society for Clinical Microbiology and Infectious
Diseases (ESCMID), and was formed in 1997 as the successor of an earlier working
group. Under the Chairmanship of Professor I Phillips until 2001, when Dr G.
Kahlmeter succeeded him, its main aim has been the rationalisation of antimicrobial
susceptibility testing in Europe.
Rationalisation has become necessary because there has developed a great diversity of
methodology in different countries and in different laboratories within countries since
the work of the International Collaborative Study in the 1960s. Different media,
different inocula and different breakpoints are used, including National Committee
for Clinical Laboratory Standards (NCCLS) methodology and interpretive criteria
originating in the United States of America. This has meant that it has been difficult if
not impossible to compare results of tests, and particularly reports, on the prevalence
of resistance both within the European Union and with the rest of the world. I shall
describe the work of the Committee up to the change of Chairmanship.
Until 2001 the Committee was made up of representatives appointed by each
European country – thirty-four in all – plus two representatives for the
Pharmaceutical Industry and two for the Manufacturers of Susceptibility-testing
Devices. All of these representatives were to be appointed for two years and were
charged with acting as intermediaries between the Committee and those who
appointed them. In the event, it took longer to set up the Committee than had been
visualised, and most members served for longer periods until there were changes to
the constitution on the appointment of the new Chairman.
The Committee attempted to make progress towards rationalisation by the agreement
of reference methodology, but not, as has sometimes been understood, by the
agreement of a single standard methodology, since it was quite clear that those
countries that had developed their own methodology – for example, France, Sweden
and the United Kingdom – as well as those who used NCCLS methods, would be loth
to change. If correlations with the results of a reference methodology could be
achieved, there was actually no reason why they should change. This is a point that has
not always been understood by those not directly involved in the practice of
susceptibility testing, who appeared to believe that comparability could be achieved
only by standardisation and the use of a single method by all. The initial aim was to
achieve comparability of quantitative data minimum inhibitory concentrations (MICs)
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5. Laboratory method
and subsequently of interpretations (susceptible, intermediate and resistant). In all this
we were attempting to produce results that were of value to the prescribing clinician,
taking into account not only antimicrobial susceptibility but also antibiotic
pharmacology and the results of therapy.
The Committee worked via sub-committees appointed for specific purposes. These
sub-committees produced discussion documents (the E.Dis series), and, after
consultation, definitive documents (the E.Def series) published in the Society’s official
journal, Clinical Microbiology and Infection (CMI).
The first subcommittee to produce a definitive report was the Terminology group,
which had actually started work under the earlier working party. By 2000, it had
produced a second edition of its document, E.Def 1.2 (2). It was hoped that this
document would aid international understanding, but it was not intended to endorse
any particular methodology.
Two sub-committees worked on quantitative susceptibility testing. The first produced
its definitive report on agar-dilution MIC determination, E.Def 3.1, following
consultation, in 2000 (3). The reference method agreed is fully compatible with the
NCCLS reference methodology. The second group, dealing with broth microdilution,
took longer but its report is expected to be pubished this year in CMI. Again, it is
compatible with the NCCLS reference method.
In order to aid the progress of the setting of breakpoints for specific agents, a further
sub-committee produced a document in 2000 on the criteria to be considered by those
undertaking the process, E.Def 2.1 (4). As an experiment, an effort was made to
follow the layout of a similar document produced by the NCCLS, but this fell foul of
copyright and intellectual property considerations – despite the fact that the actual
practice of breakpoint setting had developed along similar but independent lines in
Europe and the USA since the logic was common. The methodology was used to set
breakpoints for the new antibiotic linezolid, reported in E.Def 4 (5). In an effort to
define the problem of agreeing to standard breakpoints for existing antibiotics, a
further document was produced listing current breakpoints used in different countries
in Europe (1). It has to be said that the differences are not so great, at least in relation
to the identification of susceptible populations of bacteria, as to be a real threat to
consensus, although amour propre could be!
Because of the particular diversity of disc susceptibility testing methods, it was decided
to defer consideration until MIC reference methodology had been agreed. By then it
was time for the new chairman to take action, and it was not by chance that his main
area of expertise is the achievement of comparable results from diverse disc
methodology. The results of his initiatives are awaited.
Still within the ambit of main-line susceptibility testing, working groups on
automation, on molecular methodology and on quality assurance, were unable to
achieve consensus documents for consultation within the timeframe.
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Outside main-line susceptibility testing, discussion documents were produced on
Intracellular Pathogens, E.Dis 6.1 (6), and mycobacteria, E.Dis 8.1 (7), and another
was planned on antifungals.
The EUCAST tried at all times to co-ordinate its activities with other bodies involved
in the methodology of susceptibility testing. Perhaps least successful was coordination with national bodies who were naturally wary of its activities but at the
same time critical of the time taken to attain consensus. The new Chairman has taken
the solution of this problem to be one of his main priorities. Much more successful
was co-ordination with NCCLS, and for a period of four years Professor Phillips acted
as a formal advisor to its Antimicrobial Susceptibility Testing (AST) Subcommittee,
attending its twice-yearly meetings in the USA. The NCCLS AST sent an observer to
annual EUCAST meetings. The Committee also co-ordinated with the European
Standards Organisation in the hope that when the time was ripe the Reference
Methods might help in the production of legal standards. Finally, the Committee
attempted to work with the European Medicines Evaluation Agency: although they
gave some support to our work, the power of the national groups that make up the
Agency’s committees was a tempering influence. It is still hoped that they will accept
the results of surveillance of antibiotic resistance based on demonstrated agreement
with our reference methods.
In its work during the four years leading up to the change of chairmanship in 2001,
the EUCAST took a number of important steps towards the achievement of
comparability of the results of quantitative antibiotic susceptibility testing and their
interpretation, outlined in this paper. On the table are reference methods for agardilution and broth-microdilution testing, and an agreed method of setting breakpoints.
It is for official bodies in Europe to accept them and encourage their use.
All of the publications may be obtained from Ms Cornelia Hasselmann, Martin-BuberWeg 17, D-81245 Munich, by e-mail via [email protected] or on the
net via http://www.escmid.org.
References
1. Degener J. E. & Phillips I. (2001). – Comparison of antimicrobial susceptibility test
breakpoints of national societies. Clin. microbiol. Infect., 7, 51-54.
2. European Committee for Antimicrobial Susceptibility Testing (EUCAST) (2000). –
Terminology relating to methods for the determination of susceptibility of bacteria to
antimicrobial agents: E.Def 1.2. Clin. microbiol. Infect., 6, 503-508.
3. European Committee for Antimicrobial Susceptibility Testing (EUCAST) (2000). –
Determination of minimum inhibitory concentrations of antibacterial agents by agar dilution:
E.Def 3.1. Clin. microbiol. Infect., 6, 509-515.
4. European Committee for Antimicrobial Susceptibility Testing (EUCAST) (2000). –
Determination of antimicrobial susceptibility test breakpoints: E.Def 2.1. Clin. microbiol. Infect.,
6, 570-572.
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5. European Committee for Antimicrobial Susceptibility Testing (EUCAST) (2001). –
Linezolid breakpoints: E.Def 4. Clin. microbiol. Infect., 7, 1-3.
6. European Committee for Antimicrobial Susceptibility Testing (EUCAST) (2001). –
Antimicrobial susceptibility testing of intracellular and cell-associated pathogens: E.Dis 6.1.
Clin. microbiol. Infect., 12.
7. European Committee for Antimicrobial Susceptibility Testing (EUCAST) (2000). –
Antimicrobial susceptibility testing of Mycobacterium tuberculosis: E.Dis 8.1.
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National Committee for Clinical Laboratory
Standards: a perspective on antimicrobial
susceptibility testing methods
T.R. Shryock, Ph.D
Elanco Animal Health, 2001 W. Main St., GL21, Greenfield, IN, USA 46140
The vision, mission, and organisational goals of the National Committee for Clinical
Laboratory Standards (NCCLS) are fundamentally grounded in the ideals of service
and leadership. The NCCLS achieves this through member support, volunteer
commitment, organisational partnerships, and collaborative efforts. Global Consensus
Standardization for Health Technologies, the NCCLS tagline, creates the context for,
and a declaration of, NCCLS’s commitment to providing a global forum for the
development of harmonised standards and guidelines that facilitate safety, best
practices, and quality patient care in the world’s medical testing and healthcare services
community. This work is conducted by volunteers in academia/professions, industry,
and government. NCCLS provides clinical laboratory Standards on clinical chemistry,
hematology, molecular methods, parasitology, lab safety, healthcare services,
immunology, automation, virology, and microbiology.
The documents produced by NCCLS cover:
– bacteria, mycobacteria, fungi, viruses, etc.
– disk and dilution testing (media, inoculum, incubation conditions, antibiotic
selection, endpoint determination and interpretation, reporting)
– quality control (QC) (protocols, flowcharts)
– sponsor development of QC (multilaboratory studies) and interpretive criteria
(based on pharmacokinetics-efficacy-epidemiology).
The main objective of both the subcommittee on Antimicrobial Susceptibility Testing
and the subcommittee on Veterinary Antimicrobial Susceptibility Testing is to provide
information that enables laboratories to assist the clinician in the selection of
appropriate antimicrobial therapy for patient care. Their mission is to foster
appropriate antimicrobial susceptibility testing methodology, sanction quality control
data, establish interpretive criteria, provide suggestions to users for routine laboratory
testing and reporting, and to educate users. NCCLS Standards may be used by outside
organisations for demonstrating conformance with accrediting or proficiency testing
requirements or as purchase specifications.
The NCCLS provides standardised methodology that is considered a reference
method for both animal and human bacterial pathogens. The clinical application of
these methods guides the practitioner in the selection of the appropriate antimicrobial
agent to treat the patient (animal or human), consistent with the implementation of
judicious use guidelines.
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5. Laboratory method
If the results of susceptibility tests done by non-NCCLS methods are to be compared
with results from tests done by NCCLS methods, then a study for equivalency should
be done. Differences in media formulation, inoculum density, etc., could influence the
outcome of susceptibility testing. The application of NCCLS interpretive criteria to
results generated by non-NCCLS methods may lead to improper antibiotic selections.
The similarity of NCCLS testing methods for bacteria isolated from both animals and
humans (e.g. foodborne bacteria) allows a direct comparison of results. This is useful
for the design and/or application of monitoring programme data when conducting
risk assessments on the potential impact of antibiotic use in food animals on public
health.
In conclusion, the NCCLS provides Standards for those interested in applying
antimicrobial susceptibility testing methodology, validated through quality control;
with interpretive criteria for the results. With the global application of NCCLS
methods, comparisons of results of antimicrobial resistance monitoring programmes
are possible.
References
Specific NCCLS documents for each topic area can be purchased on www.nccls.org
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Harmonisation of antimicrobial resistance testing
results – the outcome of the international Enter-net
study
I.S.T. Fisher (1), O.N. Gill, W.J. Reilly, H.R. Smith & E.J. Threlfall on behalf of the
Enter-net participants
(1)
Enter-net Scientific Co-ordinator, PHLS Communicable Disease Surveillance Centre, 61 Colindale Avenue,
London, NW9 5EQ, United Kingdom
There has been, and still is, much discussion about the requirement for standardising
antimicrobial susceptibility testing results. Which standards should be adopted and
which method should be used? The importance of doing this is to allow the
meaningful comparison of resistance patterns between laboratories and even
countries. The problem with standardisation of methods is that every laboratory
wishing to be involved would have to conform to a single method.
Enter-net – the international surveillance network for enteric pathogens – took the
radical step of looking at whether it would be possible to harmonise the results of
antimicrobial testing rather than the methods behind them. Forty-eight salmonella
strains, with resistance patterns ranging from fully sensitive to being resistant to
twelve different antimicrobial agents, were sent to eighteen national salmonella
reference laboratories in Western Europe for antimicrobial tests to be performed.
These tests were performed under each laboratory’s own standards and methods. The
qualitative results (resistant, intermediate or sensitive) were returned to the Laboratory
of Enteric Pathogens for comparison and analysis.
The results showed that, with the exception of low-level resistance to ciprofloxacin,
there is a very high level of agreement between laboratories. Therefore, data on
antimicrobial resistance results were incorporated in the international database that
had already been created. This has provided a definitive method for the meaningful
international surveillance of antimicrobial susceptibility results. Already in the EU this
has contributed to an important assessment of the role of antimicrobials in humans
and food animals in development of drug resistance in zoonotic Salmonella species.
Similarly, it has resulted in the exchange of harmonised antimicrobial resistance data in
addition to phage typing results in the investigation of international outbreaks of
multi-resistant S. typhimurium DTs 104 and 204b in several European countries.
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6.
Prudent use and containment of resistance
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Antimicrobial resistance: responsible and prudent use
of antimicrobial agents in veterinary medicine
F. Anthony (1), J. Acar (2), A. Franklin (3), R. Gupta (4), †T. Nicholls (5), Y. Tamura (6),
S. Thompson (7), E.J. Threlfall (8), D. Vose (9), M. van Vuuren (10) & D.G. White (11)
(1)
Fresh Acre Veterinary Surgery, Flaggoners Green, Bromyard, Herefordshire HR7 4QR, United Kingdom
(2)
Université Pierre et Marie Curie, Service de Microbiologie Médicale, Fondation Hôpital Saint-Joseph, 185 rue
Raymond Losserand, 75674 Paris Cedex 14, France
(3)
The National Veterinary Institute (SVA), Department of Antibiotics, SE 751 89 Uppsala, Sweden
(4)
College of Veterinary Sciences, Veterinary Bacteriology, Department of Microbiology, G.B. Pant University of
Agriculture and Technology, Pantnagar 263 145 Uttar Pradesh, India
(5)
National Offices of Animal and Plant Health and Food Safety, Animal Health Science and Emergency
Management Branch, Department of Agriculture, Fisheries and Forestry, P.O. Box 858, Canberra ACT 2601, Australia
(6)
National Veterinary Assay Laboratory, Ministry of Agriculture, Forestry and Fisheries, 1-51-1 Tolura,
Kokubunji, Tokyo 185-8511, Japan
(7)
Joint Institute for Food Safety Research, Department for Health and Human Services Liaison, 1400
Independence Avenue, SW, Mail Stop 2256, Washington, DC 20250-2256, United States of America
(8)
Public Health Laboratory Service, Central Public Health Laboratory, Laboratory of Enteric Pathogens, 61
Collindale Avenue, London NW9 5HT, United Kingdom
(9)
David Vose Consulting, Le Bourg, 24400 Les Lèches, France
(10) University of Pretoria, Faculty of Veterinary Science, Department of Veterinary Tropical Diseases, Private Bag
X04, Onderstepoort 0110, South Africa
(11) Centre for Veterinary Medicine, Food and Drug Administration, Office of Research, HFV-530, 8401 Muirkirk
Road, Laurel, Maryland 20708, United States of America
This report, prepared by the OIE Ad hoc Group of experts on antimicrobial resistance, has not yet received the
approval of the International Committee of the OIE
Summary
A guideline on the responsible and prudent use of antimicrobials in animal husbandry has been
developed by the Ad hoc Group of experts on antimicrobial resistance, created by the OIE (World
organisation for animal health). The objectives of responsible use are to maintain antibiotic efficacy, to
avoid the dissemination of resistant bacteria or resistance determinants and to avoid the exposure of
humans to resistance through food. The guideline attributes a central role to the competent authorities
responsible for granting marketing authorisations for antimicrobial substances. Requirements before
and after granting of marketing authorisations are defined. Important aspects include the control of the
pharmaceutical product quality and the therapeutic efficacy, the assessment of the selection pressure, the
protection of the environment, specific and non-specific antimicrobial resistance surveillance. The
guideline is also addressed to the veterinary pharmaceutical industry, veterinary practitioners,
dispensing pharmacists and farmers. The respective roles and responsibilities of these groups are
defined.
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Keywords
Antimicrobial resistance – Competent authorities – Containment of resistance – Food
– Human medicine – International standards – Marketing authorisation – Public
health – Veterinary medicine – World Organisation for Animal Health.
Introduction
This document provides guidance for the responsible and prudent use of
antimicrobials in veterinary medicine, with the aim of protecting both animal and
human health. The authors define the respective responsibilities of authorities and
groups involved in the registration, production, control, distribution and use of
veterinary antimicrobials, such as national competent authorities, the veterinary
pharmaceutical industry, veterinarians, pharmacists and livestock producers.
Prudent use is principally determined by the outcome of the marketing authorisation
procedure and by the implementation of specifications when antimicrobials are
administered to animals.
A number of codes of practice, relating to the use of antimicrobials and the conditions
thereof have been developed by different organisations. These codes were taken into
consideration and some elements were included in the preparation of this guideline.
Aims and objectives
It is imperative that all who are involved in the authorisation, manufacture, sale and
supply, prescription and use of antimicrobials in livestock act legally, responsibly and
with the utmost care, in order to limit the spread of resistant bacteria among animals
and to protect the health of consumers.
Antimicrobial agents: powerful tools for treating and
preventing/controlling bacterial diseases in animals
Guidelines for the responsible use of antimicrobial agents in veterinary medicine
include a set of practical measures and recommendations intended to prevent and/or
reduce the selection of antimicrobial resistant bacteria in animals, with the following
aims:
a) to maintain the efficacy of antimicrobial agents and to ensure the rational use of
antimicrobials in animals with the purpose of optimising both their efficacy and safety
in animals
b) to comply with the ethical obligation and economic need to keep animals in good
health
c) to prevent, or reduce as far as possible, the transfer of bacteria (with their
resistance determinants) within animal populations, to maintain the efficacy of
antimicrobial agents used in livestock
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d) to prevent or reduce the transfer of resistant bacteria or resistance determinants
from animals to humans, to maintain the efficacy of antimicrobial agents used in
human medicine
e) to prevent the contamination of animal-derived food with antimicrobial residues
which exceed the established maximum residue limit (MRL)
f) to protect consumer health by ensuring the safety of food of animal origin
intended for human consumption.
The responsible use of antimicrobials in veterinary medicine
The Ad hoc Group described responsible use as follows:
a) represents the scientific and technically directed use of these compounds that are
the responsibility of professionals with the required expertise
b) is part of good veterinary and animal husbandry practice and takes into
consideration disease prevention practices such as the use of vaccination and
improvements in husbandry conditions when disease problems become evident
c) aims to reduce the use of antimicrobial agents to their approved and intended
uses
d) takes into consideration on-farm sampling and testing of isolates from foodproducing animals during their production (where appropriate), and makes
adjustments to therapy when problems become evident
e) should be based on the results of resistance surveillance and monitoring
(bacterial cultures and antimicrobial sensitivity testing)
f) is aimed at all the relevant professionals, including the following:
– administrative and scientific authorities
– the veterinary pharmaceutical industry
– distributors and others handling antimicrobials
– veterinarians, pharmacists and livestock producers.
Responsibilities of the regulatory authorities
The national regulatory authorities, which are responsible for granting the marketing
authorisation, have a significant role in specifying the terms of this authorisation and
in providing the appropriate information to the veterinarian through product labelling
in support of the prudent use of antimicrobials in veterinary medicine.
It is the responsibility of the pharmaceutical industry to submit the data requested for
the granting of the marketing authorisation.
The use of an antimicrobial agent in veterinary medicine requires a marketing
authorisation, which is granted by the competent authorities only if the criteria of
safety, quality and efficacy are met. The examination of applications for drug
authorisation must include an assessment of the risks to both the animal and the
consumer resulting from the use of antimicrobial agents in food-producing animals.
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The evaluation should focus on each individual antimicrobial product and not be
generalised to the class of antimicrobials to which the particular active principle
belongs. The safety evaluation should include consideration of the potential impact on
human health of the proposed use in food-producing animals. If dose ranges or
different durations of treatment are suggested, the national authorities should give
guidance on the approved product labelling regarding the conditions that will
minimise the development of resistance.
Regulatory authorities should, where possible, expedite the market approval process
of new antimicrobial molecule formulation, which is considered to have the potential
to help the control of resistance. The preparation of internationally accepted
guidelines would assist in this regard.
Countries lacking the necessary resources to implement an efficient registration
procedure for veterinary medicinal products and whose supply of veterinary medicinal
products principally depends on imports from foreign countries must undertake the
following measures:
– check the efficacy of administrative controls on the import of these veterinary
medicinal products
– check the validity of the registration procedures of the exporting country
– develop the necessary technical co-operation with experienced authorities to
check the quality of imported veterinary medicinal products as well as the validity of
the recommended conditions of use.
Regulatory authorities of importing countries could request the pharmaceutical
industry to provide quality certificates prepared by the competent authority of the
exporting country.
All countries should make every effort to actively combat the trade, distribution and
use of illegal and counterfeit products.
Quality control of antimicrobial agents
Quality controls should be performed as follows:
– in compliance with the provisions of good manufacturing practices
– to ensure that analysis specifications of antimicrobial agents used as active
ingredients comply with the provisions of approved monographs
– to ensure that the quality and concentration (stability) of antimicrobial agents in
the marketed dosage form(s) is maintained until the expiry date, established under the
recommended storage conditions
– to ensure the stability of antimicrobials when mixed with feed or drinking water
– to ensure that all antimicrobials are manufactured to the appropriate quality and
purity in order to guarantee safety and efficacy.
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Control of the therapeutic efficacy
Preclinical trials
Preclinical trials should be undertaken, with the following aims:
– to assess the ability of the antimicrobial agent to select for resistant bacteria in
vitro and in vivo. The design of in vivo studies is currently under development. In certain
cases, preclinical trials should evaluate not only the bacteria of the target animals for
resistance, but also the impact of the antimicrobial use on food-borne and/or
commensal bacteria
– to establish an appropriate dosage regimen necessary to ensure the therapeutic
efficacy of the antimicrobial agent and limit the selection of antimicrobial resistant
bacteria.
Pharmacodynamics and the establishment of the activity of antimicrobial
agents towards the targeted bacteria
The following criteria should be taken into account:
– mode of action
– minimum inhibitory and bactericidal concentrations
– time- or concentration-dependent activity
– activity at the site of infection.
Pharmacokinetics and the establishment of the dosage regimens allowing
maintenance of effective antimicrobial levels
The following criteria should be taken into account:
– bio-availability according to the route of administration
– concentration of the antimicrobial at the site of infection and its distribution in
the treated animal
– metabolism which may lead to the inactivation of antimicrobials
– excretion routes.
The use of combinations of antimicrobial agents should be justified, taking into
account the following:
– pharmacodynamics (additive or synergistic effects towards the target bacteria)
– pharmacokinetics (maintenance of the levels of associated antibiotics responsible
for additive or synergistic effects at the site of infection throughout the treatment
period).
Clinical trials
Clinical trials should be performed to confirm the validity of the claimed therapeutic
indications and dosage regimens established during the preclinical phase.
The following criteria should be taken into account:
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– diversity of the clinical cases encountered when performing multi-centre trials
– compliance of the protocols of clinical trials with good clinical practice
– eligibility of the studied clinical cases, based on appropriate criteria of clinical and
bacteriological diagnoses
– parameters for qualitatively and quantitatively assessing the efficacy of the
treatment.
Assessment of the potential of antimicrobials to select for resistant
bacteria
Studies may be appropriate and requested in support of the assessment of the
potential of antimicrobials to select for resistant bacteria.
However, it should be noted that the results from these in vivo studies may be very
different from the resistance that develops under normal conditions. Therefore, the
interpretation should be undertaken with great caution.
The party applying for market authorisation for antimicrobials for veterinary use
should, where possible, supply data derived from the testing of antimicrobials for the
development of antimicrobial resistance in target animal species under the intended
conditions of use.
To reduce the potential selection of resistance, preclinical and clinical trials should, in
certain cases, evaluate not only pathogenic bacteria of target animals for resistance,
but also the impact of the antimicrobial use on food-borne and/or commensal
(indicator) bacteria.
In these cases, considerations may include the following:
– the concentration of active compound in the gut of the animal (where the
majority of potential food-borne pathogens reside) at the defined dosage level
– the level of human exposure to food-borne or other resistant bacteria
– the degree of cross-resistance within the class of antimicrobials and between
classes of antimicrobials
– the pre-existing level of resistance in the pathogens of human health concern
(baseline determination).
Establishment of acceptable daily intake, maximum residue limit and
withdrawal periods for antimicrobial compounds
a) When setting the acceptable daily intake (ADI) and MRL for an antimicrobial
substance, the safety evaluation should, for this class of substances, also include the
potential biological effects on the intestinal flora of humans. Using in vitro and/or in
vivo tests and/or data originating from human medicine, an assessment should be
undertaken regarding the capability of antimicrobial residues, ingested by the
consumer, to disturb the intestinal flora of humans by selecting resistant bacteria
and/or weakening the barrier effect against the colonisation of pathogenic bacteria.
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b) The establishment of an ADI for each antimicrobial agent, and an MRL for each
animal-derived food, should be undertaken. An MRL is necessary in order that
officially approved control laboratories can verify that all foods comply with the safety
standards.
c) For each veterinary medicinal product containing antimicrobial agents,
withdrawal periods should be established which make it possible to produce safe food
in compliance with the MRL.
Withdrawal periods should be established for each veterinary medicinal product by
taking into account the following:
– the MRL established for the antimicrobial agent under consideration
– the pharmaceutical form
– the target animal species
– the dosage regimen and the duration of treatment
– the route of administration.
The applicant should provide methods for regulatory testing of residues in food.
Protection of the environment
An assessment of the impact of the proposed antimicrobial use on the environment
should be conducted. Efforts should be made to ensure that environmental
contamination with antimicrobials is restricted to a minimum.
Establishment of a summary of product characteristics for each
veterinary medicinal product
The summary of product characteristics contains the information necessary for the
appropriate use of veterinary medicinal products containing antimicrobial agents. It
constitutes, for each veterinary medicinal product, the official reference of the content
of its labelling and package insert. This summary contains the following items:
– pharmacological properties
– target animal species
– therapeutic indications
– target bacteria
– dosage and administration route
– withdrawal periods
– incompatibilities
– expiry date
– operator safety
– particular precautions before use
– particular precautions for the proper disposal of un-used products.
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The conditions of prudent use of an antimicrobial agent in veterinary medicine should
be based on a safety evaluation, which takes into particular consideration the
importance of the drug, or other antimicrobial agents belonging to the same
therapeutic class, in human and/or veterinary medicine. Antimicrobials which are
considered important in treating critical diseases in humans should only be used in
animals when alternatives are either unavailable or inappropriate. Consideration
should be given to providing such guidance to the veterinarian by means of the
product label.
The oral route, which enhances the access of antimicrobial agents to the complex
intestinal flora, and hence the possibility of the selection and the transfer of resistance
genes, should be used with caution. For certain antimicrobial classes, other
administration routes may also cause similar selection of resistance. Specific mention
should be made on the product label.
Post-marketing antimicrobial surveillance
A structured approach is required to the investigation and reporting of the incidence
and prevalence of resistance.
Regulatory authorities should have implemented a pharmacovigilance programme for
the monitoring, reporting and recording of adverse reactions to antimicrobials,
including the lack of efficacy related to antimicrobial resistance. The information
collected through the pharmacovigilance programme should form part of the
comprehensive strategy to minimise antimicrobial resistance.
A surveillance programme
A specific surveillance programme to assess the impact of the use of an authorised
antimicrobial agent on the selection of antimicrobial resistant bacteria in foodproducing animals may be implemented after the granting of the marketing
authorisation. In certain cases, the surveillance programme should evaluate not only
resistance development in target animal pathogens, but also in food-borne pathogens
and/or commensals. This protocol of surveillance should be implemented if justified
by the safety evaluation performed during the registration process.
Specific surveillance
The surveillance of animal bacteria resistant to antimicrobial agents is essential. The
relevant authorities should implement a programme, established from the results of a
risk analysis, which allows the ranking of priorities regarding antimicrobials and animal
bacteria, whether or not they are pathogenic for animals and humans. For reasons of
efficiency, the methods used to establish such programmes (laboratory techniques,
sampling, choice of antimicrobial agents and bacteria, etc.) should be harmonised as
much as possible at the international level (see Antimicrobial resistance: standardisation and
harmonisation of laboratory methodologies for the detection and quantification of antimicrobial
resistance and Antimicrobial resistance: harmonisation of national antimicrobial resistance
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monitoring and surveillance programmes in animals and in animal-derived food, later in this
volume).
This epidemiological surveillance of antimicrobial resistance should be accompanied
by a continuous survey on the amounts of antimicrobial agents used by veterinarians
and other authorised users, in order to encourage the most appropriate prescription of
these medicinal products.
If justified by the results of this post-registration surveillance of antimicrobial
resistance, whether specific or not, the conditions of use of the antimicrobial agents in
veterinary medicine should be modified.
Distribution of the antimicrobial agents used in veterinary medicine
The relevant authorities should, where possible, ensure that all the antimicrobial
agents used in food animals fulfil the following criteria:
– are prescribed by a veterinarian or other suitably trained and authorised person
– are delivered by an authorised animal health professional
– are supplied only through licensed/authorised distribution systems
– are administered to animals by a veterinarian or under the supervision of a
veterinarian or by his/her agent.
Control of advertising
All advertising of antimicrobials should be controlled by a code of advertising
standards, and the relevant authorities must ensure that the advertising of
antimicrobial products fulfils the following criteria:
– compliance with the marketing authorisation granted, in particular regarding the
content of the summary of product characteristics
– restriction to authorised professionals, according to national legislation in each
country.
Training of antibiotic users
Training of antibiotic users, involving all the relevant professional organisations,
including regulatory authorities, the pharmaceutical industry, veterinary schools,
research institutes and professional associations, should focus on the following:
– information on disease prevention and management strategies to reduce the need
to prescribe antimicrobials
– the ability of antimicrobials to select for resistant bacteria in food-producing
animals, which may cause animal and/or human health problems
– the need to observe responsible use recommendations and the use of
antimicrobial agents in animal husbandry in agreement with the provisions of the
marketing authorisations, and veterinary advice, in order to assure the safety to the
consumer of animal-derived food, and therefore the protection of public health
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– relevant pharmacokinetic and pharmacodynamic information to enable the
veterinarian to use antimicrobials prudently.
Development of research
The relevant authorities should encourage public and private research with the
following aims:
– to improve knowledge regarding the mechanisms of action of antimicrobials, to
optimise the dosage regimens and the therapeutic activity of these medicinal products
– to improve knowledge about the mechanisms of selection, emergence and
dissemination of bacterial genes encoding resistance against antimicrobial agents
– to develop practical models for applying the concept of risk analysis to assess the
public health concern precipitated by the development of resistant bacteria
– to further develop protocols to predict, during the registration process, the
impact of the proposed use of the antimicrobials on the rate and extent of resistance
development
– to develop alternative methods to control bacterial diseases (vaccines, changes in
husbandry practices, etc.).
Responsibilities of the veterinary pharmaceutical industry
Marketing authorisation of veterinary medicinal products
The veterinary pharmaceutical industry has responsibilities in the following areas:
– to supply all the information requested by the national regulatory authority in
order to establish objectively the quality, safety and efficacy of veterinary medicinal
products
– to guarantee the quality of this information on the basis of the implementation of
procedures, tests and trials in compliance with the provisions of good manufacturing,
laboratory and clinical practices.
The pharmaceutical industry should be encouraged to perform post-approval studies,
as practised for human medicinal products, in order to seek an extension of the
authorised indications in the light of practical experience. This would limit the need
for off-label use.
Marketing and export of veterinary medicinal products
In regard to marketing and export of veterinary medicinal products, the following
suggestions are presented:
– only officially licensed and approved veterinary medicinal products should be
sold and supplied, and then only through licensed/authorised distribution systems
– only veterinary medicinal products which have been authorised in the (exporting)
country in which the product(s) is approved for sale or the quality of which is certified
by a regulatory authority should be exported
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– the national regulatory authority should be provided with the information
necessary to evaluate the amount of antimicrobial agents marketed.
Advertising
The following are the responsibilities of the veterinary pharmaceutical industry:
– to disseminate information in compliance with the provisions of the granted
authorisation and to ensure that this dissemination reaches only those authorised
professionals involved in the prescription and distribution of the products
– to ensure that the advertising of antimicrobials directly to the livestock producer
is discouraged.
Training
The veterinary pharmaceutical industry is responsible for participation in training
programmes as defined in the earlier section entitled ‘Training of antibiotic users’.
Research
It is the responsibility of the veterinary pharmaceutical industry to contribute to the
research effort as defined in the earlier section entitled ‘Development of research’.
Responsibilities of pharmacists
Pharmacists distributing veterinary antimicrobials should only do so on the
prescription of a veterinarian, and all products should be appropriately labelled (see
later section entitled ‘Labelling’).
The guidelines on the responsible use of antimicrobials should be reinforced by
pharmacists, who should keep detailed records of all antimicrobials supplied, including
the following:
– date of supply
– name of prescribing veterinarian
– name of user
– name of product
– batch number
– quantity supplied.
Pharmacists should also be involved in training programmes on the responsible use of
antimicrobials.
Responsibilities of veterinarians
The use of antimicrobials is no substitute for good management practices and the
prime concern of the veterinarian is to encourage good farming practice in order to
minimise the need for antimicrobial use in livestock.
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In the frame of good management practice, the veterinarian is responsible for
identifying recurrent disease problems and developing alternative strategies to prevent
or control disease. These may include changes in husbandry conditions and
vaccination programmes where vaccines are available.
Veterinarians should only prescribe antimicrobials for animals under their care, which
means that:
– the veterinarian must have been assigned responsibility for the health of the
animal or the herd/flock by the producer or an agent of the producer
– that responsibility must be real and not merely nominal
– that the animal(s) or herd/flock must have been examined immediately before
the prescription and supply or sufficiently recently or frequently for the veterinarian to
have personal knowledge of the condition of the animal(s) or current health status of
the herd or flock to make a diagnosis and prescribe
– the veterinarian should maintain clinical records of the animal(s)/herd/flock.
It is recommended that veterinary professional organisations develop for their
members, species-specific clinical practice guidelines on the responsible use of
antimicrobials, with particular reference to the choice of product, disease prevention
strategies and treatment protocols.
The responsibilities of veterinarians in this area are described below.
Use of antimicrobial agents when necessary
The appropriate use of antimicrobials in practice is a critical decision which, where
possible, should be based on the following:
– the experience and local expertise of the prescribing veterinarian
– an accurate diagnosis, based on adequate diagnostic procedures.
On certain occasions, a group of animals which may have been exposed to pathogenic
bacteria may need to be treated without recourse to an accurate diagnosis and
antimicrobial susceptibility testing, to prevent the development of clinical disease and
for reasons of animal welfare.
Determination of the choice of an antimicrobial
The expected efficacy of the treatment
The expected efficacy of the treatment is based on the following:
– the clinical experience of the veterinarian
– the activity towards the pathogenic bacteria involved
– the epidemiological history of the rearing unit, particularly in relation to the
antimicrobial resistance profiles of the pathogenic bacteria involved. Ideally, the
antibiotic profiles should be established before the commencement of treatment.
Should a first line antibiotic treatment fail or should the disease recur, the use of a
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second line antimicrobial agent should be based on the results of the microbiological
tests
– the appropriate route of administration
– results of initial treatment
– known pharmacokinetics/tissue distribution to ensure that the selected
therapeutic agent is active at the site of infection
– prognosis.
To minimise the likelihood of antimicrobial resistance developing, it is recommended
that antimicrobials be targeted to bacteria likely to be the cause of infection.
Absence of selection or limited selection of antimicrobial resistant
bacteria
The absence of selection or limited selection of antimicrobial resistant bacteria is
influenced by the following:
– the choice of the activity spectrum of the antimicrobial
– the targeting of specific bacteria
– known or predictable susceptibilities using antimicrobial susceptibility testing
– the correct dosing regimens
– the use of combinations of antimicrobial agents
– the importance of the drug to human and/or veterinary medicine. Antimicrobials
which are considered important to treat critical diseases in humans and/or animals,
should be used only when other therapies are unavailable or inappropriate
– the route of administration.
Combinations of antimicrobials
Combinations of antimicrobials are used for their synergistic effect to increase
therapeutic efficacy or to broaden the spectrum of activity.
Furthermore, the use of combinations of antimicrobials can be protective against the
selection of resistance in cases in which bacteria exhibit a high mutation rate against a
given antimicrobial.
However, a bad choice of a combination of antimicrobials may, in certain cases, lead
to an increase of the selection of resistance.
If the use of a combination of antimicrobials is justified, the veterinarian should
ensure that there is no antagonism between the chosen antimicrobials and should
check the ability of these antibiotics to reach the infection site under similar time and
concentration conditions, to maintain effective therapeutic concentrations as long as
required.
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Appropriate use of the antimicrobial agent chosen
A prescription for antimicrobial agents must precisely indicate the treatment regime,
the dose, the dosage intervals, the duration of the treatment, the withdrawal period
and the amount of drug to be delivered, depending on the dosage and the number of
animals to be treated.
All medicinal products should be prescribed and used according to the conditions of
the marketing authorisation, which are reflected in the summary of product
characteristics provided by the manufacturer.
If the label conditions allow for some flexibility, the veterinarian should consider a
therapeutic regimen that is sufficiently long to allow the effective recovery of the
animal, but sufficiently short to limit the selection of resistance in food-borne and/or
commensal bacteria.
‘Off label use’(extra-label use) of veterinary medicinal products
Although all medicinal products should be prescribed and used in accordance with the
specifications of the marketing authorisation, the prescribing veterinarian should have
the discretion to adapt these in exceptional circumstances.
The ‘off label use’ of an antimicrobial agent may be permitted in appropriate
circumstances and should be in agreement with the national legislation in force. The
veterinarian has the responsibility to define the conditions of responsible use in such a
case, including the therapeutic regimen, the route of administration and the duration
of the treatment.
Recording
All available information should be consolidated into one form or database, such that
this information should:
– allow monitoring of the quantities of medication used
– contain a list of all medicines supplied to each livestock holding
– contain a list of medicine withdrawal periods and a system for allowing
information to be updated
– contain a record of antimicrobial susceptibilities
– provide comments concerning the response of animals to medication
– allow the investigation of adverse reactions to antimicrobial treatment, including
lack of response due to antimicrobial resistance. Suspected adverse reactions should
be reported to the appropriate regulatory authorities.
Labelling
All medicines supplied by a veterinarian should be adequately labelled with the
following minimum information:
– the name of the owner/keeper or person who has control of the animal(s)
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–
–
–
–
–
–
the address of the premises where the animal(s) is kept
the name and address of the prescribing veterinarian
the date of supply
the indication ‘For animal treatment only’
the warning ‘Keep out of the reach of children’
the relevant withdrawal period, even if this is nil.
The label should not obscure the expiry date of the preparation or any important
information supplied by the manufacturer.
Training
Veterinary professional organisations should participate in the training programmes as
defined in the earlier section entitled ‘Training of antibiotic users’.
Responsibilities of producers
Producers are responsible for preventing outbreaks of disease and implementing
health and welfare programmes on their farms. They may, as appropriate, call on the
assistance of their veterinarian in undertaking these duties. All those involved with the
livestock on the farm have an important role to play in ensuring the responsible use of
antimicrobials.
Therapeutic antimicrobial products should be regarded as complementing good
management, vaccination and farm hygiene.
Efforts should be made to ensure that environmental contamination both by
antimicrobials and by resistant bacteria is kept to a minimum.
Livestock producers have the following responsibilities:
a) to draw up a health plan with the veterinarian in charge of the animals that
outlines preventative measures (mastitis plan, worming and vaccination programmes,
etc.)
b) to use antimicrobial agents only on veterinary prescription and according to the
provisions of the prescription
c) to use antimicrobial agents in the species, for the uses and at the doses on the
approved/registered labels and in accordance with product label instructions or the
advice of a veterinarian familiar with the animals and the production site
d) to isolate sick animals, when appropriate, to avoid the transfer of resistant
bacteria
e) to comply with the storage conditions of antimicrobials in the rearing unit,
according to the provisions of the leaflet and package insert
f) to address hygienic conditions regarding contacts between people (veterinarians,
breeders, owners, children) and the animals treated
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g) to comply with the recommended withdrawal periods to ensure that residue
levels in animal-derived food do not present a risk for the consumer
h) to dispose of surplus antimicrobials under safe conditions for the environment.
Partially-used medicines should only be used within the expiry date, for the condition
for which they were prescribed and, if possible, in consultation with the prescribing
veterinarian
i) to maintain all the laboratory records of bacteriological and susceptibility tests.
These data should be made available to the veterinarian responsible for treating the
animals to optimise the use of antimicrobials in that unit
j) to keep adequate records of all medicines used, including the following:
– name of the product/active substance and batch number
– name of supplier
– date of administration
– identification of the animal or group of animals to which the antimicrobial agent
was administered
– diagnosis/clinical conditions treated
– quantity of the antimicrobial agent administered
– withdrawal periods
– result of laboratory tests
– effectiveness of therapy
k) to inform the veterinarian responsible for the unit of recurrent disease problems.
Conclusion
Antimicrobial agents are very important tools for controlling a great number of
bacterial diseases in both animals and humans. It is vital that all countries implement
the appropriate systems to ensure that antimicrobials are manufactured, marketed,
distributed, prescribed, supplied and used responsibly, and that these systems are
adequately audited.
The OIE Ad hoc Group of experts on antimicrobial resistance is well aware of the
difficulties that a number of countries may face in the immediate implementation of
all elements of this guideline.
This document is designed to provide the framework which countries should
implement in accordance with their capabilities and resources, but within a reasonable
period of time. A step-by-step approach may be appropriate for a number of
countries, to properly implement all of the elements. The continued availability of
veterinary medicines, which are essential for animal welfare and health, and
consequently for human health, will ultimately depend on the responsible use of these
products by all those involved in the authorisation, production, control, distribution
and use of antimicrobials in animals.
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Antibiorésistance : utilisation responsable et prudente des
antibiotiques en médecine vétérinaire
F. Anthony, J. Acar, A. Franklin, R. Gupta, †T. Nicholls, Y. Tamura, S. Thompson,
E.J. Threlfall, D. Vose, M. van Vuuren & D.G. White
Résumé
Le Groupe ad hoc d’experts sur l’antibiorésistance mis en place par l’Organisation mondiale pour la
santé animale a mis au point une ligne directrice sur l’utilisation prudente et responsable des
antibiotiques dans la production animale. L’utilisation responsable a pour objectif de perpétuer
l’activité des antibiotiques, d’éviter la dissémination de bactéries résistantes ou des facteurs favorisant
la résistance ainsi que l’exposition de l’homme à celle-ci au travers des aliments. La ligne directrice
attribue un rôle majeur aux autorités compétentes chargées de la délivrance des autorisations de mise
sur le marché (AMM) des substances antimicrobiennes. Les auteurs définissent les conditions
préalables et consécutives à la délivrance de ces AMM. L’accent est mis sur le contrôle de la qualité et
de l’efficacité thérapeutique des produits pharmaceutiques, sur l’évaluation de la pression sélective, sur
la protection de l’environnement ainsi que sur la surveillance de l’antibiorésistance, spécifique et non
spécifique. La ligne directrice s’adresse également à l’industrie des médicaments vétérinaires, aux
praticiens, aux pharmaciens et aux éleveurs. Les rôles et responsabilités respectifs de ces groupes sont
également définis.
Mots-clés
Antibiorésistance – Autorisation de mise sur le marché – Autorités compétentes –
Denrées alimentaires – Maîtrise de la résistance – Médecine humaine – Médecine
vétérinaire – Normes internationales – Organisation mondiale pour la santé animale –
Santé publique.
Resistencia a los antimicrobianos: uso prudente y responsable
de productos antimicrobianos en medicina veterinaria
F. Anthony, J. Acar, A. Franklin, R. Gupta, †T. Nicholls, Y. Tamura, S. Thompson,
E.J. Threlfall, D. Vose, M. van Vuuren & D.G. White
Resumen
El Grupo Ad hoc de expertos sobre la resistencia de las bacterias a los productos antimicrobianos,
creado por la Organización mundial de sanidad animal, ha elaborado una directriz sobre el uso
prudente y responsable de productos antimicrobianos en producción animal. El uso responsable ha de
servir para: mantener la eficacia antibiótica de los productos; evitar la diseminación de bacterias
resistentes o de determinantes de resistencia; y evitar que el ser humano se vea expuesto por vía
alimentaria a organismos resistentes. Esta directriz asigna un papel básico a las autoridades
responsables de conceder las licencias de comercialización de sustancias antimicrobianas y define los
requisitos que éstas deben cumplir (antes y después de la autorización de comercialización). Entre los
aspectos más importantes cabe destacar: el control de la calidad y eficacia terapéutica de los productos
farmacéuticos; la evaluación del grado de presión selectiva; la necesidad de proteger el medio ambiente;
OIE International Standards on Antimicrobial Resistance, 2003
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6. Prudent use and containment of resistance
y la vigilancia de la aparición de resistencias específicas e inespecíficas a los antimicrobianos. La
directriz establece también las respectivas funciones y responsabilidades de la industria farmacéutica
veterinaria, los veterinarios, los farmacéuticos y los productores agropecuarios.
Palabras clave
Alimentos – Autoridades competentes – Autorización de comercialización –
Contención de las resistencias – Medicina humana – Medicina veterinaria – Normas
internacionales – Organización mundial de sanidad animal – Resistencia a los
productos antimicrobianos – Salud pública.
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Antibiotic use in animals and the emergence of
antibiotic resistance in human commensal microbes
and zoonotic pathogens
D.L. Smith (1) & J.A. Johnson (2)
(1)
Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, 660 West
Redwood St., Baltimore, MD 21201, United States of America
(2)
Veterans Affairs Maryland Health Care System and Department of Pathology, University of Maryland School of
Medicine, 660 West Redwood St., Baltimore, MD 21201, United States of America
Introduction
Policy makers have the unenviable task of making a decision about the use of
antibiotics for animal growth promotion. There is very limited scientific data on which
to base such a decision, and its interpretation is highly controversial. Mathematical
models can be an extremely useful policy tool by generating reasonable expectations
about the relationship between cause and effect, and the likely impact of a policy. I
discuss mathematical models for the chain of events leading from antibiotic use in
animals to a nosocomial infection, and make some general observations about the
kind of impact that should be expected.
Risk assessment
As antimicrobial resistance has increased in the clinical setting, the use of avoparcin
and virginiamycin in agriculture for growth promotion and fluoroquinolones for
treating infection in poultry has become the focus of intense debate. Agricultural use
of antibiotics has potential negative public health impacts because similar antibiotics
are important in human medicine. In response to calls for a science-based policy,
governments have recently commissioned risk assessments. Risk assessment provides
well-developed methodology and a common framework to synthesise vast amounts of
information from multiple academic disciplines. A risk assessment generates three
kinds of output: a best guess, an assessment of how close the best guess would
approximate an outcome if reality is exactly like the model, and a guess about how
different reality and the risk model might be. Risk assessment methodology is
transparent, but the mathematical language and methods are not familiar to many
stakeholders. Despite a familiarity with the concepts, they remain excluded from the
debate about the merits or failings of the model. Most critically, the availability of high
quality data is often limited; scientists do not usually collect data that are useful for a
risk assessment. When they do collect useful data, they are rarely reported in a form
that can be integrated into a risk assessment. The current lack of good quantitative
data about antibiotic resistant bacteria at each step severely limits the usefulness of the
standard risk assessment in making policy decisions regarding antibiotic use.
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The virtues of simple models
Simple mathematical models are an important companion to risk assessment, and a
useful tool for studying the spread of antibiotic resistance (1). They provide a clearer
picture of basic concepts than do highly detailed risk assessments because they are
based on concise but vastly simplified assumptions about the underlying processes.
Simple models are a much easier way to relate cause and effect in long chains of
causation by linking several flexible links in a chain into a single stiff one. The strength
of simple models is that the relationships between major assumptions and the output
become much easier to understand because several quantitative relationships are
reduced to one. The weakness is that the estimates are probably biased by the stiffness
of the single relationship, and sometimes difficult to parameterise with data. On the
other hand, a simple model may be a more useful representation than a perfect model
that includes more detail (3). Each step in a mathematical representation of the world
is a set of assumptions and parameters; these must be estimated. Each parameter
estimate and assumption has uncertainty associated with it. The uncertainty from one
step is propagated through each subsequent step, and the conclusion of the
complicated model may be far more variable than the simple one. The trick is to find a
model that is an appropriate tradeoff between simple but biased and complex but
variable. This is the essence of good model building and parsimony, a fundamental
principle governing all of science.
Farm-to-fork
For example, it is widely recognised that the use of antibiotics for growth promotion
has selected for antibiotic resistance in bacteria in the gut of food animals. These
resistant bacteria contaminate meat during production, and can be recovered on retail
products. Consumers are exposed to resistant bacteria through improper handling of
the meat. Farm-to-fork risk assessments provide detailed descriptions of each step in
this process, from the pen, through transport and processing, to the time that the
bacteria colonise the consumer. Thus, the use of antibiotics in farm animals
contributes to an increased prevalence of antibiotic resistant bacteria in the gut of
humans through a long chain of events. It follows that if antibiotic use in agriculture is
stopped, the rate of exposure to resistant bacteria on food will eventually decline. One
important question is, ‘How fast will exposure decline?’ Since resistance to antibiotics
is often naturally occurring or comes from clinical antibiotic exposure, a second
question is ‘What fraction of exposure to resistant bacteria is caused by the use of
antibiotics in agriculture?’ A simple farm-to-fork model can be reduced to two
parameters and a function that prescribes the ‘shape’ of the curve. Very simple farmto-fork models of this sort are descriptive, but they can be used to ask how well a
policy would work when other factors also affect the emergence of resistance to
antibiotics. The choice of a model depends on what happens after exposure.
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Bacteria life-history variability
Different types of models are needed for different types of resistant bacteria. The
bacteria that cause human infections vary widely in their ecology, epidemiology and
life-history traits. At two extremes are Campylobacter jejuni and Enterococcus faecium.
According to common wisdom, C. jejuni are zoonotic pathogens exclusively acquired
through contaminated food. Following exposure, they may establish transient
populations that are usually associated with disease, and they are never or rarely
transmitted from human-to-human. In contrast, E. faecium are human commensals
(harmless or beneficial bacteria). Colonisation is often transient, but occasionally
persists for months or possibly years. Human-to-human transmission of E. faecium is
common. More accurately stated, colonised humans frequently shed E. faecium and
others are exposed, but colonisation is less common, and poorly understood. C. jejuni
are rarely found in humans, except when they cause disease. Although E. faecium are
commonly found in humans, they may not be the same strains that circulate among
farm animals. One hypothesis is that E. faecium are host specific; strains isolated from
animal populations are adapted to the unique environment of that host species’ gut,
and may be unlikely to colonise a different species. Bacterial species vary in their
degree of host specificity, their propensity for human-to-human transmission, and
their propensity to colonise without causing disease.
Antibiotic resistance in zoonotic infections
Assuming the common wisdom about C. jejuni is correct, it follows that
campylobacteriosis is always the direct result of exposure to C. jejuni on contaminated
food. Computing the fraction of fluoroquinalone (FQ) resistance that is attributable to
FQ use in animals is straightforward. If an infection is FQ resistant, resistance either
preceded infection, or it evolved in response to FQ use in humans. It follows that an
increase in the fraction of FQ resistance among human cases of campylobacteriosis is
due to some change in the C. jejuni populations in animals, since there is no human
reservoir. Therefore, all the increases in FQ resistance from a baseline rate are directly
attributable to FQ use in farm animals. One alternative is that FQ resistance
accumulates in some human commensal bacteria, and is subsequently acquired by
C. jejuni. If this is true, the attributable fraction must account for the more complex
dynamics associated with commensal bacteria.
Antibiotic resistance in commensal pathogens
Resistance to antibiotics among human commensals may occur in two ways. Direct
exposure to antibiotic resistant bacteria on food may lead to increased prevalence of
resistant bacteria in humans if the bacteria from animals colonise the human gut or
transfer mobile genetic elements including resistance genes. Once resistant bacteria
colonise humans, they may spread to other humans. Farm-to-fork models describe
only half the problem; they must be coupled to models of the infectious process from
household-to-hospital (1). Evidence suggests that transmission rates are higher in
places where antibiotics are heavily used in human medicine. Simple models predict
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6. Prudent use and containment of resistance
that prevalence of resistance over time follows a sigmoidal curve. At any point,
prevalence depends on the previous history of antibiotic use in farm animals and
subsequent transmission aided by its use in human medicine. A simple model,
simulating a ‘counter-factual’ population where growth promoters were never used,
can illustrate the impact of antibiotic use, but the non-linearity in the model leads to
counter-intuitive conclusions.
Basic reproductive number
One key term is called the basic reproductive number, usually denoted R0, and defined
in this case as the number of new people who would be colonised by an average
individual, carrying resistant bacteria, introduced into a population with no resistance.
The concept plays a central role in the understanding of infectious processes in
populations by providing a simple criterion for determining when an infectious agent
will spread: if the first case generates more than one new case (R0 > 1), resistance
persists. When resistance is being introduced into a population from external sources,
R0 and the rate of introduction co-determine the prevalence. When R0 is low (as with
C. jejuni), the rate of exposure from animal antibiotics is the main determinant of
prevalence. For intermediate values of R0, the two interact in complicated ways. When
R0 is high, exposure from animal antibiotics may initiate an epidemic, but thereafter
plays a minor role (4).
Rare but important events
A key insight from this simple model is that rare events may be enormously
important, especially for intermediate and high values of R0 that are characteristic of
human commensal microbes. For example, the first case of vancomycin resistant
Staphylococcus aureus (VRSA) was a product of peculiar circumstances (2), but if it had
not been discovered then, it might have triggered an epidemic that would be
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6. Prudent use and containment of resistance
devastating. The value of delaying that epidemic is the sum of all cases prevented
between the actual start and the counterfactual start of the epidemic (Figure). The
concurrent use of an antibiotic in a hospital and on a farm provides ideal conditions
for new strains of resistance to appear in hospitals. Farms and hospitals are probably
ideal environments for genes conferring high-level resistance to move from
environmental bacteria species into the nosocomially important bacteria; from the
perspective of resistance, they are evolutionary incubators. With heavy antibiotic use
in hospitals, the emergence of nosocomially important strains seems inevitable, but
they may happen much earlier if a drug is concurrently used in animals. Such effects
are not studied from the paradigm of ‘experimental,’ but must be examined using the
paradigm of a ‘historical’ science, such as evolutionary biology. For policy makers, it
represents a real and credible threat, though such a threat may be difficult to estimate.
How does one estimate R0 for a nosocomial pathogen that has not yet emerged? How
does one attribute an impact that is historical? These are open questions, but the
simple models illustrate that they are the relevant ones for this debate.
Prudent use
The potential medical impact of using an antibiotic for animal growth promotion is
most critical in the honeymoon period, when antibiotic resistance is virtually absent. It
follows that prudent use of antibiotics in animals can occur only after medically
important resistant bacteria have become common in human populations. What about
the antibiotics that have already been used for animal growth promotion, such as
quinupristin/dalfopristin (QD)? The answer depends on how QD (Synercid) is used
in humans, how fast QD resistance declines in animals after a ban, and how rare QD
resistance becomes. The approval of oxazolidinone (Linezolid) may have reduced the
demands on QD use in humans, opened a window of opportunity and increased the
positive effect of a ban. On the other hand, it is possible that the impact of QD use
for animal growth promotion for nearly three decades is not reversible in the short
term since QD is approved for treating vancomycin-resistant enterococci.
Conclusion
The conclusions of mathematical models are only as good as the assumptions they are
based on, but models should also be judged by their ability to help us understand what
we are studying. The assumptions of our model are based on well-established general
principles in biology; the conclusions depend upon the values of key parameters.
Substantial disagreement exists about the value of these parameters, and the associated
conclusions. Making complicated risk assessment models can’t eliminate disagreement
about uncertain scientific principles, but they can certainly disguise the central issues.
When little is known, it is probably best to keep the models simple.
References
1. Bonten M.J.M., Austin D.J. & Lipsitch M. (2001). – Understanding the spread of
antibiotic resistant pathogens in hospitals: mathematical models as tools for control. Clin. infect.
Dis., 33, 1739-1746.
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2. Centers for Disease Control (2002). – Staphylococcus aureus resistant to vancomycin –
United States. MMWR, 51, 565-567.
3. Ludwig D. & Walters C.J. (1985). – Are age-structured models appropriate for catcheffort data? Can. J. Fish. aquat. Sci., 42, 1066-1072.
4. Smith D.L., Harris A.D., Johnson J.A., Silbergeld E.K. & Morris J.G. Jr. (2002). – Animal
antibiotic use has an early but important impact on the emergence of antibiotic resistance in
human commensal bacteria. Proc. natl Acad. Sci. USA., 94, 1152-1156.
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Prudent use of antibiotics and containment of
antimicrobial resistance: the role of medical
associations, guidelines and interventions
I.M. Gould
Department of Medical Microbiology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, AB25 2ZN, United
Kingdom
Introduction
Prudent use of antibiotics is a responsibility of all people, not just all health
professionals and especially not just medical specialists in the field of infection. This
makes the problem all the more difficult to address. Antibiotics are unlike any other
group of pharmaceutical products in that all areas of medical practice have cause to
use them and thus they are usually prescribed by non-specialists, often with very little
knowledge of antibiotics or the consequences of their actions. In addition, they are
often available (legally or illegally) as over-the-counter purchases, with or without
trained medical or pharmaceutical advice. This makes education, which must be the
main responsibility of Medical Societies, a daunting task.
Education
Public education is not a traditional area that medical societies have been involved in
and in the area of antibiotic prescribing, great efforts have recently been made by
societies specifically formed for that purpose such as, Stichting Werkgroep
Antibioticabeleid
([email protected])
(Holland),
Strategigruppen
för
Rationell
Antibiotikaanvändning och Minskad Antibiotikaresistens (www.strama.org) (Sweden) and
Alliance
for
the
Prudent
Use
of
Antibiotics
(www.healthsci.tufts.edu/apua/apua.html). In the United Kingdom (UK) this has
been the responsibility of the Government and there is some soft evidence that it has
been beneficial. Certainly, the levels of community antibiotic prescribing have
decreased substantially in the past five years and are now back to 1991 levels. This still
leaves them at twice the level of corresponding figures from Holland, so there is scope
for further improvement.
Some of this improvement may be due to improved professional education of General
Practitioners (primary care prescribers) using advice prepared by government advisory
committees which had medical society representation. There is clearly a role for
improved post-graduate education by medical societies. Here there is an obvious need
for better links between specialist societies such as the British Society for
Antimicrobial Chemotherapy (BSAC – www.bsac.org) and primary care medical
associations. BSAC has produced CD-roms on treatment of community respiratory
infections. In the UK, the Royal Colleges and in Europe the European Society of
Clinical Microbiology & Infectious Diseases are the main players in continuous
professional education but other specialist infection societies, such as the Hospital
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6. Prudent use and containment of resistance
Infection Society (www.his.org.uk) and the British Infection Society, also have an
important role to play. Again, liaison between the specialist societies such as the
European Society of Clinical Microbiology and Infectious Diseases and the general
medical societies in each country should become a priority to ensure that they have
access to the correct educational material.
When it comes to undergraduate medical education, a BSAC working group
recommended, in 1993, that antibiotic prescribing be given a higher priority. At the
request of the UK government, that working group has been re-formed and has
written to the Deans of the medical schools to ascertain any progress in their areas,
which over the past fifteen years have suffered keen competition from other areas.
Clinical practice guidelines
These are the preserve of the specialist societies and this is a rapidly expanding area
with the potential for great benefit. The legal basis of guidelines and the ability to
implement them successfully are, however, an area of great debate. Computerisation
of prescribing allows for much easier implementation of guidelines, as there are too
many available for non-specialists to be knowledgeable on them all or to retain access
to paper copies.
These days, evidence based guidelines, drawn up according to strict methodological
regulations, are considered best, as opposed to previously popular ‘expert opinion’
guidelines.
To those involved in drawing up these guidelines it is evident that much of modern
medical practice has a deficient evidence base. The Scottish Intercollegiate Guideline
Network (SIGN) are leaders in the field and are based at the Royal College of
Physicians in Edinburgh. They have several guidelines on areas of antibiotic
prescribing as do many specialist societies, although currently, not many of those from
other societies are truly evidence-based due to the resources needed to produce such
documents. Currently BSAC, with the help of Cochrane are producing evidence-based
guidelines on antibiotic control measures in hospitals and a Canadian group are doing
the same for community prescribing. (1).
Evidence based clinical guidelines can form the basis for standards of clinical
governance and Minimum Standards of Antibiotic Stewardship for hospital and
community health-care administration can be set from recommendations made
originally by the Infectious Diseases Society of America (IDSA) and BSAC and more
recently by the European Society of Clinical Microbiology and Infectious Diseases
(ESCMID).
There are also more detailed practical recommendations set at two levels, one for
countries with little established infrastructure in this area and another for those
countries with well developed systems of antibiotic stewardship (2).
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Evidence based interventions
A recent evidence based review of the literature, using the criteria of the Cochrane
Effective Practice and Organisation of Care Group, has identified only about 10% of
studies on hospital antibiotic prescribing intervention as qualifying, mainly as timeseries analysis, for inclusion in an evidence based review when outcomes other than
reduced prescribing are needed. Such outcome measurements include reduction in
resistance, clinical outcome measures and colonisation with C. difficile.
Nevertheless, if one includes a broader literature on intervention to change prescriber
behaviour (non-antibiotic), then there are six Cochrane reviews identifying education,
guidelines, academic detailing and audit/review as being effective, although trying to
change the habits of doctors has been described as an exercise in futility designed to
induce premature ageing!
Education can obviously take on many forms: it can be either persuasive or restrictive
and must be appropriate to the local situation, taking account of cultural and social
factors and financial aspects. Barriers to change will mostly be physician based but
may, of course, involve the system and patient. The attitude, knowledge and behaviour
of physicians must be addressed, always looking for hidden agendas and making clear
the benefits of changing practices.
There are 2 new initiatives from the European Commission: Antibiotic Resistance
Prevention and Control (ARPAC) and European Surveillance of Antibiotic
Consumption (ESAC). The overall aim of ARPAC (www.abdn.ac.uk/arpac) is to lay
the foundations for a better understanding of the emergence and epidemiology of
antibiotic resistance in human pathogens and to evaluate and harmonise strategies for
prevention and control of antibiotic resistant pathogens in European hospitals. The
main aims of ESAC ([email protected]) are to collect, validate, and present in a
standardised and meaningful manner, data pertaining to the use of antimicrobials in
human medicine in all Member States of the European Community, in countries
signatories to the Agreement on the European Economic Area and in associated
countries of Central and Eastern Europe.
In the future it is hoped that Medical Associations will be more involved in a two way
liaison process with industry, regulating authorities, politicians and healthcare
strategists to advise on key issues and formalise a greater role, not only in education,
but also in clinical governance.
References
1. Gould I.M. (2001). – Minimum antibiotic stewardship measures. Clin. Microbiol., 7
(Suppl. 6), 22-26.
2. Keuleyan E. & Gould I.M. (2001). – Key issues in developing antibiotic policies: from an
institutional level to Europe-wide. European study group on antibiotic policy (ESCAP),
subgroup III. Clin microbiol. Infect., 7 (Suppl. 6), 16-21.
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Prudent use of antibiotics and containment of
antimicrobial resistance
J. Edwards
Kakariki Grove, Waikanze 6454, New Zealand
It was not until the last decade of the 20th Century that antimicrobial resistance
became recognised as a serious public health issue. In just sixty years after the first
parenteral use of benzyl penicillin, a nanosecond in evolutionary time, real increases in
antimicrobial resistance have been reported from all corners of the globe.
Antimicrobial resistance is now acknowledged as a serious public health issue, not
only in hospital settings, but also in the community.
The World Veterinary Association (WVA) recognises the importance of emerging
antimicrobial resistance in both human and veterinary medicine
Recent attention has focused on antimicrobial use in agriculture.
There is limited but conclusive evidence that resistant bacteria in food producing
animals have spread to humans, either directly or through the food chain.
In the case of E. coli and enterococci the transfer of genetic material that confers
resistance is equally or more important. The risk and rate of transfer differ between
bacteria and the location of resistant genes. There is general agreement that
monitoring of resistance is needed in agriculture.
Surveillance information on the prevalence and trends in antimicrobial resistance will
contribute to:
– the formation of local and national antimicrobial treatment guidelines
– infection control policies
– the development of strategies to contain the emergence and spread of resistance
– the measurement of the effectiveness of intervention strategies.
Over the last two to three years, various international and national expert groups have
considered and reported on the problem of increasing antimicrobial resistance. This
issue has been subject to on-going development of international polices, and
highlights the need for increasing collaboration between the major international
organisations. We need to develop a cohesive international policy in a timely manner
and plan for future collaboration where more than one organisation has an interest.
Veterinary involvement is critically important in the formulation and implementation
of measures to control antimicrobial resistance. This includes non-government
veterinarians because of their role in pre-harvest food safety and the control and
responsible prescription of medicines intended for use in animals. It is essential that
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6. Prudent use and containment of resistance
veterinarians in private practice be involved in general and world-wide policy
formulation.
The OIE (World organisation for animal health) is the forum for government
veterinary services. The WVA is the only non-governmental organization representing
the veterinary profession globally and is working to strengthen its role. The WVA
appreciates its involvement with the OIE and offers to assist the OIE in all matters of
veterinary concern.
The veterinary profession:
– takes its responsibilities very seriously
– will support initiatives as part of meeting it’s societal obligation to assist in the
drive for food security and food safety.
The WVA has a communication network to distribute policies, adopted conclusions
and information on new developments to the veterinary profession around the world.
In 1999 the WVA joined the International Federation for Animal Health (IFAH) and
the International Federation of Agricultural Producers (IFAP) in the proactive
development of guidelines for the prudent use of antibiotics.
Recognising that antibiotics are health management tools that enhance good
husbandry practices for the purpose of disease prevention, disease treatment and
production enhancement, the following were promoted:
– the responsible and prudent use of antibiotics
– codes of good practice
– quality assurance programmes
– herd health surveillance programmes
– education programmes.
Antibiotics shall be used under the supervision of a veterinarian. Therapeutic
antibiotics should be used when it is known or suspected that an infectious agent is
present which will be susceptible to therapy. It is the responsibility of the veterinarian
to choose the antibiotic on the basis of his/her informed professional judgement,
balancing the risks and benefits for humans and animals. When antibiotics need to be
used for therapy, sensitivity testing should, whenever possible, be part of the informed
professional clinical judgement. There should be careful attention paid to the species
and disease indications and contra-indications, withdrawal periods and storage
instructions. Off-label use of antibiotics should only be exceptional and always be
under the professional responsibility of a veterinarian.
Antibiotics used for therapy should be used:
– for as long as needed
– over as short a dosage period as possible
– at the appropriate dosage regimen.
Records should be kept of all antibiotic administrations.
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6. Prudent use and containment of resistance
Co-ordinated susceptibility surveillance should be conducted.
Efficacious, scientifically proven alternatives to antibiotics are needed as an important
part of good husbandry practices.
In the drive for food security and food safety; globalisation and opening of borders
will put animal production industries under a lot of pressure.
The economic aspects of animal production will continue to be of major importance
in the future.
The WVA encourages all parties involved in the development of animal management
systems, especially those dealing with intensive animal production, to respect all
available data on the basic and essential needs of animals.
The WVA encourages the pharmaceutical industry to continue to research the
improvement of existing feed additives, as well as the development of new
compounds of non-antibiotic origin, such as bacteria, binders and organic acids which
can replace the use of antibiotics as feed additives.
Alternatives to antibiotics are a necessary tool to assist the economic feasibility of
intensive animal production.
The WVA urges regulatory bodies globally to:
– implement regulations to prevent misuse of antibiotics and reduce the possibility
of development of resistant strains.
– implement viable structures to monitor the development of resistance and adopt
measures to prevent such development.
The WVA encourages national veterinary organisations to adopt clear policies and
guidelines about the use and misuse of antibiotics.
Conclusion
The WVA will continue to:
– collaborate with global organisations in the development of policies and
programmes to restrict and contain antimicrobial resistance
– advise veterinarians around the world about the risks of antimicrobial resistance
and encourage veterinarians to take all reasonable safeguards to minimise the
development and spread of antimicrobial resistance.
The World Veterinary Association: http://www.worldvet.org/.
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6. Prudent use and containment of resistance
Prudent use and containment of antimicrobial
resistance – the work of the responsible use of
medicines in agriculture alliance
B. Jennings
NFU, 164 Shaftesbury Avenue, London WC2 H8HL, United Kingdom
Antimicrobials have made a major contribution to farm animal health and welfare for
several decades. They are vital for the treatment and control of animal disease. The
use of a limited group of them at low levels as digestive enhancers has also made them
a useful tool for farmers.
The Responsible Use of Medicines in Agriculture (RUMA) alliance was established in
November 1997. Its aim was to facilitate and promote, by means of a co-ordinated
and integrated approach involving all stakeholders, best practice in the use of
veterinary medicines, beginning with antimicrobials. This was in direct response to
concerns about the crossover of resistant bacteria from livestock to the human
population, and the associated possibility of medical antimicrobial treatments
becoming less effective.
The RUMA alliance is a coalition of agricultural, veterinary, welfare, pharmaceutical,
retail and consumer interests which aims to keep under review the use of
antimicrobials in food animals, and establish practical strategies to enable farmers to
reduce the need for their use. It is an independent voice, based on science.
Best practice guidelines have now been produced for all major farmed species, and in
some cases they are already being used as part of farm assurance schemes. Part of the
future work of RUMA will be to monitor uptake, and modify the guidelines if
necessary in the light of experience. RUMA is not a political organisation, but will
always encourage a rational and scientific approach to the availability of antimicrobial
availability, and help farmers comply with any legislative changes.
The future aims of the RUMA alliance are:
– to identify issues of scientific and public concern in the areas of public health,
animal health, animal welfare, and the environment
– to provide an informed consensus view on the identified issues which will be
developed by discussion and consultation
– to communicate as widely as possible the guidelines which describe best practice
in the use of medicines
– to advise industry in the implementation of ‘best practice’, especially in the
development of Codes of Practice and Assurance schemes
– to influence the way medicines are used and the way in which that use is
perceived by consumers, the public health authorities, the media, and others.
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279
6. Prudent use and containment of resistance
Prudent use and containment of antimicrobial
resistance in developing countries
D.K. Byarugaba
Department of Veterinary Microbiology and Parasitology, Faculty of Veterinary Medicine, Makerere University,
P.O. Box 7062, Kampala, Uganda
Introduction
When antimicrobials are used for too short a time, at too low a dose, at inadequate
potency or when poorly indicated, the likelihood that bacteria and other microbes will
adapt and replicate rather than be killed is greatly enhanced. Much evidence supports
the view that the high consumption of antimicrobials in animals and man is the critical
factor in selecting resistance (3). While overuse is responsible for much of the
antimicrobial resistance in developed nations, paradoxically it is underuse that is
responsible for resistance in developing countries (DCs). Antimicrobial use whether
for therapy, prevention of infectious diseases or as performance enhancers leads to
selection for antibiotic resistant micro-organisms, not only among pathogens but also
among bacteria of the endogenous microflora of animals and man. Many other
interconnected factors fuel the emergence of antimicrobial resistance. In DCs, where
poverty, lack of commitment by governments, greed, corruption, hunger and, recently,
the acquired immune deficiency syndrome (AIDS) pandemic, limit access to
antimicrobials and lead to underuse, misuse, and use of poor quality counterfeit drugs
leading to more rapid selection of resistance. It is therefore important that
interventions that can be used to slow the emergence and reduce the spread of
resistance be used. Particular attention to interventions that encourage prudent use of
the available antimicrobials is very important in the strategy for controlling
antimicrobial resistance.
Situational analysis
Some studies that have been carried out in DCs have revealed that antimicrobial
agents are grossly misused (2). The most commonly available antimicrobial agents
which have been used for many years: penicillins and tetracyclines, have suffered the
greatest abuse. The factors that influence antimicrobial abuse can be categorised into
three:
a) those related to the overall regulatory framework and policies regarding health
systems
b) those related to the service providers
c) those related to the users.
These factors are interrelated and their interactions make the problem very complex.
The majority of people in many DCs suffer from chronic poverty, socio-economic
marginalisation, food insecurity and, most recently, the devastating impact of the
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6. Prudent use and containment of resistance
human immunodeficency virus (HIV)/AIDS pandemic. Poverty is the most important
underlying factor that leads to misuse of antimicrobial agents and resistance in DCs.
Lack of purchasing power for full doses or for seeking professional advice, lack of
access to proper facilities, lack of education etc. lead to problems such as self
prescription and under dosing, which may precipitate microbial resistance
(summarised in Figure 1 below). Related to poverty and lack of resources, is the lack
of reliable diagnostic facilities in general and, especially for culture and sensitivity
testing to make differential diagnosis, organism identification and to obtain reliable
data on antimicrobial susceptibility patterns on which to base prescription. This means
that greater amounts of antimicrobials are often prescribed to cover any possible
infection without supporting reliable laboratory data. In many DCs, HIV/AIDS has
caused severe economic constraints that have had negative impacts on various sectors
and have induced governments to refocus their attention and resources to other
critical areas. The problem of inadequate resources compounded with lack of relevant
laws and their implementation, as well as service provider behavior, make the situation
of antimicrobial resistance in DCs precarious.
Poverty
‘Unrestricted
availability’
Over or under
use and self
prescription
Wrong
conceptions
Stocking excess
drugs on farms
Underdevelopment
Imprudent use
Regulatory
related factors
Advertisment
pressure by drug cos.
Treatment
expectations
Services proivider
related factors
Antimicrobial resistance
Fig. 1
Summary of some of the factors responsible for irrational use of antimicrobial
agents in DCs
In many institutions in DCs, antimicrobial resistance is never emphasised during the
training of students and prudent drug use is never taught. The practical significance of
the problem is never presented to students. Thus, they leave school un-informed and
without practical understanding of antimicrobial resistance and its implications. This
lack of practical knowledge may play a role in irrational or no prescribing at all.
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6. Prudent use and containment of resistance
Most pharmacies are manned by attendants who are not the licence holders and do
not have the qualifications to enable them to handle drugs professionally. This factor
is extremely important as antimicrobials and other drugs are frequently purchased
without prescription. Antimicrobials are often sold at subtherapeutic doses because
the users insist on a specific quantity. Also, the smaller pharmacies keep a limited
range of antimicrobial drugs and even if users have a prescription they may be advised
to buy available alternatives. Users may demand antimicrobials of their choice either
based on their own or somebody else’s experience or from advertisements on TV,
radio or very attractive posters. Others demand specific antibiotics for simple ailments
which do not require antibiotics.
Pharmaceutical companies market some of the drugs available on prescription directly
to the public by very attractive direct-to-user advertising through multi-media such as
television and radio. This has the potential to stimulate demand by playing on the
users’ relative lack of education about the evidence supporting the use of one
treatment over another. These advertising methods are very effective. Many
pharmaceutical companies also give incentives or commissions to drug agents and
outlets which may encourage crude methods of advertising. In addition, pharmacists
and dispensers gain financially from over-dispensing and dispensing more expensive
broad-spectrum agents when cheaper narrow spectrum agents would suffice.
The regulatory mechanisms for control of antimicrobial manufacture, market
authorisation, distribution and use are still very weak. Many DCs still depend on
ancient laws but even where new laws have been made, their implementation and
enforcement are weak. Some reports have indicated the sale of expired drugs not only
in urban centres but also in rural settings. Antibiotics are sold in cattle markets next to
cowsheds in direct sunlight despite laws or guidelines. Counterfeit products also enter
DCs, especially through smuggling or corruption. Structural adjustment policies such
as privatisation and liberalisation have also affected the procurement and supply of
antimicrobial agents and as DCs adjust to these changes, new challenges emerge.
Improving antimicrobial drug use
The improvement of antimicrobial use in order to contain antimicrobial resistance is
crucial and requires world-wide concerted efforts. Several recommendations have
been made and these revolve around a combination of educational measures,
regulatory and managerial issues. Integrated mechanisms will be required, to educate,
train and sensitise all stakeholders, such as health service providers, policy makers, and
users to understand and appreciate the problems and the consequences of failing to
institute measures to contain the problem. With proper sensitisation of all the
stakeholders, containment will be much easier as proper policies will be formulated,
services will be delivered professionally and users will utilise drugs properly. These
sensitisation programmes may involve massive campaigns to educate users about
prudent antimicrobial use. Increased interaction and planning among informed policy
makers, service providers and users will go a long way in improving antimicrobial use.
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6. Prudent use and containment of resistance
This partnership is essential for influencing policies such as the incorporation of
proper antimicrobial use in education systems.
There are opportunities for the promotion of prudent use of antimicrobial agents in
DCs.
These include:
– optimal utilisation of available resources such as facilities, equipment, technical
personnel
– incorporation of prudent drug use and antimicrobial resistance issues in
programmes such as in schools or universities, farmer education, extension and
training programmes
– a role for professionals societies to sensitise and regulate their members
– the formation of a collaborative partnership with other developed nations
– support from international agencies such as, the United Nations Development
Programme, the OIE (World organisation for animal health) and the World Health
Organization (WHO) etc.
Conclusion
Imprudent use of antimicrobial agents is the major factor responsible for the
emergence of antimicrobial resistance world-wide and requires immediate action. Both
the OIE and the WHO have published guidelines for containing the problem of
antimicrobial resistance in veterinary medicine (1, 4). Developing countries, therefore,
need to carry out situational analyses of the problems and opportunities in their
countries and introduce those interventions that are feasible within the limits of
available resources (financial, human and physical) in order to improve the use of
antimicrobials.
References
1. Anthony F., Acar J., Franklin A., Gupta R., †Nicholls T., Tamura Y., Thompson S.,
Threlfall E.J., Vose D., van Vuuren M. & White D.G. (2001). – Antimicrobial resistance:
responsible and prudent use of antimicrobial agents in veterinary medicine. Rev. sci. tech. Off. int.
Epiz., 20 (3), 829-839.
2. Byarugaba D.K. et al. (2001). – Development of sustainable strategies for the
management of antimicrobial resistance in man and animals at district and national level in
Uganda. Feasibility Study Report. May, Makerere University, Kampala.
3. Danish Integrated Resistance Monitoring and Research Programme (2000). – DANMAP
99 – consumption of antimicrobial agents and occurrence of antimicrobial resistance in
bacteria from food animals, food and humans in Denmark. Statens Serum Institut, Danish
Veterinary and Food Administration, Danish Medicines Agency and Danish Veterinary
Laboratory, July.
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6. Prudent use and containment of resistance
4. World Health Organization (WHO) (2000). – WHO global principles for the
containment
of
antimicrobial
resistance
in animals
intended
for
food.
WHO/CDS/CSR/APH/2000.4.
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Web links
ƒ http://212.3.246.142/1/CINLADPBFCOCOANBLLJOGIFNPDBY9DBW
EW9DW3F71KM/BEUC/docs/DLS/2002-00868-01-F.pdf
ƒ http://dx.doi.org./10.1099/ijs.0.02408-0
ƒ http://europa.eu.int/comm/food/fs/sc/ssc/out50_en.pdf
ƒ www.abdn.ac.uk/arpac
ƒ www.anmv.afssa.fr/ccoie/documents/cdrom1999/Antibiotics/index.htm
ƒ www.arru.saa.ars.usda.gov/main.htm
ƒ www.bsac.org
ƒ www.cdc.gov/epiinfo/Epi6/EI6dnjp.htm
ƒ www.cdc.gov/narms/
ƒ www.consumersinternational.org
ƒ www.ers.usda.gov/data/sdp/view.asp?f=food/89015/
ƒ www.escmid.org
ƒ www.fda.gov/cvm/antimicrobial/antimicrobial.html
ƒ www.fda.gov/cvm/antimicrobial/Risk_asses.htm
ƒ www.foodriskclearinghouse.umd.edu/risk_assessments.htm
ƒ www.fsis.usda.gov/OPHS/ecolrisk/home.htm
ƒ www.fsis.usda.gov/ophs/risk/index.htm
ƒ www.health.gov.au/pubs/jetacar.pdf
ƒ www.his.org.uk
ƒ www.iatp.org/EatWell/orgResults.cfm
ƒ www.KeepAntibioticsWorking.com
ƒ www.laegemiddelstyrelsen.dk
ƒ www.nal.usda.gov/fnic/foodborne/risk.htm
ƒ www.nccls.org
ƒ www.nval.go.jp/taisei/taisei.html
ƒ www.oie.int
ƒ www.onerba.org
ƒ www.strama.org
ƒ www.SVS.dk
ƒ www.tacd.org
ƒ www.tufts.edu/med/apua/
ƒ www.vetinst.dk/file/danmap2000.pdf
ƒ www.who.int/emc/amr.html
ƒ www.whocc.no/atcddd/atcsystem.html
ƒ www.worldvet.org/
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