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Critical appraisal of evidence that lowdose, long term (growth promotion)
antimicrobial use augments public health
risks from antimicrobial resistant organisms
Peter Davies, Carie Alexander, Jeein Chung,
Sylvia Wanzala
College of Veterinary Medicine
University of Minnesota
Background and objectives
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Pressures to restrict antimicrobial use in food
animals
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Particularly low-dose group treatments
‘low hanging fruit’
European changes
Science vs. precautionary principle
Danish data indicating that AGP use was
Aggregate antimicrobial use in
Danish swine industry
Initial scope
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Not a systematic review
Evidence cited in 4 key documents arguing for
removal of AGP use in the USA
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PAMTA
FDA guidance 209
Pew Commission report on Industrial Farm Animal
Production
Keep Antibiotics Working annotated bibliography
Methods
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Compile reference list for each document
 FDA-209; PAMTA; PEW; KAW
Screen references cited to identify relevant papers
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Only articles clearly unrelated to AMU or AMR eliminated
Obtain original papers and compile in RefWorks
database
Assess relevance of retained papers
Use specific appraisal tools to assess relevant papers
Tools for detailed appraisal
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Design of tools based on Steinberg et al.
(2000) and Shamliyan (2010)
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Check list approach
Questions refined iteratively by research team
Original plan to use a single too
6 screening questions for relevance
Two tools developed
Appraisal tool for descriptive studies
Study population
7. Are inclusion/exclusion criteria for selecting subjects described?
8. Is the study population animal or human?
9. If animal, are they swine or other animals?
10. Is the age of the subjects described?
11. Is the housing system described?
12. Is the nutrition of the animals described?
13. Was the study done in an experimental or commercial/clinical setting?
Treatments
14. Were multiple groups (treatments) included?
Appraisal tool for descriptive studies
Antimicrobial Use
17. Was antimicrobial use reported?
18. Was the antimicrobial specified?
19. Was antimicrobial use recorded, or obtained by survey questionnaire?
20. Was the antimicrobial dose reported?
21. Was the antimicrobial route recorded?
22. Was the antimicrobial duration recorded?
23. Were antimicrobial blood (or tissue/urine/other) levels measured?
Antimicrobial Resistance
24. Was antimicrobial resistance reported?
Appraisal tool for descriptive studies
Statistical Analysis
28.
29.
30.
31.
Was it conducted?
Were specific statistical tests indicated?
Were multivariate methods used?
Were confidence intervals included?
Results
32. Does the analysis directly compare antimicrobial resistance in
relation to use?
33. Is there comparison of antimicrobial dose and resistance?
Appraisal tool for descriptive studies
Discussion
34. Were the limitations of the study discussed?
35. Was the relationship of the study population to other populations
discussed?
36. Is the use of antimicrobials in food animals in relation to
resistance discussed?
37. Is antimicrobial use in animals implicated in the development of
resistance?
38. If so, is this with direct evidence or by inference?
Appraisal process – review papers
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Appraisal of review studies included
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documentation of the number of papers cited
number of citations that were original studies
Examined abstracts of all citations
Book chapters deemed not to be original studies
and were not examined further
Some references cited in reviews could not be
located and were recorded as “cannot find”.
Detailed appraisal
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Selected studies
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Specifically addressed AMU in food animals in
relation AMR
Implicated AMU in animals in AMR based on direct
evidence
Panel of 3 veterinarians
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Critically read all papers
Collectively assess the design, results and
Results
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Screening - 154 papers likely to provide some
information on relationship between AMU in
food animals and AMR
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Analytical (n = 37)
Descriptive (n = 48)
Reviews (n = 69)
Results: screening questions for
analytical studies (n = 37)
Abstract present
Clear Objective stated
Abstract refers to AMU
Abstract refers to AMR
Objective refers to AMU
Objective refers to AMR
Abstract refers to AMU and AMR
Objective refers to AMU and AMR
AMU or AMR stated in abstract or objectives
Yes
21
21
13
19
11
19
11
8
21
No
16
16
24
18
26
18
26
29
16
Results of analytical studies
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Study subjects
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(n = 21)
5 human subjects only
10 had animal subjects (5 in swine)
6 both human and animal subjects.
9 studies stated criteria for selecting subjects.
Setting
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19 in clinical/commercial settings
Results of analytical studies
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19 reported measurement of AMR
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(n = 21)
14 reported MIC method (11 with breakpoints)
4 zone diffusion methods
1 genotyping method
Statistical methods
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4 with no analysis or method not specified
8 studies only univariate analysis (12 used
multivariate approaches)
Analytical studies reporting details of AMU
(n = 14)
Table 2: Number of analytical studies reporting details of measuring antimicrobial u
and of the antimicrobial compound, dose, route, and duration of administration
AMU
measured
Recorded (n = 9)
Survey (n = 4)
Unknown (n = 1)
Total (n = 14)
Compound
specified
9
2
1
12
Dose
stated
6
0
1
7
Route
stated
7
0
1
8
Duration
stated
7
1
1
9
All
stated
6
0
1
7
Results of analytical studies(n = 21)
Compared AMU
and AMR
No (n = 9)
Yes (n = 12)
Total (n = 21)
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Discussed
Limitations
4
5
9
Discussed
Representativeness
8
8
16
Discussed
AMU and AMR
8
11
19
Implicated
AMU in AMR
7
10
17
12 studies for detailed review
7 of 9 studies that did not compare AMU
and AMR implicated use in resistance
Quality indicators of studies (n = 12)
Subjects
Animal (n = 7)
Human (n = 3)
Both(n = 2)
Total (n = 12)
Subjects
Animal (n = 7)
Both (n = 2)
Human (n = 3)
Total
Age
5
2
1
8
Compound
specified
7
2
1
10
Housing
3
0
1
4
Dose
stated
5
1
0
6
Nutrition
3
0
1
4
Route
stated
5
1
0
6
Control
group
5
1
1
7
Duration
stated
6
1
0
7
Replication
2
0
0
2
All
stated
5
1
0
6
Summary
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48 descriptive studies were collectively uninformative
regarding association with AMR of low-dose/long
term use of antimicrobials in food animals
1 (0.6%) of 154 relevant cited papers) directly
compared a low and therapeutic doses of AM to food
animals (poultry) on the prevalence of AMR
Measurement and recording of AMU suboptimal in
most studies
Appraisal of review papers
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37 reviews specifically on AMU or AMR
All narrative reviews (29) or reports (8)
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no systematic review
One review included search methods and one
(different) review specified inclusion and
exclusion criteria for studies
Only 3 discussed validity in analyzing studies
Specific organism-antimicrobial pairs
cited in 25 review papers
Enterococci
Vancomycin
Quinupristin/dalfopristin
Salmonella
Multiple drug resistance
Fluoroquinolones
Ceftriaxone
Campylobacter
Fluoroquinolones
Macrolides, Tetracyclines
E. coli/coliforms
Nourseothricin
Tetracyclines
Fluoroquinolones
Extended spectrum beta lactams
Gentacycin, apramycin
STEC
Multiple drug resistance
Streptococci
Tylosin
20
13
7
16
10
3
3
13
12
1
11
4
3
2
1
1
1
1
Appraisal of review papers
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37 sources cited 1,869 publications
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1,012 (54.2%) were determined to be original
studies providing original data
Generally reiterated the most storied
examples linking AMU in animals and AMR.
Most examples related to
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antimicrobials used only therapeutically in the USA
antimicrobials never used in the USA (avoparcin,
Appraisal of review papers
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Individually and collectively do not
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identify studies contrasting impacts of low-dose,
long duration AMU relative to other AMU
provide evidence of any differential effects among
specific modes of AMU in selecting for AMR.
no evidence that measures to reduce low-dose,
long term AMU that do not reduce aggregate
antimicrobial use would provide benefits upon:
Overall summary
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Enduring uncertainty over the public health
consequences of AMU in animals has
frustrated groups who have pursued greater
regulation
Vast majority of papers cited by key sources
contain no primary data
Shortcomings in design or reporting common
Overall summary
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Dearth of RCT contributes to difficulty in drawing
inferences about this question
Available evidence inadequate for meaningful
comparison of different modes of AMU in relation to
emergence of AMR in pathogens or commensals in
commercial swine populations
The conservative position is that reducing aggregate
use of antimicrobials is the most appropriate goal
Removal of Growth Promoters
in Denmark
1995
National ban on avoparcin
Voluntary agreement to minimize the use of AGP’s
1998
National ban on virginiamycin (Jan)
Voluntary agreement re. finishers (Mar)
National tax on AGP’s (Sep) about $2 per pig
1999
EU ban: tylosin, bacitracin, spiramycin and virginiamycin
EU ban: olaquindox and carbadox
2000
Voluntary agreement to ban AGP’s for weaners (DK)
Expectations for the Restrictions
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Reduction of antibiotic use in food animals
Minimal impact on production
Reduction of antibiotic resistance
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Animal isolates
Human isolates
Reduced risk to human health
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Zoonotic and foodborne pathogens
Response of Danish producers (2004)
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Increased weaning age by more than 3 days
Reduced ration density (protein/energy)
Practice limit feeding where possible
Added ZnO and organic acids to diets
Utilized more therapeutic antimicrobials
Aggregate antimicrobial use in
Danish swine industry
Effects on weaned pig performance
Percent Change Nursery Mortality
v. 1998 Baseline
30%
25%
20%
15%
10%
5%
0%
-5%
1998
1999
2000
2001
DANMAP 2004
Antimicrobial resistance in Salmonella
DANMAP 2004
Antimicrobial resistance in Salmonella
AMR in Salmonella in pigs
Danmap 2004/2012
Non-susceptibility of in S. pneumoniae
isolates from humans in Denmark
Human MRSA cases in Denmark
(DANMAP 2012)
Summary of Danish experience
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Anticipated decrease in aggregate AMU in food
animals not realized
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Measurable animal health impact
Reduction in AMR of zoonotic and commensal
isolates from pigs variable
AMR in major human pathogens increased
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Silver lining of public health benefit hard to perceive
Can we extrapolate this to the USA
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Differences in regulations
Virtual elimination of vet dispensing (1995)
Mandatory herd health consultations per year
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12 farm visits per year
35 day limit in prescriptions
Changes preceded AGP bans by several years
To the future
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Growth promotant usage being phased out in
USA
Are we prepared?
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Earlier weaned pigs
More disease challenge (?) – PRRS
Less veterinary oversight