Download Diapositive 1

The prudent use of antibiotics in veterinary
medicine:
the right drug, the right time, the right dose
the right duration of treatment
P.L. Toutain
National Veterinary School ; Toulouse, France
The Bunge y Born foundation, 18th November 2011
Tandil, Argentina
1
The priorities of a sustainable
veterinary antimicrobial
therapy is related to public
health issues, not to animal
health issues: Why?
2
Medical consequences of
antimicrobial resistance
3
The antibiotic ecosystem:
One world, One health
Treatment & prophylaxis
Human medicine
Community
Hospital
Veterinary
medicine
Animal feed additives
Agriculture
Plant protection
Environment
Industry
4
Prevent emergence of resistance:
but of what resistance?
Target pathogens
Drug efficacy in
animal:
A vet issue
Possible
overuse of
antibiotics
Animal issue
Zoonotics
Drug
efficacy in
man
Natural
eradication
Individual issue
Commensal flora
Resistance gene
reservoir
Global ecological
problem
Risk for
permanent
colonisation
Population issue
5
Emergence of resistance for Salmonella
typhimurium DT104 in UK to quinolones following
the market autorisation of enrofloxacin
6
Stöhr & Wegener, Drug resistance Updates, 2000, 3:207-209
Commensal bacteria:
transmission of resistance
genes from animal to man:
7
Horizontal genes exchanges
(BLSE) in the gut
The gut is the main animal ecosystem in which veterinary
antibiotics are able to promote resistance in man
8
Gut flora & antimicrobial resistance
AB: oral route
Proximal
G.I.T
1-F%
Distal
Gut flora
•Zoonotic (salmonella, campylobacter
•commensal ( enterococcus)
Food chain
Environmental
exposure
Blood
Target biophase
Bug of vet interest
Résistance = lack of efficacy
Résistance = public health concern
9
Gut flora & antimicrobial resistance
Gastrointestinal tract
Proximal
Gut flora
•Zoonotic (salmonella, campylobacter
•commensal ( enterococcus)
Intestinal secretion
Bile
Systemic Administration
Distal
Quinolones
Macrolides
Tétracyclines
Food chain
Environment
Blood
Biophase
Target pathogen
Résistance =public health issue
Résistance = lack of efficacy
10
The aim was to assess the impact of 3 ampicillin
dosage regimens on ampicillin resistance among
Entrobacteriaceae recovered from swine feces and
on the excretion in feces of the blaTEM gene
11
% ampicillin-resistant
Enterobacteria
Result: Percent of ampicillin-resistant
Enterobacteriaceae for each mode of
administration
100
80
oral route
fed
60
oral route
fasted
40
intramuscular
route
20
control
0
0
1
2
3
4
5
6
7
Days
12
Hazard associated to the release
of antibiotic in environment
13
Fate of antibiotics, zoonotic pathogens and
resistance genes: residence time in the
different biotopes
Digestive tract: 48h
Lagoon: few weeks
Ex:T1/2 tiamuline=180 days
Bio-aérosol
Air, water & ground pollution
Air pollution
14
What are the solutions to these
critical issues
• No or few solution for the veterinarians
– For mastistis, use local intramammary treatment, not
systemic treatment
• We need innovations from pharmaceutical
companies
15
Innovation: PK selectivity of antibiotics
G.I.T
AB: oral route
Proximal
Distal
0%
Gut flora
•Zoonotic (salmonella, campylobacter
•commensal ( enterococcus)
100%
Food chain
environment
Blood
Kidney
Biophase
Résistance = public health concern
Animal health
16
Innovation: PK selectivity of antibiotics
G.I.T
Proximal
Distal
Gut flora
•Zoonotic (salmonella, campylobacter
•commensal ( enterococcus)
AB: IMroute
Food chain
Quinolones, macrolides
environment
Blood
Kidney
Biophase
Résistance = public health concern
Animal health
17
Judicious, prudent,responsible
sustainable… use of antibiotics
18
1- No misuse
19
An example of misuse:
in ovo administration of ceftiofur
20
Correlation between the prévalence of chicken meat contaminated by
E.coli and Salmonella enterica résistant to ceftiofur and human
infection to resistant Salmonella Heidelberg (r=0.91 pour Salmonella)
Salmonella Heidelberg
Salmonella
E Coli enterica
21
Effect of the withdrawal of ceftiofur
in hatchery
Salmonella Heidelberg
Salmonella
E Coli
22
2- No overuse
23
Human and veterinary antibiotic usage:
US vs EU
6%
9%
6%
29%
65%
85%
Human
Animal therapy
Source: UCS 2000
Non-therapeutic
Human
Veterinary
Source: FEDESA
2001
Growth promotion
24
No overuse means no
antibiotics as growth promotor
25
we have evidence that
market introduction of
generics or of “me-too’
drugs has influence on
antibiotic consumption;
26
Generics for antibiotics (quinolones) :
conclusions
More generics/”me too”
Decrease relative price
Increase antibiotic consumption
(not true for all antibiotics)
Increase resistance
27
Generics and antibiotic
consumption
28
Use of fluoroquinolones in veterinary
medicine: Germany, DK, UK
From Hellmann: Assoc Vet Consult. SAGAM 2005
29
Use of fluoroquinolones in veterinary
medicine: Eastern EU, Spain, Portugal
From Hellmann: Assoc Vet Consult. SAGAM 2005
30
Issues associated to ‘generics’
that are not bioequivalence
31
Non-bioequivalence of various
trademarks of enrofloxacin in cow
Sumano & al 2001 Dtsch tierärztl Wschr 108 281-320
32
3-The right drug
33
Old or more recent drugs?
• Many recommendations to
establish list of essential
antibiotics for human
medicine
• Where is the science
demonstrating the benefit in
terms or resistance to only
use old antibiotics in
veterinary medicine?
34
For three antibiotic classes (quinolones, cephalosporins
and carbapenems), it was observed that the less active
drugs could be worse at hastening the spread of
resistance than more active drugs in the same class.
This led the authors to qualify the (WHO) stratagem of
recommending the use of old antibiotics as part of
microbiological folklore.
35
How a vet can select the best
drug amongst competitors (the
so-called me-too)
for pulmonary infection?
36
Amongst the different macrolides marketed for
treatment and prevention of bovine respiratory
disease (BRD) associated with Mannheimia
haemolytica, Pasteurella multocida, Histophilus
somni diseases, what is the best one?
•
•
•
•
Tulathromycine,Draxxin (Pfizer)
Tilmicosine, Micotil (Elanco)
Gamithromycine, Zactran (Merial)
Tildipirosin, Zuprevo (Intervet)
37
The need of comparative clinical
trials for the newest antibiotics
38
Currently, antibiotics are compared
only by non-inferiority trials
Types of
Hypothesis testing
for antimicrobial drugs
Non-inferiority
(not worse)
Equivalence
(similar)
Superiority
(better)
39
Draxxin vs. Micotil by Pfizer
Micotil vs . Draxxin by Elanco
40
Draxxin vs Micotil by Pfizer
Take home message:
•Draxxin superior to Micotil P<0.00x
Micotil vs . Draxxin by Elanco
Take home message:
• Micotil not significantly different of Draxxin for most
endpoints (P>0.05) but Micotil is more cost-effective
(CAN$8/animal) and the lower initial BRD treatment
costs in the DRAX group did not offset the higher
metaphylactic cost of DRAX
41
4-The right time to start a
treatment
42
The different modalities of antimicrobial
therapy
Disease
health
Antibiotic consumption
Therapy
Metaphylaxis
(Control)
Pathogen load
Prophylaxis
(prévention)
Growth
promotion
Only a risk factor
High
Small
No
43NA
44
Progression of
infection
Inoculation of
Pasteurella multocida
1500 CFU/lung
Bacteria counts per lung (CFU/lung)
A mouse model to compare
metaphylaxis and curative treatment
anorexia
lethargy
dehydration
no clinical
signs of
infection
1010
108
106
104
102
100
0
10
20
30
40
50
Time (h)
early (10h)
Administration
Late (32h)
Administration
45
What we demonstrated
• For a same dose of marbofloxacin, early
treatments (10 hours after the infection) were
associated to
– more frequent clinical cure
– more frequent bacteriological cure
– less frequent selection of resistant bacteria
than late treatments (32 hours after the infection)
Early administrations were more favourable
than late administrations
46
5-The right dose
for efficacy
47
Why to optimize dosage
regimen for antibiotics
1. To optimize efficacy
2. Reduce the emergence and selection
of resistance
48
How to find and confirm a dose
(dosage regimen)
• Dose titration
– Animal infectious model
• PK/PD
• Clinical trials
49
Dose titration
Dose
Response
clinical
Black box
Dose titration for antibiotic using infectious model
PK/PD
PK
Dose
PD
Body
pathogen
Plasma
concentration
response
50
Why plasma concentrations
rather than the dose for an
antibiotic ?
51
Most of our pathogens are located
in extracellular fluids
Cell
Extra Cellular Fluid
Bug
Most bacteria of
clinical interest
- respiratory infection
- wound infection
- digestive tract inf.
(in phagocytic cell most often)
•
•
•
•
•
mycoplasma (some)
chlamydiae
Cryptosporidiosis
Salmonella
Rhodococcus equi
Free plasma concentration is equal to free extracellular concentration
52
Do not confuse science, marketing and
and propaganda
53
PK/PD indices as indicator of
antibiotic efficacy
54
It has been developed surrogates
indices (predictors) of antibiotic efficacy
taking into account MIC (PD) and
exposure antibiotic metrics (PK)
Practically, 3 indices cover all situations:
•AUC/MIC: quinolones; macrolides
•Time>MIC: Penicillins, cephalosporins
• Cmax/MIC: aminoglycosies
We know the average critical values to achieve for
theses indices to cure animals and we can
compute the appropriate doses
55
To compute a dose, we have to
take into account inter-animal
variability using population
approaches
56
PK Variability
1.6
Doxycycline
Concentrations mg/mL
1.4
n = 215
1.2
1
0.8
0.6
0.4
0.2
0
-5
0
5
10
15
20
25
30
Time (h)
57
Pathogens %
PD variability: MIC distribution
Pasteurella multocida (n=205)
40
35
30
25
20
15
10
5
0
SUSCEPTIBLE
0.06250.125 0.25
0.5
1
2
4
MIC (m g/mL)
58
The goal of population kinetics is to
document sources of variability to
determine a dosage regimen
controlling a given quantile (e.g. 90%)
of a population and not an average
dosage regimen
Monte Carlo simulations
59
6-The right dose to
prevent resistance
60
Traditional explanation for
enrichment of mutants
Concentration
MIC
Selective Pressure
Time
61
Mutant Prevention
Concentration (MPC)
and the Selection Window
(SW) hypothesis
62
Blocking Growth of Single Mutants Forces Cells to Have a
Double Mutation to Overcome Drug
10-8
Without antibiotics
single mutant population
10-8
Wild pop
With antibiotics
10-8
single mutant population
Wild population
éradication
sensible
single mutant
63
Double mutant
The selection window hypothesis
Plasma concentrations
Mutant prevention concentration (MPC)
(to inhibit growth of the least susceptible, single step mutant)
MIC
Selective concentration (SC)
to block wild-type bacteria
Mutant selection
window
All bacteria
inhibited
Growth of only
the most
resistant
subpopulation
Growth of all
bacteria
64
Mutants are not selected
at concentrations below MIC
or above the MPC
65
7-The right duration of a
treatment
66
Duration of treatment
• The shortest as possible
• Many epidemiological evidences that the
likelihood of resistance increase with the
duration of treatment
67
Conclusion: for a rational antibiotic use,
what is the priority?
• Environmental safety
• target animal safety
• efficacy
• resistance in target
pathogens
• operator safety
• consumer safety
•resistance in non-target
pathogens (salmonella,
campylobacters)
•Transfer of resistance
genes
68
Bourgelat & the first veterinary
school in the world at Lyon
69
Toulouse & El Francesito
Born here on
the 11th Dec
1890
70
Toulouse:
Rugby, Vet School and Airbus
Vet School campus
71