p.l. toutain national veterinary school ; toulouse, france
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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 2011Tandil, Argentina
2
The priorities of a sustainable veterinary antimicrobial
therapy is related to public health issues, not to animal
health issues: Why?
3
Medical consequences of antimicrobial resistance
4
The antibiotic ecosystem: One world, One health
Treatment & prophylaxis
Human medicineCommunity
Veterinary medicine Animal feed additives
Environment
Hospital Agriculture
Plant protection
Industry
5
Prevent emergence of resistance: but of what resistance?
Target pathogens Zoonotics Commensal flora
Drug efficacy in animal:
A vet issue
Drug efficacy in
man
Resistance genereservoir
Global ecologicalproblem
Possible overuse of antibiotics
Natural eradication
Risk for permanent
colonisation
Individual issue Population issueAnimal issueAnimal issue
Target pathogens Zoonotics Commensal flora
Drug efficacy in animal:
A vet issue
Drug efficacy in
man
Resistance genereservoir
Global ecologicalproblem
Possible overuse of antibiotics
Natural eradication
Risk for permanent
colonisation
Individual issue Population issueAnimal issueAnimal issue
Target pathogens Zoonotics Commensal flora
Drug efficacy in animal:
A vet issue
Drug efficacy in
man
Resistance genereservoir
Global ecologicalproblem
Possible overuse of antibiotics
Natural eradication
Risk for permanent
colonisation
Individual issue Population issueAnimal issueAnimal issue
6
Emergence of resistance for Salmonella typhimurium DT104 in UK to quinolones following
the market autorisation of enrofloxacin
Stöhr & Wegener, Drug resistance Updates, 2000, 3:207-209
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Commensal bacteria:transmission of resistance genes from animal to man:
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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
9
Gut flora & antimicrobial resistance
G.I.TProximal Distal
Résistance = lack of efficacy
Blood
Gut flora•Zoonotic (salmonella, campylobacter •commensal ( enterococcus)
1-F%
F%
Target biophaseBug of vet interest
AB: oral route
Résistance = public health concern
Food chain Environmental exposure
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Gut flora & antimicrobial resistance
Gastrointestinal tract
Proximal DistalIntestinal secretion
Bile
Résistance = lack of efficacyRésistance =public health issue
BiophaseTarget pathogen
Blood
Food chain
Environment
Systemic Administration
QuinolonesMacrolidesTétracyclines
Gut flora•Zoonotic (salmonella, campylobacter •commensal ( enterococcus)
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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
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Result: Percent of ampicillin-resistant Enterobacteriaceae for each mode of
administration
0
20
40
60
80
100
0 1 2 3 4 5 6 7
Days
% a
mp
icill
in-r
es
ista
nt
En
tero
ba
cte
ria
oral routefed
oral routefasted
intramuscularroute
control
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Hazard associated to the release of antibiotic in environment
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Fate of antibiotics, zoonotic pathogens and resistance genes: residence time in the
different biotopes
Digestive tract: 48hLagoon: few weeks
Air pollution
Bio-aérosol
Air, water & ground pollution
Ex:T1/2 tiamuline=180 days
15
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
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Innovation: PK selectivity of antibiotics
environment
G.I.TProximal Distal
Blood
Gut flora•Zoonotic (salmonella, campylobacter •commensal ( enterococcus)
Biophase
AB: oral route
Résistance = public health concern
Food chain
0%
100%
Animal health
Kidney
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Innovation: PK selectivity of antibiotics
environment
G.I.TProximal Distal
Blood
Gut flora•Zoonotic (salmonella, campylobacter •commensal ( enterococcus)
Biophase
AB: IMroute
Résistance = public health concern
Food chain
Animal health
Kidney
Quinolones, macrolides
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Judicious, prudent,responsible sustainable… use of antibiotics
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1- No misuse
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An example of misuse: in ovo administration of ceftiofur
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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 enterica E Coli
Salmonella Heidelberg
22
Effect of the withdrawal of ceftiofur in hatchery
Salmonella Heidelberg
Salmonella
E Coli
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2- No overuse
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Human and veterinary antibiotic usage: US vs EU
9%
6%
85%
Human Animal therapy Non-therapeutic
Source: Source: UCS 2000UCS 2000
65%
29%
6%
Human Veterinary Growth promotion
65%
29%
6%
Human Veterinary Growth promotion
Source: Source: FEDESA FEDESA 20012001
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No overuse means no antibiotics as growth promotor
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we have evidence that market introduction of generics or of “me-too’ drugs has influence on antibiotic consumption;
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Generics for antibiotics (quinolones) : conclusions
More generics/”me too”
Decrease relative price
Increase antibiotic consumption(not true for all antibiotics)
Increase resistance
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Generics and antibiotic consumption
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Use of fluoroquinolones in veterinary medicine: Germany, DK, UK
From Hellmann: Assoc Vet Consult. SAGAM 2005
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Use of fluoroquinolones in veterinary
medicine: Eastern EU, Spain, Portugal
From Hellmann: Assoc Vet Consult. SAGAM 2005
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Issues associated to ‘generics’ that are not bioequivalence
32
Non-bioequivalence of various
trademarks of enrofloxacin in cow
Sumano & al 2001 Dtsch tierärztl Wschr 108 281-320
33
3-The right drug
34
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?
35
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.
36
How a vet can select the best drug amongst competitors (the
so-called me-too)for pulmonary infection?
37
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)
38
The need of comparative clinical trials for the newest antibiotics
39
Currently, antibiotics are compared only by non-inferiority trials
Types of Hypothesis testing
for antimicrobial drugs
Non-inferiority(not worse)
Equivalence(similar)
Superiority(better)
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Draxxin vs. Micotil by Pfizer
Micotil vs . Draxxin by Elanco
41
Draxxin vs Micotil by Pfizer
Micotil vs . Draxxin by Elanco
Take home message:•Draxxin superior to Micotil P<0.00x
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
42
4-The right time to start a treatment
43
Disease health
TherapyMetaphylaxis
(Control)Prophylaxis(prévention)
Growth promotion
The different modalities of antimicrobial therapy
HighHighPathogen loadPathogen load
SmallSmallNoNo
NANA
Antibiotic consumptionAntibiotic consumption
Only a risk factor
44
45
A mouse model to compare metaphylaxis and curative treatment
Progression of infection
early (10h)Administration
Late (32h)Administration
Inoculation of Pasteurella multocida
1500 CFU/lung
0 10 20 30 40 50
Time (h) Bac
teria
cou
nts
per
lung
(C
FU
/lung
)
100
102
104
106
108
1010no clinical signs of infection
anorexia lethargy
dehydration
46
• 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)
What we demonstrated
Early administrations were more favourable than late administrations
47
5-The right dose for efficacy
48
Why to optimize dosage regimen for antibiotics
1. To optimize efficacy
2. Reduce the emergence and selection of resistance
49
How to find and confirm a dose (dosage regimen)
• Dose titration
– Animal infectious model
• PK/PD
• Clinical trials
50
Dose titration
DoseResponseclinicalBlack box
PK/PD
Dose response
PK PD
Plasmaconcentration
Body pathogen
Dose titration for antibiotic using infectious model
51
Why plasma concentrations rather than the dose for an
antibiotic ?
52
Most of our pathogens are located in extracellular fluids
Extra Cellular Fluid
Most bacteria of clinical interest
- respiratory infection
- wound infection
- digestive tract inf.
Cell(in phagocytic cell most often)• mycoplasma (some)• chlamydiae• Cryptosporidiosis• Salmonella• Rhodococcus equi
Free plasma concentration is equal to free extracellular concentration
Bug
53
Do not confuse science, marketing and and propaganda
54
PK/PD indices as indicator of antibiotic efficacy
55
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
56
To compute a dose, we have to take into account inter-animal variability using population
approaches
57
PK Variability
n = 215
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
-5 0 5 10 15 20 25 30
Time (h)
Co
nc
en
tra
tio
ns
mg
/mL
Doxycycline
58
PD variability: MIC distributionPasteurella multocida (n=205)
0
MIC (g/mL)
5
10
15
20
25
30
35
40
0.06250.125 0.25 0.5 1 2 4
Pat
ho
gen
s %
SUSCEPTIBLE
59
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
60
6-The right dose to prevent resistance
61
Selective Pressure
MIC
Time
Concentration
Traditional explanation for enrichment of mutants
62
Mutant Prevention Concentration (MPC)
and the Selection Window (SW) hypothesis
63
Without antibiotics
Blocking Growth of Single Mutants Forces Cells to Have a Double Mutation to Overcome Drug
With antibiotics
10-8
10-8
10-8
Wild population éradication
sensible single mutant Double mutant
Wild pop
single mutant population
single mutant population
64
The selection window hypothesis
Mutant prevention concentration (MPC)(to inhibit growth of the least susceptible, single step mutant)
MICSelective concentration (SC)
to block wild-type bacteria
Pla
sma
con
cen
trat
ion
s
All bacteria inhibited
Growth of only the most resistant
subpopulation
Growth of all bacteria
Mutant selection window
65
Mutants are not selected at concentrations below MIC
or above the MPC
66
7-The right duration of a treatment
67
Duration of treatment
• The shortest as possible
• Many epidemiological evidences that the likelihood of resistance increase with the duration of treatment
68
Conclusion: for a rational antibiotic use, what is the priority?
• target animal safety• efficacy • resistance in target
pathogens
• Environmental safety
• operator safety• consumer safety
•resistance in non-target pathogens (salmonella, campylobacters)
•Transfer of resistance genes
69
Bourgelat & the first veterinary school in the world at Lyon
70
Toulouse & El Francesito
Born here on the 11th Dec
1890
71
Toulouse: Rugby, Vet School and Airbus
Vet School campus
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