P.L. Toutain National Veterinary School ; Toulouse, France

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

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The priorities of a sustainable veterinary antimicrobial

therapy is related to public health issues, not to animal

health issues: Why?

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Medical consequences of antimicrobial resistance

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The antibiotic ecosystem: One world, One health

Treatment & prophylaxis

Human medicineCommunity

Veterinary medicine Animal feed additives

Environment

Hospital Agriculture

Plant protection

Industry

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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

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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

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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

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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

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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

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Non-bioequivalence of various

trademarks of enrofloxacin in cow

Sumano & al 2001 Dtsch tierärztl Wschr 108 281-320

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3-The right drug

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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?

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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.

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How a vet can select the best drug amongst competitors (the

so-called me-too)for pulmonary infection?

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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)

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The need of comparative clinical trials for the newest antibiotics

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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

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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

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4-The right time to start a treatment

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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

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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

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• 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

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5-The right dose for efficacy

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Why to optimize dosage regimen for antibiotics

1. To optimize efficacy

2. Reduce the emergence and selection of resistance

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How to find and confirm a dose (dosage regimen)

• Dose titration

– Animal infectious model

• PK/PD

• Clinical trials

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Dose titration

DoseResponseclinicalBlack box

PK/PD

Dose response

PK PD

Plasmaconcentration

Body pathogen

Dose titration for antibiotic using infectious model

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Why plasma concentrations rather than the dose for an

antibiotic ?

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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

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Do not confuse science, marketing and and propaganda

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PK/PD indices as indicator of antibiotic efficacy

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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

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To compute a dose, we have to take into account inter-animal variability using population

approaches

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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

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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

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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

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6-The right dose to prevent resistance

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Selective Pressure

MIC

Time

Concentration

Traditional explanation for enrichment of mutants

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Mutant Prevention Concentration (MPC)

and the Selection Window (SW) hypothesis

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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

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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

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Mutants are not selected at concentrations below MIC

or above the MPC

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7-The right duration of a treatment

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Duration of treatment

• The shortest as possible

• Many epidemiological evidences that the likelihood of resistance increase with the duration of treatment

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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

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Bourgelat & the first veterinary school in the world at Lyon

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Toulouse & El Francesito

Born here on the 11th Dec

1890

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Toulouse: Rugby, Vet School and Airbus

Vet School campus