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

The priorities of a sustainable veterinary antimicrobial therapy is related to public health issues, not to animal health issues: Why?

Medical consequences of antimicrobial resistance

The antibiotic ecosystem: One world, One health Treatment & prophylaxis Veterinary medicine Human medicine Community Animal feed additives Hospital Agriculture Plant protection Environment Industry

Prevent emergence of resistance: but of what resistance?

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

Commensal bacteria: transmission of resistance genes from animal to man:

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

Gut flora & antimicrobial resistance G.I.T Proximal Distal AB: oral route 1-F% Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus) Résistance = public health concern Food chain Environmental exposure F% Blood Target biophase Bug of vet interest Résistance = lack of efficacy

Gut flora & antimicrobial resistance Gastrointestinal tract Proximal Distal Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus) Intestinal secretion Bile Quinolones Macrolides Tétracyclines Food chain Systemic Administration Environment Blood Biophase Target pathogen Résistance =public health issue Résistance = lack of efficacy

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

Result: Percent of ampicillin-resistant Enterobacteriaceae for each mode of administration

Hazard associated to the release of antibiotic in environment

Air, water & ground pollution Fate of antibiotics, zoonotic pathogens and resistance genes: residence time in the different biotopes Lagoon: few weeks Digestive tract: 48h Ex:T1/2 tiamuline=180 days Bio-aérosol Air, water & ground pollution Air pollution

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

Innovation: PK selectivity of antibiotics G.I.T Proximal Distal AB: oral route 0% Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus) 100% Food chain environment Blood Kidney Biophase Résistance = public health concern Animal health

Innovation: PK selectivity of antibiotics G.I.T Proximal Distal Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus) Food chain AB: IMroute Quinolones, macrolides environment Blood Kidney Biophase Résistance = public health concern Animal health

Judicious, prudent,responsible sustainable… use of antibiotics

1- No misuse

An example of misuse: in ovo administration of ceftiofur

Correlation between the prévalence of chicken meat contaminated by E 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 enterica E Coli

Effect of the withdrawal of ceftiofur in hatchery Salmonella Heidelberg Salmonella E Coli

2- No overuse

Human and veterinary antibiotic usage: US vs EU Source: UCS 2000 Source: FEDESA 2001

No overuse means no antibiotics as growth promotor

we have evidence that market introduction of generics or of “me-too’ drugs has influence on antibiotic consumption;

Generics for antibiotics (quinolones) : conclusions

Generics and antibiotic consumption

Use of fluoroquinolones in veterinary medicine: Germany, DK, UK From Hellmann: Assoc Vet Consult. SAGAM 2005

From Hellmann: Assoc Vet Consult. SAGAM 2005 Use of fluoroquinolones in veterinary medicine: Eastern EU, Spain, Portugal From Hellmann: Assoc Vet Consult. SAGAM 2005

Issues associated to ‘generics’ that are not bioequivalence

Non-bioequivalence of various trademarks of enrofloxacin in cow Sumano & al 2001 Dtsch tierärztl Wschr 108 281-320

3-The right drug

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?

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.

How a vet can select the best drug amongst competitors (the so-called me-too) for pulmonary infection?

Tulathromycine,Draxxin (Pfizer) Tilmicosine, Micotil (Elanco) 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)

The need of comparative clinical trials for the newest antibiotics

Currently, antibiotics are compared only by non-inferiority trials

Draxxin vs. Micotil by Pfizer Micotil vs . Draxxin by Elanco

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

4-The right time to start a treatment

The different modalities of antimicrobial therapy Disease health Antibiotic consumption Metaphylaxis (Control) Prophylaxis (prévention) Growth promotion Therapy High Pathogen load Only a risk factor No Small NA

A mouse model to compare metaphylaxis and curative treatment anorexia lethargy dehydration no clinical signs of infection 100 102 104 106 108 1010 Progression of infection Bacteria counts per lung (CFU/lung) Inoculation of Pasteurella multocida 1500 CFU/lung 10 20 30 40 50 Time (h) Late (32h) Administration early (10h) Administration

Early administrations were more favourable than late administrations 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

5-The right dose for efficacy

Why to optimize dosage regimen for antibiotics To optimize efficacy Reduce the emergence and selection of resistance

How to find and confirm a dose (dosage regimen) Dose titration Animal infectious model PK/PD Clinical trials

Dose titration for antibiotic using infectious model Response clinical Black box Dose titration for antibiotic using infectious model PK/PD PK PD Body pathogen Dose response Plasma concentration

Why plasma concentrations rather than the dose for an antibiotic ?

Most of our pathogens are located in extracellular fluids (in phagocytic cell most often) mycoplasma (some) chlamydiae Cryptosporidiosis Salmonella Rhodococcus equi Extra Cellular Fluid Most bacteria of clinical interest - respiratory infection - wound infection - digestive tract inf. Bug Free plasma concentration is equal to free extracellular concentration

Do not confuse science, marketing and and propaganda

PK/PD indices as indicator of antibiotic efficacy

AUC/MIC: quinolones; macrolides 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

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

PK Variability Doxycycline n = 215

PD variability: MIC distribution Pasteurella multocida (n=205) 40 35 30 Pathogens % 25 20 15 10 SUSCEPTIBLE 5 0.0625 0.125 0.25 0.5 1 2 4 MIC ( m g/mL)

Monte Carlo simulations 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

6-The right dose to prevent resistance

Traditional explanation for enrichment of mutants Concentration MIC Selective Pressure Time

Mutant Prevention Concentration (MPC) and the Selection Window (SW) hypothesis This lecture was prepared on April 5, 2003. Literature cited is listed as a note to the last slide.

Blocking Growth of Single Mutants Forces Cells to Have a Double Mutation to Overcome Drug Without antibiotics 10-8 single mutant population 10-8 Wild pop With antibiotics 10-8 single mutant population Wild population éradication sensible single mutant Double mutant

The selection window hypothesis Mutant prevention concentration (MPC) (to inhibit growth of the least susceptible, single step mutant) MIC Selective concentration (SC) to block wild-type bacteria Plasma concentrations Mutant selection window All bacteria inhibited Growth of only the most resistant subpopulation Growth of all bacteria

Mutants are not selected at concentrations below MIC or above the MPC For emphasis we restate that as a rule mutants are not selectively enriched at drug concentrations below MIC. As an aside, we note some selective pressure exists at concentrations below the standard MIC because it measures inhibition of growth of a large number of cells (100,000). Indeed, some enrichment of mutants does occur upon repeated serial passage of a strain (6). These data stress that the bottom boundary of the window can be fuzzy. That is why we define it to be MIC(99), the minimal concentration that blocks growth of 99% of the cells in a culture. MIC(50) would be a more precise lower boundary, but it is more difficult to determine experimentally.

7-The right duration of a treatment

Duration of treatment The shortest as possible Many epidemiological evidences that the likelihood of resistance increase with the duration of treatment

Conclusion: for a rational antibiotic use, what is the priority? Environmental safety operator safety consumer safety resistance in non-target pathogens (salmonella, campylobacters) Transfer of resistance genes target animal safety efficacy resistance in target pathogens

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