Presentation on theme: "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."— Presentation transcript:
1The prudent use of antibiotics in veterinary medicine: the right drug, the right time, the right dose & the right duration of treatmentP.L. ToutainNational Veterinary School ; Toulouse, FranceThe Bunge y Born foundation, 18th November 2011Tandil, Argentina
2The priorities of a sustainable veterinary antimicrobial therapy is related to public health issues, not to animal health issues: Why?
11The 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
12Result: Percent of ampicillin-resistant Enterobacteriaceae for each mode of administration
13Hazard associated to the release of antibiotic in environment
14Air, water & ground pollution Fate of antibiotics, zoonotic pathogens and resistance genes: residence time in the different biotopesLagoon: few weeksDigestive tract: 48hEx:T1/2 tiamuline=180 daysBio-aérosolAir, water & ground pollutionAir pollution
15What are the solutions to these critical issues No or few solution for the veterinariansFor mastistis, use local intramammary treatment, not systemic treatmentWe need innovations from pharmaceutical companies
16Innovation: PK selectivity of antibiotics G.I.TProximalDistalAB: oral route0%Gut floraZoonotic (salmonella, campylobactercommensal ( enterococcus)100%Food chainenvironmentBloodKidneyBiophaseRésistance = public health concernAnimal health
17Innovation: PK selectivity of antibiotics G.I.TProximalDistalGut floraZoonotic (salmonella, campylobactercommensal ( enterococcus)Food chainAB: IMrouteQuinolones, macrolidesenvironmentBloodKidneyBiophaseRésistance = public health concernAnimal health
18Judicious, prudent,responsible sustainable… use of antibiotics
20An example of misuse: in ovo administration of ceftiofur
21Correlation 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 HeidelbergSalmonellaentericaE Coli
22Effect of the withdrawal of ceftiofur in hatchery Salmonella HeidelbergSalmonellaE Coli
34Old or more recent drugs? Many recommendations to establish list of essential antibiotics for human medicineWhere is the science demonstrating the benefit in terms or resistance to only use old antibiotics in veterinary medicine?
35For 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.
36How a vet can select the best drug amongst competitors (the so-called me-too) for pulmonary infection?
37Tulathromycine,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)
38The need of comparative clinical trials for the newest antibiotics
39Currently, antibiotics are compared only by non-inferiority trials
40Draxxin vs. Micotil by Pfizer Micotil vs . Draxxin by Elanco
41Draxxin vs Micotil by Pfizer Take home message:Draxxin superior to Micotil P<0.00xMicotil vs . Draxxin by ElancoTake 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
45A mouse model to compare metaphylaxis and curative treatment anorexia lethargy dehydrationno clinical signs of infection1001021041061081010Progression of infectionBacteria counts per lung (CFU/lung)Inoculation of Pasteurella multocida1500 CFU/lung1020304050Time (h)Late (32h)Administrationearly (10h)Administration
46Early administrations were more favourable than late administrations What we demonstratedFor a same dose of marbofloxacin, early treatments (10 hours after the infection) were associated tomore frequent clinical curemore frequent bacteriological cureless frequent selection of resistant bacteriathan late treatments (32 hours after the infection)Early administrations were more favourable than late administrations
48Why to optimize dosage regimen for antibiotics To optimize efficacyReduce the emergence and selection of resistance
49How to find and confirm a dose (dosage regimen) Dose titrationAnimal infectious modelPK/PDClinical trials
50Dose titration for antibiotic using infectious model ResponseclinicalBlack boxDose titration for antibiotic using infectious modelPK/PDPKPDBodypathogenDoseresponsePlasmaconcentration
51Why plasma concentrations rather than the dose for an antibiotic ?
52Most of our pathogens are located in extracellular fluids (in phagocytic cell most often)mycoplasma (some)chlamydiaeCryptosporidiosisSalmonellaRhodococcus equiExtra Cellular FluidMost bacteria of clinical interest- respiratory infection- wound infection- digestive tract inf.BugFree plasma concentration is equal to free extracellular concentration
53Do not confuse science, marketing and and propaganda
54PK/PD indices as indicator of antibiotic efficacy
55AUC/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; macrolidesTime>MIC: Penicillins, cephalosporinsCmax/MIC: aminoglycosiesWe know the average critical values to achieve for theses indices to cure animals and we can compute the appropriate doses
56To compute a dose, we have to take into account inter-animal variability using population approaches
58PD variability: MIC distribution Pasteurella multocida (n=205) 403530Pathogens %25201510SUSCEPTIBLE50.06250.1250.250.5124MIC (mg/mL)
59Monte 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 regimenMonte Carlo simulations
61Traditional explanation for enrichment of mutants ConcentrationMICSelective PressureTime
62Mutant Prevention Concentration (MPC) and the Selection Window (SW) hypothesis This lecture was prepared on April 5, Literature cited is listed as a note to the last slide.
63Blocking Growth of Single Mutants Forces Cells to Have a Double Mutation to Overcome Drug Without antibiotics10-8single mutant population10-8Wild popWith antibiotics10-8single mutant populationWild population éradicationsensiblesingle mutantDouble mutant
64The selection window hypothesis Mutant prevention concentration (MPC)(to inhibit growth of the least susceptible, single step mutant)MICSelective concentration (SC)to block wild-type bacteriaPlasma concentrationsMutant selection windowAll bacteria inhibitedGrowth of only the most resistant subpopulationGrowth of all bacteria
65Mutants 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.
67Duration of treatment The shortest as possible Many epidemiological evidences that the likelihood of resistance increase with the duration of treatment
68Conclusion: for a rational antibiotic use, what is the priority? Environmental safetyoperator safetyconsumer safetyresistance in non-target pathogens (salmonella, campylobacters)Transfer of resistance genestarget animal safetyefficacyresistance in target pathogens
69Bourgelat & the first veterinary school in the world at Lyon
70Toulouse & El Francesito Born here on the 11th Dec 1890
71Toulouse: Rugby, Vet School and Airbus Vet School campus