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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, 18 th November 2011 Tandil, Argentina Slide 2 2 The priorities of a sustainable veterinary antimicrobial therapy is related to public health issues, not to animal health issues: Why? Slide 3 3 Medical consequences of antimicrobial resistance Slide 4 4 The antibiotic ecosystem: One world, One health Treatment & prophylaxis Human medicine Community Veterinary medicine Animal feed additives Environment Hospital Agriculture Plant protection Industry Slide 5 5 Prevent emergence of resistance: but of what resistance? Slide 6 6 Emergence of resistance for Salmonella typhimurium DT104 in UK to quinolones following the market autorisation of enrofloxacin Sthr & Wegener, Drug resistance Updates, 2000, 3:207-209 Slide 7 7 Commensal bacteria: transmission of resistance genes from animal to man: Slide 8 8 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 Slide 9 9 Gut flora & antimicrobial resistance G.I.T Proximal Distal Rsistance = lack of efficacy Blood Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus) 1-F% F% Target biophase Bug of vet interest AB: oral route Rsistance = public health concern Food chain Environmental exposure Slide 10 10 Gut flora & antimicrobial resistance Gastrointestinal tract Proximal Distal Intestinal secretion Bile Rsistance = lack of efficacy Rsistance =public health issue Biophase Target pathogen Blood Food chain Environment Systemic Administration Quinolones Macrolides Ttracyclines Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus) Slide 11 11 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 bla TEM gene Slide 12 12 Result: Percent of ampicillin-resistant Enterobacteriaceae for each mode of administration Slide 13 13 Hazard associated to the release of antibiotic in environment Slide 14 14 Fate of antibiotics, zoonotic pathogens and resistance genes: residence time in the different biotopes Digestive tract: 48h Lagoon: few weeks Air pollution Bio-arosol Air, water & ground pollution Ex:T1/2 tiamuline=180 days Slide 15 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 Slide 16 16 Innovation: PK selectivity of antibiotics environment G.I.T Proximal Distal Blood Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus) Biophase AB: oral route Rsistance = public health concern Food chain 0% 100% Animal health Kidney Slide 17 17 Innovation: PK selectivity of antibiotics environment G.I.T Proximal Distal Blood Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus) Biophase AB: IMroute Rsistance = public health concern Food chain Animal health Kidney Quinolones, macrolides Slide 18 18 Judicious, prudent,responsible sustainable use of antibiotics Slide 19 19 1- No misuse Slide 20 20 An example of misuse: in ovo administration of ceftiofur Slide 21 21 Correlation between the prvalence of chicken meat contaminated by E.coli and Salmonella enterica rsistant to ceftiofur and human infection to resistant Salmonella Heidelberg (r=0.91 pour Salmonella) Salmonella enterica E Coli Salmonella Heidelberg Slide 22 22 Effect of the withdrawal of ceftiofur in hatchery Salmonella Heidelberg Salmonella E Coli Slide 23 23 2- No overuse Slide 24 24 Human and veterinary antibiotic usage: US vs EU Source: UCS 2000 Source: FEDESA 2001 Slide 25 25 No overuse means no antibiotics as growth promotor Slide 26 26 we have evidence that market introduction of generics or of me-too drugs has influence on antibiotic consumption ; Slide 27 27 Generics for antibiotics (quinolones) : conclusions Slide 28 28 Generics and antibiotic consumption Slide 29 29 Use of fluoroquinolones in veterinary medicine: Germany, DK, UK From Hellmann: Assoc Vet Consult. SAGAM 2005 Slide 30 30 Use of fluoroquinolones in veterinary medicine: Eastern EU, Spain, Portugal From Hellmann: Assoc Vet Consult. SAGAM 2005 Slide 31 31 Issues associated to generics that are not bioequivalence Slide 32 32 Non-bioequivalence of various trademarks of enrofloxacin in cow Sumano & al 2001 Dtsch tierrztl Wschr 108 281-320 Slide 33 33 3-The right drug Slide 34 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? Slide 35 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. Slide 36 36 How a vet can select the best drug amongst competitors (the so-called me-too) for pulmonary infection? Slide 37 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) Slide 38 38 The need of comparative clinical trials for the newest antibiotics Slide 39 39 Currently, antibiotics are compared only by non-inferiority trials Slide 40 40 Draxxin vs. Micotil by Pfizer Micotil vs. Draxxin by Elanco Slide 41 41 Draxxin vs Micotil by Pfizer Micotil vs. Draxxin by Elanco Take home message: Draxxin superior to Micotil P0.05) 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 Slide 42 42 4-The right time to start a treatment Slide 43 43 Diseasehealth Therapy Metaphylaxis (Control) Prophylaxis (prvention) Growth promotion The different modalities of antimicrobial therapy High Pathogen load Small No NA Antibiotic consumption Only a risk factor Slide 44 44 Slide 45 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 01020304050 Time (h) Bacteria counts per lung (CFU/lung) 10 0 10 2 10 4 10 6 10 810 no clinical signs of infection anorexia lethargy dehydration Slide 46 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 Slide 47 47 5-The right dose for efficacy Slide 48 48 Why to optimize dosage regimen for antibiotics 1.To optimize efficacy 2.Reduce the emergence and selection of resistance Slide 49 49 How to find and confirm a dose (dosage regimen) Dose titration Animal infectious model PK/PD Clinical trials Slide 50 50 Dose titration Dose Response clinical Black box PK/PD Dose response PKPD Plasma concentration Bodypathogen Dose titration for antibiotic using infectious model Slide 51 51 Why plasma concentrations rather than the dose for an antibiotic ? Slide 52 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 Slide 53 53 Do not confuse science, marketing and and propaganda Slide 54 54 PK/PD indices as indicator of antibiotic efficacy Slide 55 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 Slide 56 56 To compute a dose, we have to take into account inter-animal variability using population approaches Slide 57 57 PK Variability n = 215 Doxycycline Slide 58 58 PD variability: MIC distribution Pasteurella multocida (n=205) 0 MIC ( g/mL) 5 10 15 20 25 30 35 40 0.06250.1250.250.5124 Pathogens % SUSCEPTIBLE Slide 59 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 Slide 60 60 6-The right dose to prevent resistance Slide 61 61 Selective Pressure MIC Time Concentration Traditional explanation for enrichment of mutants Slide 62 62 Mutant Prevention Concentration (MPC) and the Selection Window (SW) hypothesis Slide 63 63 Without antibiotics Blocking Growth of Single Mutants Forces Cells to Have a Double Mutation to Overcome Drug With antibiotics 10 -8 Wild population radication sensible single mutantDouble mutant Wild pop single mutant population Slide 64 64 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 All bacteria inhibited Growth of only the most resistant subpopulation Growth of all bacteria Mutant selection window Slide 65 65 Mutants are not selected at concentrations below MIC or above the MPC Slide 66 66 7-The right duration of a treatment Slide 67 67 Duration of treatment The shortest as possible Many epidemiological evidences that the likelihood of resistance increase with the duration of treatment Slide 68 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 Slide 69 69 Bourgelat & the first veterinary school in the world at Lyon Slide 70 70 Toulouse & El Francesito Born here on the 11 th Dec 1890 Slide 71 71 Toulouse: Rugby, Vet School and Airbus Vet School campus