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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.

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Presentation on theme: "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."— Presentation transcript:

1 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

2 2 The priorities of a sustainable veterinary antimicrobial therapy is related to public health issues, not to animal health issues: Why?

3 3 Medical consequences of antimicrobial resistance

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

5 5 Prevent emergence of resistance: but of what resistance?

6 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:

7 7 Commensal bacteria: transmission of resistance genes from animal to man:

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

9 9 Gut flora & antimicrobial resistance G.I.T Proximal Distal Résistance = lack of efficacy Blood Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus) 1-F% F% Target biophase Bug of vet interest AB: oral route Résistance = public health concern Food chain Environmental exposure

10 10 Gut flora & antimicrobial resistance Gastrointestinal tract Proximal Distal Intestinal secretion Bile Résistance = lack of efficacy Résistance =public health issue Biophase Target pathogen Blood Food chain Environment Systemic Administration Quinolones Macrolides Tétracyclines Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus)

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

12 12 Result: Percent of ampicillin-resistant Enterobacteriaceae for each mode of administration

13 13 Hazard associated to the release of antibiotic in environment

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-aérosol Air, water & ground pollution Ex:T1/2 tiamuline=180 days

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

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 Résistance = public health concern Food chain 0% 100% Animal health Kidney

17 17 Innovation: PK selectivity of antibiotics environment G.I.T Proximal Distal Blood Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus) Biophase AB: IMroute Résistance = public health concern Food chain Animal health Kidney Quinolones, macrolides

18 18 Judicious, prudent,responsible sustainable… use of antibiotics

19 19 1- No misuse

20 20 An example of misuse: in ovo administration of ceftiofur

21 21 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 22 Effect of the withdrawal of ceftiofur in hatchery Salmonella Heidelberg Salmonella E Coli

23 23 2- No overuse

24 24 Human and veterinary antibiotic usage: US vs EU Source: UCS 2000 Source: FEDESA 2001

25 25 No overuse means no antibiotics as growth promotor

26 26 we have evidence that market introduction of generics or of “me-too’ drugs has influence on antibiotic consumption ;

27 27 Generics for antibiotics (quinolones) : conclusions

28 28 Generics and antibiotic consumption

29 29 Use of fluoroquinolones in veterinary medicine: Germany, DK, UK From Hellmann: Assoc Vet Consult. SAGAM 2005

30 30 Use of fluoroquinolones in veterinary medicine: Eastern EU, Spain, Portugal From Hellmann: Assoc Vet Consult. SAGAM 2005

31 31 Issues associated to ‘generics’ that are not bioequivalence

32 32 Non-bioequivalence of various trademarks of enrofloxacin in cow Sumano & al 2001 Dtsch tierärztl Wschr

33 33 3-The right drug

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?

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.

36 36 How a vet can select the best drug amongst competitors (the so-called me-too) for pulmonary infection?

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)

38 38 The need of comparative clinical trials for the newest antibiotics

39 39 Currently, antibiotics are compared only by non-inferiority trials

40 40 Draxxin vs. Micotil by Pfizer Micotil vs. Draxxin by Elanco

41 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 42 4-The right time to start a treatment

43 43 Diseasehealth Therapy Metaphylaxis (Control) Prophylaxis (prévention) Growth promotion The different modalities of antimicrobial therapy High Pathogen load Small No NA Antibiotic consumption Only a risk factor

44 44

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 Time (h) Bacteria counts per lung (CFU/lung) no clinical signs of infection anorexia lethargy dehydration

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

47 47 5-The right dose for efficacy

48 48 Why to optimize dosage regimen for antibiotics 1.To optimize efficacy 2.Reduce the emergence and selection of resistance

49 49 How to find and confirm a dose (dosage regimen) Dose titration –Animal infectious model PK/PD Clinical trials

50 50 Dose titration Dose Response clinical Black box PK/PD Dose response PKPD Plasma concentration Bodypathogen Dose titration for antibiotic using infectious model

51 51 Why plasma concentrations rather than the dose for an antibiotic ?

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

53 53 Do not confuse science, marketing and and propaganda

54 54 PK/PD indices as indicator of antibiotic efficacy

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

56 56 To compute a dose, we have to take into account inter-animal variability using population approaches

57 57 PK Variability n = 215 Doxycycline

58 58 PD variability: MIC distribution Pasteurella multocida (n=205) 0 MIC (  g/mL) Pathogens % SUSCEPTIBLE

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

60 60 6-The right dose to prevent resistance

61 61 Selective Pressure MIC Time Concentration Traditional explanation for enrichment of mutants

62 62 Mutant Prevention Concentration (MPC) and the Selection Window (SW) hypothesis

63 63 Without antibiotics Blocking Growth of Single Mutants Forces Cells to Have a Double Mutation to Overcome Drug With antibiotics Wild population éradication sensible single mutantDouble mutant Wild pop single mutant population

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

65 65 Mutants are not selected at concentrations below MIC or above the MPC

66 66 7-The right duration of a treatment

67 67 Duration of treatment The shortest as possible Many epidemiological evidences that the likelihood of resistance increase with the duration of treatment

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

69 69 Bourgelat & the first veterinary school in the world at Lyon

70 70 Toulouse & El Francesito Born here on the 11 th Dec 1890

71 71 Toulouse: Rugby, Vet School and Airbus Vet School campus

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