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 2011 Tandil, Argentina

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

3. Medical consequences of antimicrobial resistance

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

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

6. Emergence of resistance for Salmonella typhimurium DT104 in UK to quinolones following the market autorisation of enrofloxacin Stöhr & Wegener, Drug resistance Updates, 2000, 3:207-209

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

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

10. 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

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 blaTEM gene

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

13. Hazard associated to the release of antibiotic in environment

14. 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

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

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

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

19. 1- No misuse

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

21. Correlation between the prévalence of chicken meat contaminated by E.coli and Salmonella entericarésistant to ceftiofur and human infection to resistant Salmonella Heidelberg (r=0.91 pour Salmonella) Salmonella Heidelberg Salmonella enterica E Coli

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

23. 2- No overuse

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

25. No overuse means no antibiotics as growth promotor

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

27. Generics for antibiotics (quinolones) : conclusions

28. Generics and antibiotic consumption

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

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

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

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

33. 3-The right drug

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

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. The need of comparative clinical trials for the newest antibiotics

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

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

41. Draxxin vs Micotil by Pfizer 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 • Take home message: • Draxxin superior to Micotil P<0.00x Micotil vs . Draxxin by Elanco

42. 4-The right time to start a treatment

43. 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

45. 1010 108 106 104 102 100 0 10 20 30 40 50 A mouse model to compare metaphylaxis and curative treatment anorexia lethargy dehydration no clinical signs of infection Progression of infection Bacteria counts per lung (CFU/lung) Inoculation of Pasteurella multocida 1500 CFU/lung Time (h) Late (32h) Administration early (10h) Administration

46. 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

47. 5-The right dose for efficacy

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

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

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