Pierre-Louis Toutain Ecole Nationale Vétérinaire de Toulouse France AVIA, Québec 21 octobre 2016

1. Tout ce qu’un praticien devrait savoir pour mettre en œuvre une antibiothérapie raisonnée chez le porc:II les solutions Pierre-Louis Toutain Ecole Nationale Vétérinaire de Toulouse France AVIA, Québec 21 octobre 2016

2. Principe de précaution

3. Principe de prévention

4. The prudent use of antibiotics Commensal flora Most recommendations are copy and paste from human medicine May be counterproductive Target pathogens

5. Possible conflict of interest between animal and public health in veterinary medicine • Selected examples • Revision (increase) of dosage regimen • Restriction of prophylaxis/metaphylaxis in EU • Ignore the inoculum effect for metaphylaxis • Local route of administration at drying off • Ignore bad farming practices consisting to recycle contaminated milk • Systematic recourse to Antimicrobial Susceptibility Testing (AST) • Few or lack of clinical breakpoint • resistance results encouraging to select more critical AMD

6. Comment réduire l’impact des antibiotiques en termes de santé publique

7. Travel is a major risk factor The first prospective study demonstrating that international travel is a major risk factor for colonization with ESBL-producing Enterobacteriaceae

8. International trade for food About 40% of trades for agricultural products are between rich and emerging countries World globalisation from a bug point of view

9. The welltraveledsaladillustratesthatantimicrobialresistanceis a global ecological issue

10. Comment réduire l’impact sur les flores commensales et de l’environnement via les doses • Réduction globale de la consommation des antibiotiques • Réduction sélective de la consommation des antibiotiques • Antibiotiques critiques • Réduction des doses: la métaphylaxie • Réduction de la durée des traitements • Les antibiotiques verts • Les alternatives thérapeutiques aux antibiotiques • Les alternatives non-thérapeutiques & démarches qualité

11. 1-Réduire la consommation globale (mondiale) d’antibiotique dans les élevages

12. Consommation relative d’antibiotiques vétérinaires par pays La lutte contre l’antibiorésistance est (doit être) mondialisée

13. Global consumption of AMD in food animals for 2010 & projection for the year 2030 based on growth projections of the consumption of livestock products

14. Largest five consumers of antimicrobials in livestock in 2010 (A) and 2030 (B) +67% over the next 20 years

15. Consumption by type of livestock • Mg per PCU ( population per correction unit) • cattle (45 mg),chickens (148 mg) pigs (172 mg). PIGS

16. Expression pondérale de la consommation d’antibiotique

17. What is the richest country?

19. DDDA definition • In veterinary medicine, the ESVAC consortium has defined the DDDA as ‘the assumed average maintenance dose per day per kg body weight for the main indication in a specified species’. ESVAC (European Surveillance of Veterinary Antimicrobial Consumption)

20. 2-Effets attendus de la réduction de la consommation d’antibiotiques

21. Trend in antibacterial usage and resistance in Enterococcus faecium in Denmark : Avoparcin 30 000 80 60 20 000 % resistant isolates 40 Kg active compound used 10 000 20 0 0 94 95 96 97 98 99 Swine broilers Avoparcin Stöhr & Wegener, Drug resistance Updates, 2000, 3:207-209

22. Objectives: To examine the tetracycline resistance properties of fecal bacteria from swine from organic farms had been free of antibiotic use for 4 years and feral swine Sameresults for the total anaerobicmicrobiota

23. High prevalence of nasal MRSA carriage in Dutch slaughter pigs: virtually all pigs and all slaughter batches were MRSA positive. • Unexpected as antibiotic usage within slaughter pigs decreased significantly since 2009 (-58%) • The prevalence found in the present study is also much higher than the prevalence reported in other European countries (1-2%in Switzerland) • Explanation might be the differences in management systems between the Netherlands and other countries.

24. MRSA in pigs : a risk factor analysis Antibiotic use is not a risk factor

25. The lack of an association between MRSA and various measures of antibiotic usage • One possible explanation for this lack of association is the use of therapeutic concentrations of in-feed zinc as a replacement for antibiotic therapy. • The possibility for zinc to act as a confounder that can influence the association between antibiotic usage and MRSA

26. 3: Reduction of the AMD consumption: why some regulatory decisions are counterproductive: the case of generics

27. Generics and antibiotic consumption

28. Number of ciprofloxacin trade names (black line) and the median price per DDD (red line) and the influence of the introduction of generics

29. The influence of the introduction of generics on the total use of ciprofloxacin (black line) and median price per DDD (red line)

30. Trends in the frequency of ciprofloxacin resistance among E. coli urine (brown line) and the consumption of ciprofloxacin (black line) from 1995 to 2005

31. Generics and misuse of antibiotics • Another possible undesirable consequence of generic promotion is the encouragement to use old rather than more recent antibiotics.

32. 4: Restriction d’usage de certaines classes d’antibiotiques

33. « Tout le monde sert d’abord le bon vin et, quand les gens sont ivres, alors le moins bon » Evangile selon Saint Jean; Les noces de Cana; Q: les vétérinaires sont-ils devenus ivres?

34. Affirmation de l’OMS pour le critère 2: • The panel did not consider that transmission of such organisms (zoonotic, commensal) or their genes must be proven, but only the potential for such transmission to occur.

35. Retour d’expérience de la politique de l’OMS en matière d’antibiotique critique • Années 90: l’OMS recommande de traiter les infections à Shigella en Asie du Sud-Est par l’acide nalidixique plutôt que par les fluoroquinolones. • L’hypothèse de l’OMS: • le recours en première intention aux antibiotiques les moins actifs préserverait, le moment venu, l’activité des fluoroquinolones plus efficaces vis-à-vis de germes qui seraient devenus résistants.

36. 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.

37. Tetracyclines: half the amount of veterinary antibiotic used worldwide • Soils may be hot spots for gene transfer, • Correlation between environmental contamination with animal and human faecal run-off and an increased incidence of antibiotic resistance plasmids and genes in bacteria found in those environments • Coselection for resistance to multiple late-generation human therapeutic antibiotics encoded on tetracycline resistance plasmids captured from uncultivated stream and soil bacteria

38. Our data suggest that chlortetracycline is contraindicated when attempting to avoid expansion of resistance to critically important third-generation cephalosporins.

39. Les décisions de prohibition bloquent toute innovations notamment des green antibiotics

40. 5- metaphylaxis & dose reduction and why metaphylaxis could be the future of veterinary antimicrobial therapy

41. Terms to describe herd or flock antibiotic use Disease health Metaphylaxis (Control) Growth promotion Prophylaxis (prévention) Therapy • Administration of an AB to exposed healthy animals considered to be at risk,( before onset of disease) • Risk factor present Administration of an antimicrobial, usually as a feed additive, to growing animals that results in improved physiological performance. Administration of an AB to animals, usually as a herd or flock, in which morbidity and/or mortality has exceeded baseline norms. Hazard present Administration of an AB to an animal, or group of animals, which exhibit clinical disease

42. Metaphylaxis: the point of view of the microbiologist

43. The different uses of antibiotics in veterinary medicine Disease health Antibiotic consumption Metaphylaxis (Control) Prophylaxis (prevention) Growth promotion Therapy High Pathogen load Only a risk factor No Small NA

44. Linezolid Oxacillin Ciprofloxacin Daptomycin Gentamicin Vancomycin MICs estimated with different inoculmum densities, relative to that MIC at 2x105

45. prophylaxis prevention Therapy Metaphylaxis Pathogen load:Wild and mutant subpopulations Wild large Subpopulation First mutant No pathogen Pathogen load Some AMD increase the mutation rate Low Dose High Dose

46. Rodent model of metaphylaxis

48. 1010 108 106 104 102 100 0 10 20 30 40 50 Time of marbofloxacin administration 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 administration early administration

49. marbofloxacin administrations 1-Clinical outcome (survival) early late late 100 % 80 60 % mice alive 40 20 0 control 1 mg/kg 40 mg/kg marbofloxacin doses

50. Marbofloxacin administrations 2-Bacterial eradication Early low dose= late high dose Early Late 100 % 80 60 % of mice with bacterial eradication 40 20 0 control 1 mg/kg 40 mg/kg Marbofloxacindoses