P.L. Toutain National Veterinary School ; Toulouse, France Noordwijkerhout July 8-12 2012 NL

1. What are the public health issues that practitioners have to consider to enforce a sustainable use of antibiotics P.L. Toutain National Veterinary School ; Toulouse, France Noordwijkerhout July 8-12 2012 NL

2. The priorities of a sustainable veterinary antibiotherapy is related to public health issues, not to animal health issues

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. But of what resistance are we speaking?

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

7. The 4 human risks associated to the use of antibiotics in veterinary medicine to minimize • Decrease in susceptibility or full resistance of zoonotic pathogens passing from animal to man either directly or throughout the food chain • Development of resistance in commensal flora and passage of resistance gene throughout the food chain or the environment • Release of antibiotics in the environment with different consequences including emergence of resistance (gene, pathogens) • Antibiotic residues in food

8. Q1-For AR, what are the critical veterinary ecosystems in terms of public health (commensals)

9. The critical animal ecosystems in terms of emergence and spreading of resistance • Open and large ecosystems • Digestive tract • Skin • Open but small ecosystem • Respiratory tract • Closed and small ecosystem • Mammary gland

10. Bacterial load exposed to antibiotics during a treatment Digestive tract Manure Sludge waste Infected Lungs Test tube 1µg Several tons 1 mg 2-3Kg Food chain Soil, plant….

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

12. Biodisponibilité orale des tétracyclines chez le porc • Chlortétracycline: • Pigs Fasted or fed: 18 to 19% • Doxycycline: • Pigs :23% • Oxytétracycline: • Pigs:4.8% • Piglets, weaned, 10 weeks of age: by drench: 9%;in medicated feed for 3 days: 3.7% . • Tétracycline: • Pigs fasted:23% . • La majeure partie des doses administrées de tétracyclines n’est pas utile pour l’animal mais expose inutilement ses flores digestives et l’environnement

13. Biophases & antibiorésistance 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

14. Marbofloxacin impact on E. coli in pig intestinal flora(From P. sanders, Anses, Fougères) IM 3 days IV • Before treatment : E. coli R (0.01 to 0.1%) • After IV. :Decrease of total E coli , slight increase of E. coli R (4 to 8 %) • Back to initial level • After repeated IM (3d) : Decrease below LoD E. coli (2 days), fast growth (~ 3 106 ufc/g 1 d). E. coli R followed to a slow decrease back to initial level after 12 days

15. Influence d’une administration d’amoxicilline sur la flore digestive du porc(excrétion du gène blaTEM)

16. Performance-enhancing antibiotics (old antibiotics) • chlortetracycline, sulfamethazine, and penicillin (known as ASP250)] • phylogenetic, metagenomic, and quantitative PCR-based approaches to address the impact of antibiotics on the swine gut microbiota

17. It was shown that antibiotic resistance genes increased in abundance and diversity in the medicated swine microbiome despite a high background of resistance genes in nonmedicated swine. • Some enriched genes, demonstrated the potential for indirect selection of resistance to classes of antibiotics not fed.

18. Daily bacterialshedding for a growerpigs • E coli: 7.5 g per days • Enterococcus: about 300 µg per days =7.5x106 A 20- to 100-fold greater E. coli abundance in medicated than nonmedicated swine

19. Innovation: PK selectivity of antibiotics Proximal Distal 1-F=90% • Gut flora • Zoonotic (salmonella, campylobacter • commensal ( enterococcus) Oral Efflux F=10% Food chain Quinolones, macrolides environment IM Blood Kidney Biophase Résistance = public health concern Animal health

20. Q2-What is the actual veterinary contribution to the human AR

21. What is the actual veterinary contribution to the human AR • A direct contribution to resistance for zoonotic pathogens(Salmonella, Campylobacter…) • A possible transmission of commensal bacteria that may transmit resistance determinants to human pathogens • An indirect contribution for MRSA (pets as carriers and reservoirs)

22. Trends and Sources of Zoonosis in EU EFSA/ECDC 2011

23. Reported zoonoses in UE, 2010 VTEC: E Coli verotoxinogène Within Y. enterocolitica, the majority of isolates from food and environmental sources are non-pathogenic types.

24. Deaths due to salmonellosis, campylobacteriosis & E coli (report2010) • Based on the reported fatality rates and the total numbers of reported confirmed cases, it is estimated that there were approximately 130 deaths due to salmonellosis, 212 due to campylobacteriosis and 16 due to E coli in EU.

25. Treatments of salmonellosis & campylobacteriosis • Usually no antibiotics • Only to treat sever cases in a risky patients

26. Antibiotics used to treat salmonellosis & campylobacteriosis Salmonella • Fluoroquinolones • Cephalosporins (third generation) • No quinolones for children Campylobacter • Macrolides • Fluoroquinolones

27. Antibiotics used to treat Verotoxigenic E coli • The use of antimicrobials for the treatment of human infections with VTEC is controversial. • In general, antimicrobials are not recommended as their usage may exacerbate symptoms, particularly haemolytic uraemic syndrome.

28. Treatments of zoonotic pathogens in man : is there some AR?

29. Salmonella & campylobacter :AR in human in US

30. Percentage of non-typhoidal Salmonella isolates resistant to nalidixic acid, by year, 1996–2010

31. Percentage of non-typhoidal Salmonella isolates resistant to ceftriaxone, by year, 1996–2010

32. Whilst there has been much debate about the contribution of antibiotic use in veterinary medicine to the overall resistance development in human pathogens, these data suggest that clinical resistance to fluoroquinolones in E. coli and nontyphoidal Salmonella is uncommon, except for a few countries.

33. Travelling is the origin of salmonellosis dues to Salmonella enterica sérotype Kentucky ST198 & resistance to ciprofloxacin

34. What could be the human health consequence of exposure to resistant zoonotic bacteria

35. Impact of AR on the human mortality due to salmonellosis

36. Macrolide resistance in Campylobacter jejuni and Campylobacter coli

37. Q3: What are the transmission pathways between animals and man

38. Pathways of transmission between animals and man Slaughter house • Soil • Water • Air Direct professional risk meat Environment 3 possible pathways

39. Campylobacter: prevalenceThe food chain is a critical pathway for resistance transmission of resistance from animal to man Prevalence: 0-<5% for meat Prevalence: 60-100% in feces Prevalence: 0-32% for carcass

40. Prevalence of salmonella contamination (EU 2009) The high prevalence in poultryis due to someanatomical and physiologicalspecificcity

41. Several critical steps when processing chickens • Feed withdrawal • Not too long, not too short • Collecting and transportation of the chickens • Stacked several raw high and top to bottom contamination during transportation • Feather removal • Scalding tanks to remove the feather • Removal of the internal organs • Carcass contamination

42. Transportation of poultry • Campylobacter : Top to bottom contamination by feces during transportation

43. Feather removal in a contaminated environment by feces (scald tank)

44. Contamination of the carcass During evisceration, some degree of faecal contamination is inevitable no matter how stringent the hygiene measures that are applied

45. Direct transfer from animal to man(professional risk ) Also direct contact with antibiotic

46. The case of Methicillin-Resistant Staphylococcus Aureus (MRSA)

47. MRSA

48. MRSA prevalence in animals • There are differences in the occurrence of MRSA between companion animals (pets and horses) and livestock (mostly pigs, poultry, cattle and sheep).

49. MRSA: animal reservoir • The most common MRSA isolates from animals are ST398, the main reservoirs being pigs and veal calves. • This type, which is also isolated from chickens and horses, can be transferred to humans. • There is a limited overlap with humans, and transmission to humans is rare. • Most isolates are multidrug resistant, and some PVL-positive isolates are found. • MRSA is rarely found in meat and then only in low quantities; the source is thought to be the butcher/meat handler rather than animals

50. MRSA in pigs • The prevalence of MRSA-positive herds was 67% in breeding herds and 71% in finishing herds. • The most likely explanation for the observed increase in MRSA-positive herds is that MRSA is easily transmitted between herds (e.g. when purchasing animals).