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Pierre-Louis Toutain Ecole Nationale Vétérinaire de Toulouse France

Antibiorésistances Vétérinaire & humaine, Un problème écologique global: enjeux et principes de solution. Pierre-Louis Toutain Ecole Nationale Vétérinaire de Toulouse France.

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Pierre-Louis Toutain Ecole Nationale Vétérinaire de Toulouse France

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  1. Antibiorésistances Vétérinaire & humaine,Un problème écologique global: enjeux et principes de solution Pierre-Louis Toutain Ecole Nationale Vétérinaire de Toulouse France

  2. Expected Annual deaths attributable to AMR compared to other major causes of death in 2050.Source: Antimicrobial resistance: tackling a crisis for the health and wealth of nations. Review on Antimicrobial Resistance

  3. 46: Antimicrobial resistance (AMR) poses a serious threat to public health, growth and global economic stability. We affirm the need to explore in an inclusive manner to fight antimicrobial resistance by developing evidence-based ways to prevent and mitigate resistance, and unlock research and development into new and existing antimicrobials from a G20 value-added perspective, and call on the WHO, FAO, OIE and OECD to collectively report back in 2017 on options to address this including the economic aspects. In this context, we will promote prudent use of antibiotics and take into consideration huge challenges of affordability and access of antimicrobials and their impact on public health. We strongly support the work of the WHO, FAO and the OIE and look forward to a successful high-level meeting on AMR during the UN General Assembly. We look forward to the discussion under the upcoming presidency for dealing with these issues.

  4. One world, one health & one resistome Treatment & prophylaxis Veterinary medicine Human medicine Community Animal feed additives Hospital Agriculture Plant protection Environment Industry

  5. The priorities of a sustainable veterinary antimicrobial therapy is related to public health issues, not to animal health issues

  6. Q1: What types of antimicrobial drug resistance does veterinary medicine face and which raise public health issues?

  7. The three types of AMR faced by vet medicine Target pathogen Zoonotic Commensal Global ecological problem Efficacy in animal Efficacy in man Farm Environment Food chain Animal health Issue Human health issue Public health Issue

  8. Q2: What are the animal’s ecosystems potentially able to raise public health concerns in terms of resistance to antibiotics

  9. Bacterial load & duration of exposition to antibiotics during treatment Manure Sludge Waste Infected Lungs Test tube Digestive tract Tons Months Kg Weeks µg Hours mg Days Food chain Environment

  10. Q3: what is the pathways for transmission between animal and human resistomes

  11. “Classical” natural history of bacterial infections (at hospital) Disease Specific pathogen Andremont et al, The lancet infection 2011 11 6-8

  12. « New » natural history of bacterial infections(in the community) Commensal bacteria of a future patient (100g) Colonization/carriage Gene of resistance ESBL: CTX-M… Disease To have a clean commensal flora is an individual issue Specific pathogen Disselmination of gene of resistance Dissemination of genes of resistance Adapted from Andremont et al, The lancet infection 2011 11 6-8

  13. The link animal/man environment globalisation… The commensal genetic pool is large and encompasses the potential for many different mechanisms conferring AMR

  14. Greening our AB One world, one health Environment Food chain Most of the prudent use recommendations do not address this question

  15. Q5: Why veterinary antibiotic treatments are able to alter the resistome of the animal gut microbiota.

  16. AMD: oral route Oral route of administration Gastro-intestinal tract Proximal Distal Microbiota • Zoonotics (salmonella, campylobacter • commensal ( enterococcus) 1-F% F% Food chain Blood Environment Biophase Target pathogen Resistance :animal health issue Resistance: public health issue

  17. Non-oral route of adminsitration Gastro-intestinal tract Proximal Distal Microbiota • Zoonotics (salmonella, campylobacter ) • commensal ( enterococcus) Intestinal efflux Bile Quinolones Macrolides Tetracyclines Food chain Non oral route Blood Environment Biophase Target pathogen Resistance: animal health issue Resistance: public health issue

  18. Genotypic evaluation of ampicillin resistance:copy of blaTEM genes per gram of feces A significant effect of route of administration on blaTEM fecal elimination (p<0.001).

  19. 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

  20. Q6-How antibiotics increase the prevalence of resistance in Commensal microbiota

  21. Horizontal genes exchanges(BLSE)

  22. How antibiotics promote colonization by resistant bacteriaFate of a multi-antibiotic-resistant strain of Serratia liquefaciens in presence or absence of antibiotics Gnotobioticmice harboring a susceptible strain of E. coli From Duval-Yflah Y. et al. IAI 1980; 28 :981

  23. Q7: Why development of resistance in the G.i.t may appears with some delay after the end of a treatment:Differential Time development of the Mutant Selective Window: target pathogen vs. commensal microbiota

  24. In the present study, we used fecal samples collected from these volunteers during and after ciprofloxacin treatment to analyze the dynamics of the emergence of resistance in E. coli over time in each volunteer.

  25. Mutant Selective Window can be longer and delayed in the GIT QREC From environment Stools MPC MIC GIT/commensal Target pathogen Plasma/Lung

  26. Q9-What are the hazard associated to the release of antibiotic and genes of resistance in environment

  27. Feces production • About 5 tons of feces per american per year The fecal peril

  28. 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

  29. Rate of antibiotic degradation in manure, soil, waste…

  30. PL Toutain Ecole vétérinaire Toulouse

  31. many of the resistance factors we see in clinics today have been recruited from nonpathogenic bacteria around us (Bonomo and Szabo 2006).

  32. Q10: what are epidemiological evidence of the veterinary contribution to the human antimicrobial resistance

  33. The historical and emblematic case:Nourseothricin in animal husbandry for growth promotion, Nouseothricin as AGP

  34. Investigations épidémiologiques

  35. Corrélation entre le niveau d’antibiorésistance chez le porc et chez l’homme pour E coli dans 11 pays de l’UE Viera et al

  36. Evidence provided by metagenomic of a potential contribution of veterinary antimicrobials to the human resistome

  37. Antibiotics approved for animal use and that have a longer use have significantly higher resistance potential Genome research: 2013 23 1163-1169

  38. L’antibiorésistance doit être comprise comme un problème écologique global et non comme une simple impasse médicale

  39. Principe de précaution

  40. Principe de prévention

  41. A possible conflict of interest • Optimisingoutcomeisdirected at the animal patient levelwhereasemergence of resistanceis an ecological issue and a trade-off between the twoobjectivesis not alwayseasy to achieve Pathogens Commensal microbiota ????

  42. Q11: Why the paradigm of prudent use of AMDs in veterinary medicine has some shortcomings

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

  44. The shortcomings of the paradigm of a prudent use of antibiotics in veterinary medicine • Three Selected examples • Revision (increase) of dosage regimen • 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 • Reduction of antimicrobial consumption…

  45. 93% of respondents used antibiotic intramammary tubes to treat mastitis • 83% per cent of respondents (413) fed waste milk to calves

  46. Antimicrobial Susceptibility Testing: VETCAST

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

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

  49. Q12: Why some regulatory decisions are conterproductive

  50. Generics and antibiotic consumption

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