Ter gelegenheid van het emeritaat van Johanna Fink gremmels Utrecht NL 10 july 2014 PL Toutain National Veterinary School of Toulouse France The priorities of a sustainable veterinary antimicrobial therapy is related to public health issues not to animal health issu ID: 1040310
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1. 1Strategies to avoid the risk of antimicrobial resistance in veterinary medicineTer gelegenheid van het emeritaat van Johanna Fink-gremmelsUtrecht, NL10 july 2014P.L. ToutainNational Veterinary School of Toulouse, France
2. The priorities of a sustainable veterinary antimicrobial therapy is related to public health issues, not to animal health issues
3. Strategies to avoid the risk of antimicrobial resistance in veterinary medicine: Q1: But of what resistance are we speaking?
4. We have to prevent emergence of resistance: but of what resistance?
5. Q2-For AR, what are the critical veterinary ecosystems in terms of public health (commensals)
6. The critical animal ecosystems in terms of emergence and spreading of resistance Open and large ecosystems Digestive tractSkinOpen but small ecosystemRespiratory tractClosed and small ecosystem Mammary gland
7. Bacterial load exposed to antibiotics during a treatmentInfected LungsDigestive tract1 mgSeveral KgManurewasteFood chainSeveral tonsSoil, plant….1µgTest tube
8. Duration of exposure of bacteria exposed to antibioticsInfected LungsDigestive tractFew daysManureSludgewasteFood chainSeveral weeks/monthsSoil, plant….24hTest tube
9. Biophases & antimicrobial resistanceG.I.TProximalDistalRésistance = lack of efficacyBloodGut floraZoonotic (salmonella, campylobacter commensal ( enterococcus)1-F%F%Target biophaseBug of vet interestAB: oral routeRésistance = public health concernFood chainEnvironmental exposure
10. Biophases & antimicrobial resistanceGastrointestinal tractProximalDistalIntestinal secretion BileRésistance = lack of efficacyRésistance =public health issueBiophaseTarget pathogenBloodFood chainEnvironmentSystemic AdministrationQuinolonesMacrolidesTetracyclinesGut floraZoonotic (salmonella, campylobacter commensal ( enterococcus)
11. Q3: What are the consequences of antibiotic elimination by the GIT on the gut flora
12. Genotypic evaluation of ampicillin resistance:copy of blaTEM genes per gram of fecesA significant effect of route of administration on blaTEM fecal elimination (p<0.001).
13. Q4: what about Persistence of Antibiotics in Manure, sludge, …..
14. Elimination of antibiotics into the environmentAs much as 75% of the antibiotics administered to food producing animals are directly excreted into the environment without any benefit for the animal
15. Rate of antibiotic degradation in manure, soil, waste…AntibioticsmatrixDégradation %DaysChlortétracyclineCattle manure2484TétracyclinePig manure 5048OxytetracyclineSoil+contam manure0180OxytetracyclineSediment slurry , aeobiose5043TMPSewage sludge5022-41SulfamidesManure/sludge028Aminoglycosidesmanure030Tiamuline 5026TylosinePig manure, anaerobic 502BacitracinSandy loam & manure7730EnrofloxacinCattle mannure<156
16. Ecological consequences of the commensal flora exposure by antibioticAMR should be viewed as a global ecological problem with the animal and human commensal flora as the turntable of the system
17. Q5: what is the link between animals and man
18. The link animal/manThe commensal genetic pool is large and encompasses the potential for many different mechanisms conferring AMR
19. One world, one healthEnvironmentFood chainGreening our AB
20. Action1: Reduction/suppression of antibiotic uses for prophylaxia
21. DiseasehealthTherapyMetaphylaxis(Control)Prophylaxis(prévention)Growth promotionclinical diseaseRisk factor presentBut no infection thus no antibioticsphysiological performance.Banned Terms to describe herd or flock antibiotic useHazard present
22. Action 2Revision of dosage regimens for metaphylaxia (control)
23. DiseasehealthTherapyMetaphylaxis(Control)Prophylaxis(prévention)Growth promotionclinical diseaseRisk factor presentphysiological performance.Banned Terms to describe herd or flock antibiotic useHazard present But Dosage regimen to be revised
24. MICs estimated with different inoculmum densities, relative to that MIC at 2x105CiprofloxacinGentamicinLinezolidDaptomycinOxacillinVancomycin
25. The inoculum effect and Very Early Treatment (VET)Tested hypothesisEfficacious dosage regimen is different when the pathogen load is large, low or null Treatment should start as early as possible
26.
27. Metaphylaxis vs. curativePulmonary infectious model by inhalation (P multocida)Marbofloxaxine, Amoxicillin & et cefquinomeTreatment during the prepatent (incubation) period (24h) vs. when symptoms are present27M V. Vasseur, A A. Ferran, M Z. Lacroix, PL Toutain and A Bousquet-Mélou,
28. Effect of amoxicillin (clinical cure )metaphylaxis vs. curative28Dose mg/kg
29. Effect of cefquinome (clinical cure )metaphylaxis vs. curative29Dose mg/kg
30. 020406080100 %1 mg/kgMarbofloxacin doses40 mg/kgearlylateMarbofloxacin administrations Pourcentages of mice alive controlEffect marbofloxacin (clinical cure )metaphylaxis vs. curative
31. PCR in lung tissues samples (110h after an experimental lung infection P haemolytica)Detection of M. h DNA in lung tissues (PCR Tavqvet M.h., Vetlife, Fisher)DNA of M. haemolytica in ¾ calves of Control groupElimination of bacteria in 5/6 calves in E2 groupVarious and moderate titers in L2 and L10 groupEarly +12hLate +24-36h 2mg/kg2mg/kg10mg/kg
32. An early/low dose treatment is better for both bacteriological cure, clinical cure and emergence of resistance than a late/high dose for three antibiotics: marbofloxacin, amoxicillin & cefquinome
33. In the target species, when to start a treatment?
34. Fever Alert: fever tags, intraruminal transponders, eye temperature, locomotor activity…., .
35. Action 3: The rudent use of currently used antibiotic is not enough and we need new « green » antibiotics i.e. antibiotics without impact on the gut flora
36. We need new antibiotic eco-friendly with less implications for human healthThese new antibiotics should be developed in respect for public health ecologic concerns. They should not influence the gut flora so to avoid the contamination of the environment with resistant bacteria. This implies to develop antibiotics having a good selectivity for for parenteral and oral use.
37. Selectivity of antimicrobial drugs in veterinary medicine
38. - 38Innovation: PK selectivity of antibioticsenvironmentProximalDistalBloodGut floraZoonotic (salmonella, campylobacter commensal ( enterococcus)BiophaseRésistance = public health concernFood chainAnimal healthEffluxQuinolones, macrolidesIMKidneyOral
39. 39My view of an ideal antibiotic for vet medicineHigh plasma clearanceRapidly metabolized (in vivo, environment) to inactive metabolite(s)High renal clearanceElimination by non-GIT route (not bile or enterocyte efflux)volume of distribution not too highPathogens are extracellular; half-life rather short; not too short to compensate a relatively high clearanceHigh bioavailability by oral routeTo avoid to expose distal GIT to active ABLow binding to plasma protein Only free antibiotic is active; to reduce the possible nominal dosage regimen and environmental loadHigh binding to cellulosisTo inactivate AB in large GITLikely a Low potencyTo avoid the most lipophilic AB that are excreted in the GITHigh PK selectivity (biophase)To distribute only to target biophase
40. Renal clearance of different quinolones(all quinolones are not equals)Drugs% of total clearanceOfloxacin70Levofloxacin65Ciprofloxacin50Sparfloxacin13Grepafloxacin10Trovafloxacin5-10Hooper DC CID 2000;30:243-254
41. Is there a successful antibiotic development complying with Eco-Evo concept?
42. New Eco-Evo drugs and strategies should be considered in vet medicine
43. Telavancin (Telavancin is a semi-synthetic derivative of vancomycin) is a new agent (FDA approcval 2009) for the treatment of Gram-positiveIt is excreted primarily by renal elimination, with 60–70% of the dose excreted unchanged in the urine and <1% in the faeces.No faecal concentration of telavancin was found, which probably explains the lack of an effect on the intestinal microfloraBased on the microbiological data on the intestinal microflora as well as the results of the bioassays for antibiotic concentrations in faecal samples, telavancin has a favourable ecological profile.
44. Bottleneck for discovery of new AB in veterinary medicine1980-1990Human Health target amenable to Animal Health useHH: 2000Remaining HH projects targeting resistant pathogen with unique marketAH: PresentEco-evo drugs are neededAH will be on their own to develop green ATB
45. Discovery of new veterinary antibiotics need appropriate incentives
46. Generic marketing
47. Action 4:Degradation or inactivation of AB and gene of resistance in the environment
48. Hazard associated to the release of antibiotic in the environment
49. ConclusionsAppropriate use of antibiotics should not only include knowledge of the pathogen and its susceptibility, but also the spectrum and pharmacokinetic properties of the respective antimicrobial drug.