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Are we over-rating the risk of low- dose drug exposure on the selection of resistant strains? Pierre-Louis Toutain National veterinary School Toulouse.

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Presentation on theme: "Are we over-rating the risk of low- dose drug exposure on the selection of resistant strains? Pierre-Louis Toutain National veterinary School Toulouse."— Presentation transcript:

1 Are we over-rating the risk of low- dose drug exposure on the selection of resistant strains? Pierre-Louis Toutain National veterinary School Toulouse France

2 The question: Are we over-rating the risk of low-dose drug exposure on the selection of resistant strains But of what resistance are we speaking?

3 Prevent emergence of resistance: but of what resistance?

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

5 The question: Are we over-rating the risk of low-dose drug exposure on the selection of resistant strains? The public health issues being critical, we have to investigate both: – The case of target pathogens – The case of non-target pathogens Zoonotic Commensal flora And also acknowledge possible conflict of interest

6 1-The case of target pathogens

7 7 Selective pressure for antibiotic concentration lower than the MIC CMI Time Concentration Traditional hypothesis on emergence of AMR

8 Current view for the emergence and selection of resistance for the target pathogen: The selective window

9 No antibiotics Current view for the emergence and selection of resistance With antibiotics Mutation rate10-8 eradication susceptible Mutants population résistant Wild pop Mutant pop

10 Current view for the emergence and selection of resistance: with antibiotic 10 Eradication of all bacteria Low inoculum size No mutants Large inoculum with AB few mutants Wild population Usual MIC Mutant MIC=MPC Large inoculum MIC<[AB]MPC

11 Growth R Growth S Selective Window (SW) S R Time in SW Antibiotic concentration Selection of R Current view for the emergence and selection of resistance: The selective window MIC Wild population MIC mutant=MPC

12 MICs estimated with different inoculmum densities, relative to that MIC at 2x10 5 Ciprofloxacin Gentamicin Linezolid Daptomycin Oxacillin Vancomycin

13 13 MIC & MPC for the main veterinary quinolones for E. coli & S. aureus

14 14

15 Comparative MIC and MPC values for 285 M. haemolytica strains collected from cattle MIC 50 MIC 90 MPC 50 MPC 90 MPC/MIC Ceftiofur Enrofloxacine Florfenicol22484 Tilmicosine2816>328 Tulathromycine

16 Consequences of a selective window associated to an inoculum effect for a rational treatment for veterinary medicine

17 When to start a treatment?

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

19 The inoculum effect and Very Early Treatment (VET) Tested hypothesis – Efficacious dosage regimen is different when the pathogen load is large, low or null – Treatment should start as early as possible

20

21 Inoculation of Pasteurella multocida 1500 CFU/lung Model of pulmonary infection Materials and methods A strain of Pasteurella multocida isolated from the trachea of a pig with clinical symptoms of a bacterial lung infection

22 Inoculation of Pasteurella multocida 1500 CFU/lung Model of pulmonary infection Materials and methods Progression of infection Time after infection (h) Bacteria counts per lung (CFU/lung) control mice were used to assess the natural growth of Pasteurella multocida in the lungs.

23 Materials and methods Progression of infection early (10h) Administration Late (32h) Administration Inoculation of Pasteurella multocida 1500 CFU/lung Time (h) Bacteria counts per lung (CFU/lung) no clinical signs of infection anorexia lethargy dehydration

24 Materials and methods 10 hours after the infection (n=14) 32 hours after the infection (n=14) A single administration of marbofloxacin Two doses tested for each group 1 mg/kg and 40 mg/kg Inoculation of Pasteurella multocida 1500 CFU/lung

25 % 1 mg/kg Marbofloxacin doses 40 mg/kg early late Marbofloxacin administrations Pourcentages of mice alive contro l 1-Clinical outcome (survival) A low early dose better than a late high dose

26 2-Bacterial eradication Early low dose= late high dose % % of mice with bacterial eradication 1 mg/kg Marbofloxacin doses 40 mg/kg Early Late Marbofloxacin administrations control

27 3-Selection of resistant target bacteria An early 1 mg/kg marbofloxacin dose has no more impact on resistance than a high late treatment while this low dose is selecting resistance when administered later % +38h observation 16 hours after marbofloxacin administration = 48 hours after the infection = like early administration 1 mg/kg Marbofloxacin doses 40 mg/kg % of mice with resistant bacteria control Early late Marbofloxacin administrations +38h 1 mg/kg 40 mg/kg

28 Metaphylaxis vs. curative Pulmonary infectious model by inhalation (P multocida) Amoxicillin & et cefquinome Treatment during the prepatent (incubation) period (24h) vs. when symptoms are present 28 M V. Vasseur, A A. Ferran, M Z. Lacroix, PL Toutain and A Bousquet-Mélou,

29 Effect of amoxicillin (clinical cure ) metaphylaxis vs. curative 29 Dose mg/kg

30 Effect of amoxicillin (bacteriological cure) metaphylaxis vs. curative 30 Dose mg/kg

31 Effect of cefquinome (clinical cure ) metaphylaxis vs. curative 31 Dose mg/kg

32 Effect of cefquinome (bacteriological cure) metaphylaxis vs. curative 32 Dose mg/kg

33 An early/low dose treatment is better for bacteriological cure than a late/high dose for three antibiotics: marbofloxacin, amoxicillin & cefquinome

34 Q:Are we over-rating the risk of low-dose drug exposure on the selection of resistant strains? A: Apparently not for the target pathogen when an early treatment is initiated i.e when antibiotic only a low inoculum is exposed to an antibiotic But what about other non-targeted bacteria?

35 The question: Are we over-rating the risk of low-dose drug exposure on the selection of resistant strains? The public health issues being critical, we have to investigate both: – The case of target pathogens – The case of non-target pathogens Zoonotics Commensal flora And acknowledge possible conflict of interest

36 Example of conflict of interest the antimicrobial treatments should not only aim at curing the diseased animals but also at limiting the resistance on non target flora. Optimal dosing for treatment optimal to prevent resistance!

37 For AR, what are the critical veterinary ecosystems in terms of public health (commensals)

38 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

39 Bacterial load exposed to antibiotics during a treatment Infected Lungs Digestive tract 1 mgSeveral Kg Manure waste Food chain Several tons Soil, plant…. 1µg Test tube

40 Duration of exposure of bacteria exposed to antibiotics Infected Lungs Digestive tract Few days Manure Sludge waste Food chain Several weeks/months Soil, plant…. 24h Test tube

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

42 Bioavailability of oral tetracyclins Chlortetracycline: – Chickens:1% – Pigs Fasted or fed: 18 to 19% – Turkeys:6% Doxycycline: – Chickens:41.3%. – Pigs :23% Oxytetracycline: – Pigs:4.8% – Piglets, weaned, 10 weeks of age: by drench: 9%;in medicated feed for 3 days: 3.7%. – Turkeys: Fasted: 47.6% ;. Fed: 9.4% Tetracycline: – Pigs fasted:23%.

43 Biophases & antibiorésistance Gastrointestinal tract Proximal Distal Intestinal secretion Bile Résistance = lack of efficacy Résistance =public health issue Biophase Target pathogen Blood Food chain Environment Systemic Administration Quinolones Macrolides Tétracyclines Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus)

44 44 Fluoroquinolone impact on E. coli in pig intestinal flora (From P. sanders, Anses, Fougères) 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 (~ ufc/g 1 d). E. coli R followed to a slow decrease back to initial level after 12 days IV IM 3 days

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

46 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

47 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.

48 Ecological consequences of the commensal flora exposure by antibiotic

49 Commensal flora Zoonotic pathogens Gene of resistance one world, one health Vet AB Resistance is contagious! It will continue to spread even after infection has been cleared Transmissible genetic elements allow antibiotic resistance genes to spread both to commensal bacteria and to strains that cause disease.

50 One world, one health Environment Food chain AMR should be viewed as a global ecological problem with commensal flora as the turntable of the system Greening our AB

51 Selectivity of antimicrobial drugs in veterinary medicine

52 - 52 Innovation: PK selectivity of antibiotics environment Proximal Distal Blood Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus) Biophase Résistance = public health concern Food chain 1-F=90% F=10% Animal health Efflux Quinolones, macrolides IM Kidney Oral

53 Currently no veterinary antibiotic is selective of target pathogens and our hypothesis was that a low dose would be more selective than a high, regular, dose

54 In vitro assessment of the selectivity of antibiotics on the target pathogen vs. commensal flora: eradication of a low vs. high inoculum size of P multocida

55 Selectivity of amoxicillin & cefquinome Using killing curves selectivity was tested using E.coli, as a commensal bacterium in condition for which the two tested antibiotics were able to eradicate a low or a large inoculum of P.multocida,

56 Development of a selectivity index (SI)

57 Selectivity of amoxicillin to eradicate a low a or a high inoculum size of P. multocida SI=51 SI=5.54 Low: 10 5 CFU/mL High:10 7 CFU/mL P. Multocida (10 5 or 10 7 CFU/ml) E coli (10 7 CFU/mL)

58 Selectivity of cefquinome to eradicate a low a or a high inoculum size of P. multocida SI=2.9 SI=0.66 Low:10 5 CFU/mL High:10 7 CFU/mL P. Multocida (10 5 or 10 7 CFU/ml) E coli (10 7 CFU/mL)

59 I there a selective window for the commensal flora

60 All macrolides are not equals The normal flora is disturbed more or less according to the pharmacokinetic profiles of the respective macrolides. 85% of patients treated with azithromycin were colonized by macrolide-resistant organisms 6 weeks after therapy, compared to 17% treated with clarithromycin

61 Clarithromycin Azithromycin Selective Window MAC MIC Concentration ( ug/ml ) Weeks Longer half-life antibiotics may create a greater window of opportunity for the development of resistance Guggenbichler JP, Kastner H Infect Med 14 Suppl C: (1997) Effect of Elimination Kinetics on Bacterial Resistance

62 Selective window can be longer and delayed in the GIT Plasma/Lung GIT/commensal

63 A long half-life is desirable for convenience in vet medicine: two possible options Macrolides/FQ Beta-lactams/sulfonamides

64 Longer half-life antibiotics may create a greater window of opportunity for the development of resistance

65 One size does NOT fit all! We need to broaden the concept of selection of resistance when devising optimal dosing strategies – both for guidelines for future and existing antibiotics Conclusions

66 When to finish a treatment? ASAP Should be determined in clinics Should be when clinical cure is actually achieved Should not be a hidden prophylactic treatment for a possible next infectious episode

67 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) Conclusion Early administrations were more favourable than late administrations

68 Treatment exerts selection on innocent bacteria Most of the harm done by use of a drug may be on species OTHER than the target of treatment Most of the exposure of a given species to a given drug may be due to treatment of OTHER infections Normal flora: Consequences

69 One world, one health Environment Food chain Vet AB Hazard AMR should be viewed as a global ecological problem with commensal flora as the turntable of the system

70 New Eco-Evo drugs and strategies should be considered in vet medicine

71

72 - 72 Innovation: PK selectivity of antibiotics environment G.I.T Proximal Distal Blood Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus) Biophase Résistance = public health concern Food chain 90% 0% Animal health Trapping or destruction of the antibiotic Efflux Quinolones, macrolides IM Kidney

73 73 My view of an ideal antibiotic for vet medicine High 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 high Pathogens are extracellular; half-life rather short; not too short to compensate a relatively high clearance High bioavailability by oral route To avoid to expose distal GIT to active AB Low binding to plasma proteinOnly free antibiotic is active; to reduce the possible nominal dosage regimen and environmental load High binding to cellulosisTo inactivate AB in large GIT High potencyTo be able to select a low dose High PK selectivity (biophase)To distribute only to target biophase

74 Innovation pour une voie systémique Tractus digestif Proximal Distal Biophase Pathogène visé sang Chaîne alimentaire Environment Administration Elimination par efflux ou biliaire=0% flore Zoonotiques (salmonella, campylobacter ) commensaux ( enterococcus) Elimination rénale=100%

75 Renal clearance of different quinolones Drugs% of total clearance Ofloxacin70 Levofloxacin65 Ciprofloxacin50 Sparfloxacin13 Grepafloxacin10 Trovafloxacin5-10 Hooper DC CID 2000;30:

76 Conclusions Appropriate 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.

77 S R Sensitive population Resistant population Traditional pharmacokinetic/ pharmacodynamic models

78 SR Sensitive population Resistant population Incorporating the immune response S I Sensitive population Immune response

79 Possible pathogen dynamics Unregulated bacterial dynamics: Commensal bacteria that uses body as a habitat Regulated bacterial dynamics: Bacteria and the immune response settles an equilibrium


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