How to establish a dosage regimen for a sustainable use of antibiotics in veterinary medicine

1. How to establish a dosage regimen for a sustainable use of antibiotics in veterinary medicine P.L. Toutain National Veterinary School ; Toulouse, France

2. The workshop • A general presentation by PLT • Three questions to be discussed in subgroups animated by team leaders: • Peter Lees: • the needs of innovation • Ted Whittem: • PKPD, pop kinetics & MCS in antibiotic development • Marilyn Martinez: • regulatory hurdles to antibiotic development

3. "The design of appropriate dosage regimens may be the single most important contribution of clinical pharmacology to the resistance problem" Schentag et al. Annals of Pharmacotherapy, 30: 1029-1031

4. EMEA "Points to consider" July 2000 • Inadequate dosing of antibiotics is probably an important reason for misuse and subsequent risk of resistance • A recommendation on proper dosing regimens for different infections would be an important part of comprehensive strategy • The possibility to produce such a dose recommendation based on pharmacokinetic and pharmacodynamic considerations will be further investigated in one of the CPMP working parties...

5. Medical consequences of AMR

6. The antibiotic ecosystem: one world, one health Treatment & prophylaxis Veterinary medicine Human medicine Community Animal feed additives Hospital Agriculture Plant protection Environment Industry

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

8. The three (not 2) endpoints to consider in veterinary medicine • Efficacy in animal • No promotion of resistance in animal (target pathogen) • No promotion of resistance in man

9. But of what resistance are we speaking?

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

11. What are the animal’s ecosystems potentially able to raise public health concerns in terms of antimicrobial resistance?

12. The critical animal ecosystem's 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

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

14. 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

15. 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% .

16. 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

17. 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).

18. 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

19. 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

20. 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.

21. The three (not 2) endpoints to consider in veterinary medicine • Efficacy in animal • No promotion of resistance in animal (target pathogen) • No promotion of resistance in man???????

22. 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

23. Question 1:Peter Lees • Do we need new antibiotics to fit our expectation in terms of public health or rather to encourage the use of old antibiotics and the promotion of generics

24. The right dosage regimen

25. What are the elements of a dosage regimen • The dose & The dosing interval • The treatment duration • When to start • When to finish

26. How to find and to confirm a dose (dosage regimen) • Dose titration • Animal infectious model • PK/PD

27. Dose titration Dose Response clinical Black box PK/PD PK PD Body pathogen Dose Response An exposure variable scaled by MIC

28. The dose-titration

29. Selected dose Only the parallel design for antibiotics: Statistical model Response NS • The null hypothesis • placebo = D1 = D2 = D3 • The statistical linear model • Yj = wj + j • Conclusion • D3 = D2 > D1 > Placebo * * Dose 1 2 3 Placebo

30. The parallel design • Advantages • easy to execute • total study lasts over one period • approved by Authorities • Disadvantages • "local information" (response at a given dose does not provide any information about another dose) • no information about the distribution of the individual patient's dose response.

31. The dose-titration: experimental infectious model • Severe • not representative of the real world • Prophylaxis vs. metaphylaxis vs. curative • power of the design generally low for large species • influence of the endpoints

32. Antibiotic dosage regimen based on PK-PD and population PK concepts

33. Measuring exposure and response in PK/PD trial

34. It has been developed surrogates indices (predictors) of antibiotic efficacy taking into account MIC (PD) and exposure antibiotic metrics (PK) • Practically, 3 indices cover all situations: • AUC/MIC • Time>MIC • Cmax/MIC

35. PK/PD predictors of efficacy • Cmax/MIC : aminoglycosides • AUC/MIC : quinolones, tetracyclines, azithromycins, • T>MIC : penicillins, cephalosporins, macrolides, Cmax Cmax/MIC AUC MIC AUIC = Concentrations MIC Time 24h T>CMI

36. Appropriate PK/PD indices for the different antibiotics according to their bactericidal properties

37. What is the appropriate magnitude of PK/PD indices to guarantee efficacy i.e. how establish PK/PD breakpoint values: • To optimize efficacy • To minimize resistance towards the target pathogen

38. Breakpoint values in veterinary medicine • Starting values • From human medicine • From in vitro/ex vivo (tissue cage) experiments • In vivo experimental determination

39. First step of the PKPD approach • To establish experimentaly the numerical value of the PKPD surrogate that garantee a Probability of cure (POC) or any other relevant endpoint (bacteriokogical cure…) • E. g what is the numerical value of the AUC/MIC for a new quinolone to obtain more than 90% of clinical success in pigs treated metaphylactically for a lung condition?

40. A working example

41. Your development project • You are developing a new antibiotic in pigs (e.g. a quinolone) to treat respiratory conditions and you wish to use this drug in for metaphylaxis (control) • collective treatment & oral route

42. Questions for the developers • What is the optimal dosage regimen for this new quinolone for metaphylaxis ings • To answer this question, you have, first, to define what is an “optimal dosage regimen”

43. Step 1: Define what is an optimal dosage regimen

44. What is an optimal dosage regimen ? • Efficacy : • it is expected to cure at least 90% of pigs • “Probability of cure” = POC = 0.90 • We know that the appropriate PK/PD index for that drug (quinolone) is AUC/MIC • We have only to determine (or to assume) its optimal breakpoint value for this new quinolone

45. What is an optimal dosage regimen ? • Emergence of resistance • The dosage regimen should avoid the mutant selection window (MSW) in at least 90% of pigs

46. The selection window hypothesis Mutant prevention concentration (MPC) (to inhibit growth of the least susceptible, single step mutant) MIC Selective concentration (SC) to block wild-type bacteria Mutant Selection window Plasma concentrations All bacteria inhibited Growth of only the most resistant subpopulation Growth of all bacteria

47. Two endpoints for an optimal dosing regimen • Probability of “cure” = POC = 0.90 • Time out of the MSW should be higher than 12h (50% of the dosing interval) in 90% of pigs

48. Step 2: Determination of the AUC/MIC clinical breakpoint value for the new quinolone in pigs

49. Determination of the PK/PD clinical breakpoint value • Dose titration in field trials : • 4 groups of 10 animals • Blood samples were obtained • MIC of the pathogen is known • Possible to establish the relationship between AUC/MIC and the clinical success

50. AUC/MIC vs. POC: Metaphylaxis Data points were derived by forming ranges with 6 groups of 5 individual AUC/MICs and calculating mean probability of cure POC 10 Control pigs (no drug) AUC/MIC