Prophylaxis & Metaphylaxis in Veterinary Antimicrobial Therapy

1. ECOLE NATIONALE VETERINAIRE T O U L O U S E Prophylaxis & Metaphylaxis in Veterinary Antimicrobial Therapy Alain Bousquet-Mélou National Veterinary School, Toulouse, France Tel Aviv May 2010

2. Antimicrobial resistance : from animals to humans Treatment & prophylaxis Veterinary medicine Human medicine Community Animal feed additives Hospital Agriculture Plant protection Environment Industry

3. Antimicrobial resistance : from animals to humans • Antimicrobial resistance is an ineluctable adverse effect of antibiotics use • The association between the consumption of an antimicrobial agent and the occurrence of antimicrobial resistance is well established • The prudent use of antibiotics requires to reduce the overall consumption

4. Prudent use in relation with antimicrobial resistance • To target the major uses contributing to antibiotics consumption • Massive and collective administrations in food animals • Oral routes Growth factor prophylaxis Metaphylaxis Therapeutics GROWTH (Ban in EU) PREVENTION CONTROL THERAPY

5. Are prophylaxis and metaphylaxis the same type of use ? Prophylaxis • when antibiotics are administered to a herd or flock of animals at risk of a disease outbreak • A measure taken to maintain health and prevent disease • A measure to protect against infection

6. Are prophylaxis and metaphylaxis the same type of use ? Metaphylaxis • when antimicrobials are administered to clinically healthy animals belonging to the same flock or pen as animals with clinical signs • infections are treated before their clinical appearance • “… a form of prophylaxis called metaphylaxis …” • “… the use of the term metaphylaxis is controversial …” • refers to situations where antimicrobials are used for both therapeutic and prophylactic purposes • refers to a particular form of prophylaxis in the presence of the pathogen with a high likelihood of disease

7. Are prophylaxis and metaphylaxis the same type of use ? • Phylaxis = PROTECTION • From phylax = guard, watchman Arctophylaxis (Boote) the « bear-driver » (Ursus Minor, Ursus Major) • In relation with the start of the aggression • Pro - : before the aggression begins • Meta - : after the aggression begins

8. The time course of the bacterial disease Start of the infectious disease Health Disease No symptoms Symptoms • Bacterial contamination / Host defenses • Growth of the initial inoculum

9. The time course of the bacterial disease Start of the infectious disease Health Disease No symptoms Symptoms PROPHYLAXIS PREVENTIVE

10. The time course of the bacterial disease Start of the infectious disease Health Disease No symptoms Symptoms METAPHYLAXIS (few) EARLY conventional (few ?) CURATIVE TREATMENT PREVENTIVE

11. The time course of the bacterial disease • Metaphylaxis • “Metaphylaxis is treatment given to animals experiencing any level of (viral or) bacterial disease before overt disease occurs” (Young, 1995) • Metaphylaxis is an early curative treatment launched after the start of the disease (pathogen contamination, host defenses alteration) but before clinical expression with the goal of the bacteriological cure of the infected animals, which subsequently warrants the final protection against infection outbreaks • Metaphylaxis should be compared to “conventional” (later) curative treatments of sick animals, not to prophylaxis

12. Early versus later (conventional) treatments • Bacterial loadat the infection site and pathophysiological status of the host are at the origin of differences in the responses to the drugs, at both pharmacodynamic and pharmacokinetic levels • Pharmacodynamics : bug-drug interactions • Inoculum size impacts both antimicrobial activity (bacteriological cure) and resistant bacteria selection

13. Early versus later (conventional) treatments • Clinical and microbiological cure ? • In vitro evidences of the effect of inoculum size on antimicrobial activity • In vivo evidences • Resistance selection/prevention at the infection site ? • Resistance selection/prevention in the gut flora ?

14. Inoculum size and antimicrobial activity • Inoculum effect on in vitro bacterial susceptibility assessment • Description in the literature since more than 40 years • Higher MICs when using high density bacterial inocula compared to the standard 105 CFU inocula (beta-lactams, fluoroquinolones …) • “Antibiotics with inoculum effects … administered empirically in clinical practice at a higher dose than the microbiological and pharmacokinetic data would indicate” Soriano et al. JAC 1990 • Inoculum effect on in vitro antibacterial activity • Higher antibacterial activity against low versus high bacterial inoculum • Mizunaga et al. JAC 2005 ; Ferran et al. AAC 2007

15. Low Interm. High 100% 80% 60% Bactericidal effect (%) 40% 20% 0% 0.001 0.01 0.1 Concentrations (µg/mL) Inoculum size and antimicrobial activity • Ciprofloxacin and imipenem against Staphylococcus aureus (Mizunaga et al. JAC 2005) • Marbofloxacin against Escherichia coli (Ferran et al. unpublished) 105 109

16. Early versus later (conventional) treatments • Clinical and microbiological cure ? • In vitro evidences of the effect of inoculum size on antimicrobial activity • In vivo evidences • Resistance selection/prevention at the infection site ? • Resistance selection/prevention in the gut flora ?

17. Inoculum size and clinical or microbiological cure • Fluoroquinolones and beta-lactams against Staphylococcus aureus and Pseudomonas aeruginosa (Mizunaga et al. JAC 2005) • Intraperitoneal infection in mice • Doses associated with survival Low High Low High

18. Inoculum size and clinical or microbiological cure • Fluoroquinolone against Pseudomonas aeruginosa (Jumbe et al. JCI 2003) • Thigh infection in mice • Doses associated with log10 CFU reduction Low High 28 mg/kg 180 mg/kg

19. 16 mg/kg 64 mg/kg 100 mg/kg 10 Early treatment lung infection 105 CFU – 4h after Later treatment lung infection 109 CFU – 24h after 8 6 Log10 CFU / Lung 4 2 Fractionated Single Fractionated Single Inoculum size and clinical or microbiological cure • Marbofloxacin against klebsiella pneumoniae (Kesteman et al. AAC 2009)

20. Early versus later (conventional) treatments • Clinical and microbiological cure ? • In vitro evidences of the effect of inoculum size on antimicrobial activity • In vivo evidences • Resistance selection/prevention at the infection site ? • Resistance selection/prevention in the gut flora ?

21. In vitro evidence: • For the same exposure, the likelihood of resistant mutant selection is lower with a small inoculum: 105 versus 109CFU/mL • Marbofloxacin against Escherichia coli: Ferran et al. AAC 2007 Inoculum size and resistant mutant selection • In vivo evidences: • Thigh infection in mice : marbofloxacin against Escherichia coli (Ferran et al. AAC 2009) • Lung infection in rats : marbofloxacin against Klebsiella pneumoniae (Kesteman et al. AAC 2009)

22. 16 mg/kg 64 mg/kg 100 mg/kg Early treatment 105 CFU – 4h after Later treatment 109 CFU – 24h after 70% 55% 50% 27% 0% 0% 0% 0% Fractionated Single Fractionated Single Percentages of rats with resistant*K. pneumoniae in their lungs 96h after the start of marbofloxacin treatment * Growth in the presence of half MPC 100% 80% 60% 40% 20% 0%

23. Early versus later (conventional) treatments • Clinical and microbiological cure ? • In vitro evidences of the effect of inoculum size on antimicrobial activity • In vivo evidences • Resistance selection/prevention at the infection site ? • The same dose provides much better results for items 1 & 2 when given early before clinical signs • To reach “optimal” outcomes for items 1 and 2, (much more ?) lower doses are needed when given early to animals without clinical signs compared to sick animals • Reinforced by the work presented by A. Ferran

24. Early versus later (conventional) treatments • Clinical and microbiological cure ? • In vitro evidences of the effect of inoculum size on antimicrobial activity • In vivo evidences • Resistance selection/prevention at the infection site ? • Resistance selection/prevention in the gut flora ?

25. Proximal AB: Oral route • Resistant zoonotic pathogens (salmonella, campylobacter spp) • Commensal flora (resistance genes) Food chain Blood Contact AB: Parenteral route Environment genes flux Infectious site Pathogens of veterinary interest HUMAN ANIMAL HEALTH PUBLIC HEALTH Critical bacterial flora for antimicrobial resistance Digestive tract Distal Resistance Therapeutic failures

26. Proximal AB: Oral route • Resistant zoonotic pathogens (salmonella, campylobacter spp) • Commensal flora (resistance genes) Blood AB: Parenteral route Infectious site Pathogens of veterinary interest ANIMAL HEALTH Critical bacterial flora for antimicrobial resistance Digestive tract Distal Effects of early vs later treatments ? • Dose levels ? • Treatment duration ?

27. Early versus later (conventional) treatments • Bacterial load at the infectious site and pathophysiological status of the host are at the origin of differences in the responses to the drugs, at both pharmacodynamics and pharmacokinetics levels • Pharmacodynamics : bug-drug interactions • Inoculum size impacts both antimicrobial activity (bacteriological cure) and resistant bacteria selection • Pharmacokinetics : drug exposure • The disease impacts the relation between the dose and systemic exposure and is a source of variability of exposure between animals

28. 10 1 0.1 0.01 0.001 0.0001 Marbofloxacin (µg/mL) High inoculum Low inoculum 0 6 12 18 24 Time (h) Effects of infection on dose-exposure relation • Healthy versus sick animals • Review by Martinez & Modric JVPT 2010 • Higher inter-individual variability in sick animals, increasing the likelihood of occurrence of under-exposure (Peyrou et al. JVPT 2004) • Low versus high inoculum • Ferran et al. AAC 2009 • E. coli thigh infection in mice

29. To conclude • Favorables features of early treatments at the individual level • Higher antimicrobial activity and prevention of resistance : different doses • Probably more predictable dose-exposure relationships • Currently all regulatory PK, including for antibiotics, are obtained in healthy animals, which is irrelevant for severe infections but probably not for early treatments • Important questions to address when moving from early treatment to metaphylaxis • Heterogeneity of the treated group : effect of inter-individual variability ? • Bacterial load : what is the risk to under-expose high inocula ? • Collective (oral) treatments : influence of inter-individual variability of drug intake • Finally, whether metaphylactic setting (intervention at the group level) should really benefit to the potential advantages of early curative treatment (at the individual level) remains to be investigated, ideally in controlled clinical trials with special attention for dose levels and duration of treatments

30. Last remark In term of risk communication it is probably better to promote the concept of early curative treatment in place of the misleading word of metaphylaxis

32. susceptible population susceptible population resistant mutants population resistant mutants population Inoculum size and resistant mutant selection Low bacterial load (size < mutation rate) High bacterial load (size >> mutation rate) The same dosage regimen Resistant mutants prevention Resistant mutants selection