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Antibiotic dosage regimen based on PK-PD concepts and the possible minimization of resistance

Antibiotic dosage regimen based on PK-PD concepts and the possible minimization of resistance. ECOLE NATIONALE VETERINAIRE T O U L O U S E. PL Toutain UMR 181 Physiopathologie et Toxicologie Expérimentales INRA/ENVT. 24th World Buiatric Congress. France. 15. October 2006.

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Antibiotic dosage regimen based on PK-PD concepts and the possible minimization of resistance

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  1. Antibiotic dosage regimen based on PK-PD concepts and the possible minimization of resistance ECOLE NATIONALE VETERINAIRE T O U L O U S E PL Toutain UMR 181 Physiopathologie et Toxicologie Expérimentales INRA/ENVT 24th World Buiatric Congress. France. 15. October 2006

  2. Why to optimize dosage regimen for antibiotics • To optimize efficacy • Reduce the emergence and selection of resistance

  3. Dosage regimen and antibioresistance • The design of appropriate dosage regimens may be the single most important contribution of clinical pharmacology to the resistance problem Schentag, Annal. Pharm. 1996 • Little attention has been focused on delineating the correct drug dose to suppress the amplification of less susceptible mutant bacterial sub-populations Drusano et al (2005)

  4. Selecting a dosage regimen for a particular animal or group of animals Individual animal (or herd) issues Probability of “cure” without side effects Public health issues Probability for avoiding enriching a resistant bacterial subpopulation The prescribing veterinarian is the steward of a valuable resource and must consider both individual health issues as well as public health ones Possible conflict of interest between the two goals

  5. Why to optimize dosage regimen for antibiotics • To optimize efficacy • Reduce the emergence and selection of resistance • Target pathogen: efficacy issue • Non target pathogen: human safety issue • Zoonotic bacteria (food borne pathogens) • Commensal flora (resistance gene reservoir)

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

  7. Biophases & antibiorésistance G.I.T Proximal Distal • Gut flora • Zoonotic (salmonella, campylobacter • commensal ( enterococcus) Intestinal secretion Bile Quinolones Macrolides Tétracyclines Food chain Environmental exposure Systemic administration Man Blood Biophase Bug of vet interest Résistance = public health concern Résistance = lack of efficacy

  8. Public Health Concerns :Human pathogenic bacteria spreading from animal reservoirs Current main concerns: Resistance emerging to commonly used empiric therapies for acute GI tract infections • Salmonella • Fluoroquinolone-resistance • 3rd gen. Cephalosporin-resistance • Campylobacter • Fluoroquinolone-resistance • Macrolide-resistance

  9. Emergence of quinolone resistance in Salmonella typhimurium DT104 in UK following licensing of fluoroquinolones for use in food animals Stöhr & Wegener, Drug resistance Updates, 2000, 3:207-209

  10. Dosage regimen and resistance:Epidemiological evidences

  11. Dosage regimen and prevention of resistance • Many factors (e.g.; broad vs. narrow spectrum…) can contribute to the development of bacteria resistance • the most important risk factor is repeated exposure to inappropriate antibiotic concentrations (exposure) • dosage regimen should minimize the likelihood of exposing pathogens to sublethal drug levels

  12. Drug factors influencing resistance • Regimen • Route of administration, dose, interval of administration, duration of treatment

  13. Effect on Penicillin resistance in pneumococcus isolates (n=465) of duration of b-lactam use, 6 months before swab collection Nb of days of b-lactam use 1-7 8-14 >14 Odd ratios 0.86 1.5 2.5 95% CI 0.37- 2.02 0.73- 3.06 1.3 - 4.82 Nasrin et al. BMJ, 2002

  14. Effect of 14-day antibiotic dosing regimen on sensitivity (MIC, µg/mL) to apramycin by E. coli recovered AB dosing day post challenge regimen 3 6 10 13 17 31 Control (no AB) 4.3 3.9 3.5 3.1 2.3 2.6 Label 5.9 41.1 56 49 50 6.6 Rotation Similar AB 3.5 4.2 200 182 141 7.6 Rotation Dissimilar AB 2.6 38.8 44 14 14.0 3.8 Gradient 50, 100, 150 3.5 3.5 3.5 68.5 109.9 2.8 Pulse (3 days) 5.2 4.3 3.6 4.0 7.0 3.7 Mathew, 2003

  15. How to determine a dosage regimen that is both efficacious and that minimizes the risk to promote resistance

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

  17. The dose-titration

  18. 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

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

  20. Bacteriological vs clinical success:the pollyanna phenomenon

  21. The Pollyanna phenomenon If efficacy is measured by symptomatic response, drugs with excellent antibacterial activity will appear less efficacious than they really are and drugs with poor antibacterial activity will appear more efficacious than they really are. • The clinical efficacy does not always indicate bacteriological efficacy making it difficult to distinguish between antimicrobials on clinical outcomes only

  22. 100% 100% 89% 80% 74% 60% 40% 27% 20% 0% The Pollyanna effect Discrepency between clinical and bacteriological results Otitis media Antibiotic effect Efficacy (%) Clinical success Placebo effect Bacteriological cure Merchant et al. Pediatrics 1992

  23. The Pollyanna effect Ceftiofur – oral 90 Mortality Bacterial 60 shedding Response % 30 0 0 0.5 2 16 64 Dose (mg/kg) Yancey et al. 1990 Am. J. Vet.Res.

  24. EFFICACY OF ORAL PRADOFLOXACIN AND AMOXYCILLIN/CLAVULANATE IN CANINE CYSTITIS AND PROSTATITIS Data from Bayer Animal Health (VERAFLOX SYMPOSIUM)

  25. The Pollyanna phenomenon • The clinical efficacy does not always indicate bacteriological efficacy and a good clinical efficacy is not enough to validate an appropriate dosage regimen

  26. The role of antibiotics is to eradicate the causative organisms from the site of infection Jacobs. Istambul, 2001

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

  28. The main goal of a PK/PD trial in veterinary pharmacology • To be an alternative to dose-titration studies to discover an optimal dosage regimen

  29. What is PK/PD?

  30. Dose titration Dose Response clinical Black box PK/PD PK PD Body pathogen Dose Response Plasma concentration

  31. PK/PD: in vitro In vitro Medium concentration Response MIC Test tube MIC is very variable from pathogen to pathogen and should be acknowledged The idea at the back of the PK/PD indices were to develop surrogates able to predict clinical success by scaling a PK variable by the MIC

  32. Dose titration Dose Response clinical Black box PK/PD PK PD Body pathogen Dose Response A plasma concentration variable scaled by MIC

  33. Dose titration vs. PK/PD : the explicative variable A PK/PD SURROGATE Effect Effect effect AUC/MIC, Dose AUC EXPOSURE (internal dose) DOSE (external dose) Exposure scaled by MIC

  34. PK/PD indices as indicator of antibiotic efficacy

  35. The surrogates (predictors) of antibiotic efficacy AUC/MIC, T>MIC, Cmax/MIC

  36. 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

  37. Why these indices are termed PK/PD AUIC # = PK AUC CMI Dose / Clearance CMI50(90) PD  Dual dosage regimen adaptation

  38. Relationship between dose and PK/PD predictors of efficacy Breakpoint value e.g. 125 PD Bioavailability PK Free fraction

  39. Why plasma concentrationThe site of infection Update : 7 janvier 2020

  40. Only the free (non-bound) fraction (concentration) of the drug can interact with bacterial receptors • Only the concentration of free drug that is of concern for its PK/PD relationship

  41. MIC is a reasonable approximate of the concentration of free drug needed at the site of infection

  42. Most infections of interest are located extra-cellularly and direct comparisons to total tissue concentration with PD parameters are meaningless Cars, 1991

  43. Where are located the pathogens ECF Most bacteria of clinical interest - respiratory infection - wound infection - digestive tract inf. Cell (in phagocytic cell most often) • Legionnella spp • mycoplasma (some) • chlamydiae • Brucella • Cryptosporidiosis • Listeria monocytogene • Salmonella • Mycobacteria • Meningococci • Rhodococcus equi

  44. Barrier, efflux pump Porous capillaries Plasma Interstitial fluid Brain, retina, prostate Biophase for most bacteria of veterinary therapeutical interest Surrogate marker (T>MIC, AUIC, Cmax/MIC) Tissular barrier B Bound  F Mannhemia, Pasteurella Haemophilus, Streptococcus, Staphylococcus, Coli, Klebsiella Bound  F B lipophilicity F Efflux pump Total concentration Biophase for facultative and obligatory intracellular pathogens Bound Cytosol (Listeria, Shigella) B Phagosome (Chlamydiae) F Cell Cell membrane Bound B F B B Obligatory or facultative bacteria Phagolysosome (S. aureus, Brucella, Salmonella)

  45. Tissue concentrations According to EMEA "unreliable information is generated from assays of drug concentrations in whole tissues (e.g. homogenates)" EMEA 2000

  46. Relationship Between T>MIC and Efficacy for Carbapenems (Red), Penicillins (Aqua) and Cephalosporins (Yellow)

  47. Relationship between PK/PD parameters and efficacy for cefotaxime against Klebsiella pneumoniae in a pneumonia model 10 10 10 R² = 94% 9 9 9 8 8 8 Log10 CFU per lung at 24 h 7 7 7 6 6 6 5 5 5 3 10 30 100 300 1000 3000 01 1 10 100 1000 10000 100 60 80 20 40 0 24 h AUC/MIC ratio Time above MIC (%) Peak MIC ratio Craig CID, 1998

  48. Efficacy index: clinical validation Bacteriological cure versus time above MIC in otitis media (from Craig and Andes 1996) • Free serum concentration need to exceed the MIC of the pathogen for 40-50% of the dosing interval to obtain bacteriological cure in 80% of patients 100 S. pneumoniae Penicillin cephalosporins 50 Bacteriologic cure (%) H. influenzae Penicillin cephalosporins 0 0 100 50 Time above MIC (%)

  49. PK/PD parameters: -lactams • Time above MIC is the important parameter determining efficacy of the -lactams • T>MIC required for static dose vary from 25-40% of dosing interval for penicillins and cephalosporins. • Free druglevels of penicillins andcephalosporins need to exceed the MIC for 40-50% of the dosing interval to produce maximum survival Graig

  50. Betalactam • Goal: to maximize the duration of exposure over which free drug levels in biophase exceed the MIC • no further significant reduction in bacteria count when concentration exceed 4 MIC

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