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Effect of Increasing Concentrations on Killing of Pneumococci in Thighs of Neutropenic Mice

Pharmacodynamics of Antimicrobials in Animal Models William A. Craig, M.D. University of Wisconsin-Madison. Effect of Increasing Concentrations on Killing of Pneumococci in Thighs of Neutropenic Mice. Telithromycin. Azithromycin. Clarithromycin. 8. 6. Log 10 CFU per Thigh. 4. 4. 0. m.

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Effect of Increasing Concentrations on Killing of Pneumococci in Thighs of Neutropenic Mice

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  1. Pharmacodynamics of Antimicrobialsin Animal ModelsWilliam A. Craig, M.D.University of Wisconsin-Madison

  2. Effect of Increasing Concentrations on Killing of Pneumococci in Thighs of Neutropenic Mice Telithromycin Azithromycin Clarithromycin 8 6 Log10 CFU per Thigh 4 4 0 m g / k g 4 0 m g / k g 1 8 . 8 m g / k g 1 0 m g / k g 1 0 m g / k g 4 . 7 m g / k g 2 2 . 5 m g / k g 2 . 5 m g / k g 1 . 1 7 m g / k g 0 2 4 6 0 2 4 6 0 2 4 6 Time (hours) CFU = colony-forming unit. Craig WA, et al. 40th ICAAC Toronto, Ontario, September 17-20, 2000.

  3. In Vivo PAE for Azithromycin withStreptococcus pneumoniae ATCC 10813 in Thighs of Neutropenic Mice

  4. Patterns of Antimicrobial Activity • Concentration-dependent killing and prolonged persistent effects • Seen with aminoglycosides, quinolones, daptomycin, ketolides, amphotericin B and echinocandins • Goal of dosing regimen: maximize concentrations • AUC/MIC and Peak/MIC major parameters correlating with efficacy

  5. Patterns of Antimicrobial Activity • Time-dependent killing and minimal or no persistent effects • Seen with all beta-lactams and flucytosine • Goal of dosing regimen: optimize duration of exposure • Time above MIC major parameter correlating with efficacy

  6. Patterns of Antimicrobial Activity • Time-dependent killing and moderate to prolonged persistent effects • Seen with macrolides, azithromycin, clindamycin, tetracyclines, oxazolidinones, streptogramins, glycopeptides and azoles • Goal of dosing regimen: optimize amount of drug • AUC/MIC major parameter correlating with efficacy

  7. Neutropenic Murine Thigh and Lung Infection Models • Cyclophosphamide 150 and 100 mg/kg at 4 and 1 day before infection • Thigh infection produced by injection of 0.1 ml of 107 CFU/ml 2 hrs before treatment • Lung infection produced by 45 min aerosol of 109 CFU/ml 14 hrs before treatment • 107-8 CFU/g in thigh or lung at start of therapy

  8. Correlation of Pharmacodynamic Parameters with Efficacy • Use neutropenic murine thigh-and lung-infection models • Evaluate 20-30 different dosing regimens (5 different total doses given at 4-6 different dosing intervals) • Measure efficacy from change in Log10 CFU per thigh or lung at the end of 24 hours of therapy • Correlate efficacy with various pharmacodynamic parameters (Time above MIC, peak/MIC, 24-Hr AUC/MIC)

  9. Correlation of PK/PD Parameters with Efficacy of Temafloxacin against Streptococcus pneumoniaein Thighs of Neutropenic Mice Craig in Antimicrobial Pharmacodynamics in Theory and Clinical Practice, p 1, 2002

  10. Correlation of PK/PD Parameters and Efficacy for Ceftazidime against Klebsiella pneumoniae in a Murine Pneumonia Model Craig in Antimicrobial Pharmacodynamics in Theory and Clinical Practice, p 1, 2002

  11. PK/PD Parameters Does the magnitude of the parameter vary markedly with: 1. different animal species 2. the dosing regimen? 3. different drugs within the same class? 4. different organisms ? 5. different sites of infection (e.g. blood, lung, peritoneum, soft tissue)? 6. the presence of neutrophils?

  12. Mathematical Analysis of Dose-Response Data from Animal Models after 24 Hours of Therapy Nonlinear regression and Hill equation to estimate Emax (difference from untreated control), P50 (dose giving 50% of Emax) and slope (N) of the dose-response relationship (Emax) DoseN CFU= DoseN + P50N

  13. 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 to 10-25% for carbapenems Free drug levels of penicillins and cephalosporins need to exceed the MIC for 40-50% of the dosing interval to produce maximum survival PK/PD Parameters: -Lactams

  14. Time Above MIC Required for a Static Effect After 24-hrs of Therapy with Three ß-Lactam Classes Time Above MIC (Percent of Dosing Interval) Drug q1-2 h q3-4h q6-8h q12-24h Cephalosporins 53 ± 20 43 ± 15 42 ± 14 35 ± 11 Penicillins 29 ± 10 31 ± 14 34 ± 16 31 ± 12 Carbapenem 20 ± 4 26 ± 10 23 ± 6 20 ± 4 Craig et al 33rd ICAAC, 1993 (Abstract 86)

  15. Time Above MIC Required for a Bacteriostatic Effect with Four Cephalosporins Time Above MIC (% of Dosing Interval) Drug Enterobacteriaceae S. pneumoniae S.aureus Ceftazidime 36 (27-42) 39 (35-42) 20,25 Cefepime 35 (29-40) 37 (33-39) 21,24 Cefotaxime 38 (36-40) 38 (36-40) 22,25 Ceftriaxone (T) 62 (56-69) 64 (59-68) 46,69 Ceftriaxone (F) 38 (34-42) 39 (37-41) 24,26

  16. Relationship Between MIC and T>MIC for the Static Dose for Cefpodoxime and Cefditoren with Various Strains of S. pneumoniae Urban et al. 19th ICC 1995 (Abstract 2229); Craig, Andes 40th ICAAC (Abstract 2248);

  17. Literature Review for T>MIC for Beta-Lactams Versus Mortality in Animal Models • At least 48 hrs of treatment • Mortality 80-100% in untreated controls • Pharmacokinetics provided to calculate magnitude of PK/PD parameter • Mortality recorded within 24 hrs after last dose of drug • Data from 3 animal species and 4 sites of infection Craig CID 26:1, 1998; Nicolau et al. AAC 44:1291, 2000

  18. Relationship Between T>MIC and Bacterial Eradication with Beta-Lactams in Otitis Media (Circles) and Maxillary Sinusitis (Squares) • Bacteriologic cure for different ß-lactams with S. pneumoniae and H. influenzae from double tap studies in acute otitis media and acute maxillary sinusitis • Time above MIC calculated from serum levels and MICs for different organisms Craig & Andes, Pediatr Infect Dis J 15:255, 1996; Dagan et al JAC 47:129, 2001;Dagan et al Pediatr Infect Dis J 20:829, 2001

  19. 24-hr AUC/MIC is the parameter that best predicts activity of fluoroquinolones. 24-hr AUC/MIC (using free drug levels) for static dose range from 25-50 for most organisms in neutropenic mice PK/PD Paramters with Fluoroquinolones

  20. 24-Hr AUC/MIC with Total and Free Drug for the Static Dose of Different Fluoroquinolones with S. pneumoniae ATCC 10813 Andes & Craig 40th and 41st ICAAC, 2000 and 2001

  21. Pharmacodynamics of Fluoroquinolones • Magnitude of 24-Hr AUC/MIC in serum required for 90-100% survival in animal infection models varies from about 25 in immunocompentent animals for Streptococcus pneumoniae to about 100 in immunocompromised animals for gram-negative bacilli • 24-Hr AUC/MIC values of 25 and 100 are equivalent to averaging one and four times the MIC over a 24-hr period

  22. Relationship Between 24 Hr AUC/MIC and Mortality in Animals for Fluoroquinolones against Gram-Negative Bacilli Andes & Craig, Int J of Antimicrob Agents 19:259, 2002

  23. Comparison of Relationships Between 24-Hr AUC/MIC and Efficacy against Pneumococci for Fluoroquinolones in Animals and Patients Animals - Literature Review Patients with CAP and AECB • 58 patients enrolled in a comparative trial of levofloxacin vs gatifloxacin • Free-drug 24-hr AUC/MIC <33.7, the probability of a microbiologic cure was 64% • Free-drug 24-hr AUC/MIC >33.7, the probability of a microbiologic cure was 100% Andes & Craig, Int J of Antimicrob Agents 19:259, 2002 Ambrose et al AAC 45:2793, 2001

  24. Impact of Dosing Interval on Static Dose for Amikacin against K. Pneumoniae and E. coli in Mice with Normal and Impaired Renal Function Reddington and Craig, JAC 1995

  25. Impact of Dosing Frequency on Static Dose for Macrolides and Azalides with Streptococcus pneumoniae ATCC 10813 Drug

  26. 24-Hr AUC/MIC with Total and Free Drug for the Static Dose of Different Macrolides, Ketolides and Clindamycin with S. pneumoniae ATCC 10813 Craig et al. 42nd ICAAC, 2002

  27. Simulate human pharmacokinetics in animals (induce renal impairment with uranyl nitrate) Infect groups of animals with organisms with varying MICs Treat the animals for at least 24 hours with dosage regimen used to treat human infections Find the MIC value that separates bacterial killing from bacterial growth Animal Models for Susceptibility Breakpoint Determinations

  28. Effect of Amoxicillin (7 mg/kg) on 17 Strains of S. pneumoniae in Thighs of Neutropenic Mice

  29. PK/PD Parameters Does the magnitude of the parameter vary markedly with: 1. different animal species NO 2. the dosing regimen? NO 3. different drugs within the same class? NO providing free drug levels are used 4. different organisms ? Some (S. aureus-ß-lactams) 5. different sites of infection (e.g. blood, lung, peritoneum, soft tissue)? NO 6. the presence of neutrophils? YES, some drugs more than others

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