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Comparision of Mutant Selection Window Hypothesis with Traditional Pharmacodynamics

Comparision of Mutant Selection Window Hypothesis with Traditional Pharmacodynamics. C max /MIC. C max. Pharmacodynamic Correlates with Cure. Time above MIC. AUC above MIC. Serum drug concentration. MIC. Time. Time post-administration. Dosing Strategies and Mutant Enrichment. >MPC.

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Comparision of Mutant Selection Window Hypothesis with Traditional Pharmacodynamics

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  1. Comparision of Mutant Selection Window Hypothesis with Traditional Pharmacodynamics

  2. Cmax/MIC Cmax Pharmacodynamic Correlates with Cure Time above MIC AUC above MIC Serum drug concentration MIC Time Time post-administration

  3. Dosing Strategies and Mutant Enrichment >MPC Cmax/MIC and AUC/MIC Serum or tissue drug concentration MPC Mutant Selection Window MIC Time post-administration

  4. Comparison of MPC Approach and Traditional Pharmacodynamics • MPC • Designed to block • resistance • Indexed to mutant • growth • Conceptual threshold • Clinical correlates • unknown • Traditional PD • Designed to cure • patients • Indexed to susceptible • cell growth • Empirical threshold • Based on clinical data

  5. Applications to Streptococcus neumoniae

  6. O O F OH N N HN H ciprofloxacin Fluoroquinolone Structure O O F OH N N N O CH3 H3C levofloxacin O O O O F OH OH H N N N N HN O O H3C F H H3C F Moxifloxacin Garenoxacin

  7. Pharmacodynamic Comparison with S. pneumoniae levo 10 cipro MPC Plasma drug concentration (fold of MIC) MIC 1 0.1 0 5 10 15 20 25 Time post-administration (hr)

  8. Two Situations Producing Concentrations Inside the Window levo with S. pneumoniae 10 MPC cipro with S. aureus Plasma drug concentration (fold of MIC) MIC 1 0.1 0 5 10 15 20 25 Time post-administration (hr)

  9. Levofloxacin resistance among clinical isolates of S. pneumoniae

  10. Recovery of Fluoroquinolone-resistant S. pneumoniae Levo 1 Moxi 10-2 MIC99 MIC99 10-4 Fraction of cells recovered 10-6 10-8 10-10  0.1 1 [Fluoroquinolone] (μg/ml)

  11. 10 9 8 7 6 5 4 3 2 1 0 MPC and Fluoroquinolone Pharmacokinetics 10 Moxifloxacin Levofloxacin 9 MPC90 8 7 750 mg 500 mg 6 Plasma drug concentration (mg/ml) 5 4 3 MPC90 2 MIC90 MIC90 1 0 0 10 20 30 40 50 0 10 20 30 40 50 Time post-administration (hr)

  12. Comparison of Fluoroquinolones by MPC-based Pharmacodynamics t MPC Serum Concentration MIC Time Fluoroquinolone MPC90 (mg/ml) Time above MPC90 (hr) Moxifloxacin 2 18 Gemifloxacin 1 4 Gatifloxacin 4 1-2 Levofloxacin 8 0

  13. Recovery of Fluoroquinolone-resistant S. pneumoniae Levo 1 Moxi MIC99 MIC99 10-2 10-4 Fraction of cells recovered 10-6 10-8 10-10  0.1 1 [Fluoroquinolone] (ug/ml)

  14. Topoisomerase Mutants Selected by Levofloxacin and Moxifloxacin Fraction of Identity of mutants* cells recovered Selected by moxi Selected by levo as mutants gyrA gyrB parC parE gyrA gyrB parC parE 3.0 X 10-5 none none none none 4.4 X 10-6 none none none none none none none none none none none none 1.8 X 10-6 none none S79Y none 2.0 X 10-7 none none none nonenone none S79Y none none none S79Y none none none D83H none 1.3 X 10-7 none none none none 5.6 X 10-9 none none none none none none none none none none none none none none none none 1.2 X 10-9 none none none none none none S79Y none S81Y none none none none none S79Y none 2.9 X10-10S81Y none none none S81Y none none none 1.6 X10-10S81Y none none none S81Y none none none * Changes in QRDR of the indicated genes 103

  15. Effect of a parCr mutation on recovery of resistant mutants 1 MIC99 parCr MIC99 wt 10-2 Fraction of cfu recovered 10-4 10-6 10-8 10-10 MPC MPC 0.1 1 10 [Moxifloxacin] (mg/ml) S. pneumoniae

  16. Fluoroquinolone Challenge Adds Topoisomerase Mutations to S. pneumoniae Strain AgentChanges in QRDR ParCParE GyrA GyrB 70 D83G, K137N none E85K none 70 multiple D83GI460VE85K none Gemi K137N, S79FE474KS81Y 70 Moxi-1 D83G, K137Nnone E85K, S81Fnone 70 Moxi-2 D83Gnone E85K, S81Fnone K137N, S79F

  17. Applications to Staphylococcus aureus

  18. 7 6 5 0 2 4 6 8 4 3 2 1 16 14 12 10 8 6 4 2 0 Mutant Selection Window and Fluoroquinolone Pharmacokinetics: S. aureus Garenoxacin (BMS284756) Ciprofloxacin 10 MPC90 30 MPC90 cipS cipR [Drug] (mg/ml) 1 MIC90 MPC90 MIC90 MIC90 0.03 0.2 0 5 10 15 20 25 0 5 10 15 20 25 Time post-administration (hr)

  19. Dose above MPC Serum or tissue drug con. MPC-based Potencywith S. aureus Time post-administration Compound MPC (mg/ml) Cmax (mg/ml) half-life (hr) Norfloxacin 22 1.45 3.25 Tobramycin 20 52 1.8 Chloramphenicol 40 26 6.5 Rifampicin 480 9.5 2 Penicillin G 1 512 0.9 Vancomycin 40 39 6.5 Moxifloxacin 0.6 4.5 12

  20. Narrow the window Serum or tissue drug con. Time post-administration Mutant Selection Window with S. aureus Compound MPC (mg/ml) MIC99 (mg/ml) MPC/MIC99 Norfloxacin 22 0.85 26 Tobramycin 20 0.27 74 Chloramphenicol 40 1.9 21 Rifampicin 480 0.003 160,000 Penicillin G 1 0.015 67 Vancomycin 40 0.65 62 Moxifloxacin 0.6 0.05 12

  21. Is the Mutant Selection Window Restricted to Fluoroquinolones?

  22. Mutant Selection with Erythromycin and Penicillin M. smegmatis S. aureus 10-1 Fraction of input cfu recovered 10-3 10-5 10-7 10-9 0.1 1 10 100 1000 0.01 0.1 1 10 100 1000 [Erythromycin] (mg/ml) [Penicillin] (mg/ml)

  23. Mutant Selection with Yeast (Canadia glabrata) clinical resistant isolate 1 10-2 10-4 wild-ytpe Fraction of input CFU recovered 10-6 10-8 0.001 0.01 0.1 1 10 100 [Miconazole] (mg/ml)

  24. Why is the Selection Window Hypothesis Useful?

  25. Gradual Increase of Resistance breakpoint Number of isolates MIC

  26. Problems for implementing direct attack of mutants • No animal or clinical studies done • Currently requires altruism (dosing higher than needed for cure) • With S. pneumoniae time is running out (cross-resistance)

  27. Literature Cited

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