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Mutant Prevention Concentration and the Selection Window Hypothesis

Mutant Prevention Concentration and the Selection Window Hypothesis Karl Drlica, Xilin Zhao, and Tao Lu Public Health Research Institute Newark, NJ. Selecting a treatment plan for a particular patient. Individual patient issues Probability of “cure” without serious side effects.

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Mutant Prevention Concentration and the Selection Window Hypothesis

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  1. Mutant Prevention Concentration and the Selection Window Hypothesis Karl Drlica, Xilin Zhao, and Tao Lu Public Health Research Institute Newark, NJ

  2. Selecting a treatment plan for a particular patient Individual patient issues Probability of “cure” without serious side effects Public health issues Probability for avoiding enriching a resistant bacterial subpopulation

  3. Blocking Growth of Single Mutants Forces Cells to Have a Double Mutation to Overcome Drug attack by drug frequency ~ 10-7 frequency ~ 10-7 wild type double mutant single mutant frequency ~ 10-14 (number of bacteria during infection: < 1010)

  4. Introduction to MPC • Mutant Selection Window • Dosing above the MPC • Closing the Window • Combination Therapy • Comparison with Traditional PK/PD • Application to S. pneumoniae • Application to S. aureus • Other antimicrobial-pathogen combinations

  5. Introduction to MPC: Fluoroquinolone studies with mycobacteria

  6. Intracellular Consequences of Fluoroquinolone Treatment + DNA Gyrase (a) Gyrase mutations (b) Quinolone Blocks DNA replication and cell growth (MIC) Cell lysis SDS Cm (c) (d) Cell death

  7. O O O O F F OH H5C2 OH H5C2 N N N N HN O HN H3C Fluoroquinolone Structure C-8-methoxy compound C-8-H compound

  8. Bacteriostatic Activity with M. bovis BCG Fluoroquinolone C-8-moiety ID50 (mg/ml) gyrA+gyrAr ciprofloxacin H 0.15 6.1 PD161148 OMe 0.05 0.61 PD160793 H 0.08 7.0

  9. C-8-OMe C-8-H Bactericidal Activity of Fluoroquinolones with M. bovis BCG gyrA mutant wild type A B 103 102 Survival (%) 10 1 10-1 10-2 10 1 10 100 0.01 0.1 1 [Fluoroquinolone] (mg/ml) Incubation time: 6 days

  10. Effect of Fluoroquinolone Concentration on Mutant Recovery A B C D 1 100 10-2 80 Percent recovered 10-4 Fraction of cells recovered 60 A 10-6 40 B 10-8 C D 20 0.01 0.1 1 10 0 D95G G89C D95H D95G G89C D95Y D95A D95N D95G A91V D95H [Fluoroquinolone] (mg/ml) non-gyrA Mycobacterium smegmatis

  11. Mutant Selection Window

  12. Mutant Prevention Concentration (MPC) C-8-H MIC99 C-8-OMe 10-1 MIC99 10-3 10-5 Fraction of cells recovered 10-7 MPC MPC 10-9 0.01 0.1 1 10 [Fluoroquinolone] (µg/ml) M. bovis BCG

  13. A MIC MPC C-8-methoxy Fraction of colonies recovered (log10) Mutant Selection Window C-8-hydrogen MPC MIC Drug Concentration (log10) Mutant Selection Window B Cmax Serum or tissue drug concentration MPC Mutant Selection Window MIC Time post-administration

  14. A 10 1 MPC MIC 0.1 Selection Window Demonstrated by Dynamic, in vitro Model Dosing Protocol Analysis of recovered cells 0.3 0.2 0.1 0 0.3 B [Moxifloxacin] (μg/ml) 10 0.2 MIC (mg/ml) 1 MPC 0.1 MIC 0.1 0 0.3 C 10 0.2 1 MPC 0.1 MIC 0.1 0 before treatment 24 48 72 96 120 at 24 h Time (h) Data from Firsov et al. Organism: Staphylococcus aereus at 48 h at 72 h

  15. Traditional Explanation for Enrichment of Mutants Concentration MIC Sele ctive Pres Selective Pressure Time

  16. Mutants are not selected at concentrations below MIC

  17. Strategies for Restricting the Development of Resistance Dose above MPC Narrow the window 2-drug therapy Serum or tissue drug concentration MPC MPC~MIC MPC=MIC MIC Time post-administration

  18. Dosing Above the Window

  19. Dose above MPC Serum or tissue drug con. Time post-administration Relationship of Pharmacokinetics and MPC in M. tuberculosis Antibiotic MPC Cmax MPC/Cmax Rifampicin >80 9.5 >8 Streptomycin >320 34 >9 Isoniazid 20 7.6 2.6 Ethionamide 35 20 1.8 Ethambutol 50 6 8.3 Capreomycin 160 33 4.8 Kanamycin >800 21 >38 Cycloserine 70 35 2 Fluoroquinolones Ciprofloxacin 8.0 4.4 1.8 Levofloxacin 7.5 5.7 1.3 Sparfloxacin 2.5 1.4 1.6 Moxifloxacin 2.5 4.5 0.55 Gatifloxacin 1.5 3.7 0.41

  20. Closing the Window

  21. Narrow the window Serum or tissue drug con. O O Time post-administration F OH N N N O H3C O O F OH O O N N N F OH N N HN O O F OH N N HN O H3C Narrowing the Selection Window with S. aureus MPC MIC(99) MPC/MIC(99) (mg/ml) (mg/ml) 0.6 0.05 12 1.7 0.05 34 4 0.3 13 0.45 0.08 6

  22. Problems with Combination Therapy

  23. Closing The Mutant Selection Window Mutant Selection Window open closed open #2 #3 #1 Serum or tissue drug concentration MIC Drug 1 Drug 2 Time post-administration

  24. Treatment Protocol for a Dual-drug Failure HIV+ TB patients (drug-susceptible) Treat with INH, Rif, Pz, Em (2 months; DOT) INH/Rif (2/wk, 4 months; DOT) INH/Rifapentine (1/wk, 4 months; DOT) 3/31 relapse 5/30 relapse 4/5 Rif-resistant 0/3 Rif-resistant Source: A. Vernon et al. Lancet 353: 1843-1847 (1999)

  25. Pharmacodynamic Comparison of Rifampicin and Isoniazid 1000 Plasma drug concentration (fold of MIC) 100 Isoniazid 10 Rifampicin MIC 1 0 10 20 30 Time post-administration (hr) M. tuberculosis

  26. Pharmacokinetic mismatch between rifapentine and isoniazid 1000 Rifapentine 100 Plasma drug concentration (fold of MIC) Isoniazid 10 MIC 1 0 10 20 30 40 50 60 70 Time post-administration (hr) M. tuberculosis

  27. Normalized pharmacokinetic profiles of Rifater 500 100 INH 10 Serum drug concentration (fold of MIC) Rifampicin 1 MIC Pyrazinamide (M. tuberculosis) 0.1 0 2 4 6 8 10 12 14 Time post-administration (hr)

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