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- Title
A unified anti-mutant dosing strategy.
- Authors
Xilin Zhao; Karl Drlica
- Abstract
Antimicrobial dosing is currently attracting attention as a way to minimize the emergence of resistance. Three dose-based strategies have been advocated, each with shortcomings. Focus on killing susceptible cells overlooks resistant mutant subpopulations that may be present before treatment or generated during therapy; keeping therapeutic drug concentrations above the mutant prevention concentration (MPC; resistant mutant MIC) may be overly stringent; and dosage escalation modelling uses indirect estimates of resistant mutant subpopulation susceptibility (multiples of bulk population susceptibility, MIC) rather than direct estimates from MPC. The latter is significant because MPC and MIC are discordant with multiple pathogen isolates. Combining the strategies leads to MPC-based PK/PD thresholds (e.g. AUC24/MPC and t > MPC) for restricting resistant subpopulation enrichment and amplification. Using MPC-based thresholds to model dosing regimens that will restrict emergence of resistance requires generation of databases in which MPC is determined for many isolates.
- Subjects
MILITARY strategy; MILITARY science; DEFENSIVE (Military science); MILITARY doctrine
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2008, Vol 62, Issue 3, p434
- ISSN
0305-7453
- Publication type
Article
- DOI
10.1093/jac/dkn229