A unified anti-mutant dosing strategy

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. AUC(24)/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.

Figure 1

Effect of PK/PD thresholds on major susceptible and minor resistant pathogen populations treated with a lethal agent. (a) Unchallenged bacterial population contains a majority of susceptible cells (open circles) and a small subpopulation of resistant mutants (filled circles). (b) When drug exposure passes an AUC₂₄/MIC threshold above which mutants, but not susceptible cells, can survive and proliferate, enrichment and amplification of resistant mutant subpopulations occur. (c) When drug exposure exceeds an AUC₂₄/MPC threshold above which resistant mutants and susceptible cells are both killed, acquisition of resistance fails to occur (a few pathogen cells may persist, as shown). With fluoroquinolones, AUC₂₄/MPC of 20–70 restricts emergence of resistance.