Time inside the mutant selection window as a predictor of staphylococcal resistance to linezolid

Abstract

To explore if the time inside the mutant selection window (T_MSW) is a reliable predictor of emergence of bacterial resistance to linezolid, mixed inocula of each of three methicillin-resistant Staphylococcus aureus strains (MIC of linezolid 2 μg ml^-1) and their previously selected resistant mutants (MIC 8 μg ml^-1) were exposed to linezolid pharmacokinetics using an in vitro dynamic model. In five-day treatments simulated over a wide range of the 24-h area under the concentration-time curve (AUC₂₄) to the MIC ratio, mutants resistant to 4 × MIC of antibiotic were enriched in a T_MSW-dependent manner. With each strain, T_MSW relationships with the area under the bacterial mutant concentration-time curve (AUBC_M) exhibited a hysteresis loop, with the upper portion corresponding to the time above the mutant prevention concentration (MPC; T_>MPC) of 0 and the lower portion-to the T_>MPC > 0. Using AUBC_M related to the maximal value observed with a given strain (normalized AUBC_M) at T_>MPC > 0, a strain-independent sigmoid relationship was established between AUBC_M and T_MSW, as well as T_>MPC (r² 0.99 for both). AUC₂₄/MIC and AUC₂₄/MPC relationships with normalized AUBC_M for combined data on the three studied S. aureus strains were bell-shaped (r² 0.85 and 0.80, respectively). These findings suggest that T_MSW at T_>MPC > 0, T_>MPC, AUC₂₄/MIC and AUC₂₄/MPC are useful bacterial strain-independent predictors of the emergence of staphylococcal resistance to linezolid.