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

To explore if the time inside the mutant selection window (TMSW) 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 TMSW-dependent manner. With each strain, TMSW relationships with the area under the bacterial mutant concentration-time curve (AUBCM) 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 AUBCM related to the maximal value observed with a given strain (normalized AUBCM) at T>MPC > 0, a strain-independent sigmoid relationship was established between AUBCM and TMSW, as well as T>MPC (r2 0.99 for both). AUC24/MIC and AUC24/MPC relationships with normalized AUBCM for combined data on the three studied S. aureus strains were bell-shaped (r2 0.85 and 0.80, respectively). These findings suggest that TMSW 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.