Concentration-Dependent Enrichment of Linezolid-Resistant Staphylococcus aureus in an in vitro Dynamic Model.

Abstract

To establish the relationships between the enrichment of resistant Staphylococcus aureus mutants and the ratio of daily area under the concentration - time curve (AUC24) to the MIC of linezolid, a mixed inoculum of linezolid-susceptible and -resistant cells of three strains of S.aureus was exposed to twice daily linezolid in an in vitro dynamic model. Simulated pharmacokinetic profiles mimicked five-day treatments with linezolid dosing over a 32-fold range of the AUC24/MIC ratio. Population analysis of linezolid-exposed staphylococci was performed daily over 120 h after the start of the treatments. Minor if any enrichment of mutants resistant to 2X, 4X and 8XMIC of antibiotic was observed at the lowest and the highest AUC24/MIC ratios in contrast to pro- nounced enrichment of resistant mutants at the intermediate AUC24/MICs. An integral parameter AUBCm, the area under the time course of resistance mutants, was shown to be a more appropriate endpoint to establish AUC24/MIC relationships with resistance than postexposure number of mutants (NM).