In vitro analysis of resistance selection by linezolid in vancomycin-susceptible and -resistant Enterococcus faecalis and Enterococcus faecium

The pharmacodynamics of resistance development to linezolid has not been extensively studied, especially when a large bacterial inoculum is exposed to this agent. We simulated the usual therapeutic dose of linezolid, 600 mg intravenously every 12 h [estimated maximum concentration, area under the concentration-time curve (AUC) and half-life of 10.4 mg/L, 61.9 mu g h/mL and 4.8 h, respectively], in an in vitro pharmacodynamic model and investigated the applicability of the mutant selection window (MSW) to linezolid against vancomycin-susceptible and -resistant Enterococcus faecalis and Enterococcus faecium. Four strains were studied, including vancomycin-susceptible (ATCC 29212) and -resistant (ATCC 51299) E. faecalis and vancomycin-susceptible (GP33) and -resistant (GP32) E. faecium. The minimum inhibitory concentration (MIC) for all strains was 2 mg/L; mutant prevention concentration (MPC) values were 4 mg/L for ATCC 29212 and GP33 and 8 mg/L for ATCC 51299 and GP32. Linezolid failed to achieve bactericidal action against ATCC 29212 and GP33 [AUC/MIC = 30.95, AUC/MPC = 15.48, %T(MSW) (% of the dosing interval that concentrations fall in the MSW)= 40%] and ATCC 51299 and GP32 (AUC/MIC = 30.95, AUC/MPC = 7.74, %T(MSW) = 80.1%). Linezolid-resistant subpopulations (MIC = 8 mg/L) of all isolates were selected. Our data suggest that linezolid resistance in enterococci will continue to emerge upon continued use of this antimicrobial. (C) 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.