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 μg 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, %TMSW (% of the dosing interval that concentrations fall in the MSW) = 40%] and ATCC 51299 and GP32 (AUC/MIC = 30.95, AUC/MPC = 7.74, %TMSW = 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.