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

Abstract

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 12h [estimated maximum concentration, area under the concentration-time curve (AUC) and half-life of 10.4 mg/L, 61.9 microg h/mL and 4.8h, 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 2mg/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.