title: 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.
authors.affiliation: Oregon State University College of Pharmacy at Oregon Health and Science University, 3303 SW Bond Avenue, Mail Code CH12C, Portland, OR 97239-4501, USA. allenge@ohsu.edu
authors.forename: George P
authors.initials: GP
authors.lastname: Allen
authors.forename: Betsy C
authors.initials: BC
authors.lastname: Bierman
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D015169:Colony Count, Microbial; D024881:Drug Resistance, Bacterial; D013293:Enterococcus faecalis / Q000187:drug effects*; D016984:Enterococcus faecium / Q000187:drug effects*; D006801:Humans; D000069349:Linezolid; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D023303:Oxazolidinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D012641:Selection, Genetic; D020713:Vancomycin Resistance
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D000069349:Linezolid