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

• Published in: International journal of antimicrobial agents 2009-07, Vol.34 (1), p.21-24
• Main Authors: Allen, George P, Bierman, Betsy C
• Format: Article
• Language: English
• Subjects: Acetamides - pharmacokinetics; Acetamides - pharmacology; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimicrobial resistance; Biological and medical sciences; Colony Count, Microbial; Drug Resistance, Bacterial; Enterococci; Enterococcus faecalis; Enterococcus faecalis - drug effects; Enterococcus faecium; Enterococcus faecium - drug effects; Humans; Infectious Disease; Linezolid; Medical sciences; Microbial Sensitivity Tests; Models, Theoretical; Mutant prevention concentration; Oxazolidinones - pharmacokinetics; Oxazolidinones - pharmacology; Pharmacology. Drug treatments; Selection, Genetic; Vancomycin Resistance
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2008.12.011

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 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.