Pharmacodynamics of early, high-dose linezolid against vancomycin-resistant enterococci with elevated MICs and pre-existing genetic mutations

Brian Tsuji, Jurgen Bernd Bulitta, Tanya Brown, Alan Forrest, Pamela A Kelchlin, Patricia N Holden, Charles Arthur Peloquin, Laura A Skerlos, Debra Hanna

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23 Citations (Scopus)

Abstract

Objectives: Vancomycin-resistant enterococci (VRE) have emerged as an important nosocomial pathogen in medical centres worldwide. This study evaluated the impact of front-loading of linezolid on bacterial killing and suppression of resistance against VRE strains with defined genetic mutations. Methods: Time-killing experiments over 48 h assessed the concentration effect relationship of linezolid against eight strains of vancomycin-resistant Enterococcus faecalis. A hollow fibre infection model (HFIM) simulated traditional and front-loaded human therapeutic linezolid regimens against VRE strains at 106 cfu/mL over 240 h. Translational modelling was performed using S-ADAPT and NONMEM. Results: Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity with >2 log10 cfu/mL killing for all strains with an MIC of 4 and minimal activity against VRE with MICs of 16 and 64 mg/L. Against one strain with no resistant alleles (MIC 4 mg/L), 600 mg of linezolid every 12 h achieved maximal reductions of 0.96 log10 cfu/mL over 240 h in the HFIM, whereas front-loaded 1200 mg of linezolid every 12 h ?10 doses or 2400 mg of linezolid every 12 h ?10 doses followed by 600 mg of linezolid every 12 h provided significantly improved killing with maximal reductions of 3.02 and 3.46 log10 cfu/mL. Front-loaded regimens suppressed amplification of resistant subpopulations against VRE strains with no resistant alleles (MIC 4 mg/L) and postponed regrowth of resistant subpopulations against a VRE with 3.2 resistant alleles (MIC 4 mg/L). Modelling yielded excellent population fits (r = 0.934) and identified the number of sensitive alleles as a critical covariate. Conclusions: Early, high-dose regimens of linezolid provided promising killing against selected susceptible strains and may be clinically beneficial if early bactericidal activity is necessary.
Original languageEnglish
Pages (from-to)2182 - 2190
Number of pages9
JournalJournal of Antimicrobial Chemotherapy
Volume67
Issue number9
DOIs
Publication statusPublished - 2012

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