title: Evaluation of standard- and high-dose daptomycin versus linezolid against vancomycin-resistant Enterococcus isolates in an in vitro pharmacokinetic/pharmacodynamic model with simulated endocardial vegetations.
abstract: Daptomycin MICs for enterococci are typically 1- to 2-fold higher than those for Staphylococcus aureus, and there is an imminent need to establish the optimal dose for appropriate treatment of enterococcal infections. We investigated the bactericidal activity of daptomycin at various dose exposures compared to that of linezolid against vancomycin-resistant enterococcus (VRE) in an in vitro pharmacokinetic/pharmacodynamic model utilizing simulated endocardial vegetations over 96 h. Daptomycin at doses of 6, 8, 10, and 12 mg/kg of body weight/day and linezolid at a dose of 600 mg every 12 h were evaluated against two clinical vancomycin-resistant Enterococcus faecium strains (EFm11499 and 09-184D1051), one of which was linezolid resistant (09-184D1051), and one clinical vancomycin-resistant Enterococcus faecalis strain (EFs11496). Daptomycin MICs were 4, 2, and 0.5 μg/ml for EFm11499, 09-184D1051, and EFs11496, respectively. Bactericidal activity, defined as a ≥ 3 log(10) CFU/g reduction from the initial colony count, was demonstrated against all three isolates with all doses of daptomycin; however, bactericidal activity was not sustained with the daptomycin 6- and 8-mg/kg/day regimens. Linezolid was bacteriostatic against EFm11499 and displayed no appreciable activity against 09-184D1051 or EFs11496. Concentration-dependent killing was displayed with more sustained reduction in colony count (3.58 to 6.46 and 5.89 to 6.56 log(10) CFU/g) at 96 h for the simulated regimen of daptomycin at doses of 10 and 12 mg/kg/day, respectively (P ≤ 0.012). No E. faecium mutants with reduced susceptibility were recovered at any dosage regimen; however, the E. faecalis strain developed reduced daptomycin susceptibility with daptomycin at 6, 8, and 10 but not at 12 mg/kg/day. Daptomycin displayed a dose-dependent response against three VRE isolates, with high-dose daptomycin producing sustained bactericidal activity. Further research is warranted.
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.
authors.forename: Ashley D
authors.initials: AD
authors.lastname: Hall
authors.forename: Molly E
authors.initials: ME
authors.lastname: Steed
authors.forename: Cesar A
authors.initials: CA
authors.lastname: Arias
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Murray
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rybak
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D017576:Daptomycin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004697:Endocarditis, Bacterial / Q000382:microbiology; D016983:Enterococcus / Q000187:drug effects*; D013293:Enterococcus faecalis / Q000187:drug effects; D000069349:Linezolid; D008826:Microbial Sensitivity Tests; D023303:Oxazolidinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D014640:Vancomycin / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000081:Acetamides; D023303:Oxazolidinones; D014640:Vancomycin; D000069349:Linezolid; D017576:Daptomycin