title: Assessment of the in vitro synergy of daptomycin plus linezolid against multidrug-resistant enterococci.
abstract: The widespread incidence of enterococci resistant to ampicillin, vancomycin and aminoglycosides, the first-line anti-enterococcal antibiotics, has made the treatment of severe enterococcal infections difficult and alternatives should be explored. We investigated the activity of daptomycin combined with linezolid against three Enterococcus faecalis and four Enterococcus faecium strains resistant to standard drugs used for therapy. Minimum inhibitory concentrations (MICs) were determined by the broth dilution method. Drug interactions were assessed by the checkerboard and time-kill methods. Synergy was defined by a fractional inhibitory concentration index (FICI) of ≤0.5 or a ≥2log10CFU/mL killing at 24h with the combination in comparison with killing by the most active single agent. Indifference was defined by a FICI>0.5-4.0 or a 1-2log10CFU/mL killing compared with the most active single agent. MICs of daptomycin were 2-4μg/mL for E. faecalis and 2-8μg/mL for E. faecium. MICs of linezolid were 1-2μg/mL for all bacteria. In the checkerboard assay, five isolates showed synergism (FICI<0.5) and two showed indifference (FICIs of 0.53 and 2). Killing studies revealed synergy of daptomycin plus linezolid against four isolates (2.2-3.7log10CFU/mL kill) and indifference (1.1-1.6log10CFU/mL kill) for the other three strains. Antagonism was not observed. In conclusion, the combination of daptomycin and linezolid had a synergistic or indifferent effect against multidrug-resistant enterococci. Additional studies are needed to explore the potential of this combination for severe enterococcal infections when first-line antibiotic combinations cannot be used.
authors.affiliation: Department of Fundamental Microbiology, Biophore Building, University of Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: José M
authors.initials: JM
authors.lastname: Entenza
authors.affiliation: Department of Fundamental Microbiology, Biophore Building, University of Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Marlyse
authors.initials: M
authors.lastname: Giddey
authors.affiliation: Department of Fundamental Microbiology, Biophore Building, University of Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Vouillamoz
authors.affiliation: Department of Fundamental Microbiology, Biophore Building, University of Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreillon
authors.affiliation: Department of Fundamental Microbiology, Biophore Building, University of Lausanne, CH-1015 Lausanne, Switzerland. Electronic address: stefano.mancini@unil.ch.
authors.forename: Stefano
authors.initials: S
authors.lastname: Mancini
keywords: Daptomycin; Enterococcus faecalis; Enterococcus faecium; Linezolid; Synergy