title: Time-kill kinetics of oritavancin and comparator agents against Streptococcus pyogenes.
abstract: The activity of oritavancin in vitro against recent clinical isolates of Streptococcus pyogenes, including antibiotic-resistant strains, was characterised by determination of broth microdilution minimal inhibitory concentrations as well as time-kill assays. Ten clinical isolates of S. pyogenes, three of which were resistant to erythromycin, as well as one reference S. pyogenes strain were tested. In the time-kill assays, oritavancin and the comparators vancomycin, teicoplanin, linezolid, penicillin, erythromycin and daptomycin were tested at static concentrations approximating their free peak (fC(max)) and free trough (fC(min)) concentrations in plasma when administered at approved doses for skin and skin-structure infections. At its fC(max) predicted from a 200 mg dose in humans, oritavancin exerted bactericidal activity (> or = 3 log kill relative to the starting inoculum) within 15 min to 3 h against all tested strains. Daptomycin exhibited bactericidal activity at its fC(max) for all but one strain; time to cidality was between 15 min and 6 h. At fC(min), only oritavancin was bactericidal against all the tested strains. Oritavancin displayed concentration-dependent killing of all isolates in vitro. Oritavancin was more rapidly bactericidal than the comparators at physiologically relevant concentrations against all strains tested. These data support the potential utility of oritavancin in infections with contemporary isolates of S. pyogenes, including drug-resistant strains.
authors.affiliation: The Medicines Company, St Laurent, Quebec, Canada. francis.arhin@themedco.com
authors.forename: Francis F
authors.initials: FF
authors.lastname: Arhin
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: McKay
authors.forename: Sylvain
authors.initials: S
authors.lastname: Beaulieu
authors.forename: Ingrid
authors.initials: I
authors.lastname: Sarmiento
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Parr
authors.forename: Gregory
authors.initials: G
authors.lastname: Moeck
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology*; D006801:Humans; D000077427:Lipoglycopeptides; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects*; D013290:Streptococcal Infections / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000187:drug effects* / Q000302:isolation & purification; D013997:Time Factors; D014640:Vancomycin / Q000031:analogs & derivatives
chemical_list: D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D000077427:Lipoglycopeptides; C100708:oritavancin; D014640:Vancomycin