title: Oritavancin kills stationary-phase and biofilm Staphylococcus aureus cells in vitro.
abstract: Slow-growing bacteria and biofilms are notoriously tolerant to antibiotics. Oritavancin is a lipoglycopeptide with multiple mechanisms of action that contribute to its bactericidal action against exponentially growing gram-positive pathogens, including the inhibition of cell wall synthesis and perturbation of membrane barrier function. We sought to determine whether oritavancin could eradicate cells known to be tolerant to many antimicrobial agents, that is, stationary-phase and biofilm cultures of Staphylococcus aureus in vitro. Oritavancin exhibited concentration-dependent bactericidal activity against stationary-phase inocula of methicillin-susceptible S. aureus (MSSA) ATCC 29213, methicillin-resistant S. aureus (MRSA) ATCC 33591, and vancomycin-resistant S. aureus (VRSA) VRS5 inoculated into nutrient-depleted cation-adjusted Mueller-Hinton broth. As has been described for exponential-phase cells, oritavancin induced membrane depolarization, increased membrane permeability, and caused ultrastructural defects including a loss of nascent septal cross walls in stationary-phase MSSA. Furthermore, oritavancin sterilized biofilms of MSSA, MRSA, and VRSA at minimal biofilm eradication concentrations (MBECs) of between 0.5 and 8 mug/ml. Importantly, MBECs for oritavancin were within 1 doubling dilution of their respective planktonic broth MICs, highlighting the potency of oritavancin against biofilms. These results demonstrate a significant activity of oritavancin against S. aureus in phases of growth that exhibit tolerance to other antimicrobial agents.
authors.affiliation: Targanta Therapeutics Incorporated, 7170 Frederick Banting, St Laurent, Quebec, Canada.
authors.forename: Adam
authors.initials: A
authors.lastname: Belley
authors.forename: Eve
authors.initials: E
authors.lastname: Neesham-Grenon
authors.forename: Geoffrey
authors.initials: G
authors.lastname: McKay
authors.forename: Francis F
authors.initials: FF
authors.lastname: Arhin
authors.forename: Robert
authors.initials: R
authors.lastname: Harris
authors.forename: Terry
authors.initials: T
authors.lastname: Beveridge
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*; D018441:Biofilms / Q000187:drug effects*; D015169:Colony Count, Microbial; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D006020:Glycopeptides / Q000494:pharmacology*; D007700:Kinetics; D000077427:Lipoglycopeptides; D008712:Methicillin / Q000494:pharmacology / Q000627:therapeutic use; D016106:Methicillin Resistance / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D010933:Plankton / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development* / Q000648:ultrastructure; D014640:Vancomycin / Q000494:pharmacology / Q000627:therapeutic use / Q000031:analogs & derivatives; D020713:Vancomycin Resistance / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D000077427:Lipoglycopeptides; D014640:Vancomycin; C100708:oritavancin; D008712:Methicillin