title: In vitro prevention of the emergence of daptomycin resistance in Staphylococcus aureus and enterococci following combination with amoxicillin/clavulanic acid or ampicillin.
abstract: Daptomycin is bactericidal against meticillin-resistant Staphylococcus aureus (MRSA), glycopeptide-intermediate-resistant S. aureus (GISA) and vancomycin-susceptible and -resistant enterococci. However, selection for daptomycin-resistant derivatives has occasionally been reported during therapy in humans. Here we evaluate whether selection for daptomycin-resistant S. aureus or enterococci could be prevented in vitro by combining daptomycin with amoxicillin/clavulanic acid, ampicillin, gentamicin or rifampicin. Six strains of S. aureus (four MRSA and two GISA) and four strains of enterococci (two Enterococcus faecalis and two Enterococcus faecium) were serially exposed in broth to two-fold stepwise increasing concentrations of daptomycin alone or in combination with a fixed concentration [0.25x minimum inhibitory concentration (MIC)] of either of the second agents. The daptomycin MIC was examined after each cycle. Exposure to daptomycin alone gradually selected for S. aureus and enterococci with an increased MIC. Gentamicin did not prevent the emergence of daptomycin-resistant bacteria. Rifampicin was also unable to prevent daptomycin resistance, although resistance was slightly delayed. In contrast, amoxicillin/clavulanic acid or ampicillin prevented or greatly delayed the selection of daptomycin-resistant mutants in S. aureus and enterococci, respectively. Addition of amoxicillin/clavulanic acid or ampicillin to daptomycin prevents, or greatly delays, daptomycin resistance in vitro. Future studies in animal models are needed to predict the utility of these combinations in humans.
authors.affiliation: Department of Fundamental Microbiology, Biophore Building, University of Lausanne, CH-1015 Lausanne, Switzerland. jose.entenza@unil.ch
authors.forename: José M
authors.initials: JM
authors.lastname: Entenza
authors.forename: Marlyse
authors.initials: M
authors.lastname: Giddey
authors.forename: Jacques
authors.initials: J
authors.lastname: Vouillamoz
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreillon
mesh_terms: D019980:Amoxicillin-Potassium Clavulanate Combination / Q000494:pharmacology*; D000667:Ampicillin / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017576:Daptomycin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D016983:Enterococcus / Q000187:drug effects* / Q000302:isolation & purification; D016908:Gram-Positive Bacterial Infections / Q000382:microbiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D012641:Selection, Genetic; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents; D019980:Amoxicillin-Potassium Clavulanate Combination; D000667:Ampicillin; D017576:Daptomycin