title: In vitro activity of daptomycin in combination with β-lactams, gentamicin, rifampin, and tigecycline against daptomycin-nonsusceptible enterococci.
abstract: Enterococci that are nonsusceptible (NS; MIC > 4 μg/ml) to daptomycin are an emerging clinical concern. The synergistic combination of daptomycin plus beta-lactams has been shown to be effective against vancomycin-resistant Enterococcus (VRE) species in vitro. This study systematically evaluated by in vitro time-kill studies the effect of daptomycin in combination with ampicillin, cefazolin, ceftriaxone, ceftaroline, ertapenem, gentamicin, tigecycline, and rifampin, for a collection of 9 daptomycin-NS enterococci that exhibited a broad range of MICs and different resistance-conferring mutations. We found that ampicillin plus daptomycin yielded the most consistent synergy but did so only for isolates with mutations to the liaFSR system. Daptomycin binding was found to be enhanced by ampicillin in a representative isolate with such mutations but not for an isolate with mutation to the yycFGHIJ system. In contrast, ampicillin enhanced the killing of the LL-37 human antimicrobial peptide against daptomycin-NS E. faecium with either the liaFSR or yycFGHIJ mutation. Antagonism was noted only for rifampin and tigecycline and only for 2 or 3 isolates. These data add support to the growing body of evidence indicating that therapy combining daptomycin and ampicillin may be helpful in eradicating refractory VRE infections.
authors.affiliation: Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Janet A
authors.initials: JA
authors.lastname: Hindler
authors.affiliation: School of Pharmacy, University of Southern California, Los Angeles, Los Angeles, California, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Wong-Beringer
authors.affiliation: Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA Laboratory Medicine and Pathology, University of Alberta, and the Provincial Laboratory for Public Health (ProvLab), Edmonton, AB, Canada.
authors.forename: Carmen L
authors.initials: CL
authors.lastname: Charlton
authors.affiliation: Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Shelley A
authors.initials: SA
authors.lastname: Miller
authors.affiliation: Division of Infectious Diseases, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Kelesidis
authors.affiliation: Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Marissa
authors.initials: M
authors.lastname: Carvalho
authors.affiliation: Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA.
authors.forename: George
authors.initials: G
authors.lastname: Sakoulas
authors.affiliation: Department of Biological Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Poochit
authors.initials: P
authors.lastname: Nonejuie
authors.affiliation: Department of Biological Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Pogliano
authors.affiliation: Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.affiliation: Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA rhumphries@mednet.ucla.edu.
authors.forename: Romney
authors.initials: R
authors.lastname: Humphries
mesh_terms: D000667:Ampicillin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D004252:DNA Mutational Analysis; D004269:DNA, Bacterial / Q000235:genetics; D017576:Daptomycin / Q000494:pharmacology*; D004338:Drug Combinations; D004347:Drug Interactions; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D016983:Enterococcus / Q000187:drug effects* / Q000235:genetics; D016984:Enterococcus faecium / Q000187:drug effects; D000077727:Ertapenem; D005839:Gentamicins / Q000494:pharmacology; D016908:Gram-Positive Bacterial Infections / Q000382:microbiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics / Q000502:physiology; D012293:Rifampin / Q000494:pharmacology; D020713:Vancomycin Resistance; D047090:beta-Lactams / Q000494:pharmacology*; D054804:Cathelicidins
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D004269:DNA, Bacterial; D004338:Drug Combinations; D005839:Gentamicins; D047090:beta-Lactams; D000667:Ampicillin; D000077727:Ertapenem; D017576:Daptomycin; D012293:Rifampin; D054804:Cathelicidins