title: Classical β-Lactamase Inhibitors Potentiate the Activity of Daptomycin against Methicillin-Resistant Staphylococcus aureus and Colistin against Acinetobacter baumannii.
abstract: We asked whether beta-lactamase inhibitors (BLIs) increased the activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA), the peptide antibiotic colistin (COL) against the emerging Gram-negative nosocomial pathogen Acinetobacter baumannii, and the human host defense peptide cathelicidin LL37 against either pathogen. DAP and LL37 kill curves were performed with or without BLIs against MRSA, vancomycin-intermediate S. aureus (VISA), and heterogeneous VISA (hVISA). COL and LL37 kill curves were performed against A. baumannii Boron-dipyrromethene (BODIPY)-labeled DAP binding to MRSA grown with the BLI tazobactam (TAZ) was assessed microscopically. The combination of COL plus TAZ was studied in a murine model of A. baumannii pneumonia. TAZ alone lacked in vitro activity against MRSA or A. baumannii The addition of TAZ to DAP resulted in a 2- to 5-log10reduction in recoverable MRSA CFU at 24 h compared to the recoverable CFU with DAP alone. TAZ plus COL showed synergy by kill curves for 4 of 5 strains of A. baumannii tested. Growth with 20 mg/liter TAZ resulted in 2- to 2.5-fold increases in the intensity of BODIPY-DAP binding to MRSA and hVISA strains. TAZ significantly increased the killing of MRSA and A. baumannii by LL37 in vitro TAZ increased the activity of COL in a murine model of A. baumannii pneumonia. Classical BLIs demonstrate synergy with peptide antibiotics. Since BLIs have scant antimicrobial activity on their own and are thus not expected to increase selective pressure toward antibiotic resistance, their use in combination with peptide antibiotics warrants further study.
authors.affiliation: University of California-San Diego School of Medicine, La Jolla, California, USA gsakoulas@ucsd.edu.|Sharp Healthcare System, San Diego, California, USA.
authors.forename: George
authors.initials: G
authors.lastname: Sakoulas
authors.affiliation: University of Wisconsin-Madison School of Pharmacy, Madison, Wisconsin, USA.
authors.forename: Warren
authors.initials: W
authors.lastname: Rose
authors.affiliation: University of Wisconsin-Madison School of Pharmacy, Madison, Wisconsin, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Berti
authors.affiliation: University of California-San Diego School of Medicine, La Jolla, California, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Olson
authors.affiliation: University of California-San Diego School of Medicine, La Jolla, California, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Munguia
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: University of California-San Diego School of Medicine, La Jolla, California, USA.
authors.forename: Eleanna
authors.initials: E
authors.lastname: Sakoulas
authors.affiliation: Eugene Appelbaum College of Pharmacy, Wayne State University, Detroit, Michigan, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rybak
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: University of California-San Diego School of Medicine, La Jolla, California, USA.|Skaggs School of Pharmacy, University of California-San Diego, La Jolla, California, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000472:pathogenicity; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects; D003091:Colistin / Q000494:pharmacology*; D017576:Daptomycin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D018410:Pneumonia, Bacterial / Q000188:drug therapy; D000078142:Tazobactam; D065093:beta-Lactamase Inhibitors / Q000494:pharmacology*; D054804:Cathelicidins
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D065093:beta-Lactamase Inhibitors; D010397:Penicillanic Acid; D017576:Daptomycin; D000078142:Tazobactam; D003091:Colistin; D054804:Cathelicidins
keywords: beta-lactamase inhibitor; cathelicidin; colistin; daptomycin; peptide antibiotic