title: Fosfomycin Enhances the Activity of Daptomycin against Vancomycin-Resistant Enterococci in an In Vitro Pharmacokinetic-Pharmacodynamic Model.
abstract: Daptomycin (DAP) is being used more frequently to treat infections caused by vancomycin-resistant enterococcus (VRE). DAP tends to be less active against enterococci than staphylococci and may require high doses or combination therapy to be bactericidal. Fosfomycin (FOF) has activity against VRE and has demonstrated synergistic bactericidal activity with DAP in vitro The objective of this study was to evaluate the activity of DAP alone and in combination with FOF against VRE in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model. The activity of DAP at 8 and 12 mg/kg of body weight/day (DAP 8 and DAP 12, respectively) and FOF of 40 mg/kg intravenously every 8 h, alone and in combination, were evaluated against 2 vancomycin-resistant Enterococcus faecium strains (8019 and 5938) and 2 vancomycin-resistant E. faecalis strains (V583 and R7302) in an in vitro PK/PD model over 72 h. Cell surface charge in the presence and absence of FOF was evaluated by zeta potential analysis. Daptomycin-boron-dipyrromethene (bodipy) binding was assessed by fluorescence microscopy. The addition of FOF to DAP 8 and DAP 12 resulted in significantly increased killing over DAP alone at 72 h for 8019, V583, and R7302 (P < 0.05). Therapeutic enhancement was observed with DAP 12 plus FOF against 8019, V583, and R7302. Cell surface charge became more negative after exposure to FOF by ∼2 to 8mV in all 4 strains. Daptomycin-bodipy binding increased by 2.6 times in the presence of fosfomycin (P < 0.0001). The combination of DAP plus FOF may provide improved killing against VRE (including DAP-resistant strains) through modulation of cell surface charge. Further studies to clarify the role of intravenous FOF are warranted.
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.
authors.forename: Ashley D
authors.initials: AD
authors.lastname: Hall Snyder
authors.affiliation: School of Pharmacy, University of Washington, Seattle, Washington, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Werth
authors.affiliation: University of California San Diego Division of Biology, La Jolla, California, USA.
authors.forename: Poochit
authors.initials: P
authors.lastname: Nonejuie
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: McRoberts
authors.affiliation: University of California San Diego Division of Biology, La Jolla, California, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Pogliano
authors.affiliation: Center for Immunity, Infection & Inflammation, Division of Pediatric Pharmacology & Drug Discovery, University of San Diego School of Medicine, San Diego, California, USA.
authors.forename: George
authors.initials: G
authors.lastname: Sakoulas
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.
authors.forename: Juwon
authors.initials: J
authors.lastname: Yim
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.
authors.forename: Nivedita
authors.initials: N
authors.lastname: Singh
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA School of Medicine, Wayne State University, Detroit, Michigan, USA m.rybak@wayne.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rybak
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017576:Daptomycin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005578:Fosfomycin / Q000493:pharmacokinetics / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D065507:Vancomycin-Resistant Enterococci / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D005578:Fosfomycin; D017576:Daptomycin