title: Ceftobiprole and ampicillin increase daptomycin susceptibility of daptomycin-susceptible and -resistant VRE.
abstract: The synergistic combination of daptomycin plus ampicillin has proven to be effective against VRE including daptomycin-non-susceptible strains. Ceftobiprole is a cephalosporin with broad binding affinity for enterococcal PBP subtypes including PBP5. Given the synergy between β-lactams and daptomycin against VRE, it was of interest to determine whether ceftobiprole offered any synergistic advantage with daptomycin compared with ampicillin.
  
  
  
  MICs were determined by broth microdilution in the presence and absence of ampicillin or ceftobiprole for 20 ampicillin-resistant VRE. Six strains, including two isogenic pairs of vancomycin-resistant Enterococcus faecium and two vancomycin-resistant Enterococcus faecalis, were evaluated for synergy using time-kill methods. Synergy was defined as a ≥2 log10 cfu/mL reduction of the combination over the most active single agent. Binding of daptomycin-bodipy in the presence and absence of ceftobiprole was quantified.
  
  
  
  Daptomycin MICs ranged from 2 to 256 mg/L. The addition of ceftobiprole and ampicillin reduced daptomycin MICs by a median of 3 and 4 log2 dilutions, respectively. In time-kill studies, daptomycin plus either ceftobiprole or ampicillin was synergistic against four of six strains, but not the same strains. Both combinations were synergistic against the vancomycin-resistant E. faecalis strains. Ceftobiprole exposure increased daptomycin-bodipy binding by 2.8 times (P<0.0001).
  
  
  
  Ceftobiprole appears to offer a similar degree of synergistic activity to ampicillin when combined with daptomycin against VRE. Further research should explore the genetic and phenotypic qualities of strains that respond preferentially to ceftobiprole as opposed to ampicillin.
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Werth
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Katie E
authors.initials: KE
authors.lastname: Barber
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Nikki
authors.initials: N
authors.lastname: Tran
authors.affiliation: University of California San Diego Division of Biology, La Jolla, CA 92093, USA.
authors.forename: P
authors.initials: P
authors.lastname: Nonejuie
authors.affiliation: University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
authors.forename: G
authors.initials: G
authors.lastname: Sakoulas
authors.affiliation: University of California San Diego Division of Biology, La Jolla, CA 92093, USA.
authors.forename: J
authors.initials: J
authors.lastname: Pogliano
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA School of Medicine, Wayne State University, Detroit, MI 48201, USA m.rybak@wayne.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rybak
mesh_terms: D000667:Ampicillin / Q000494:pharmacology*; D002511:Cephalosporins / Q000494:pharmacology*; D017576:Daptomycin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016983:Enterococcus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D020713:Vancomycin Resistance
chemical_list: D002511:Cephalosporins; C443755:ceftobiprole; D000667:Ampicillin; D017576:Daptomycin
keywords: combination therapy; synergy; β-lactams