title: Potent synergy of ceftobiprole plus daptomycin against multiple strains of Staphylococcus aureus with various resistance phenotypes.
abstract: OBJECTIVE
  Ceftobiprole is a broad-spectrum cephalosporin that demonstrates activity against Staphylococcus aureus resistant to methicillin, including strains with reduced susceptibility to glycopeptides and lipopeptides. The addition of this agent provides a potential therapeutic option for difficult-to-treat infections. Synergy has been demonstrated between β-lactams combined with glycopeptides and lipopeptides against S. aureus. This study sought to determine whether ceftobiprole was synergistic with daptomycin, vancomycin or standard-of-care combination agents (gentamicin or rifampicin) against methicillin-resistant S. aureus (MRSA) strains with varying degrees of vancomycin susceptibility.
  
  
  METHODS
  Broth microdilution MICs of ceftobiprole, daptomycin, vancomycin, rifampicin and gentamicin were evaluated for 20 MRSA isolates. Combination MICs were additionally evaluated in the presence of subinhibitory concentrations of ceftobiprole to assess synergism. Time-kill curves for five representative isolates were performed utilizing combinations of ceftobiprole plus daptomycin, vancomycin, rifampicin and gentamicin to further quantify the degree of synergy for each regimen.
  
  
  RESULTS
  Ceftobiprole plus daptomycin represented the most potent combination with a 4-fold decrease in MIC and synergy against all strains evaluated in time-kill evaluations. Additionally, binding studies demonstrated enhanced daptomycin binding in the presence of subinhibitory concentrations of ceftobiprole.
  
  
  CONCLUSIONS
  The use of combination therapy with ceftobiprole may provide a needed addition for the treatment of Gram-positive infections resistant to daptomycin or vancomycin. Consistent with what has been observed with other β-lactams, ceftobiprole increased bodipy-tagged daptomycin binding on the surface of S. aureus, potentially explaining this potent synergy observed in time-kill evaluations. More detailed evaluation of ceftobiprole is warranted to better characterize observed synergy.
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, 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, 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, Detroit, MI 48201, USA.
authors.forename: Cortney E
authors.initials: CE
authors.lastname: Ireland
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI 48201, USA.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Stone
authors.affiliation: University of California San Diego, Division of Biology, La Jolla, CA 92093, USA.
authors.forename: Poochit
authors.initials: P
authors.lastname: Nonejuie
authors.affiliation: University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
authors.forename: George
authors.initials: G
authors.lastname: Sakoulas
authors.affiliation: University of California San Diego, Division of Biology, La Jolla, CA 92093, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Pogliano
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, 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: D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D002511:Cephalosporins / Q000008:administration & dosage*; D017576:Daptomycin / Q000008:administration & dosage*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D010641:Phenotype; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C443755:ceftobiprole; D017576:Daptomycin
keywords: MRSA; VISA; hVISA; seesaw effect