title: The combination of ceftaroline plus daptomycin allows for therapeutic de-escalation and daptomycin sparing against MRSA.
abstract: OBJECTIVE
  We previously demonstrated that ceftaroline enhances daptomycin against MRSA in vitro. However, prolonged combination therapy is clinically undesirable and possibly unnecessary. The purpose of this study was to determine if this combination could be de-escalated to a single agent without compromising efficacy.
  
  
  METHODS
  We investigated the following simulated regimens against two clinical, daptomycin-non-susceptible MRSA isolates in an in vitro pharmacokinetic/pharmacodynamic hollow-fibre model over 192 h: 600 mg of ceftaroline every 12 h (fCmax 17.0 mg/L, t½ 2.66 h); 10 mg/kg/day daptomycin (fCmax 11.3 mg/L, t½ 8 h); 6 mg/kg/day daptomycin (fCmax 7.5 mg/L, t½ 8 h); ceftaroline+daptomycin; and ceftaroline+daptomycin de-escalated to ceftaroline, daptomycin or drug-free simulations.
  
  
  RESULTS
  Daptomycin and ceftaroline MICs were 2 and 2 and 0.5 and 1 mg/L for strains R6063 and R5563, respectively. Ceftaroline+daptomycin (6 or 10 mg/kg/day) achieved a >5 log10 cfu/mL reduction within 96 h against both strains. Bacterial counts remained <1.5 log10 cfu/mL from 96 to 192 h regardless of de-escalation to either agent. There were no significant differences between combination or de-escalation regimens for either organism at either daptomycin dose. All combination/de-escalation to monotherapy regimens resulted in significantly improved activity compared with drug-free control, ceftaroline or daptomycin monotherapy (P<0.01).
  
  
  CONCLUSIONS
  These findings confirm that ceftaroline+daptomycin is a potent combination against MRSA. The high degree of bactericidal activity observed with this combination appears sufficiently robust to allow for de-escalation to a single agent without bacterial regrowth. The equivalent activity observed with ceftaroline+daptomycin (6 and 10 mg/kg/day) suggests this combination could also be daptomycin sparing. Further research is warranted to optimize dose and de-escalation timing.
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, 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, 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, USA m.rybak@wayne.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rybak
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002511:Cephalosporins / Q000494:pharmacology*; D017576:Daptomycin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004357:Drug Synergism; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics; D008826:Microbial Sensitivity Tests; D009154:Mutation; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D017576:Daptomycin; D000097583:Ceftaroline
keywords: VISA; daptomycin non-susceptibility; hVISA; refractory