title: Evaluation of the combination of daptomycin and nafcillin against vancomycin-intermediate Staphylococcus aureus.
abstract: OBJECTIVE
  Continued selective pressure from glycopeptide use has led to non-susceptible strains of Staphylococcus aureus, including vancomycin-intermediate S. aureus (VISA). Though relatively uncommon, VISA presents a particularly difficult clinical challenge when it arises. Pertinent to this investigation is the correlation between vancomycin intermediacy and daptomycin non-susceptibility. The aim of this study was to evaluate the potential for synergy between daptomycin and nafcillin against VISA.
  
  
  METHODS
  Twenty VISA strains were evaluated for daptomycin and nafcillin MICs by broth microdilution in duplicate. Potential for synergy was assessed by time-kill at 0.5× MIC in triplicate. Four strains displaying synergy in time-kill analysis were analysed in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model in duplicate over 72 h.
  
  
  RESULTS
  In time-kill experiments, 55% of strains (11/20) displayed synergy with the combination. In the PK/PD model, no differences between daptomycin-alone and combination regimens were observed for the strain with the lowest daptomycin MIC (0.5 mg/L). For the strain with a daptomycin MIC of 1 mg/L, 6 mg/kg daptomycin+nafcillin was superior to 6 mg/kg daptomycin alone (P=0.002) and 10 mg/kg daptomycin+nafcillin was superior to all other regimens (P ≤ 0.004). When the daptomycin MIC increased to 2 mg/L, 10 mg/kg daptomycin+nafcillin was superior to 6 mg/kg daptomycin+nafcillin, which was superior to both 6 and 10 mg/kg daptomycin alone (P ≤ 0.019).
  
  
  CONCLUSIONS
  Daptomycin and nafcillin in combination significantly improved antibacterial activity against VISA. This effect was more pronounced as the daptomycin susceptibility of the strain declined.
authors.affiliation: Northeastern University, Bouvé College of Health Sciences, School of Pharmacy, 360 Huntington Ave, R218 TF, Boston, MA 02115, USA. s.leonard@neu.edu
authors.forename: Steven N
authors.initials: SN
authors.lastname: Leonard
authors.forename: Kiri M
authors.initials: KM
authors.lastname: Rolek
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003198:Computer Simulation; D017576:Daptomycin / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D009254:Nafcillin / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects*; D020713:Vancomycin Resistance
chemical_list: D000900:Anti-Bacterial Agents; D009254:Nafcillin; D017576:Daptomycin