title: β-Lactam combinations with daptomycin provide synergy against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium.
abstract: OBJECTIVE
  Enterococcus faecalis (Efc) and Enterococcus faecium (Efm) are frequently resistant to vancomycin and β-lactams (BLs). In vitro data suggest synergy between several BLs and glycopeptides or lipopeptides against resistant pathogens. Our objective was to conduct combination MIC and time-kill experiments to evaluate BL synergy with daptomycin against enterococci.
  
  
  METHODS
  Fifteen Efc and 20 Efm strains were evaluated for daptomycin enhancement via combination MICs. Daptomycin MICs were obtained by microdilution in the absence and presence of ceftaroline, ertapenem, cefepime, ceftriaxone, cefotaxime, cefazolin and ampicillin. Two Efc strains (R6981 and R7808) and one isogenic daptomycin-susceptible/daptomycin-non-susceptible Efm pair (8019/5938) were evaluated in time-kill experiments. Daptomycin at 0.5 × MIC was used in combination with BL at biological free concentration. Strain 5938 was evaluated for enhancement of daptomycin binding in fluorescently labelled daptomycin (BoDipy) experiments.
  
  
  RESULTS
  Ceftaroline reduced daptomycin MIC values the most against all strains. In time-kill experiments, ceftaroline, ertapenem, cefepime, ceftriaxone and ampicillin demonstrated synergy with daptomycin against all strains, cefazolin demonstrated none and cefotaxime demonstrated synergy against only R7808. Bacterial reduction at 24 h was greater for daptomycin + ceftaroline, ertapenem, cefepime, ceftriaxone or ampicillin for all strains compared with any single agent or daptomycin + cefazolin or cefotaxime (P < 0.001). In BoDipy daptomycin experiments, ceftaroline enhanced daptomycin binding most compared with all other agents (P < 0.001).
  
  
  CONCLUSIONS
  The data support the potential use of daptomycin/BL combination therapy in infections caused by VRE. Combination regimens, other than those involving cefazolin and cefotaxime, provide better kill compared with daptomycin alone. Further clinical research involving daptomycin combinations is warranted.
authors: Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI, USA.
authors: Jordan R
authors: JR
authors: Smith
authors: Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI, USA.
authors: Katie E
authors: KE
authors: Barber
authors: Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI, USA.
authors: Animesh
authors: A
authors: Raut
authors: Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI, USA.
authors: Mostafa
authors: M
authors: Aboutaleb
authors: University of California San Diego School of Medicine, La Jolla, CA, USA University of California San Diego Division of Biology, La Jolla, CA, USA.
authors: George
authors: G
authors: Sakoulas
authors: Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI, USA Wayne State University School of Medicine, Detroit, MI, USA aa1592@wayne.edu.
authors: Michael J
authors: MJ
authors: Rybak
mesh_terms: D017576:Daptomycin / Q000494:pharmacology*; D004357:Drug Synergism; D013293:Enterococcus faecalis / Q000187:drug effects*; D016984:Enterococcus faecium / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects*; D065507:Vancomycin-Resistant Enterococci / Q000187:drug effects*; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D047090:beta-Lactams; D017576:Daptomycin
keywords: bacteria; combination therapy; in vitro; infection; time–kill
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