title: Antifungal interactions within the triple combination of amphotericin B, caspofungin and voriconazole against Aspergillus species.
abstract: OBJECTIVE
  The in vitro effects of caspofungin combined with voriconazole and amphotericin B were tested in triplicate experiments against nine clinical isolates of Aspergillus fumigatus, Aspergillus flavus and Aspergillus terreus.
  
  
  METHODS
  The isolates were tested against a range of concentrations of voriconazole (0.015-1.0 mg/L), caspofungin (0.125-256 mg/L) and five concentrations of amphotericin B (0.1-0.5 mg/L) with a microdilution chequerboard method based on the CLSI M38-A reference method and the results were analysed with the fractional inhibitory concentration (FIC) index. The effect of individual drugs on the FIC index of each of the double combinations was also evaluated.
  
  
  RESULTS
  The triple combination of voriconazole, caspofungin and amphotericin B against all Aspergillus spp. was synergistic (FIC index 0.49-0.57) at low median concentrations of amphotericin B (0.10-0.22 mg/L) and voriconazole (0.07-0.15 mg/L) over a wide range of caspofungin concentrations (4.32-17.28 mg/L). Antagonistic interactions (FIC index 1.65-2.15) were found at higher median concentrations of amphotericin B (0.3-0.5 mg/L) and voriconazole (0.23-0.68 mg/L) over a similarly wide range of caspofungin concentrations (1.47-32 mg/L).
  
  
  CONCLUSIONS
  These concentration-dependent interactions may have important clinical implications, which require further evaluation in animal models of invasive aspergillosis.
authors.affiliation: Immunocompromised Host Section, Pediatric Oncology Branch, Clinical Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: O'Shaughnessy
authors.forename: Joseph
authors.initials: J
authors.lastname: Meletiadis
authors.forename: Theodouli
authors.initials: T
authors.lastname: Stergiopoulou
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Demchok
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D001230:Aspergillus / Q000187:drug effects*; D000077336:Caspofungin; D004336:Drug Antagonism; D004338:Drug Combinations; D004357:Drug Synergism; D054714:Echinocandins; D055666:Lipopeptides; D008826:Microbial Sensitivity Tests / Q000379:methods; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D004338:Drug Combinations; D054714:Echinocandins; D055666:Lipopeptides; D010456:Peptides, Cyclic; D011743:Pyrimidines; D014230:Triazoles; D000666:Amphotericin B; D000077336:Caspofungin; D065819:Voriconazole