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JAC Advance Access originally published online on October 27, 2006
Journal of Antimicrobial Chemotherapy 2006 58(6):1168-1176; doi:10.1093/jac/dkl392
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Published by Oxford University Press 2006

Antifungal interactions within the triple combination of amphotericin B, caspofungin and voriconazole against Aspergillus species

Elizabeth M. O'Shaughnessy, Joseph Meletiadis, Theodouli Stergiopoulou, Joanne P. Demchok and Thomas J. Walsh*

Immunocompromised Host Section, Pediatric Oncology Branch, Clinical Cancer Research, National Cancer Institute National Institutes of Health, Bethesda, MD, USA

Received 15 April 2006; returned 26 May 2006; revised 5 September 2006; accepted 7 September 2006

*Correspondence address. 10 Center Drive, Building 10, Room 1-5888, National Cancer Institute, Pediatric Oncology Branch, Bethesda, MD 20892, USA. Tel: +1-301-402-20023; Fax: +1-301-480-2308; E-mail: walsht{at}mail.nih.gov

Objectives: 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.

Keywords: azoles , polyenes , echinocandins , synergy , antagonism , fractional inhibitory concentration index


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Home page
 Antimicrob. Agents Chemother.Home page
J. Meletiadis, T. Stergiopoulou, E. M. O'Shaughnessy, J. Peter, and T. J. Walsh
Concentration-Dependent Synergy and Antagonism within a Triple Antifungal Drug Combination against Aspergillus Species: Analysis by a New Response Surface Model
Antimicrob. Agents Chemother., June 1, 2007; 51(6): 2053 - 2064.
[Abstract] [Full Text] [PDF]


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