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Antimicrobial Agents and Chemotherapy, June 2007, p. 2053-2064, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.00873-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Concentration-Dependent Synergy and Antagonism within a Triple Antifungal Drug Combination against Aspergillus Species: Analysis by a New Response Surface Model{triangledown}

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

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

Received 14 July 2006/ Returned for modification 11 December 2006/ Accepted 12 February 2007

Triple antifungal combinations are used against refractory invasive aspergillosis without an adequate understanding of their pharmacodynamic interactions. We initially studied the in vitro triple combination of voriconazole, amphotericin B, and caspofungin against Aspergillus fumigatus, A. flavus, and A. terreus by a spectrophotometric microdilution broth method after 48 h of incubation. We then analyzed these results with a recently described nonlinear mixture response surface Emax-based model modified to assess pharmacodynamic interactions at various growth levels. The new model allows flexibility in all four parameters of the Emax model and is able to describe complex pharmacodynamic interactions. Concentration-dependent pharmacodynamic interactions were found within the triple antifungal combination. At the 50% growth level, synergy (median interaction indices of 0.43 to 0.82) was observed at low concentrations of voriconazole (<0.03 mg/liter) and amphotericin B (≤0.20 mg/liter) and at intermediate concentrations of caspofungin (0.95 to 14.88 mg/liter), whereas antagonism (median interaction indices of 1.17 to 1.80) was found at higher concentrations of voriconazole and amphotericin B. Ternary plot and interaction surface analysis further revealed the complexity of these concentration-dependent interactions. With increasing concentrations of amphotericin B, the synergistic interactions of voriconazole-caspofungin double combination decreased while the antagonistic interactions increased. A similar effect was observed when voriconazole was added to the double combination of amphotericin B and caspofungin. In conclusion, the new nonlinear mixture-amount response surface modeling of the triple antifungal combination demonstrated a net antagonism or synergy against Aspergillus species depending upon drug concentrations and species.

* Corresponding author. Mailing address: 10 Center Drive, Bldg. 10, Rm. 1-5888, National Cancer Institute, Pediatric Oncology Branch, Bethesda, MD 20892. Phone: (301) 402-0023. Fax: (301) 480-2308. E-mail: walsht{at}mail.nih.gov

{triangledown} Published ahead of print on 26 March 2007.

Antimicrobial Agents and Chemotherapy, June 2007, p. 2053-2064, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.00873-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Stergiopoulou, T., Meletiadis, J., Sein, T., Papaioannidou, P., Tsiouris, I., Roilides, E., Walsh, T. J. (2008). Isobolographic Analysis of Pharmacodynamic Interactions between Antifungal Agents and Ciprofloxacin against Candida albicans and Aspergillus fumigatus. Antimicrob. Agents Chemother. 52: 2196-2204 [Abstract] [Full Text]  


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