Affiliation:
1. Immunocompromised Host Section, Pediatric Oncology Branch, Clinical Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
Abstract
ABSTRACT
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
E
max
-based model modified to assess pharmacodynamic interactions at various growth levels. The new model allows flexibility in all four parameters of the
E
max
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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
55 articles.
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