Differential Activity of Triazoles in 2-Drug Combination with the Echinocandin Caspofungin against Aspergillus fumigatus

E. K. MANAVATHU, G. J. ALANGADEN, M. D., P. H. CHANDRASEKAR, M. D

Author address: 

Wayne State University, Detroit, MI.

Abstract: 

The echinocandins and the triazoles are different classes of antifungal drugs with distinct modes of action. Thus, combination of an azole with an echinocandin should provide synergistic interaction against susceptible microorganisms. We therefore investigated the in vitro activity of various triazoles in 2-drug combination with the echinocandin caspofungin (CFG) against clinical isolates of Aspergillus fumigatus. Conidial suspensions were prepared from 20 clinical isolates of A. fumigatus highly susceptible to itraconazole (ITZ), voriconazole (VCZ), posaconazole (PCZ), ravuconazole (RCZ) (MIC range 0.25-0.5 mg/ml) and CFG (MIC 64 mg/ml). The in vitro susceptibility of A. fumigatus to 2-drug combination of ITZ, VCZ, PCZ and RCZ with CFG was evaluated by the fractional inhibitory concentration index (FICI) method. The FICI was determined by a 2-dimensional checker-board using the M38-P broth microdilution technique proposed by the National Committee for Clinical Laboratory Standards except that the MIC was defined as the concentration of the drug that provided no visible growth. The FICI was calculated by the formula: FICI = (Ac í· Aa) + (Bc í· Ba) where Ac and Bc are the MICs of drugs A and B in combination and Aa and Ba are the MICs of drugs A and B. The drug interactions were classified as synergistic (FICI ≤ 0.5), additive (FICI > 0.5 but ≤1), indifferent (FICI >1 but ≤2) and antagonistic (FICI >2). Two-drug combinations of CFG with ITZ (FICI = 0.49 ± 0.04) and PCZ (FICI = 0.32 ± 0.09) provided synergistic interaction. On the other hand, RCZ (FICI = 0.61 ± 0.31) in combination with CFG provided additive interaction whereas VCZ (FICI = 1.61 ± 0.42) in combination with CFG provided indifferent interaction against A. fumigatus. These results show that the in vitro interaction of two classes of drug cannot be always predicted strictly based on their mode of action alone. Whether this in vitro finding has any in vivo significance needs to be further investigated.
2002

abstract No: 

M-854

Full conference title: 

42nd Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 42nd