Combined Activity In Vitro of Caspofungin plus Amphotericin B or plus Azole Agents against Itraconazole Resistant Clinical Isolates of aspergillus fumigatus.


Author address: 

Inst. de Salud Carlos III, Majadahonda, Spain.


Background: There has been an increase in reported cases of itraconazole resistant strains of A. fumigatus causing human mycoses. Combined therapy could be an alternative to monotherapy for invasive mycoses due to resistant isolates. We have analyzed the combined activity in vitro of caspofungin (CPF) plus amphotericin B (AMB), itraconazole (ITC) or voriconazole (VOR) against a collection of 14 ITC resistant (MIC ³ 8 µg/ml) clinical isolates of A. fumigatus. These isolates were susceptible to AMB (MIC £ 0.5 µg/ml). Twelve strains exhibited MIC of VOR £ 2 µg/ml and two organisms had MIC of VOR ³ 4 µg/ml. Methods: A checkerboard technique was performed. Combinations tested were CPF-AMB, CPF-ITC, and CPF-VOR. Two different visual determinations of the endpoint were performed: (i) Complete inhibition of growth (MIC) and (ii) lowest drug concentration that showed changes in growth, the minimum effective concentration (MEC). The combined effects were analyzed by the summation of fractional concentration index (FIC). The interactions were defined as synergistic if FIC £ 0.5, additive if > 0.5 but £ 1; indifferent if > 1 but £ 4, and antagonistic if > 4. Experiments were performed in duplicate on different days. Results: The means of FIC per combination tested and per endpoint (MIC and MEC) were as follows: CPF-AMB: FIC with MIC: 0.73, FIC with MEC: 0.64; CPF-ITC: FIC with MIC: 1.84, FIC with MEC: 0.54; CPF-VOR: FIC with MIC: 0.44, FIC with MEC: 0.43. Conclusions: CPF-AMB combination exhibited an additive effect against the isolates tested. CPF-ITC had an additive interaction when MEC endpoint was used, and an indifferent interaction if MIC endpoint was determined. CPF-VOR exhibited synergistic effects against the ITC resistant strains of A. fumigatus, even against the two strains that had MIC of VOR ³ 4 µg/ml. (We thank Merck Sharp and Dohme, Pfizer and Janssen-Cilag for supplying the antifungal powders)

abstract No: 


Full conference title: 

43rd Interscience Conference on Antimicrobial Agents
    • ICAAC 43rd