Organism-dependent fungicidal activity of azoles

Itraconazole (ITZ) and voriconazole (VCZ) exhibit broadspectrum activity against both pathogenic yeasts and filamentous fungi. In vitro susceptibility studies with ITZ and VCZ have revealed that clearcut MIC end-points are readily obtained against Aspergillus species but not for Candida species. We investigated the fungicidal activity of ITZ and VCZ against A. fumigatus by kill-curve experiments and the results were compared with those obtained for C. albicans. Approximately 5 × 10⁶ colony forming units (CPUs) of C. albicans [ATCC 90028; MICs μg/ml; ITZ = 0.02, VCZ = 0.02, amphotericin B (AMB) = 0.01] and A. fumigatus (clinical isolate W73355; MICs ITZ = 0.25, VCZ = 0.5, AMB 0.5) in 5 ml peptone yeast extract glucose (PYG) medium were exposed to 0-10 μg/ml of ITZ and VCZ at 35°C; 0.1 ml aliquots were removed at various time intervals, serial dilutions were prepared and aliquots of the diluted cell suspension were spread on PYG agar. The plates were incubated at 35°C for 24 h, and CPUs per ml for various drug concentrations at each time point were determined. ITZ and VCZ killed A. fumigatus conidia, and the amount of killing was dependent on the time of exposure and the concentration of the antifungal agent used. At 5μg/ml, ITZ and VCZ killed approximately 85% and 95% conidia, respectively after 24 h of exposure; AMB provided 99.9% killing. In contrast, ITZ and VCZ provided 80% and 85% growth inhibition of C. albicans compared to the drug-free control; AMB provided 99.9% killing. No killing of Candida occurred with azoles. These results indicate that both ITZ and VCZ are cytocidal agents for A fumigatus, but not for C. albicans suggesting that the fungicidal activity of ITZ and VCZ is organism-dependent.