Peter A Warn1, Andrew Sharp, David W Denning. 1. School of Medicine, 1.800 Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK. peter.warn@manchester.ac.uk
Abstract
OBJECTIVES: BAL4815 is the active component of the antifungal triazole agent BAL8557 (the water-soluble prodrug). We compared the in vitro activity of BAL4815 with that of itraconazole, voriconazole, caspofungin and amphotericin B against 118 isolates of Aspergillus comprising four different species (fumigatus, terreus, flavus and niger); the isolates were pre-selected to include 16 isolates demonstrating in vitro resistance to other agents. METHODS: Susceptibilities were determined for BAL4815, amphotericin B, itraconazole and voriconazole using the microdilution plate modification of the NCCLS M38-A method with RPMI 1640 buffered to pH 7.0 with MOPS; for caspofungin the method was modified using incubation in a gas mixture of 1% O2/5% CO2/94% N2 to aid reading. MFCs (> or =99% kill) were also determined for all drugs other than caspofungin. RESULTS: For all isolates, geometric mean (GM) MIC values and ranges (in mg/L) were: BAL4815, 0.620 and 0.125-2.0; itraconazole, 0.399 and 0.063->8.0; voriconazole, 0.347 and 0.125-8.0; caspofungin, 0.341 and 0.125-4.0; amphotericin B, 0.452 and 0.06-4.0. No significant differences in susceptibility to BAL4815 were seen between species and in contrast to itraconazole no isolates demonstrated MICs >2.0 mg/L. For all isolates, GM MFC values and ranges (in mg/L) were: BAL4815, 1.68 and 0.25->8.0; itraconazole, 1.78 and 0.06->8.0; voriconazole, 1.09 and 0.25->8.0; amphotericin B, 0.98 and 0.25->4.0. CONCLUSIONS: BAL4815 demonstrated promising antifungal activity against all four Aspergillus species in vitro including strains resistant to itraconazole, caspofungin or amphotericin B.
OBJECTIVES: BAL4815 is the active component of the antifungal triazole agent BAL8557 (the water-soluble prodrug). We compared the in vitro activity of BAL4815 with that of itraconazole, voriconazole, caspofungin and amphotericin B against 118 isolates of Aspergillus comprising four different species (fumigatus, terreus, flavus and niger); the isolates were pre-selected to include 16 isolates demonstrating in vitro resistance to other agents. METHODS: Susceptibilities were determined for BAL4815, amphotericin B, itraconazole and voriconazole using the microdilution plate modification of the NCCLS M38-A method with RPMI 1640 buffered to pH 7.0 with MOPS; for caspofungin the method was modified using incubation in a gas mixture of 1% O2/5% CO2/94% N2 to aid reading. MFCs (> or =99% kill) were also determined for all drugs other than caspofungin. RESULTS: For all isolates, geometric mean (GM) MIC values and ranges (in mg/L) were: BAL4815, 0.620 and 0.125-2.0; itraconazole, 0.399 and 0.063->8.0; voriconazole, 0.347 and 0.125-8.0; caspofungin, 0.341 and 0.125-4.0; amphotericin B, 0.452 and 0.06-4.0. No significant differences in susceptibility to BAL4815 were seen between species and in contrast to itraconazole no isolates demonstrated MICs >2.0 mg/L. For all isolates, GM MFC values and ranges (in mg/L) were: BAL4815, 1.68 and 0.25->8.0; itraconazole, 1.78 and 0.06->8.0; voriconazole, 1.09 and 0.25->8.0; amphotericin B, 0.98 and 0.25->4.0. CONCLUSIONS: BAL4815 demonstrated promising antifungal activity against all four Aspergillus species in vitro including strains resistant to itraconazole, caspofungin or amphotericin B.
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