In-Vitro Activity of a New Triazole BAL4815, the Active Component of BAL8557 (the Water-Soluble Prodrug) against Aspergillus spp.

P. Warn, A. Sharp, D.W. Denning

Author address: 

University of Manchester, Manchester, UK

Abstract: 

Abstract

Background: BAL4815 is the active component of the antifungal agent BAL8557 (the water-soluble prodrug) of the triazole class with broadspectrum antifungal activity. We compared the in vitro activity of BAL4815 with that of itraconazole (ITC), voriconazole (VOR), caspofungin (CAS) and amphotericin B (AMB) against 118 isolates of Aspergillus comprising of four different species (fumigatus, terreus, flavus niger); the isolates were pre-selected to include 16 isolates demonstrating resistance to either ITC or AMB.

Methods: Susceptibilities were determined for BAL4815, AMB, ITC and VOR using the microdilution plate modification of the NCCLS M38-A method using RPMI 1640 buffered to pH 7.0 with MOPS, for CAS the method was modified using incubation in a gas mixture of 1% O2, 5% CO2 94% N2 to aid reading. The MIC was taken as the lowest drug concentration that inhibited all growth at 48 hr for BAL4815, ITC, VOR and AMB; for CAS the MIC was taken as the lowest drug concentration that which reduced growth by 80% compared with the drug-free control at 48 hours for BAL4815, ITC, VOR AND CAS; for AMB the MIC was taken as that which inhibited all growth. MFCs (≥99% kill) were also determined for all drugs other than CAS.

Results: For all isolates, geometric mean (GM) MIC values and ranges (in mg/L) were: BAL4815 0.345 and 0.125-2.0, ITC 0.178 and 0.063- >8.0, VOR 0.223 and 0.125-4.0, CAS 0.341 and 0.125-4.0, AMB 0.450 and 0.06-4.0. No significant differences in susceptibility to BAL4815 were seen between species and in contrast to ITC no isolates demonstrated MICs greater than 2.0mg/L. For all isolates, GM MFC values and ranges (in mg/L) were: BAL4815 1.68 and 0.25->8.0, ITC 1.78 and 0.06->8.0, VOR 1.09 and 0.25->8.0, AMB 0.98 and 0.25- >4.0. A reproducibility study on 20% of the isolates showed that 87.5%, 87.5%, 87.5%, 91.7% and 95.8% of isolates retested were within one well of the original MIC value for BAL4815, ITC, VOR, CAS and AMB, respectively.


Conclusions: BAL4815 demonstrated promising antifungal activity against all four Aspergillus species in vitro including strains resistant to ITC, CAS and AMB and warrants further in vivo investigation.

    • ICAAC 44th