Introduction: BAL8557 is a new water-soluble azole (WSA) derivative with a favorable safety profile and pharmacokinetic properties allowing for once daily or intermittent (up to once-weekly) IV and oral administration. The active metabolite BAL4815, released from prodrug BAL8557, is a potent inhibitor of fungal sterol 14 α-demethylase. Invitro broad-spectrum antifungal activity has been demonstrated in Candida albicans, non-albicans Candida species, fluconazole resistant Candida species, Aspergillus species and other fungal pathogens including zygomycetes. In vivo, efficacy or median effective dose (ED50) of BAL8557 was similar when administered orally and intravenously, indicating excellent bioavailability. No cyclodextrin excipients are required and no nephrotoxicity or visual disturbance was reported in human clinical trials. BAL8557 is currently entering phase III clinical development. Here we compare the in-vitro activity of BAL4815 with that of fluconazole (FLC) and voriconazole (VRC), against 231 Candida isolates. The panel was pre-selected for isolates and species demonstrating decreased susceptibility to FLC and was compiled from 4 collections at the Canisius Wilhelmina Hospital and the Radboud University Hospital, Nijmegen; Hope Hospital, Manchester; Basilea Pharmaceutica, Basle; and Center for Medical Mycology, Cleveland.
Methods: Susceptibilities were determined using the microdilution plate modification of the CLSI (formerly NCCLS) M27A2 standard (2); in total 231 strains have been investigated. QC strain C. krusei ATCC6258 was included at all sites. MICs for BAL4815 and voriconazole were investigated over a range of 0.004 to 4 μg/ml, for isolates outside this range the MIC was not determined systematically. Over all, MIC values and MIC50 of BAL4815 tended to be lower (p < 0.05) than those of voriconazole. Among Candida albicans, wild-type isolates were very susceptible to BAL4815. Most fluconazole-resistant isolates were inhibited by voriconazole and BAL4815 at concentrations achievable in vivo. For C. glabrata, MICs of BAL4815 usually were lower than those of voriconazole by at least one dilution step (p< 0.05)
Conclusion: BAL4815 demonstrated potent antifungal activity against fluconazole-resistant species in vitro.
- TIMM 2nd (2010)