The efficacy of
intravenous injection of
FK463, a novel water-soluble
lipopeptide, was evaluated in mouse models of disseminated
candidiasis and
aspergillosis and was compared with those of
fluconazole (FLCZ) and
amphotericin B (AMPH-B). In the
candidiasis model,
FK463 significantly prolonged the survival of intravenously infected mice at doses of 0.125 mg/kg of
body weight or higher. In disseminated
candidiasis caused by Candida species, including FLCZ-resistant Candida albicans,
FK463 exhibited an efficacy 1.4 to 18 times inferior to that of AMPH-B, with 50% effective doses (ED(50)s) ranging from 0.21 to 1.00 mg/kg and 0.06 to 0.26 mg/kg, respectively, and was much more active than FLCZ. The protective effect of
FK463 was not obviously influenced by the fungal inoculum size, the starting time of the treatment, or the immunosuppressed status of the host. The reduction in efficacy was less than that observed with FLCZ or AMPH-B. The efficacy of
FK463 was also evaluated in the disseminated
candidiasis target organ assay and was compared with those of FLCZ and AMPH-B. Efficacies were evaluated on the basis of a comparison between the mean log(10) CFU in kidneys in the groups treated with
antifungal agents and that in control group. A single dose of
FK463 at 0.5 mg/kg or higher significantly reduced the viable counts in kidneys compared with the numbers of yeast cells before treatment, and its efficacy was comparable to that of AMPH-B, while FLCZ at 4 mg/kg showed only a suppressive effect on the growth of C. albicans in the kidneys. In the disseminated
aspergillosis model,
FK463 given at doses of 0.5 mg/kg or higher significantly prolonged the survival of mice infected intravenously with Aspergillus fumigatus conidia. The efficacy of
FK463 was about 2 times inferior to that of AMPH-B, with ED(50)s ranging from 0.25 to 0.50 mg/kg and 0.11 to 0.29 mg/kg, respectively. These results indicate that
FK463 may be a potent parenterally administered therapeutic agent for disseminated
candidiasis and
aspergillosis.