Efficacy of FK463, a new lipopeptide antifungal agent, in mouse models of disseminated candidiasis and aspergillosis

The efficacy of intravenous injection of FK463, a novel water-soluble lipop eptide, was evaluated in mouse models of disseminated candidiasis and asper gillosis and was compared with those of fluconazole (FLCZ) and amphotericin B (AMPH-B). In the candidiasis model, FK463 significantly prolonged the su rvival of intravenously infected mice at doses of 0.125 mg/kg of body weigh t or higher. In disseminated candidiasis caused by Candida species, includi ng FLCZ-resistant Candida albicans, FK463 exhibited an efficacy 1.4 to 18 t imes 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 in fluenced by the fungal inoculum size, the starting time of the treatment, o r the immunosuppressed status of the host. The reduction in efficacy was le ss than that observed with FLCZ or AMPH-B. The efficacy of FK463 was also e valuated in the disseminated candidiasis target organ assay and was compare d 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 com pared with the numbers of yeast cells before treatment, and its efficacy wa s comparable to that of AMPH-B, while FLCZ at 4 mg/kg showed only a suppres sive effect on the growth of C. albicans in the kidneys. In the disseminate d aspergillosis model, FK463 given at doses of 0.5 mg/kg or higher signific antly prolonged the survival of mice infected intravenously with Aspergillu s fumigatus conidia. The efficacy of FK463 was about 2 times inferior to th at 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 par enterally administered therapeutic agent for disseminated candidiasis and a spergillosis.