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

Abstract

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.

FIG. 1

Efficacy of FK463 in disseminated C. albicans 16010 infection (intravenous challenge with 4.0 × 10⁵ CFU/mouse) in ICR mice (cyclophosphamide was administered intraperitoneally at 200 mg/kg 4 days before and 1 day after infection). FK463 was administered intravenously once daily for 4 days, starting at 1 h after infection. Symbols: ●, 1.0 mg/kg; ▴, 0.5 mg/kg; ■, 0.25 mg/kg; ⧫, 0.125 mg/kg; ▾, 0.0625 mg/kg; ○, sham treatment; ∗, significantly different from the control (P < 0.01 by the Wilcoxon rank sum test).

FIG. 2

Efficacy of FK463 in disseminated A. fumigatus IFM41209 infection (intravenous challenge with 3.4 × 10⁴ CFU/mouse) in ICR mice (cyclophosphamide was administered intraperitoneally at 200 mg/kg 4 days before and 1 day after infection). FK463 was administered intravenously once daily for 4 days, starting at 1 h after infection. Symbols: ●, 1.0 mg/kg; ▴, 0.5 mg/kg; ■, 0.25 mg/kg; ⧫, 0.125 mg/kg; ○, sham treatment; ∗, significantly different from the control (P < 0.01 by the Wilcoxon rank sum test).