The activities of the water-soluble
pneumocandin derivatives
L-733560,
L-705589, and
L-731373 were evaluated in mouse models of disseminated
aspergillosis,
candidiasis, and
cryptococcosis and were compared with those of commercially available
antifungal agents.
Pneumocandins are inhibitors of 1,3-beta-D-glucan synthesis. In the
aspergillosis model,
L-733560 and
L-705589 significantly prolonged the survival of DBA/2N mice challenged intravenously with Aspergillus fumigatus conidia.
L-733560 and
L-705589 exhibited efficacies comparable to that of
amphotericin B (AMB) with 90% effective doses of 0.48, 0.12, and 0.36 mg/kg of
body weight, respectively. Two mouse models of disseminated
candidiasis were used to evaluate these compounds. In both models, mice were challenged intravenously with Candida albicans. In a C. albicans survival model with DBA/2N and CD-1 mice, the efficacy of
L-733560 was comparable to that of AMB, while
L-731373 and
L-705589 were somewhat less active. In a previously described C. albicans target organ kidney assay, the
pneumocandin analogs and AMB at doses of > or = 0.09 mg/kg were effective in sterilizing kidneys, while
fluconazole and
ketoconazole were considerably less active and did not sterilize kidneys when they were used at concentrations of < or = 100 mg/kg. Although orally administered
L-733560 showed activity in both
candidiasis models, its efficacy was reduced compared with that of parenterally administered
drug. In a disseminated
cryptococcosis mouse model that measures the number of CFU of Cryptococcus neoformans per gram of brain and spleen,
L-733560 at 10 mg/kg was ineffective in reducing the counts in organs, while AMB at 0.31 mg/kg sterilized the organs. These results indicate that the
pneumocandins may be beneficial as potent parenterally administered therapeutic agents for disseminated
aspergillosis and
candidiasis.