EVALUATION OF WATER-SOLUBLE PNEUMOCANDIN ANALOGS L-733560, L-705589, AND L-731373 WITH MOUSE MODELS OF DISSEMINATED ASPERGILLOSIS, CANDIDIASIS, AND CRYPTOCOCCOSIS

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-73 3560 and L-705589 exhibited efficacies comparable to that of amphoteri cin 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 candidiasi s were used to evaluate these compounds. In both models, mice were cha llenged intravenously with Candida albicans. In a C. albicans survival model with DBA/2N and CD-1 mice, the efficacy of L-733560 was compara ble to that of AMB, while L-731373 and L-705589 were somewhat less act ive. In a previously described C. albicans target organ kidney assay, the pneumocandin analogs ana AMB at doses of greater than or equal to 0.09 mg/kg were effective in sterilizing kidneys, while fluconazole an d ketoconazole were considerably less active and did not sterilize kid neys when they were used at concentrations of less than or equal to 10 0 mg/kg. Although orally administered L-733560 showed activity in both candidiasis models, its efficacy was reduced compared with that of pa renterally administered drug. In a disseminated cryptococcosis mouse m odel that measures the number of CFU of Cryptococcus neoformans per gr am of brain and spleen, L-733560 at 10 mg/kg was ineffective in reduci ng the counts in organs, while AMB at 0.31 mg/kg sterilized the organs . These results indicate that the pneumocandins may be beneficial as p otent parenterally administered therapeutic agents for disseminated as pergillosis and candidiasis.