Evaluation of water-soluble pneumocandin analogs L-733560, L-705589, and L-731373 with mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis

Abstract

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-␤-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 Ն0.09 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 Յ100 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.

Efficacy of FK463, a New Lipopeptide Antifungal Agent, in Mouse Models of Disseminated Candidiasis and Aspergillosis

“…These compounds have been shown to be effective in experimental disseminated and pulmonary aspergillosis models in rodents (1,13,17). FK463 did not completely inhibit the growth of A. fumigatus in the broth microdilution assay, but it showed a suppressive effect on hyphal growth and a morphological effect (Maki et al, 38th ICAAC), similar to pneumocandins.…”

Direct Comparison of the Pharmacodynamics of Four Antifungal Drugs in a Mouse Model of Disseminated Candidiasis Using Microbiological Assays of Serum Drug Concentrations

“…Groups of 4 or 10 mice were treated once with either the vehicle or the antifungal agents at the concentrations indicated 1 hr after inoculation. The endpoint for the experiments was kidney burden: experimental groups of mice were euthanised at the time points indicated and kidney fungal burden determined using a modification of the method described by Abruzzo et al (1). Kidneys were homogenized in 5 ml of sterile 0.9% saline using a homogenizer.…”

Sphingolipids as Targets for Treatment of Fungal Infections

“…However, zygomycetes usually lack this molecule and, consequently, are resistant to these drugs [51]. In addition, although echinocandins can enhance the activity of amphotericin B and fluconazole against C. neoformans in vitro [52] they are ineffective against disseminated cryptococcosis [53] and in some cases they could be detrimental [54]. Besides this limited spectrum, echinocandins present other limitations.…”