Efficacy of the echinocandin caspofungin against disseminated aspergillosis and candidiasis in cyclophosphamide-induced immunosuppressed mice

Abstract

The in vivo efficacy of the echinocandin antifungal caspofungin acetate (caspofungin; MK-0991) was evaluated in models of disseminated aspergillosis and candidiasis in mice with cyclophosphamide (CY)-induced immunosuppression. Caspofungin is a 1, 3-beta-D-glucan synthesis inhibitor efficacious against a number of clinically relevant fungi including Aspergillus and Candida species. Models of CY-induced transient or chronic leukopenia were used with once daily administration of therapy initiated 24 h after microbial challenge. Caspofungin was effective in treating disseminated aspergillosis in mice that were transiently leukopenic (significant prolongation of survival at doses of > or =0.125 mg/kg of body weight and a 50% protective dose [PD(50)] of 0.245 mg/kg/day at 28 days after challenge) or chronically leukopenic (50 to 100% survival at doses of > or =0.5 mg/kg and PD(50)s ranging from 0.173 to 0.400 mg/kg/day). Caspofungin was effective in the treatment and sterilization of Candida infections in mice with transient leukopenia with a 99% effective dose based on reduction in log(10) CFU of Candida albicans/gram of kidneys of 0.119 mg/kg and 80 to 100% of the caspofungin-treated mice having sterile kidneys at caspofungin doses from 0.25 to 2.0 mg/kg. In Candida-infected mice with chronic leukopenia, caspofungin was effective at all dose levels tested (0.25 to 1.0 mg/kg), with the log(10) CFU of C. albicans/gram of kidneys of caspofungin-treated mice being significantly lower (>99% reduction) than that of sham-treated mice from day 4 to day 28 after challenge. Also, 70 to 100% of the caspofungin-treated, chronic leukopenic mice had sterile kidneys at caspofungin doses of 0.5 to 1.0 mg/kg from day 8 to 28 after challenge. Sterilization of Candida infections by caspofungin in the absence of host leukocytes provides compelling in vivo evidence for fungicidal activity against C. albicans. Further human clinical trials with caspofungin against serious fungal infections are in progress.

FIG. 1

Efficacy in the transient-suppression model of disseminated aspergillosis. ICR mice were immunosuppressed with a 6-mg/mouse dose of CY administered i.p. 3 days prior to infection with 1.6 × 10⁴ CFU of A. fumigatus MF5668 (i.v.) per mouse. Immunosuppression was maintained by additional doses of CY (2 mg/mouse, i.p.) on days 1, 4, 7, and 10 after infection. Therapy was initiated 24 h after infection, and mice (10/group) were treated i.p., q.d., for 14 days. (A) Caspofungin; (B) AmB.

FIG. 2

Efficacy of delayed therapy against disseminated C. albicans MY1055 infection in CY-treated, transient-suppression model in ICR mice. Mice were challenged i.v. with C. albicans MY1055 at 2.0 × 10⁴ CFU/mouse. Mice (10/group) received first treatment 24 h after challenge (delayed therapy) and were treated i.p., q.d., for 7 days. Mice were immunosuppressed with a 6-mg/mouse dose of CY on day −3. Immunosuppression was maintained by additional doses of CY on days 1 and 4 after challenge. (A) Caspofungin; (B) AmB.

FIG. 3

Efficacy of delayed therapy against disseminated C. albicans MY1055 infection in CY-treated, chronically immunosuppressed ICR mice. Mice were challenged i.v. with C. albicans MY1055 at 5.6 × 10⁴ CFU/mouse (study 1) and 1.22 × 10⁵ CFU/mouse (Study 2). Mice received first treatment 24 h after challenge (delayed therapy) and were treated i.p., q.d., for 7 days. Survival data were pooled from both studies (20 mice total). Mice were immunosuppressed throughout the experimental period (28 days). (A) Caspofungin; (B) AmB.

FIG. 4

Efficacy of delayed therapy with FCZ against disseminated C. albicans MY1055 infection in CY-treated, chronically immunosuppressed ICR mice. Mice were challenged i.v. with C. albicans MY1055 at 5.6 × 10⁴ CFU/mouse (study 1) and 1.22 × 10⁵ CFU/mouse (study 2). Mice (10/group) received first treatment 24 h after challenge (delayed therapy) and were treated i.p., q.d., for 7 days. Mice were immunosuppressed throughout the experimental period (28 days).