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

The in vivo efficacy of the echinocandin antifungal caspofungin acetate (ca spofungin; MK-0991) was evaluated in models of disseminated aspergillosis a nd candidiasis in mice with cyclophosphamide (CY)-induced immunosuppression . Caspofungin is a 1,3-beta-D-glucan synthesis inhibitor efficacious agains t a number of clinically relevant fungi including Aspergillus and Candida s pecies. Models of CY-induced transient or chronic leukopenia were used with once daily administration of therapy initiated 24 h after microbial challe nge. Caspofungin was effective in treating disseminated aspergillosis in mi ce that were transiently leukopenic (significant prolongation of survival a t doses of greater than or equal to 0.125 mg/kg of body weight and a 50% pr otective dose [PD50] of 0.245 mg/kg/day at 28 days after challenge) or chro nically leukopenic (50 to 100% survival at doses of greater than or equal t o 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 t o 100% of the caspofungintreated mice having sterile kidneys at caspofungin doses from 0.25 to 2.0 mg/kg. In Candida-infected mice with chronic leukop enia, caspofungin was effective at all dose levels tested (0.25 to 1.0 mg/k g), with the log(10) CFU of C. albicans/gram of kidneys of caspofungin-trea ted mice being significantly lower (>99% reduction) than that of sham-treat ed mice from day 4 to day 28 after challenge. Also, 70 to 100% of the caspo fungin-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 o f Candida infections by caspofungin in the absence of host leukocytes provi des compelling in vivo evidence for fungicidal activity against C. albicans . Further human clinical trials with caspofungin against serious fungal inf ections are in progress.