EVALUATION OF THE ECHINOCANDIN ANTIFUNGAL MK-0991 (L-743,872) - EFFICACIES IN MOUSE MODELS OF DISSEMINATED ASPERGILLOSIS, CANDIDIASIS, AND CRYPTOCOCCOSIS

The in vivo activity of the Merck antifungal echinocandin drug candida te MK-0991 (L-743,872) was evaluated in mouse models of disseminated c andidiasis, aspergillosis, and cryptococcosis. The echinocandins are p otent inhibitors of 1,3-beta-D-glucan synthase. Two models of dissemin ated candidiasis were used, In a Candida albicans mouse survival model with both DBA/2N and CD-1 mice, estimates of the 50% effective doses (ED(50)s) of MK-0991 were 0.04 and 0.10 mg/kg of body weight/dose at 2 1 days after challenge, respectively. In a C. albicans target organ as say (TOA) with DBA/2N mice, MIK-0991 at levels of greater than or equa l to 0.09 mg/kg/dose significantly reduced the numbers of C. albicans CFU/g of kidneys compared to the numbers in the kidneys of control mic e from 1 to 28 days after challenge. Even when given as a single intra peritoneal dose either 30 min or 24 h after challenge, MK-0991 was eff ective and significantly reduced the numbers of C. albicans CFU/g of k idney compared to those in the controls, MK-0991 was >300-fold less ac tive when it was administered orally than when it was administered par enterally. MK-0991 was efficacious in mouse TOAs against other C. albi cans strains and Candida species including Candida tropicalis, Candida (Torulopsis) glabrata, Candida lusitaniae, Candida parapsilosis, and Candida krusei. MK-0991 was ineffective against disseminated Cryptococ cus neoformans infections. In the model of disseminated aspergillosis in mice, MK-0991 at doses of greater than or equal to 0.02 mg/kg/dose significantly prolonged the survival of DBA/2N mice, with estimates of the ED50 and ED90 of MK-0991 being 0.03 and 0.12 mg/kg/dose, respecti vely, at 28 days after challenge. MK-0991 is a potent, parenterally ad ministered therapeutic agent against disseminated candidiasis and aspe rgillosis that warrants further investigation in human clinical trials .