IN-VITRO PRECLINICAL EVALUATION STUDIES WITH THE ECHINOCANDIN ANTIFUNGAL MK-0991 (L-743,872)

The echinocandin MK-0991, formerly L-743,872, is a water-soluble lipop eptide that has been demonstrated in preclinical studies to have poten t activity against Candida spp., Aspergillus fumigatus, and Pneumocyst is carinii. An extensive in vitro biological evaluation of MK-0991 was performed to better define the potential activities of this novel com pound. Susceptibility testing with MK-0991 against approximately 200 c linical isolates of Candida, Cryptococcus neoformans, and Aspergillus isolates was conducted to determine MICs and minimum fungicidal concen trations MF(s). The MFC at which 90% of isolates are inhibited for 40 C. albicans clinical isolates was 0.5 mu g/ml. Susceptibility testing with panels of antifungal agent-resistant species of Candida and C. ne oformans isolates indicated that the MK-0991 MFCs for these isolates a te comparable to those obtained for susceptible isolates. Growth kinet ic studies of MK-0991 against Candida albicans and Candida tropicalis isolates showed that the compound exhibited fungicidal activity (i.e., a 99% reduction in viability) within 3 to 7 h at concentrations raggi ng from 0.06 to 1 mu g/ml (0.25 to 4 times the MIC). Drug combination studies with MK-0991 plus amphotericin B found that this combination w as not antagonistic against C. albicans, C. neoformans, or A. fumigatu s in vitro. Studies with 0 to 50% pooled human or mouse serum establis hed that fungal susceptibility to MK-0991 was not significantly influe nced by the presence of human or mouse serum. Results from resistance induction studies suggested that the susceptibility of C. albicans was not altered by repeated exposure (40 passages) to MK-0991. Erythrocyt e hemolysis studies with MK-0991 with washed and unwashed human or mou se erythrocytes indicated minimal hemolytic potential with this compou nd. These favorable results of preclinical studies support further stu dies with MK-0991 with humans.