title: In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872).
abstract: The echinocandin MK-0991, formerly L-743,872, is a water-soluble lipopeptide that has been demonstrated in preclinical studies to have potent activity against Candida spp., Aspergillus fumigatus, and Pneumocystis carinii. An extensive in vitro biological evaluation of MK-0991 was performed to better define the potential activities of this novel compound. Susceptibility testing with MK-0991 against approximately 200 clinical isolates of Candida, Cryptococcus neoformans, and Aspergillus isolates was conducted to determine MICs and minimum fungicidal concentrations MF(s). The MFC at which 90% of isolates are inhibited for 40 C. albicans clinical isolates was 0.5 microg/ml. Susceptibility testing with panels of antifungal agent-resistant species of Candida and C. neoformans isolates indicated that the MK-0991 MFCs for these isolates are comparable to those obtained for susceptible isolates. Growth kinetic 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 ranging from 0.06 to 1 microg/ml (0.25 to 4 times the MIC). Drug combination studies with MK-0991 plus amphotericin B found that this combination was not antagonistic against C. albicans, C. neoformans, or A. fumigatus in vitro. Studies with 0 to 50% pooled human or mouse serum established that fungal susceptibility to MK-0991 was not significantly influenced 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. Erythrocyte hemolysis studies with MK-0991 with washed and unwashed human or mouse erythrocytes indicated minimal hemolytic potential with this compound. These favorable results of preclinical studies support further studies with MK-0991 with humans.
authors.affiliation: Antibiotic Discovery and Development, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA.
authors.forename: K
authors.initials: K
authors.lastname: Bartizal
authors.forename: C J
authors.initials: CJ
authors.lastname: Gill
authors.forename: G K
authors.initials: GK
authors.lastname: Abruzzo
authors.forename: A M
authors.initials: AM
authors.lastname: Flattery
authors.forename: L
authors.initials: L
authors.lastname: Kong
authors.forename: P M
authors.initials: PM
authors.lastname: Scott
authors.forename: J G
authors.initials: JG
authors.lastname: Smith
authors.forename: C E
authors.initials: CE
authors.lastname: Leighton
authors.forename: A
authors.initials: A
authors.lastname: Bouffard
authors.forename: J F
authors.initials: JF
authors.lastname: Dropinski
authors.forename: J
authors.initials: J
authors.lastname: Balkovec
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D001230:Aspergillus / Q000187:drug effects; D002175:Candida / Q000187:drug effects; D000077336:Caspofungin; D003455:Cryptococcus neoformans / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D054714:Echinocandins; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D055666:Lipopeptides; D051379:Mice; D008826:Microbial Sensitivity Tests; D010455:Peptides; D010456:Peptides, Cyclic
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D010455:Peptides; D010456:Peptides, Cyclic; D000666:Amphotericin B; D000077336:Caspofungin