BMY-28864, a water-soluble pradimicin derivative, had potent in vitro activity against a wide variety of fungi, including those associated with deep-seated mycosis; it inhibited the growth of standard strains and clinical isolates at concentrations of 12.5 micrograms/ml or less. At the MIC or higher concentrations,
BMY-28864 was fungicidal for Candida albicans under both growing and nongrowing conditions.
BMY-28864 expressed fungicidal activity only in the presence of Ca2+, and its activity was totally diminished when
ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic
acid (
EGTA), a Ca2+
chelator, was added to the test medium. The effectiveness of intravenously administered
BMY-28864 in vivo was examined and compared with that of
amphotericin B in mouse models of
fungal infections. Both normal and
cyclophosphamide-treated immunosuppressed mice infected with C. albicans, Cryptococcus neoformans, or Aspergillus fumigatus responded to
therapy with
BMY-28864 (50% protective doses of 17, 18, and 37 mg/kg of
body weight in normal mice and of 32, 35, and 51 mg/kg in
cyclophosphamide-treated mice, respectively). Lethal lung
infections were also established with C. albicans or A. fumigatus in
cyclophosphamide-treated mice. The 50% protective doses of
BMY-28864 were 15 and 23 mg/kg per dose against C. albicans and A. fumigatus, respectively. The immunosuppression induced by intraperitoneal administration of 200 mg of
cyclophosphamide per kg lasted for 5 days, and total recovery was observed by day 7.