In vitro and in vivo anti-Candida activity and toxicology of LY121019

LY121019 (N-p-octyloxybenzoylechinocandin B nucleus) is a semisynthetic antifungal antibiotic that possesses potent anti-Candida activity. The MIC50 and the MIC90 for both LY121019 and amphotericin B were 0.625 and 1.25 micrograms/ml, respectively. Only an 8-fold increase in the MIC against C. albicans occurred during 34-day exposure to subinhibitory concentrations indicating that LY121019 has a low potential for causing resistance development. Scanning electron microscopic studies revealed that LY121019 caused severe damage to the C. albicans cell. The ED50's for LY121019 and amphotericin B administered parenterally to mice were 7.4 and 2.5 mg/kg, respectively. Parenterally administered LY121019 at doses of 6.25 mg/kg significantly reduced the recovery of C. albicans from infected mouse kidneys. Orally administered 50 and 100 mg/kg doses of LY121019 were effective in eliminating C. albicans from the gastrointestinal tract of infected mice. Topical application of 5% LY121019 was as effective as 3% nystatin in the treatment of superficial C. albicans infections. Local administration of LY121019, nystatin, or miconazole was effective against rat vaginal candidiasis. LY121019 was administered intravenously to dogs at doses up to 100 mg/kg/day, 5 days a week for 3 months; all dogs survived. Compound related effects included a histamine-like reaction, increased serum alkaline phosphatase and SGPT, fatty vacuolization of the liver, and some tissue damage at the injection site. The no effect dose in dog was 10 mg/kg. LY121019 had no more than 1/20 the toxicity of amphotericin B in the dog.