In vitro and in vivo antifungal activities of ER-30346, a novel oral triazole with a broad antifungal spectrum.
ER-30346 is a novel oral triazole with a broad spectrum of potent activity against a wide range of fungi. ER-30346, with MICs at which 90% of the strains tested are inhibited (MIC90s) ranging from 0.025 to 0.78 microgram/ml, was 4 to 32 times more active than itraconazole, fluconazole, and amphotericin B against Candida albicans, Candida parapsilosis, and Candida glabrata. Against Candida tropicalis, ER-30346, with an MIC90 of 12.5 micrograms/ml, was 2 to > 8 times more active than itraconazole and fluconazole, but was 16 times less active than amphotericin B. ER-30346 (MIC90, 0.78 microgram/ml) was four to eight times more active than fluconazole and amphotericin B and had activity comparable to that of itraconazole against Trichosporon beigelli. The MIC90s of ER-30346 were 0.10 microgram/ml for Cryptococcus neoformans and 0.39 microgram/ml for Aspergillus fumigatus. ER-30346 was 2 to 8 times more active than itraconazole and amphotericin B and 32 to > 256 times more active than fluconazole. ER-30346 also showed good activity against dermatophytes, with MICs ranging from 0.05 to 0.39 microgram/ml, and its activity was comparable to or 2 to 16 times higher than those of itraconazole and amphotericin B and > 32 times higher than that of fluconazole. In vivo activity was evaluated with systemic infections in mice. Against systemic candidiasis and cryptococcosis, ER-30346 was comparable in efficacy to fluconazole and was more effective than itraconazole. Of the drugs tested, ER-30346 was the most effective drug against systemic aspergillosis. We studied the levels of ER-30346 in mouse plasma. The maximum concentration of drug in plasma and the area under the concentration-time curve for ER-30346 showed good linearity over a range of doses from 2 to 40 mg/kg of body weight.
Hata
K
K
Department of Microbiology and Infectious Disease, Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Kimura
J
J
Miki
H
H
Toyosawa
T
T
Nakamura
T
T
Katsu
K
K
D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy / Q000382:microbiology; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D003453:Cryptococcosis / Q000188:drug therapy / Q000382:microbiology; D005260:Female; D015725:Fluconazole / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D005658:Fungi / Q000187:drug effects*; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
D000935:Antifungal Agents; D013844:Thiazoles; D014230:Triazoles; D015725:Fluconazole; C104066:ER 30346