In Vitro and In Vivo Studies of Ambruticin (W7783): New Class of Antifungal Antibiotics

Abstract

Ambruticin is a cyclopropyl-pyran acid, representing a new class of antibiotics. It has a relatively broad antifungal spectrum in vitro and is highly active against dimorphic as well as filamentous organisms. Of 24 strains of dermatophytic fungi tested, the majority were susceptible to ambruticin at 0.049 ug/ml or less. The minimal inhibitory concentration for the systemic fungi Histoplasma capsulatum and Blastomyces dermatitidis was 0.049 to 0.39 pg/ml. Ambruticin is fungicidal for metabolizing cells of Microsporum fulvum and does not cause cell leakage of 260-nm absorbing material. The antibiotic is effective orally as well as topically in guinea pigs experimentally infected with Trichophyton mentagrophytes. In mice, a single oral dose of 75 mg/kg produced peak serum levels of 45 pig/ml in 1 h with a serum half-life of 3.1 h. Excretion of the antibiotic is principally by the biliary route.

Activity of UK-49,858, a bis-triazole derivative, against experimental infections with Candida albicans and Trichophyton mentagrophytes

“…Trichophytosis in guinea pigs is a well-established predictive model for testing topical (5-7) and systemic antifunigal agents (7,13,14). Published data from studies with animals show that p.o.…”

In Vivo Studies with Ambruticin in Murine Histoplasmosis

“…Results were compared with those obtained with amphotericin B, the drug of choice in human histoplasmosis. In one experiment, ambruticin was shown to be capable of curing infected animals as evidenced by totally negative liver and spleen cultures obtained when mice were sacrificed after 4 weeks of oral treatment with 150 mg of drug per kg per day. The 50% cure dose for ambruticin was between 75 and 150 mg/kg per day; the 50% cure dose for oral amphotericin B in this experiment was between 1.56 and 6.25 mg/kg per day.…”

“…Ambruticin (W7883) has been shown to be a relatively broad-spectrum antifungal agent active in vitro against a variety of filamentous and dimorphic fungal pathogens (4)(5)(6). It already has been shown to be active in vivo in mice experimentally infected with Coccidioides immitis and, moreover, capable both of protecting experimental animals against infection with this organism and of producing biological cures (1,2).…”

An Experimental Model for Evaluation of Antifungal Agents in a <i>Trichophyton mentagrophytes </i>Infection of Guinea Pigs

“…Abrasion [1][2][3] or scarification [4][5][6][7] of the epidermis prior to spore appli cation has been used as a means of induc ing infection, and the duration of the in fection has been prolonged by injection of a steroid [5,6], Greenberg et al [8] de scribed a method by which lesions were in duced in an occluded area without damag ing the skin, and the scoring of the lesions produced by this method was described by Kerbs et al [9]. The occlusive approach was used as a basis for experiments pre sented here.…”