Antifungal efficacy of GM237354, a sordarin derivative, in experimental oral candidiasis in immunosuppressed rats

GM237354 is a novel sordarin derivative with a broad spectrum of potent act ivity against a wide range of fungi. The members of this new class of antif ungal agents act as potent inhibitors of fungal protein synthesis. In this study, the therapeutic effects of GM237354 were investigated in a novel exp erimental oral Candida albicans infection model in immunosuppressed rats. T he animals were immunosuppressed with dexamethasone in their drinking water and infected on three alternate days. GM237354 was given three times per d ay for seven consecutive days at 1.25, 2.5, 5, or 10 mg/kg of body weight p er dose. In addition, to provide a preliminary idea of the correlation betw een regimen administration and therapeutic efficacy, GM237354 was administe red to two additional groups of rats at 5 mg/kg once or twice a day for 7 d ays. The drug efficacy was assessed microbiologically, histologically, and by a morphometric study of lesions. Evident agreement was observed among re sults obtained by the different methods in all of the animals studied. Micr obiologically, the efficacy of GM237354 was determined by measuring the num ber of C. albicans organisms in the oral cavities of rats in the middle (da y 4) and at the end (day 7) of the treatment, GM237354 administered at 5, 7 .5, 10, 15, or 30 mg/kg/day for 7 days significantly reduced the number of CFU in the oral cavities of treated rats compared with the number of CFU in the oral cavities of the untreated controls. A significant reduction was a lso observed when GM237354 was administered at 7.5, 10, 15, or 30 mg/kg/day for 4 days. Furthermore, C. albicans was not detected in oral swabs from a ny infected rats after I week of treatment when GM237354 was administered a t 15 or 30 mg/kg/day or after 4 days of treatment at 30 mg/kg/day. Histolog ically, untreated control animals showed extensive colonization of the epit helium of the dorsal tongue by numerous hyphae. Animals treated with GM2373 54 at 7.5 mg/kg/day showed small areas with superficial hyphal penetration into the epithelium that produced intraepithelial microabscesses. However, animals treated with GM237354 at 15 mg/kg/day showed multiple regenerative areas of the covering epithelium, and only focalized zones of the tongue su rface were occupied by hyphae. No hyphal colonization of the epithelium was seen in rats treated with GM237354 at 30 mg/kg/day and which showed extens ive areas of epithelial regeneration of the tongue. The histopathology find ings were confirmed by morphometry studies, and the percentage of epitheliu m occupied by C, albicans hyphae decreased from 17.5% in the control group to 4.8 and 0.1% in animals treated with GM237354 at 7.5 and 15 mg/kg/day, r espectively. These results demonstrated that the sordarin derivative GM2373 54 was effective against experimental oral candidiasis in immunosuppressed rats, and further studies are needed to determine the potential of GM237354 for use in the treatment of this infection in humans.