NEW MODEL OF OROPHARYNGEAL AND GASTROINTESTINAL COLONIZATION BY CANDIDA-ALBICANS IN CD4(-CELL-DEFICIENT MICE FOR EVALUATION OF ANTIFUNGAL AGENTS() T)

A new model for the evaluation of antifungal compounds against orophar yngeal and gastrointestinal mucosal colonization by Candida albicans w as del eloped. To simulate the immune deficiency observed in AIDS pati ents, mice were depleted of CD4(+) T lymphocytes by the injection of e ither GK1.5 hybridoma cells or purified anti-CD4(+) monoclonal antibod y derived from GK1.5 hybridoma cells in tissue culture. Fluorescence-a ctivated cell sorter analysis of splenic lymphocytes confirmed the eli mination of the CD4(+) T-cell population, Gentamicin, a broad-spectrum , nonabsorbable aminoglycoside antibiotic, was given via the drinking water to reduce the normal gastrointestinal microflora, allowing less competition for colonization of the gastrointestinal tract by the C. a lbicans isolates. Mice were challenged by gavage and swabbing their or al mucosae with a pure culture of C. albicans. Gentamicin was withdraw n 3 days postchallenge, and antifungal compounds were administered via the drinking water ad libitum at concentrations ranging from 25 to 40 0 mu g/ml. L-693989, a water-soluble phosphorylated cyclic lipopeptide prodrug of pneumocandin B-0, and L-733560, a semisynthetic derivative of pneumocandin B-0, are inhibitors of 1,3-beta-D-glucan synthesis th at exhibit potent in vivo anti-Candida spp, and anti-Pneumocystis cari nii activities, The efficacies of L-693989, L-733560, fluconazole, ket oconazole, and nystatin were evaluated in this new oropharyngeal and g astrointestinal model of mucosal colonization, L-693989, L-733560, flu conazole, and ketoconazole showed superior efficacies in reducing the numbers of C. albicans CFU per gram of feces and the numbers of oral C FU relative to those in sham-treated controls in this model, while nys tatin was moderately effective in reducing oral and fecal colonization by C. albicaus in this model.