New model of oropharyngeal and gastrointestinal colonization by Candida albicans in CD4+ T-cell-deficient mice for evaluation of antifungal agents.
A new model for the evaluation of antifungal compounds against oropharyngeal and gastrointestinal mucosal colonization by Candida albicans was developed. To simulate the immune deficiency observed in AIDS patients, mice were depleted of CD4+ T lymphocytes by the injection of either GK1.5 hybridoma cells or purified anti-CD4+ T lymphocytes by the injection of either GK1.5 hybridoma cells or purified anti-CD4+ monoclonal antibody derived from GK1.5 hybridoma cells in tissue culture. Fluorescence-activated cell sorter analysis of splenic lymphocytes confirmed the elimination 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. albicans isolates. Mice were challenged by gavage and swabbing their oral mucosae with a pure culture of C. albicans. Gentamicin was withdrawn 3 days postchallenge, and antifungal compounds were administered via the drinking water ad libitum at concentrations ranging from 25 to 400 micrograms/ml. L-693989, a water-soluble phosphorylated cyclic lipopeptide prodrug of pneumocandin Bo, and L-733560, a semisynthetic derivative of pneumocandin Bo, are inhibitors of 1,3-beta-D-glucan synthesis that exhibit potent in vivo anti-Candida spp. and anti-Pneumocystis carinii activities. The efficacies of L-693989, L-733560, fluconazole, ketoconazole, and nystatin were evaluated in this new oropharyngeal and gastrointestinal model of mucosal colonization. L-693989, L-733560, fluconazole, and ketoconazole showed superior efficacies in reducing the numbers of C. albicans CFU per gram of feces and the numbers of oral CFU relative to those in sham-treated controls in this model, while nystatin was moderately effective in reducing oral and fecal colonization by C. albicans in this model.
Flattery
A M
AM
Antibiotic Discovery and Development, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA.
Abruzzo
G K
GK
Gill
C J
CJ
Smith
J G
JG
Bartizal
K
K
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal; D000935:Antifungal Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002176:Candida albicans / Q000187:drug effects*; D004064:Digestive System / Q000187:drug effects* / Q000382:microbiology*; D004195:Disease Models, Animal; D005260:Female; D015725:Fluconazole / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D008826:Microbial Sensitivity Tests; D009761:Nystatin / Q000494:pharmacology; D009960:Oropharynx / Q000187:drug effects* / Q000382:microbiology*; D010455:Peptides; D010456:Peptides, Cyclic / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D000935:Antifungal Agents; C089367:L 733560; D010455:Peptides; D010456:Peptides, Cyclic; C077459:L 693989; D009761:Nystatin; D015725:Fluconazole; D007654:Ketoconazole