Treatment of orogastrointestinal candidosis in SCID mice with fluconazole alone or in combination with recombinant granulocyte colony-stimulating factor or interferon-gamma.
Mucosal candidosis is common in acquired immune deficiency syndrome (AIDS) patients, where there is extensive mucosal involvement, but rarely dissemination. To mimic this disease, SCID mice were inoculated orally with Candida albicans, which could be recovered from standardized tissue samples of the esophagus, stomach, small intestine and caecum of all mice. Treatment with fluconazole at 5 or 10 mg kg(-1) per day were equivalent to each other and efficacious in reducing the fungal burden from all four tissues compared with no treatment or lower doses of fluconazole (P < 0.01-0.001). Fluconazole at 5 or 10 mg kg(-1) reduced fungal burden in the stomach by about 200 or 580-fold, respectively, and by approximately 25-fold in the other tissues, with 80 or 100% of mice cleared of esophageal infection, and 40 or 80% cleared of infection in the small intestine, respectively; the same doses cleared < or =20% of stomach infection and none of caecal infection. Treatment with recombinant human granulocyte colony-stimulating factor (G-CSF) up to 500 microg kg(-1) per day or 10(5) U of murine interferon-gamma (IFN-gamma) alone was ineffective, nor were combinations with a suboptimal dose fluconazole synergistic. Overall, fluconazole had dose-responsive efficacy, whereas neither G-CSF nor IFN-gamma alone or in combination with fluconazole improved efficacy. These studies demonstrate the utility of this model for examining antifungal efficacy in a situation that mimics clinical disease in AIDS patients.
Clemons
K V
KV
California Institute for Medical Research, and Department of Medicine, Santa Clara Valley Medical Center, San Jose, CA 95128, USA. Karl.Clemons@slip.net
Stevens
D A
DA
D000818:Animals; D002176:Candida albicans / Q000302:isolation & purification; D002177:Candidiasis / Q000188:drug therapy*; D002180:Candidiasis, Oral / Q000188:drug therapy*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004947:Esophagus / Q000382:microbiology; D005260:Female; D000069585:Filgrastim; D015725:Fluconazole / Q000627:therapeutic use*; D005753:Gastric Mucosa / Q000382:microbiology; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D007371:Interferon-gamma / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000382:microbiology; D051379:Mice; D016513:Mice, SCID; D009092:Mucous Membrane / Q000382:microbiology; D011994:Recombinant Proteins
D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D007371:Interferon-gamma; D015725:Fluconazole; D000069585:Filgrastim