Efficacy of UK-49,858 (fluconazole) against Candida albicans experimental infections in mice

Abstract

UK-49,858 (fluconazole), a new, orally absorbed bis-triazole derivative, has been evaluated against systemic infections with Candida albicans in normal and immunosuppressed mice and against an intestinal infection with C. albicans in immunosuppressed mice. Orally administered ketoconazole was used as a comparison agent throughout, and orally administered amphotericin B was included for comparative in the experimental intestinal infection. In a 10-day dosage regimen, UK-49,858 was far more active than ketoconazole against systemic infections with C. albicans in normal and immunosuppressed mice. In normal mice, extension of UK-49,858 dosing to 30 days resulted in prolongation of survival to over 90 days, and up to 60% of treated animals had no detectable C. albicans in their kidneys. In addition, over 90% of mice with intestinal candidiasis had culture-negative feces after a 3-day treatment with UK-49,858, but only 62 and 23% of mice gave this response after amphotericin B and ketoconazole therapy, respectively. These data suggest that UK-49,858 may be of value in the treatment of systemic and gastrointestinal infections due to C. albicans in humans.The high morbidity and mortality caused by opportunistic systemic fungal infections (10, 12), their increasing incidence (2, 3), and the lack of safe, effective therapy (4, 11, 18) has prompted a search for safer and more effective drugs. UK-49,858 (fluconazole) is a new bis-triazole derivative, developed at Pfizer Ltd., which has been reported (15) to exhibit superior efficacy to that of ketoconazole in fulminating systemic candidiasis (107 CFU per animal) of normal and immunosuppressed animals as well as in superficial infections (15). Candida albicans is the most common opportunistic fungal pathogen (9,12,22), and so we have examined UK-49,858 in comparison with ketoconazole in less rapidly progressing but still lethal systemic infections (104 to 105 CFU per animal) and with ketoconazole and amphotericin B in a gastrointestinal infection in mice.MATERIALS AND METHODS Fungi. C. albicans Y0102 from the Pfizer culture collection (Pfizer Central Research, Sandwich, Kent, England) was stored freeze-dried or under liquid nitrogen, and when needed fresh cultures were grown on Sabouraud dextrose agar for 24 h at 28°C. This isolate is a standard test strain used in our laboratory and responds to azoles in a manner typical of other isolates (9, 15). Inocula for the in vivo models were prepared from washed blastospores in saline, standardized by turbidimetry with an absorptiometer (Evans Electroselenium Ltd., Halstead, England), and checked by hemocytometer counts.

Overview of medically important antifungal azole derivatives

“…Viability studies of three isolates of Candida species exposed to fluconazole demonstrated that the drug was fungistatic and not fungicidal whether tested against the yeast in stationary or early logarithmic phase (144 Fluconazole is active in the treatment of experimental candidiasis as well. In normal and immunosuppressed mice, fluconazole administered for 10 days was found to be significantly more active than ketoconazole against systemic infections with C. albicans (308). In normal mice, fluconazole administered for 30 days prolonged survival of infected mice for >90 days, and up to 60% of the animals had no detectable C. albicans cells in their kidneys.…”

Effects of amphotericin B and fluconazole on the extracellular and intracellular growth of Candida albicans

“…One of these antifungal agents is the triazole fluconazole (Flu) (4,10,14,33,34,41). In vivo experimental studies suggested that Flu is active against disseminated candidiasis (8,9,29,31,32,35,37). Recently, the antifungal efficacy of Flu was demonstrated in persistently granulocytopenic rabbits when it was used for prevention or early treatment (39,40).…”

Comparison of fluconazole and amphotericin B in treating histoplasmosis in immunosuppressed mice

“…injection in treating normal AKR and C57BL/6 mice infected with Histoplasma capsulatum (7). Others have reported that fluconazole was more effective than the imidazole ketoconazole in treating normal mice (12,14) and rats (12,13) (14) reported that fluconazole was more than 20 times as effective as ketoconazole in C. albicans-infected mice that were immunocompromised by daily administration of dexamethasone. Fluconazole is an attractive antifungal agent in that (i) it is less toxic than amphotericin B, (ii) it is renally excreted, (iii) it readily penetrates cerebral spinal fluid, and (iv) it has a high serum half-life that can be maintained by daily oral administration (5).…”