Abstract
Ketoconazole (KCZ), a new water soluble oral imidazole, showed a broad antifungal spectrum in vitro including various dermatophytes, dimorphic fungi and pathogenic yeasts. Candida albicans, however, proved to be relatively insensitive to this drug and minimal inhibitory concentration (MIC) was determined as 50μg/ml for this fungus. With mice, 14μg/ml of the peak blood level was reached after a single oral administration of 80mg/kg of KCZ. Contrary to these observations, high survival rates were recorded in the experimental chemotherapy of murine candidiasis even with a single, relatively small dose (less than 50mg/kg) of the drug by intraperitoneal as well as oral administration. Detailed studies on the anti-Candida activity of KCZ in vitro revealed that the drug caused some inhibition of C. albicans growth at the concentration far below the minimal inhibitory concentration. Very low concentrations of the drug significantly delayed germ tube formation and subsequent development of pseudomycelia of C. albicans. In consequence, mouse peritoneal exudate cells were able to phagocytose readily C. albicans cells in the presence of KCZ as determined by 3H-uridine uptake. Furthermore, the intracellular killing rate was higher with KCZ treated C. albicans than that with untreated organisms. The conclusion was thus drawn that the excellent in vivo effectiveness of KCZ to C. albicans infection, despite of its relatively low in vitro activity, might be at least in part attributed to the inhibition of germ tube formation at low concentration and to the enhancement of phagocytotic and subsequent intracellular fungicidal activity of macrophages.
