The activity of ketoconazole in mixed cultures of leukocytes and Candida albicans

A system is described which allows the semi-quantitative investigation of the interaction between Candida albicans and leukocytes in culture with and without the addition of chemotherapeutic agents. Both polymorphonuclear leukocytes and macrophages avidly engulfed added yeast cells. However, they did not succeed in eradicating the fungus even when only 450 yeast cells were added to 3 X 10(6) leukocytes. This is probably due to several factors, including the decline in the functiontional capacity of the leukocytes with time in culture. The major way for the fungus to escape intracellular killing, however, seems to be the switch to the mycellial form in the presence of leukocytes. Engulfed yeasts produce germ tubes, grow out of the leukocytes and form hyphae which are much more resistant to the lytic action of the leukocytes. The leukocytes become necrotic through their interaction with the mycelia. Ketoconazole, a potent, orally active systemic antifungal agent inhibited the growth of C. albicans and completely suppressed the formation of mycelia in culture at very low concentrations (0.01 microgram ml-1). It was toxic to the leukocytes themselves only at 100 microgram ml-1. Addition of ketoconazole (10 (10-1.01 microgram ml-1) to mixed cultures of leukocytes and C. albicans allowed complete elimination of the fungus, probably because the leukocytes could easily remove the remaining yeast cells. The data show the usefulness of the system in the search for systemic antifungals and provide a possible explanation for the efficacy of ketoconazole in vivo.