The Effect of the New Triazole, Voriconazole (UK-109,496), on the Interactions of Candida albicans and Candida krusei with Endothelial Cells

Abstract

In this study, we investigated how voriconazole affects specific endothelial cell interactions utilizing both fluconazole-susceptible^S and resistant^R Candida albican^s strains (C. albicans^s and C. albicans^R, respectively) as well as Candida krusei. Our data show that exposing C. albicansS to voriconazole significantly reduced its adherence to endothelial cells (p <0.001). The adherence of C. albicans^R to endothelial cells was not affected by treatment with either antifungal agent. Exposure of C. albicans to both agents inhibited germ tube formation; however, voriconazole showed higher ability in inhibiting germination as compared with fluconazole. The effect of antifungals on germination was also tested during co-incubation of yeast cells with endothelial cells. Pretreated C. albicans^S cells germinated on endothelial cells in the presence of voriconazole or fluconazole. However, the degree of germination was reduced by 81% and 16%, respectively. Similar results were observed with C. albicans^R. Our data demonstrate that voriconazole treatment reduced the median germ tube length of C. albicans^S and C. albicans^R by approximately 60%, whereas fluconazole reduced the germ tube length of these strains by 27% and 63%, respectively (P < 0.0001 for each comparison). We compared the efficacy of voriconazole and fluconazole in protecting endothelial cells against damage caused by C. albicans^S, C. albicans^R, and C. krusei. Voriconazole and fluconazole reduced C. albicans-mediated endothelial cell injury by about 90% and 40%, respectively (P < 0.01 for each comparison). Additionally, voriconazole treatment significantly reduced C. krusei-mediated injury to endothelial cells by 69% (P < 0.01), whereas fluconazole did not exhibit significant protection (P < 0.6). These results demonstrate that voriconazole, in addition to its direct inhibitory activity against fungi, may act against Candida spp. by interfering with critical host/parasite interactions, such as adherence and endothelial cell damage, as well as germination. Therefore, this triazole represents a new and promising agent for the treatment of disseminated candidal infections caused by both fluconazole-susceptible and-resistant species.