Fratti R A, Belanger P H, Sanati H, Ghannoum M A
Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, California 90509, USA.
J Chemother. 1998 Feb;10(1):7-16. doi: 10.1179/joc.1998.10.1.7.
In this study, we investigated how voriconazole affects specific endothelial cell interactions utilizing both fluconazole-susceptibles and resistantR Candida albicans strains (C. albicansS and C. albicansR, 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. albicansR 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. albicansS 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. albicansR. Our data demonstrate that voriconazole treatment reduced the median germ tube length of C. albicansS and C. albicansR 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. albicansS, C. albicansR, 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.
在本研究中，我们利用氟康唑敏感和耐药的白色念珠菌菌株（分别为白色念珠菌敏感株和白色念珠菌耐药株）以及克鲁斯念珠菌，研究了伏立康唑如何影响特定的内皮细胞相互作用。我们的数据表明，将白色念珠菌敏感株暴露于伏立康唑可显著降低其对内皮细胞的黏附（p<0.001）。白色念珠菌耐药株对内皮细胞的黏附不受任何一种抗真菌药物治疗的影响。白色念珠菌暴露于这两种药物均可抑制芽管形成；然而，与氟康唑相比，伏立康唑在抑制发芽方面表现出更高的能力。在酵母细胞与内皮细胞共孵育期间，也测试了抗真菌药物对发芽的影响。预先处理的白色念珠菌敏感株细胞在存在伏立康唑或氟康唑的情况下在内皮细胞上发芽。然而，发芽程度分别降低了81%和16%。白色念珠菌耐药株也观察到类似结果。我们的数据表明，伏立康唑治疗使白色念珠菌敏感株和白色念珠菌耐药株的芽管长度中位数分别减少了约60%，而氟康唑使这些菌株的芽管长度分别减少了27%和63%（每次比较P<0.0001）。我们比较了伏立康唑和氟康唑在保护内皮细胞免受白色念珠菌敏感株、白色念珠菌耐药株和克鲁斯念珠菌所致损伤方面的疗效。伏立康唑和氟康唑分别将白色念珠菌介导的内皮细胞损伤降低了约90%和40%（每次比较P<0.01）。此外，伏立康唑治疗使克鲁斯念珠菌介导的内皮细胞损伤显著降低了69%（P<0.01），而氟康唑未表现出显著的保护作用（P<0.6）。这些结果表明，伏立康唑除了对真菌具有直接抑制活性外，还可能通过干扰关键的宿主/寄生虫相互作用，如黏附、内皮细胞损伤以及发芽，来对抗念珠菌属。因此，这种三唑类药物是治疗由氟康唑敏感和耐药菌株引起的播散性念珠菌感染的一种新的有前景的药物。
