Department of Chemotherapy and Mycosis, National Institute of Infectious Diseases, Tokyo, Japan.
Med Mycol. 2010 Jun;48(4):606-12. doi: 10.3109/13693780903426721.
We have conducted an in vitro evaluation of the efficacy of a voriconazole-micafungin combination against Candida albicans. When used alone, both micafungin and voriconazole decreased the metabolic activity of planktonic cells, but only micafungin displayed potent anti-biofilm activity. Their combination appeared to have an additive effect against planktonic cells. However, voriconazole significantly antagonized the fungicidal effect of micafungin against Candida biofilms. Time-lag experiments showed that pre-treatment with voriconazole induced resistance to micafungin in Candida biofilms. The micafungin-antagonizing effect of voriconazole persisted even when the biofilm was no longer exposed to voriconazole. In contrast, voriconazole addition after 24 h of micafungin treatment did not alter micafungin sensitivity. To investigate the mechanism of antagonism, we used inhibitors of Hsp90 and its effectors because Hsp90 seems to be implicated in the resistance to micafungin. These molecules reversed the voriconazole-induced resistance to micafungin which suggests that Hsp90-related stress responses are involved in the antagonism. Our results may provide clues as to the mechanism of increased drug resistance in Candida biofilms and raises concerns about the use of the voriconazole-micafungin combination in clinical settings.
我们对伏立康唑-米卡芬净联合用药治疗白色念珠菌的疗效进行了体外评估。单独使用时，米卡芬净和伏立康唑均降低浮游细胞的代谢活性，但只有米卡芬净显示出强大的抗生物膜活性。两者联合使用对浮游细胞似乎具有相加作用。然而，伏立康唑显著拮抗米卡芬净对念珠菌生物膜的杀菌作用。时滞实验表明，伏立康唑预处理诱导念珠菌生物膜对米卡芬净产生耐药性。即使生物膜不再暴露于伏立康唑，伏立康唑的米卡芬净拮抗作用仍然存在。相比之下，米卡芬净治疗 24 小时后再加入伏立康唑并不改变米卡芬净的敏感性。为了研究拮抗作用的机制，我们使用了 Hsp90 及其效应物的抑制剂，因为 Hsp90 似乎与米卡芬净的耐药性有关。这些分子逆转了伏立康唑诱导的米卡芬净耐药性，这表明 Hsp90 相关的应激反应参与了拮抗作用。我们的结果可能为念珠菌生物膜中药物耐药性增加的机制提供线索，并对临床应用伏立康唑-米卡芬净联合用药提出了担忧。
