特比萘芬与氟康唑或伊曲康唑联合对氟康唑诱导耐药稳定白念珠菌的影响

Synergisic effects of terbinafine combined with fluconazole or itraconazole on stable fluconazole-resistant Candida albicans induced by fluconazole in vitro

目的探讨特比萘芬与氟康唑或伊曲康唑联合抗氟康唑诱导产生的耐药稳定白念珠菌的作用。方法采用多步诱导法,在YEPD培养基中,利用氟康唑诱导白念珠菌敏感株产生耐药稳定菌株。根据美国国家临床实验标准委员会(NCCLS)制定的标准,采用棋盘微量稀释法测定特比萘芬与氟康唑或伊曲康唑对耐药稳定菌株的联合药敏试验,并对诱导耐药稳定菌株ERG11基因的编码区序列进行 DNA测序。结果临床敏感菌株和标准敏感菌株能被诱导形成耐药菌株,但大部分不稳定,诱导耐药稳定株ERG11基因的编码区DNA测序有突变点存在,特比萘芬与氟康唑或伊曲康唑联用对诱导耐药稳定株可产生协同作用。结论特比萘芬与氟康唑或伊曲康唑联合应用对基因突变产生的耐药株有协同作用,可阻止或延迟氟康唑诱导的耐药性白念珠菌菌株的产生。

Objective To investigate the effects of terbinafine combined with flueonazole or itraconazole on stable fluconazole-resistant Candida albicans induced by fluconazole in vitro. Methods Eleven fluconazole-sensitive isolates were serially subcultured in YEPD medium containing different concentrations of fluconazole to induce stable flueonazole-resistant strains （MIC≥ 128 μg/ml）. The checkerboard microdilution method was applied according to M27-A to study the interaction of terbinafine with fluconazole or itraconazole against stable fluconazole-resistant strains in vitro. Nucleotide sequence of the encoded region in ERG11 genes of stable fluconazole resistant strains was examined. Results Resistant strains were induced by fluconazole in 11 fluconazole-sensitive isolates but most were not stable. Mutations were detected in the nucleotide sequence of the encoded region in ERGI 1 of the stable drug acquired resistant isolates. The synergy in terbinafine-fluconazale or itraconazole interaction was observed in stable drug acquired resistant isolates. Conclusion The combinations of terbinafine and fluconazole or itraconazole can show synergisic antifungal effects on fluconazole-resistant mutants.