The Journal of antimicrobial chemotherapy · 2025
Potential risk of cross-resistance to voriconazole in HIV/AIDS patients with Talaromyces marneffei infection and the mechanisms of the cross-resistance.
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Zheng Yan-Qing, Li Qiang-Guo, Latge Jean-Paul, Tang Xi-Ke, Najwa Al-Odaini, Pan Kai-Su, Yang Shi-Xiong, Cao Cun-Wei
Аннотация
BACKGROUND: The use of fluconazole for long-term oral candidiasis treatment in HIV/AIDS patients can potentially affect the clearance rate and antifungal efficacy of voriconazole against Talaromyces marneffei infection. We isolated two T. marneffei strains that were both resistant to fluconazole and voriconazole. To investigate the mechanism underlying the induction of the cross-resistance in T. marneffei.
METHODS: Fluconazole-resistant strains were induced in vitro. The target enzyme 14-α sterol demethylase Cyp51B was sequenced, and drug efflux pump expression was determined by RT-qPCR in all strains.
RESULTS: The sensitivity of fluconazole-induced resistant strains to fluconazole was greater than 128 mg/L, and this resistance was stably inherited after fluconazole pressure was removed. MICs of voriconazole for resistant strains were 4∼16 times greater than FRR (0.25-1 versus 0.06 mg/L). Two mutation hotspots in Cyp51B were detected: G441D and G441V. The AtrF, Mdr1 and Pmfcz genes were significantly overexpressed in the vast majority of the fluconazole-resistant strains (P < 0.05).
CONCLUSIONS: The growth of T. marneffei in the presence of fluconazole could induce voriconazole resistance in vitro. The main cause of this cross-resistance in T. marneffei appears to be related to a mutation in Cyp51B at G441 and overexpression of the efflux pumps AtrF, Mdr1 and Pmfcz.
METHODS: Fluconazole-resistant strains were induced in vitro. The target enzyme 14-α sterol demethylase Cyp51B was sequenced, and drug efflux pump expression was determined by RT-qPCR in all strains.
RESULTS: The sensitivity of fluconazole-induced resistant strains to fluconazole was greater than 128 mg/L, and this resistance was stably inherited after fluconazole pressure was removed. MICs of voriconazole for resistant strains were 4∼16 times greater than FRR (0.25-1 versus 0.06 mg/L). Two mutation hotspots in Cyp51B were detected: G441D and G441V. The AtrF, Mdr1 and Pmfcz genes were significantly overexpressed in the vast majority of the fluconazole-resistant strains (P < 0.05).
CONCLUSIONS: The growth of T. marneffei in the presence of fluconazole could induce voriconazole resistance in vitro. The main cause of this cross-resistance in T. marneffei appears to be related to a mutation in Cyp51B at G441 and overexpression of the efflux pumps AtrF, Mdr1 and Pmfcz.