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    克拉霉素联合抗真菌药物作用于马尔尼菲篮状菌的体外药敏研究

    In vitro susceptibility study of clarithromycin combined with antifungal agents against Talaromyces marneffei

      摘要
    • 摘要: 目的：评估克拉霉素（clarithromycin,CLA）与4种抗真菌药物对马尔尼菲篮状菌（Talaromyces marneffei,TM）的体外联合效应，并比较不同判读标准对联合药敏结果的影响，为临床治疗TM和非结核分枝杆菌（nontuberculous mycobacteria,NTM）合并感染提供理论依据。方法：采用棋盘格法，对20株TM（19株临床株+1株标准株）进行CLA与两性霉素B（amphotericin B,AmB）、氟康唑（fluconazole,FLC）、伊曲康唑（itraconazole,ITC）、伏立康唑（voriconazole,VOC）的联合药敏实验。唑类药物分别采用50%抑制浓度(IC50)与完全抑制浓度(IC100)两种判读标准，使用部分抑制浓度指数（fractional inhibitory concentration index,FICI）判定联合效应。结果：AmB+CLA协同率最高（18/20,90%），联合后AmB的IC100几何均数从2.297μg/mL降至0.536μg/mL（P<0.001）。ITC+CLA在两种判读标准下均表现稳定（协同率45%～65%，相加率35%～55%）。FLC和VOC联合CLA的效应高度依赖判读标准：IC50判读时以无关作用为主（100%和85%）,IC100判读时转变为相加作用为主（85%和75%）。所有组合均未观察到拮抗作用。结论：AmB+CLA协同效应最强，提示其可能作为重症合并感染联合治疗的潜在优选方案；ITC联合CLA效应稳定，提示其具有适用于口服序贯治疗的潜力；FLC和VOC联合CLA需达到完全抑制浓度方能体现联合优势。判读标准的选择可显著影响唑类药物联合药敏的定性结论。

       

      Abstract: Objective: To evaluate the in vitro combined effects of clarithromycin（CLA） with 4 antifungal agents against Talaromyces marneffei（TM）, and to compare the impacts of different interpretive criteria on the combined susceptibility results, thereby providing a theoretical basis for the clinical treatment of co-infection caused by TM and nontuberculous mycobacteria（NTM）. Methods: The checkerboard microdilution method was adopted to perform the combination susceptibility testing of CLA with amphotericin B（AmB）, fluconazole（FLC）, itraconazole（ITC） and voriconazole（VOC） against 20 TM strains（19 clinical isolates+1 reference strain）. For azoles, 2 interpretive criteria were respectively adopted: half-maximal inhibitory concentration(IC50) and complete-inhibitory concentration(IC100), and the combined effects were assessed using fractional inhibitory concentration index（FICI）. Results: The combination of AmB and CLA showed the highest synergy rate（18/20, 90%）, and the geometric mean of IC100 of AmB decreased from 2.297 μg/mL to 0.536 μg/mL after the combination（P<0.001）. The combination of ITC and CLA showed consistent activity under both interpretive criteria, with synergy rates of 45%-65% and additive rates of 35%-55%. The synergistic effects of the FLC-CLA and VOC-CLA combinations were highly dependent on the interpretive criteria: indifferent interactions predominated at IC50（100% and 85%, respectively）, whereas additive interactions predominated at IC100（85% and 75%, respectively）. No antagonism was observed for any combination. Conclusion: The combination of AmB and CLA exhibits the strongest synergistic effect, suggesting its potential as a preferred option for combined therapy in severe co-infections. The combination of ITC and CLA exhibits a stable synergistic effect, suggesting its potential for oral sequential therapy. The synergistic effects of the FLC-CLA and VOC-CLA combinations can only be observed at IC100. The choice of interpretive criteria significantly affects the qualitative outcomes of azolecombination susceptibility testing.

       

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