Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Antimicrob Agents Chemother. 2013 Oct;57(10):4656-63. doi: 10.1128/AAC.00597-13. Epub 2013 Jul 15.
Antifungal combination therapy with voriconazole or amphotericin B and an echinocandin is often employed as primary or salvage therapy for management particularly of refractory aspergillosis. The pharmacodynamic interactions of amphotericin B- and voriconazole-based combinations with the three echinocandins caspofungin, micafungin, and anidulafungin in the presence of serum were tested against 15 Aspergillus fumigatus complex, A. flavus complex, and A. terreus complex isolates to assess both their growth-inhibitory and fungicidal activities. The in vitro activity of each drug alone and in combination at a 1:1 fixed concentration ratio was tested with a broth microdilution colorimetric method, and interactions were assessed by isobolographic analysis. Synergy was found for all amphotericin B- and voriconazole-based combinations, with amphotericin B-based combinations showing strong inhibitory synergistic interactions (interaction indices of 0.20 to 0.52) and with voriconazole-based combinations demonstrating strong fungicidal synergistic interactions (interaction indices of 0.10 to 0.29) (P < 0.001). Drug- and species-specific differences were found, with caspofungin and the A. fumigatus complex exhibiting the weakest synergistic interactions. In the presence of serum, the synergistic interactions were reduced in the order (from largest to smallest decrease) micafungin > anidulafungin > caspofungin, and A. flavus complex > A. fumigatus complex > A. terreus complex, resulting in additive interactions, particularly for inhibitory activities of amphotericin B-echinocandin combinations and fungicidal activities of voriconazole-echinocandin combinations. Drug- and species-specific differences were found in the presence of serum for inhibitory activities of antifungal drugs, with the lowest interaction indices being observed for amphotericin B-caspofungin (median, 0.77) and for the A. terreus complex (median, 0.56). The present in vitro data showed that serum had a major impact on synergistic interactions of amphotericin B-echinocandin and voriconazole-echinocandin combinations, resulting in additive interactions and explaining the indifferent outcomes usually observed in vivo.
抗真菌联合治疗方案常采用伏立康唑或两性霉素 B 与棘白菌素类药物联合治疗，主要用于治疗尤其是难治性曲霉病。为评估血清中两性霉素 B 类和伏立康唑类药物与三种棘白菌素类药物（卡泊芬净、米卡芬净和阿尼芬净）联合应用时的药效学相互作用，我们针对 15 株烟曲霉复合体、黄曲霉复合体和土曲霉复合体分离株进行了检测，评估其生长抑制和杀菌活性。采用肉汤微量稀释比色法检测了每种药物单独使用以及以 1:1 固定浓度比联合使用时的体外活性，并通过棋盘格分析评估了相互作用。结果发现，所有两性霉素 B 类和伏立康唑类联合治疗方案均具有协同作用，其中两性霉素 B 类联合治疗方案显示出强烈的抑制协同相互作用（相互作用指数为 0.20 至 0.52），伏立康唑类联合治疗方案显示出强烈的杀菌协同相互作用（相互作用指数为 0.10 至 0.29）（P＜0.001）。发现了药物和物种特异性差异，其中卡泊芬净和烟曲霉复合体表现出的协同作用最弱。在血清存在的情况下，协同作用按以下顺序减弱（从最大到最小的降低）：米卡芬净＞阿尼芬净＞卡泊芬净，黄曲霉复合体＞烟曲霉复合体＞土曲霉复合体，导致相加作用，特别是对于两性霉素 B-棘白菌素联合治疗方案的抑制活性和伏立康唑-棘白菌素联合治疗方案的杀菌活性。在血清存在的情况下，抗真菌药物的抑制活性存在药物和物种特异性差异，观察到两性霉素 B-卡泊芬净（中位数，0.77）和土曲霉复合体（中位数，0.56）的相互作用指数最低。本体外数据表明，血清对抗真菌药物的两性霉素 B-棘白菌素和伏立康唑-棘白菌素联合治疗方案的协同作用有重大影响，导致相加作用，从而解释了体内通常观察到的不一致结果。
