PDF(Pubmed)
Abstract：
Primary cerebral phaeohyphomycosis is a life-threatening disease caused by neurotropic dematiaceous fungi. At present, there are no consensus guidelines regarding optimal antifungal therapy in such cases. Generally, a combination of antifungal agents is recommended for treatment. However, the activities of antifungal combinations against these fungi have not been investigated. In this study, we evaluated the in vitro activities of 13 double and five triple antifungal combinations against clinical isolates of Cladophialophora bantiana (n = 7), Fonsecaea monophora (n = 2), and Cladosporium cladosporioides (n = 1), using a simplified checkerboard procedure. The minimum inhibitory concentrations (MICs) of nine antifungal drugs were determined by the broth microdilution method, and the interaction between antifungal agents in each combination was assessed by the fractional inhibitory concentration index. Excellent activity was observed for posaconazole and itraconazole. Flucytosine had potent activity against C. bantiana but was ineffective against F. monophora, and C. cladosporioides. The echinocandins demonstrated high MICs for all the isolates. Synergistic interactions were observed for all the double combinations, except when itraconazole was combined with either amphotericin B or flucytosine. The combination of amphotericin B with caspofungin showed synergistic interactions against 40% of the isolates. Antagonism was observed with isavuconazole-flucytosine combination against two C. bantiana isolates. The triple combinations of caspofungin and flucytosine with amphotericin B or posaconazole were synergistic against one isolate of F. monophora. For C. cladosporioides, synergy was observed for the triple combination of amphotericin B with caspofungin and flucytosine. Our results indicate that combination of caspofungin with amphotericin B or a triazole, with or without 5-flucytosine has great potential against neurotropic dematiaceous fungi.IMPORTANCEThis research uses a modified version of the checkerboard assay to standardize the in vitro testing of double and triple combinations of antifungal agents against neurotropic dematiaceous fungi. Antifungal combination therapy is associated with improved outcomes in cerebral phaeohyphomycosis. In this study, we demonstrate that posaconazole is the single most active antifungal drug against this group of fungi. The double combination of amphotericin B with caspofungin or a trizole, and the triple combinations of caspofungin and flucytosine with amphotericin B or posaconazole might hold promise in the treatment of cerebral phaeohyphomycosis. Our findings will guide in developing optimal therapeutic strategies for these refractory infections.
摘要：
原发性脑型真菌病是由嗜神经性发质真菌引起的危及生命的疾病。目前,对于此类病例的最佳抗真菌治疗尚无共识指南.一般来说,抗真菌药物的组合被推荐用于治疗。然而,抗真菌组合对这些真菌的活性尚未研究。在这项研究中,我们评估了13种双重和5种三重抗真菌组合对临床分离株的体外活性（n=7），MonophoraFonsecaea（n=2），和枝孢霉（n=1），使用简化的棋盘程序。用肉汤微量稀释法测定了9种抗真菌药物的最低抑菌浓度(MIC),并通过分数抑制浓度指数评估每种组合中抗真菌药物之间的相互作用。泊沙康唑和伊曲康唑具有优异的活性。氟胞嘧啶对C.bantiana具有有效的活性，但对F.monophora无效，和C.cladosporioides。棘白菌素对所有分离株都表现出高的MIC。观察到所有双重组合的协同相互作用，除非伊曲康唑与两性霉素B或氟胞嘧啶联合使用。两性霉素B与卡泊芬净的组合对40%的分离物显示出协同相互作用。观察到伊沙武康唑-氟胞嘧啶组合对两种C.bantiana分离株的拮抗作用。卡泊芬净和氟胞嘧啶与两性霉素B或泊沙康唑的三重组合对一种F.monophora分离株具有协同作用。对于Cladosporioides，两性霉素B与卡泊芬净和氟胞嘧啶的三重组合观察到协同作用。我们的结果表明，卡泊芬净与两性霉素B或三唑的组合，含或不含5-氟胞嘧啶具有巨大的潜力，可以对抗神经嗜性皮质真菌。重要意义本研究使用棋盘测定法的修改版本，以标准化抗真菌剂双重和三重组合对神经嗜性皮质真菌的体外测试。抗真菌药物联合治疗与改善脑型真菌病的预后相关。在这项研究中,我们证明泊沙康唑是针对这类真菌最有效的单一抗真菌药物。两性霉素B与卡泊芬净或曲唑的双重组合，卡泊芬净和氟胞嘧啶与两性霉素B或泊沙康唑的三重组合可能有望治疗脑真菌病。我们的发现将指导为这些难治性感染制定最佳治疗策略。
