Fusarium species are the fungal pathogens most commonly responsible for the mycotic keratitis, which are resistant to the majority of currently available antifungal agents. The present study was designed to assess the efficacy of a combination of low doses chlorhexidine with two other commonly used drugs (voriconazole and natamycin) to treat Fusarium infections. We utilized combinations of chlorhexidine and natamycin or voriconazole against 20 clinical Fusarium strains in vitro using a checkerboard-based microdilution strategy. In order to more fully understand the synergistic interactions between voriconazole and chlorhexidine, we utilized a Galleria mellonella model to confirm the combined antifungal efficacy of chlorhexidine and voriconazole in vivo. We found that for voriconazole, natamycin, and chlorhexidine as single agents, the minimum inhibitory concentration (MIC) ranges were 2–8, 4–16, and > 16 μg/ml, respectively. In contrast, the MIC values for voriconazole and chlorhexidine were reduced to 0.25–1 and 1–2 μg/ml, respectively, when these agents were administered in combination, with synergy being observed for 90% of tested Fusarium strains. Combined chlorhexidine and natamycin treatment, in contrast, exhibited synergistic activity for only 10% of tested Fusarium strains. We observed no evidence of antagonism. Our in vivo model results further confirmed the synergistic antifungal activity of chlorhexidine and voriconazole. Our results offer novel evidence that voriconazole and chlorhexidine exhibit synergistic activity when used to suppress the growth of Fusarium spp., and these agents may thus offer value as a combination topical antifungal treatment strategy.

中文翻译：

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氯己定和伏立康唑或纳他霉素联合使用对抗镰刀菌感染。

镰刀菌属是最常导致真菌性角膜炎的真菌病原体，它们对大多数当前可用的抗真菌剂具有抗性。本研究旨在评估低剂量氯己定与其他两种常用药物（伏立康唑和那他霉素）联合治疗镰刀菌感染的疗效。我们使用基于棋盘格的微稀释策略在体外对 20 种临床镰刀菌菌株使用氯己定和那他霉素或伏立康唑的组合。为了更全面地了解伏立康唑和氯己定之间的协同相互作用，我们利用大蜡螟模型来确认氯己定和伏立康唑在体内的联合抗真菌功效。我们发现伏立康唑、那他霉素和氯己定作为单药，最低抑菌浓度 (MIC) 范围分别为 2–8、4–16 和 > 16 μg/ml。相比之下，伏立康唑和氯己定的 MIC 值分别降低至 0.25-1 和 1-2 μg/ml，当这些药物联合使用时，90% 的镰刀菌菌株观察到协同作用。相比之下，氯己定和那他霉素联合处理仅对 10% 的测试镰刀菌菌株表现出协同活性。我们没有观察到拮抗作用的证据。我们的体内模型结果进一步证实了氯己定和伏立康唑的协同抗真菌活性。我们的结果提供了新的证据，表明伏立康唑和洗必泰在用于抑制镰刀菌属的生长时表现出协同活性，因此这些药物可能作为组合局部抗真菌治疗策略提供价值。