Background: Fusarium keratitis is an infection of the cornea that often results in corneal perforation requiring corneal transplantation even with topical ocular antifungal therapy. The polyene natamycin remains the current antifungal of choice for Fusarium keratitis, but prompt sterilization of the cornea is often not achieved with contemporary therapy. Recently, natamycin synergy with the beta-adrenergic antagonist timolol against Fusarium species was reported. Objective: Our objective in this study was to characterize the in vitro antifungal effects of additional beta-adrenergic antagonists alone or in combination with natamycin on Fusarium keratitis isolates from the Mycotic Ulcer Treatment Trial (MUTT) and USA. Methods: Microbroth dilution assays were used to determine the minimal inhibitory concentration (MIC) of beta-adrenergic antagonists against 18 Fusarium spp. keratitis (10 from MUTT, 8 from USA) and 3 Aspergillus fumigatus isolates. The fractional inhibitory concentration index (FICI) was calculated to assess interactions with natamycin. Results: Most beta-blockers did not show antifungal activity or synergy with natamycin with the exception of propranolol. A racemic mix of propranolol had fungicidal activity with MIC between 31 and 83 µg/mL for the Fusarium isolates. The MIC of the less cardioactive R enantiomer was lower (27-83 µg/mL) than the MIC of the S enantiomer (42-104 µg/mL). The MICs of both propranolol and natamycin were lower in combination but were not synergistic. The MIC of propranolol was 156 µg/mL for the A. fumigatus isolates. Conclusions: Propranolol has intrinsic in vitro fungicidal activity and lowers the MIC of natamycin. Both the R and S enantiomers of propranolol had antifungal activity with the MIC modestly but significantly lower for R-propranolol. These findings have relevance both for the treatment of fungal keratitis and of glaucoma in the setting of fungal keratitis. Further study of propranolols antifungal activity may lead to a novel treatment for fungal keratitis and possibly other fungal infections.

中文翻译：

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从霉菌性溃疡治疗试验（MUTT）和美国分离到的普萘洛尔对镰刀菌性角膜炎的抗真菌活性。

背景：镰刀菌性角膜炎是一种角膜感染，即使使用局部眼部抗真菌治疗，也常常导致角膜穿孔，需要角膜移植。多烯那他霉素仍然是镰刀菌性角膜炎目前选择的抗真菌药物，但是当代疗法通常无法实现对角膜的迅速灭菌。最近，据报道纳他霉素与β-肾上腺素拮抗剂替莫洛尔对镰刀菌属物种具有协同作用。目的：我们在这项研究中的目的是表征单独的或与纳他霉素联合使用的其他β-肾上腺素能拮抗剂对霉菌性溃疡治疗试验（MUTT）和美国分离的镰刀菌性角膜炎的体外抗真菌作用。方法：微肉汤稀释法用于确定β-肾上腺素能拮抗剂对18镰刀菌属的最低抑制浓度（MIC）。角膜炎（来自MUTT的10个，来自美国的8个）和3个烟曲霉分离株。计算分数抑制浓度指数（FICI）以评估与纳他霉素的相互作用。结果：除心得安外，大多数β受体阻滞剂均未显示出与纳他霉素的抗真菌活性或协同作用。普萘洛尔的外消旋混合物对枯萎病菌具有杀菌活性，MIC在31至83 µg / mL之间。心脏活性较低的R对映体的MIC（S-对映体的MIC（42-104 µg / mL））较低（27-83 µg / mL）。普萘洛尔和纳他霉素的MIC较低，但没有协同作用。烟曲霉菌株的普萘洛尔MIC为156 µg / mL。结论：普萘洛尔具有固有的体外杀真菌活性，可降低纳他霉素的MIC。普萘洛尔的R和S对映异构体均具有适度的抗真菌活性，但MIC对R-普萘洛尔的抑菌活性明显较低。这些发现与真菌性角膜炎的治疗均与真菌性角膜炎和青光眼的治疗均相关。普萘洛尔抗真菌活性的进一步研究可能会导致真菌性角膜炎和其他真菌感染的新型治疗方法。