两性霉素 B 制剂和伏立康唑与人类中性粒细胞对成熟枝顶孢霉和镰刀菌生物膜的药效学和免疫学相互作用。
Pharmacodynamic and immunological interactions of amphotericin B formulations and voriconazole with human neutrophils against mature Scedosporium apiospermum and Fusarium spp. biofilms.
机构信息
Infectious Diseases Unit, 3rd Department Pediatrics, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki and Hippokration General Hospital, Thessaloniki, Greece.
Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.
出版信息
J Antimicrob Chemother. 2023 Apr 3;78(4):1076-1083. doi: 10.1093/jac/dkad050.
BACKGROUND
Mould infections caused by Scedosporium apiospermum and Fusarium solani species complex (FSSC) biofilms are rising among immunocompromised and immunocompetent patients. Little is known about the immunomodulatory effects of antifungal agents against these moulds. We examined the effects of deoxycholate and liposomal amphotericin B (DAmB, LAmB) and voriconazole on antifungal activities and immune responses of neutrophils (PMNs) against mature biofilms compared with their planktonic counterparts.
METHODS
Antifungal activity of human PMNs exposed to mature biofilms and planktonic cells for 24 h was determined at effector-to-target ratios of 2:1 and 5:1, alone or combined with DAmB, LAmB and voriconazole, assessed as fungal damage by XTT assay. Cytokine production was evaluated by multiplex ELISA, following PMN stimulation with biofilms in the presence/absence of each drug.
RESULTS
All drugs showed additive or synergistic effects with PMNs against S. apiospermum at 0.03-32 mg/L. They showed antagonism primarily against FSSC at 0.06-64 mg/L. Increased IL-8 was produced by PMNs exposed to S. apiospermum biofilms plus DAmB or voriconazole compared with PMNs exposed to biofilms alone (P < 0.01). During combined exposure, IL-1β was increased, an effect only counteracted by increased levels of IL-10 caused by DAmB (P < 0.01). LAmB and voriconazole caused similar IL-10 levels with those released by biofilm-exposed PMNs.
CONCLUSIONS
The synergistic, additive or antagonistic effects of DAmB, LAmB or voriconazole on biofilm-exposed PMNs are organism-specific, with FSSC exhibiting greater resilience than S. apiospermum to antifungals. Biofilms of both moulds caused dampened immune responses. The drug-mediated immunomodulating effect on PMNs, evidenced by IL-1β, enhanced host protective functions.
背景
免疫功能低下和免疫功能正常的患者中，由枝顶孢霉和镰孢菌属复合种（FSSC）生物膜引起的霉菌感染正在增加。对于这些霉菌的抗真菌药物的免疫调节作用知之甚少。我们研究了脱氧胆酸盐和两性霉素 B 脂质体（DAmB，LAmB）和伏立康唑对成熟生物膜的抗真菌活性和中性粒细胞（PMN）免疫反应的影响，与浮游细胞相比。
方法
在效应细胞与靶细胞的比例为 2:1 和 5:1 时，单独或联合使用 DAmB、LAmB 和伏立康唑，通过 XTT 测定评估人 PMN 暴露于成熟生物膜和浮游细胞 24 小时后的抗真菌活性。通过在存在/不存在每种药物的情况下，用生物膜刺激 PMN 后，通过多重 ELISA 评估细胞因子的产生。
结果
所有药物在 0.03-32 mg/L 时对枝顶孢霉均表现出与 PMN 的相加或协同作用。在 0.06-64 mg/L 时主要表现为对抗 FSSC 的拮抗作用。与单独暴露于生物膜的 PMN 相比，暴露于枝顶孢霉生物膜加 DAmB 或伏立康唑的 PMN 产生的 IL-8 增加（P<0.01）。在联合暴露期间，IL-1β 增加，这种作用仅被 DAmB 引起的 IL-10 水平增加所抵消（P<0.01）。LAmB 和伏立康唑引起的 IL-10 水平与暴露于生物膜的 PMN 释放的 IL-10 水平相似。
结论
DAmB、LAmB 或伏立康唑对暴露于生物膜的 PMN 的协同、相加或拮抗作用是针对特定生物体的，FSSC 对抗真菌药物的抵抗力大于枝顶孢霉。两种霉菌的生物膜都导致免疫反应减弱。药物对 PMN 的免疫调节作用，通过 IL-1β 表现出来，增强了宿主的保护功能。
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