Obermeier Mariella, Esparza-Mora M Alejandra, Heese Olivia, Cohen Nir, Varma Sreejith Jayasree, Tober-Lau Pinkus, Hartl Johannes, Kurth Florian, Berman Judith, Ralser Markus
Department of Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Department of Infectious Diseases and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.
J Med Microbiol. 2025 Jul;74(7). doi: 10.1099/jmm.0.002046.
Fungal infections are increasingly concerning, particularly in immunocompromised patients. These patients often suffer from comorbidities and receive multiple, non-antifungal medications. The effects of these co-administered medications on fungal cells - and their potential to influence antifungal drug efficacy - are poorly understood. This study investigates non-antifungal medications commonly administered in parallel to antifungals and evaluates their impact on fungal susceptibility. We systematically reviewed clinical guidelines to identify non-antifungal medications frequently co-prescribed with antifungals. Focusing on , the most prevalent fungal pathogen, we examined whether the presence of these drugs influences antifungal responses of . First, we tested the selected compounds together with antifungals in combination assays. Interactions were then characterized using checkerboard assays, and the impact on antifungal resistance and tolerance was evaluated through disc diffusion assays. To further explore these effects , the influence of selected antagonistic interactions on treatment efficacy was assessed using a model of disseminated candidiasis. From 119 medications used to manage 40 conditions linked to a high risk of fungal infections, we identified 34 compounds that altered the effectiveness of the antifungals fluconazole (FLC) and/or anidulafungin. Most of these compounds reduced or antagonized antifungal efficacy, often due to increased resistance or tolerance. Validation in a infection model confirmed that compounds antagonistic to FLC, including loperamide, estradiol and levothyroxine, interfere with antifungal treatment efficacy in this model. Our findings highlight that medications frequently used by patients at risk for fungal infections can inadvertently increase fungal pathogen drug tolerance or resistance. We suggest that drugs targeting non-fungal conditions yet affecting fungal pathogens might represent an underestimated factor contributing to rising antifungal resistance and tolerance.
真菌感染日益引起关注，尤其是在免疫功能低下的患者中。这些患者常伴有多种合并症，并接受多种非抗真菌药物治疗。人们对这些联合使用的药物对真菌细胞的影响及其影响抗真菌药物疗效的可能性了解甚少。本研究调查了通常与抗真菌药物并行使用的非抗真菌药物，并评估了它们对真菌易感性的影响。我们系统地回顾了临床指南，以确定经常与抗真菌药物联合处方的非抗真菌药物。以最常见的真菌病原体为重点，我们研究了这些药物的存在是否会影响其抗真菌反应。首先，我们在联合试验中将选定的化合物与抗真菌药物一起进行测试。然后使用棋盘法对相互作用进行表征，并通过纸片扩散试验评估对耐药性和耐受性的影响。为了进一步探索这些影响，我们使用播散性念珠菌病模型评估了选定的拮抗相互作用对治疗效果的影响。在用于治疗与真菌感染高风险相关的40种病症的119种药物中，我们鉴定出34种化合物改变了抗真菌药物氟康唑（FLC）和/或阿尼芬净的有效性。这些化合物中的大多数降低或拮抗了抗真菌疗效，这通常是由于耐药性或耐受性增加所致。在感染模型中的验证证实，与氟康唑拮抗的化合物，包括洛哌丁胺、雌二醇和左甲状腺素，在该模型中会干扰抗真菌治疗效果。我们的研究结果突出表明，有真菌感染风险的患者经常使用的药物可能会无意中增加真菌病原体的耐药性或耐受性。我们认为，针对非真菌病症但影响真菌病原体的药物可能是导致抗真菌耐药性和耐受性上升的一个被低估的因素。
