Zeitoun Hend, Salem Rawan A, El-Guink Nadia M, Tolba Nesrin S, Mohamed Nelly M
Department of Microbiology and Immunology, Faculty of Pharmacy, Alexandria University, El-Khartoom Square, Azarita, Alexandria, Egypt.
Department of Pathology, Medical Research Institute, Alexandria University, Alexandria, Egypt.
BMC Microbiol. 2024 Oct 1;24(1):383. doi: 10.1186/s12866-024-03512-0.
The incidence of fungal urinary tract infections (UTIs) has dramatically increased in the past decades, with Candida arising as the predominant etiological agent. Managing these infections poses a serious challenge to clinicians, especially with the emergence of fluconazole-resistant (FLC-R) Candida species. In this study, we aimed to determine the mechanisms of fluconazole resistance in urinary Candida spp. isolated from hospitalized patients in Alexandria, Egypt, assess the correlation between fluconazole resistance and virulence, and explore potential treatment options for UTIs caused by FLC-R Candida strains.
Fluconazole susceptibility testing of 34 urinary Candida isolates indicated that 76.5% were FLC-R, with a higher prevalence of resistance recorded in non-albicans Candida spp. (88.9%) than in Candida albicans (62.5%). The calculated Spearman's correlation coefficients implied significant positive correlations between fluconazole minimum inhibitory concentrations and both biofilm formation and phospholipase production. Real-time PCR results revealed that most FLC-R isolates (60%) significantly overexpressed at least one efflux pump gene, while 42.3% significantly upregulated the ERG11 gene. The most prevalent mutation detected upon ERG11 sequencing was G464S, which is conclusively linked to fluconazole resistance. The five repurposed agents: amikacin, colistin, dexamethasone, ketorolac, and sulfamethoxazole demonstrated variable fluconazole-sensitizing activities in vitro, with amikacin, dexamethasone, and colistin being the most effective. However, the fluconazole/colistin combination produced a notable reduction (49.1%) in bladder bioburden, a 50% decrease in the inflammatory response, and tripled the median survival span relative to the untreated murine models.
The fluconazole/colistin combination offers a promising treatment option for UTIs caused by FLC-R Candida, providing an alternative to the high-cost, tedious process of novel antifungal drug discovery in the battle against antifungal resistance.
在过去几十年中，真菌性尿路感染（UTIs）的发病率急剧上升，念珠菌成为主要病原体。管理这些感染对临床医生构成了严峻挑战，尤其是随着耐氟康唑（FLC-R）念珠菌属的出现。在本研究中，我们旨在确定从埃及亚历山大港住院患者中分离出的尿路念珠菌属对氟康唑耐药的机制，评估氟康唑耐药性与毒力之间的相关性，并探索由FLC-R念珠菌菌株引起的UTIs的潜在治疗方案。
对34株尿路念珠菌分离株进行氟康唑敏感性测试表明，76.5%为FLC-R，非白色念珠菌属（88.9%）的耐药率高于白色念珠菌（62.5%）。计算得出的斯皮尔曼相关系数表明，氟康唑最低抑菌浓度与生物膜形成和磷脂酶产生之间存在显著正相关。实时PCR结果显示，大多数FLC-R分离株（60%）至少有一个外排泵基因显著过表达，而42.3%的分离株ERG11基因显著上调。ERG11测序检测到的最常见突变是G464S，这与氟康唑耐药性有明确关联。五种重新利用的药物：阿米卡星、黏菌素、地塞米松、酮咯酸和磺胺甲恶唑在体外表现出不同的氟康唑增敏活性，其中阿米卡星、地塞米松和黏菌素最有效。然而，与未治疗的小鼠模型相比，氟康唑/黏菌素组合使膀胱生物负荷显著降低（49.1%），炎症反应降低50%，中位生存期延长两倍。
氟康唑/黏菌素组合为FLC-R念珠菌引起的UTIs提供了一种有前景的治疗选择，为对抗真菌耐药性的高成本、繁琐的新型抗真菌药物研发过程提供了替代方案。
