Department of General Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei Province, China.
Department of Dermatology, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei Province, China.
Microbiol Spectr. 2023 Jun 15;11(3):e0530222. doi: 10.1128/spectrum.05302-22. Epub 2023 May 4.
To investigate the combined function of the novel oral mTOR inhibitor, everolimus, with antifungal agents and their potential mechanisms against , the CLSI microliquid-based dilution method M38-A2, chequerboard technique, and disk diffusion testing were performed. The efficacy of everolimus was evaluated in combination with itraconazole, voriconazole, posaconazole, and amphotericin B against 16 clinically isolated strains of . The synergistic effect was determined by measuring the MIC and fractional inhibitory concentration index. Dihydrorhodamine 123 was used for the quantification of ROS levels. The differences in the expression of antifungal susceptibility-associated genes were analyzed following different types of treatment. Galleria mellonella was used as the model. While everolimus alone showed minimal antifungal effects, combinations with itraconazole, voriconazole, posaconazole, or amphotericin B resulted in synergy in 13/16 (81.25%), 2/16 (12.5%), 14/16 (87.75%), and 5/16 (31.25%) of isolates, respectively. The disk diffusion assay revealed that the combination of everolimus and antifungal drugs showed no significant increase in the inhibition zones compared with the single agent, but no antagonistic effects were observed. Combination of everolimus and antifungal agents resulted in increased ROS activity (everolimus + posaconazole versus posaconazole [ < 0.05], everolimus + amphotericin B versus amphotericin B [ < 0.002]). Simultaneously, compared to mono-treatment, the combination of everolimus + itraconazole suppressed the expression of ( < 0.05) and the combination of everolimus + amphotericin B suppressed the expression of ( < 0.05) and ( < 0.02). , combinations of everolimus and antifungal agents improved survival rates, particularly the combination of everolimus + amphotericin B ( < 0.05). In summary, the and experiments performed in our study suggest that the combination of everolimus with azoles or amphotericin B can have synergistic effects against , potentially due to the induction of ROS activity and inhibition of efflux pumps, providing a promising new approach for the treatment of infections. Cancer patients with infection have high mortality if untreated. Clinically, the conventional treatment of is poor due to the long-term use of antifungal drugs. In this study, we have for the first time investigated the interaction and action mechanism of everolimus combined with itraconazole, voriconazole, posaconazole, and amphotericin B on and , which provided new ideas and direction for further exploring the mechanism of drug combination and clinical treatment of
为了研究新型口服 mTOR 抑制剂依维莫司与抗真菌药物联合应用的作用及其潜在机制，我们采用 CLSI 微量肉汤稀释法 M38-A2、棋盘技术和药敏纸片扩散法进行了实验。我们评估了依维莫司与伊曲康唑、伏立康唑、泊沙康唑和两性霉素 B 联合应用对 16 株临床分离的 的疗效。通过测定 MIC 和部分抑菌浓度指数（FICI）来确定协同作用。采用二氢罗丹明 123 定量检测 ROS 水平。分析不同处理方式下与抗真菌药物敏感性相关基因的表达差异。使用大蜡螟作为动物模型。结果显示，依维莫司单独使用时几乎没有抗真菌作用，但与伊曲康唑、伏立康唑、泊沙康唑或两性霉素 B 联合使用时，分别在 13/16（81.25%）、2/16（12.5%）、14/16（87.75%）和 5/16（31.25%）的分离株中表现出协同作用。药敏纸片扩散试验显示，与单药相比，依维莫司与抗真菌药物联合应用并未显著增加抑菌圈，但未观察到拮抗作用。依维莫司与抗真菌药物联合应用可增加 ROS 活性（依维莫司+泊沙康唑与泊沙康唑相比[<0.05]，依维莫司+两性霉素 B 与两性霉素 B 相比[<0.002]）。同时，与单药治疗相比，依维莫司+伊曲康唑联合用药可抑制 的表达（<0.05），依维莫司+两性霉素 B 联合用药可抑制 的表达（<0.05）和 的表达（<0.02）。此外，依维莫司与抗真菌药物联合应用可提高生存率，尤其是依维莫司+两性霉素 B 联合应用（<0.05）。综上所述，本研究中的 实验和 实验表明，依维莫司与唑类或两性霉素 B 联合应用可能对 具有协同作用，这可能是由于 ROS 活性的诱导和外排泵的抑制所致，为 感染的治疗提供了一种有前景的新方法。患有 感染的癌症患者如果不治疗，死亡率很高。临床上，由于长期使用抗真菌药物， 感染的常规治疗效果不佳。在这项研究中，我们首次研究了依维莫司与伊曲康唑、伏立康唑、泊沙康唑和两性霉素 B 联合应用对 和 的相互作用和作用机制，为进一步探索药物联合应用的机制和临床治疗提供了新的思路和方向。
