Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98., 4032 Debrecen, Hungary.
Doctoral School of Pharmaceutical Sciences, University of Debrecen, Nagyerdei krt. 98, 4032 Debrecen, Hungary.
Med Mycol. 2021 Oct 4;59(10):1015-1023. doi: 10.1093/mmy/myab032.
The in vitro and in vivo efficacy of caspofungin was determined in combination with isavuconazole against Candida auris. Drug-drug interactions were assessed utilizing the fractional inhibitory concentration indices (FICIs), the Bliss independence model and an immunocompromised mouse model. Median planktonic minimum inhibitory concentrations (pMICs) of 23 C. auris isolates were between 0.5 and 2 mg/l and between 0.015 and 4 mg/l for caspofungin and isavuconazole, respectively. Median pMICs for caspofungin and isavuconazole in combination showed 2-128-fold and 2-256-fold decreases, respectively. Caspofungin and isavuconazole showed synergism in 14 out of 23 planktonic isolates (FICI range 0.03-0.5; Bliss cumulative synergy volume range 0-4.83). Median sessile MICs (sMIC) of 14 biofilm-forming isolates were between 32 and >32 mg/l and between 0.5 and >2 mg/l for caspofungin and isavuconazole, respectively. Median sMICs for caspofungin and isavuconazole in combination showed 0-128-fold and 0-512-fold decreases, respectively. Caspofungin and isavuconazole showed synergistic interaction in 12 out of 14 sessile isolates (FICI range 0.023-0.5; Bliss cumulative synergy volume range 0.13-234.32). In line with the in vitro findings, synergistic interactions were confirmed by in vivo experiments. The fungal kidney burden decreases were more than three log volumes in mice treated with combination of 1 mg/kg caspofungin and 20 mg/kg isavuconazole daily; this difference was statistically significant compared with control mice (P < 0.001). Despite the favorable effect of isavuconazole in combination with caspofungin, further studies are needed to confirm the therapeutic advantage of this combination when treating an infection caused by C. auris.
研究了卡泊芬净与伊曲康唑联合治疗耳念珠菌的体外和体内疗效。利用部分抑菌浓度指数（FICI）、 Bliss 独立性模型和免疫抑制小鼠模型评估了药物相互作用。23 株耳念珠菌分离株的浮游最小抑菌浓度（pMIC）中位数分别为 0.5-2mg/L 和 0.015-4mg/L，卡泊芬净和伊曲康唑的 pMIC 中位数分别为 0.5-2mg/L 和 0.015-4mg/L。卡泊芬净与伊曲康唑联合用药的 pMIC 中位数分别降低了 2-128 倍和 2-256 倍。23 株浮游分离株中，有 14 株（FICI 范围为 0.03-0.5； Bliss 累积协同体积范围为 0-4.83）显示协同作用。14 株生物膜形成分离株的固定 MIC（sMIC）中位数分别为 32-＞32mg/L 和 0.5-＞2mg/L，卡泊芬净和伊曲康唑的 sMIC 中位数分别为 0-128 倍和 0-512 倍。卡泊芬净与伊曲康唑联合用药的 sMIC 中位数分别降低了 0-128 倍和 0-512 倍。14 株固定分离株中有 12 株（FICI 范围为 0.023-0.5； Bliss 累积协同体积范围为 0.13-234.32）显示协同作用。与体外研究结果一致，体内实验也证实了协同作用。与对照组相比，每日给予 1mg/kg 卡泊芬净和 20mg/kg 伊曲康唑联合治疗的小鼠肾脏真菌负荷减少了 3 个对数体积以上，差异有统计学意义（P＜0.001）。尽管伊曲康唑与卡泊芬净联合具有良好的效果，但仍需要进一步研究以确认该联合治疗方案在治疗耳念珠菌感染时的治疗优势。
