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.

中文翻译：

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卡泊芬净与艾沙康唑对耳念珠菌浮游细胞和生物膜的体外和体内相互作用

卡泊芬净与艾沙康唑联用对耳念珠菌的体外和体内功效进行了测定。利用分数抑制浓度指数 (FICI)、Bliss 独立模型和免疫功能低下的小鼠模型评估药物-药物相互作用。卡泊芬净和艾沙康唑的 23 种耳念珠菌分离株的中位浮游最低抑制浓度 (pMIC) 分别在 0.5 和 2 mg/l 之间和 0.015 和 4 mg/l 之间。卡泊芬净和艾沙康唑联合使用的 pMIC 中值分别降低了 2-128 倍和 2-256 倍。卡泊芬净和艾沙康唑在 23 个浮游分离物中的 14 个中显示出协同作用（FICI 范围 0.03-0.5；Bliss 累积协同作用量范围 0-4.83）。14 个生物膜形成分离物的中位固着 MIC (sMIC) 介于 32 和＞10 之间。卡泊芬净和艾沙康唑分别为 32 mg/l 和 0.5 至＞2 mg/l。卡泊芬净和艾沙康唑联合使用的中位 sMIC 分别下降 0-128 倍和 0-512 倍。卡泊芬净和艾沙康唑在 14 个固着分离物中的 12 个中显示出协同作用（FICI 范围 0.023-0.5；Bliss 累积协同作用量范围 0.13-234.32）。与体外研究结果一致，体内实验证实了协同作用。每天用 1 mg/kg 卡泊芬净和 20 mg/kg 艾沙康唑联合治疗的小鼠，真菌肾脏负荷减少超过 3 log 体积；与对照小鼠相比，这种差异具有统计学意义（P < 0.001）。尽管艾沙康唑与卡泊芬净联合使用具有良好的效果，