Efficacy of the echinocandin caspofungin against disseminated aspergillosis and candidiasis in cyclophosphamide-induced immunosuppressed mice
Efficacy of the echinocandin caspofungin against disseminated aspergillosis and candidiasis in cyclophosphamide-induced immunosuppressed mice
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DOI：
10.1128/aac.44.9.2310-2318.2000
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发表时间：
2000-09-01
影响因子：
4.9
通讯作者：
Rosen, H
中科院分区：
文献类型：
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作者：
Abruzzo, GK;Gill, CJ;Rosen, H
在环磷酰胺（CY）诱导的免疫抑制小鼠播散性曲霉病和念珠菌病模型中评价了棘白菌素抗真菌剂醋酸卡泊芬净（卡泊芬净; MK-0991）的体内疗效。卡泊芬净是一种1，3-β-D-葡聚糖合成抑制剂，对许多临床相关真菌（包括曲霉菌和念珠菌属）有效。使用CY诱导的一过性或慢性白细胞减少症模型，在微生物挑战后24小时开始每日一次给药治疗。卡泊芬净可有效治疗一过性白细胞减少小鼠的播散性曲霉病（在剂量大于或等于0.125 mg/kg体重和攻毒后28天50%保护剂量[PD 50]为0.245 mg/kg/天时，生存期显著延长）或慢性白细胞减少（剂量大于或等于0.5 mg/kg时存活率为50 - 100%，PD（50）范围为0.173 - 0.400 mg/kg/天）。卡泊芬净对一过性白细胞减少症小鼠念珠菌感染的治疗和灭菌有效，有效剂量为99%（基于白色念珠菌对数（10）CFU/克肾脏减少0.119 mg/kg），卡泊芬净剂量为0.25 - 2.0 mg/kg时，80%-100%的卡泊芬净治疗小鼠肾脏无菌。卡泊芬净在所有剂量水平（0.25 - 1.0 mg/kg）下对慢性白细胞减少症的念珠菌感染小鼠均有效，卡泊芬净治疗小鼠的肾中白念珠菌/克的数量从攻击后第4天至第28天显著低于（>99%减少）假治疗小鼠。此外，卡泊芬净剂量为0.5 - 1.0 mg/kg时，攻毒后第8 - 28天，70 - 100%的卡泊芬净治疗慢性白细胞减少小鼠的肾脏无菌。卡泊芬净在无宿主白细胞存在下对念珠菌感染的杀菌作用为抗念珠菌的杀真菌活性提供了令人信服的体内证据。白色念珠菌卡泊芬净对严重真菌感染的进一步人体临床试验正在进行中。
The in vivo efficacy of the echinocandin antifungal caspofungin acetate (caspofungin; MK-0991) was evaluated in models of disseminated aspergillosis and candidiasis in mice with cyclophosphamide (CY)-induced immunosuppression. Caspofungin is a 1,3-beta-D-glucan synthesis inhibitor efficacious against a number of clinically relevant fungi including Aspergillus and Candida species. Models of CY-induced transient or chronic leukopenia were used with once daily administration of therapy initiated 24 h after microbial challenge. Caspofungin was effective in treating disseminated aspergillosis in mice that were transiently leukopenic (significant prolongation of survival at doses of greater than or equal to 0.125 mg/kg of body weight and a 50% protective dose [PD50] of 0.245 mg/kg/day at 28 days after challenge) or chronically leukopenic (50 to 100% survival at doses of greater than or equal to 0.5 mg/kg and PD(50)s ranging from 0.173 to 0.400 mg/kg/day). Caspofungin was effective in the treatment and sterilization of Candida infections in mice with transient leukopenia with a 99% effective dose based on reduction in log(10) CFU of Candida albicans/gram of kidneys of 0.119 mg/kg and 80 to 100% of the caspofungintreated mice having sterile kidneys at caspofungin doses from 0.25 to 2.0 mg/kg. In Candida-infected mice with chronic leukopenia, caspofungin was effective at all dose levels tested (0.25 to 1.0 mg/kg), with the log(10) CFU of C. albicans/gram of kidneys of caspofungin-treated mice being significantly lower (>99% reduction) than that of sham-treated mice from day 4 to day 28 after challenge. Also, 70 to 100% of the caspofungin-treated, chronic leukopenic mice had sterile kidneys at caspofungin doses of 0.5 to 1.0 mg/kg from day 8 to 28 after challenge. Sterilization of Candida infections by caspofungin in the absence of host leukocytes provides compelling in vivo evidence for fungicidal activity against C. albicans. Further human clinical trials with caspofungin against serious fungal infections are in progress.