Efficacies of fluconazole, caspofungin, and amphotericin B in Candida glabrata-infected p47phox-/- knockout mice
Efficacies of fluconazole, caspofungin, and amphotericin B in Candida glabrata-infected p47phox-/- knockout mice
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DOI：
10.1128/aac.46.5.1240-1245.2002
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发表时间：
2002-05-01
影响因子：
4.9
通讯作者：
Bennett, JE
中科院分区：
文献类型：
--
作者：
Ju, JY;Polhamus, C;Bennett, JE
光滑念珠菌是成人念珠菌血症的第二大致病原因，导致高死亡率。两性霉素B被认为是治疗的首选，而氟康唑的疗效存在争议，卡泊芬净的疗效尚不清楚。为了确定药物在体内的疗效，研究了光滑毛囊线虫感染的小鼠模型的实用性。当静脉注射光滑毛囊线虫到C57BL/6小鼠体内时，由于p47(Phox)基因的敲除，其氧化杀菌能力降低，被发现会导致进行性、致命性感染。各组小鼠于感染当天开始每日6天的腹腔药物治疗后2天测定脾、肾脏器CFU计数。与生理盐水对照组相比，每天注射80 mg/kg的氟康唑并不能减少感染体外氟康唑MIC为2、32或256µg/ml的光滑念珠菌菌株后的脾或肾CFU计数。然而，这种氟康唑方案减少了感染白色念珠菌的小鼠的脾CFU计数，众所周知，这种感染对氟康唑有反应。卡泊芬净(5 mg/kg)和两性霉素B(5 mg/kg)均能有效降低光肩星毛虫感染小鼠的脾、肾真菌负荷。用卡泊芬净1 mg/kg治疗6天后，10只小鼠存活15天，但10只注射生理盐水的小鼠全部死亡或病情严重，必须在感染后96小时前处死。这一小鼠模型提供了两性霉素B和卡泊芬净的疗效证据，但不能证明氟康唑对光滑念珠菌感染的疗效。
Candida glabrata is the second leading cause of adult candidemia, resulting in high mortality. Amphotericin B is considered the treatment of choice, while the efficacy of fluconazole is controversial and caspofungin efficacy is unknown. To ascertain drug efficacy in vivo, the utility of a murine model of C. glabrata infection was investigated. C. glabrata was found to cause progressive, lethal infection when injected intravenously into C57BL/6 mice with reduced oxidative microbicidal capacity due to knockout of the p47(phox) gene. Spleen and kidney organ CFU counts were determined in groups of mice 2 days after the mice completed 6 days of daily intraperitoneal drug treatment, which began on the day of infection. Daily injections of fluconazole at 80 mg/kg did not reduce spleen or kidney CFU counts after infection with C. glabrata strains having in vitro fluconazole MICs of 2, 32, or 256 mug/ml compared to saline-treated controls. However, this fluconazole regimen reduced spleen CFU counts in mice infected with Candida albicans, an infection that is known to be responsive to fluconazole. Caspofungin at 5 mg/kg and amphotericin B at 5 mg/kg were both effective in reducing fungal burden in spleens and kidneys of C. glabrata-infected mice. Ten mice treated for 6 days with caspofungin at I mg/kg survived for 15 days, though all 10 saline-injected mice died or were so ill that they had to be sacrificed by 96 h postinfection. This murine model provided evidence of the efficacy of amphotericin B and caspofungin but not of fluconazole against C. glabrata infection.