Khardori N, Nguyen H, Stephens L C, Kalvakuntla L, Rosenbaum B, Bodey G P
Department of Medical Specialities, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Antimicrob Agents Chemother. 1993 Apr;37(4):729-36. doi: 10.1128/AAC.37.4.729.
The efficacies of cilofungin (Ly121019), a semisynthetic lipopeptide antifungal agent, and amphotericin B in the treatment of disseminated candidiasis in normal and neutropenic mice were compared. In mice infected with 2 x 10(6) CFU of Candida albicans, treatment with cilofungin in twice-daily doses of 25 or 35 mg/kg of body weight by intraperitoneal injection for 10 days gave survival rates of 83 and 90%. In contrast, there was 97% mortality in infected controls receiving 2 x 10(6) CFU intravenously and 93% survival in mice treated with 1 mg of amphotericin B per kg once a day. Mice rendered granulocytopenic by the administration of cyclophosphamide showed survival rates of 83 and 80% when treated with 25 or 35 mg of cilofungin per kg for 10 days compared with 43% survival rate in mice treated with 1 mg of amphotericin B per kg (P = 0.0030 and P = 0.0080, respectively). Similar results were obtained when the two antifungal agents were administered for a period of 30 days. Administration of 25 or 35 mg of cilofungin per kg twice a day to granulocytopenic mice receiving 10(6) CFU of C. albicans gave survival rates of 93% and 93% compared with 53% survival with amphotericin B. With 15 mg of cilofungin per kg twice a day for 10 days, a survival rate of 43 to 50% was observed in both normal and granulocytopenic mice compared with 56 and 60%, respectively, when this dosage was continued for 30 days. Cilofungin eradicated C. albicans from the kidneys, spleens, and livers of surviving animals. No toxic effects were observed with any of the dosage regimens used. The clearance of C. albicans from the kidneys, spleens, livers, and brains in normal mice was studied following infection with 5 x 10(5) and 1 x 10(5) intravenously. The mice in the treatment groups received 25 mg of cilofungin per kg twice a day for 10 days. In 8 to 12 days, this treatment was able to clear the organisms from the kidneys, spleens, and livers of mice infected with 5 x 10(5) C. albicans. Mice infected with 10(5) C. albicans and treated with cilofungin (25 mg/kg) twice a day for 10 days had no organisms in the kidney, spleen, and liver at days 8, 2, and 8, respectively. There was 1-log-unit reduction in C. albicans counts in brain tissue from mice of one of the treated groups between 2 h and 2 days postinfection, after which the numbers of organisms remained the same until day 12. These data demonstrate the efficacy of cilofungin in the treatment of disseminated C. albicans infections in normal and granulocytopenic mice. The treatment regimen used in this study was able to clear C. albicans from the kidneys, spleen, and liver but not from brain tissue.
比较了半合成脂肽抗真菌药西洛芬净（Ly121019）和两性霉素B对正常小鼠和中性粒细胞减少小鼠播散性念珠菌病的治疗效果。给感染2×10⁶CFU白色念珠菌的小鼠腹腔注射西洛芬净，每日2次，剂量为25或35mg/kg体重，持续10天，存活率分别为83%和90%。相比之下，静脉注射2×10⁶CFU的感染对照组死亡率为97%，而每日1次给予1mg/kg两性霉素B治疗的小鼠存活率为93%。通过给予环磷酰胺使小鼠粒细胞减少，用25或35mg/kg西洛芬净治疗10天，存活率分别为83%和80%，而用1mg/kg两性霉素B治疗的小鼠存活率为43%（P分别为0.0030和0.0080）。当两种抗真菌药给药30天时也得到了类似结果。给接受10⁶CFU白色念珠菌的粒细胞减少小鼠每日2次腹腔注射25或35mg/kg西洛芬净，存活率为93%和93%，而两性霉素B治疗的存活率为53%。每日2次给予15mg/kg西洛芬净，持续10天，正常小鼠和粒细胞减少小鼠的存活率分别为43%至50%，而持续给药30天时分别为56%和60%。西洛芬净可使存活动物的肾脏、脾脏和肝脏中的白色念珠菌消失。所用任何剂量方案均未观察到毒性作用。研究了正常小鼠静脉注射5×10⁵和1×10⁵CFU白色念珠菌后，肾脏、脾脏、肝脏和大脑中白色念珠菌的清除情况。治疗组小鼠每日2次腹腔注射25mg/kg西洛芬净，持续10天。在8至12天内，该治疗能够清除感染5×10⁵CFU白色念珠菌小鼠的肾脏、脾脏和肝脏中的病原体。感染10⁵CFU白色念珠菌并每日2次用西洛芬净（25mg/kg）治疗10天的小鼠，在第8天、第2天和第8天时，肾脏、脾脏和肝脏中分别没有病原体。在感染后2小时至2天之间，其中一个治疗组小鼠脑组织中的白色念珠菌数量减少了1个对数单位，此后直到第12天病原体数量保持不变。这些数据证明了西洛芬净对正常小鼠和粒细胞减少小鼠播散性白色念珠菌感染的治疗效果。本研究中使用的治疗方案能够清除肾脏、脾脏和肝脏中的白色念珠菌，但不能清除脑组织中的白色念珠菌。
