Warn P A, Morrissey J, Moore C B, Denning D W
Department of Medicine, Section of Infectious Diseases, Hope Hospital, University of Manchester, United Kingdom.
Antimicrob Agents Chemother. 2000 Oct;44(10):2664-71. doi: 10.1128/AAC.44.10.2664-2671.2000.
We compared four doses of amphotericin B lipid complex (ABLC) with three doses of fluconazole in temporarily neutropenic mice in a murine model of disseminated candidiasis due to four different isolates of Candida tropicalis. The mice were infected with a 90% lethal dose of four strains of C. tropicalis for which the fluconazole MICs ranged from 1 to >125 mg/liter 3 days after receiving 200 mg of cyclophosphamide/kg of body weight. Treatment was started 18 h after infection and lasted for 7 days. ABLC (1, 2, 5, and 10 mg/kg) was administered once a day intravenously, fluconazole was administered by oral gavage once daily (25 and 50 mg/kg/day) or twice daily (125 mg/kg). MICs determined in five different ways with 24- and 48-h endpoints were also compared. The overall survival rates were controls, 14%; fluconazole, 64%; and ABLC, 82%. Treatment with ABLC at 2 to 10 mg/kg increased survival compared to controls (P = <0.0001) and was also superior to fluconazole at 25 and 50 mg/kg (P = 0.006). In the fluconazole-resistant C. tropicalis model (MIC, 128 microg/ml), ABLC at 2 to 10 mg/kg was superior to fluconazole at 250 mg/kg and ABLC at 10 mg/kg was superior to all fluconazole doses (P = <0.05). Fluconazole at 250 mg/kg daily was superior to both 25 and 50 mg/kg at reducing mortality with most isolates. ABLC was superior to fluconazole (P = <0.01), and fluconazole at 250 mg/kg was superior to fluconazole at both 25 and 50 mg/kg (P = 0.02) in all models at reducing C. tropicalis counts in the kidneys. Neither drug consistently sterilized the brain or kidneys. A 48-h endpoint reading with the NCCLS susceptibility testing microtiter variation overestimates resistance to fluconazole. ABLC is an effective treatment for fluconazole-resistant C. tropicalis at all doses tested.
在一个由四种不同热带念珠菌分离株引起的播散性念珠菌病小鼠模型中，我们将四种剂量的两性霉素B脂质复合物（ABLC）与三种剂量的氟康唑在暂时中性粒细胞减少的小鼠中进行了比较。给小鼠腹腔注射200mg/kg体重的环磷酰胺3天后，用90%致死剂量的四株热带念珠菌进行感染，这四株菌的氟康唑最低抑菌浓度（MIC）范围为1至>125mg/L。感染后18小时开始治疗，持续7天。ABLC（1、2、5和10mg/kg）每天静脉注射一次，氟康唑通过口服灌胃给药，每天一次（25和50mg/kg/天）或每天两次（125mg/kg）。还比较了用五种不同方法在24小时和48小时终点测定的MIC。总体生存率为：对照组14%；氟康唑组64%；ABLC组82%。与对照组相比，2至10mg/kg的ABLC治疗可提高生存率（P =<0.0001），并且也优于25和50mg/kg的氟康唑（P = 0.006）。在耐氟康唑的热带念珠菌模型（MIC，128μg/ml）中，2至10mg/kg的ABLC优于250mg/kg的氟康唑，10mg/kg的ABLC优于所有氟康唑剂量（P =<0.05）。对于大多数分离株，每天250mg/kg的氟康唑在降低死亡率方面优于25和50mg/kg的氟康唑。在所有模型中，ABLC在降低肾脏中热带念珠菌数量方面优于氟康唑（P =<0.01），250mg/kg的氟康唑在降低肾脏中热带念珠菌数量方面优于25和50mg/kg的氟康唑（P = 0.02）。两种药物均不能持续清除脑或肾脏中的细菌。用美国国家临床实验室标准化委员会（NCCLS）药敏试验微量滴定法在48小时终点读数会高估对氟康唑的耐药性。在所有测试剂量下，ABLC都是治疗耐氟康唑热带念珠菌的有效药物。
