Clemons K V, Stevens D A
Department of Medicine, Santa Clara Valley Medical Center, California 95128.
J Antimicrob Chemother. 1992 Sep;30(3):353-63. doi: 10.1093/jac/30.3.353.
The comparative activities of two preparations of amphotericin B against Coccidioides immitis were investigated. These preparations were a deoxycholate suspension (conventional amphotericin B) and a lipid-based formulation, amphotericin B lipid complex (ABLC). In-vitro susceptibility testing demonstrated that the MICs of ABLC were < or = 0.25 mg/L and of conventional amphotericin B were 0.5 mg/L for C. immitis. However, conventional amphotericin B was at least four-fold more fungicidal, with a minimum fungicidal concentration of 4.0 vs > 16 mg/L for ABLC. The therapeutic efficacies were tested in murine models of acute systemic coccidioidomycosis. Female CD-1 mice were infected iv with C. immitis arthroconidia to establish high (> 50%) or low (< 50%) mortality models. Therapy with conventional amphotericin B or ABLC was given three times per week for two weeks starting three days post-infection. Controls received no therapy or drug-free diluent only. Survival was tallied up to 49 days post-infection and the fungal cfu counts in spleen, liver, and lungs of all survivors were determined. In the low mortality study all treated mice survived and all therapy regimens reduced infection in all organs. All mice given ABLC 6.6 or 13.2 mg/kg/dose and 80% given ABLC 16.5 mg/kg/dose, as well as 90% given conventional amphotericin B 0.66 mg/kg/dose were free of infection; all controls remained infected. In two high mortality studies, all mice given ABLC 0.66-20 mg/kg/dose or conventional amphotericin B 0.22 or 0.66 mg/kg/dose survived compared with 0-20% of controls. Thirty per cent of uninfected mice given ABLC 20 mg/kg/dose and 40% given conventional amphotericin B 2.0 mg/kg/dose died due to drug toxicity. Mice given ABLC or conventional amphotericin B had lower residual cfu counts of C. immitis in all organs than did controls. Sixty to one hundred per cent of mice given ABLC regimens > or = 6.6 mg/kg/dose were cured, whereas all controls and 50-60% of mice receiving the highest non-toxic conventional amphotericin B regimen (0.66 mg/kg/dose) remained infected. At equal non-toxic amphotericin B doses, conventional amphotericin B was more effective than ABLC in reducing cfu in infected organs.(ABSTRACT TRUNCATED AT 400 WORDS)
对两种两性霉素B制剂抗粗球孢子菌的活性进行了比较研究。这两种制剂分别是脱氧胆酸盐悬液（传统两性霉素B）和脂质体制剂两性霉素B脂质复合物（ABLC）。体外药敏试验表明，ABLC对粗球孢子菌的最低抑菌浓度（MIC）≤0.25mg/L，而传统两性霉素B的MIC为0.5mg/L。然而，传统两性霉素B的杀菌活性至少高4倍，其最低杀菌浓度为4.0mg/L，而ABLC的最低杀菌浓度>16mg/L。在急性系统性球孢子菌病的小鼠模型中测试了治疗效果。雌性CD-1小鼠经静脉注射粗球孢子菌关节孢子以建立高死亡率（>50%）或低死亡率（<50%）模型。从感染后3天开始，每周3次给予传统两性霉素B或ABLC治疗，持续2周。对照组不接受治疗或仅接受无药物的稀释剂。记录感染后49天内的存活率，并测定所有存活小鼠脾脏、肝脏和肺部的真菌菌落形成单位（cfu）计数。在低死亡率研究中，所有治疗组小鼠均存活，所有治疗方案均降低了所有器官的感染。所有给予ABLC 6.6或13.2mg/kg/剂量的小鼠以及80%给予ABLC 16.5mg/kg/剂量的小鼠，还有90%给予传统两性霉素B 0.66mg/kg/剂量的小鼠均无感染；所有对照组小鼠仍有感染。在两项高死亡率研究中，所有给予ABLC 0.66 - 20mg/kg/剂量或传统两性霉素B 0.22或0.66mg/kg/剂量的小鼠均存活，而对照组的存活率为0 - 20%。30%给予ABLC 20mg/kg/剂量的未感染小鼠和40%给予传统两性霉素B 2.0mg/kg/剂量的小鼠因药物毒性死亡。给予ABLC或传统两性霉素B的小鼠所有器官中粗球孢子菌的残留cfu计数均低于对照组。给予ABLC剂量≥6.6mg/kg/剂量的小鼠中有60% - 100%被治愈，而所有对照组以及50% - 60%接受最高无毒传统两性霉素B方案（0.66mg/kg/剂量）的小鼠仍有感染。在两性霉素B剂量相等且无毒的情况下，传统两性霉素B在降低感染器官中的cfu方面比ABLC更有效。（摘要截短至400字）
