Hanson L H, Perlman A M, Clemons K V, Stevens D A
California Institute for Medical Research, San Jose.
Antimicrob Agents Chemother. 1991 Jul;35(7):1334-7. doi: 10.1128/AAC.35.7.1334.
The efficacies of cilofungin and amphotericin B separately and together in mice with disseminated candidiasis were studied. Male CD-1 mice (age, 5 weeks) were infected intravenously with 3 X 10(5) CFU of Candida albicans. At 4 days postinfection, intraperitoneal therapy was initiated and was continued for 14 days. Therapy groups included those given cilofungin at 6.25 or 62.5 mg/kg/day (given twice daily), amphotericin B at 0.625 mg/kg/day (given once daily), cilofungin at 6.25 mg/kg/day plus amphotericin B, and cilofungin at 62.5 mg/kg/day plus amphotericin B. Mice were observed through 30 days postinfection. All infected untreated mice died of infection between days 6 and 18. Eighty-five percent of mice receiving cilofungin at 6.25 mg/kg/day died between days 13 and 30. All other mice survived. Quantitative determination of the number of CFU of C. albicans in the spleens and kidneys of all survivors revealed that mice that had received both drugs had lower residual burdens of C. albicans. All mice treated with cilofungin at 62.5 mg/kg/day plus amphotericin B had sterile spleens, whereas 42 to 58% of mice given cilofungin or amphotericin B monotherapy had sterile spleens. All kidneys were infected in mice which had received cilofungin at 62.5 mg/kg/day or amphotericin B. Neither organ was infected in 17% of each group receiving combination therapy with cilofungin and amphotericin B. The number of CFU in the kidneys of mice treated with cilofungin at 62.5 mg/kg/day plus amphotericin B was lower than those cultured from mice treated with cilofungin at 62.5 mg/kg/day (P less than 0.001, Mann-Whitney) or amhotericin B (P less than 0.05). Modest synergy was noted in inhibition of the C. albicans isolate in vitro. Pharmacokinetic studies showed elevated levels of cilofungin but not amphotericin B in sera of mice treated with combined therapy compared with those in mice given monotherapy. No overt toxicity was evident with any regimen. The mechanism of increased efficacy may be altered cilofungin distribution, excretion, or metabolism; antifungal synergy; or both. These results indicate that concurrent cilofungin-amphotericin B therapy has synergistic or additive efficacy in vivo.
研究了西洛芬净和两性霉素B单独及联合应用对播散性念珠菌病小鼠的疗效。雄性CD-1小鼠（5周龄）静脉注射3×10⁵CFU白色念珠菌。感染后4天开始腹腔给药，持续14天。治疗组包括给予6.25或62.5mg/kg/天西洛芬净（每日两次给药）、0.625mg/kg/天两性霉素B（每日一次给药）、6.25mg/kg/天西洛芬净加两性霉素B以及62.5mg/kg/天西洛芬净加两性霉素B的小鼠。观察小鼠至感染后30天。所有未治疗的感染小鼠在第6天至第18天之间死于感染。接受6.25mg/kg/天西洛芬净治疗的小鼠中，85%在第13天至第30天之间死亡。所有其他小鼠存活。对所有存活小鼠脾脏和肾脏中白色念珠菌CFU数量的定量测定显示，接受两种药物治疗的小鼠白色念珠菌残留负荷较低。所有接受62.5mg/kg/天西洛芬净加两性霉素B治疗的小鼠脾脏无菌，而接受西洛芬净或两性霉素B单药治疗的小鼠中，42%至58%的小鼠脾脏无菌。接受62.5mg/kg/天西洛芬净或两性霉素B治疗的小鼠所有肾脏均被感染。在接受西洛芬净和两性霉素B联合治疗的每组小鼠中，17%的小鼠两个器官均未被感染。接受62.5mg/kg/天西洛芬净加两性霉素B治疗的小鼠肾脏中的CFU数量低于接受62.5mg/kg/天西洛芬净治疗的小鼠（P<0.001，曼-惠特尼检验）或两性霉素B治疗的小鼠（P<0.05）。在体外对白色念珠菌分离株的抑制中观察到适度的协同作用。药代动力学研究表明，与单药治疗的小鼠相比，联合治疗的小鼠血清中西洛芬净水平升高，但两性霉素B水平未升高。任何治疗方案均未出现明显毒性。疗效增加的机制可能是西洛芬净的分布、排泄或代谢改变；抗真菌协同作用；或两者兼有。这些结果表明，西洛芬净-两性霉素B联合治疗在体内具有协同或相加疗效。
