Comparative efficacies of conventional amphotericin B, liposomal amphotericin B (AmBisome), caspofungin, micafungin, and voriconazole alone and in combination against experimental murine central nervous system aspergillosis
Comparative efficacies of conventional amphotericin B, liposomal amphotericin B (AmBisome), caspofungin, micafungin, and voriconazole alone and in combination against experimental murine central nervous system aspergillosis
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DOI：
10.1128/aac.49.12.4867-4875.2005
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发表时间：
2005-12-01
影响因子：
4.9
通讯作者：
Stevens, DA
中科院分区：
文献类型：
--
作者：
Clemons, KV;Espiritu, M;Stevens, DA
中枢神经系统（CNS）曲霉病是一种严重的疾病，目前的治疗效果不佳。目前的研究检查了几种抗真菌药物单独或与CNS曲霉病小鼠模型联合使用的疗效。免疫抑制小鼠脑内感染烟曲霉菌，并单独或联合给予阿替霉素B制剂、棘白菌素或伏立康唑（VCZ）。单药治疗研究显示，米卡芬净（云母）、卡泊芬净（CAS）、VCZ、常规阿替霉素B（AMB）、Abelcet（ABLC）（一种脂质携带的AMB制剂; Enzon Pharmaceuticals，Inc.），和AmBisome（AmBi）（脂质体AMB;吉利德科学公司）是有效的然而，高于15 mg/kg体重的AmBi剂量显示出降低的功效。在试验剂量（1、5或10 mg/kg）下，云母和CAS均未显示剂量反应性。只有40 mg/kg剂量的VCZ有效。AmBi和ABLC显示出剂量反应性，10 mg/kg剂量导致真菌负荷显著降低;它们在10 mg/kg剂量下具有等效活性。亚最佳剂量的AmBi与云母、CAS或VCZ组合可有效延长存活。然而，仅用AmBi和VCZ组合证明了显著增强的活性。AmBi与云母或CAS组合显示出增强活性的趋势，但该组合并不显著上级单药治疗。在最佳剂量下使用AmBi与CAS或VCZ没有改善疗效。任何剂量组合均未达到治愈。这些结果表明，AmBi与VCZ联合治疗CNS曲霉病可能具有上级优势; AmBi与云母或CAS联合治疗无拮抗作用，可能略有获益。
Central nervous system (CNS) aspergillosis is a severe disease that responds poorly to current therapies. The current studies examined the efficacies of several antifungal agents alone or in combination with a murine model of CNS aspergillosis. Immunosuppressed mice were infected intracerebrally with Aspergillus fumigatus and treated with an amphotericin B preparation, an echinocandin, or voriconazole (VCZ) given alone or in combination. Monotherapy studies showed that micafungin (MICA), caspofungin (CAS), VCZ, conventional amphotericin B (AMB), Abelcet (ABLC) (a lipid-carried AMB formulation; Enzon Pharmaceuticals, Inc.), and AmBisome (AmBi) (liposomal AMB; Gilead Sciences, Inc.) were efficacious. However, doses of AmBi above 15 mg/kg of body weight showed reduced efficacy. Neither MICA nor CAS showed dose responsiveness at the doses tested (1, 5, or 10 mg/kg). Only the 40-mg/kg dose of VCZ was effective. AmBi and ABLC showed dose responsiveness, with 10-mg/kg doses causing a significant reduction in fungal burden; they had equivalent activities at the 10-mg/kg dose. Suboptimal dosages of AmBi in combination with MICA, CAS, or VCZ were effective in prolonging survival. However, significantly enhanced activity was demonstrated only with AmBi and VCZ in combination. AmBi in combination with MICA or CAS showed a trend toward enhanced activity, but the combination was not significantly superior to monotherapy. The use of AmBi with CAS or VCZ at optimal doses did not improve efficacy. Cure was not attained with any dosage combinations. These results indicate that AmBi in combination with VCZ may be superior for treatment of CNS aspergillosis; combinations of AmBi and MICA or CAS were not antagonistic and may have a slight benefit.