Clemons Karl V, Espiritu Marife, Parmar Rachana, Stevens David A
California Institute for Medical Research, Division of Infectious Diseases, Santa Clara Valley Medical Center, 751 South Bascom Ave., San Jose, California 95128-2699, USA.
Antimicrob Agents Chemother. 2005 Dec;49(12):4867-75. doi: 10.1128/AAC.49.12.4867-4875.2005.
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.
中枢神经系统（CNS）曲霉病是一种严重疾病，对当前治疗反应不佳。当前研究使用中枢神经系统曲霉病小鼠模型，单独或联合使用几种抗真菌药物来检测其疗效。对免疫抑制小鼠进行脑内烟曲霉感染，并单独或联合给予两性霉素B制剂、棘白菌素或伏立康唑（VCZ）进行治疗。单药治疗研究表明，米卡芬净（MICA）、卡泊芬净（CAS）、VCZ、传统两性霉素B（AMB）、阿贝西普（ABLC）（一种脂质体两性霉素B制剂；恩宗制药公司）和安必素（AmBi）（脂质体两性霉素B；吉利德科学公司）均有效。然而，体重超过15mg/kg的安必素剂量显示疗效降低。在测试剂量（1、5或10mg/kg）下，MICA和CAS均未显示出剂量反应性。仅40mg/kg剂量的VCZ有效。AmBi和ABLC显示出剂量反应性，10mg/kg剂量可显著降低真菌负荷；它们在10mg/kg剂量下具有同等活性。亚最佳剂量的AmBi与MICA、CAS或VCZ联合使用可有效延长生存期。然而，仅AmBi与VCZ联合使用显示出显著增强的活性。AmBi与MICA或CAS联合使用显示出活性增强的趋势，但联合用药并不显著优于单药治疗。以最佳剂量使用AmBi与CAS或VCZ联合用药并未提高疗效。任何剂量组合均未实现治愈目标。这些结果表明，AmBi与VCZ联合使用可能对中枢神经系统曲霉病治疗效果更佳；AmBi与MICA或CAS联合使用并无拮抗作用，可能有轻微益处。
