Efficacy of an Abbreviated Induction Regimen of Amphotericin B Deoxycholate for Cryptococcal Meningoencephalitis: 3 Days of Therapy Is Equivalent to 14 Days
Efficacy of an Abbreviated Induction Regimen of Amphotericin B Deoxycholate for Cryptococcal Meningoencephalitis: 3 Days of Therapy Is Equivalent to 14 Days
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DOI：
10.1128/mbio.00725-13
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发表时间：
2014-01-01
期刊：
影响因子：
6.4
通讯作者：
Hope, William W.
中科院分区：
文献类型：
--
作者：
Livermore, Joanne;Howard, Susan J.;Hope, William W.
隐球菌脑膜脑炎是一个紧迫的全球性健康问题。使用14天阿替西霉素B脱氧胆酸盐（dAm B）的诱导方案被认为是标准治疗，但可能不适合资源匮乏的环境。我们研究了dAmB的常规和简化方案在隐球菌脑膜脑炎小鼠和兔模型中对隐球菌脑膜脑炎的疗效。我们研究了免疫效应子对抗真菌作用的贡献程度。我们将结果与人类联系起来，作为确定适合在临床试验中进一步研究的方案的第一个关键步骤。小鼠血浆与大脑dAmB浓度-时间曲线存在显著差异。在整个实验期间，甚至在仅给予三次剂量的3 mg/kg后，在大脑中也可检测到dAmB。dAmB在大脑中诱导了真菌抑制作用，与对照相比减少了2- 3-log（10）CFU/g。治疗3天的效果与每日治疗14天的效果相同。没有证据表明给药小鼠中的CD 3 + CD 4+或CD 3 + CD 8+细胞数量增加，以解释简化方案的持续抗真菌作用。以lmg/kg/天施用dAmB持续3天与兔中的每日治疗相同。桥接研究表明，0.7 mg/kg/天持续3天的人体给药方案在大脑和脑脊液中产生了几乎最大的抗真菌活性。一个简短的方案（3天的治疗）dAmB似乎是一样有效的常规诱导治疗隐球菌脑膜脑炎。重要性隐球菌脑膜炎是一个重要的和被忽视的感染，是与过度的发病率和死亡率。在资源充足的医疗机构中，提倡使用至少2周的阿替霉素B脱氧胆酸盐（dAm B）进行诱导治疗。多项临床研究表明，dAmB是隐球菌脑膜炎的首选药物。在世界上隐球菌脑膜炎负担最高的许多地区，长期施用dAmB是不可行的。本文为dAmB简化方案治疗隐球菌性脑膜炎的疗效提供了实验依据。在两个经过充分验证的隐球菌脑膜炎实验室动物模型中探索了这一概念，并通过使用一系列数学建模技术将结果与人类联系起来。3天的疗程与标准的14天疗程一样有效。一个简短的方案是显着更可行的，并可能使更好的抗真菌治疗，以管理许多患者这种经常致命的疾病。
Cryptococcal meningoencephalitis is an urgent global health problem. Induction regimens using 14 days of amphotericin B deoxycholate (dAmB) are considered the standard of care but may not be suitable for resource-poor settings. We investigated the efficacy of conventional and abbreviated regimens of dAmB for cryptococcal meningoencephalitis in both murine and rabbit models of cryptococcal meningoencephalitis. We examined the extent to which immunological effectors contribute to the antifungal effect. We bridged the results to humans as a first critical step to define regimens suitable for further study in clinical trials. There were significant differences in the murine plasma-versus-cerebrum dAmB concentration-time profiles. dAmB was detectable in the cerebrum throughout the experimental period, even following the administration of only three doses of 3 mg/kg. dAmB induced a fungistatic effect in the cerebrum with a 2- to 3-log(10) CFU/g reduction compared with controls. The effect of 3 days of therapy was the same as that of daily therapy for 14 days. There was no evidence of increased numbers of CD3+ CD4+ or CD3+ CD8+ cells in treated mice to account for the persistent antifungal effect of an abbreviated regimen. The administration of dAmB at 1 mg/kg/day for 3 days was the same as daily therapy in rabbits. The bridging studies suggested that a human regimen of 0.7 mg/kg/day for 3 days resulted in nearly maximal antifungal activity in both the cerebrum and cerebrospinal fluid. An abbreviated regimen (3 days of therapy) of dAmB appears to be just as effective as conventional induction therapy for cryptococcal meningoencephalitis.IMPORTANCE Cryptococcal meningitis is a significant and neglected infection that is associated with excessive morbidity and mortality. In well-resourced health care settings, induction therapy with at least 2 weeks of amphotericin B deoxycholate (dAmB) is advocated. Multiple clinical studies suggest that dAmB is the drug of choice for cryptococcal meningitis. In many parts of the world where the burden of cryptococcal meningitis is highest, it is infeasible to administer dAmB for prolonged periods. This paper provides the experimental basis for the efficacy of abbreviated regimens of dAmB for cryptococcal meningitis. The concept was explored in two well-validated laboratory animal models of cryptococcal meningitis, and the results were bridged to humans by using a range of mathematical modeling techniques. A 3-day regimen is as effective as the standard 14-day course. An abbreviated regimen is significantly more feasible and may enable better antifungal therapy to be administered to many patients with this frequently lethal disease.