NEJM：两性霉素B联合氟胞嘧啶治疗隐球菌性脑膜炎效果优于单药

联合抗真菌治疗（两性霉素B去脱氧胆酸和氟胞嘧啶）被推荐用于隐球菌性脑膜炎的治疗，但与单独使用两性霉素B相比，联合治疗并未显示出降低死亡率的效果。越南胡志明市牛津大学临床研究部Jeremy N. Day博士等人进行了一项随机对照研究，以明确氟胞嘧啶或大剂量氟康唑联合大剂量两性霉素B是否能改善患者的14天和70天生存率。日前，他们发表于国际权威杂志NEJM 2103年4月最新一期在线版的论文结果显示，与两性霉素B单独治疗相比，两性霉素B联合氟胞嘧啶治疗与隐球菌性脑膜炎患者生存率改善相关。未发现两性霉素B加氟康唑的联合治疗在生存率方面有获益。
研究人员在感染人类免疫缺陷病毒（HIV）的患者中，进行了一项隐球菌性脑膜炎诱导治疗的随机、分为三组的开放标签试验。所有患者均接受两性霉素B治疗，剂量为每天1 mg/kg体重，第1组患者治疗4周，第2、3组患者治疗2周。第2组患者同时接受氟胞嘧啶治疗，剂量为每天100 mg/kg体重，共2周，第3组患者同时接受氟康唑治疗，剂量为400 mg，2次/天，共2周。
试验共纳入299例患者。结果显示，14天和70天内，接受两性霉素B联合氟胞嘧啶治疗患者中的死亡例数少于接受两性霉素B单独治疗的患者（14天时，死亡例数为15例比25例，风险比为0.57，95%可信区间〔CI〕为0.30～1.08，未校正的P值为0.08；70天时，死亡例数为30例比44例，风险比为0.61，95%CI为0.39～0.97，未校正P值为0.04）。研究人员观察到，与单药治疗相比，氟康唑联合治疗对生存率无显著影响（14天内死亡风险比为0.78，95% CI 0.44～1.41，P=0.42；70天死亡的风险比为0.71，95% CI为0.45～1.11，P=0.13）。两性霉素B加氟胞嘧啶联合用药与脑脊液中酵母的清除率显著增高相关（每天-0.42 log10菌落形成单位[CFU]/ml对第1、3组的每天-0.31和-0.32 log10 CFU /ml，所有比较的P值均<0.001）。虽然联合用药患者中的中性粒细胞减少更为多见，但各组不良事件发生率相似。
作者总结道：与两性霉素B单独治疗相比，两性霉素B联合氟胞嘧啶治疗与隐球菌性脑膜炎患者生存率改善相关。未发现两性霉素B加氟康唑的联合治疗在生存率方面有获益。
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Combination antifungal therapy for cryptococcal meningitis.
Background
Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days.
Methods
We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks.
Results
A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P=0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P=0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P=0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P=0.13). Amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (−0.42 log10 colony-forming units [CFU] per milliliter per day vs. −0.31 and −0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy.
Conclusions
Amphotericin B plus flucytosine, as compared with amphotericin B alone, is associated with improved survival among patients with cryptococcal meningitis. A survival benefit of amphotericin B plus fluconazole was not found. (Funded by the Wellcome Trust and the British Infection Society; Controlled-Trials.com number, ISRCTN95123928.)