近日，英国布莱顿和苏塞克斯医学院Fiona V. Cresswell团队报道了大剂量口服利福平治疗成人结核性脑膜炎的试验。该研究于2025年12月18日发表在《新英格兰医学杂志》上。

结核性脑膜炎通常是致命的，尽管进行了抗菌药物治疗和辅助糖皮质激素治疗，许多幸存者仍有残疾。标准剂量的利福平对中枢神经系统的渗透有限。大剂量利福平是否能改善生存结果尚不清楚。

研究组对印度尼西亚、南非和乌干达的成人结核性脑膜炎患者进行了一项双盲、随机、安慰剂对照的临床试验。研究组将人类免疫缺陷病毒（HIV）合并感染者和未合并感染者分配给标准每日异烟肼、利福平（剂量为每公斤体重10毫克）、乙胺丁醇和吡嗪酰胺加上额外的利福平（累积剂量为每公斤35毫克；高剂量组）或匹配的安慰剂（标准剂量组），持续8周；两组的参与者在剩下的9-12个月的治疗过程中都接受了标准治疗。主要终点为6个月死亡率。

共有499名参与者被纳入意向治疗人群（249名随机分配到高剂量组，250名随机分配到标准剂量组），其中304名（60.9%）是艾滋病毒感染者，428名（85.8%）患有明确或可能的结核性脑膜炎。随访6个月，高剂量组109例（Kaplan-Meier估计，44.6%）死亡，标准剂量组100例（Kaplan-Meier估计，40.7%）死亡（风险比1.17；95%可信区间0.89 ~ 1.54；P=0.25）。在6个月内死亡的参与者中，高剂量组的中位死亡时间为13天（四分位数范围，4至39），标准剂量组的中位死亡时间为24天（四分位数范围，6至56）。高剂量组8.0%的受试者发生药物性肝损伤，标准剂量组4.4%的受试者发生药物性肝损伤，但未发生药物性肝损伤死亡。

研究结果表明，在结核性脑膜炎患者中，没有观察到高剂量利福平有益作用的证据，不能排除潜在的有害作用。

附：英文原文

Title: Trial of High-Dose Oral Rifampin in Adults with Tuberculous Meningitis

Author: David B. Meya, Fiona V. Cresswell, Biyue Dai, Nicole Engen, Kogieleum Naidoo, Ahmad Rizal Ganiem, Darma Imran, Mable Kabahubya, Richard J. Lessells, Vycke Yunivita, Riwanti Estiasari, Lillian Tugume, Bongeka Hlabisa, Media Yuni Kurniawati, Noveline Sagita, Enock Kagimu, Kartika Maharani, Jane Gakuru, Maula N. Gaharu, Timothy Mugabi, Sarah Kimuda, Suzan Namombwe, Lindsey te Brake, Rob Aarnoutse, Elin M. Svensson, Ananta S. Bangdiwala, Sylvia Namanda, Nathan C Bahr, Abdu K. Musubire, Mahomed Yunus Suleman Moosa, Raph L. Hamers, Suzaan Marais, David R. Boulware, Reinout van Crevel, Rovina Ruslami

Issue&Volume: 2025-12-18

Abstract:

Background

Tuberculous meningitis is often lethal, and many survivors have disabilities despite antimicrobial treatment and adjunctive glucocorticoid therapy. Standard-dose rifampin has limited central nervous system penetration. Whether high-dose rifampin could improve survival outcomes is unknown.

Methods

We performed a double-blind, randomized, placebo-controlled clinical trial involving adults with tuberculous meningitis in Indonesia, South Africa, and Uganda. We assigned persons with and those without human immunodeficiency virus (HIV) coinfection to receive standard daily isoniazid, rifampin (at a dose of 10 mg per kilogram of body weight), ethambutol, and pyrazinamide plus either additional rifampin (for a cumulative dose of 35 mg per kilogram; high-dose group) or matched placebo (standard-dose group) for 8 weeks; participants in both groups received standard therapy for the remainder of the 9-to-12-month treatment course. The primary outcome was 6-month mortality.

Results

A total of 499 participants were included in the intention-to-treat population (249 randomly assigned to the high-dose group and 250 to the standard-dose group), of whom 304 (60.9%) were persons living with HIV and 428 (85.8%) had definite or probable tuberculous meningitis. During 6 months of follow-up, 109 participants (Kaplan–Meier estimate, 44.6%) in the high-dose group and 100 participants (Kaplan–Meier estimate, 40.7%) in the standard-dose group died (hazard ratio, 1.17; 95% confidence interval, 0.89 to 1.54; P=0.25). Among the participants who died within 6 months, the median time to death was 13 days (interquartile range, 4 to 39) in the high-dose group and 24 days (interquartile range, 6 to 56) in the standard-dose group. Drug-induced liver injury occurred in 8.0% of the participants in the high-dose group and in 4.4% of those in the standard-dose group, but no deaths from drug-induced liver injury occurred.

Conclusions

Among persons with tuberculous meningitis, no evidence of beneficial effect from high-dose rifampin was observed, and the potential for a harmful effect cannot be ruled out.

DOI: NJ202512183932409

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2502866