TOPLINE:

High-dose rifampin — 35 mg/kg daily — administered for 8 weeks showed no reduction in mortality rate compared with standard-dose rifampin — 10 mg/kg daily — in patients with tuberculous meningitis but was accompanied by more early deaths and slower normalization of mental status. 

METHODOLOGY:

• Researchers conducted a randomized, phase 3 study across sites in Indonesia, South Africa, and Uganda to determine the effects of high-dose oral rifampin use on survival among patients with tuberculous meningitis
• A total of 499 patients were randomly assigned to receive oral rifampin at either a high dose (n = 249; median age, 38 years; 40.6% women) or a standard dose with matched placebo (n = 250; median age, 35 years; 48.4% women) for 8 weeks and were followed up for 52 weeks.
• The high-dose group received oral rifampin at a dose of 35 mg/kg daily, whereas the standard-dose group received a dose of 10 mg/kg daily; both groups also received standard 9- to 12-month tuberculosis (TB) therapy and adjunctive glucocorticoids.
• The primary outcome was 6-month mortality, and secondary outcomes included 12-month mortality, functional status, neurologic function assessed using the Glasgow Coma Scale (with a lower score indicating poor functioning), duration of hospitalization, and adverse events.

TAKEAWAY:

• During the initial 6 months of follow-up, more deaths occurred in the high‑dose group vs the standard-dose group (44.6% vs 40.7%; hazard ratio [HR], 1.17; P = .25), and the median time to death was shorter in the high-dose group (13 vs 24 days).
• Increased risks for mortality were observed in two subgroups with high-dose rifampin use: patients with white-cell counts < 5 cells/mm³ in their cerebrospinal fluid (HR, 2.01; 95% CI, 1.14-3.54) and those receiving antiretroviral therapy at presentation (HR, 2.01; 95% CI, 1.07-3.78).
• Among patients who had a baseline Glasgow Coma Score < 15, only 28.4% in the high‑dose group vs 39.9% in the standard‑dose group had normal neurologic function by day 20, indicating slower normalization of mental status in the high-dose group.
• Drug-induced liver injury and aspiration pneumonia occurred more frequently in the high-dose group vs the standard-dose group. No benefits of high-dose rifampin use were observed for other secondary outcomes.

IN PRACTICE:

“We found that high-dose rifampin did not benefit adults with tuberculous meningitis; however, this trial showed that high-quality multinational trials can be conducted successfully, despite the complexities of care,” the authors wrote.

SOURCE:

This study was led by David B. Meya, PhD, Makerere University, Kampala, Uganda. It was published online on December 17, 2025, in The New England Journal of Medicine. 

LIMITATIONS:

The study was limited by its potential for misdiagnosis due to difficulties in microbiologic confirmation of tuberculous meningitis, and any interventional therapy would not benefit patients who did not truly have TB. The study involved limited follow-up for cerebrospinal fluid sampling over time.

DISCLOSURES:

This study was supported by the UK Medical Research Council, the Department of Health and Social Care, the Foreign, Commonwealth & Development Office, and a grant from Wellcome Trust Medical Research Council Joint Global Health Trials. Several authors reported receiving grants from, holding contracts with, and/or serving as consultants for various institutions and pharmaceutical companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.