Tuberculosis (TB) infects about 11 million people globally each year and causes 1.4 million deaths. The most severe complication—tuberculous meningitis—occurs when TB bacteria reach the brain. Tuberculous meningitis is often lethal, and even with antimicrobial treatment and adjunctive glucocorticoid therapy, nearly half of such patients die or suffer permanent neurological damage, including deafness or paralysis.
Hospital pharmacist and clinical pharmacologist Prof. Rob Aarnoutse noted that earlier research showed standard doses of rifampicin—the key anti-TB drug—barely reach the brain. 'In previous studies, we saw that very little rifampicin—the most important antibiotic against tuberculosis—reaches the brain. That means the bacteria are not effectively cleared there. But those studies also showed a link between higher dosing and reduced mortality. Based on that, we and many international researchers started investigating a higher dose of rifampicin.'
To test whether higher doses improve survival, Radboudumc and partners conducted a randomized trial in Indonesia, Uganda and South Africa. A total of 499 adults with TB meningitis received standard therapy with four antibiotics. Half also received high-dose rifampicin (up to 35 mg/kg), while the rest received a placebo for eight weeks. Sixty percent of participants were HIV-positive.
The outcome was disappointing. The study found no evidence of a beneficial effect from high-dose rifampicin. In fact, some subgroups there appeared to be at an increased risk of death. After six months, 44.6% of the high-dose group had died, compared to 40.7% in the standard group. 'The higher mortality seems to occur mainly in the first weeks after diagnosis’, said researcher Reinout van Crevel, internist-infectiologist and professor at Radboudumc. Van Crevel has studied tuberculosis for 25 years, especially in Indonesia. He added: 'It was, of course, disappointing that this is not the solution. But these are important results—we now know we need to take a different path. That’s how science works.'
Researchers are now trying to understand why the higher dose failed. Follow-up studies led by biomedical scientist and toxicologist Lindsey te Brake are analysing stored blood and cerebrospinal fluid samples for clues. Initial findings suggest inflammation in the brain membranes may be causing fatal injury.
“Analysis of cerebrospinal fluid and blood showed more inflammation in patients who died,” Van Crevel said. “We suspect the protein TNF plays a key role. TNF helps clear bacteria but can also cause severe damage to the brain.”
Since current antibiotics and anti-inflammatory drugs cannot adequately control the inflammatory response, investigators are exploring the early use of TNF-inhibiting drugs—already used later when corticosteroids fail. “We have had good experiences with them both here in our own TB center and in Jakarta,” Van Crevel saids. “But no one has used TNF inhibitors at the start of treatment—when most patients die. That’s what we will investigate in the next clinical trial.”
The findings were published in the New England Journal of Medicine under the title "Trial of High-Dose Oral Rifampin in Adults with Tuberculous Meningitis."
The WHO Global Tuberculosis Report 2025 released recently presents a mixed assessment of India’s TB control efforts—showing the fastest global decline in TB incidence, yet confirming that India continues to bear the largest TB and drug-resistant TB burden worldwide.
