Each year, tuberculosis affects around 11 million people globally and leads to about 1.4 million deaths. Tuberculous meningitis, which develops in 1–2% of tuberculosis cases when the bacteria reach the brain, is considered the most severe complication of the disease. Despite antibiotic treatment, approximately half of those with TB meningitis either die or experience permanent disabilities such as deafness or paralysis.
Rob Aarnoutse, a hospital pharmacist, clinical pharmacologist, and professor, explained: "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."
A recent international study co-designed by Radboudumc and conducted in Indonesia, Uganda, and South Africa examined whether increasing the dose of rifampicin could improve survival rates for adults with tuberculous meningitis. The trial included 499 adult patients who received standard treatment with four antibiotics: isoniazid, rifampicin at 10 mg/kg, pyrazinamide, and ethambutol. Half of these patients were given an additional high dose of rifampicin (up to 35 mg/kg), while the other half received a placebo over eight weeks. The average age was 37 years old and about 60% were HIV-positive.
The findings did not show any benefit from using high-dose rifampicin. In some subgroups there appeared to be an increased risk of death among those receiving higher doses. After six months, mortality was slightly higher in the high-dose group (44.6%) compared to those receiving standard treatment (40.7%). Researcher Reinout van Crevel commented: "The higher mortality seems to occur mainly in the first weeks after diagnosis." 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."
Follow-up research at Radboudumc is underway using stored blood and cerebrospinal fluid samples to investigate why increased doses did not help patient outcomes; this work is led by biomedical scientist and toxicologist Lindsey te Brake.
Van Crevel noted that analysis has shown more inflammation in patients who died than in survivors and suspects that tumor necrosis factor (TNF) may play a significant role: "Analysis of cerebrospinal fluid and blood showed more inflammation in patients who died than in others. We suspect the protein TNF plays a key role. TNF helps clear bacteria but can also cause severe damage to the brain," he said.
Current treatments combining antibiotics with anti-inflammatory drugs have proven insufficient for many patients with TB meningitis. There is growing interest in therapies targeting inflammatory responses—potentially using TNF inhibitors—to better protect patients early during treatment when most deaths occur.
Van Crevel stated: "These drugs are sometimes used later in treatment of tuberculous meningitis when corticosteroids fail. We have had good experiences with them both here in our own TB center and in Jakarta. 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."
