Tuberculosis meningitis drug under dose research gives shocking results

Each year, 11 million people worldwide develop tuberculosis (TB), and about 1.4 million die from it.

Meanwhile meningitis occurs in 1–2% of patients with tuberculosis and is the disease’s most severe complication, arising when the bacteria reach the brain.

Despite antibiotic treatment, about half of patients with TB meningitis die or suffer permanent damage such as deafness or paralysis.

“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," said Rob Aarnoutse, hospital pharmacist, clinical pharmacologist, and professor.

Worldwide, several studies examined the effects of higher rifampicin doses, and the first trial has now been completed.

This study, co-designed by Radboudumc and conducted in Indonesia, Uganda, and South Africa, investigated whether a high dose of rifampicin could improve survival.

499 adults with tuberculous meningitis received the standard treatment of four antibiotics (isoniazid, rifampicin 10 mg/kg, pyrazinamide and ethambutol).

Half also received an extra dose of rifampicin (up to 35 mg/kg), while the other half received a placebo for eight weeks. The average patient age was 37, and 60% were HIV-positive. Researchers assessed survival after six months.

The study found no evidence of a beneficial effect from high-dose rifampicin. In fact, some subgroups there appeared to be 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,” researcher Reinout van Crevel, internist-infectiologist and professor at Radboudumc, stated.

Current treatment with antibiotics and anti-inflammatory drugs offers insufficient protection. There is an urgent need for therapies that better control this inflammatory response.