Every year, 11 million people worldwide develop tuberculosis (TB) and approximately 1.4 million people die from it.
Meanwhile, meningitis occurs in 1 to 2% of patients with tuberculosis and is the most serious complication of the disease, which occurs when the bacteria reach the brain.
Despite treatment with antibiotics, about half of patients with tuberculosis 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. This means that the bacteria are not effectively cleared there. But those studies also showed a link between higher doses and reduced mortality. On this basis, we and many international researchers started investigating a higher dose of rifampicin,” says Rob Aarnoutse, hospital pharmacist, clinical pharmacologist and professor.
Several studies worldwide have examined the effects of higher doses of rifampicin and the first trial has now been completed.
This study, co-designed by Radboud university medical center 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 mean age of the patients was 37 years and 60% were HIV positive. Researchers assessed survival after six months.
The study found no evidence of a beneficial effect of high doses of rifampicin. Some subgroups even appeared to have an increased risk of death.
After six months, 44.6% of the high-dose group had died, compared with 40.7% in the standard group.
“The higher mortality seems to occur mainly in the first weeks after diagnosis,” says researcher Reinout van Crevel, internist-infectiologist and professor at Radboud university medical center.
Current treatment with antibiotics and anti-inflammatories does not provide sufficient protection. There is an urgent need for therapies that can better control this inflammatory response.
