High-dose antibiotic does not reduce mortality in tuberculous meningitis

Each year, 11 million people worldwide develop tuberculosis, and about 1.4 million die from it. Meningitis occurs in 1–2% of patients and is the most severe complication of tuberculosis, 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.

Hospital pharmacist, clinical pharmacologist, and professor Rob Aarnoutse explains: '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.'

Higher dose antibiotic

Worldwide, several studies began examining 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.

No effect

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’, says researcher Reinout van Crevel, internist-infectiologist and professor at Radboudumc. Van Crevel has studied tuberculosis for 25 years, especially in Indonesia. He adds: '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

Follow-up studies at Radboudumc using stored blood and cerebrospinal fluid samples, led by biomedical scientist and toxicologist Lindsey te Brake, aim to uncover why high-dose rifampicin had no beneficial effect. Meanwhile, Van Crevel and colleagues are shifting focus from the tuberculosis bacteria to the inflammation in the brain membranes. '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,' Van Crevel explains.

Current treatment with antibiotics and anti-inflammatory drugs offers insufficient protection. There is an urgent need for therapies that better control this inflammatory response, possibly using TNF inhibitors. Van Crevel: '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.'

About the publication

This research is published in New England Journal of Medicine: Trial of High-Dose Oral Rifampin in Adults with Tuberculous Meningitis. Authors: David B. Meya, Fiona V. Cresswell, Biyue Dai, Nicole Engen, Kogieleum Naidoo, Ahmad Rizal Ganiem, Darma Imran, Mable Kabahubya, Richard J. Lessells, Vycke Yunivita, Riwanti Estiasari, Lillian Tugume, Bongeka Hlabisa, Media Yuni Kurniawati, Noveline Sagita, Enock Kagimu, Kartika Maharani, Jane Gakuru, Maula N. Gaharu, Timothy Mugabi, Sarah Kimuda, Suzan Namombwe, Lindsey te Brake, Rob Aarnoutse, Elin M. Svensson, Ananta S. Bangdiwala, Sylvia Namanda, Nathan C Bahr, Abdu K. Musubire, Mahomed Yunus Suleman Moosa, Raph L. Hamers, Suzaan Marais, David R. Boulware, Reinout van Crevel, and Rovina Ruslami, for the HARVEST Trial Team.