Intensified antibiotic treatment for tuberculous meningitis

Tuberculosis (TB) is second only to HIV as the greatest killer worldwide due to a single infectious agent. Last year, an estimated 8.7 million people developed TB, and 1.4 million died from TB globally. The large majority of cases and over 95% of TB deaths occur in low-and middle-income countries.

TB meningitis (TB of the protective membranes covering the brain and spinal cord) is the most severe form of TB, resulting in death or neurological disability in up to 50% of patients or more. TB meningitis is relatively rare (1-5% of all TB cases) but due to its high mortality it accounts for a significant number of deaths, also among patients treated in the Netherlands. The treatment of TB meningitis is similar to that of lung TB, consists of a combination of anti-TB drugs, and has not changed essentially in the last 40 years. Other brain infections are often treated with higher doses of antibiotics, but for TB meningitis this has not been examined. This seems very relevant as some TB drugs, especially rifampicin, do not penetrate well into the brain. In addition, newer, more potent TB drugs might be more effective compared to the ones currently used.

Intensified treatment

Reinout van Crevel (department of Internal Medicine), Rob Aarnoutse (department of Pharmacy) and colleagues from Indonesia have now examined 'intensified' antibiotic treatment in TB meningitis. In a referral hospital in Indonesia, 60 patients were included in a randomized controlled trial comparing standard (oral) six months of TB treatment with intensified treatment that included a higher dose of rifampicin given intravenously and standard or higher-dose moxifloxacin for the first two weeks. Intensified antibiotic treatment led to much higher concentrations of antibiotics in blood and cerebrospinal fluid. Drug toxicity was not different, but 35% of patients given high-dose rifampicin intravenously had died after six months, compared with 65% who had received the standard oral dose, and this large difference was not explained by HIV status or severity of disease before start of antibiotic treatment (adjusted HR 0.42, 95% confidence interval 0.20-0.91). This study, the first of its kind globally, challenges the current treatment model for TB meningitis. Since this study was conducted, several patients in the Netherlands have also been treated with higher dose intravenous antibiotics, all with good success.

Longstanding collaboration

This study also exemplifies the very fruitful and longstanding collaboration between Radboud University Medical Centre and academic institutes in Indonesia in the field of TB and HIV. In Indonesia the trial was led by Rovina Ruslami and Ahmed Rizal Ganiem from Padjadjaran university / Hasan Sadikin hospital. Dr Ruslami is one of several four Indonesian researchers who completed a PhD in TB research in Nijmegen, and Dr Ganiem will do so next year. Besides them, a number of others are following the same path in HIV.

Further research in the field of TB meningitis is planned. The group led by van Crevel and Aarnoutse is planning a bigger trial, combining high-dose antibiotics and aspirin, which will hopefully reduce stroke, a common complication of TB meningitis. In addition, fundamental research will be done, supported by the Radboud research institute N4i, to try and understand why some people develop TB meningitis while others develop lung TB or remain asymptomatic after infection with TB.