A recent study found that increasing the dose of one of the main antibiotics used to treat tuberculous meningitis does not reduce death rates, despite high hopes for this approach to improve chances of survival and prevent brain damage. Tuberculosis meningitis is the most serious complication of tuberculosis, as it occurs when tuberculosis bacteria reach the brain and the membranes that surround it. The study, published by the New England Journal of Medicine, stated that despite the availability of antibiotic treatment, approximately half of patients with this condition lose their lives, or suffer permanent damage such as paralysis or hearing loss. About 11 million people worldwide are infected with tuberculosis each year, and the disease kills about 1.4 million people each year. Although meningitis occurs in only 1-2% of tuberculosis patients, it is considered the most lethal and complex form of the disease. Because of its direct effect on the brain. Tuberculosis meningitis The study’s lead researcher, Rob Arnotze, a clinical pharmacist and professor of clinical pharmacology at Radboud University Medical Center in the Netherlands, said the main problem is that very small amounts of the drug “rifampicin”, which is the most important antibiotic in the treatment of tuberculosis, reach the brain. He added: “This means that the bacteria are not effectively eliminated within the central nervous system.” However, previous studies have indicated an association between higher doses of rifampicin and lower mortality rates, prompting international research teams to systematically test this option. The first large clinical trial was conducted to test the effectiveness of high doses of “rifampicin” in improving the chances of survival. The study was co-designed by the Radboud University Medical Center and carried out in Indonesia, Uganda and South Africa. The study included 499 adults with tuberculous meningitis, all of whom received the standard treatment consisting of four antibiotics: isoniazid, rifampicin at a dose of 10 mg per kilogram of weight, pyrazinamide and ethambutol. The researchers divided the participants into two groups: One of them received an additional high dose of “rifampicin”, reaching 35 milligrams per kilogram of weight, while the other group received a placebo, for a period of 8 weeks. The average age of the patients was 37 years, and 60% of them were infected with HIV, a factor that increases the complexity and severity of the disease, and the researchers evaluated survival rates 6 months after starting treatment. Disappointing results: The results showed that there was no significant benefit from the use of high doses of “rifampicin”. On the contrary, some subgroups of patients appeared to face a greater risk of death. After 6 months, 44.6% of patients in the high-dose group had died, compared with 40.7% in the standard treatment group. “Excess deaths in the high-dose group appear to be concentrated in the first weeks after diagnosis,” says study co-researcher Reinout van Crevel, a specialist in internal medicine and infectious diseases. Krevel, who has been studying tuberculosis for more than 25 years, especially in Indonesia, added: “Of course the results were disappointing because we were hoping that this would be the solution, but these are important results because they clearly tell us that we need to look for another path… This is how science progresses.” Following these findings, researchers began to shift their focus from the bacteria themselves to the inflammatory response within the brain. Analyzes of blood samples and cerebrospinal fluid suggest that patients who died had higher levels of inflammation than survivors. The study’s co-researcher, Lindsey T. Brake, a scientist specializing in biomedical sciences and toxicology at the Radboud Center, explained that the team is currently analyzing preserved samples of blood and cerebrospinal fluid; To understand why high doses of rifampicin do not achieve the desired benefit. Van Crevel noted that the protein tumor necrosis factor (TNF) may be a crucial component in this process. “That protein helps to eliminate bacteria, but at the same time it can cause serious damage to the brain. We seem to push the immune system into an overreaction that harms the patient instead of protecting him.” New therapeutic strategies The researchers confirmed that the current treatment, which combines antibiotics and anti-inflammatory drugs, such as corticosteroids, does not provide sufficient protection for the brain, therefore the urgent need arises for new therapeutic strategies aimed at controlling the inflammatory response more precisely. One option is the use of tumor necrosis factor inhibitors, which are sometimes used in the late stages of treatment for tuberculous meningitis when corticosteroids have failed. Van Crevel said there are positive experiences with these drugs, “but they have not yet been used at the beginning of treatment, which is the stage at which most patients die.” The researchers plan to start a new clinical trial to test the use of TNF inhibitors in the early stages of treating tuberculous meningitis, hoping to reduce mortality and prevent permanent brain damage. Researchers hope that this approach will represent a shift in the treatment of one of the most dangerous forms of tuberculosis, after increasing doses of antibiotics alone have proven not to be the desired solution.