How Effective is the New Drug to Fight the Deadliest Form of Tuberculosis?

A U.S. Food and Drug Administration (FDA)-approved antibiotic regimen for multidrug-resistant (MDR) tuberculosis (TB) may not work for TB meningitis, according to findings from a Johns Hopkins Children’s Center study in animal models. Studies on a small number of people also provide evidence that a new combination of drugs is needed to develop effective treatments for TB meningitis due to MDR strains.

Tuberculosis, caused by the bacteria Mycobacterium tuberculosis, is a global public health threat. According to the World Health Organization, it is one of the leading killers by a single infectious agent.

About 1%–2% of TB cases progress into TB meningitis, the worst form of TB, which leads to an infection in the brain that causes increased fluid and inflammation. Most treatments for TB meningitis are based on studies of treatments for pulmonary TB, so we don’t have good treatment options for TB meningitis.

In 2019, the FDA approved the BPaL regimen to treat MDR strains of TB, specifically those that lead to pulmonary TB. However, there is limited data on how well these antibiotics cross the blood-brain barrier.

FDA-Approved TB Regimen may not Work Against the Deadliest Form of TB

In a study published in Nature Communications, the investigators showed that the FDA-approved regimen of three antibiotics — bedaquiline, pretomanid, and linezolid (BPaL) — was used for treating TB of the lungs due to MDR strains.

It is not effective in treating TB meningitis because bedaquiline and linezolid are restricted in crossing the blood-brain barrier, a network of cells that prevents the entry of germs and toxins into the brain.

To learn more, the research team synthesized a chemically identical and imageable version of the antibiotic pretomanid. They conducted experiments in mouse and rabbit models of TB meningitis using positron emission tomography (PET) imaging to noninvasively measure pretomanid penetration into the central nervous system as well as using direct drug measurements in mouse brains.

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In both models, PET imaging demonstrated excellent penetration of pretomanid into the brain or the central nervous system. However, the pretomanid levels in the cerebrospinal fluid (CSF) that bathes the brain were severalfold lower than in the brains of mice.

Next, researchers measured the efficacy of the BPaL regimen compared with the standard TB treatment — a combination of the antibiotics rifampin, isoniazid, and pyrazinamide — used to treat drug-susceptible forms of TB.

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Results showed that the ability to kill bacteria in the brain using the BPaL regimen in the mouse model was about 50 times lower than the standard TB regimen after six weeks of treatment, likely due to restricted penetration of bedaquiline and linezolid into the brain.

In another experiment involving six healthy adults — three men and three women between 20 and 53 years old — at The Johns Hopkins Hospital, first-in-human PET imaging was used to showing pretomanid distribution to major organs.

Similar to what was seen in the mice, the study revealed high penetration of pretomanid into the brain or central nervous system, with CSF levels lower than those seen in the brain.

These findings suggest pretomanid-based regimens, in combination with other antibiotics active against MDR strains with high brain penetration, should be tested for treating MDR-TB meningitis.

The investigators noted limitations, including the small quantities of the imageable version of pretomanid per subject (micrograms) used. However, current evidence suggests that studies with small quantities of a drug are a reliable predictor of drug biodistribution.



Source-Eurekalert