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• Posted January 30, 2023

Troubling Signs TB Is Gaining Resistance Against Combo Antibiotics

New drugs may be needed to fight the deadliest form of tuberculosis, because it may no longer respond to current treatments.

An animal study by Johns Hopkins University researchers found that an approved antibiotic regimen may not work for TB meningitis due to multidrug-resistant strains. Small human studies have also provided evidence that a new combination of drugs is needed.

Doctors currently use a regimen of three antibiotics -- bedaquiline, pretomanid and linezolid (BPaL) -- to treat TB of the lungs due to multidrug-resistant (MDR) strains. The new study showed that is not effective in treating TB meningitis because bedaquiline and linezolid are restricted in crossing the blood-brain barrier, a network of cells that stops germs and toxins from entering the brain.

About 1% to 2% of TB cases progress into TB meningitis. This leads to brain infection that causes increased fluid and inflammation.

Tuberculosis is caused by the bacteria Mycobacterium tuberculosis and is considered a global health threat.

"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,"senior author Dr. Sanjay Jain said in a Hopkins news release. He's director of the university's Center for Infection and Inflammation Imaging Research in Baltimore.

The BPaL regimen has been approved for MDR strains of TB since 2019.

For the study, researchers synthesized a chemically identical version of the antibiotic pretomanid. They conducted experiments with mouse and rabbit models of TB meningitis.

They used positron emission tomography (PET) imaging to measure penetration of the antibiotic into the central nervous system and used direct drug measurements in mouse brains.

Imaging showed excellent penetration of pretomanid into the brain or the central nervous system of the mouse and rabbit models. But levels in the cerebrospinal fluid (CSF) that bathes the brain were several times lower than in the brains of mice.

"When we have measured drug concentrations in the spinal fluid, we have found that many times they have no relation to what's happening in the brain,"study co-author Dr. Elizabeth Tucker said in the release. She's an assistant professor of anesthesiology and critical care medicine. "This finding will change how we interpret data from clinical trials and, ultimately, treat infections in the brain."

The researchers also compared effectiveness of the BPaL regimen to the standard treatment -- a combination of the antibiotics rifampin, isoniazid and pyrazinamide -- used to treat drug-susceptible forms of TB.

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. This was likely due to restricted penetration of bedaquiline and linezolid into the brain, researchers said.

That means that the "regimen that we think works really well for MDR-TB in the lung does not work in the brain,"Jain said.

Another experiment involved six healthy adults -- three men and three women ages 20 to 53 years. PET imaging was used to show pretomanid distribution to major organs, according to researchers.

Results in the people were similar to those found in mice.

"Our 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,"said co-author Dr. Xueyi Chen, a pediatric infectious diseases fellow at Hopkins, who is now studying combinations of such therapies.

The findings were recently published in Nature Communications.

More information

The U.S. National Library of Medicine has more on tuberculosis meningitis.

SOURCE: Johns Hopkins Medicine, news release, Jan. 27, 2023