PET imaging shows pretomanid distribution, which revealed high penetration of pretomanid into the brain. Credit: Sanjay Jain Lab
Key points:
- The FDA-approved BPal regimen for treating multidrug-resistant strains of TB meningitis may not cross the blood-brain barrier, rendering it ineffective
- An imaging-focused study showed the regimen works well in the lungs, but not the brain.
- Researchers now suggest a different antibiotic—pretomanid—as the base for treating multidrug-resistant TB meningitis.
A study by Johns Hopkins Children's Center indicates that the FDA-approved antibiotic regimen for tuberculosis may not work for TB meningitis due to multidrug resistance.
Published in Nature Communications, the study shows the approved regimen of three antibiotics—bedaquiline, pretomanid and linezolid (BPal)— is not effective in treating multidrug-resistant TB meningitis because bedaquiline and linezolid are restricted in crossing the blood-brain barrier.
About 1% to 2% of TB cases progress to TB meningitis, the worst form of T.B. that may lead to infection in the brain that causes fluid and inflammation. The BPal regimen for treating multidrug-resistant strains was approved by the FDA in 2019.
In the study, the researchers synthesized chemically identical and imageable versions of the antibiotic pretomanid for use in mouse and rabbit models of TB meningitis. The team used positron emission tomography (PET) imaging to noninvasively measure pretomanid penetration into the central nervous system, in addition to direct drug measurements in the brains of mice. While PET imaging demonstrated excellent penetration of pretomanid into the brain or the central nervous system, the team noted that pretomanid levels in the cerebrospinal fluid that bathes the brain were several-fold lower than in the brains of mice than rabbits.
The researchers also measured the efficacy of the BPal regimen compared with the standard TB treatment—a combination of the antibiotics rifampin, isoniazid and pyrazinamide. 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.
Following further PET experiments with six healthy adults that showed the same high penetration of pretomanid into the brain or central nervous system with lower cerebrospinal fluid levels, the scientists suggest pretomanid-based regimens should be tested for treating multidrug-resistant TB meningitis.
“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,” said Elizabeth Tucker, one of the study’s first authors and an assistant professor of anesthesiology and critical care medicine at Johns Hopkins Medicine. “This finding will change how we interpret data from clinical trials and, ultimately, treat infections in the brain.”