An animal model study by investigators at Johns Hopkins Children’s Center demonstrates that an FDA-approved drug regimen for multidrug-resistant (MDR) tuberculosis (TB) may not work against TB meningitis. Their studies in a small cohort of patients provides evidence that a new drug combination is needed to thwart MDR strains in TB meningitis.
The study, published in Nature Genetics showed that the currently approved three-drug combination of bedaquiline, pretomanid, and linezolid (BPaL) that is currently used for TB of the lungs for infected by MDR strains won’t work on TB meningitis due to problems bedaquiline and linezolid have crossing the blood-brain barrier. TB meningitis is considered the worst form of TB and results in an infection of the brain leading to increased fluid and inflammation. Between one and two percent of all TB cases progress to this form of the disease.
“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,” said Sanjay Jain, MD, senior author of the study and director of the Johns Hopkins Medicine Center for Infection and Inflammation Imaging Research.
The FDA approved the BPaL antibiotic drug combination to treat MDR strains of TB, especially those the manifest pulmonary TB in 2019. The Hopkins team noted, however, that there is very little data detailing how well the drugs cross the blood-brain barrier. For their research, the investigators created a chemically identical version of pretomanid that would be visible via positron emission tomography (PET) imaging in mouse models. This non-invasive technique allowed the team to measure the drug’s penetration into the central nervous system as well using direct drug measurements in the mouse brains.
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 several-fold 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,” said Elizabeth Tucker, MD, a first author and an assistant professor of anesthesiology and critical care medicine at the Johns Hopkins University School of Medicine. “This finding will change how we interpret data from clinical trials and, ultimately, treat infections in the brain.”
The researchers then compared the BPaL MDR regimen against the standard treatment for TB, a combination of the antibiotics rifampin, isoniazid, and pyrazinamide, which are used again drug-susceptible forms of TB. The BPaL regimen performed very poorly, killing bacteria at a rate that was 50 times lower after six weeks of treatment compared with the standard TB regimen. The researchers attributed this as likely due to the poor penetration into the brain of both bedaquiline and linezolid.
A small in-human study of six healthy adults, three men and three women aged 20 to 53 used PET imaging show pretomanid distribution to major organs. Results from this study provided similar results compared with the mouse study showing a high penetration of pretomanid into the brain or CNS with cerebrospinal fluid levels lower than those seen in the brain.
“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,” concluded Xueyi Chen, MD, a pediatric infectious diseases fellow, who is now studying combinations of such therapies.