Although relatively rare in the United States, and accounting for fewer than 5 percent of tuberculosis cases worldwide, TB of the brain—or tuberculosis meningitis (TBM)—is often deadly, always hard to treat, and a particular threat to young children. It may leave survivors with lifelong brain damage. Now, researchers at Johns Hopkins Medicine report they have used PET scans, a rabbit model and a specially tagged version of the TB drug rifampin to advance physicians’ understanding of this disease by showing precisely how little rifampin ever reaches the sites of TB infection in the brain.
“Really precise information has never been easy to come by for how much rifampin gets to any given patient where it’s needed,” says corresponding author Sanjay Jain, M.D., professor of pediatrics, radiology and international health at the Johns Hopkins University School of Medicine. “We’ve been able to use technology to find that long-needed information about this very troubling disease.”
Jain, along with lead authors Elizabeth Tucker, M.D., assistant professor of anesthesiology and critical care medicine, and Alvaro Ordonez, M.D., research associate, pediatric infectious diseases at the Johns Hopkins University School of Medicine, as well as other Johns Hopkins and University of Maryland colleagues, published their findings Dec. 5 in Science Translational Medicine.
Tuberculosis, which mostly infects the lungs, sickens more than 10 million people around the world each year, causes more than 1 million deaths and costs the global economy billions of dollars, according to the World Health Organization. TBM, caused when Mycobacterium tuberculosis infects brain tissue and the fluid surrounding the brain and spinal cord, is considered the most lethal and disabling form of TB. Children under the age of 5, and those with chronic diseases—notably diabetes and HIV—are mostly likely to develop TBM. Like all TB diseases, TBM is treated with a combination of drugs, including isoniazid, rifampin and pyrazinamide, taken for a year. However, even with treatment, over half of patients die or have significant neurological injury lasting a lifetime, especially young children.
In the new study, Johns Hopkins researchers engineered a version of rifampin with a charged particle—called a positron—attached to the drug ([11C]rifampin) that allowed them to follow its movement throughout the body using PET (positron emission tomography) scans.
Because TBM symptoms are similar among rabbits and humans, the researchers created an experimentally infected colony of rabbits with TBM, injected them with the tagged drug and tracked levels of the tagged [11C]rifampin throughout the rabbits’ brains over six weeks. PET scans revealed that after two weeks of treatment, the penetration of [11C]rifampin into TBM brain lesions significantly decreased, from 32 percent to only 11 percent of the levels of the drug noted in the blood. Significantly, they say, the decrease was not reflected in samples of cerebrospinal fluid (CSF) taken from the rabbits, despite that CSF is currently used as a standard proxy for determining drug and infection levels in people.