“Up until now, the only way we’ve known that rifampin sometimes does not reach the bacteria inside cavities has been by examining portions of lungs surgically resected from patients for whom standard anti-TB therapy failed,” says Alvaro Ordonez, M.D., a research associate in pediatrics at Johns Hopkins Medicine and lead author on the Nature Medicine paper. Besides being invasive and difficult for the patient, such evaluations have two major shortcomings.

“Depending on which pulmonary lesions or cavities are resected, one may see rifampin levels adequate enough to kill the TB bugs,” he explains. “But resect a different area of the lung where the drug wasn’t able to reach lesions and cavities and you’ll get a very different result. More importantly, the overall effectiveness of the treatment course cannot be properly measured since the resections are taken at single points in time and aren’t from every location where there could be an infection.”


Working with animals over the past decade, Jain and his colleagues developed a noninvasive imaging technique called dynamic 11C-rifampin PET/CT to open a clearer window on the previously hidden battle taking place between microbe and medicine in the lungs. The isotope-tagged version of rifampin, 11C-rifampin, emits a charged particle — called a positron — that enables the drug to be detected and tracked by a PET scan.

In studies published in 2015 and 2018, Jain and others demonstrated first in mice with pulmonary TB and then in rabbits with TB meningitis that dynamic 11C-rifampin PET/CT could successfully follow the movement of the tagged drug into lesions and cavities, both in the lungs and the brain. In both cases, the data revealed that the penetration of 11C-rifampin into the TB pockets was consistently low and could change over a period of a few weeks.

For the most recent trial, the researchers looked for the first time at how well the dynamic 11C-rifampin PET/CT tool monitored the levels of rifampin given to 12 human patients with TB in the lungs. The participants were first given an injected microdose of 11C-rifampin that was tracked by PET to determine the drug’s concentration over time in TB-infected lesions in the lungs and other areas throughout the body (uninfected sections of the lungs, brain, liver and blood plasma).

Following this imaging, the patients were given untagged rifampin intravenously at the recommended treatment dosage level. Blood was drawn from the patients at various times and the levels of rifampin were measured by mass spectrometry. This showed that the microdose amount of 11C-rifampin could accurately represent the behavior of the traditional clinical dosage.

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