PET Scans Help Identify Effective Tuberculosis Drugs

The new findings indicate that the animal model can effectively predict which experimental drugs have the best likelihood for success in human trials.

In 2012, an estimated 8.6 million people worldwide contracted TB, for which the first-line treatment demands taking four different drugs for six to eight months to get a durable cure, explained senior investigator JoAnne L. Flynn, PhD, professor of microbiology and molecular genetics, University of Pittsburgh (Pitt) School of Medicine (PA, USA). Patients who are not cured of the infection (approximately 500,000 per year) can develop multidrug resistant TB, and have to take as many as six drugs for two years.

The study’s findings were published online December 4, 2014, in the journal Science Translational Medicine. “Some of those people don’t get cured, either, and develop what we call extensively drug-resistant, or XDR, TB, which has a very poor prognosis,” she said. “Our challenge is to find more effective treatments that work in a shorter time period, but the standard preclinical models for testing new drugs have occasionally led to contradictory results when they are evaluated in human trials.”

In an earlier study, Dr. Flynn’s colleagues at the US National Institutes of Health (Bethesda, MD, USA) found that the drug linezolid effectively treated XDR-TB patients who had not improved with conventional treatment, even though mouse studies suggested it would have no impact on the disease. To further examine the effects of linezolid and another drug of the same class, Dr. Flynn and her NIH collaborators, led by Clifton E. Barry III, Ph.D., performed PET/computed tomography (PET/CT) scans in TB-infected humans and macaques, which also get lesions known as granulomas in the lungs. In a PET scan, a tiny amount of a radioactive probe is injected into the blood that gets captured by metabolically active cells, leaving a “hot spot” on the image.

The researchers noted that humans and macaques had very similar disease profiles, and that both groups had hot spots of TB in the lungs that in most cases improved after drug treatment. In addition, CT scans, which show anatomic detail of the lungs, indicated post-treatment improvement. One patient had a hot spot that got worse, and further testing revealed his TB strain was resistant to linezolid.

The findings show that a macaque model and PET scanning can better predict which drugs are likely to be effective in clinical trials, and that could help get new treatments to patients faster, Dr. Flynn said. The scans also could be useful as a way of confirming drug resistance, but aren’t likely to be implemented routinely. “We plan to use this PET scanning strategy to determine why some lesions don’t respond to certain drugs, and to test candidate anti-TB agents,” she said. “This might give us a way of tailoring treatment to individuals.”

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