Tuberculosis infects millions of people every year and requires at least 6 months of treatment with multiple drugs. Granulomas are complex lung lesions that are the hallmark of tuberculosis (TB). Understanding antibiotic dynamics within lung granulomas will be vital to improving and shortening the long course of TB treatment. Three fluoroquinolones (FQs) are commonly prescribed as part of multi-drug resistant TB therapy: moxifloxacin (MXF), levofloxacin (LVX) or gatifloxacin (GFX).
To date, insufficient data was available to support selection of one FQ over another, or to show that these drugs are clinically equivalent. Now however, Elsje Pienaar and colleagues at the University of Michigan in Ann Arbor and Rutgers have developed a computer model to simulate the effects of the three drugs on granulomas — clusters of host cells and bacteria that develop in the lungs of tuberculosis patients.
Moxifloxacin, levofloxacin, and gatifloxacin are three fluoroquinolones prescribed for treating drug-resistant TB. The WHO recommends levofloxacin over moxifloxacin, and moxifloxacin over gatifloxacin, but there haven’t been any clinical trials that show one drug kills the bacteria better than the others; to date, it is unclear if one FQ is better than the others at treating TB, in part because little is known about how
these drugs distribute and work inside the lung granulomas. Pienaar and her colleagues used a computer model that simulated granuloma formation and function, along with drug concentrations at the granulomas to predict which fluoroquinolone would perform best.“The exciting thing about this study is that we are able [to] perform a side-by-side comparison of fluoroquinolones in identical infections. The potential practical application of our findings is to guide selection of individual fluoroquinolones for tuberculosis treatment,” said Pienaar in a press release.
The research team used the computer simulation model called GranSim to simulate treatment with each of the three drugs and compared them according to multiple criteria. In the simulations, MOXI appeared to be superior to both LEVO and GATI because it killed bacteria in granulomas more quickly, and it performed better when the simulated patients missed doses. LEVO killed bacteria more quickly than GATI. However, all three drugs were unable to kill bacteria at the very center of the granulomas.
The study authors concluded that moxifloxacin has a small, but potentially clinically significant, advantage over levofloxacin and levofloxacin performed better than gatifloxacin.
Pienaar says that the predictions of the simulations are now being tested in animal experiments. The team is also enhancing the computer model to test fluoroquinolones alongside other tuberculosis drugs, which could help narrow down the best possible drug combinations for tuberculosis treatment.
