Tuberculosis Drug Dosing Gets a Closer Look
Inaccurate dosing may be a culprit in the evolution of drug-resistant strains.
Even though antibiotics have been available for more than 50 years, tuberculosis remains a major killer: In 2009, 1.7 million people, largely from poor countries, died from the disease, according to a recent World Health Organization (WHO) report. Tawanda Gumbo, a physician and researcher at the University of Texas Southwestern Medical School, aims to change that by better tailoring courses of antibiotics to individual patients.
Gumbo has spent the last 10 years studying the effects of common tuberculosis drugs in test tubes and in animals in an effort to find the most effective doses. He has also employed mathematical simulations—a technique borrowed from engineering—to figure out how different variables, such as weight, gender, and genetic variations in both the microbe and the patient, change the optimal dose. “If you give the same dose to 100 children, you get 100 different pictures,” says Gumbo. “Given all of this variability, how should I dose different children?”
Gumbo is now ready to test his theories with the launch of a clinical trial of TB-infected children in South Africa. He hopes that tailoring doses to the individual will help shorten treatment regimens, which typically last six months, and slow the development of drug-resistant strains of the bacterium. The emergence of multidrug resistant cases—a form of the disease that is difficult and costly to treat because it does not respond to first-line drugs—is at its highest rate ever, according to WHO.
In the clinical trial, Gumbo and his collaborators will examine genetic variability of the microbe infecting a particular patient by assessing its genome as well as how susceptible it is to particular drug. Patients will get genotyping tests to determine whether they have specific mutations that influence how well they metabolize specific drugs.
Public health agencies largely blame the development of drug resistance to TB on patients not finishing their antibiotic regimens. But Gumbo thinks chronic underdosing could be a major contributor as well. “If you go to places with good treatment programs, where they administer and monitor drugs [according to guidelines], you still see high failure rates,” says Gumbo. “If they are doing everything they are supposed to do, why is there still drug resistance?”
According to his research, “the doses needed have almost always been much higher than what we’ve been giving currently,” says Gumbo. “And we know from what we have done in the lab that if you achieve these higher concentrations, you can probably treat for shorter periods of time.”
The idea is still somewhat controversial, but “he is slowly winning converts in the TB community about the importance of proper dose selection,” says Paul Ambrose, director of the Institute for Clinical Pharmacodynamics at the Ordway Research Institute, and a former collaborator of Gumbo’s.
Ambrose says that similar types of studies have been done for other drugs, but not for those used to treat TB, probably because they are so old. No new treatments have emerged for TB since the 1970s, though some new compounds are now being tested.
In the past, this type of individualized drug monitoring for TB has been done “only in patients who were failing therapy, and it has been largely limited to resource-rich settings like the U.S. and Europe,” says Eric Nuermberger, a physician at Johns Hopkins. Nuermberger is not involved in the study.
While pharmacogenomics—targeting drug dosages and selections of drugs to an individual’s genetic makeup—is only part of Gumbo’s strategy, experts say it will likely prove to be an important aspect of TB treatment. “We know that for isoniazid [a common TB drug], the global population as a whole splits into three different phenotypes; those who metabolize the drug quickly, those who metabolize it slowly, and intermediate metabolizers,” says Nuermberger. A dose that is appropriate for a slow metabolizer might be too low for a fast metabolizer; likewise, a higher dose appropriate for a fast metabolizer might increase side effects for a slow metabolizer.
“The other cornerstone first-line drug for TB, rifampicin, has been notorious for having highly variable drug exposures,” adds Nuermberger. “If you look at 100 people who take it, you’ll see a tenfold difference in exposure,” the concentration and length of time that drug is in a person’s bloodstream before being metabolized, he says. “We are now starting to understand there are genetic differences that determine drug exposure. And there is hope that we can develop genetic tests to use in the field.”
While it may be difficult to imagine implementing genetic testing in a poor country with an already strained medical system, Nuermberger doesn’t rule it out. “We will continually develop cheaper and easier tests that could be implemented at the point of care,” he says. “We thought it would be difficult to implement drug-resistance tests, but those are now being used in reference labs, and a new device is moving even closer to the point of care.”