A UT Southwestern Medical Center study using a sophisticated "glass mouse" research model has found that multidrug-resistant tuberculosis¹（肺结核） (TB) is more likely caused in patients by speedy drug metabolism² rather than inconsistent doses, as is widely believed. If the study published in The Journal of Infectious Diseases is borne out in future investigations³, it may lead to better ways to treat one of the world's major infectious diseases. Health workers worldwide currently are required to witness each administration of the combination of drugs during months of therapy.

"Tuberculosis is a common ailment⁴（小病，不安） , accounting⁵ for up to 3 percent of all deaths in many countries. Although effective therapy exists, there are still cases of treatment failure and drug resistance remains⁶ a threat," said Dr. Tawanda Gumbo, associate professor of internal medicine and senior author of the study.

The results seem to challenge the current approach endorsed⁷（支持，赞同） by the World Health Organization.

Under that method, directly observed therapy-short-course strategy (DOTS), TB that responds to medication is treated with a cocktail⁸ of drugs under the supervision⁹ of health care workers, who in many countries must travel to isolated¹⁰ villages -- a costly¹¹ and time-consuming process.

"Every TB patient is supposed to be watched as they swallow their pills in order to increase adherence¹² and decrease emergence¹³ of drug resistance. This is the most expensive part of the program, but has been felt to be cost-effective since it improves compliance¹⁴," said Dr. Gumbo, administrative¹⁵ director of research programs for the Office of Global Health at UT Southwestern.

In this study, UT Southwestern researchers created a sophisticated system of high-tech¹⁶ test tubes, which they called a "glass mouse," that mimicked¹⁷ standard therapy being given daily for 28 to 56 days, with dosing adherence varying between 0 percent and 100 percent. The threshold for defined non-adherence (failure to take a required dose of medication) was reached at 60 percent of the time or more.

"The first main finding in our laboratory model was that in fact non-adherence did not lead to multidrug resistance or emergence of any drug resistance in repeated studies, even when therapy failed. In fact, even when we started with a bacterial¹⁸ population that had been spiked¹⁹ with drug-resistant bacteria, non-adherence still did not lead to drug resistance," he said.

In fact, using computer simulations based on 10,000 TB patients in Cape²⁰ Town, South Africa, the researchers discovered that approximately 1 percent of all TB patients with perfect adherence still developed drug resistance because they cleared the drugs from their bodies more quickly.

The body sees drugs as foreign chemicals and tries to rid itself of them, Dr. Gumbo said. A population of individuals with a genetic²¹ trait that speeds the process has been found in one area of South Africa that has a high rate of multidrug-resistant TB. In that population, patients who receive standard doses of drugs end up with concentrations in their bodies that are too low to kill the TB bacillus and drug resistance develops, he said.

A Journal of Infectious Diseases editorial that accompanies the study suggests that monitoring the levels of TB drugs in a patient's blood could be as important as monitoring compliance with therapy -- in contrast to current WHO guidelines.

"These data, based on our preclinical model, show that non-adherence alone is insufficient²² for the emergence of multidrug-resistant TB," Dr. Gumbo said. "It might be more cost-effective to measure patients' drug concentrations during treatment and intervene with dosage（剂量） increases in those who quickly clear the drugs from their systems."

The work was supported by a grant from the National Institute of Allergy²³ and Infectious Diseases of the National Institutes of Health.