Genetic Reasons for Anti-Tuberculosis Drug Resistance

Tuberculosis, very commonly known as T.B., is highly contagious and often found to be associated with multiple drug resistance. Till now multidrug-resistant tuberculosis (MDR-TB) is thought due to discrepant drug intake by the patient or drug schedule not followed according to doctor’s prescription.

A new study published in The Journal of Infectious Diseases revealed an interesting fact that, multidrug-resistant tuberculosis (TB) is probably due to rapid drug metabolism instead of inconsistent drugs dosages, as believed globally. Such substantial result opens new ways to combat one of the major public health problems in the world.

Tuberculosis: Worldwide Burden

Tuberculosis is a highly infectious disease caused by bacteria, Mycobacterium tuberculosis, which commonly targets the lungs. Infection is transmitted from person to person via cough droplets containing enormous bacteria.

People with good immunity are often asymptomatic, as it acts as a fence against the bacteria. Patient with active TB of the lung presents with productive cough, fatigue, weight loss, fever, night sweats and sometimes sputum with blood.

According to World Health Organization (WHO) Global Tuberculosis Control 2011 Report, in 2010, incident cases of TB were approximately 8.8 million while deaths from TB among HIV-negative people were 1.1 million and an additional 0.35 million deaths were reported from HIV-associated TB.

[box type=”important”]Tuberculosis is effectively treatable with wider range of broad-spectrum antibiotics. But still some cases of disease show relapse, treatment failure and drug resistance. [/box]

Limitation of DOTS

Directly observed therapy-short-course strategy (DOTS), a conventional approach implemented by WHO to treat multidrug-resistant tuberculosis cases,  has its own limitations. In DOTS strategy, TB is treated with combinations of 2 to 6 anti-tubercular medications under various regimens. Drugs are administered under the supervision of health care workers, who have to travel to isolated and remote villages. Hence the procedure is not only costly but also  time-consuming. Also health worker have to watch that every TB patient swallow their pills in order to increase adherence and decrease emergence of drug resistance. This may not be followed in each and every case due to negligence. In such cases the new results seem to be challenging.

For the current study, UT Southwestern researchers prepared an advanced system of high-tech test tubes, which they called a “glass mouse.”  The system behaved like standard therapy and patients were given daily doses of medication for 28 to 56 days. The extent of non-adherence varied between 0 percent and 100 percent. Therapy failure was found to encounter at extents of non-adherence of 60 percent or more.

In South Africa, a specific population of individuals has been identified who exhibit  a genetic trait that enhances the drug clearance process.  These individuals consequently have a high rate of multidrug-resistant TB. After using computer simulations based on 10,000 TB patients from such population in Cape Town, South Africa, the researchers detected that nearly 1 percent of all TB patients developed drug resistance even with regular drug intake. This was due to rapid clearance of the drugs from their bodies.

Essentially, their bodies identified the drugs as foreign chemicals were able to rapidly metabolize them.  In such populations, though patients received standard doses of drugs, their concentrations were too low to kill the TB bacillus and hence developed drug resistance.

Dr. Tawanda Gumbo, associate professor of internal medicine and senior author of the study said:

“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 bacterial population that had been spiked with drug-resistant bacteria, non-adherence still did not lead to drug resistance.”

This preclinical study data concluded that non-compliance is not only the cause for the emergence of multidrug-resistant TB. In such cases monitoring the concentration of TB drugs in a patient’s blood during treatment and increasing drug dosage in those who quickly clear the drugs from their systems is as significant as supervising adherence to therapy. Though it seems inconsistent with the current WHO guidelines, it might be more cost-effective than conventional DOTS approach.





Dr. Minakshi Welukar

I am Pune based medical doctor (M.B.B.S) and certified medical writer from InfocusRx, Hyderabad, working as a family physician and freelance medical writer for health magazines and websites. Five years of clinical experience faced me to handle variety of patients to get best possible results, keep up-to-date knowledge about new medicinal advances and build-up medical specialist and social contacts.

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