Tuberculosis (TB) remains a persistent global health challenge, affecting millions worldwide. While often curable, the disease has evolved, giving rise to more severe, drug-resistant forms that are increasingly difficult to treat. This emergence complicates efforts to control and eradicate TB.
Understanding Drug-Resistant Tuberculosis
Tuberculosis is an infectious disease caused by the bacterium Mycobacterium tuberculosis. This bacterium primarily attacks the lungs, but it can also affect other parts of the body, such as the kidney, spine, and brain. Standard TB is typically treated with a combination of four first-line anti-TB drugs: isoniazid, rifampicin, pyrazinamide, and ethambutol.
Multidrug-resistant TB (MDR-TB) is a more serious form of the disease where Mycobacterium tuberculosis has developed resistance to at least two of the most potent first-line anti-TB medications: isoniazid and rifampicin. This means these drugs, effective against susceptible TB, can no longer kill the bacteria. Extensively drug-resistant TB (XDR-TB) occurs when bacteria are resistant to isoniazid and rifampicin, plus any fluoroquinolone and at least one of the three injectable second-line drugs (amikacin, kanamycin, or capreomycin). The most severe form, totally drug-resistant TB (TDR-TB), describes strains resistant to nearly all available anti-TB drugs.
How Drug Resistance Emerges
Drug resistance in Mycobacterium tuberculosis arises from genetic mutations within the bacterial DNA. These mutations can alter the bacteria’s drug targets or the enzymes that activate the drugs, rendering medications ineffective. Unlike some other bacteria, Mycobacterium tuberculosis does not typically acquire resistance through genetic material transfer from other bacteria.
The development of drug resistance is linked to human factors rather than an inherent bacterial property. A primary cause is improper or incomplete TB treatment, such as patients not finishing their full course of medication, receiving incorrect drug dosages, or using poor-quality drugs. Mutations in the rpoB gene are responsible for rifampicin resistance, while resistance to isoniazid is linked to mutations in the katG gene.
Mismanagement of TB control programs also contributes to resistance. This includes inadequate drug supply, poor laboratory capacity for diagnosis, and a lack of standardized treatment guidelines. When treatment is not properly supervised, or patients do not adhere to their regimen, the bacteria can survive and develop resistance, which can then be transmitted to others. Directly Observed Therapy (DOTS), where healthcare workers observe patients taking their medication, is a strategy aimed at improving adherence and preventing the emergence of resistance.
Diagnosing and Treating Drug-Resistant TB
Diagnosing MDR-TB presents challenges. Standard TB tests, such as acid-fast bacillus (AFB) microscopy, may not detect drug resistance and have limited sensitivity. Traditional culture-based methods, while considered the gold standard for detecting Mycobacterium tuberculosis and determining drug susceptibility, can take weeks to yield results, delaying appropriate treatment.
Rapid molecular tests, such as GeneXpert MTB/RIF, have improved diagnosis by detecting rifampicin resistance, often an indicator of MDR-TB, within hours. Other molecular tests, like line probe assays, can also identify resistance to both rifampicin and isoniazid, offering quicker insights into the resistance profile. However, these molecular tests may not detect all forms of resistance, necessitating a combination of molecular and phenotypic drug susceptibility testing (DST).
Treating MDR-TB is a lengthy process, often requiring a combination of second-line anti-TB drugs. Treatment regimens last longer than for drug-susceptible TB, ranging from 9 to 24 months. These second-line drugs are more expensive and associated with a higher incidence of severe side effects compared to first-line medications. Common adverse effects include gastrointestinal disturbances, hearing loss (ototoxicity), kidney damage (nephrotoxicity), psychiatric disorders, and peripheral neuropathy. Managing these side effects and the extended duration of treatment requires comprehensive patient support and close medical supervision to ensure adherence and improve outcomes.
Global Implications and Prevention
MDR-TB represents a significant global public health concern, with an estimated 410,000 people developing multidrug- or rifampicin-resistant tuberculosis in 2022. High-burden countries face challenges due to the disease’s impact on healthcare systems and economies. The cost of treating MDR-TB can be substantially higher, sometimes 10 to 100 times more, than treating drug-susceptible TB, further straining limited resources.
Preventing the development and spread of drug resistance is essential. This involves ensuring all TB cases, whether drug-susceptible or resistant, are diagnosed accurately and treated completely with appropriate drug regimens. Strengthening healthcare systems, particularly laboratory capacity for drug susceptibility testing, is important for early detection of resistance. Implementing infection control measures in healthcare facilities and communities helps curb the transmission of resistant strains. Continued investment in research and development for new drugs, diagnostics, and vaccines is also necessary to provide more effective and shorter treatment options and to achieve global TB control.