Tuberculosis (TB) is an infectious disease primarily affecting the lungs, caused by the bacterium Mycobacterium tuberculosis. While typically treatable with antibiotics, drug-resistant TB (DR-TB) has emerged. This variant occurs when the bacteria no longer respond to standard medications, making the disease harder to cure. DR-TB requires specialized and often lengthier treatment regimens.
Understanding Drug Resistance
Drug resistance in Mycobacterium tuberculosis primarily arises from genetic mutations within the bacterial DNA. These changes can alter the drug’s target or interfere with the activation of a prodrug, rendering the medication ineffective. For instance, resistance to rifampicin, a potent first-line drug, frequently involves mutations in the rpoB gene, particularly in a specific 81-base pair “hot-spot region”. Similarly, isoniazid resistance often stems from partial loss-of-function mutations in the katG gene, which is responsible for activating the drug.
Causes of drug resistance include inadequate or incomplete treatment, incorrect prescribing practices, and poor adherence to medication regimens. When patients do not take their full course of antibiotics, or if the wrong drugs or dosages are used, some bacteria with natural mutations may survive and multiply, leading to a resistant population. This acquired resistance can then be transmitted to other individuals, who will develop DR-TB without ever having been treated for the disease.
Drug resistance manifests in different forms. Monoresistance refers to resistance to a single anti-TB drug. Multidrug-resistant TB (MDR-TB) is defined by resistance to at least isoniazid and rifampicin, the two most effective first-line anti-TB drugs. Extensively drug-resistant TB (XDR-TB) means MDR-TB strains also show resistance to any fluoroquinolone and at least one additional potent group A drug, such as bedaquiline or linezolid.
Recognizing Drug-Resistant TB
The symptoms of drug-resistant TB are similar to those of drug-susceptible TB, often including a persistent cough, fever, night sweats, and unexplained weight loss. However, a key indicator for DR-TB is the persistence or worsening of these symptoms despite receiving initial, standard TB treatment. Individuals might experience chest pain or cough up blood, particularly if the infection affects the lungs.
Diagnosing drug-resistant TB involves specialized tests to identify specific drug resistances. The diagnostic process begins with sputum tests, where samples are collected and cultured to grow the Mycobacterium tuberculosis bacteria. Once cultured, drug susceptibility testing (DST) determines which antibiotics are effective against the patient’s specific strain.
Rapid diagnostic tools, such as molecular tests like Xpert MTB/RIF Ultra and Truenat assays, are important. These tests quickly detect M. tuberculosis and simultaneously identify rifampicin resistance, allowing faster initiation of appropriate treatment. While rapid tests provide timely information, traditional culture-based DST still confirms broader resistance profiles, though results can take several weeks.
Treatment Approaches for Drug-Resistant TB
Treating drug-resistant TB is a complex and prolonged process. Regimens involve a combination of second-line anti-TB drugs, which are less effective, more toxic, and associated with more side effects compared to first-line medications. These side effects can range from gastrointestinal issues and nerve damage to hearing loss.
The duration of treatment for DR-TB is longer, extending from 9 to 24 months, depending on the specific resistance profile and patient response. For instance, some regimens for pre-extensively drug-resistant TB (pre-XDR-TB) have been explored for 6 to 9 months, while standard regimens can last 18 to 24 months. This extended duration, coupled with potential for severe adverse effects, presents challenges for patient adherence.
Close monitoring of patients is necessary throughout treatment to manage side effects and ensure medication adherence. Newer drugs like bedaquiline, delamanid, and pretomanid have improved DR-TB treatment by offering more effective, all-oral regimens, reducing reliance on daily injections. The World Health Organization (WHO) now prioritizes shorter, all-oral regimens, such as the 6-month BPaLM/BPaL regimen, for eligible patients with MDR/RR-TB, which can improve outcomes and reduce patient burden.
Global Impact and Prevention
Drug-resistant TB presents a public health threat globally, characterized by higher mortality rates and increased healthcare costs. The disease poses a risk of community transmission, as resistant strains can spread through the air just like drug-susceptible forms. In 2023, an estimated 10.8 million people fell ill with TB worldwide, with MDR-TB a significant concern, and only about two in five people with drug-resistant TB accessing treatment.
Prevention strategies for DR-TB focus on several approaches. Ensuring proper and complete treatment of drug-susceptible TB is key, preventing initial resistance development. This includes providing all TB diagnostic and treatment services free of charge to minimize patient barriers.
Other prevention strategies include:
Improving diagnostic capabilities, particularly through widespread use of rapid molecular tests, for early detection of resistance and prompt initiation of appropriate treatment, which helps reduce transmission.
Public health surveillance systems for monitoring the spread of resistant strains.
Infection control measures in healthcare settings, such as proper ventilation and patient isolation, to prevent transmission, especially in high-risk environments.
Continued investment in research and development for new drugs, improved diagnostics, and a more effective vaccine to enhance global efforts against DR-TB.