Drug Resistant Tuberculosis

Drug-resistant tuberculosis (DR-TB) refers to forms of tuberculosis (TB) that do not respond to one or more of the standard anti-tubercular drugs used in treatment. It occurs when the Mycobacterium tuberculosis bacterium develops the ability to survive despite exposure to drugs that would normally kill it. Drug resistance poses one of the most serious global health challenges, threatening to reverse decades of progress in TB control.

Nature and Classification

Drug-resistant TB arises primarily through mutations in the bacterial genome that alter drug targets or mechanisms of drug uptake. The disease can be classified according to the type and number of drugs to which the strain is resistant:

1. Mono-Resistant TB: Resistance to a single first-line anti-TB drug (for example, isoniazid or rifampicin).
2. Poly-Resistant TB: Resistance to more than one first-line drug, but not both isoniazid and rifampicin simultaneously.
3. Multidrug-Resistant TB (MDR-TB): Resistance to at least isoniazid (INH) and rifampicin (RIF), the two most powerful first-line drugs.
4. Extensively Drug-Resistant TB (XDR-TB): Resistance to INH and RIF, plus any fluoroquinolone and at least one of the second-line injectable drugs (such as amikacin, kanamycin, or capreomycin).
5. Totally Drug-Resistant TB (TDR-TB): Strains that are resistant to all first- and second-line anti-TB drugs. This category is rare and not yet formally recognised by the World Health Organization (WHO) due to limited global data.

Causes and Mechanisms of Resistance

Drug resistance in TB arises when treatment is inadequate, inconsistent, or incomplete, allowing resistant bacteria to survive and multiply. Major contributing factors include:

• Improper or irregular drug use: Patients not completing the full treatment course or missing doses.
• Incorrect prescription practices: Wrong drug combinations, dosages, or treatment duration prescribed by healthcare providers.
• Poor-quality medicines: Use of substandard or counterfeit drugs with insufficient active ingredients.
• Inadequate healthcare systems: Lack of access to diagnostic facilities, treatment supervision, and follow-up.
• Transmission of resistant strains: Drug-resistant TB can spread directly from person to person through airborne droplets.

On a biological level, spontaneous genetic mutations in the M. tuberculosis genome lead to resistance, particularly when bacteria are exposed to sub-therapeutic drug concentrations. For example:

• katG and inhA gene mutations cause resistance to isoniazid.
• rpoB gene mutations cause resistance to rifampicin.
• gyrA/gyrB mutations lead to fluoroquinolone resistance.

Global Burden

According to global tuberculosis surveillance data:

• Each year, approximately 450,000 to 500,000 new cases of MDR-TB are estimated worldwide.
• Drug-resistant TB accounts for about 3–4% of new TB cases and up to 20% of previously treated cases.
• The WHO South-East Asia Region, particularly India, China, and the Russian Federation, carries the highest burden of MDR-TB.
• India alone contributes nearly one-fourth of global MDR-TB cases, making it a major public health priority.

Clinical Manifestations

The symptoms of drug-resistant TB are similar to those of drug-sensitive TB, but patients often remain ill despite standard treatment. Common symptoms include:

• Persistent cough lasting more than two weeks.
• Fever, night sweats, and fatigue.
• Weight loss and appetite reduction.
• Chest pain or haemoptysis (coughing up blood).

Failure to improve after conventional therapy should raise suspicion of drug resistance.

Diagnosis

Early and accurate diagnosis of drug-resistant TB is critical for effective control. Modern diagnostic methods include:

1. Sputum Smear Microscopy: Detects acid-fast bacilli but cannot determine drug resistance.
2. Culture and Drug Susceptibility Testing (DST): Gold-standard test using solid or liquid media to assess bacterial growth in the presence of drugs.
3. Molecular Methods:
   • GeneXpert MTB/RIF (CBNAAT): Detects M. tuberculosis DNA and rifampicin resistance within two hours.
   • Line Probe Assay (LPA): Identifies genetic mutations conferring resistance to isoniazid, rifampicin, and fluoroquinolones.
   • Whole Genome Sequencing (WGS): Provides detailed resistance profiles and epidemiological data.

Rapid molecular tests have revolutionised TB control by enabling early detection of MDR and XDR strains, allowing prompt initiation of appropriate treatment.

Treatment and Management

Treatment of drug-resistant TB is more complex, longer, and more toxic than that of drug-susceptible TB. It requires combinations of second-line and newer drugs to prevent further resistance.
1. Multidrug-Resistant TB (MDR-TB):

• Treated using second-line drugs, including fluoroquinolones (levofloxacin, moxifloxacin) and injectables (amikacin, kanamycin).
• Traditional treatment duration: 18–24 months, though newer regimens may shorten therapy to 9–12 months.
• Side effects include nausea, hearing loss, kidney damage, and psychiatric symptoms.

2. Newer Treatment Regimens:

• Bedaquiline and Delamanid: Novel anti-TB agents targeting ATP synthase and cell wall synthesis, respectively.
• Pretomanid-based regimens (BPaL/BPaLM): Combination therapy involving bedaquiline, pretomanid, linezolid, and moxifloxacin, showing high cure rates and shorter duration (6–9 months).
• All-Oral Regimens: Replacing injectable drugs to improve safety and compliance.

3. Supportive Measures:

• Nutritional support, counselling, and close monitoring of adherence.
• Directly Observed Treatment, Short-course (DOTS-Plus) for supervised drug intake.
• Contact tracing and infection control measures to prevent transmission.

Prevention and Control

Prevention of drug-resistant TB requires a combination of medical, social, and public health measures:

• Ensuring proper adherence to first-line treatment to prevent resistance.
• Universal access to rapid diagnostic tests for early detection.
• Use of quality-assured medications under standardised treatment protocols.
• Strengthening public health systems to ensure consistent supply and monitoring.
• Vaccination: The BCG vaccine provides partial protection in children but has limited efficacy against adult pulmonary TB.
• Infection Control: Adequate ventilation, respiratory hygiene, and use of masks in healthcare settings.

Challenges in Managing Drug-Resistant TB

• Long and toxic treatment: Extended duration and side effects lead to poor adherence.
• High cost: Second-line drugs and diagnostic technologies are expensive.
• Limited access: Many developing countries lack adequate laboratory infrastructure.
• Stigma and social barriers: Patients often face discrimination, leading to treatment default.
• Emergence of XDR and TDR-TB: Continuous mutation of M. tuberculosis threatens existing treatment options.

Global and National Initiatives

The World Health Organization’s End TB Strategy (2015–2035) aims to reduce TB deaths by 95% and incidence by 90% by 2035. It emphasises universal drug susceptibility testing, shorter regimens, and development of new vaccines and diagnostics.
In India, the National Tuberculosis Elimination Programme (NTEP) (formerly RNTCP) has introduced initiatives such as:

• Nikshay Poshan Yojana: Nutritional support for TB patients.
• Nikshay portal: Digital tracking of TB cases.
• PM TB Mukt Bharat Abhiyan: Campaign to eliminate TB by 2025, five years ahead of global targets.
• Universal Drug Resistance Testing (UDRT): Ensures every diagnosed TB case is tested for drug susceptibility.