Define MDR and XDR tuberculosis. Describe how resistance arises and its diagnosis and treatment.

Definitions

How Resistance Arises

Spontaneous mutations arise randomly at about 1 in 106 for isoniazid and 1 in 108 for rifampicin, independent of the drug → A cavity contains up to 108 to 109 bacilli, so resistant mutants to any single drug are already present before treatment starts → Giving one effective drug kills the sensitive majority → The resistant mutants multiply without competition — the drug selects rather than creates resistance → Because resistance to two drugs requires both mutations, its probability is the product — about 1 in 1014, which exceeds the number of bacilli in any lesion → Hence multidrug therapy prevents resistance, and adding a single drug to a failing regimen creates it

• Key mutations — rpoB for rifampicin (which is why molecular detection is straightforward and why rifampicin resistance is a useful proxy for MDR); katG and inhA for isoniazid; gyrA for fluoroquinolones; pncA for pyrazinamide; rrs for aminoglycosides
• Causes in practice — incomplete or interrupted treatment, inadequate regimens, monotherapy (including the addition of a single drug to a failing regimen), poor drug quality, malabsorption, and unsupervised treatment

Diagnosis and Treatment

• CBNAAT (GeneXpert MTB/RIF) detects rifampicin resistance in about 2 hours and is the entry point; line probe assay extends this to isoniazid, fluoroquinolones and injectables within days; liquid culture with phenotypic sensitivity testing remains the reference
• Universal drug susceptibility testing is now policy in India — every diagnosed patient should have at least rifampicin resistance tested before treatment begins
• Modern regimens are oral, the injectable agents having been largely abandoned because of irreversible deafness and renal damage
• Bedaquiline (an ATP synthase inhibitor, which prolongs the QT interval), linezolid (causing myelosuppression and optic and peripheral neuropathy), pretomanid, fluoroquinolones (levofloxacin, moxifloxacin), clofazimine and cycloserine form the core of current regimens
• Shorter all-oral regimens of 6 to 9 months have replaced the former 18 to 24 month courses for eligible patients, which has greatly improved completion and cure rates
• Treatment is free through the national programme, with nutritional support under the Nikshay Poshan Yojana, and outcomes are followed through the Nikshay system

Applied Aspects

• Never add a single drug to a failing regimen — the single most important rule in tuberculosis management
• Test for rifampicin resistance in every patient before starting, and particularly in previously treated patients, contacts of resistant cases, those failing treatment, and people living with HIV
• Ensure treatment is completed; supervision, patient support, addressing cost and distance, and treating adverse effects promptly do more to prevent resistance than any drug
• India has among the largest burdens of drug-resistant tuberculosis in the world, driven by a large private sector with variable regimens, over-the-counter sale of antitubercular drugs, and incomplete treatment
• Screen contacts of drug-resistant cases, since primary transmission of resistant strains is now a major contributor and such patients have never taken a drug
• Monitor for toxicity actively — electrocardiogram for bedaquiline and moxifloxacin, blood counts and visual acuity for linezolid; the regimens are long and the adverse effects are what cause patients to stop