Discuss the diagnosis and management of multidrug-resistant tuberculosis (DOTS-Plus regime)

MDR-TB = resistance to at least isoniazid and rifampicin. RR-TB = rifampicin resistance with or without other resistance; the two are managed together as MDR/RR-TB. Pre-XDR-TB = MDR/RR-TB plus resistance to any fluoroquinolone. XDR-TB = MDR/RR-TB plus fluoroquinolone resistance plus resistance to at least one of bedaquiline or linezolid (2021 revised definition).

DOTS-Plus is the programmatic strategy for managing MDR-TB within the DOTS framework, requiring the five DOTS elements plus quality-assured drug-susceptibility testing, second-line drug supply, standardised regimens, active drug-safety monitoring (aDSM) and a recording/reporting system. In India it is delivered as PMDT (Programmatic Management of Drug-Resistant TB) under the National TB Elimination Programme (NTEP).

India carries the largest MDR/RR-TB burden in the world — roughly a quarter of global cases — with about 1.1–1.3 lakh incident MDR/RR-TB cases annually. Globally there are approximately 4 lakh MDR/RR-TB cases each year.

Mechanisms of resistance: spontaneous chromosomal mutations (rpoB for rifampicin, katG and inhA for isoniazid, gyrA/gyrB for fluoroquinolones, rrs and eis for injectables, Rv0678 for bedaquiline) selected by inadequate treatment — monotherapy, poor adherence, erratic drug supply, poor-quality drugs and unsupervised private-sector prescribing.

In older people TB is usually reactivation of remote infection as immunosenescence weakens cell-mediated containment; rates in institutional and nursing-home populations exceed those in the community, and staff as well as residents can spread infection.

Presentation is atypical: older patients are less likely to report fever, sweating and haemoptysis, more likely to present with dyspnoea, and have a lower likelihood of radiographic cavitation — with more lower-lobe, miliary and extrapulmonary disease. Suspect tuberculosis whenever an older patient is inexplicably failing.

Immunological tests are less reliable: both tuberculin skin testing and IGRAs show lower positivity in the elderly despite comparable exposure. A simply positive or negative Mantoux neither confirms nor excludes active disease, and IGRA performance in the very old — most of whom have had lifetime contact with the organism — is not well documented.

Treatment tolerance is poorer: age-related decline in renal and hepatic clearance, polypharmacy and QT-prolonging drug interactions, pre-existing peripheral neuropathy, cataract and hearing loss, and low body weight all raise the risk of adverse events on second-line drugs.

Universal drug-susceptibility testing is now mandatory — every diagnosed TB patient in India must have at least rifampicin resistance determined at diagnosis, and no patient should be started on first-line therapy without it.

Rapid molecular tests are the front line: CBNAAT / Xpert MTB/RIF and Xpert Ultra and Truenat MTB/Rif Dx (an indigenous Indian chip-based platform used at peripheral level) detect M. tuberculosis and rifampicin resistance within two hours. Specimens: sputum (two samples), or induced sputum, gastric aspirate or bronchoalveolar lavage in the frail or non-expectorating older patient.

Line probe assay (LPA): first-line LPA detects rpoB, katG and inhA mutations (rifampicin and isoniazid, including high- versus low-level isoniazid resistance); second-line LPA detects fluoroquinolone and second-line injectable resistance. Xpert MTB/XDR gives resistance to isoniazid, fluoroquinolones, ethionamide and amikacin in a single cartridge.

Culture and phenotypic DST on liquid medium (MGIT, 2–3 weeks) remains the reference standard and is essential for bedaquiline, linezolid, clofazimine and delamanid susceptibility, for treatment monitoring and for regimen modification. Targeted next-generation sequencing is now WHO-endorsed for comprehensive resistance prediction directly from sputum.

Baseline pre-treatment evaluation (PTE): weight and BMI, haemogram, blood sugar (diabetes screening is mandatory), renal and liver function, serum electrolytes including potassium, magnesium and calcium, thyroid-stimulating hormone, HIV testing, chest radiograph, ECG for QTc, visual acuity and colour vision, audiometry where an injectable is contemplated, and a pregnancy test in women of child-bearing age.

Six-month BPaLM is the preferred regimen for MDR/RR-TB and pre-XDR-TB: Bedaquiline + Paretomanid + Linezolid (600 mg once daily) + Moxifloxacin for 6 months, extendable to 9 months. In TB-PRACTECAL, BPaLM achieved 89% treatment success compared with 52% for the standard of care. Moxifloxacin is dropped (giving BPaL) where fluoroquinolone resistance is documented. Not for pregnant or breastfeeding women, or those with more than 1 month's prior exposure to these drugs unless resistance is excluded.

Nine-month all-oral bedaquiline-containing regimen for MDR/RR-TB in whom fluoroquinolone resistance has been excluded and who have no extensive disease: 4–6 months of bedaquiline + levofloxacin/moxifloxacin + ethionamide (or 2 months of linezolid) + ethambutol + high-dose isoniazid + pyrazinamide + clofazimine, followed by 5 months of levofloxacin + clofazimine + ethambutol + pyrazinamide.

Longer individualised all-oral regimen (18–20 months) for extensive, XDR or intolerant disease, built from: Group A — levofloxacin/moxifloxacin, bedaquiline, linezolid (all three included); Group B — clofazimine, cycloserine/terizidone (one or both added); Group C — ethambutol, delamanid, pyrazinamide, imipenem–cilastatin or meropenem (with amoxicillin–clavulanate), amikacin/streptomycin, ethionamide/prothionamide, p-aminosalicylic acid — added to complete at least four effective drugs. Injectable-free regimens are now the norm; kanamycin and capreomycin have been withdrawn.

Isoniazid mono-resistant (Hr) TB: rifampicin + ethambutol + pyrazinamide + levofloxacin for 6 months (6 REZ-Lfx).

Monitoring: monthly sputum smear and culture (the response is judged on culture conversion), monthly weight, monthly haemogram and renal/liver function, ECG for QTc at baseline, weeks 2, 4, 8, 12 and monthly thereafter (bedaquiline, moxifloxacin, clofazimine and delamanid are all QT-prolonging), TSH on ethionamide and PAS, monthly visual acuity/colour vision on ethambutol and linezolid, and audiometry if an injectable is used.

Key adverse effects: linezolid — myelosuppression, peripheral and optic neuropathy, lactic acidosis (the dominant toxicity, requiring dose reduction to 300 mg or interruption); bedaquiline — QT prolongation, hepatotoxicity; pretomanid — hepatotoxicity, peripheral neuropathy; clofazimine — skin hyperpigmentation, ichthyosis, QT prolongation; cycloserine — psychosis, depression, seizures (a particular hazard in the older brain); fluoroquinolones — tendinopathy, dysglycaemia, delirium, QT prolongation. Manage through active drug-safety monitoring (aDSM) with mandatory reporting.

Adjunctive and programmatic care: pyridoxine with linezolid, cycloserine and high-dose isoniazid; nutritional support — under NTEP through the Ni-kshay Poshan Yojana direct benefit transfer (enhanced to Rs 1000 per month in 2024) and the Pradhan Mantri TB Mukt Bharat Abhiyaan with Ni-kshay Mitra community adoption; airborne infection control; contact screening and TB preventive treatment for contacts; treatment support through DOT providers, video-observed therapy and 99DOTS; and screening/management of diabetes, HIV, alcohol use and undernutrition.

Geriatric-specific management: review and reduce polypharmacy before starting, screen for and stop other QT-prolonging drugs (macrolides, antipsychotics, antiemetics, antiarrhythmics), correct hypokalaemia and hypomagnesaemia, adjust doses for weight and renal function, monitor for delirium on cycloserine and fluoroquinolones, arrange family or caregiver-supported adherence, and involve the multidisciplinary team for nutrition, mobility and depression.

Outcomes: historically MDR-TB treatment success was only 50–60% with 18–24-month injectable regimens; with the all-oral shorter regimens success now approaches 85–90%, with far lower loss to follow-up. Outcomes in the elderly remain poorer because of comorbidity, drug intolerance and higher all-cause mortality.