Tuberculosis, MDR-TB diagnosis and antituberculous drug side effects and interactions

Overview

Tuberculosis (TB) is infection with Mycobacterium tuberculosis, an aerobic, slow-growing, acid-fast bacillus spread by airborne droplets from people with active lung disease.

Pakistan is a high-burden country for both ordinary TB and drug-resistant TB, so every house officer must recognise it, confirm it quickly and treat it safely.

PGET questions focus on three things named in the TOS: diagnosing MDR-TB, the side effects (complications) of antituberculous therapy (ATT) and its drug interactions.

Pathogenesis in brief

• Primary TB: inhaled bacilli are taken up by alveolar macrophages. A caseating granuloma forms (central caseation, epithelioid cells, Langhans giant cells). The healed, often calcified lung lesion is the Ghon focus; with the hilar node it is the Ghon complex.
• Latent TB: the immune system contains the bacilli. There are no symptoms and the person is not infectious.
• Reactivation (post-primary) TB: most adult disease. It favours the apices (high oxygen) and often cavitates.
• Risk factors for reactivation: HIV, diabetes, steroids and other immunosuppressants (including anti-TNF drugs), chronic kidney disease, malnutrition, silicosis, older age.

Clinical features

• Pulmonary: cough for more than 2 weeks, sputum, haemoptysis, fever (often evening), night sweats, weight loss and loss of appetite.
• Lymph node TB (the commonest extrapulmonary site): firm, matted, non-tender cervical nodes that may soften into a cold abscess (no redness or heat) and form sinuses.
• Miliary TB: blood-borne spread; innumerable tiny "millet-seed" nodules on chest X-ray, choroidal tubercles, liver involvement. Image the brain, because the CNS is often involved.
• TB meningitis: CSF shows lymphocytes, very high protein and glucose less than half of blood glucose.
• Other sites: pleura, pericardium, spine (Pott disease), abdomen, genitourinary tract, skin.

Diagnosis of pulmonary TB

Tests for latent infection

• Tuberculin skin test (Mantoux): intradermal PPD, read at 48–72 hours as induration. False positives with BCG and non-tuberculous mycobacteria; false negatives (anergy) in HIV, steroids, malnutrition, miliary TB and the very old or young.
• Interferon-gamma release assay (IGRA): blood test using TB-specific antigens (ESAT-6, CFP-10). Not affected by BCG and needs one visit.
• Neither test separates latent from active disease.

Treatment of drug-sensitive TB

• Check liver function, renal function, hepatitis B and C and HIV before starting.
• Give fixed-dose combination tablets dosed by weight, with directly observed treatment where adherence is a concern.
• Pyrazinamide kills slow-growing bacilli in acidic sites; this is why the course can be 6 months rather than 9.
• Ethambutol protects the regimen in case of unrecognised isoniazid resistance.
• Treatment failure: smear or culture still positive at month 5 or later.

Latent TB

Treat contacts and high-risk groups (HIV, before anti-TNF drugs or transplant, child contacts of a smear-positive case) with 6 months of isoniazid (6H) or 3 months of isoniazid plus rifampicin (3HR), after active disease has been excluded.

Drug-resistant TB

Definitions

Who is at risk

• Previous TB treatment, especially irregular or unsupervised.
• Failure to improve despite good adherence.
• Contact with a known drug-resistant case.
• HIV with previous TB treatment.
• Repeated fluoroquinolone courses for "chest infections".
• Health workers exposed to resistant TB.

How MDR-TB is diagnosed

1. Xpert MTB/RIF on sputum: TB detected and rifampicin resistance detected → treat as RR/MDR-TB.
2. Line probe assay (LPA): molecular strips on smear-positive sputum or culture.
   • First-line LPA: rpoB (rifampicin), katG (high-level isoniazid resistance) and inhA (low-level isoniazid resistance, with cross-resistance to ethionamide).
   • Second-line LPA: resistance to fluoroquinolones and injectables.
3. Phenotypic drug susceptibility testing on culture: the reference method, but takes weeks.
4. Whole-genome sequencing is replacing culture-based testing in some countries.

Treatment principles for MDR-TB

• Treated in a programmatic drug-resistant TB unit (in Pakistan, through the national TB programme's PMDT sites).
• Current WHO approach uses all-oral regimens. A 6-month regimen of bedaquiline, pretomanid, linezolid and moxifloxacin (BPaLM) is used for many patients; longer individualised regimens use drugs such as bedaquiline, linezolid, levofloxacin or moxifloxacin, clofazimine and cycloserine.
• Injectable aminoglycosides are now rarely used because of deafness.
• Guidance changes often; check the current Pakistan national guideline.

Side effects of antituberculous drugs

Second-line drug toxicities

Drug-induced hepatitis: what to do

• Mild rise in transaminases is common and often settles.
• Stop the hepatotoxic drugs (H, R, Z) if bilirubin rises (jaundice) or transaminases rise more than three times normal with symptoms.
• If the patient is very ill or smear-positive, cover with non-hepatotoxic drugs (e.g. ethambutol plus a fluoroquinolone, with or without an injectable) until the liver recovers.
• Reintroduce drugs one at a time with LFT monitoring; pyrazinamide is usually the last and may be left out (the course is then extended).
• In established liver disease, ethambutol is the least hepatotoxic first-line choice.

Drug interactions

Rifampicin (enzyme inducer)

Rifampicin induces liver cytochrome P450 enzymes and P-glycoprotein, so it lowers the levels of many drugs:

• Combined oral contraceptive pill → contraceptive failure; advise a copper IUD or other non-hormonal method.
• Warfarin → INR falls; needs a much higher dose and close INR checks. DOACs are also reduced.
• Corticosteroids → steroid effect falls; in Addison disease the hydrocortisone dose must be increased (often doubled) to avoid crisis.
• Antiretrovirals: protease inhibitors levels fall (switch rifampicin to rifabutin); dolutegravir is given twice daily with rifampicin.
• Others: phenytoin, sulfonylureas, methadone, ciclosporin, tacrolimus, azole antifungals, some antidepressants.

Isoniazid (enzyme inhibitor)

Isoniazid raises phenytoin and carbamazepine levels, causing ataxia, nystagmus and drowsiness.

Special situations

• Pregnancy: H, R, Z and E are safe; give pyridoxine. Avoid streptomycin.
• Renal failure: ethambutol and pyrazinamide are cleared by the kidney; give them three times a week after dialysis.
• Liver disease: use fewer hepatotoxic drugs, with close monitoring.
• HIV co-infection: start ART within about 2 weeks of ATT in most patients, but delay ART (4–8 weeks) in TB meningitis. Watch for immune reconstitution inflammatory syndrome (IRIS): fever and enlarging nodes after starting ART while the viral load falls.
• M. bovis (unpasteurised milk) is naturally resistant to pyrazinamide.

Complications of TB

• Massive haemoptysis (e.g. Rasmussen aneurysm in a cavity wall).
• Aspergilloma in an old cavity.
• Bronchiectasis and fibrosis; respiratory failure.
• Pneumothorax, empyema.
• Constrictive pericarditis, Addison disease, infertility, hydrocephalus.

Quick revision

• Xpert MTB/RIF: TB DNA + rpoB (rifampicin resistance) in under 2 hours.
• MDR = H + R resistance; pre-XDR adds fluoroquinolone; XDR (WHO 2021) adds bedaquiline or linezolid.
• 2HRZE + 4HR; CNS TB 12 months with dexamethasone.
• H: neuropathy (B6), hepatitis, raises phenytoin.
• R: orange secretions, enzyme inducer (pill, warfarin, steroids, protease inhibitors).
• Z: most hepatotoxic, gout. E: optic neuritis, red–green. S: ototoxic, avoid in pregnancy.
• Jaundice on ATT: stop H, R, Z; reintroduce one at a time.
• Second line: bedaquiline QT, linezolid marrow and nerves, cycloserine psychosis, ethionamide hypothyroidism.

Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Park's Textbook of Preventive and Social Medicine).

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