20.4 Tuberculosis: Diagnosis & Anti-Tuberculous Therapy
Key Takeaways
- Standard treatment is rifampicin and isoniazid for six months with pyrazinamide and ethambutol for the first two months, extended to twelve months for CNS disease.
- Ethambutol causes dose-related optic neuritis with red-green colour blindness; isoniazid causes peripheral neuropathy prevented by pyridoxine; pyrazinamide causes hyperuricaemia and hepatitis.
- Rifampicin is a potent CYP450 inducer that turns secretions orange and renders the combined oral contraceptive ineffective.
Last updated: September 2026
3. Diagnostic Modalities: Active vs. Latent TB
Microbiological Diagnostics for Active Disease
- Sputum Smear Microscopy: Examination of three early morning sputum samples (including at least one supervised or induced sample via nebulised hypertonic saline). Requires a minimum of $5,000\text{–}10,000\text{ bacilli/mL}$ for visualization.
- Ziehl-Neelsen (ZN) Stain: Acid-fast bacilli resist decolourization by acid-alcohol and retain primary carbol fuchsin, appearing as bright red beaded rods against a brilliant green or blue background.
- Auramine-Rhodamine Fluorochrome Stain: Bacilli fluoresce bright yellow-green under ultraviolet microscopy; provides higher sensitivity and allows rapid scanning at lower magnification.
- Mycobacterial Culture (The Gold Standard):
- Solid Culture (Lowenstein-Jensen [LJ] Egg-Based Medium): Produces characteristic rough, buff, crumbly colonies; requires 4 to 8 weeks due to slow mycobacterial doubling time (18–24 hours).
- Automated Liquid Culture (Bactec MGIT [Mycobacteria Growth Indicator Tube]): Detects mycobacterial oxygen consumption fluorometrically; significantly faster turnaround time (1 to 3 weeks). Enables phenotypic drug susceptibility testing (DST) against first- and second-line antimicrobials.
- GeneXpert MTB/RIF (Nucleic Acid Amplification Test [NAAT]):
- An automated, cartridge-based real-time PCR assay endorsed by the World Health Organization and NICE.
- Simultaneously amplifies M. tuberculosis complex DNA and detects point mutations in the $rpoB$ gene (the RNA polymerase beta-subunit gene responsible for $> 95%$ of rifampicin resistance).
- Delivers results within 2 hours with high sensitivity ($> 98%$ in smear-positive cases) and serves as an early surrogate marker for multidrug-resistant TB (MDR-TB, defined as resistance to at least both rifampicin and isoniazid).
Latent TB Screening: Mantoux Test vs. IGRA
| Diagnostic Feature | Tuberculin Skin Test (TST / Mantoux) | Interferon-Gamma Release Assay (IGRA) |
|---|---|---|
| Biological Principle | In vivo delayed-type (Type IV) cell-mediated hypersensitivity reaction to Purified Protein Derivative (PPD) | Ex vivo quantification of IFN-$\gamma$ released by sensitized T-lymphocytes upon exposure to specific antigens |
| Specific Antigens Used | Crude cocktail of $> 200$ shared mycobacterial proteins (PPD) | Highly specific recombinant M. tuberculosis antigens: ESAT-6 and CFP-10 (and TB7.7) |
| Effect of Prior BCG Vaccination | Frequent false-positive results (BCG strain M. bovis shares many PPD antigens) | Zero cross-reactivity with BCG; entirely unaffected by prior BCG vaccination status |
| Non-Tuberculous Mycobacteria (NTM) | Frequent false-positives from environmental NTM exposure | Negative in most environmental NTM infections (except M. kansasii, M. marinum, M. szulgai) |
| Logistical Requirements | Requires intradermal forearm injection; patient must return strictly at 48 to 72 hours for induration measurement | Single venepuncture blood test (QuantiFERON-TB Gold Plus or T-SPOT.TB); requires no return visit |
| Reading Metric | Transverse diameter of palpable induration (not erythema): $\ge 5\text{ mm}$ (immunosuppressed/HIV), $\ge 10\text{ mm}$ (high-risk), $\ge 15\text{ mm}$ (general) | Automated laboratory ELISA (optical density) or ELISpot (enumerating IFN-$\gamma$ spot-forming cells) |
| UK Guidelines (NICE) | Second-line or in young children | First-line screening modality for LTBI in adults, healthcare workers, contacts, and prior to anti-TNF initiation |
4. Anti-Tuberculous Pharmacotherapy (BTS & NICE Guidelines)
Standard Regimen for Active Drug-Susceptible Pulmonary Tuberculosis
Standard treatment consists of a 6-month short-course regimen combining four bactericidal and sterilizing agents, categorized into two distinct phases to suppress rapid mutational resistance:
- Initial Intensive Phase (2 Months): Quadruple therapy with Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol (RIPE). Rapidly reduces the mycobacterial load and prevents the emergence of drug-resistant mutants.
- Continuation Phase (4 Months): Dual therapy with Rifampicin and Isoniazid (RH). Eliminates slow-replicating semi-dormant 'persister' bacilli within necrotic lesions, preventing late relapse.
Special Treatment Durations & Corticosteroid Indications
- Central Nervous System (Tuberculous Meningitis): Extended to a 12-month total course (2 months RIPE followed by 10 months RH). Adjunctive systemic dexamethasone ($0.4\text{ mg/kg/day}$ tapered over 6 to 8 weeks) is mandatory; it reduces mortality by $30%$ by attenuating cerebral vasculitis and basal exudate inflammation.
- Tuberculous Pericarditis: Standard 6-month antimicrobial course plus adjunctive oral prednisolone tapered over 6 weeks to reduce the incidence of constrictive pericarditis and pericardiectomy.
- Osteoarticular Tuberculosis: 6 to 9 months depending on clinical and radiological response.
Comprehensive Drug Mechanisms, Toxicities & Monitoring
| First-Line Agent | Mechanism of Action & Resistance Gene | Classical Adverse Effects & Toxicities | Clinical Management & Monitoring Mandates |
|---|---|---|---|
| Rifampicin (R) | Inhibits DNA-dependent RNA polymerase by binding beta-subunit; resistance via rpoB gene mutations | • Potent hepatic CYP450 enzyme inducer (CYP3A4, 2C9, 2C19)<br>• Harmless orange-red discolouration of urine, tears, saliva, sweat, and soft contact lenses<br>• Cholestatic/hepatocellular hepatotoxicity<br>• Acute interstitial nephritis, thrombocytopenic purpura, flu-like syndrome | Dramatically lowers circulating serum concentrations of warfarin, direct oral anticoagulants, oral contraceptives (must use barrier contraception), antiretrovirals, anticonvulsants, and corticosteroids. Baseline and monthly LFTs. |
| Isoniazid (H) | Inhibits mycolic acid synthesis via inhibition of NADH-dependent enoyl-ACP reductase; resistance via katG (catalase-peroxidase) or inhA promoter mutations | • Dose-dependent peripheral neuropathy (interferes with pyridoxine / vitamin B6 metabolism)<br>• Hepatotoxicity (transaminitis; metabolite acetylhydrazine)<br>• Drug-induced lupus erythematosus (anti-histone antibodies positive)<br>• Sideroblastic anaemia, agranulocytosis | Mandatory co-prescription of Pyridoxine (Vitamin B6) $10\text{ mg}$ daily in all patients at risk of neuropathy (diabetes, alcohol misuse, CKD, malnutrition, pregnancy, HIV). Stop if transaminases exceed $5\times$ normal (or $3\times$ if symptomatic). |
| Pyrazinamide (Z) | Converted to active pyrazinoic acid by bacterial pyrazinamidase (encoded by pncA); disrupts cell membrane potential and transport | • Hyperuricaemia (inhibits renal tubular urate excretion; precipitates acute gout and arthralgia)<br>• Most hepatotoxic first-line agent<br>• Cutaneous photosensitivity, gastrointestinal upset | Monitor serum uric acid. Treat mild non-gouty arthralgias symptomatically with NSAIDs without discontinuing drug; discontinue if acute podagra/gout or severe hepatitis develops. |
| Ethambutol (E) | Inhibits arabinosyl transferase (encoded by embB), halting synthesis of cell wall arabinogalactan | • Retrobulbar optic neuritis (dose- and duration-dependent demyelinating optic neuropathy)<br>• Earliest clinical sign: loss of red-green colour discrimination<br>• Reduced visual acuity, central scotoma | Mandatory baseline testing of visual acuity (Snellen chart) and colour vision (Ishihara plates) prior to initiation. Excreted renally: requires mandatory dose adjustment in renal failure. Advise immediate cessation if visual symptoms occur. |
Test Your Knowledge
A 28-year-old nurse who emigrated from India three years ago attends the occupational health department for employment pre-screening. She is completely asymptomatic, has no cough, fever, or weight loss, and has a completely normal chest radiograph. She received the BCG vaccination in infancy and has a visible deltoid scar. An initial tuberculin skin test (Mantoux) demonstrates 14 mm of palpable induration at 48 hours. What is the most appropriate next step to determine whether she has latent tuberculosis infection?
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Test Your Knowledge
A 45-year-old man who was diagnosed with smear-positive pulmonary tuberculosis six weeks ago attends the respiratory clinic for routine follow-up. He has been taking daily weight-based fixed-dose combination therapy comprising rifampicin, isoniazid, pyrazinamide, and ethambutol. He reports compliance with his medication. However, over the past 10 days, he has noted blurred vision in both eyes and increasing difficulty reading traffic signs, specifically struggling to distinguish between red and green signals. Physical examination demonstrates reduced visual acuity (6/18 bilaterally on Snellen chart) and abnormal colour plates on Ishihara testing. Which medication is the culprit, what is its molecular mechanism, and what baseline evaluation was mandatory prior to prescription?
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