Tuberculosis

What is tuberculosis and what causes it?

A chronic infectious disease caused by Mycobacterium tuberculosis — primarily affects the lungs but can involve other organs

What type of organism is Mycobacterium tuberculosis?

An acid-fast bacillus with a lipid-rich waxy cell wall containing mycolic acids — obligate aerobe, slow-growing, survives intracellularly

How is TB detected by staining?

Ziehl-Neelsen (ZN) stain — the mycolic acid-rich cell wall retains the red carbol fuchsin dye even after acid decolourisation

Why does TB predominantly affect the upper lung lobes?

M. tuberculosis is aerobic — it thrives in the oxygen-rich environment of the upper lobes of the lungs

How is TB transmitted?

Airborne transmission via respiratory droplets released when an infected person coughs, sneezes, or speaks — prolonged exposure usually required

What is latent TB infection?

A state where an individual is infected with M. tuberculosis but is asymptomatic and non-contagious — the immune system has contained the bacteria in granulomas

What triggers progression from latent TB to active TB?

Failure of the immune system to control the infection — commonly due to HIV, malnutrition, immunosuppressive drugs, or ageing

Define MDR-TB

Multidrug-resistant TB — resistant to at least isoniazid AND rifampicin, the two most important first-line drugs

Define XDR-TB

Extensively drug-resistant TB — resistant to isoniazid, rifampicin, fluoroquinolones, AND at least one second-line injectable drug

What is the gold standard for TB diagnosis?

Bacterial culture — but takes weeks to yield results

What does GeneXpert MTB/RIF detect?

M. tuberculosis AND rifampicin resistance — a rapid molecular diagnostic test

Which test is used for latent TB diagnosis?

Tuberculin Skin Test (TST) or Interferon-Gamma Release Assay (IGRA)

What are the five principles of TB chemotherapy?

Combination therapy prevents resistance; adequate duration (6–12 months) needed; adherence is critical; treatment has intensive and continuation phases; DOT improves adherence

What are the three goals of TB treatment?

Cure the patient; prevent transmission; minimise development of drug resistance

What happens in the intensive phase of TB treatment?

Kills rapidly dividing bacilli — reduces bacterial load quickly

What happens in the continuation phase of TB treatment?

Kills dormant/persistent bacilli and prevents relapse

Name the five first-line anti-TB drugs and their abbreviations

Isoniazid (INH/H), Rifampicin (RIF/R), Pyrazinamide (PZA/Z), Ethambutol (EMB/E), Streptomycin (SM/S)

What is the mechanism of action of Isoniazid?

A prodrug activated by mycobacterial KatG catalase-peroxidase enzyme — inhibits mycolic acid synthesis, destroying cell wall integrity — primarily bactericidal against rapidly growing bacilli

What enzyme activates Isoniazid and why is this important for resistance?

KatG catalase-peroxidase — mutations in KatG prevent activation of INH, rendering it ineffective (principal resistance mechanism)

How is Isoniazid metabolised and why does this matter?

Acetylated in the liver by NAT2 — genetically polymorphic: fast acetylators have lower drug levels; slow acetylators have higher drug levels with greater toxicity risk

What are the two most important adverse effects of Isoniazid?

Hepatotoxicity (especially in older patients and alcoholics) and peripheral neuropathy (due to pyridoxine/Vitamin B6 deficiency)

Why does Isoniazid cause peripheral neuropathy and how is it prevented?

INH competes with pyridoxine (Vitamin B6) — always co-administer pyridoxine 10–25mg/day in high-risk groups (pregnancy, diabetes, malnutrition, HIV)

What effect does Isoniazid have on CYP450 enzymes?

Inhibits CYP450 — increases plasma levels of phenytoin, carbamazepine, and warfarin

What is the adult dose of Isoniazid in TB treatment?

5mg/kg/day, usually 300mg/day

What is the mechanism of action of Rifampicin?

Inhibits DNA-dependent RNA polymerase — suppresses RNA synthesis — effective against intracellular and dormant bacilli (sterilising action)

What is meant by Rifampicin's sterilising action?

It can kill both rapidly dividing and dormant/slow-growing bacilli — making it essential in the continuation phase to prevent relapse

Why does food reduce Rifampicin bioavailability?

Rifampicin should ideally be taken on an empty stomach — food decreases its absorption

What is the most clinically significant pharmacokinetic property of Rifampicin?

Potent CYP450 inducer — reduces plasma levels of many drugs including oral contraceptives, warfarin, protease inhibitors, NNRTIs, and antiepileptics

What alternative to Rifampicin is used in HIV patients on protease inhibitors?

Rifabutin — a less potent CYP450 inducer that does not reduce HIV drug levels as much

What warning must every patient on Rifampicin receive?

Orange-red discoloration of body fluids (urine, sweat, tears, saliva) — harmless but alarming if unexpected

What is the adult dose of Rifampicin?

10mg/kg/day, usually 600mg/day

What is unique about Pyrazinamide's mechanism of action compared to other anti-TB drugs?

It is a prodrug converted to pyrazinoic acid by pyrazinamidase — active in acidic environments (inside macrophages/granulomas) — the only drug that effectively kills dormant bacilli hiding inside macrophages at low pH

What does Pyrazinamide disrupt inside the mycobacterium?

Membrane transport and energy metabolism — in the acidic environment of phagolysosomes

What is the signature metabolic adverse effect of Pyrazinamide?

Hyperuricaemia — blocks renal uric acid excretion, which can precipitate gout

What adverse effect does Pyrazinamide share with INH and RIF?

Hepatotoxicity — all three bactericidal first-line drugs cause hepatotoxicity

In which patients should Pyrazinamide be avoided?

Patients with active gout — and dose adjustment is needed in renal impairment

What is the mechanism of action of Ethambutol?

Inhibits arabinosyl transferase III — blocking synthesis of arabinogalactan, an essential component of the mycobacterial cell wall

Is Ethambutol bactericidal or bacteriostatic?

Bacteriostatic — it slows growth and prevents the emergence of resistance to other drugs in the regimen

What is the unique and most important adverse effect of Ethambutol?

Optic neuritis (dose-related) — decreased visual acuity and red-green colour blindness

Why must Ethambutol be avoided in children under 5 years?

Young children cannot reliably report visual changes needed to detect optic neuritis early

What monitoring is required for Ethambutol?

Regular visual acuity and colour perception testing throughout therapy

What accumulates Ethambutol in the body and requires caution?

Renal impairment — Ethambutol is renally excreted and accumulates, increasing toxicity risk

What is the standard drug-susceptible TB regimen?

2HRZE followed by 4HR — two months of Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol; then four months of Isoniazid and Rifampicin

What are the four regimen options for treating latent TB?

6H or 9H (isoniazid 6–9 months); 3HP (isoniazid + rifapentine weekly for 3 months); 3HR (isoniazid + rifampicin daily for 3 months); 4R (rifampicin alone for 4 months)

What is the mechanism of Fluoroquinolones in MDR-TB?

Inhibit DNA gyrase (Topoisomerase II) and Topoisomerase IV — prevents bacterial DNA replication — bactericidal

Which fluoroquinolones are used in MDR-TB?

Levofloxacin (750–1000mg/day) and Moxifloxacin (400mg/day)

What is the most serious cardiac adverse effect of fluoroquinolones in TB treatment?

QT interval prolongation — risk is particularly significant with Moxifloxacin

What is the unique mechanism of action of Bedaquiline?

Inhibits mycobacterial ATP synthase — the enzyme responsible for energy (ATP) generation — starves the bacterium of energy

Why is Bedaquiline important in MDR-TB treatment?

It has a completely novel target (ATP synthase) unlike any first-line drug — effective against strains resistant to all first-line agents

What is the half-life of Bedaquiline and why is this clinically relevant?

Approximately 5 months — very long; drug persists in tissues long after stopping; also means long washout period

Why should Rifampicin not be co-administered with Bedaquiline?

Rifampicin is a CYP3A4 inducer and significantly reduces bedaquiline plasma levels, compromising its efficacy

What is the dosing schedule for Bedaquiline?

400mg once daily for 2 weeks, then 200mg three times weekly for 22 weeks — always under DOT with other effective TB drugs

What QT prolongation combination must be monitored in MDR-TB regimens?

Bedaquiline + Clofazimine + Moxifloxacin — all three prolong QT; ECG monitoring is mandatory when combined

What is the mechanism of Linezolid in TB?

Binds to 23S rRNA of the 50S ribosomal subunit — prevents formation of initiation complex — bacteriostatic for most organisms but bactericidal against some TB strains

What is the most serious haematological adverse effect of Linezolid?

Bone marrow suppression — especially thrombocytopenia; regular CBCs must be monitored

What serious drug interaction does Linezolid have with SSRIs and MAOIs?

Risk of serotonin syndrome — potentially life-threatening

What dietary restriction applies to Linezolid therapy?

Avoid tyramine-rich foods (aged cheese, cured meats, fermented products) — risk of hypertensive crisis due to MAO-inhibiting property

What is the mechanism of Cycloserine in TB?

Structural analogue of D-alanine — inhibits alanine racemase (L-alanine → D-alanine) and D-alanine:D-alanine ligase — blocking peptidoglycan synthesis in the mycobacterial cell wall

What is the main adverse effect of Cycloserine?

Neurotoxicity — psychosis, depression, seizures, headache, tremors

Why should Cycloserine not be combined with Isoniazid?

Additive neurotoxicity — both can cause CNS toxicity through different mechanisms

What co-medication is given with Cycloserine to reduce neurotoxicity?

Pyridoxine (Vitamin B6)

In which patients should Cycloserine be avoided?

Patients with unstable psychiatric illness — due to risk of psychosis and depression

What is the mechanism of Ethionamide?

A prodrug activated by mycobacterial monooxygenase (EthA) — inhibits mycolic acid synthesis, similar to INH

What cross-resistance concern exists between Ethionamide and Isoniazid?

Because both inhibit mycolic acid synthesis, cross-resistance can occur in some INH-resistant strains

What is the most common adverse effect of Ethionamide?

GI intolerance — nausea and vomiting; also causes hepatotoxicity and neurotoxicity

What co-medication is required with Ethionamide?

Pyridoxine — to reduce neurotoxicity

What is the BPaLM regimen and when is it used?

Bedaquiline + Pretomanid + Linezolid + Moxifloxacin — 6-month regimen for MDR/RR-TB without fluoroquinolone resistance

What is the BPaL regimen and when is it used?

Bedaquiline + Pretomanid + Linezolid — 6-month regimen reserved for Pre-XDR-TB (MDR-TB with additional fluoroquinolone resistance)

What is the 9-month all-oral MDR-TB regimen and who is eligible?

Bedaquiline + Levofloxacin + Linezolid + Clofazimine — used when fluoroquinolone resistance has been explicitly excluded by molecular testing

What advantage do newer all-oral MDR-TB regimens offer over older regimens?

They entirely replace painful aminoglycoside injections, are shorter, and are better tolerated

Why does TB-HIV co-infection complicate management?

Rifampicin induces CYP3A4 reducing PI and NNRTI levels; ART must be started during TB treatment; risk of Immune Reconstitution Inflammatory Syndrome (IRIS)

What is IRIS in the context of TB-HIV co-infection?

Immune Reconstitution Inflammatory Syndrome — paradoxical worsening of TB symptoms when ART is started, as the recovering immune system mounts an inflammatory response against the mycobacterium

What alternative rifamycin is used in HIV patients on protease inhibitors?

Rifabutin — less potent CYP3A4 inducer than Rifampicin

What is the BCG vaccine and what does it protect against?

Bacille Calmette-Guérin vaccine — protects against severe forms of childhood TB (TB meningitis and miliary TB) but not reliably against adult pulmonary TB

Which three first-line anti-TB drugs all share hepatotoxicity as an adverse effect?

Isoniazid, Rifampicin, and Pyrazinamide — all three bactericidal drugs; LFTs must be monitored during treatment

Which vitamin must be given with Isoniazid, Cycloserine, and Ethionamide and why?

Pyridoxine (Vitamin B6) — all three cause neurotoxicity related to B6 depletion or competition

What monitoring is required for the four main first-line TB drugs?

INH: LFTs and peripheral neuropathy; RIF: LFTs and drug levels; PZA: LFTs and uric acid; EMB: visual acuity and colour perception