Antituberculous drugs
Antituberculous and Antileprosy Drugs: Regimens and Toxicity for FCPS Part 1
Isoniazid, rifampicin, pyrazinamide, ethambutol, second-line MDR-TB drugs and leprosy multidrug therapy for FCPS Part 1. Explains why combination therapy prevents resistance, pyrazinamide's sterilising role, rifampicin interactions, isoniazid overdose and ethambutol colour vision loss.
Why TB needs several drugs for months
- A large cavity holds around 10^8 to 10^9 bacilli. Spontaneous resistance mutations occur at roughly 1 in 10^6 for isoniazid and 1 in 10^8 for rifampicin, so a cavity almost always contains some single-drug-resistant mutants. Monotherapy kills the sensitive majority and selects the resistant mutants: symptoms improve, then return with an isoniazid-resistant organism.
- Mutants resistant to two drugs at once are vanishingly rare (the product of the two rates), so combination therapy prevents resistance. Adding a single new drug to a failing regimen is effectively monotherapy and breeds more resistance.
- Bacilli exist in different populations: rapidly dividing extracellular bacilli in cavities (killed by isoniazid), slowly metabolising bacilli with bursts of activity (killed by rifampicin), and dormant bacilli in acidic macrophages and caseous foci (killed by pyrazinamide).
- Pyrazinamide is active at acid pH and kills these slow-growing intracellular bacilli. This sterilising effect in the first 2 months shortened treatment from 9 months to 6 months.
First-line drugs
| Drug | Mechanism | Key toxicity |
|---|---|---|
| Isoniazid (H) | Prodrug activated by KatG; inhibits InhA, blocking mycolic acid synthesis | Peripheral neuropathy (prevent with pyridoxine), hepatitis (age, alcohol, slow acetylators), drug-induced lupus, sideroblastic anaemia; inhibits CYP450 |
| Rifampicin (R) | Inhibits bacterial DNA-dependent RNA polymerase (*rpoB*) | Orange-red urine, tears and sweat; hepatitis; flu-like syndrome; thrombocytopenia; potent enzyme inducer |
| Pyrazinamide (Z) | Converted to pyrazinoic acid in acidic sites; disrupts membrane energetics | Most hepatotoxic; hyperuricaemia and gout (reduces urate excretion) |
| Ethambutol (E) | Inhibits arabinosyl transferase (arabinogalactan of the wall) | Optic neuritis: reduced acuity and red–green colour blindness (cannot tell traffic-light colours); test vision before and during; reduce in renal failure |
| Streptomycin (S) | Aminoglycoside (30S) | Ototoxicity and nephrotoxicity; avoided in pregnancy (fetal deafness) |
- Isoniazid in pregnancy without pyridoxine risks maternal neuropathy; pyridoxine is given routinely in pregnancy, HIV, diabetes, alcohol misuse and malnutrition.
- Isoniazid overdose: isoniazid depletes active pyridoxine, so GABA synthesis (a pyridoxal phosphate-dependent step) fails. Result: refractory seizures, coma and severe lactic acidosis, resistant to benzodiazepines. The specific treatment is IV pyridoxine, gram for gram of isoniazid ingested (5 g if unknown).
- Isoniazid with phenytoin: isoniazid inhibits phenytoin metabolism; because phenytoin has zero-order kinetics, levels climb steeply: nystagmus, ataxia, slurred speech.
Rifampicin interactions
Rifampicin induces CYP3A4 and other enzymes and transporters, reaching full effect in about 2 weeks and fading over about 2 weeks after stopping.
| Affected drug | Consequence |
|---|---|
| Hydrocortisone in Addison disease | Faster hepatic cortisol clearance: adrenal crisis despite usual doses; double the replacement dose |
| Dolutegravir | Levels fall: give 50 mg twice daily during rifampicin and for 2 weeks after |
| Protease inhibitors, some NNRTIs | Major interactions; rifabutin is an alternative |
| Combined pill, warfarin, steroids, methadone, azoles, sulphonylureas | Reduced effect; contraceptive failure |
- Hyperkalaemia with hyponatraemia in such a crisis confirms primary adrenal failure (aldosterone also lost).
Standard regimens
- Drug-sensitive pulmonary TB: 2HRZE then 4HR (6 months), fixed-dose combinations under directly observed therapy.
- TB meningitis: 2HRZE plus 10HR (12 months) with dexamethasone. Spinal TB 9–12 months.
- Pregnancy: HRZE with pyridoxine; avoid streptomycin. HIV: start ART within 2 weeks (delay in TB meningitis); watch for IRIS.
- Hepatitis on treatment (ALT over 3 times normal with symptoms, over 5 times without, or jaundice): stop H, R and Z; continue ethambutol with a non-hepatotoxic drug if TB is severe; reintroduce sequentially.
- A moderately raised ESR after 2 months of treatment can persist during healing and is not, by itself, evidence of failure.
Exam trap Never add a single drug to a failing TB regimen.
Latent TB and BCG
- Diagnosed by tuberculin skin test or interferon-γ release assay (not affected by BCG). Screen before anti-TNF therapy (infliximab), transplantation and in HIV; TB on anti-TNF is often extrapulmonary.
- Treat with 3 months isoniazid plus rifampicin, 6–9 months isoniazid, or 4 months rifampicin.
- BCG: live attenuated *M. bovis*, intradermal at birth in Pakistan; protects best against miliary and meningeal TB in children; contraindicated in immunosuppression.
- *Mycobacterium avium* complex causes disseminated infection in advanced HIV and is resistant to standard TB drugs (treated with clarithromycin and ethambutol).
Drug-resistant TB
- MDR-TB: resistant to isoniazid and rifampicin; detected by GeneXpert (*rpoB*), culture and line probe assays.
- Line probe assay interpretation:
| Mutation | Meaning |
|---|---|
| katG | High-level isoniazid resistance |
| inhA promoter | Low-level isoniazid resistance plus ethionamide cross-resistance (both act on InhA) |
| rpoB | Rifampicin resistance |
- XDR-TB: MDR plus resistance to a fluoroquinolone and to bedaquiline or linezolid.
- All-oral 6-month regimen (BPaLM): bedaquiline, pretomanid, linezolid, moxifloxacin.
| Second-line drug | Mechanism or key toxicity |
|---|---|
| Bedaquiline | Inhibits mycobacterial ATP synthase; QT prolongation (boxed warning), additive with moxifloxacin and clofazimine |
| Linezolid | Binds the 23S rRNA of the 50S subunit, blocking the initiation complex; toxicity from inhibiting mitochondrial protein synthesis: peripheral and optic neuropathy, anaemia, thrombocytopenia, lactic acidosis; weak MAO inhibitor |
| Fluoroquinolones | QT, tendons |
| Cycloserine | Depression, psychosis, seizures (pyridoxine is co-prescribed to reduce this CNS toxicity but does not reliably prevent it) |
| Ethionamide, PAS | Hypothyroidism and goitre |
| Clofazimine | Skin pigmentation, QT |
Leprosy
- *M. leprae* prefers cool tissues (skin, peripheral nerves, nose); it cannot be cultured in vitro.
- WHO multidrug therapy: rifampicin (monthly supervised), dapsone (daily) and clofazimine for 6 months (paucibacillary) or 12 months (multibacillary).
| Drug | Notes |
|---|---|
| Dapsone | Folate synthesis inhibitor; haemolysis (G6PD), methaemoglobinaemia, agranulocytosis, hypersensitivity syndrome; can cause macrocytosis; dermatitis herpetiformis, PCP prophylaxis |
| Clofazimine | Red-brown to black skin pigmentation, ichthyosis; useful in erythema nodosum leprosum |
| Rifampicin | Most bactericidal |
- Type 1 (reversal) reaction: cell-mediated, borderline leprosy, neuritis: steroids. Type 2 (erythema nodosum leprosum): immune complex, lepromatous: steroids, thalidomide, clofazimine. Continue MDT.
Other drugs tested with this chapter
| Question | Answer |
|---|---|
| Mature fetal lungs at 30 weeks | Betamethasone |
| Woman who should not take the combined pill | 37-year-old smoking 20 a day |
| First drug in phaeochromocytoma preparation | Phenoxybenzamine |
| Latanoprost mechanism | Increases uveoscleral outflow |
| Donepezil mechanism | Acetylcholinesterase inhibition |
| Denosumab mechanism | Anti-RANKL antibody |
| Delay a period | Norethisterone |
| Drug never given via the endotracheal tube | Sodium bicarbonate |
| Vasospasm after subarachnoid haemorrhage | Oral nimodipine |
| C. difficile with metronidazole hypersensitivity | Oral vancomycin or fidaxomicin |
Remember Isoniazid kills the fast, rifampicin the bursting, pyrazinamide the acid-sheltered.
How FCPS asks about this
- Standard regimen: 2HRZE then 4HR.
- Red–green colour loss on ATT: ethambutol optic neuritis.
- Isoniazid neuropathy prevention: pyridoxine; overdose seizures need IV pyridoxine gram for gram.
- Gout on ATT: pyrazinamide; orange urine: rifampicin.
- Adrenal crisis after starting ATT in Addison disease: rifampicin speeds cortisol clearance.
- Why combination therapy prevents resistance: double-resistant mutants are very rare.
- Bedaquiline target and toxicity: mycobacterial ATP synthase; QT prolongation.
Test yourself on this topic
5 of the 46 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A man with epilepsy controlled on phenytoin starts isoniazid for tuberculosis. Two weeks later he has nystagmus, ataxia and slurred speech. What explains this?
Answer: Isoniazid inhibits phenytoin metabolism
Isoniazid inhibits cytochrome P450 enzymes (especially CYP2C19 and 2C9) that metabolise phenytoin. Because phenytoin has saturable (zero-order) kinetics, a small fall in metabolism causes a large rise in level and toxicity: nystagmus, ataxia, dysarthria and confusion. The effect is greatest in slow acetylators. Rifampicin, given with isoniazid, induces enzymes and can partly offset this, so levels must be monitored.
Isoniazid interactions
- Isoniazid: enzyme inhibitor
- Raises phenytoin levels
- Worse in slow acetylators
- Rifampicin: enzyme inducer
Remember Isoniazid inhibits; rifampicin induces.
Exam trap Phenytoin's zero-order kinetics magnify small changes in metabolism.
Why the other options are wrong
- Isoniazid induces liver enzymes Rifampicin induces; isoniazid inhibits.
- Isoniazid causes cerebellar degeneration Not a recognised effect.
- Pyridoxine deficiency Causes neuropathy, not this cerebellar picture.
- Phenytoin blocks isoniazid acetylation Not the mechanism.
A patient with decompensated cirrhosis has active pulmonary TB. Which first-line drug is least likely to damage his liver?
Answer: Ethambutol
Isoniazid, rifampicin and pyrazinamide are all hepatotoxic, pyrazinamide the most. Ethambutol is not hepatotoxic (its main problem is optic neuritis, and it is renally excreted). In advanced liver disease, regimens use fewer hepatotoxic drugs, such as ethambutol with a fluoroquinolone and an aminoglycoside, under specialist care.
TB drugs and the liver
- Hepatotoxic: isoniazid, rifampicin, pyrazinamide
- Worst: pyrazinamide
- Liver-safe: ethambutol
- Ethambutol: eyes, renal dosing
Remember Ethambutol spares the liver but watch the eyes.
Exam trap Ethambutol needs dose reduction in kidney failure.
Why the other options are wrong
- Isoniazid Hepatotoxic.
- Rifampicin Hepatotoxic; also causes cholestasis.
- Pyrazinamide Most hepatotoxic of the first-line drugs.
- Rifampicin with isoniazid Both hepatotoxic.
A 58-year-old man on regular haemodialysis is diagnosed with pulmonary TB. Which of the following changes to the standard first-line regimen is most appropriate?
Answer: Ethambutol and PZA three times a week
Isoniazid and rifampicin are cleared mainly by the liver, so their doses do not change in kidney failure. Ethambutol and the metabolites of pyrazinamide are excreted by the kidney and accumulate, so they are given three times a week, after dialysis, at the usual dose rather than a lower daily dose. This keeps peak levels effective while avoiding toxicity. Pyridoxine is given with isoniazid, as neuropathy risk is higher in renal failure.
TB drugs and kidneys
- Liver-cleared: isoniazid, rifampicin
- Kidney-cleared: ethambutol, PZA
- Ethambutol, PZA 3 times a week
- Give after dialysis; add pyridoxine
Remember Keep the dose, stretch the interval.
Exam trap Reducing each daily dose instead of spacing them can give peaks too low to be effective.
Why the other options are wrong
- Halve the daily rifampicin dose Rifampicin is cleared by the liver; no change is needed.
- Omit isoniazid to avoid neuropathy Isoniazid is needed; give pyridoxine to prevent neuropathy.
- Replace pyrazinamide with streptomycin Streptomycin is nephrotoxic and ototoxic and best avoided.
- Give all four drugs on alternate days Isoniazid and rifampicin should still be given daily.
A woman on first-line TB treatment becomes pregnant despite taking the combined oral contraceptive pill, and notices orange urine. Which drug explains both?
Answer: Rifampicin
Rifampicin inhibits bacterial DNA-dependent RNA polymerase. It strongly induces hepatic CYP450 enzymes (CYP3A4 and others), increasing metabolism of oral contraceptives, warfarin, corticosteroids, antiretrovirals, sulphonylureas and others—women need alternative contraception. It turns urine, sweat and tears orange-red (staining contact lenses) and can cause hepatitis and a flu-like syndrome with intermittent dosing. Isoniazid is an enzyme inhibitor (raises phenytoin levels) causing peripheral neuropathy (give pyridoxine) and hepatitis; ethambutol causes optic neuritis (red–green colour loss); pyrazinamide causes hepatotoxicity and hyperuricaemia (gout).
First-line TB drugs
- Rifampicin: CYP inducer, orange secretions, hepatitis
- Isoniazid: neuropathy (give pyridoxine), hepatitis, enzyme inhibitor
- Pyrazinamide: hepatitis, gout
- Ethambutol: optic neuritis (colour vision)
Remember Rifampicin: red urine, ruined pill.
Why the other options are wrong
- Isoniazid Inhibitor; neuropathy.
- Ethambutol Optic neuritis.
- Pyrazinamide Hepatotoxicity, gout.
- Streptomycin Ototoxicity, nephrotoxicity.
A man with HIV on second-line therapy with lopinavir boosted by ritonavir develops drug-sensitive pulmonary TB. Which of the following is preferred in place of rifampicin?
Answer: Rifabutin
Rifampicin is such a strong CYP3A4 inducer that it lowers protease inhibitor levels to ineffective values, even with ritonavir boosting. Rifabutin is a rifamycin with the same sterilising action but much weaker enzyme induction, so it can be given with boosted protease inhibitors. Because ritonavir raises rifabutin levels, its dose is reduced to 150 mg daily, and patients are watched for uveitis and neutropenia. Rifapentine is also a strong inducer.
Rifabutin
- Rifamycin with weak induction
- Used with boosted protease inhibitors
- Ritonavir raises its levels: 150 mg daily
- Watch for uveitis, neutropenia
Remember Protease inhibitor plus TB: swap rifampicin for rifabutin.
Exam trap Without dose reduction, ritonavir raises rifabutin to toxic levels causing uveitis.
Why the other options are wrong
- Rifapentine A strong CYP3A4 inducer, like rifampicin.
- Levofloxacin Would leave the regimen without a rifamycin, reducing cure rates.
- Streptomycin Injectable, toxic and not a rifamycin replacement.
- Ethionamide A second-line drug, not a substitute for a rifamycin.
Where this sits in the CPSP syllabus
- Paper 1: Chemotherapy, Antituberculous and antileprosy drugs
- Medicine & Allied, Paper 2: Antimicrobials, Antituberculous drugs
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