Pyrazinamide
PZA — pyrazine analogue of nicotinamide
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Active tuberculosis — initial intensive phase | Adults and children | Combination therapy (first 2 months of standard 6-month regimen) | FDA Approved |
| Drug-resistant TB | Adults and children | Component of individualized multi-drug regimen | FDA Approved |
Pyrazinamide is a uniquely sterilising agent that targets semi-dormant M. tuberculosis organisms residing in the acidic intracellular environment of macrophages. Its inclusion in the intensive phase was the key innovation that allowed the standard TB treatment regimen to be shortened from 9–12 months to 6 months. Pyrazinamide is always used in combination with other first-line agents (isoniazid, rifampin, ethambutol) and is typically discontinued after the initial 2-month intensive phase.
Multidrug-resistant TB (MDR-TB): Frequently included in longer individualized MDR-TB regimens when susceptibility is confirmed or suspected. Evidence quality: High (WHO guidelines).
Dosing
Adult Weight-Based Dosing (ATS/CDC/IDSA)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Active TB intensive phase — daily (40–55 kg) | 1000 mg once daily | 1000 mg once daily | 2000 mg/day | Part of 4-drug regimen for 2 months Dose based on lean body weight |
| Active TB intensive phase — daily (56–75 kg) | 1500 mg once daily | 1500 mg once daily | 2000 mg/day | Most common weight band Can be given as 3 × 500 mg tablets |
| Active TB intensive phase — daily (76–90 kg) | 2000 mg once daily | 2000 mg once daily | 2000 mg/day | Max daily dose per CDC FDA PI allows up to 3000 mg/day |
| Active TB — twice-weekly DOT (40–55 kg) | 2000 mg twice weekly | 2000 mg twice weekly | 4000 mg/dose | Only under DOT; not for HIV or cavitary disease Use only after completing 2-week daily intensive phase |
| Active TB — twice-weekly DOT (56–75 kg) | 3000 mg twice weekly | 3000 mg twice weekly | 4000 mg/dose | Higher individual doses compensate for intermittent schedule |
| Active TB — twice-weekly DOT (76–90 kg) | 4000 mg twice weekly | 4000 mg twice weekly | 4000 mg/dose | Max twice-weekly dose per ATS/CDC/IDSA |
| Active TB — three-times-weekly DOT (56–75 kg) | 2500 mg 3×/week | 2500 mg 3×/week | 3000 mg/dose | Alternative intermittent schedule under DOT |
| End-stage renal disease / hemodialysis | 25–35 mg/kg 3×/week | 25–35 mg/kg 3×/week | Per weight band | Administer after dialysis sessions PZA is dialysable |
Pediatric Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Active TB intensive phase — daily (<40 kg) | 30–40 mg/kg once daily | 30–40 mg/kg once daily | 2000 mg/day | ATS/CDC/IDSA recommended range; duration 2 months AAP recommends 20–40 mg/kg; FDA PI: 15–30 mg/kg |
| Active TB — twice-weekly DOT (<40 kg) | 50 mg/kg twice weekly | 50 mg/kg twice weekly | 2000 mg/dose | Only under directly observed therapy |
Pyrazinamide is used exclusively during the initial 2-month intensive phase and then discontinued. It is NOT continued into the continuation phase. Extending pyrazinamide beyond 2 months does not improve outcomes but increases cumulative hepatotoxicity risk. The exception is drug-resistant TB, where PZA may be used for longer durations as part of an individualised regimen under specialist guidance.
Pharmacology
Mechanism of Action
The precise mechanism of pyrazinamide’s antimycobacterial activity is not fully elucidated. It functions as a prodrug: mycobacterial pyrazinamidase (encoded by the pncA gene) converts pyrazinamide to its active form, pyrazinoic acid (POA). POA accumulates in the acidic intracellular environment of activated macrophages, where it disrupts mycobacterial membrane energetics and inhibits fatty acid synthase I, impairing mycolic acid synthesis. Pyrazinamide is uniquely active against semi-dormant, slowly metabolising bacilli in acidic conditions, which explains its critical sterilising role during the intensive phase. Resistance arises primarily through mutations in the pncA gene, reducing pyrazinamidase activity and preventing prodrug conversion. M. bovis is naturally resistant to pyrazinamide due to a pncA polymorphism.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Well absorbed orally; Tmax ~2 h; Cmax 30–50 mcg/mL at 20–25 mg/kg | Can be taken with or without food; no clinically significant food effect reported in the PI |
| Distribution | Widely distributed to liver, lungs, and CSF; ~10% protein bound; CSF levels ≈ plasma (inflamed meninges) | Excellent CNS penetration makes PZA valuable in TB meningitis regimens. Freely enters macrophages where acidic conditions activate the drug. |
| Metabolism | Hepatic hydrolysis by microsomal deaminase to pyrazinoic acid (POA); POA hydroxylated by xanthine oxidase to 5-hydroxypyrazinoic acid | POA competitively inhibits renal tubular urate secretion, causing dose-dependent hyperuricemia in nearly all patients. Xanthine oxidase involvement links PZA metabolism to uric acid handling. |
| Elimination | Primarily renal; ~4% excreted unchanged, ~70% as metabolites; t½ 9–10 h | Half-life may be prolonged in renal or hepatic impairment. Drug is dialysable; administer post-dialysis for ESRD patients. |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hyperuricemia (asymptomatic) | 43–100% | Nearly universal at therapeutic doses; caused by pyrazinoic acid inhibiting renal tubular urate secretion. Usually asymptomatic and reversible on discontinuation. Does not require treatment unless symptomatic gout develops. |
| Arthralgia / myalgia | ~20–40% | Non-gouty joint pain is common, especially with daily dosing; usually mild and manageable with NSAIDs. Distinguish from true gout by absence of monosodium urate crystals. |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nausea / vomiting / anorexia | 1–5% | GI intolerance may overlap with symptoms from other TB drugs in the regimen |
| Hepatotoxicity (elevated transaminases) | ~4–6% | Dose-related; can appear at any time during the 2-month course. PZA is considered the most hepatotoxic of the first-line TB drugs at a population level. |
| Gout (acute gouty arthritis) | ~1–5% | Secondary to hyperuricemia; more likely in patients with pre-existing gout or renal impairment. Manage with NSAIDs or colchicine; avoid allopurinol acutely. |
| Rash / urticaria / pruritus | 1–3% | Hypersensitivity reaction; discontinue if severe |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Severe hepatitis / fulminant liver failure | ~1–2% (in combination regimens) | Any time during 2-month course; may occur early | Discontinue immediately if ALT >3× ULN with symptoms or >5× ULN without symptoms. PZA was identified as the principal hepatotoxin in the now-abandoned 2-month RIF+PZA LTBI regimen. |
| Thrombocytopenia | Rare | Variable | Check CBC urgently; discontinue if confirmed |
| Sideroblastic anemia | Rare | Weeks | Discontinue; consider pyridoxine supplementation; haematology referral |
| Interstitial nephritis | Rare | Variable | Discontinue; renal consultation; supportive care |
| Photosensitivity | Rare | Days to weeks of sun exposure | Sun protection; consider discontinuation if severe |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Hepatotoxicity | ~1–3% | Usually occurs within the 2-month course; attribution can be difficult in multi-drug regimens |
| Intolerable arthralgia / gout | <1% | Rarely requires discontinuation; usually manageable with analgesics |
Asymptomatic hyperuricemia does not require treatment or PZA discontinuation. If acute gouty arthritis develops, manage with NSAIDs or colchicine. Allopurinol or febuxostat can be used if gout is recurrent, but they may have limited efficacy against PZA-induced hyperuricemia because the primary mechanism involves inhibition of renal urate secretion rather than overproduction. Uric acid levels return to baseline within weeks of PZA discontinuation at the end of the 2-month intensive phase.
Drug Interactions
Pyrazinamide has a relatively narrow drug interaction profile compared to rifampin or isoniazid. It is not a significant CYP450 inducer or inhibitor. The principal interactions relate to its effects on uric acid metabolism and additive hepatotoxicity with other hepatotoxic agents.
Monitoring
- Hepatic Enzymes (ALT, AST)Baseline; every 2–4 weeks during PZA therapy
RoutinePZA is the most hepatotoxic first-line TB drug. Obtain baseline LFTs for all patients. Patients with pre-existing liver disease, alcohol use, or HIV should have LFTs checked every 2 weeks during the 2-month course. Hold all hepatotoxic TB drugs if ALT >3× ULN with symptoms or >5× ULN without symptoms. - Serum Uric AcidBaseline; periodically during therapy
RoutineHyperuricemia is expected in nearly all patients. Routine monitoring allows early detection of extreme elevations. Clinical intervention is only needed if symptomatic gout develops. Levels normalise after PZA discontinuation. - Clinical Symptom ReviewMonthly (at minimum)
RoutineAsk about anorexia, nausea, vomiting, dark urine, jaundice, abdominal pain, joint pain, and rash at each visit. - Joint SymptomsAt each visit
Trigger-basedDistinguish between PZA-associated non-gouty arthralgia (common, mild, bilateral) and acute gout (sudden, severe, monoarticular). If gout is suspected, aspirate joint for crystal analysis when feasible. - Sputum CulturesBaseline and monthly until conversion
RoutineConfirm susceptibility including PZA susceptibility testing. Persistent culture positivity at 2 months warrants reassessment.
Contraindications & Cautions
Absolute Contraindications
- Severe hepatic damage (FDA PI)
- Known hypersensitivity to pyrazinamide
- Acute gout (FDA PI)
Relative Contraindications (Specialist Input Recommended)
- Chronic liver disease or active hepatitis: Use only under close supervision with frequent LFT monitoring if PZA is essential to the regimen
- History of gout: Risk of flare; consider prophylactic colchicine or NSAID; ensure uric acid monitoring
- Concurrent hepatotoxic drugs: Additive liver toxicity risk with isoniazid, rifampin, alcohol, methotrexate
- Pregnancy: ATS/CDC/IDSA state that routine use is not recommended in pregnancy, but benefits may outweigh unquantified risks in some situations
Use with Caution
- Renal impairment: Select doses at the lower end of the range; administer post-dialysis in ESRD
- Elderly patients: Start at low end of dosing range; higher risk of hepatotoxicity and hyperuricemia complications
- Diabetes mellitus: PZA may interfere with urine ketone testing (Acetest/Ketostix); use alternative methods
- Porphyria: Rare exacerbation has been reported
Hepatotoxicity is the principal adverse effect of pyrazinamide. It appears to be dose-related and may occur at any time during therapy. Patients should have baseline hepatic enzyme determinations before initiating PZA. Those with pre-existing liver disease or increased risk of drug-related hepatitis (including alcohol users) should receive frequent liver function monitoring. Discontinue PZA if evidence of significant hepatic damage develops.
Patient Counselling
Purpose of Therapy
Pyrazinamide is one of four antibiotics used together to treat tuberculosis. It works best in the first 2 months of treatment by killing TB bacteria that are hiding inside your cells. After 2 months, your doctor will stop pyrazinamide but you will continue taking other TB medicines for several more months.
How to Take
Take pyrazinamide once daily with or without food, as directed by your doctor. Swallow the tablets whole with water. Complete the full 2-month course even if you feel better.
Sources
- Pyrazinamide Tablets, USP prescribing information. Various manufacturers. Drugs.com PIPrimary regulatory source for approved indications, dosing, contraindications, adverse reactions, and PK data used throughout this monograph.
- DailyMed. Pyrazinamide tablet — drug label information. National Library of Medicine. DailyMedSupplementary FDA label source for generic pyrazinamide formulations.
- Pasipanodya JG, Gumbo T. Clinical and toxicodynamic evidence that high-dose pyrazinamide is not more hepatotoxic than the low doses currently used. Antimicrob Agents Chemother. 2010;54(7):2847–2854. DOIMeta-analysis and pharmacodynamic study demonstrating that PZA hepatotoxicity rates are similar across dose ranges, and arthralgia is dose-dependent.
- Jasmer RM, Saukkonen JJ, Blumberg HM, et al. Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection. Ann Intern Med. 2002;137(8):640–647. DOIStudy contributing to the evidence base that led to withdrawal of the 2-month RIF+PZA LTBI regimen due to unacceptable hepatotoxicity.
- Nahid P, Dorman SE, Alipanah N, et al. Official ATS/CDC/IDSA clinical practice guidelines: treatment of drug-susceptible tuberculosis. Clin Infect Dis. 2016;63(7):e147–e195. DOIComprehensive active TB treatment guidelines providing weight-band dosing tables for PZA in daily and intermittent regimens.
- Saukkonen JJ, Cohn DL, Jasmer RM, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006;174(8):935–952. DOIATS consensus on monitoring, risk factors, and management of anti-TB hepatotoxicity, including PZA-specific guidance.
- CDC. Update: Fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection. MMWR. 2001;50(34):733–735. CDCCDC safety alert documenting fatal hepatitis cases that led to withdrawal of the 2-month RIF+PZA LTBI regimen.
- Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J Tuberc Lung Dis. 2003;7(1):6–21. PubMedComprehensive review of PZA’s unique mechanism of action in acidic environments and the role of pncA mutations in resistance.
- LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Pyrazinamide. NIDDK, 2020. NCBINIH resource on PZA hepatotoxicity patterns, severity spectrum, and comparison to other first-line TB drugs.
- Savic RM, Weiner M, Mac Kenzie WR, et al. Pyrazinamide safety, efficacy, and dosing for treating drug-susceptible pulmonary tuberculosis. Am J Respir Crit Care Med. 2024. DOIPhase 3 PK/PD analysis from S31/A5349 evaluating PZA exposure-response relationships and proposing optimised dosing strategies.
- Stamathakis G, Montes C, Trouvin JH, et al. Pyrazinamide and pyrazinoic acid pharmacokinetics in patients with chronic renal failure. Clin Nephrol. 1988;30(4):230–234. PubMedPK study in renal impairment supporting post-dialysis dosing recommendations for ESRD patients.