What is the recommended dose of pyrazinamide for adults?

Pyrazinamide Dosing for Adults

For adults with drug-susceptible tuberculosis, pyrazinamide should be dosed at 15-30 mg/kg once daily (maximum 2 g/day) using weight-banded dosing: 1,000 mg for 40-55 kg, 1,500 mg for 56-75 kg, and 2,000 mg for 76-90 kg, administered for the initial 2 months only as part of a multi-drug regimen. 1, 2, 3

Standard Daily Dosing Regimen

Weight-banded dosing is the preferred approach:

• 40-55 kg: 1,000 mg daily (18.2-25.0 mg/kg) 1, 2
• 56-75 kg: 1,500 mg daily (20.0-26.8 mg/kg) 1, 2
• 76-90 kg: 2,000 mg daily (22.2-26.3 mg/kg) 1, 2

The CDC and FDA explicitly state that 2 grams per day should not be exceeded when using daily dosing, even though 3 grams per day is the absolute maximum 1, 3. This weight-banded approach ensures adequate drug exposure while minimizing toxicity 2.

Intermittent Dosing Options

For twice-weekly directly observed therapy (DOT):

• 40-55 kg: 2,000 mg (36.4-50.0 mg/kg) 1, 2
• 56-75 kg: 3,000 mg (40.0-53.6 mg/kg) 1, 2
• 76-90 kg: 4,000 mg (44.4-52.6 mg/kg) 1, 2

For thrice-weekly dosing:

• 40-55 kg: 1,500 mg (27.3-37.5 mg/kg) 2
• 56-75 kg: 2,500 mg (33.3-44.6 mg/kg) 2
• 76-90 kg: 3,000 mg (33.3-39.5 mg/kg) 2

The twice-weekly regimen is based on 50-70 mg/kg dosing and has been developed specifically to promote outpatient compliance 1, 3. However, daily dosing is strongly preferred over intermittent dosing for HIV-infected patients with low CD4 counts due to higher treatment failure rates with twice-weekly regimens 2.

Duration of Therapy

Pyrazinamide must be administered for the initial 2 months only of a 6-month treatment regimen for drug-susceptible tuberculosis 1, 2, 3. This applies even when the total treatment duration is extended to 9 months for patients with cavitation on initial chest radiograph and positive cultures at 2 months—pyrazinamide is still discontinued after 2 months 2.

Drug-Resistant Tuberculosis Dosing

For multidrug-resistant tuberculosis (MDR-TB), higher doses may be used throughout the treatment course:

• 25-40 mg/kg daily for adults 1
• 30-40 mg/kg daily for children 1
• Three times weekly dosing is an option in renal insufficiency 1

Recent pharmacokinetic data suggest that MDR-TB patients may benefit from weight-banded dosing of 1,500 mg (33-50 kg), 1,750 mg (51-70 kg), and 2,000 mg (>70 kg) to achieve optimal drug exposure 4.

Critical Monitoring Requirements

Baseline laboratory assessment must include:

• Aspartate transaminase (AST) 1
• Alanine transaminase (ALT) 1
• Bilirubin 1
• Alkaline phosphatase 1
• Serum creatinine 1
• Platelet count 1

Monthly monitoring is required for:

• Adherence assessment 2
• Adverse effects 2
• Liver function tests in patients with chronic liver disease 2

Pyrazinamide must be stopped immediately if:

• Liver function tests rise to 5 times normal 2
• Bilirubin rises significantly 2

Dose Adjustments in Special Populations

Renal insufficiency:

• Creatinine clearance <10 mL/min: 50-100% of full dose daily 1
• Hemodialysis: 25-30 mg/kg after dialysis 1
• Three times weekly dosing may be used for MDR-TB patients with decreased renal function 1

HIV coinfection:

• Use the same dosing as HIV-negative patients 2
• Consider rifabutin-based regimens when using protease inhibitors or NNRTIs 2
• Strongly prefer daily over intermittent dosing for patients with low CD4 counts 2

Common Pitfalls to Avoid

Patients at the upper end of weight bands should receive the higher dose to ensure adequate drug exposure 2. For example, a 74 kg patient should receive 2,000 mg daily rather than 1,500 mg 2.

Do not continue pyrazinamide beyond 2 months in drug-susceptible TB, even when extending total treatment duration 2. This is a critical error that increases toxicity without improving efficacy 1, 2.

Do not use fixed-dose combination tablets for patients weighing >90 kg without adding additional pyrazinamide tablets to achieve adequate dosing 2.

Avoid underdosing in patients <55 kg, as more than 50% of these patients achieve subtherapeutic exposures with standard dosing 4. Consider adding 400 mg to the dose for patients weighing 30-54 kg 4.

Evidence on Hepatotoxicity Concerns

The historical fear of pyrazinamide hepatotoxicity at standard doses is not supported by modern evidence. Hepatotoxicity rates are similar between pyrazinamide-containing regimens (4.4%) and non-pyrazinamide regimens (4.0%) 5. Meta-analysis demonstrates hepatotoxicity frequencies of 4.2% at 30 mg/kg, 5.5% at 40 mg/kg, and 9.8% at 60 mg/kg, with much of this toxicity being idiosyncratic rather than dose-dependent 5.

Arthralgia is dose-dependent with daily dosing (occurring in up to 40% of patients) but is less common with intermittent dosing and rarely requires drug discontinuation 1, 5. This adverse effect responds to aspirin or other NSAIDs 1.

Mandatory Combination Therapy

Pyrazinamide must always be administered with other effective antituberculosis drugs, typically in combination with isoniazid, rifampin, and ethambutol 1, 2, 3. Monotherapy is never appropriate and leads to rapid emergence of resistance within 2-3 weeks 6.