What is the proper use and dosage of Pyrazinamide (PZA) in the treatment of tuberculosis (TB)?

Pyrazinamide Dosing for Tuberculosis Treatment

Standard Dosing for Drug-Susceptible TB

For drug-susceptible tuberculosis, pyrazinamide should be administered at 15-30 mg/kg orally once daily (maximum 2 g/day) for the initial 2 months of a 6-month treatment regimen, always in combination with other effective antituberculous drugs. 1

Daily Dosing Regimen

• Adults: 15-30 mg/kg once daily, with a maximum of 2 g per day when given as daily dosing 1, 2
• Children: 30-40 mg/kg once daily 2
• The CDC and American Thoracic Society recommend once-daily dosing over the older divided-dose regimens 1

Twice-Weekly Dosing (Alternative)

• Adults: 50-70 mg/kg twice weekly based on lean body weight 1, 2
• Children: 50-70 mg/kg twice weekly 1
• This regimen was developed to promote outpatient compliance, though doses may exceed 3 g per administration without reported increased adverse reactions 1

Recent Evidence on Optimal Dosing

The most recent high-quality evidence from a 2024 phase 3 randomized controlled trial (the largest to date) suggests that flat dosing of pyrazinamide at 1,000 mg daily would optimize treatment outcomes better than current weight-banded dosing. 3 This study of 2,255 participants found that:

• Flat dosing at 1,000 mg/day would permit an additional 13.1% of participants to achieve therapeutic drug levels compared to weight-banded dosing 3
• The therapeutic window for optimal efficacy and safety was 231-355 mg·h/L 3
• Body weight was not a clinically relevant predictor of drug clearance, challenging the rationale for weight-banded dosing 3

Dosing for Multidrug-Resistant TB (MDR-TB)

For MDR-TB, pyrazinamide should be included in the regimen at 25-40 mg/kg daily for adults and 30-40 mg/kg daily for children, but only when the isolate is documented to be susceptible to pyrazinamide. 2

Critical Caveat for MDR-TB

• Pyrazinamide resistance is highly associated with rifampin resistance, occurring in a substantial proportion of MDR-TB cases 2
• Drug susceptibility testing (DST) by whole genome sequencing, molecular tests, or traditional DST is essential before including pyrazinamide in MDR-TB regimens 2
• Pyrazinamide is only effective when the isolate is susceptible—using it against resistant strains provides no benefit and may compromise the regimen 2

Evidence Supporting Use in MDR-TB

• A propensity score-matched analysis of 1,986 individuals showed that pyrazinamide use in susceptible isolates was associated with significantly better outcomes (aOR 1.6,95% CI 1.3-2.1 for cure/complete versus failure/relapse/death) 2
• However, mortality may increase if only four likely effective drugs are used when pyrazinamide is not effective (adjusted HR 2.76,95% CI 0.92-8.27) 4

MDR-TB Dosing by Weight (2017 Research)

For patients with MDR-TB and documented susceptibility, pharmacokinetic modeling suggests:

• 33-50 kg: 1,500 mg daily 5
• 51-70 kg: 1,750 mg daily 5
• >70 kg: 2,000 mg daily 5

Dose Adjustments for Renal Impairment

Patients with reduced renal function should receive pyrazinamide three times weekly rather than daily. 2

• The specific dose per administration remains 25-40 mg/kg, but frequency is reduced to allow for drug clearance 2
• For patients on hemodialysis, administer after dialysis sessions 2

Pharmacokinetic Considerations

Absorption and Distribution

• Oral absorption is nearly complete, with peak serum concentrations of 30-50 mg/ml occurring approximately 2 hours after ingestion of 20-25 mg/kg doses 2
• Pyrazinamide penetrates well into cerebrospinal fluid, making it valuable for tuberculous meningitis 2

Factors Affecting Exposure

• More than 50% of patients weighing less than 55 kg achieve lower pyrazinamide exposures than targeted with standard weight-banded dosing 5
• Clearance increases by 14% from day 1 to day 29 of treatment 5
• Pyrazinamide displays sevenfold exposure variability (151-1,053 mg·h/L) among patients 3

Drug Interactions

• No known interactions exist between pyrazinamide and antiretroviral medications, making it safe for HIV/TB coinfected patients 2
• Patients with HIV coinfection may require longer treatment courses 1

Mechanism of Action and Efficacy

Pyrazinamide is bactericidal for M. tuberculosis in acidic environments (pH 5.5), with activity primarily against organisms within macrophages. 2

• The drug has substantial sterilizing activity that allows treatment shortening in drug-susceptible TB 2
• It is synergistic with novel and existing TB drugs 6
• Higher pyrazinamide concentrations are associated with shorter time to culture conversion and higher probability of 2-month culture conversion 6

Limitations of Dose Escalation

• While efficacy increases with drug concentration, very high doses (>4,500 mg) would be required to achieve targets for further treatment shortening 6
• Doses of 40-70 mg/kg were found too toxic in human studies despite effectiveness in animal models 2
• Optimizing pyrazinamide alone is unlikely to shorten treatment duration; rifampin dose would need to be increased in parallel 6

Safety Profile and Adverse Effects

Common Adverse Effects

• Gastrointestinal upset is the most common side effect 2, 1
• Hyperuricemia occurs frequently but acute gout is uncommon 2
• Nongouty polyarthralgias can occur 2

Hepatotoxicity

• Hepatic enzyme elevations are common, but significant hepatotoxicity is less common 2
• Serious adverse events occurred in 2.8% of patients (56 of 2,023) in a recent review 2
• No substantial increase in hepatotoxicity results from adding 15-30 mg/kg pyrazinamide to rifampin during 2 months of therapy 2
• In the 2024 phase 3 trial, liver toxicity was rare (3.9% with grade 3 or higher liver function tests), with no relationship between pyrazinamide exposure and liver enzyme levels 6

Safety Monitoring

• Baseline liver function tests should be obtained 2
• Monitor for symptoms of hepatotoxicity, particularly in the first 2 months 2
• Hypersensitivity reactions can occur and require drug discontinuation 2

Critical Clinical Pitfalls to Avoid

1. Never use pyrazinamide as monotherapy—it must always be combined with other effective antituberculous drugs 1

2. Do not assume pyrazinamide is effective in MDR-TB without susceptibility testing—resistance is common in rifampin-resistant strains 2

3. Do not count pyrazinamide as one of the "likely effective drugs" in MDR-TB regimens unless susceptibility is documented—this may lead to inadequate treatment and increased mortality 4

4. Avoid exceeding 2 g/day with daily dosing regimens to minimize toxicity risk 1

5. Do not use standard daily dosing in patients with renal impairment—switch to three times weekly dosing 2

6. Be alert for gout flares in patients with prior gouty arthritis history 2

Special Populations

Pregnancy

• Pyrazinamide is part of standard TB treatment regimens and can be used in pregnancy when indicated 1
• The benefits of treating active TB typically outweigh theoretical risks 1

HIV Coinfection

• Standard dosing applies, with no dose adjustment needed 2
• Treatment duration may need to be extended beyond 6 months 1
• No drug interactions with antiretroviral medications 2

Children

• Higher weight-adjusted doses (30-40 mg/kg) are recommended compared to adults 2
• Pharmacokinetic data suggest children may require higher doses to achieve adult-equivalent exposures 5