What is the management of a Pyrazinamide (PZA) reaction in a patient with tuberculosis (TB)?

Management of Pyrazinamide Reactions in Tuberculosis

When a patient develops a drug reaction to pyrazinamide, immediately stop the suspected medication(s), monitor liver function until normalized, then sequentially reintroduce drugs one by one to identify the offending agent, and if pyrazinamide is confirmed as the culprit, continue treatment with rifampicin and isoniazid for 9 months supplemented with ethambutol for the initial 2 months. 1

Immediate Management Based on Reaction Type

Hepatotoxicity

• Stop rifampicin, isoniazid, and pyrazinamide immediately if liver enzymes (AST/ALT) rise to five times normal or if bilirubin increases. 1, 2
• Continue treatment with non-hepatotoxic drugs (streptomycin and ethambutol) if the patient has infectious TB or is clinically unwell, until liver function normalizes. 1
• Monitor for symptoms including fever, malaise, vomiting, jaundice, or unexplained deterioration. 1, 2
• Consider viral hepatitis testing to exclude coexistent viral causes. 1

Hypersensitivity/Rash

• For mild reactions, provide symptomatic relief and consider restarting medications sequentially. 1
• For severe reactions like Stevens-Johnson syndrome, immediately stop all medications until symptoms completely resolve. 1
• Note that allergic reactions to pyrazinamide are rare and should be distinguished from flushing, which is more common. 3

Hyperuricemia and Gout

• Isolated increases in uric acid without symptoms of gout are common (occurring in 84.5% of patients) and are NOT an indication to discontinue pyrazinamide. 4, 5
• Hyperuricemia can be managed by observation alone in most cases. 5
• Only 9.29% of patients require drugs for uric acid control. 5
• Clinical gout flares can occur, especially in those with prior gouty arthritis history, and may warrant drug discontinuation. 4
• Nongouty polyarthralgias can occur but are uncommon (4.42% of patients). 5

Sequential Drug Reintroduction Protocol

Once liver function normalizes, reintroduce drugs sequentially with daily monitoring of clinical condition and liver function: 1, 2

1. Isoniazid first:

   • Start at 50 mg/day
   • Increase to 300 mg/day after 2-3 days if no reaction occurs
   • Continue for 2-3 more days without reaction before adding the next drug 1, 2

2. Rifampicin second:

   • Start at 75 mg/day
   • Increase to 300 mg after 2-3 days
   • Further increase to weight-appropriate dose after 2-3 more days 1, 2

3. Pyrazinamide last:

   • Start at 250 mg/day
   • Increase to 1.0 g after 2-3 days
   • Further increase to weight-appropriate dose 1, 2

If a reaction recurs during reintroduction, the most recently added drug is the offending agent and should be permanently excluded. 1

Alternative Regimens When Pyrazinamide Must Be Excluded

If pyrazinamide cannot be used due to confirmed adverse reaction, treat with rifampicin and isoniazid for 9 months, supplemented with ethambutol for the initial 2 months. 1

This represents a 3-month extension of therapy compared to the standard 6-month regimen, as pyrazinamide's sterilizing activity allows for treatment shortening in drug-susceptible TB. 4

Monitoring During Pyrazinamide Therapy

All patients receiving pyrazinamide should be monitored carefully for signs or symptoms of hepatotoxicity, with dose held or decreased if toxicity is detected. 4

• Hepatic enzyme elevations are common with pyrazinamide. 4
• Serious adverse events occur in approximately 2.8% of patients receiving pyrazinamide. 4
• The most common adverse effect is gastrointestinal upset or intolerance. 4

Critical Pitfalls to Avoid

• Do not discontinue pyrazinamide for asymptomatic hyperuricemia alone - this is expected and clinically insignificant in most cases. 4, 5
• Do not reintroduce all drugs simultaneously - sequential reintroduction is essential to identify the specific offending agent. 1, 2
• Do not use combined drug preparations (Rifater) during reintroduction - individual drugs must be given separately to identify the culprit. 1
• Do not assume pyrazinamide is the cause without proper rechallenge - hepatotoxicity may be due to isoniazid or rifampicin, which are more commonly hepatotoxic. 1, 2