A 45-year-old man on rifampicin, isoniazid, pyrazinamide, and ethambutol for TB develops jaundice with elevated transaminases (ALT 5× ULN). Peripheral eosinophilia and rash are absent. After stopping all anti-TB drugs, which drug should be reintroduced first during sequential rechallenge?

• A Ethambutol
• B Isoniazid
• C Pyrazinamide
• D Rifampicin ✓

Explanation

ATS/IDSA guidelines recommend reintroducing rifampicin first during rechallenge after drug-induced hepatitis because it is the least hepatotoxic of the first-line drugs and is the most potent sterilizing agent. Rifampicin is reintroduced on day 1, followed by isoniazid on day 3, then pyrazinamide on day 6-7 if transaminases remain stable. Pyrazinamide is the most hepatotoxic.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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