Which anti-tuberculosis medications should be stopped in the presence of icteric sclerae?

Management of Icteric Sclerae During Anti-Tuberculosis Treatment

When icteric sclerae (jaundice) develops during anti-tuberculosis treatment, immediately stop all three hepatotoxic drugs: isoniazid, rifampicin, and pyrazinamide. 1

Immediate Actions

• Stop rifampicin, isoniazid, and pyrazinamide immediately when jaundice appears, as this represents clinically significant hepatotoxicity requiring urgent intervention 1, 2

• Continue treatment with non-hepatotoxic alternatives (ethambutol, streptomycin, fluoroquinolones, or injectable agents like amikacin/kanamycin/capreomycin) if the patient has infectious tuberculosis or is clinically unwell 1, 2

• For non-infectious forms in stable patients, treatment can be suspended until liver function normalizes 1, 2

Diagnostic Workup

• Obtain serum aminotransferases (AST/ALT) and bilirubin levels to confirm hepatotoxicity 1

• Perform serologic testing for hepatitis viruses A, B, and C if not done at baseline 1

• Investigate non-drug etiologies including viral hepatitis, biliary tract disease, alcohol use, and other hepatotoxic medications 1

Sequential Drug Reintroduction Protocol

Once AST/ALT decreases to less than two times the upper limit of normal and symptoms significantly improve, reintroduce drugs sequentially with daily monitoring: 1, 3, 4, 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 before adding next drug 4, 2

2. Rifampicin second: Start at 75 mg/day, increase to 300 mg after 2-3 days, then to full weight-appropriate dose (450-600 mg) after another 2-3 days 4, 2

3. Pyrazinamide last: Start at 250 mg/day, increase to 1.0 g after 2-3 days, then to full weight-appropriate dose 4, 2

• Monitor liver function tests and clinical symptoms daily during reintroduction 3, 4, 2

• If hepatotoxicity recurs, the most recently added drug is the culprit and should be permanently excluded 4, 2

Alternative Regimens When Drugs Cannot Be Reintroduced

• If pyrazinamide is excluded: Use isoniazid, rifampin, and ethambutol for 2 months, followed by 7-9 months of isoniazid and rifampin 3, 4, 2

• If both isoniazid and pyrazinamide cannot be used: Use rifampin and ethambutol with a fluoroquinolone, injectable agent, or cycloserine for 12-18 months depending on disease extent 3

• If rifampicin must be excluded: Treatment duration extends to at least 12 months with alternative agents 4

Critical Pitfalls to Avoid

• Never restart all three hepatotoxic drugs simultaneously after hepatotoxicity—this prevents identification of the offending agent and risks severe recurrent liver injury 4, 2

• Do not use pyrazinamide in patients with pre-existing liver disease due to higher risk of severe hepatotoxicity with poor prognosis 5

• Rifampicin should not be discontinued for minor side effects given its critical efficacy, but jaundice mandates immediate cessation 1, 3

• Patients with chronic liver disease, alcohol use, or viral hepatitis require more intensive monitoring throughout treatment 3, 2

Monitoring During Treatment Continuation

• Weekly liver function tests for two weeks, then biweekly for the first two months in patients with known chronic liver disease 1, 2

• For patients without pre-existing liver disease, routine monitoring is not required after successful reintroduction, but repeat testing immediately if symptoms develop 1, 2

• Educate patients to report fever, malaise, vomiting, jaundice, or unexplained deterioration immediately 1, 2