What is the alternative treatment regimen for a patient with extrapulmonary tuberculosis (EPTB) who has experienced drug-induced liver injury (DILI)?

Management of Alternative Treatment Regimen for EPTB After DILI

For patients with extrapulmonary tuberculosis (EPTB) who have experienced drug-induced liver injury (DILI), the recommended approach is to use a regimen of streptomycin and ethambutol initially, followed by sequential reintroduction of first-line drugs with careful monitoring. 1

Initial Management After DILI

• When DILI occurs (defined as AST/ALT >5 times normal or elevated bilirubin), all hepatotoxic drugs (rifampicin, isoniazid, and pyrazinamide) should be stopped immediately 1
• For patients who are unwell or have infectious TB, a non-hepatotoxic regimen consisting of streptomycin and ethambutol should be initiated until liver function normalizes 1
• Streptomycin should be administered at 15 mg/kg daily (maximum 1g) or 25-30 mg/kg two to three times weekly (maximum 1.5g) 2
• Ethambutol should be given at 15-20 mg/kg daily 1, 3

Sequential Reintroduction Protocol

Once liver function tests normalize, the following sequential reintroduction protocol should be implemented with daily monitoring of clinical condition and liver function:

1. First reintroduce isoniazid:

   • Start at 50 mg/day
   • Increase to 300 mg/day after 2-3 days if no reaction occurs 1, 4

2. Then add rifampicin (after 2-3 days of full-dose isoniazid without reaction):

   • Start at 75 mg/day
   • Increase to 300 mg after 2-3 days
   • Further increase to 450 mg (<50 kg) or 600 mg (>50 kg) after another 2-3 days 1, 4

3. Finally add pyrazinamide (if needed):

   • Start at 250 mg/day
   • Increase to 1.0 g after 2-3 days
   • Then to 1.5 g (<50 kg) or 2.0 g (>50 kg) 1

Alternative Regimens Based on Drug Tolerance

If reintroduction of certain drugs causes recurrent hepatotoxicity, the following alternative regimens should be considered:

• If pyrazinamide cannot be tolerated: Use isoniazid, rifampicin, and ethambutol for 2 months, followed by isoniazid and rifampicin for 7 months (total 9 months) 1, 4

• If isoniazid cannot be tolerated: Use rifampicin, ethambutol, and a fluoroquinolone for 12 months 4, 5

• If rifampicin cannot be tolerated: Use isoniazid, ethambutol, pyrazinamide (if tolerated), and a fluoroquinolone for 18-24 months 4, 6

• If all hepatotoxic drugs cannot be tolerated: Use ethambutol, a fluoroquinolone, and streptomycin for 18-24 months 4, 5

Monitoring Protocol During Reintroduction

• Monitor liver function tests weekly for the first 2 weeks after each drug reintroduction 1, 4
• Continue monitoring every 2 weeks for the first 2 months 1, 4
• Educate patients about symptoms of hepatotoxicity (nausea, vomiting, abdominal pain, jaundice) and instruct them to stop medication and seek medical attention if these occur 1
• If liver enzyme values rise again during reintroduction, stop the most recently added hepatotoxic drug 1

Special Considerations for EPTB

• For EPTB, particularly TB meningitis, treatment duration may need to be extended to 9-12 months even with standard regimens 1
• Consider adding corticosteroids for tuberculous pericarditis or meningitis to prevent complications 1
• For disseminated TB and TB meningitis in particular, treatment should be continued for 9-12 months 1

Important Precautions

• Avoid concurrent use of other hepatotoxic medications during treatment 1, 7
• Patients with pre-existing liver disease require more careful monitoring and are at higher risk for recurrent DILI 1, 7
• Fluoroquinolones (levofloxacin or moxifloxacin) can be safely used in patients with DILI as they do not cause additional hepatotoxicity 5
• Streptomycin should be used with caution in pregnant patients due to risk of congenital deafness 1

By following this structured approach to reintroducing anti-TB drugs after DILI, most patients with EPTB can successfully complete their treatment with minimal risk of recurrent hepatotoxicity while ensuring adequate treatment of their tuberculosis infection.