Hepato and Reno Safe Anti-Tubercular Therapy
Most Hepatosafe Options
For patients with hepatic disease or hepatotoxicity, ethambutol and streptomycin are the safest first-line TB medications, as they have no hepatotoxic effects and require no dose adjustment for liver impairment. 1
- Ethambutol can be used safely in patients with hepatic disease without any dose modification 2
- Streptomycin has no documented hepatotoxic effects and is eliminated primarily by the kidneys rather than metabolized by the liver 1
- These two agents serve as the cornerstone for bridge regimens when hepatotoxicity develops during standard therapy 1, 3
Regimens for Patients with Hepatic Disease
Mild to Moderate Liver Disease
Retain rifampin and isoniazid if at all possible, as their efficacy is crucial for treatment success, even in the presence of preexisting liver disease. 2
- Monitor serum aminotransferases and total bilirubin every 1-4 weeks for at least the first 2-3 months 2
- Stop all hepatotoxic drugs immediately if ALT rises ≥5 times upper limit of normal without symptoms, or ≥3 times with hepatitis symptoms 4
Severe or Unstable Liver Disease - Alternative Regimens
Option 1 (Without Pyrazinamide): Isoniazid, rifampin, and ethambutol for 2 months, followed by 7 months of isoniazid and rifampin 2, 3
Option 2 (Without Isoniazid and Pyrazinamide): Rifampin and ethambutol with a fluoroquinolone, injectable agent, or cycloserine for 12-18 months depending on disease extent 2, 4
Option 3 (Without Isoniazid): Rifampin, pyrazinamide, and ethambutol with or without a fluoroquinolone for at least 6 months 2
Option 4 (Minimal Hepatotoxicity): Ethambutol combined with a fluoroquinolone (such as ofloxacin/levofloxacin), cycloserine, and a second-line injectable for 18-24 months 2, 5
- Ofloxacin-based regimens without rifampin have demonstrated equal efficacy to rifampin-based regimens in patients with chronic liver disease, with significantly lower hepatotoxicity rates (0% vs 26.6%) 5
Renal Safe Options
Drugs Safe in Renal Disease
Rifampin, isoniazid, and pyrazinamide require no dose adjustment for renal insufficiency. 2
Drugs Requiring Dose Adjustment
Ethambutol:
- Cleared primarily by kidneys and requires dose/interval adjustment when creatinine clearance <70 ml/minute 2
- For end-stage renal disease: administer 15-20 mg/kg three times weekly after dialysis 2
Streptomycin:
- Dosing frequency should be reduced to 12-15 mg/kg per dose two or three times weekly in renal insufficiency 2
- For hemodialysis patients: administer after dialysis to avoid premature drug removal 2
- Risk of ototoxicity and nephrotoxicity increases with cumulative doses, especially above 100-120 g 2
Ethionamide:
- For creatinine clearance <30 ml/minute or hemodialysis: reduce dose to 250-500 mg/day 2
Critical Management Pitfalls
Hepatotoxicity Monitoring
- Baseline liver function tests are mandatory before initiating hepatotoxic drugs 1
- Screen patients born in Asia/Africa, with injection drug use history, or HIV infection for hepatitis B and C at baseline 2
- Consider twice-weekly monitoring during first 2 weeks, then every 2 weeks during first 2 months for high-risk patients 6
Drug Reintroduction Protocol
When hepatotoxicity occurs and liver function normalizes to <2 times upper limit of normal 4:
- Restart isoniazid at 50 mg/day, increase to 300 mg/day after 2-3 days if no reaction 4, 3
- Add rifampin after 2-3 additional days, starting at 75 mg/day and increasing to full dose after 2-3 days 4, 3
- Consider pyrazinamide last starting at 250 mg/day, but avoid reintroduction if it caused severe hepatotoxicity due to poor prognosis with recurrence 4, 3
Common Errors to Avoid
- Never reintroduce pyrazinamide if it caused severe hepatotoxicity, as recurrence carries a poor prognosis 4
- Avoid using pyrazinamide in patients with baseline liver test abnormalities 6
- Do not use once-weekly isoniazid-rifapentine regimens in HIV patients with CD4 <100/μL due to high relapse rates 4
- Streptomycin should not be used in pregnancy due to documented fetal harm 2