What is the next management step for a patient with end-stage renal disease (ESRD) and smear-positive pulmonary tuberculosis (TB) who developed transaminitis after starting the Ethambutol (EH), Isoniazid (H), Rifampin (R), and Pyrazinamide (Z) (EHrz) regime?

Management of Transaminitis in ESRD Patient with Smear-Positive TB on EHRZ

Stop rifampicin, isoniazid, and pyrazinamide immediately and switch to streptomycin and ethambutol until liver function normalizes, given this patient has infectious (smear-positive) tuberculosis. 1, 2

Immediate Actions

Stop Hepatotoxic Drugs

• Discontinue rifampicin (R), isoniazid (H), and pyrazinamide (Z) immediately when transaminases rise to 5 times the upper limit of normal or if bilirubin increases 1, 2, 3
• Continue ethambutol (E) as it is not hepatotoxic 3

Initiate Non-Hepatotoxic Regimen

• Start streptomycin and ethambutol immediately because the patient is smear-positive (infectious) and requires continuous treatment to prevent disease progression and transmission 1, 2
• This bridging therapy should continue until liver function tests normalize 1
• For non-infectious TB in stable patients, treatment could be withheld until liver recovery, but this patient's smear-positive status mandates ongoing therapy 1

Critical ESRD Considerations

• Adjust streptomycin and ethambutol doses for renal impairment and monitor serum drug concentrations closely 1
• Standard doses of rifampicin, isoniazid, and pyrazinamide can be given in renal impairment, but streptomycin and ethambutol require dose reduction in ESRD 1
• Dialysis affects drug clearance and necessitates dosing modifications 1

Monitoring During Recovery Phase

Liver Function Surveillance

• Monitor liver function tests and clinical condition daily while on streptomycin/ethambutol 1, 2
• Check for symptoms including fever, malaise, vomiting, jaundice, or unexplained deterioration 2
• Consider viral hepatitis testing to exclude coexistent viral causes 4

Renal Function Monitoring

• Monitor renal function closely given baseline ESRD and streptomycin nephrotoxicity risk 5
• Streptomycin can cause additional nephrotoxicity, requiring careful balance in ESRD patients 3

Sequential Drug Reintroduction Protocol

Once transaminases normalize, reintroduce drugs one at a time with 2-3 day intervals to identify the culprit agent. 1, 2

Step 1: Isoniazid Reintroduction

• Start isoniazid at 50 mg/day 1, 2
• Increase to 300 mg/day after 2-3 days if no reaction occurs 1, 2
• Monitor liver function tests and clinical status daily 1, 2
• Continue for 2-3 days at full dose before proceeding 1

Step 2: Rifampicin Reintroduction

• Add rifampicin at 75 mg/day after successful isoniazid reintroduction 1, 2
• Increase to 300 mg after 2-3 days without reaction 1, 2
• Then increase to 450 mg (<50 kg) or 600 mg (>50 kg) after another 2-3 days 1, 2
• Continue daily monitoring 1

Step 3: Pyrazinamide Reintroduction

• Add pyrazinamide at 250 mg/day as the final drug 1, 2
• Increase to 1.0 g after 2-3 days, then to 1.5 g (<50 kg) or 2.0 g (>50 kg) 1
• Pyrazinamide carries the highest risk of severe late-onset hepatotoxicity with poor prognosis 3

Important Reintroduction Caveats

• Never use fixed-dose combination tablets during reintroduction as you cannot identify the specific offending drug 4
• If hepatotoxicity recurs with any drug, permanently exclude that agent and design an alternative regimen 1, 2
• Two patterns of hepatotoxicity exist: early (within 15 days, rifampicin-enhanced isoniazid toxicity with good prognosis) and late (>1 month, likely pyrazinamide-related with poor prognosis) 3

Alternative Regimen if Pyrazinamide Cannot Be Reintroduced

If pyrazinamide is identified as the culprit, treat with rifampicin and isoniazid for 9 months total, with ethambutol for the initial 2 months. 1, 4

• This represents a 3-month extension compared to standard 6-month therapy 4
• The extended duration compensates for loss of pyrazinamide's sterilizing activity 4

High-Risk Context Considerations

ESRD-Specific Risks

• Patients with ESRD have altered drug metabolism and increased toxicity risk 1
• Dialysis timing affects drug levels and requires coordination with dosing 1

Smear-Positive Status

• Infectious patients require continuous effective therapy to prevent transmission 1
• Treatment interruption risks disease progression and development of drug resistance 6
• Never allow a patient to receive monotherapy or inadequate therapy, as this promotes resistance 6, 7

Common Pitfalls to Avoid

• Do not continue all three hepatotoxic drugs at reduced doses – complete cessation is required when transaminases reach 5x normal 1, 3
• Do not reintroduce multiple drugs simultaneously – sequential reintroduction is essential to identify the offending agent 1, 4
• Do not withhold treatment in smear-positive patients – use non-hepatotoxic alternatives during recovery 1
• Do not use standard doses of streptomycin/ethambutol in ESRD – dose adjustment and monitoring are mandatory 1
• Do not ignore the possibility that pyrazinamide may be the culprit – late-onset pyrazinamide hepatotoxicity has worse prognosis than early isoniazid/rifampicin toxicity 3