Can the BPaLM regimen (bedaquiline, pretomanid, linezolid, moxifloxacin) be used to treat multidrug‑resistant or extensively drug‑resistant tuberculosis in a patient with liver cirrhosis, and what are the appropriate dosing and monitoring recommendations for compensated (Child‑Pugh A/B) versus decompensated (Child‑Pugh C) disease?

BPaLM for TB with Liver Cirrhosis

BPaLM can be used in patients with compensated cirrhosis (Child-Pugh A or B) but must be avoided in decompensated cirrhosis (Child-Pugh C), with intensive hepatic monitoring required throughout treatment. 1

Eligibility Based on Hepatic Function

Compensated Cirrhosis (Child-Pugh A/B)

• Bedaquiline is approved for use in mild to moderate hepatic impairment without dose adjustment 1
• The complete BPaLM regimen may proceed if the patient meets all other eligibility criteria: age ≥14 years, fluoroquinolone-susceptible MDR/RR-TB, no prior exposure >30 days to bedaquiline/pretomanid/linezolid, and absence of CNS/miliary/osteoarticular TB 2
• Moxifloxacin, pretomanid, and linezolid have no specific hepatic contraindications in Child-Pugh A/B disease, though data are limited 3

Decompensated Cirrhosis (Child-Pugh C)

• Bedaquiline should be avoided in severe hepatic impairment 1
• Alternative regimens must be considered: switch to an 18-20 month individualized regimen using drugs with safer hepatic profiles, such as fluoroquinolones, cycloserine, and clofazimine, avoiding bedaquiline entirely 4

Dosing Recommendations

Standard BPaLM Dosing (No Adjustment for Child-Pugh A/B)

• Bedaquiline: 400 mg once daily for 2 weeks, then 200 mg three times weekly for 22 weeks, taken with food 1
• Pretomanid: 200 mg once daily for 26 weeks 2
• Linezolid: 600 mg once daily for 26 weeks (preferred over 1200 mg due to superior risk-benefit ratio) 2, 5
• Moxifloxacin: standard dosing for 26 weeks 2

Critical Dosing Caveat

• No dose reduction is recommended for bedaquiline in Child-Pugh A/B; instead, intensify monitoring 1
• If linezolid toxicity develops (myelosuppression, neuropathy), dose reduction to 300 mg daily is acceptable and maintains efficacy 2, 5

Hepatotoxicity Monitoring Protocol

Baseline Assessment

• Obtain AST, ALT, total bilirubin, alkaline phosphatase, albumin, and INR to establish Child-Pugh score and baseline hepatic function 1
• Screen for viral hepatitis (HBV, HCV) and advise strict alcohol avoidance 1

Ongoing Monitoring in Cirrhosis

• Monthly liver function tests are mandatory; increase frequency to weekly or biweekly if baseline transaminases are elevated or if other hepatotoxic drugs are co-administered 1
• Repeat testing within 48 hours if AST/ALT rise >3× upper limit of normal (ULN) 1
• Assess for clinical hepatotoxicity weekly: fatigue, anorexia, nausea, jaundice, dark urine, right upper quadrant tenderness, or hepatomegaly 1

Thresholds for Bedaquiline Discontinuation

• Aminotransferases >8× ULN alone 1
• Aminotransferases >3× ULN plus total bilirubin >2× ULN (Hy's Law criteria) 1
• Any clinical signs of hepatic decompensation: new ascites, encephalopathy, or variceal bleeding 1

Additional Monitoring Requirements

Cardiac Surveillance

• Baseline ECG and repeat at weeks 2,12, and 24 minimum; bedaquiline and moxifloxacin both prolong QTc 1, 2
• Correct electrolyte abnormalities (potassium, magnesium, calcium) before and during treatment, as cirrhosis predisposes to hypokalemia and hypomagnesemia 1
• Discontinue bedaquiline if QTcF >500 ms or clinically significant arrhythmia develops 2

Hematologic and Neurologic Monitoring

• Monthly complete blood count to detect linezolid-induced myelosuppression (anemia, thrombocytopenia) 2, 5
• Monthly peripheral neuropathy assessment (numbness, tingling, pain in extremities) and visual acuity testing for optic neuropathy 2, 5

Microbiologic Monitoring

• Monthly sputum culture throughout treatment, even after culture conversion, to detect treatment failure or relapse 1

Common Pitfalls and How to Avoid Them

Pitfall 1: Using BPaLM in Child-Pugh C Disease

• Solution: Confirm Child-Pugh score before initiating therapy; if score is ≥10 (Class C), select an alternative regimen without bedaquiline 1

Pitfall 2: Inadequate Hepatic Monitoring Frequency

• Solution: In cirrhosis, monthly monitoring is insufficient; escalate to biweekly or weekly LFTs, especially during the first 8 weeks when bedaquiline loading occurs 1

Pitfall 3: Continuing Bedaquiline Despite Hy's Law Criteria

• Solution: Immediately discontinue bedaquiline if ALT/AST >3× ULN with bilirubin >2× ULN; switch to an 18-20 month individualized regimen 1, 4

Pitfall 4: Polypharmacy-Induced Hepatotoxicity

• Solution: Avoid concomitant hepatotoxic drugs (alcohol, acetaminophen, statins, azoles); if unavoidable, increase LFT monitoring to weekly 1

Pitfall 5: Ignoring Drug-Drug Interactions via CYP3A4

• Solution: Bedaquiline is metabolized by CYP3A4; avoid rifamycins and strong CYP3A4 inducers/inhibitors unless therapeutic drug monitoring is available 1, 3

When to Switch to an Alternative Regimen

Indications for Regimen Change

• Development of Child-Pugh C disease during treatment 1
• Hepatotoxicity meeting discontinuation criteria (see above) 1
• Fluoroquinolone resistance detected after starting BPaLM: switch to BPaL (without moxifloxacin) for 9 months total 2, 4
• Resistance to bedaquiline, pretomanid, or linezolid confirmed: switch to 18-20 month individualized regimen 2, 4

Alternative Regimen Construction

• Use Group A drugs (levofloxacin, linezolid if tolerated) plus Group B drugs (clofazimine, cycloserine) to achieve ≥4 effective drugs in the intensive phase 4
• Avoid injectable aminoglycosides unless no oral alternatives exist, due to nephrotoxicity risk in cirrhosis 4

Treatment Duration and Completion

• BPaLM duration is fixed at 6 months (26 weeks) and must not be extended; if treatment response is inadequate, switch to an 18-20 month regimen rather than prolonging BPaLM 2, 4
• Directly observed therapy (DOT) is mandatory for all doses to ensure adherence and prevent acquired resistance 1
• Do not discontinue early even after culture conversion; complete the full 26-week course unless toxicity mandates a switch 1, 2