What is the recommended all‑oral six‑month BPaLM regimen for a patient aged 14 years or older with confirmed multidrug‑resistant or rifampicin‑resistant tuberculosis who is fluoroquinolone‑susceptible and has not previously received bedaquiline, pretomanid (or delamanid) or linezolid?

BPaLM Regimen for Fluoroquinolone-Susceptible MDR/RR-TB in Patients ≥14 Years

For a patient aged 14 years or older with confirmed multidrug-resistant or rifampicin-resistant tuberculosis who is fluoroquinolone-susceptible and has not previously received bedaquiline, pretomanid, or linezolid for more than 30 days, the recommended treatment is the 6-month BPaLM regimen: bedaquiline, pretomanid 200 mg daily, linezolid 600 mg daily, and moxifloxacin, administered for 26 weeks (6 months) under directly observed therapy. 1, 2

Regimen Composition and Dosing

The BPaLM regimen consists of four drugs administered for exactly 26 weeks (6 months): 1, 2

• Bedaquiline: 400 mg orally once daily for 2 weeks, then 200 mg three times weekly (with at least 48 hours between doses) for 24 weeks 2
• Pretomanid: 200 mg orally once daily for 26 weeks, taken with food 2
• Linezolid: 600 mg orally once daily for 26 weeks (preferred dose; 1200 mg daily is an alternative but carries higher toxicity risk) 1, 2
• Moxifloxacin: Standard dose for 26 weeks 1

All doses must be administered with food and under directly observed therapy (DOT). 2

Why BPaLM Is the Preferred First-Line Option

BPaLM is superior to all alternative regimens for eligible patients. Compared to the 9-month all-oral regimen, BPaLM demonstrates more treatment success, fewer failures and recurrences, and less emerging drug resistance. 1 Compared to 18-month individualized regimens, BPaLM offers dramatically shorter duration with comparable or superior efficacy. 1 The TB-PRACTECAL trial demonstrated that BPaLM reduced unfavorable outcomes to 12% versus 41% with standard care (risk difference -29.2 percentage points, p<0.0001), establishing both non-inferiority and superiority. 3

Eligibility Confirmation Checklist

Before initiating BPaLM, verify the following criteria are met: 1, 4, 2

• Age ≥14 years (pretomanid safety data unavailable in younger children) 1, 4, 2
• Fluoroquinolone-susceptible disease (if resistance detected after starting, switch to BPaL without moxifloxacin for 9 months total) 1, 4
• No prior exposure >30 days to bedaquiline, pretomanid, or linezolid (brief exposure <30 days is acceptable) 1, 4
• Not pregnant or breastfeeding (pretomanid contraindicated due to lack of safety data) 1, 4, 2
• No central nervous system, miliary, or osteoarticular tuberculosis (absolute contraindications requiring 18-month individualized regimen) 1, 4

Important clarifications: Extensive pulmonary disease with cavitation is NOT a contraindication—BPaLM can be used but requires close monitoring. 1, 4 HIV-positive status does NOT preclude BPaLM use. 1 Low BMI (<17) is acceptable with enhanced monitoring. 1

Baseline Assessment Requirements

Before starting BPaLM, obtain: 1, 4

• ECG (baseline and repeat at weeks 2,12, and 24 minimum) to monitor QTc prolongation from bedaquiline and moxifloxacin 1, 4
• Complete blood count (monthly monitoring for linezolid-induced myelosuppression) 1, 4
• Liver function tests (AST, ALT, bilirubin, alkaline phosphatase at baseline, monthly, and if symptomatic) 1, 4
• Electrolytes (potassium, magnesium, calcium—correct abnormalities before starting) 1, 4
• Visual acuity and peripheral neuropathy assessment (linezolid toxicity monitoring) 1, 4
• Comprehensive drug susceptibility testing for fluoroquinolones and all second-line drugs (strongly encouraged but should NOT delay treatment initiation) 1, 4

Critical Monitoring During Treatment

Cardiac Monitoring

• Weekly ECG in high-risk patients (those on other QTc-prolonging drugs, baseline QTc >450 ms, electrolyte abnormalities) 1
• Discontinue entire regimen if QTcF >500 ms or clinically significant ventricular arrhythmia develops 1
• Correct electrolyte abnormalities promptly as they potentiate QTc prolongation 1

Hematologic Monitoring

• Monthly complete blood counts to detect linezolid-induced anemia, thrombocytopenia, or neutropenia 1, 4
• If significant myelosuppression develops, reduce linezolid to 300 mg daily (acceptable dose reduction that maintains efficacy) 1, 4

Hepatotoxicity Monitoring

• Monthly liver function tests for all patients; increase to weekly or bi-weekly if baseline transaminases elevated or other hepatotoxic drugs co-administered 1
• Stop bedaquiline if aminotransferases exceed 8× upper limit of normal (ULN) OR if aminotransferases exceed 3× ULN AND total bilirubin exceeds 2× ULN (Hy's Law criteria) 1

Neurologic Monitoring

• Monthly assessment for peripheral neuropathy (numbness, tingling, pain in extremities) and optic neuropathy (visual changes) 1, 4
• Obtain ophthalmologic evaluation if any visual impairment symptoms develop 1
• If neuropathy develops, reduce linezolid to 300 mg daily or interrupt dosing 1, 2

Microbiologic Monitoring

• Monthly sputum cultures throughout the 26-week regimen, even after culture conversion, to detect treatment failure or relapse 1, 4

Management of Treatment Modifications

If Fluoroquinolone Resistance Detected After Starting BPaLM

• Immediately stop moxifloxacin and continue with BPaL (bedaquiline, pretomanid, linezolid only) 1, 4
• Extend total treatment duration to 9 months (39 weeks) 1, 4

If Linezolid Toxicity Develops

• Reduce linezolid to 300 mg daily to mitigate toxicity while maintaining efficacy 1, 4
• If toxicity is severe and linezolid must be discontinued entirely, continue bedaquiline, pretomanid, and moxifloxacin and extend treatment to 9 months total 5

Missed Doses

• Doses missed for safety reasons (adverse events) can be made up at the end of treatment 2
• Doses of linezolid alone missed due to linezolid adverse reactions should NOT be made up 2
• The 26-week duration should be completed within an overall period of 7 months to account for missed doses 6, 1

When to Switch to Alternative Regimens

Switch from BPaLM to an 18-20 month individualized regimen if: 1, 4

• Confirmed resistance to bedaquiline, pretomanid, or linezolid develops 1, 4
• Sputum cultures remain positive or clinical response is poor despite adherent therapy 1
• Severe intolerance to multiple component drugs prevents adequate short-course therapy 1
• Patient has CNS, osteoarticular, or disseminated (miliary) TB (these are absolute contraindications to BPaLM from the start) 1, 4

Common Pitfalls to Avoid

• Do NOT delay BPaLM waiting for fluoroquinolone susceptibility results—start empirically and switch to BPaL if resistance is documented 1, 4
• Do NOT extend BPaLM beyond 6 months—if response is inadequate, switch to an 18-20 month individualized regimen rather than prolonging BPaLM 1, 4
• Do NOT add or remove drugs from the BPaLM regimen—it is a fixed combination studied as a specific package 4
• Do NOT use BPaLM in children <14 years—opt for the 9-month all-oral regimen instead 6, 1, 4
• Do NOT use ethionamide-containing regimens when BPaLM is available and appropriate—BPaLM is superior 1
• Do NOT assume extensive cavitary disease is a contraindication—it is eligible for BPaLM with close monitoring 1, 4

Alternative Regimens (When BPaLM Cannot Be Used)

If BPaLM is contraindicated or not tolerated, the hierarchy of alternatives is: 4

1. BPaL (6-9 months) for pre-XDR TB (fluoroquinolone-resistant) 1, 4
2. 9-month all-oral regimen (bedaquiline, linezolid/ethionamide, fluoroquinolone, clofazimine, pyrazinamide, ethambutol, high-dose isoniazid) for patients without prior second-line drug exposure 6, 4
3. 18-20 month individualized regimen based on WHO drug grouping (Groups A, B, C) when shorter regimens cannot be used 6, 4