What is the recommended treatment regimen for a patient with drug-resistant tuberculosis (TB), specifically the BPaLM (Bedaquiline, Pretomanid, Linezolid, Moxifloxacin) regimen?

BPaLM Regimen for Drug-Resistant Tuberculosis

The BPaLM regimen (Bedaquiline, Pretomanid, Linezolid 600 mg daily, and Moxifloxacin) for 6 months (26 weeks) is the preferred first-line treatment for adults with multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) who have fluoroquinolone-susceptible disease and no prior exposure (>30 days) to the component drugs. 1, 2

Core Regimen Components and Duration

BPaLM consists of four drugs administered for 26 weeks total:

• Bedaquiline: 400 mg daily for 2 weeks, then 200 mg three times weekly for 24 weeks 2
• Pretomanid: 200 mg daily for 26 weeks 3
• Linezolid: 600 mg daily for 26 weeks (preferred dose based on superior risk-benefit ratio) 1, 4
• Moxifloxacin: Standard daily dosing for 26 weeks 1

The 26-week duration should be completed within an overall period of 7 months to account for any necessary missed doses. 1

Patient Eligibility Criteria

Eligible patients include:

• Adults with pulmonary MDR/RR-TB or pre-XDR TB (fluoroquinolone-susceptible) 1, 2
• People living with HIV (HIV status does not preclude use) 1, 2
• Patients with extensive pulmonary disease (requires close monitoring) 2
• Patients with low BMI <17 (requires close monitoring) 2
• No prior exposure exceeding 30 days to bedaquiline, pretomanid, or linezolid 1, 2

Absolute contraindications:

• Age <14 years (no safety data on pretomanid in children) 1
• Pregnancy or breastfeeding (no safety data on pretomanid) 1
• Known resistance to bedaquiline, pretomanid, or linezolid 1, 3
• Central nervous system TB, osteoarticular TB, or disseminated (miliary) TB 1

Relative contraindications requiring alternative regimens:

• Hemoglobin <7 g/dL or platelets <75,000/mm³ (linezolid's myelosuppressive effects) 2
• Pre-existing Grade III-IV peripheral neuropathy (linezolid's neurotoxicity) 2

Fluoroquinolone Resistance Management

If fluoroquinolone resistance is detected after starting BPaLM, immediately switch to BPaL (without moxifloxacin) and extend total treatment duration to 9 months (39 weeks). 1, 2 Do not delay treatment initiation waiting for fluoroquinolone susceptibility results—start BPaLM empirically and adjust based on drug susceptibility testing. 2

For pre-XDR TB with known fluoroquinolone resistance from the start, use BPaL (without moxifloxacin) for 9 months rather than BPaLM. 1, 2

Linezolid Dosing and Toxicity Management

The 600 mg daily dose for 26 weeks is strongly preferred over 1200 mg daily based on the ZeNix trial, which demonstrated:

• Similar efficacy (91% favorable outcomes with 600 mg vs 93% with 1200 mg) 4
• Significantly reduced peripheral neuropathy (24% vs 38%) 4
• Reduced myelosuppression (2% vs 22%) 4
• Fewer dose modifications required (13% vs 51%) 4

If linezolid toxicity develops, dose reduction to 300 mg daily is acceptable to mitigate toxicity while maintaining efficacy. 1, 5 A structured dose reduction strategy (600 mg for 9-13 weeks followed by 300 mg for the remainder) shows equivalent efficacy with reduced peripheral neuropathy. 5

If linezolid must be discontinued entirely due to severe toxicity:

• Continue bedaquiline, pretomanid, and moxifloxacin (if fluoroquinolone-susceptible) 6
• Extend total treatment duration to 9 months (39 weeks) 6
• For fluoroquinolone-resistant cases (BPaL without moxifloxacin), consider adding clofazimine to create a BPaLC-like regimen 6

Critical Monitoring Requirements

Baseline assessments must include:

• ECG with QTc interval measurement 2, 3
• Complete blood count with differential 2, 3
• Comprehensive metabolic panel including liver function tests 2
• Electrolytes (potassium, magnesium, calcium) 2
• Visual acuity and color vision testing 2, 3
• Peripheral neuropathy assessment 2, 3

During treatment monitoring:

• Cardiac: ECG at weeks 2,4,8,12, then monthly; discontinue bedaquiline if QTcF >500 ms 2
• Hematologic: Monthly complete blood counts for myelosuppression 2
• Hepatic: Monthly liver function tests (AST, ALT, bilirubin, alkaline phosphatase) 2
• Neurologic: Weekly symptom monitoring for peripheral neuropathy (numbness, tingling, pain in extremities) 2, 3
• Ophthalmologic: Monthly visual acuity and color vision screening; immediate ophthalmology referral for any visual symptoms 2, 3
• Microbiologic: Sputum smear and culture at months 2,4, and 6 6

Correct hypokalemia, hypomagnesemia, and hypocalcemia before and during treatment to prevent QTc prolongation. 2

Superiority Over Alternative Regimens

BPaLM is preferred over:

• The 9-month all-oral regimen (with ethionamide or linezolid variations) due to more treatment success, fewer failures/recurrences, and less emerging drug resistance 1
• 18-month longer individualized regimens for eligible patients 1
• BPaLC (with clofazimine instead of moxifloxacin) due to increased pill burden, skin discoloration, and no noticeable benefits 1

The TB-PRACTECAL trial demonstrated that among 6-month BPaL-based regimens, BPaLM led to the best outcomes with little difference in adverse events compared to BPaL or BPaLC. 1

Administration Requirements

All doses must be administered with food and under directly observed therapy (DOT). 3 Doses missed for safety reasons can be made up at the end of treatment, but doses of linezolid alone missed due to linezolid adverse reactions should not be made up. 3

When to Switch to Longer Regimens

Switch to an 18-20 month individualized regimen if:

• Confirmed resistance to bedaquiline, pretomanid, or linezolid develops 1
• Sputum cultures remain positive or clinical response is poor despite continuing the shortened regimen 6
• Multiple drug intolerances prevent adequate short-course therapy 6
• Patient has CNS, osteoarticular, or disseminated (miliary) TB 1

Common Pitfalls to Avoid

Do not delay BPaLM initiation waiting for fluoroquinolone susceptibility results—start empirically and adjust to BPaL if resistance is documented. 2

Do not use 1200 mg linezolid daily—the 600 mg dose has superior risk-benefit ratio with equivalent efficacy and significantly fewer adverse events. 1, 4

Do not automatically abandon the entire regimen if linezolid must be stopped—the remaining drugs (bedaquiline, pretomanid, moxifloxacin) still provide substantial efficacy when extended to 9 months. 6

Do not use BPaLM in children <14 years, pregnant/breastfeeding women, or patients with CNS/osteoarticular/miliary TB—these populations require alternative regimens due to lack of safety data on pretomanid. 1

**Prior brief exposure (<30 days) to component drugs is not a contraindication**—only exposure >30 days requires ruling out resistance before proceeding. 1, 2

Counsel patients that linezolid-induced peripheral neuropathy may be permanent—78% of patients experience irreversible symptoms at 12 months after completing treatment. 6