What are the newer guidelines for treating Multi-Drug Resistant (MDR) Tuberculosis (TB) and Extensively Drug-Resistant (XDR) TB, including the BPaLM (Bedaquiline, Pretomanid, Linezolid, Moxifloxacin) regimen?

Updated Guidelines for MDR/XDR TB Treatment: BPaLM Regimen

The 6-month BPaLM regimen (Bedaquiline, Pretomanid, Linezolid, and Moxifloxacin) is now the preferred treatment for MDR/RR-TB, with the BPaL regimen (without moxifloxacin) recommended for pre-XDR TB with fluoroquinolone resistance. 1, 2

Current Treatment Recommendations for MDR/RR-TB

First-Line Regimen: BPaLM (6 months)

• Composition:

  • Bedaquiline: 400 mg once daily for 2 weeks, followed by 200 mg three times weekly
  • Pretomanid: 200 mg once daily
  • Linezolid: 600 mg once daily (preferred dosage)
  • Moxifloxacin: standard dose daily 1, 3

• Efficacy:

  • Superior treatment outcomes (89% favorable outcomes vs. 51% with standard care)
  • Significantly fewer adverse events (25% vs. 60% with standard care) 2
  • Recent real-world data shows 95.3% treatment success in non-trial settings 4

For Pre-XDR TB (Fluoroquinolone-resistant):

• BPaL regimen (without moxifloxacin)
• Real-world data shows 90.4% treatment success for pre-XDR TB patients treated with BPaL plus clofazimine 4

Alternative Regimens:

1. 9-month all-oral bedaquiline-containing regimen (second option for MDR/RR-TB without fluoroquinolone resistance)

   • 83% favorable outcomes vs. 71% with injectable-containing regimens
   • Significantly less hearing loss (2% vs. 9%) 2

2. Longer individualized 18-month regimens (for XDR-TB or when shorter regimens cannot be used) 2, 1

Patient Selection Criteria

BPaLM/BPaL Regimens Are Indicated For:

• MDR/RR-TB patients (BPaLM)
• Pre-XDR TB patients (fluoroquinolone-resistant) (BPaL)
• Extensive pulmonary TB
• Most extrapulmonary TB (except CNS, miliary, and osteoarticular TB)
• People living with HIV 2, 1

BPaLM/BPaL Regimens Are NOT Appropriate For:

• Extensively drug-resistant TB
• Children under 14 years of age
• Pregnant or breastfeeding women
• TB involving the central nervous system, miliary TB, or osteoarticular TB
• Prior exposure (>1 month) to bedaquiline, pretomanid, or linezolid unless resistance is ruled out 2, 1, 3

Monitoring and Management of Adverse Events

Key Adverse Events to Monitor:

• Linezolid-related:

  • Peripheral neuropathy (up to 81% of patients)
  • Myelosuppression (48% of patients) 2, 5
  • Consider dose reduction to 300 mg if toxicity develops 1

• Hepatotoxicity:

  • Monitor liver function tests regularly
  • Interrupt entire regimen if evidence of liver injury occurs 3

• QT prolongation:

  • Regular ECG monitoring required
  • Discontinue regimen if QTcF interval >500 ms or significant ventricular arrhythmia develops 1, 3

Risk Mitigation:

• Patients with BMI <17 require close monitoring
• Those with pre-existing peripheral neuropathy (grade III-IV) or low hemoglobin/platelet counts may benefit from alternative regimens 2
• Recent research suggests 600 mg linezolid dosing has fewer adverse events than 1200 mg dosing (22% vs. 35% grade 3-4 adverse events) 5

Implementation Considerations

Administration Requirements:

• Must be administered by directly observed therapy (DOT)
• Take with food
• Complete 26 weeks of prescribed doses within 7 months
• If resistance to any component is confirmed, switch to longer individualized regimen 1, 3

Emerging Research:

• Ongoing research is exploring modifications to reduce toxicity while maintaining efficacy
• Potential alternatives include replacing linezolid with inhaled spectinamides to reduce adverse events 6
• Model-based simulations suggest comparable efficacy with alternative bedaquiline (200 mg daily) and linezolid (600 mg daily) dosing 7

Common Pitfalls and Caveats

• Missed doses: Avoid missed doses; those missed for safety reasons can be made up at the end of treatment 3
• Drug interactions: Avoid concomitant use with CYP3A4 inducers (e.g., efavirenz, rifampin) 3
• Monitoring requirements: Regular monitoring of complete blood counts, liver function, visual function, and ECGs is essential 1, 3
• Resistance development: If resistance to bedaquiline, linezolid, or pretomanid is confirmed or suspected, stop the BPaLM/BPaL regimen and switch to longer individualized regimen 1

The BPaLM/BPaL regimens represent a significant advancement in MDR/RR-TB treatment, offering shorter duration, all-oral administration, and improved outcomes compared to previous standards of care.