What are the treatment regimens for Multi-Drug Resistant (MDR) Tuberculosis (TB) and Extensively Drug-Resistant (XDR) TB?

Treatment Regimens for MDR-TB and XDR-TB

For MDR-TB and XDR-TB treatment, an all-oral regimen containing bedaquiline, a later-generation fluoroquinolone, and linezolid should be used as the core drugs, with additional agents added based on drug susceptibility testing to ensure at least 4-5 effective drugs. 1

MDR-TB Treatment Regimen

Core Components

• Group A drugs (include all three when possible):
  • Bedaquiline (strong recommendation) 1
  • Levofloxacin or moxifloxacin (strong recommendation) 1
  • Linezolid (strong recommendation) [1, conditional recommendation in ATS guidelines] 1

Additional Drugs

• Group B drugs (add one or both):

  • Clofazimine (conditional recommendation) 1
  • Cycloserine or terizidone (conditional recommendation) 1

• Group C drugs (add to complete regimen when Group A and B cannot provide at least 4 effective drugs):

  • Ethambutol (conditional recommendation) 1
  • Delamanid (conditional recommendation for patients ≥3 years) 1
  • Pyrazinamide (conditional recommendation when susceptibility confirmed) 1
  • Imipenem-cilastatin or meropenem with amoxicillin-clavulanate 1
  • Ethionamide or prothionamide (conditional recommendation against if more effective drugs available) 1
  • p-aminosalicylic acid (conditional recommendation against if more effective drugs available) 1

Drugs NOT Recommended

• Kanamycin and capreomycin (conditional recommendation against) 1
• Amoxicillin-clavulanate alone (strong recommendation against) 1
• Macrolides (azithromycin, clarithromycin) (strong recommendation against) 1

Duration of Treatment

Standard MDR-TB

• Total treatment duration: 15-21 months after culture conversion 1
• Intensive phase: 5-7 months after culture conversion 1

XDR-TB

• Total treatment duration: 15-24 months after culture conversion 1
• Intensive phase: typically longer than standard MDR-TB 1

Shorter MDR-TB Regimen Option

For eligible patients (without fluoroquinolone resistance, extensive disease, or prior second-line drug exposure >1 month), a 6-month all-oral regimen may be considered:

• Intensive phase (4-6 months):

  • Bedaquiline (6 months)
  • Levofloxacin/moxifloxacin
  • Clofazimine
  • Pyrazinamide
  • Ethambutol
  • High-dose isoniazid
  • Ethionamide 1

• Continuation phase (5 months):

  • Levofloxacin/moxifloxacin
  • Clofazimine
  • Pyrazinamide
  • Ethambutol 1

Recent evidence from the NExT study supports the efficacy of an all-oral 6-month regimen containing bedaquiline, levofloxacin, and linezolid for MDR-TB, showing 2.2 times higher likelihood of favorable outcomes compared to injectable-containing regimens 2.

XDR-TB Treatment Approach

XDR-TB requires more complex regimens with:

• All available Group A drugs
• Both Group B drugs
• Additional Group C drugs to ensure at least 5 effective drugs 1
• Consider carbapenems (imipenem-cilastatin or meropenem with amoxicillin-clavulanate) 1
• Longer treatment duration (15-24 months after culture conversion) 1

Monitoring and Management

• Monthly bacteriological monitoring during the first 4-6 months
• Regular assessment for adverse effects, particularly:
  • QT interval prolongation with bedaquiline and fluoroquinolones
  • Myelosuppression, peripheral neuropathy, and optic neuritis with linezolid
  • Hearing loss with injectable agents (if used)
  • Hepatotoxicity with multiple agents

Common Pitfalls and Caveats

1. Inadequate number of effective drugs: Always ensure at least 4-5 likely effective drugs in the regimen to prevent treatment failure and development of additional resistance 3.

2. Ignoring drug susceptibility testing: Precision treatment guided by DST optimizes outcomes and minimizes resistance amplification 4.

3. Inappropriate use of injectable agents: Modern MDR-TB treatment favors all-oral regimens, as injectable agents are associated with significant toxicity and poorer outcomes 2.

4. Inadequate monitoring: Regular clinical, bacteriological, and adverse event monitoring is essential for successful outcomes.

5. Poor adherence support: Comprehensive patient support is critical for treatment success in these lengthy, complex regimens.

6. Delayed treatment initiation: Early diagnosis and prompt initiation of appropriate therapy are crucial to prevent disease progression and transmission 5.

The evidence strongly supports the use of newer all-oral regimens containing bedaquiline, a later-generation fluoroquinolone, and linezolid as the cornerstone of MDR-TB and XDR-TB treatment, with additional drugs added based on susceptibility testing and patient-specific factors to ensure optimal outcomes.