What is the recommended treatment regimen for Multi-Drug Resistant (MDR) tuberculosis (TB)?

MDR-Tuberculosis Treatment

For MDR-TB without fluoroquinolone resistance, use a shorter all-oral bedaquiline-containing regimen of 9-12 months duration in eligible patients; for those with fluoroquinolone resistance or who don't qualify for the shorter regimen, use a longer regimen (15-21 months after culture conversion) containing all three Group A agents (levofloxacin or moxifloxacin, bedaquiline, and linezolid) plus at least one Group B agent to ensure at least four effective drugs. 1, 2, 3

Treatment Regimen Selection Algorithm

First-Line Approach: Shorter All-Oral Regimen (9-12 months)

Use this regimen if ALL of the following criteria are met:

• Confirmed MDR/RR-TB with no fluoroquinolone resistance 1
• No previous exposure to second-line TB medicines for >1 month 1
• No extensive pulmonary disease or severe extrapulmonary TB 2

This shorter bedaquiline-containing regimen represents a major advance, reducing treatment duration by nearly half compared to traditional longer regimens while maintaining efficacy. 1

Second-Line Approach: Longer Regimen (15-21 months after culture conversion)

Use this regimen if the patient does NOT qualify for the shorter regimen above.

Core Drug Selection (Group A - ALL THREE must be included):

1. Levofloxacin or moxifloxacin (later-generation fluoroquinolone) - Strong recommendation 1, 2, 3
2. Bedaquiline - Strong recommendation for adults ≥18 years; conditional for ages 6-17 years 1, 2, 3
3. Linezolid - Strong recommendation 1, 2, 3

Critical point: The WHO explicitly states all three Group A agents must be used together to ensure at least four effective drugs and prevent resistance development. Using fewer than three Group A agents violates current guidelines and risks treatment failure. 3

Additional Drugs (Group B - add at least ONE):

• Clofazimine (conditional recommendation) 1
• Cycloserine or terizidone (conditional recommendation) 1, 2

Supplementary Drugs (Group C - add if needed to reach 4-5 total drugs):

• Ethambutol (if susceptibility confirmed) 1, 2
• Delamanid (for ages ≥3 years, conditional recommendation) 1, 2
• Pyrazinamide (if susceptibility confirmed) 2
• Imipenem-cilastatin or meropenem (always with amoxicillin-clavulanate, never alone) 2
• Amikacin or streptomycin (only if susceptibility confirmed and oral options limited) 2
• p-aminosalicylic acid (only if more effective drugs unavailable) 2

Special Case: Fluoroquinolone-Resistant MDR-TB (Pre-XDR)

BPaL Regimen (6-9 months):

• Bedaquiline + Pretomanid + Linezolid 1
• Use only under operational research conditions 1
• Patient must have no previous exposure to bedaquiline and linezolid for >2 weeks 1
• Treatment duration: 15-24 months after culture conversion for pre-XDR/XDR-TB 2

Treatment Duration Specifics

Intensive Phase:

• 5-7 months after culture conversion 2

Total Duration:

• 15-21 months after culture conversion for standard MDR-TB 2
• 15-24 months after culture conversion for pre-XDR/XDR-TB 2

Drugs That Should NOT Be Used

Explicitly NOT recommended:

• Kanamycin and capreomycin - Strong recommendation against use 1, 2
• Macrolides (azithromycin, clarithromycin) 2
• Amoxicillin-clavulanate alone (only use with carbapenems) 2
• Ethionamide/prothionamide (if more effective drugs available) 2

The shift away from injectable aminoglycosides (kanamycin, capreomycin) represents a major change from older guidelines, driven by their high toxicity and inferior efficacy compared to newer oral agents. 1

Essential Monitoring Requirements

Baseline Assessment:

• ECG for QTc interval (bedaquiline and fluoroquinolones prolong QTc) 3
• Electrolytes (potassium, magnesium, calcium) - correct before starting treatment 3
• Complete blood count (linezolid causes myelosuppression) 3
• Visual acuity and color vision (linezolid causes optic neuropathy) 3
• Sputum culture (monthly cultures strongly recommended to monitor response) 1

Ongoing Monitoring:

• ECG monitoring: At 2,4,8, and 12 weeks, then monthly 3
  • Action threshold: QTcF >500 msec or increase to 450-500 msec 3
• Monthly visual screening for optic neuropathy (numbness, tingling, visual changes) 3
• Monthly sputum cultures (strong recommendation) 1
• Linezolid toxicity monitoring: Assess for peripheral neuropathy; consider dose reduction to 300 mg daily if toxicity develops 3

HIV Co-infection Management

Start antiretroviral therapy (ART) in ALL HIV-positive MDR-TB patients:

• Timing: As early as possible within the first 8 weeks of TB treatment 1
• CD4 count: Irrelevant - treat regardless of CD4 count 1
• Strong recommendation despite very low-quality evidence 1

Adjunctive Measures

Surgical Intervention:

• Elective partial lung resection (lobectomy or wedge resection) may be used alongside MDR-TB regimen 1
• Conditional recommendation with very low certainty 1

Patient Support (Strong Recommendations):

• Health education and counseling on disease and adherence 1
• Material support to patients (conditional, moderate certainty) 1
• Psychological support (conditional, low certainty) 1
• Digital medication monitoring/tracers (conditional, very low certainty) 1

Critical Pitfalls to Avoid

1. Using fewer than four effective drugs in the intensive phase - violates WHO guidelines and risks treatment failure 2, 3
2. Omitting any Group A agent when using longer regimens - all three (fluoroquinolone, bedaquiline, linezolid) must be included 3
3. Delaying bedaquiline addition - increases resistance risk 3
4. Insufficient treatment duration (<15 months after culture conversion) 2
5. Inadequate linezolid toxicity monitoring - can lead to irreversible peripheral neuropathy or optic neuropathy 3
6. Missing QTc prolongation - potentially fatal cardiac arrhythmias 3
7. Using kanamycin or capreomycin - explicitly not recommended in current guidelines 1, 2
8. Accepting intermittent dosing - all MDR-TB treatment must be daily and directly observed 4