What is the first line treatment for Multi-Drug Resistant (MDR) Tuberculosis (TB)?

First-Line Treatment for Multidrug-Resistant Tuberculosis

The first-line treatment for MDR-TB consists of an individualized regimen containing at least five effective drugs in the intensive phase, with bedaquiline and a later-generation fluoroquinolone (levofloxacin or moxifloxacin) as core agents, supplemented with additional drugs based on susceptibility testing. 1

Core Drug Components

The foundation of MDR-TB treatment requires:

• Later-generation fluoroquinolones (levofloxacin or moxifloxacin) as essential backbone agents 2, 1
• Bedaquiline as a core component of the regimen 1
• At least five effective drugs during the intensive phase, followed by four drugs in the continuation phase 1

Additional Drugs to Complete the Regimen

After establishing the core with a fluoroquinolone and bedaquiline, add from the following options based on susceptibility:

• Pyrazinamide (if susceptibility is confirmed) 1
• Cycloserine or terizidone (use only one, as they have complete cross-resistance) 2, 1
• Delamanid (may be included for patients aged >3 years on longer regimens) 2, 1
• Linezolid (particularly valuable for refractory cases) 3

Injectable Agents (When Necessary)

Injectable drugs should only be used when susceptibility is confirmed and oral options are insufficient:

• Amikacin or streptomycin are preferred if susceptibility is documented 2, 1
• Kanamycin and capreomycin should NOT be used 2, 1

Carbapenems (Special Circumstances)

• Imipenem-cilastatin or meropenem may be added, but must always be combined with amoxicillin-clavulanate 2, 1

Treatment Duration

• Intensive phase: 5-7 months after culture conversion 1
• Total duration: 15-21 months after culture conversion 1
• For pre-XDR and XDR TB: 15-24 months after culture conversion 1

Drugs to Avoid

The following should NOT be included in MDR-TB regimens:

• Macrolides (azithromycin and clarithromycin) - strong recommendation against use 2, 1
• Amoxicillin-clavulanate alone (only use with carbapenems) 2, 1
• Ethionamide/prothionamide if more effective drugs are available to construct a five-drug regimen 2, 1
• Para-aminosalicylic acid if more effective drugs are available 2, 1

Regimen Construction Algorithm

Step 1: Start with a later-generation fluoroquinolone (levofloxacin or moxifloxacin) and bedaquiline 1

Step 2: Add any first-line drugs to which the organism is susceptible (pyrazinamide, ethambutol, high-dose isoniazid if low-level resistance only) 2

Step 3: Add cycloserine or terizidone 1

Step 4: If needed to reach five drugs, add delamanid 1

Step 5: Only if oral options are exhausted and susceptibility is confirmed, consider amikacin or streptomycin 2, 1

Step 6: For extensively resistant cases, consider linezolid or carbapenems with amoxicillin-clavulanate 1, 3

Critical Pitfalls to Avoid

• Never use fewer than five effective drugs in the intensive phase - this leads to treatment failure and further resistance 1
• Do not use kanamycin or capreomycin - these are specifically recommended against despite being in older regimens 2, 1
• Avoid insufficient treatment duration - stopping before 15 months after culture conversion increases relapse risk 1
• Do not use rifampin in confirmed MDR-TB cases, as the organism is by definition resistant to it 2
• Never use macrolides for MDR-TB treatment 2, 1

Special Considerations

For the WHO shorter 9-12 month regimen: The 2019 ATS/CDC/ERS/IDSA guideline cannot make a recommendation for or against this standardized regimen because it includes kanamycin (which they recommend against) and drugs with likely resistance 2. This regimen should only be considered in highly selected patients with no previous second-line drug exposure, no fluoroquinolone resistance, and non-extensive disease 1.

High-dose isoniazid (15-20 mg/kg) may overcome low-level resistance caused by inhA mutations in children, but not high-level resistance from katG mutations 2.