What is the recommended treatment regimen for drug-resistant tuberculosis (TB)?

Treatment of Drug-Resistant Tuberculosis

For multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB), use an all-oral regimen containing bedaquiline, a later-generation fluoroquinolone (levofloxacin or moxifloxacin), linezolid, and at least two additional effective drugs for a total of at least five agents. 1

Preferred Shorter Regimen (6 months)

The BPaLM regimen (bedaquiline, pretomanid, linezolid, and moxifloxacin) for 6 months is now recommended for MDR/RR-TB patients, including those with extrapulmonary disease, when there is no documented resistance to fluoroquinolones or bedaquiline. 2

• This represents a major advancement over older 9-12 month standardized regimens that included kanamycin (which is no longer recommended) 1, 2
• The 6-month duration is substantially shorter than conventional 15-24 month regimens 2

Longer Individualized Oral Regimens (15-21 months)

When the shorter BPaLM regimen cannot be used (due to drug resistance or contraindications), construct an individualized longer regimen using the following hierarchical approach: 1

Core Drugs (Group A - Include All Three):

• Bedaquiline (strong recommendation) 1
• Levofloxacin or moxifloxacin (later-generation fluoroquinolone) (strong recommendation) 1
• Linezolid (strong recommendation) 1

Additional Drugs (Group B - Add at Least One):

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

Supplementary Drugs (Group C - Add if Needed to Reach Five Drugs):

• Ethambutol (only when susceptibility confirmed and more effective drugs unavailable) 1
• Delamanid (may be included for patients ≥3 years) 1
• Pyrazinamide (when susceptibility confirmed) 1

Critical principle: Build a regimen with at least five effective drugs to which the isolate is susceptible or has low likelihood of resistance. 1

Drugs to AVOID in MDR-TB Regimens

Do NOT include the following agents: 1

• Kanamycin and capreomycin (strong recommendation against) 1
• Amoxicillin-clavulanate (except when used with a carbapenem) 1
• Macrolides (azithromycin, clarithromycin) 1

Injectable Agents - Use Only When Absolutely Necessary:

• Amikacin or streptomycin may be considered only when susceptibility is confirmed and more effective oral drugs cannot be assembled to reach five effective agents 1
• Injectable agents should be reserved for situations where adequate oral regimens cannot be constructed due to their significant toxicity 1

Isoniazid-Resistant TB (Rifampin-Susceptible)

For confirmed rifampin-susceptible, isoniazid-resistant TB, use a 6-month regimen of rifampin, ethambutol, pyrazinamide, and levofloxacin. 1, 2

• Do NOT add streptomycin or other injectable agents 1
• Treatment of isoniazid-resistant TB with standard first-line regimens results in failure/relapse rates of 15% and acquired MDR-TB in 8% of cases 3

Special Populations

HIV Co-infection:

• Extend treatment duration to at least 9 months and for at least 6 months beyond culture conversion 1, 2
• Monitor for malabsorption syndrome, which may require therapeutic drug monitoring 4
• Rapid disease progression can occur with inadequate therapy in immunosuppressed patients 1

Pediatric Patients:

• Bedaquiline may be included for children aged 6-17 years (conditional recommendation) 1
• Delamanid may be included for children ≥3 years 1

Treatment Duration

• BPaLM regimen: 6 months total 2
• Longer individualized regimens: 15-21 months after culture conversion, with intensive phase of 5-7 months after conversion 5
• Isoniazid-resistant TB: 6 months 1, 2

Essential Monitoring and Support

Directly observed therapy (DOT) is strongly recommended for all drug-resistant TB patients to prevent treatment failure and acquired resistance. 2, 5, 4

• Obtain monthly sputum cultures until conversion, then less frequently 2, 5
• Perform drug susceptibility testing on the first isolate from all patients 1
• Monitor carefully for adverse drug effects, which are common with second-line agents 6
• Consider therapeutic drug monitoring in patients with malabsorption or treatment failure 4

Critical Pitfalls to Avoid

Never add a single drug to a failing regimen - this rapidly selects for additional resistance 5, 6

• Patient non-adherence is the major cause of treatment failure and acquired resistance 4
• Consultation with a drug-resistant TB expert is essential 1, 4
• In children who are contacts of MDR-TB cases, use the source case's drug susceptibility results if the child's isolate cannot be obtained 1
• Ensure uninterrupted supply of quality-assured medications throughout the entire treatment course 4