What is the evidence for shorter treatment regimens in patients with drug-resistant tuberculosis (DRTB)?

Shorter Drug-Resistant TB Regimens: Current Evidence

For MDR/RR-TB, a 6-month all-oral BPaLM regimen (bedaquiline, pretomanid, linezolid, moxifloxacin) is now the preferred shorter treatment option based on the most recent 2025 guidelines, representing a major advance over the previous 9-12 month standardized regimen that had significant limitations. 1

The Evolution of Shorter Regimens

The 9-12 Month Standardized Regimen (2016-2019)

The WHO initially recommended a standardized 9-12 month shorter regimen in 2016, but this approach had critical flaws 2:

• The 2019 ATS/CDC/ERS/IDSA guidelines could not recommend for or against this regimen because it included kanamycin (which they recommend against) and drugs for which resistance was likely (isoniazid, ethionamide, pyrazinamide) 3
• The STREAM Stage 1 trial found this regimen noninferior to longer injectable-containing regimens, but the guideline committee emphasized the need for modified shorter regimens with newer oral agents that exclude injectables 3
• Only 10% of US MDR-TB patients were eligible for this regimen due to strict exclusion criteria (extrapulmonary TB, pregnancy, prior second-line drug exposure, or resistance to multiple drugs including fluoroquinolones or second-line injectables) 4

The 6-Month BPaLM Regimen (2025)

The 2025 ATS/CDC/ERS/IDSA guidelines now recommend the BPaLM regimen for MDR/RR-TB with extrapulmonary involvement, including intestinal TB 5, 1:

• Composition: Bedaquiline + pretomanid + linezolid + moxifloxacin 5
• Duration: 6 months (compared to 9-12 months for the older standardized regimen or 15-24 months for conventional longer regimens) 5, 6
• This represents the culmination of research recommendations from 2019 calling for trials of modified shorter regimens with newer oral agents that exclude injectables 3

When to Use Shorter vs. Longer Regimens

Shorter Regimen (6-Month BPaLM) Indications

Use the 6-month BPaLM regimen for MDR/RR-TB patients when 5, 1:

• Confirmed MDR/RR-TB (including extrapulmonary disease like intestinal TB)
• No documented resistance to fluoroquinolones or bedaquiline
• Recent clinical trial evidence supports efficacy and safety

Longer Regimen (15-24 Months) Indications

Use individualized longer oral regimens when 6:

• Resistance to fluoroquinolones or other key drugs in shorter regimens exists
• Patient ineligible for shorter regimen based on drug susceptibility testing
• Pre-extensively drug-resistant or extensively drug-resistant TB

Composition of Longer Oral Regimens

When shorter regimens are not appropriate, construct a longer regimen with at least 5 effective drugs 6:

Core Drugs (All Strong Recommendations)

• Bedaquiline (for patients ≥18 years) 6
• Later-generation fluoroquinolone (levofloxacin or moxifloxacin) 6
• Linezolid 6

Additional Agents (Conditional Recommendations)

• Clofazimine 6
• Cycloserine 6
• Pyrazinamide (if not resistant) 6
• Delamanid (for patients ≥3 years) 6

Injectable Agents (Use Only When Necessary)

• Amikacin or streptomycin only when susceptibility confirmed and no better oral options exist 6
• Avoid kanamycin and capreomycin 6

Drugs to Avoid

Do not include 6:

• Amoxicillin-clavulanate (except with carbapenems)
• Macrolides (azithromycin, clarithromycin)
• Ethionamide/prothionamide (if better drugs available)
• p-aminosalicylic acid (if better drugs available)

Special Populations

Isoniazid-Resistant TB (Not MDR)

For isoniazid-resistant TB, use a 6-month regimen 3, 5:

• Later-generation fluoroquinolone + rifampin + ethambutol + pyrazinamide for 6 months
• Pyrazinamide can be shortened to 2 months in noncavitary, lower-burden disease 3

HIV Co-infection

Extend treatment duration to at least 9 months and for at least 6 months beyond culture conversion for patients with HIV and drug-resistant TB 5

Critical Pitfalls to Avoid

• Never add a single drug to a failing regimen as this creates acquired resistance 6
• Do not use standardized shorter regimens that include drugs with documented or likely resistance 3, 6
• Avoid relying on the older 9-12 month standardized regimen given its limitations and the availability of superior 6-month BPaLM regimen 3, 1
• Ensure rapid molecular diagnostics for fluoroquinolone and second-line injectable resistance to guide regimen selection 2
• Do not delay treatment while awaiting full phenotypic drug susceptibility testing; start empiric regimen based on molecular results and adjust as needed 7

Monitoring and Support

• Monthly sputum cultures (not just smears) to monitor treatment response 6
• Directly observed therapy strongly recommended to ensure adherence 5
• Treatment adherence interventions including digital monitoring, material support, and psychological support 6
• Consider adjunctive surgery (lobectomy or wedge resection) in select cases with high risk of treatment failure 3, 6