What drugs should be considered for a patient previously treated with Short-Course Standard Oral Regimen (SSOR) and now planned for Drug-Resistant Tuberculosis (DRTB) treatment with an Intensive Treatment Regimen (ITR), assuming all tests are normal?

Drug Selection for DRTB Treatment After SSOR Failure

For a patient previously treated with Short-Course Standard Oral Regimen (SSOR) who now requires Drug-Resistant TB (DRTB) treatment with an Intensive Treatment Regimen (ITR), construct a regimen with at least five effective drugs during the intensive phase, prioritizing newer oral agents: bedaquiline (strong recommendation), a later-generation fluoroquinolone (levofloxacin or moxifloxacin), linezolid, clofazimine, and cycloserine, while avoiding drugs from the prior SSOR regimen if resistance is documented or suspected. 1, 2

Core Drug Selection Strategy

Mandatory First-Line Agents (Include These First)

• Later-generation fluoroquinolone: Levofloxacin or moxifloxacin must be included as a Group A agent (strong recommendation) 1

  • Levofloxacin is generally preferred over moxifloxacin due to fewer adverse events and less QTc prolongation 3
  • High-dose levofloxacin is the first choice among fluoroquinolones 4

• Bedaquiline: Must be included as a Group D2 agent (strong recommendation) 1, 2

  • This is one of the most effective newer oral agents with proven mortality benefit 1
  • The 2025 guidelines specifically recommend bedaquiline as part of the BPaLM regimen for MDR/RR-TB 5, 2

Strongly Recommended Additional Agents

• Linezolid: Should be included as a Group C agent (conditional recommendation, but highly effective) 1, 2

  • Part of the highly effective BPaLM regimen with 6-month duration 5, 2
  • Adverse events requiring drug adjustment are common (69.2% in recent studies) but manageable and reversible 6

• Clofazimine: Should be included as a Group C agent (conditional recommendation) 1

  • Provides additional efficacy as part of core second-line agents 1

• Cycloserine/Terizidone: Should be included as a Group C agent (conditional recommendation) 1

  • Remains an important component when constructing five-drug regimens 1

Drugs to Consider as Fifth Agent or Beyond

If Pyrazinamide Susceptibility Confirmed

• Pyrazinamide: Include if the M. tuberculosis isolate has not been found resistant (conditional recommendation) 1
  • Should be included during the intensive phase when susceptible 1
  • Testing can be performed by genotypic (pncA mutations) or phenotypic methods 1

Additional Agents When Needed

• Ethambutol: Only include when other more effective drugs cannot be assembled to achieve five drugs (conditional recommendation) 1

  • In EU/EEA, DST to ethambutol is considered reliable in quality-assured laboratories 1

• Delamanid: May be included as a Group D2 agent 1

  • The 2019 ATS/CDC/ERS/IDSA guideline could not make a recommendation for or against, but WHO conditionally recommends it 1

Injectable Agents (Use Only When Necessary)

• Amikacin or Streptomycin: Include only when susceptibility is confirmed and needed to compose five effective drugs (conditional recommendation) 1

  • Amikacin is preferred over kanamycin in the injectable hierarchy 4

• Carbapenem (imipenem-cilastatin or meropenem): Include when needed, always with amoxicillin-clavulanic acid (conditional recommendation) 1

• Avoid kanamycin and capreomycin: These are NOT recommended due to toxicity without proven benefit (conditional recommendation) 1, 3

Drugs to Explicitly AVOID

• Amoxicillin-clavulanate: Do NOT include except when using a carbapenem (strong recommendation) 1

• Macrolides (azithromycin, clarithromycin): Do NOT include (strong recommendation) 1

• Ethionamide/Prothionamide: Suggest NOT including if more effective drugs are available (conditional recommendation) 1

• p-Aminosalicylic acid (PAS): Suggest NOT including if more effective drugs are available (conditional recommendation) 1

Treatment Duration and Phases

• Intensive phase: Use at least five effective drugs for 5-7 months after culture conversion 1, 7

  • The 2018 European guidelines recommend 8 months intensive phase 1

• Continuation phase: Use at least four effective drugs 1

• Total treatment duration: 15-24 months after culture conversion for conventional regimens 1

  • For eligible patients, the 6-month BPaLM regimen (bedaquiline, pretomanid, linezolid, moxifloxacin) is now recommended 5, 2

Critical Pitfalls to Avoid

• Never add only one drug to a failing regimen: This rapidly leads to acquired resistance 1, 3

• Do not use empirical regimens: Treatment must be based on confirmed drug susceptibility patterns, as empirical regimens may cause further resistance 1

• Avoid drugs with documented resistance: No drug should be administered if resistance is documented by molecular or phenotypic DST 1

• Ensure drug susceptibility testing: Second-line DST must be performed to confirm resistance patterns and guide treatment choice 1

Monitoring Requirements

• Monthly sputum cultures until conversion, then less frequently 7, 5

• Directly observed therapy (DOT) is strongly recommended to ensure adherence 7, 5

• Frequent monitoring for adverse events: Particularly for linezolid (peripheral neuropathy, myelosuppression), bedaquiline (QTc prolongation), and fluoroquinolones (QTc prolongation) 6

• QTc monitoring: QT interval prolongation ≥500 ms occurred in 5.8% of patients in recent studies 6