What drugs should be included in an individualized regimen for an 18‑year‑old male with extensive drug‑resistant tuberculosis and a prolonged corrected QT interval (QTcF 525 ms) who cannot receive the BPaLM regimen or the short standardized oral regimen?

Individualized Regimen for Extensive DRTB with Prolonged QTc

For this 18-year-old male with extensive DRTB and baseline QTcF of 525 ms, construct a longer individualized regimen using levofloxacin (preferred over moxifloxacin due to less QT prolongation), linezolid, clofazimine, cycloserine/terizidone, and pyrazinamide—avoiding bedaquiline, delamanid, and moxifloxacin due to the severely prolonged baseline QTc. 1, 2, 3

Critical Context: Why Standard Regimens Are Contraindicated

• BPaLM is contraindicated because it contains both bedaquiline and moxifloxacin, both of which prolong QTc; with a baseline QTcF of 525 ms, adding these agents would create unacceptable arrhythmia risk. 2
• The 9-month all-oral regimen is also unsuitable because it typically includes bedaquiline plus a fluoroquinolone, and the patient's QTc already exceeds safe thresholds for these QT-prolonging drugs. 2, 3
• An 18–20 month individualized regimen is therefore mandatory, constructed according to WHO drug-grouping principles while avoiding all QT-prolonging agents. 1, 2

Regimen Construction Using WHO Drug Groups

Group A Drugs (Core Backbone)

Levofloxacin 750–1000 mg daily (weight-adjusted):

• Levofloxacin is strongly preferred over moxifloxacin because it causes significantly less QTc prolongation while maintaining equivalent efficacy. 2, 3
• Even though levofloxacin can prolong QTc, it is the least cardiotoxic fluoroquinolone and remains essential for MDR-TB treatment. 1
• Moxifloxacin must be avoided in this patient due to the baseline QTcF of 525 ms. 2, 4

Linezolid 600 mg daily (plan dose reduction to 300 mg daily after 2–4 months):

• Linezolid is a Group A drug with strong recommendation for inclusion in all longer MDR-TB regimens. 1
• Start at 600 mg daily; if peripheral neuropathy or myelosuppression develops, reduce to 300 mg daily—this lower dose maintains efficacy while reducing toxicity. 2
• Monthly CBC monitoring is mandatory to detect myelosuppression (anemia, thrombocytopenia). 2
• Monthly neurologic assessment is required to identify peripheral neuropathy and optic neuropathy early. 2

Bedaquiline is excluded despite being a Group A drug:

• Although bedaquiline has a strong WHO recommendation for patients ≥18 years, it is absolutely contraindicated here because it significantly prolongs QTc and the patient's baseline QTcF is already 525 ms. 1, 2
• Bedaquiline, moxifloxacin, and clofazimine together create additive QTc prolongation risk; even bedaquiline alone would be unsafe at this baseline. 4, 5, 6

Group B Drugs (Essential to Strengthen the Regimen)

Clofazimine 100 mg daily:

• Clofazimine is a Group B drug conditionally recommended for longer MDR-TB regimens. 1
• Critical caveat: clofazimine does prolong QTc and has been associated with QTcF ≥501 ms, especially when combined with fluoroquinolones. 4
• In this patient, clofazimine should be used cautiously with intensive ECG monitoring (baseline, weeks 2,4,8,12, then monthly) because the combination of levofloxacin + clofazimine increases QTc prolongation risk (adjusted HR 3.43 for QTcF ≥501 ms). 2, 4
• If QTcF exceeds 500 ms on treatment, clofazimine must be discontinued and replaced with cycloserine/terizidone. 2, 4

Cycloserine or terizidone 500–750 mg daily (divided doses):

• This is the alternative Group B drug if clofazimine cannot be tolerated or if QTc worsens. 1, 2
• Cycloserine does not prolong QTc, making it a safer choice in this patient. 2
• Consider starting with cycloserine instead of clofazimine given the baseline QTcF of 525 ms, to minimize cumulative QT risk. 2

Group C Drugs (Added to Reach ≥4 Effective Agents)

Pyrazinamide 1500–2000 mg daily (weight-adjusted):

• Pyrazinamide is a Group C drug conditionally recommended for longer MDR-TB regimens. 1
• MDR-TB is defined as resistance to isoniazid + rifampicin only; pyrazinamide often remains active and should be retained when susceptibility testing shows it is effective. 2, 3
• Pyrazinamide does not prolong QTc and is safe to use in this patient. 2

Ethambutol 800–1200 mg daily (weight-adjusted):

• Ethambutol is a Group C drug conditionally recommended when susceptibility is confirmed. 1
• Like pyrazinamide, ethambutol may remain active in MDR-TB and should be included if DST shows susceptibility. 2, 3
• Monthly visual-acuity testing is required to detect optic neuropathy. 2

Delamanid is excluded:

• Although delamanid is a Group C drug conditionally recommended for patients ≥3 years, it prolongs QTc and must be avoided in this patient with baseline QTcF of 525 ms. 1, 2

Imipenem-cilastatin or meropenem (if needed to reach ≥4 drugs):

• Carbapenems are Group C drugs conditionally recommended when additional agents are needed. 1
• Imipenem-cilastatin 500–1000 mg IV twice daily or meropenem 1–2 g IV three times daily, always combined with amoxicillin-clavulanate to inhibit beta-lactamases. 1, 2
• Carbapenems do not prolong QTc and are safe in this patient. 2
• Use only if five effective oral drugs cannot be assembled; given the extensive disease, carbapenems may be warranted in the intensive phase. 1, 2

Amikacin is a last resort:

• Amikacin may be included only when susceptibility is demonstrated and adequate monitoring can be ensured, and only if five effective oral drugs cannot be assembled. 1
• Kanamycin and capreomycin are strongly discouraged due to poor outcomes and high toxicity. 1, 2
• Amikacin does not prolong QTc but requires monthly audiometry to detect ototoxicity. 2

Ethionamide/prothionamide and p-aminosalicylic acid are NOT recommended:

• These drugs should be used only if bedaquiline, linezolid, clofazimine, or delamanid are not used, which is not the case here. 1
• The WHO has a conditional recommendation against their use when better options are available. 1

Proposed Regimen Summary

Intensive Phase (5–7 months after culture conversion):

1. Levofloxacin 750–1000 mg daily 1, 2, 3
2. Linezolid 600 mg daily (reduce to 300 mg after 2–4 months if tolerated) 1, 2
3. Cycloserine 500–750 mg daily (preferred over clofazimine due to baseline QTc) 1, 2
4. Pyrazinamide 1500–2000 mg daily 1, 2
5. Ethambutol 800–1200 mg daily (if susceptible) 1, 2
6. Consider adding imipenem-cilastatin or meropenem (with amoxicillin-clavulanate) in the first 2–3 months given extensive disease 1, 2

Continuation Phase (total 18–20 months):

1. Levofloxacin 750–1000 mg daily 1, 2
2. Linezolid 300 mg daily 2
3. Cycloserine 500–750 mg daily 1, 2
4. Pyrazinamide 1500–2000 mg daily 1

Mandatory Monitoring and Safety Principles

ECG monitoring:

• Baseline, weeks 2,4,8,12, then monthly to detect QTc prolongation from levofloxacin and clofazimine (if used). 2, 4
• If QTcF exceeds 500 ms, discontinue clofazimine immediately and replace with cycloserine; if QTcF exceeds 500 ms despite stopping clofazimine, consider stopping levofloxacin and adding a carbapenem. 2, 4

Hematologic monitoring:

• Monthly CBC to detect linezolid-induced myelosuppression. 2

Neurologic monitoring:

• Monthly assessment for peripheral neuropathy (linezolid, cycloserine) and optic neuropathy (linezolid, ethambutol). 2

Audiometry:

• Monthly if amikacin is used. 2

Drug susceptibility testing:

• Comprehensive DST for fluoroquinolones, linezolid, and all second-line agents must be performed before finalizing the regimen. 2, 3
• Only drugs to which the isolate is documented susceptible or has high likelihood of susceptibility should be included. 3

Critical Pitfalls to Avoid

• Never add only one effective drug to a failing regimen; this creates functional monotherapy and increases resistance risk. At least two susceptible drugs must be added if the regimen is modified. 2
• Do not use fewer than four effective drugs in the intensive phase; this predisposes to treatment failure. 2
• Do not discontinue therapy early even after culture conversion; complete the full 18–20 months. 1, 2
• Do not combine multiple QT-prolonging drugs (bedaquiline, moxifloxacin, delamanid, clofazimine) in a patient with baseline QTcF of 525 ms; this has been associated with fatal arrhythmias. 4, 5, 6
• Active drug-safety monitoring (aDSM) is mandatory for all DR-TB patients. 2