What are the recent updates in tuberculosis treatment, including recommendations for drug‑susceptible, latent, multidrug‑resistant, and pediatric cases?

Recent Updates in Tuberculosis Treatment

Drug-Susceptible Tuberculosis: Shorter Regimens Now Preferred

For adults and adolescents ≥12 years with pulmonary drug-susceptible TB, a 4-month regimen of rifapentine, isoniazid, pyrazinamide, and moxifloxacin is now conditionally recommended by the WHO, shortening treatment from the traditional 6 months. 1

• The standard 6-month HRZE regimen (2 months of isoniazid, rifampin, pyrazinamide, ethambutol followed by 4 months of isoniazid and rifampin) remains an alternative when the 4-month regimen cannot be used. 1
• Children with non-severe drug-susceptible TB can now receive a 4-month regimen using weight-adjusted standard first-line drugs, which is non-inferior to 6 months based on the SHINE trial. 1

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Isoniazid-Resistant, Rifampicin-Susceptible TB: New Fluoroquinolone-Based Regimen

When isoniazid resistance is confirmed but rifampicin remains susceptible, the WHO recommends 6 months of rifampin, ethambutol, pyrazinamide plus a fluoroquinolone (levofloxacin or moxifloxacin). 1

• Injectable agents (streptomycin, amikacin) must NOT be added to this regimen because they provide no benefit and increase toxicity. 1
• High-dose isoniazid may be added when the resistance mutation is inhA (lower-level resistance), though evidence is limited. 1
• If fluoroquinolone resistance or contraindication exists, the regimen is reduced to rifampin, ethambutol, and pyrazinamide for 6 months. 1

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Multidrug-Resistant/Rifampicin-Resistant TB: Revolutionary 6-Month All-Oral Regimens

BPaLM Regimen: The New First-Line Standard

The WHO now recommends the 6-month BPaLM regimen (bedaquiline + pretomanid + linezolid + moxifloxacin) as the preferred first-line treatment for eligible adults ≥14 years with MDR/RR-TB. 2, 1

Eligibility Criteria:

• Fluoroquinolone-susceptible MDR/RR-TB 1
• No prior exposure >30 days to bedaquiline, pretomanid, or linezolid 1
• Age ≥14 years 1
• Extensive pulmonary disease and cavitation are no longer contraindications (2023 WHO update) 3, 1
• HIV co-infection does not preclude use 4

Absolute Contraindications:

• Pregnancy or breastfeeding (pretomanid reproductive toxicity unknown) 3, 1
• Central nervous system TB, osteoarticular TB, or miliary TB (require longer therapy) 3, 1
• Confirmed resistance to any BPaLM component 1

Dosing:

• Bedaquiline: 400 mg daily × 2 weeks, then 200 mg three times weekly × 22 weeks 1
• Pretomanid: 200 mg daily × 26 weeks 1
• Linezolid: 600 mg daily × 26 weeks (reduce to 300 mg if toxicity develops) 1
• Moxifloxacin: 400 mg daily × 26 weeks 1

Critical Management Points:

• If fluoroquinolone resistance is detected after initiation, stop moxifloxacin immediately and continue as BPaL (bedaquiline + pretomanid + linezolid) for a total of 9 months. 1, 4
• Do NOT extend BPaLM beyond 6 months; if response is inadequate, switch to an individualized 18-20 month regimen rather than prolonging BPaLM. 3, 1
• Do NOT delay initiation awaiting fluoroquinolone DST—start empirically and adjust to BPaL if resistance is confirmed. 1, 4

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BPaL Regimen: For Pre-XDR TB (Fluoroquinolone-Resistant)

For MDR-TB with fluoroquinolone resistance (pre-XDR), the BPaL regimen (bedaquiline + pretomanid + linezolid, without moxifloxacin) is recommended. 2, 1

• Duration: 6 months, extendable to 9 months if sputum cultures remain positive between months 4-6. 2, 1
• Eligibility and monitoring are identical to BPaLM except fluoroquinolone resistance is expected. 1

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9-Month All-Oral Regimen: When BPaLM/BPaL Cannot Be Used

A 9-11 month all-oral regimen is recommended for patients with MDR/RR-TB not resistant to fluoroquinolones when BPaLM/BPaL are unsuitable. 2

Composition:

• Intensive phase (4-6 months): bedaquiline + linezolid (or ethionamide) + fluoroquinolone (levofloxacin/moxifloxacin) + clofazimine + pyrazinamide + ethambutol + high-dose isoniazid (if applicable) 1
• Continuation phase (≈5 months): fluoroquinolone + clofazimine + pyrazinamide + ethambutol 1

Key Requirements:

• Mandatory fluoroquinolone DST and susceptibility confirmation for all regimen drugs 2, 1
• Do NOT modify the standardized composition; adding or removing drugs increases failure and resistance risk. 3, 1
• Exclusions: severe extrapulmonary TB (CNS, miliary, osteoarticular) requires the longer 18-20 month regimen. 1
• Pregnancy contraindicates ethionamide—replace with a linezolid-based variation. 3, 1

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Individualized 18-20 Month Regimen: Last-Resort Option

When BPaLM, BPaL, or the 9-month regimen cannot be applied due to extensive resistance, intolerance, drug-drug interactions, or contraindicated disease sites, an individualized 18-20 month regimen is required. 1

WHO Drug Grouping Hierarchy:

• Group A (use all three if possible): fluoroquinolone (levofloxacin/moxifloxacin), bedaquiline, linezolid 3, 1
• Group B (add at least one): clofazimine, cycloserine/terizidone 3, 1
• Group C (add as needed to reach ≥4 effective drugs): ethambutol, delamanid (≥3 years), pyrazinamide, carbapenems + amoxicillin-clavulanate, amikacin (only if no oral alternatives) 3, 1

Core Requirements:

• ≥4 effective drugs in the intensive phase (5-7 months after culture conversion) and ≥3 in the continuation phase 3, 1
• Total duration 18-20 months (15-21 months after conversion) 1
• Do NOT add a single drug to a failing regimen; at least two susceptible drugs must be introduced together. 3, 1

Injectable Agents:

• Amikacin or streptomycin may be used only when an adequate number of effective oral drugs cannot be assembled and susceptibility is confirmed. 1
• Kanamycin and capreomycin are strongly discouraged due to poor outcomes and high toxicity. 2, 1

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Diagnostic and Monitoring Updates

Initial Testing:

• CBNAAT (GeneXpert) is the WHO-recommended first-line test for all persons with suspected TB; it simultaneously detects Mycobacterium tuberculosis and rifampicin resistance. 3, 1
• Standard CBNAAT does not detect isoniazid resistance, which requires a line-probe assay or culture-based DST. 3, 1

Baseline Evaluation Before MDR/RR-TB Therapy:

• Obtain CBC, liver function tests, renal function tests, ECG, weight, HIV status, pregnancy status, and detailed history of prior TB drug exposure. 3, 1
• Additional assessments: electrolytes (potassium, magnesium, calcium) to evaluate QTc-prolongation risk, visual-acuity testing, and audiometry when injectable agents might be used. 3, 1

Comprehensive Drug Susceptibility Testing:

• DST for fluoroquinolones and all second-line drugs is required to inform regimen selection. 3, 1
• Fluoroquinolone DST is pivotal for deciding between BPaLM, BPaL, the 9-month regimen, or longer individualized regimens. 3, 1

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Safety Monitoring During DR-TB Treatment

Cardiac Monitoring:

• ECG monitoring at baseline, weeks 2,4,8,12, then monthly to detect QTc prolongation from bedaquiline, moxifloxacin, and clofazimine. 3, 4
• Stop bedaquiline if QTcF >500 ms or clinically significant ventricular arrhythmia develops. 4

Hematologic Monitoring:

• Monthly CBC to identify linezolid-induced myelosuppression (anemia, thrombocytopenia). 3, 4
• If toxicity occurs, reducing linezolid dose to 300 mg daily preserves efficacy. 3

Hepatic Monitoring:

• Monthly liver function tests (AST, ALT, bilirubin, alkaline phosphatase). 4
• Stop bedaquiline if ALT/AST >8× ULN or ALT/AST >3× ULN + bilirubin >2× ULN (Hy's Law criteria). 4

Neurologic Monitoring:

• Monthly assessment for peripheral neuropathy (linezolid) and optic neuropathy (linezolid, ethambutol). 3, 4

Microbiologic Monitoring:

• Monthly sputum cultures throughout treatment, even after culture conversion, to detect treatment failure or relapse. 4

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Critical Pitfalls to Avoid

• Do NOT use fewer than four effective drugs in the intensive phase of long regimens—this predisposes to failure. 3, 1
• Do NOT discontinue therapy early after culture conversion; complete the full prescribed duration (6,9, or 18-20 months). 3, 1
• Do NOT give BPaLM to children <14 years (pretomanid not studied); opt for the 9-month regimen instead. 3, 1
• Do NOT use ethionamide in pregnancy; substitute with a linezolid-based variation of the 9-month regimen. 3, 1
• Do NOT modify standardized regimens (BPaLM, BPaL, 9-month); adding or removing drugs increases failure and resistance amplification risk. 3, 1

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Safety Updates for Bedaquiline

The WHO review of new data in 2019 concluded there are no major safety concerns on:

• Use of bedaquiline for >6 months' duration 2
• Use of delamanid and bedaquiline together 2
• Use of bedaquiline during pregnancy (though formal recommendations were not made) 2

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Global Implementation Trends

By 2026, BPaL/M is projected to be used in 78% of DR-TB patients globally, with BPaLM reaching 126,792 patients and BPaL reaching 43,716 patients. 5 The 9-11 month all-oral bedaquiline-based regimen is projected to reach 13,119 patients, while longer individualized regimens will be used by 15,344 patients. 5