Bedaquiline

Bedaquiline is a diarylquinoline and the first new class of antituberculosis drug in decades. It is a core component of regimens for rifampicin-resistant and multidrug-resistant tuberculosis, given for 6 months or longer. It has a very long terminal half life and QT-prolonging potential, and an early mortality imbalance in one phase 2 study led to a historic boxed warning.

Class. Diarylquinoline antimycobacterial.

Mechanism. Inhibits mycobacterial ATP synthase (atpE subunit), depleting energy. Resistance arises through atpE and Rv0678 mutations, the latter giving cross-resistance to clofazimine.

Pharmacokinetics. Absorption doubles with food, peak at 5 hours, extensive protein binding, terminal half life about 5.5 months. Metabolised by CYP3A4 to an M2 metabolite; excreted mainly in faeces.

Rifampicin-resistant or multidrug-resistant tuberculosis (adults and children 5 years and over). - Loading: 400 mg orally once daily for 2 weeks. - Maintenance: 200 mg three times weekly (for example Monday, Wednesday, Friday) for 22 weeks; total 24 weeks. - Maximum: 400 mg daily during loading. - Under age 18, doses are set by weight band in a specialist paediatric regimen.

Pre-extensively drug-resistant disease. Combined with pretomanid and linezolid for 26 weeks (with or without moxifloxacin, as the regimen requires); bedaquiline 400 mg daily for 2 weeks, then 200 mg three times weekly.

Alternative schedule. Some short oral regimens use 200 mg daily for 8 weeks, then 100 mg daily; use only as the regimen specifies.

Extended use. Courses beyond 6 months are used in selected patients using the 200 mg three-times-weekly schedule.

Titration. Not used; interrupt or stop for QT prolongation.

Contraindications. QTcF over 500 ms, uncorrected hypokalaemia, hypocalcaemia or hypomagnesaemia, congenital long QT syndrome, and hypersensitivity. Caution with other QT-prolonging drugs.

Serious adverse effects. QT prolongation, arrhythmia and hepatotoxicity.

Common adverse effects. Nausea, arthralgia, headache and raised transaminases.

Interactions. - Avoid strong CYP3A4 inducers, including rifampicin, rifapentine, efavirenz, carbamazepine and phenytoin. - Avoid courses over 14 days of strong CYP3A4 inhibitors such as ketoconazole and ritonavir-boosted regimens unless benefit is clear. - Additive QT prolongation with clofazimine, moxifloxacin, levofloxacin, delamanid, macrolides, ondansetron and antipsychotics.

Common prescribing errors. Not checking baseline ECG and electrolytes, missing the loading phase, continuing through QT prolongation, and prescribing with efavirenz or rifampicin.

Special groups. - Pregnancy: limited data; used when the benefit outweighs risk. - Breastfeeding: limited data; infant exposure is possible. - Children: dosed by weight from age 5 years. - Older adults: monitor ECG and electrolytes closely. - Kidney impairment: no adjustment in mild to moderate; caution if severe. - Liver impairment: avoid in severe disease; monitor liver tests in mild to moderate.

Formulations. Tablets 20 mg and 100 mg.

Administration. With food. Observe each dose where possible.

Baseline. ECG with QTcF, potassium, calcium, magnesium, liver tests and pregnancy test.

Monitoring. ECG at baseline, 2, 4, 8 and 12 weeks, then every 12 weeks and after any QT-prolonging drug is added; electrolytes monthly; liver tests monthly.

Stopping thresholds. Stop if QTcF is over 500 ms (confirmed) or with arrhythmia, then correct electrolytes and review. Stop for ALT over three times the upper limit of normal with symptoms, or over five times without.

Referral and escalation. All patients should be managed within a drug-resistant tuberculosis programme; cardiology for syncope or ventricular arrhythmia.