Bedaquiline
Sirturo — bedaquiline fumarate
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Pulmonary MDR-TB (resistant to at least rifampin and isoniazid) | Adults ≥18 years; pediatric patients ≥2 years weighing ≥8 kg (2024 label) | Combination therapy (≥3 other active drugs); DOT | FDA Approved |
Bedaquiline is the first drug in a novel class (diarylquinolines) developed specifically for tuberculosis, and the first new anti-TB drug with a novel mechanism of action approved in over 40 years. It received FDA accelerated approval in December 2012 for pulmonary MDR-TB when an effective regimen cannot otherwise be provided. In 2024, the FDA expanded the label to include pediatric patients aged 2 years and older weighing at least 8 kg. Bedaquiline must always be administered as directly observed therapy (DOT) and in combination with at least 3 other drugs to which the isolate is susceptible.
Pre-XDR and XDR-TB: WHO recommends bedaquiline as a core component of shorter and longer MDR/RR-TB regimens. Evidence quality: High (WHO consolidated guidelines 2022).
Non-tuberculous mycobacterial (NTM) infections: Used in refractory M. abscessus and M. avium complex infections with limited evidence. Evidence quality: Low (case series).
Dosing
Adult Dosing (≥16 years, ≥30 kg)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| MDR-TB — loading phase (weeks 1–2) | 400 mg once daily | 400 mg once daily × 14 days | 400 mg/day | MUST be taken with food (~2× absorption increase) Administer as DOT; 4 × 100 mg tablets |
| MDR-TB — continuation phase (weeks 3–24) | 200 mg three times weekly | 200 mg three times weekly | 600 mg/week | At least 48 hours between doses Total treatment duration: 24 weeks |
| Extended use beyond 24 weeks | 200 mg three times weekly | 200 mg three times weekly | 600 mg/week | May be continued if treatment deemed necessary by specialist Limited safety data beyond 24 weeks |
Bedaquiline’s extremely long terminal half-life (~5.5 months) means the drug and its active metabolite M2 persist in tissue for months after discontinuation. This supports the 3-times-weekly maintenance schedule but also means that adverse effects (especially QTc prolongation) may persist well beyond the last dose. Drug levels remain detectable for months, which must be considered when starting or modifying QTc-prolonging companion agents after bedaquiline discontinuation.
Pharmacology
Mechanism of Action
Bedaquiline is bactericidal and inhibits mycobacterial ATP synthase by binding to the c subunit of the proton pump (encoded by the atpE gene). This blocks the proton translocation required for ATP generation, a unique target not shared by any other antibiotic class. ATP depletion halts mycobacterial growth within hours, but bactericidal cell killing is delayed by several days, reflecting the organism’s dependence on ATP reserves. This novel mechanism means there is no cross-resistance with any existing TB drug. Resistance emerges through mutations in atpE and, potentially, through upregulation of drug efflux pumps (e.g., Rv0678).
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax 4–6 h; Cmax ~5.5 mg/L at 400 mg; bioavailability approximately doubled with food; linear PK | MUST be taken with food to ensure adequate drug exposure. Fasting administration leads to sub-therapeutic levels. |
| Distribution | Vd ~164 L (central compartment); >99.9% protein bound; extensive tissue penetration including lungs and macrophages | High tissue binding explains the extremely long terminal half-life. Drug concentrates in TB-affected organs. Not dialysable due to >99.9% protein binding. |
| Metabolism | CYP3A4 to M2 (N-monodesmethyl metabolite); M2 exposure is 23–31% of parent; M2 is 3–6× less antimycobacterially active | CYP3A4 inducers (rifampin) markedly reduce bedaquiline exposure (↓52%). CYP3A4 inhibitors increase exposure. M2 contributes to QTc prolongation despite lower antimicrobial potency. |
| Elimination | Primarily fecal; renal excretion <0.001%; terminal t½ ~5.5 months (due to slow tissue release); effective t½ ~24–30 h | Drug persists for months after discontinuation. No renal dose adjustment for mild/moderate impairment. Caution in severe renal impairment (no data on drug accumulation). |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nausea | ~30% | Most common adverse effect; generally manageable with antiemetics. Taking with food is required regardless. |
| Arthralgia | ~26–37% | Frequently reported in clinical trials; may be difficult to distinguish from concurrent pyrazinamide or fluoroquinolone effects |
| Headache | ~22% | Usually mild to moderate |
| Hemoptysis | ≥10% | Reported at higher frequency than placebo; may reflect underlying cavitary disease rather than drug effect |
| Chest pain | ≥10% | Non-cardiac in most cases; evaluate for cardiac aetiology given QTc risk |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Vomiting | ~8% | Consider re-dosing if vomiting within 1 hour of administration |
| Transaminase elevation (ALT/AST increased) | ~8% | More frequent than placebo; monitor LFTs regularly. Hepatotoxicity including fatalities reported. |
| Anorexia | ~7% | May compound with other TB drugs and disease-related weight loss |
| Rash / pruritus | ~6% | Hypersensitivity evaluation warranted for severe rash |
| Dizziness | ~5% | Usually mild |
| Abdominal pain | ~4% | Rule out hepatic cause |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| QTc prolongation | Mean increase ~15 ms (up to 35 ms in Study 4); QTc 450–500 ms in ~22.5% | Gradual; plateaus by week 12 | Baseline and serial ECGs (see monitoring). Discontinue if QTc >500 ms or clinically significant ventricular arrhythmia develops. Higher risk with concurrent clofazimine or fluoroquinolones. |
| Excess mortality (FDA Boxed Warning) | 10/79 (12.7%) vs 2/81 (2.5%) placebo in C208 Stage 2 | During and after treatment (some deaths occurred months post-BDQ) | Reserve for MDR-TB when effective regimen cannot otherwise be provided. No clear causal mechanism identified; most deaths attributed to TB progression. |
| Hepatotoxicity | Uncommon; fatalities reported | Variable; monitor throughout | Monitor LFTs at baseline, monthly, and as clinically indicated. Discontinue if ALT >8× ULN, ALT >5× ULN persisting >2 weeks, or ALT >3× ULN with symptoms or bilirubin elevation. |
QTc prolongation is mediated primarily by the M2 metabolite. Risk is additive with concurrent QTc-prolonging drugs (clofazimine, fluoroquinolones, delamanid). In clinical trials, mean QTc increase was ~15 ms (BDQ) vs ~6 ms (placebo) over 24 weeks, with QTc >500 ms in rare cases (predominantly when clofazimine was co-administered). Discontinue bedaquiline if QTc exceeds 500 ms or if clinically significant ventricular arrhythmia develops. Because of the ~5.5-month terminal half-life, QTc effects may persist for months after the last dose.
Drug Interactions
Bedaquiline is a CYP3A4 substrate with clinically significant interactions involving enzyme inducers, inhibitors, and QTc-prolonging agents. These interactions are critical given the narrow safety margin for QTc prolongation and the drug’s extremely long half-life.
Monitoring
- ECG (QTcF)Baseline; weeks 2, 4, 8, 12, 24; then as needed
RoutineUse Fridericia correction (QTcF). If co-administering with clofazimine or fluoroquinolones, perform ECG weekly for the first month, then monthly. Discontinue if QTcF >500 ms or if clinically significant ventricular arrhythmia occurs. Omit dose if QTcF >500 ms; resume when QTcF returns below threshold. Correct electrolytes (K+, Mg2+, Ca2+) before starting. - Hepatic Enzymes (ALT, AST, Bilirubin)Baseline; monthly during treatment
RoutineHepatotoxicity including fatalities has been reported. Discontinue if ALT >8× ULN, ALT >5× ULN persisting >2 weeks, or ALT >3× ULN with symptoms or elevated bilirubin. - Electrolytes (K+, Mg2+, Ca2+)Baseline; periodically
RoutineElectrolyte abnormalities exacerbate QTc prolongation. Correct any imbalance before and during bedaquiline therapy. - Sputum Cultures / MICBaseline and monthly until conversion
RoutineTest isolates for bedaquiline MIC at baseline and if failure to convert or relapse occurs. Resistance via atpE or Rv0678 mutations may emerge. - Symptom ReviewAt each DOT visit
RoutineAsk about palpitations, syncope, dizziness, nausea, jaundice, and joint pain at each DOT encounter.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to bedaquiline fumarate or any excipient
Relative Contraindications (Specialist Input Recommended)
- Baseline QTcF >500 ms: Do not initiate. Risk of ventricular arrhythmia is unacceptably high.
- Concurrent strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin): Avoid; reduces bedaquiline exposure by ≥50%, rendering therapy ineffective.
- Severe hepatic impairment (Child-Pugh C): Not studied; use only if benefit outweighs risk with close monitoring.
- Congenital long QT syndrome or uncompensated heart failure: Risk of torsades de pointes. Use only if no alternative exists.
Use with Caution
- Concurrent QTc-prolonging agents: Frequently unavoidable in MDR-TB regimens; requires intensive ECG monitoring
- HIV co-infection on efavirenz: ~20% reduction in bedaquiline exposure; prefer nevirapine or dolutegravir-based ART
- Severe renal impairment / ESRD: Caution due to potential M2 accumulation; dialysis will not remove bedaquiline
- Breastfeeding: High milk:plasma ratio (19–29); monitor infant for jaundice, dark urine, hepatic effects
An increased risk of death was observed in the bedaquiline treatment group (10/79, 12.7%) compared to the placebo treatment group (2/81, 2.5%) in one controlled clinical trial (C208 Stage 2). Only use bedaquiline when an effective treatment regimen cannot otherwise be provided. No clear causal relationship to bedaquiline was identified; five of the nine deaths were attributed to TB progression.
QTc prolongation can lead to ventricular arrhythmia (torsades de pointes) and sudden death. Co-administration with other QTc-prolonging drugs may cause additive QTc effects. Perform ECGs at baseline and regular intervals during treatment. Correct electrolyte abnormalities before initiation. Discontinue if QTcF >500 ms develops.
Patient Counselling
Purpose of Therapy
Bedaquiline is a newer antibiotic that works differently from all other TB medicines. It is used specifically for drug-resistant tuberculosis — TB that no longer responds to the standard medicines. You will take bedaquiline for 24 weeks (about 6 months) alongside other TB medicines. This treatment must be given under direct observation by a healthcare worker.
How to Take
Always take bedaquiline with food — this doubles the amount your body absorbs. During the first 2 weeks, take 400 mg (4 tablets) once daily. After that, take 200 mg (2 tablets) three times per week, with at least 48 hours between doses. Swallow tablets whole with water.
Sources
- SIRTURO (bedaquiline) prescribing information. Janssen Therapeutics. FDA label, revised 2024. FDA LabelPrimary regulatory source for approved indications, dosing (including pediatric), boxed warnings, adverse reactions, PK data, and CYP3A4 interactions.
- DailyMed. SIRTURO (bedaquiline fumarate) tablet. National Library of Medicine. DailyMedSupplementary FDA label source with current labeling including 2024 pediatric expansion.
- Diacon AH, Pym A, Grobusch MP, et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014;371(8):723–732. DOIPivotal C208 Stage 2 trial demonstrating faster sputum culture conversion with bedaquiline but raising mortality concerns that led to the FDA Boxed Warning.
- Diacon AH, Donald PR, Pym A, et al. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis. Antimicrob Agents Chemother. 2012;56(6):3271–3276. DOIC208 Stage 1 (exploratory) showing faster bactericidal activity with 8-week bedaquiline course.
- CDC. Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis. MMWR Recomm Rep. 2013;62(RR-09):1–12. CDCCDC guidelines providing dosing, ECG monitoring schedules, and safety recommendations for bedaquiline use in MDR-TB.
- WHO consolidated guidelines on tuberculosis. Module 4: treatment — drug-resistant tuberculosis treatment, 2022 update. WHOWHO guidelines recommending bedaquiline as a core component of shorter and longer MDR/RR-TB regimens.
- Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science. 2005;307(5707):223–227. DOIFoundational paper describing the discovery of bedaquiline and its novel ATP synthase inhibition mechanism targeting subunit c.
- Huitric E, Verhasselt P, Koul A, et al. Rates and mechanisms of resistance development in Mycobacterium tuberculosis to a novel diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother. 2010;54(3):1022–1028. DOICharacterisation of atpE mutations and efflux pump mechanisms driving bedaquiline resistance.
- WHO. “How-to” guide on the use of bedaquiline for MDR-TB treatment. Companion handbook. NCBIComprehensive WHO guide covering PK parameters (t½ 5.5 months, >99.9% protein binding, Vd 164 L), QTc monitoring protocols, and clinical implementation.
- Svensson EM, Karlsson MO. Modelling of mycobacterial load reveals bedaquiline’s exposure-response relationship in patients with drug-resistant TB. J Antimicrob Chemother. 2017;72(12):3398–3405. DOIPharmacokinetic-pharmacodynamic modelling supporting current dosing recommendations and exposure targets.
- Satti H, McLaughlin MM, Hedt-Gauthier B, et al. Outcomes of multidrug-resistant tuberculosis treatment with early initiation of bedaquiline. Am J Respir Crit Care Med. 2018;198(9):1217–1220. DOIReal-world outcomes study demonstrating high cure rates with bedaquiline-containing regimens in MDR-TB.