Bedaquiline: Uses, Dosage, Side Effects and Interactions

Bedaquiline is a breakthrough medication in the fight against multidrug-resistant tuberculosis (MDR-TB). Approved after decades without a new class of anti-tubercular agents, bedaquiline offers hope where other treatments may fail. This article explores its uses, recommended dosage, potential side effects, and important drug interactions. Each section includes a summary table and a detailed, accessible explanation, drawing from current research and clinical experience.

Uses of Bedaquiline

Bedaquiline has transformed the landscape for patients with complex and resistant forms of tuberculosis. As a novel diarylquinoline antibiotic, it specifically targets the mycobacterial ATP synthase, making it effective even against strains that have outsmarted older drugs. Let’s examine what makes bedaquiline unique and where it’s being used in modern medicine.

Use	Patient Group	Context/Regimen	Source(s)
MDR-TB Treatment	Adults	With ≥3 other anti-TB drugs	1 2 4 10 13
XDR/pre-XDR TB	Adults	As part of combination regimens	2 3 8 12
NTM Lung Disease	Select cases	Salvage/off-label, combined with others	5 17
Not Recommended	Children, Pregnancy	Insufficient safety data	4 10

Table 1: Main Clinical Uses of Bedaquiline

Mechanism of Action

• Targets ATP Synthase: Bedaquiline blocks the energy-generating machinery of Mycobacterium tuberculosis, leading to bacterial death. This mechanism is unique among anti-TB drugs and effective against both replicating and non-replicating bacteria 14 16.
• Delayed but Potent Effect: The drug’s bactericidal activity ramps up as ATP stores are depleted in the bacterial cell 14.

Approved Indications

• Multidrug-Resistant Tuberculosis (MDR-TB):

  • Bedaquiline is indicated for adults with pulmonary MDR-TB, especially those who cannot be treated with at least three other effective drugs 1 2 4 10 13.
  • It is always used in combination with other anti-TB agents, never as monotherapy 4.

• Extensively Drug-Resistant (XDR) and pre-XDR TB:

  • Clinical trials and compassionate use programs have expanded its role in treating XDR and pre-XDR TB, with encouraging success rates when combined with other agents such as linezolid, clofazimine, and pretomanid 2 3 8 12.
  • In high HIV burden settings, such as South Africa, bedaquiline-containing regimens substantially improved outcomes for pre-XDR and XDR-TB 12.

Off-Label and Investigational Uses

• Nontuberculous Mycobacterial (NTM) Infections:
  • Though not officially approved for NTM lung disease, clinical case series and laboratory studies suggest that bedaquiline may have a role, especially for Mycobacterium avium complex (MAC) and M. abscessus, when other treatments have failed 5 17.
  • Combination with drugs like clofazimine may enhance activity and help prevent resistance 17.

Who Should Not Receive Bedaquiline?

• Children and Pregnant/Lactating Women: Safety and efficacy have not been established; routine use is not recommended 4 10.
• Drug-Susceptible TB: Bedaquiline is reserved for resistant cases due to its side effect profile and risk of resistance 4.

Dosage of Bedaquiline

Administering bedaquiline correctly is crucial to maximize its benefits and minimize risks. Its unique pharmacokinetics and long half-life necessitate a specific dosing schedule, and it must always be part of a multi-drug regimen.

Dosage Schedule	Duration	Administration	Notes/Adjustment	Source(s)
400 mg daily	2 weeks	Oral, with food	Initial loading phase	1 6 10 13
200 mg, 3x/week	22 weeks	Oral, with food	Maintenance phase	1 10 13
Combination	24 weeks	With ≥3 other drugs	Never monotherapy	1 4 10
Food Effect	—	Take with meals	↑ Bioavailability	10

Table 2: Standard Bedaquiline Dosage and Administration

Standard Dosing Regimen

• Loading Phase: 400 mg once daily, orally, for the first 2 weeks 1 10 13.
• Maintenance Phase: 200 mg three times per week (with at least 48 hours between doses) for the following 22 weeks 1 10 13.
• Total Duration: 24 weeks (6 months).

Key Administration Guidelines

• With Food: Bedaquiline should be taken with meals to double its absorption and ensure therapeutic levels are reached 10.
• In Combination: Always given with at least three other effective anti-TB drugs. Monotherapy risks rapid development of resistance and is contraindicated 4.

Special Populations & Adjustments

• HIV Coinfection: No adjustment required with most antiretrovirals, but see "Interactions" section for exceptions 7 12.
• Renal/Hepatic Impairment: Data is limited; use with caution and monitor closely 10.
• Prolonged Use: Some cohorts have used bedaquiline beyond 24 weeks (up to nearly a year) in highly resistant cases, with cautious monitoring for side effects 11.

Dosing in Special Regimens

• Bedaquiline-Pretomanid-Linezolid Regimens: Dosed similarly, with modifications for the companion drugs based on toxicity 8.
• Off-Label for NTM: Dosing mirrors the TB schedule, but data are limited and use is experimental 5.

Side Effects of Bedaquiline

As with any potent medication, bedaquiline comes with a risk of side effects. Most patients tolerate it well, but some adverse reactions can be serious and require close monitoring.

Side Effect	Frequency/Severity	Management/Monitoring	Source(s)
Nausea	Common, mild	Symptomatic treatment	1 5 10
Arthralgia	Common, mild	Symptomatic treatment	5 10
Headache	Occasional	Symptomatic treatment	10
QT Prolongation	Notable, can be severe	ECG monitoring, adjust	3 4 10 11 12
Elevated LFTs	Uncommon, can be severe	LFT monitoring, adjust	3 10
Unexplained Deaths	Rare, unclear cause	Careful patient selection	1 4 10 13

Table 3: Common and Serious Side Effects of Bedaquiline

Common Adverse Effects

• Gastrointestinal: Nausea is the most frequently reported side effect, followed by anorexia; most cases are mild and manageable 1 5 10.
• Musculoskeletal: Arthralgia (joint pain) and headaches are also relatively common but rarely serious 5 10.

Serious Adverse Effects

• QT Interval Prolongation:

  • Bedaquiline can prolong the heart’s QT interval (QTcF), which can lead to dangerous arrhythmias if not monitored 3 4 10 11 12.
  • ECG monitoring is required before and during treatment; therapy may be stopped if QTcF exceeds 500 ms or increases by >60 ms from baseline 3 10 11 12.
  • Risk is increased when combined with other QT-prolonging drugs (e.g., clofazimine, fluoroquinolones) 4 12.

• Hepatotoxicity:

  • Elevated liver enzymes have been reported; severe cases are rare but require regular liver function tests (LFTs) 3 10.
  • Discontinue if significant hepatotoxicity occurs.

• Mortality Signal:

  • Clinical trials reported a higher death rate in patients treated with bedaquiline versus placebo, although no clear causal pattern was found 1 4 10 13.
  • The drug carries a black box warning for this reason; use is restricted to those with limited options.

Other Considerations

• Peripheral Neuropathy and Myelosuppression: Primarily attributed to companion drugs such as linezolid in combination regimens 8.
• Long-Term Use: Extended courses (beyond 24 weeks) appear safe in select cases, but require close cardiac and hepatic monitoring 11.
• Discontinuation Rates: Most adverse events are manageable, but therapy may need to be discontinued if severe side effects develop 2 3 11 12.

Interactions of Bedaquiline

Bedaquiline’s metabolism and long half-life make it vulnerable to interactions with several other drugs. Some interactions can dramatically reduce its effectiveness or increase toxicity, so understanding these is key to safe prescribing.

Interacting Drug/Class	Effect on Bedaquiline	Clinical Advice	Source(s)
Rifampicin/Rifapentine	↓ Levels (~80%)	Contraindicated	9 15
Rifabutin	Minimal effect	Use with caution, monitor	9
CYP3A4 Inhibitors (e.g., LPV/r)	↑ Levels (2–3x)	Monitor for toxicity, consider adjustment	7
Nevirapine	No significant effect	No adjustment needed	7
Other QT-prolonging drugs	↑ QT risk	Avoid combinations if possible	4 12
Food	↑ Absorption (2x)	Always give with meals	10

Table 4: Key Drug and Food Interactions with Bedaquiline

Rifamycins and CYP3A4 Inducers

• Rifampicin and Rifapentine:

  • Both drugs strongly induce CYP3A4, the enzyme that metabolizes bedaquiline, leading to an ~80% reduction in bedaquiline levels—rendering it ineffective 9 15.
  • Clinical advice: Do not co-administer; if rifamycins are needed (as in drug-susceptible TB), use alternative regimens 15.

• Rifabutin:

  • Has a much smaller effect on bedaquiline levels, but severe adverse events have been reported in some studies 9.
  • Clinical advice: Use with caution and monitor closely.

CYP3A4 Inhibitors

• Protease Inhibitors (e.g., Lopinavir/Ritonavir):

  • Can increase bedaquiline exposure 2–3 fold, raising the risk of toxicity and side effects 7.
  • Clinical advice: Monitor levels and ECGs; dose adjustment may be required, but more clinical data are needed 7.

• Nevirapine: No significant effect on bedaquiline levels; no dose adjustment needed 7.

QT-Prolonging Drugs

• Combining with Other QT-Prolonging Agents:
  • Drugs like clofazimine, fluoroquinolones, and macrolides can all increase the risk of dangerous heart rhythm disturbances when used with bedaquiline 4 12.
  • Clinical advice: Avoid combinations if possible; if necessary, increase ECG monitoring.

Food and Absorption

• With Meals: Taking bedaquiline with food doubles its absorption. Skipping meals can lower drug levels and compromise efficacy 10.

Other Considerations

• No Known Renal Drug Interactions: Bedaquiline is not primarily renally excreted; thus, renal drug interactions are unlikely 10.
• Long Half-Life: The terminal half-life is 5–6 months, so interactions may persist even after stopping co-administered drugs 10 15.

Conclusion

Bedaquiline represents a significant advance in the treatment of drug-resistant tuberculosis, but its use requires careful consideration due to its unique properties, potential for serious side effects, and complex drug interactions. Here’s a summary of the main points:

• Indications: Primarily for MDR-TB, XDR-TB, and select NTM cases when alternative regimens are ineffective or unavailable.
• Dosage: 400 mg daily for 2 weeks, then 200 mg three times weekly for 22 weeks, always with food and as part of a combination regimen.
• Side Effects: Most common are nausea and joint pain; most serious are QT prolongation, hepatotoxicity, and a possible increased risk of mortality.
• Interactions: Strong interactions with rifamycins (contraindicated), CYP3A4 inhibitors (require monitoring), and other QT-prolonging agents.
• Patient Selection: Not recommended for children, pregnant or lactating women, or for drug-susceptible TB.
• Monitoring: Regular ECGs and liver function tests are essential to ensure safety.
• Clinical Impact: When used correctly, bedaquiline significantly improves outcomes for patients with otherwise untreatable TB.

Bedaquiline should always be prescribed by experienced clinicians as part of a comprehensive, monitored, and individualized treatment plan.