Bedaquiline, sold under the brand name Sirturo, is a diarylquinoline antimycobacterial drug used to treat active tuberculosis. It was the first medication with a novel mechanism of action against Mycobacterium tuberculosis to be approved in over 40 years. This oral medication is specifically indicated for forms of tuberculosis that are resistant to other treatments, providing a new therapeutic option for patients with difficult-to-treat infections.
Application in Treating Tuberculosis
Bedaquiline is not a first-line therapy for all cases of tuberculosis. Its use is specifically reserved for patients diagnosed with multidrug-resistant tuberculosis (MDR-TB). MDR-TB is a form of the disease caused by bacteria that are resistant to at least isoniazid and rifampin, the two most potent TB drugs. This resistance makes standard treatment regimens ineffective, leading to a more complex and prolonged therapeutic course.
The application of bedaquiline extends to even more severe cases, known as extensively drug-resistant tuberculosis (XDR-TB). XDR-TB is defined as MDR-TB with additional resistance to any fluoroquinolone and at least one of the three injectable second-line drugs. For individuals with these highly resistant strains, treatment options are extremely limited.
This targeted application means bedaquiline is used when an effective treatment regimen cannot otherwise be constructed. Studies have shown that adding bedaquiline to a background regimen of other anti-TB drugs can lead to improved culture conversion rates in patients with MDR-TB and XDR-TB.
How Bedaquiline Works
The effectiveness of bedaquiline against drug-resistant bacteria stems from its unique mechanism of action. It targets a fundamental process in the Mycobacterium tuberculosis bacterium: energy production. The drug specifically inhibits an enzyme called adenosine triphosphate (ATP) synthase. This enzyme is responsible for synthesizing ATP, which serves as the main source of energy for cellular processes.
By binding to a specific component of the ATP synthase enzyme, known as the c subunit, bedaquiline effectively blocks its function. This process can be compared to shutting down the power plant of the bacterial cell. Without the ability to generate sufficient ATP, the bacterium cannot fuel its essential life functions, leading to cell death. This bactericidal effect works against both actively replicating and dormant, non-replicating bacteria.
This mode of action is distinct from all other classes of anti-tuberculosis drugs, which typically target processes like cell wall synthesis or DNA replication. The selectivity of bedaquiline for the mycobacterial ATP synthase over the human version of the enzyme helps to minimize certain off-target effects.
Treatment Regimen and Administration
Bedaquiline is never administered as a single drug. It is always incorporated into a multi-drug regimen, combined with at least three to four other antibiotics to which the patient’s TB isolate is susceptible. The medication is formulated as an oral tablet that should be taken with food to maximize its absorption and bioavailability.
The standard treatment course with bedaquiline lasts for 24 weeks and is divided into two distinct phases. The initial phase is a “loading dose” period, where patients take 400 mg once daily for the first two weeks. This higher initial dose helps to quickly establish a therapeutic concentration of the drug in the body.
Following the initial two weeks, the patient transitions to a “maintenance dose” phase. During this period, the dosage is reduced to 200 mg taken three times per week for the remaining 22 weeks. It is important that there are at least 48 hours between these maintenance doses. Adherence to this specific schedule under direct observation is often recommended to ensure the regimen’s effectiveness.
Potential Risks and Side Effects
The use of bedaquiline is associated with a “black box warning” from the U.S. Food and Drug Administration (FDA). This is the most serious type of warning issued by the agency. The primary concern is the risk of a condition known as QT prolongation, which is a disturbance in the heart’s electrical rhythm. This can potentially lead to a life-threatening arrhythmia called Torsades de Pointes. Regular monitoring with electrocardiograms (ECGs) before and during treatment is required to manage this risk.
Another concern noted in the black box warning is an observed increase in mortality. In a key clinical trial, there were more deaths in the group of patients receiving bedaquiline compared to the group receiving a placebo. The precise reasons for this imbalance in deaths have not been fully explained, as no clear pattern could be linked to the drug itself, disease severity, or other factors.
Beyond these serious warnings, patients may experience other, more common side effects. These frequently include nausea, arthralgia (joint pain), and headaches. Liver-related adverse reactions, such as elevated liver enzymes, have also been reported, necessitating monitoring of liver function. The combination of bedaquiline with other drugs that also prolong the QT interval, such as fluoroquinolones or clofazimine, can increase the cardiac risk and requires careful clinical management.