Bedaquiline: A Novel Antitubercular Agent for the Treatment of Multidrug-Resistant Tuberculosis

Abstract

Bedaquiline is a diarylquinoline antitubercular drug with a novel mechanism of action against Mycobacterium tuberculosis. Bedaquiline works by inhibiting bacterial adenosine triphosphate (ATP) synthase and represents the first novel class of antituberculosis agents in more than 40 years. Bedaquiline is indicated for the treatment of multidrug-resistant tuberculosis (MDR TB) in combination with at least three other antitubercular drugs when no other effective regimen is available. The recommended bedaquiline dosage is 400 mg orally once/day for 2 weeks followed by 200 mg orally 3 times/week for 22 weeks. Bedaquiline should be administered with food, which increases the bioavailability 2-fold. Bedaquiline is metabolized by cytochrome P450 isoenzyme 3A4 and is impacted by both inducers and inhibitors of this isoenzyme. Concentration-dependent bactericidal activity was observed in laboratory and murine studies. Accelerated approval was granted in the United States and European Union based on the results of two phase IIb clinical studies that used sputum culture clearance as a surrogate end point for clinical efficacy. These studies showed greater sputum culture clearance up to week 24 for the bedaquiline group compared with placebo. Common adverse events in clinical trials included nausea, arthralgia, and headache. Serious adverse events included elevated serum transaminase levels and rate-corrected QT-interval prolongation. Unexplained higher mortality was seen in patients receiving bedaquiline versus those receiving placebo. Bedaquiline is a novel agent with a unique mechanism of action and has the potential to meet a great need in patients with MDR TB who have no other treatment options. Due to safety concerns and limited clinical information, phase III trials are needed to fully determine its place in therapy.

Recent controversies about MDR and XDR‐TB: Global implementation of the WHO shorter MDR‐TB regimen and bedaquiline for all with MDR‐TB?

“…Bedaquiline distributes extensively into tissues and accumulates in cells by inducing phospholipidosis . It is unclear whether drug‐induced phospholipidosis causes toxicity, and the relationship between bedaquiline exposure and the extent of phospholipidosis is unknown.…”

Bedaquiline and delamanid in tuberculosis

“…The authors reported a statistically significant reduction in the time of sputum--culture conversion (p < 0.001), which was shorter in the bedaquiline group, and in the percentage of sputum conversion, which was higher in the bedaquiline group at 24 and 120 weeks (p = 0.008 and p = 0.04, respectively) [55]. Similar data have been reported by the same authors in a previously conducted study (C208 stage 1) with a small sample size (47 patients) and a short therapy duration (8 weeks) [ Recently, a non-comparative, single-arm, open-label trial (C209) assessed the efficacy of bedaquiline in patients with MDR-TB with varying degrees of additional resistance who failed in previous therapies: the median time to sputum culture conversion was 57 days and consistent with both C208 stage 1 and stage 2 results [59,67,68].…”

Evaluation of macrolides for possible use against multidrug-resistantMycobacterium tuberculosis

“…In 156 patients, proarrythmic potential was associated with erythromycin in 53% of cases and with CLR in 36% of cases, and 11% occurred in azalide-treated patients [93]. Since other MDR-TB drugs like moxifloxacin [94], delamanid [95] and bedaquiline [96] are also known to lengthen QT interval, adding macrolides to a MDR-TB regimen could increase the risk of cardiovascular events and mortality.…”