Bedaquiline for the treatment of multidrug-resistant tuberculosis: great promise or disappointment?

Abstract

Acquired drug resistance by Mycobacterium tuberculosis (MTB) may result in treatment failure and death. Bedaquiline was recently approved for the treatment of multidrug-resistant tuberculosis (MDR-TB). This report examines the available data on this novel drug for the treatment of MDR-TB. PubMed searches, last updated 18 February 2015, using the terms bedaquiline, TMC 207 and R207910 identified pertinent English citations. Citation reference lists were reviewed to identify other relevant reports. Pertinent MDR-TB treatment reports on the US Food and Drug Administration, Centers for Disease Control and Prevention (CDC), World Health Organization (WHO) and Cochrane websites were also evaluated. Bedaquiline is an adenosine triphosphate (ATP) synthase inhibitor specific for MTB and some nontuberculous mycobacteria. The early bactericidal activity (EBA) of bedaquiline is delayed until ATP stores are depleted but subsequently it is similar to the EBA of isoniazid and rifampin. Bedaquiline demonstrated excellent minimum inhibitory concentrations (MICs) against both drug-sensitive and MDR-TB. Adding it to the WHO-recommended MDR-TB regimen reduced the time for sputum culture conversion in pulmonary MDR-TB. Rifampin, other cytochrome oxidase 3A4 inducers or inhibitors alter its metabolism. Adverse effects are common with MDR-TB treatment regimens with or without bedaquiline. Nausea is more common with bedaquiline and it increases the QTcF interval. It is not recommended for children, pregnant or lactating women. More patients died in the bedaquiline-treatment arms despite better microbiological outcomes in two recent trials. The WHO and CDC published interim guidelines that recommend restricting its use to patients with MDR-TB or more complex drug resistance who cannot otherwise be treated with a minimum of three effective drugs. It should never be added to a regimen as a single drug nor should it be added to a failing regimen to prevent the emergence of bedaquiline-resistant strains.

Keywords: Mycobacterium tuberculosis; bedaquiline; diarylquinoline; extensively drug resistant; multidrug resistance; tuberculosis.

Figure 1.

Percentage of new tuberculosis cases with multidrug-resistant tuberculosis. Figures are based on the most recent year for which data have been reported, which varies among countries. Reproduced with permission from WHO [2013b, Figure 4.2, p. 47, chapter 4].

Figure 2.

Percentage of previously treated tuberculosis cases with multidrug-resistant tuberculosis. Figures are based on the most recent year for which data have been reported, which varies among countries. Reproduced with permission from WHO [2013b, Figure 4.3, p. 49, chapter 4].

Figure 3.

Number of multidrug-resistant tuberculosis cases estimated to occur among notified pulmonary tuberculosis cases, 2012. Reproduced with permission from WHO [2013b] (Figure 4.6, p. 54, chapter 4).