Bedaquiline as a potential agent in the treatment ofMycobacterium abscessusinfections

Abstract

Bedaquiline as a potential agent in the treatment of Mycobacterium abscessus infections To the Editor: Mycobacterium abscessus is increasingly being recognised as a significant human pathogen, especially in patients with cystic fibrosis, and the specific M. abscessus subspecies seems to influence the clinical outcome [1]. The pulmonary manifestation of this nontuberculous mycobacteria (NTM) infection is one of the most difficult to treat forms, leading to substantial morbidity and mortality in this population [1, 2]. M. abscessus strains are highly resistant to most antibacterial drugs [2]. The recent development of liposomal amikacin for inhalation for patients with cystic fibrosis suggested a therapeutic breakthrough. However, even though sputum conversion was improved in a phase 2 study, the primary end-point (change from baseline to day 84 on a semi-quantitative mycobacterial growth scale) was not reached [3]. We analysed the minimal inhibitory concentration (MIC) of another promising new anti-tuberculous drug, bedaquiline, using 20 clinical isolates of M. abscessus. No systematic studies on the distribution of MIC for M. abscessus have been performed previously. Bedaquiline is a diarylquinoline drug recently licensed for the treatment of multidrug-resistant Mycobacterium tuberculosis infections. It acts through inhibition of the mycobacterial F 1 F 0-ATP synthase, [4] and is characterised by excellent intracellular bactericidal activity and a high accumulation rate [4]. In previous studies, bedaquiline showed excellent in vitro activity against M. tuberculosis, including multidrug-resistant strains [5]. The new drug has been successfully and safely used in the treatment of both adult and paediatric multidrug-resistant and extensively drug-resistant tuberculosis alike [6, 7], even over extended periods of as long as 18 months [8]. As for other NTM, in vitro drug susceptibility testing of M. abscessus strains using conventional drugs is recommended only after treatment failure occurs [2]. We present the in vitro bedaquiline MIC results of 20 clinical strains of M. abscessus isolated in our centre between 2011 and 2016 from patients with pulmonary NTM disease, including three patients with cystic fibrosis. In this study, 4/20 strains (20%) were classified as M. abscessus subspecies bolletii, while all others belonged to the M. abscessus subspecies abscessus. The thirdM. abscessus subspecies, M. abscessus subspecies massiliense was not identified among our strains. MIC was determined by a modified agar dilution method on Middlebrook 7H10 agar, as described previously [9]. MIC was defined as the lowest drug concentration that inhibited at least 99% of the bacterial proportion after a twofold serial dilution of the respective drug (MIC99). Results are shown in table 1. All M. abscessus strains tested exhibited a MIC for bedaquiline of ⩽1 µg•mL −1 , and 17/20 (85%) had a MIC of ⩽0.5 µg•mL −1. Median MIC for all M. abscessus strains was 0.5 µg•mL −1 , only slightly higher than that for M. tuberculosis (0.4 µg•mL −1)...

Determination of MIC Distribution and Mechanisms of Decreased Susceptibility to Bedaquiline among Clinical Isolates of Mycobacterium abscessus

“…Based on our data and those of others ( 14 , 15 , 17 ), bedaquiline showed a high antibacterial activity at a very low concentration (<0.1 mg/liter). In addition, bedaquiline can maintain a mean plasma concentration of 0.6 mg/liter at standard oral doses ( 18 ), and it can be extensively distributed to tissues, including the lungs, according to the pharmacokinetic studies ( 19 ).…”

“…New drugs, especially new anti-TB drugs, against M. abscessus infections have brought new hope for treating M. abscessus infections. With the advantages of oral delivery, bedaquiline has been considered as a prospective drug in the treatment of M. abscessus infections ( 17 ). Thus, clinical data for in vitro susceptibility of M. abscessus to bedaquiline are urgently needed.…”

Mutations in the MAB_2299c TetR Regulator Confer Cross-Resistance to Clofazimine and Bedaquiline in Mycobacterium abscessus

“…BDQ acts by targeting the c subunit of the essential F o F 1 ATP synthase (24)(25)(26)(27), and studies have also proposed that it may inhibit the ATP synthase via another mechanism involving the subunit of the enzyme, in addition to binding to its c subunit (28,29). BDQ exhibits very low MICs against various NTM, including M. abscessus clinical isolates from CF and non-CF patients (27,30,31), but despite being an excellent growth inhibitor at low doses, it lacks bactericidal activity against M. abscessus (27). Studies in immunocompromised mouse models led to conflictual conclusions, reporting, on the one hand, a benefit of BDQ in reducing bacterial loads in gamma interferon knockout mice (32) and, on the other hand, no decrease in the bacillary loads in the lungs or an inability to prevent death in nude mice (33).…”

Verapamil Improves the Activity of Bedaquiline against Mycobacterium abscessusIn Vitro and in Macrophages

“…BDQ is a diarylquinoline approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of multidrug-resistant tuberculosis (10). We and others have recently shown that BDQ exhibits very low MIC values against NTM, including clinical M. abscessus strains from CF and non-CF patients (11)(12)(13). To determine the cooperative potential of BDQ with companion drugs for new treatment regimens against M. abscessus, evaluation of combinations of BDQ and other antimicrobials in synergism is necessary.…”