Bedaquiline as a potential agent in the treatment of M. intracellulare and M. avium infections

To the Editor:

Recently in this journal, Salfinger and Migliori [1] discussed the accessibility of bedaquiline drug susceptibility testing and the analysis of minimum inhibitory concentrations (MICs) for strains of Mycobacterium tuberculosis. As the recommended treatments for diseases caused by M. avium, and especially M. intracellulare, have high failure rates [2, 3], we measured the MIC of bedaquiline in 20 clinical isolates of these species.

Bedaquiline is a new anti-tuberculous drug, recently licensed for the treatment of multidrug-resistant M. tuberculosis infections. It belongs to the diarylquinoline group and acts by inhibiting mycobacterial F1Fo-ATP synthase [4]. Bedaquiline has strong in vitro activity against M. tuberculosis, including resistant strains [5, 6], and an increasing body of post-licensing evidence suggests it has excellent efficacy in the treatment of multidrug-resistant and extensively drug-resistant TB [7–10]. Bedaquiline is characterised pharmacologically by its excellent intracellular bactericidal activity and high accumulation rate [4]. For conventional drugs, in vitro drug susceptibility testing of M. avium-intracellulare complex (MAC) strains is currently recommended only after treatment failure, and the methods are not yet well established [1, 2, 5, 11].

For decades, our laboratory has routinely determined the MICs of first- and second-line TB drugs in multidrug-resistant TB and nontuberculous mycobacteria (NTM) including MAC strains [12]. Here, we present the in vitro susceptibility testing results of 11 clinical strains of M. intracellulare and nine of M. avium, isolated from patients with pulmonary NTM disease in our centre between 2008 and 2015. MICs were determined using a modified agar dilution method on Middlebrook 7H10 agar, as described elsewhere [13]. MIC was defined as the lowest drug concentration that inhibited at least 99% of the bacterial proportion after a two-fold serial dilution of the respective drug.

Results are shown in table 1. Bedaquiline had a low MIC in nine M. intracellulare strains (0.06 µg·mL⁻¹). For M. avium, the MIC was 0.12 µg·mL⁻¹ in five strains and 0.06 µg·mL⁻¹ in four. There was a nonsignificant trend towards a lower MIC in M. intracellulare than in M. avium (Chi-squared test: p=0.066). These MIC values were only slightly higher than those published for strains of M. tuberculosis [14]. In 2007, Huitric et al. [14] tested 17 M. avium strains and five M. intracellulare strains and also found low MIC values.

Bedaquiline could be an effective candidate in the second-line treatment of mycobacterial disease caused by MAC. Philley et al. [15] reported its successful use in the salvage therapy of six patients with MAC infection of the lungs without differentiated species information. In general, when treatment of NTM infections is indicated, the duration of treatment is >12 months [2, 11]. It is reasonable to consider the effects of long-term treatment with new drugs used in relapsing or complicated NTM disease. Regarding toxicity, Lewis et al. [7] recently published a first experience of long-term bedaquiline use (18 months) in a case of extensively drug-resistant TB, reporting that no clinical side effects had occurred during the whole observation period.

In view of the in vitro data, bedaquiline seems to be a good candidate for severe or relapsing diseases caused by M. intracellulare and M. avium, respectively. Clinical trials are warranted to confirm this potential use.