Bedaquiline for treatment of non-tuberculous mycobacteria (NTM): a systematic review and meta-analysis

Abstract

Background: Non-tuberculous mycobacteria (NTM) infections are increasing in incidence and associated mortality. NTM are naturally resistant to a variety of antibiotics, complicating treatment. We conducted a literature assessment on the efficacy of bedaquiline in treating NTM species in vitro and in vivo (animal models and humans); meta-analyses were performed where possible.

Method: Four databases were searched using specific terms. Publications were included according to predefined criteria. Bedaquiline's impact on NTM in vitro, MICs and epidemiological cut-off (ECOFF) values were evaluated. A meta-analysis of bedaquiline efficacy against NTM infections in animal models was performed. Culture conversion, cure and/or relapse-free cure were used to evaluate the efficacy of bedaquiline in treating NTM infection in humans.

Results: Fifty studies met the inclusion criteria: 33 assessed bedaquiline's impact on NTM in vitro, 9 in animal models and 8 in humans. Three studies assessed bedaquiline's efficacy both in vitro and in vivo. Due to data paucity, an ECOFF value of 0.5 mg/mL was estimated for Mycobacterium abscessus only. Meta-analysis of animal studies showed a 1.86× reduction in bacterial load in bedaquiline-treated versus no treatment within 30 days. In humans, bedaquiline-including regimens were effective in treating NTM extrapulmonary infection but not pulmonary infection.

Conclusions: Bedaquiline demonstrated strong antibacterial activity against various NTM species and is a promising drug to treat NTM infections. However, data on the genomic mutations associated with bedaquiline resistance were scarce, preventing statistical analyses for most mutations and NTM species. Further studies are urgently needed to better inform treatment strategies.

Figure 1.

Flow diagram of studies selection. *One animal study and two human studies performed in vitro analysis and were included in our in vitro analysis.

Figure 2.

Risk of bias of the in vitro studies. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 3.

Quality assessment of animal model studies using SYRCLE tool. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 4.

Risk of bias of case series. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 5.

Risk of bias of case reports. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 6.

MIC distribution of the common NTM species in CAMHB. The blue arrow is pointing to the eyeball value and the red arrow is showing the T-ECOFF value. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 7.

Forest plot of bedaquiline (BDQ)-treated animals versus control (no treatment) animals. Outcome 1.1: BDQ effect on bacterial load for each group up to 30 days (subgroup by organs). The effect of BDQ on bacterial load in each group was expressed as log₁₀ cfu ± SD. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 8.

Forest plot of bedaquiline (BDQ)-treated animals versus control (no treatment) animals. Outcome 1.2: BDQ effect on bacterial load up to 30 days (subgroup by NTM species). The effect of BDQ on bacterial load was expressed as log₁₀ cfu ± SD. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.