<i>In Vitro</i>
            Susceptibility Testing of Bedaquiline against Mycobacterium avium Complex

Brown‐Elliott, Barbara A.; Philley, Julie V.; Griffith, David E.; Thakkar, Foram; Wallace, Richard J.

doi:10.1128/aac.01798-16

Cited by 67 publications

(43 citation statements)

References 16 publications

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“…This range is consistent with the results of a recent study conducted by members of our group (17). Briefly, of 103 MAC isolates tested by broth microdilution, 90 (87%) isolates showed BDQ MICs of Յ0.008 g/ml, and only one isolate had an MIC of Ն0.015.…”

Section: Discussionsupporting

confidence: 80%

“…However, in vitro results do not always correlate with in vivo performance, and breakpoints for many drugs, including BDQ, have not yet been established (16). Nonetheless, we have recently implemented a BDQ susceptibility testing method for MAC that can identify isolates with elevated MICs (defined as MICs higher than those of untreated or wild strains) (17). Here, we examine MAC isolates recovered before, during, and after BDQ therapy and describe a novel genetic locus associated with microbiological relapse.…”

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confidence: 99%

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Emergence of mmpT5 Variants during Bedaquiline Treatment of Mycobacterium intracellulare Lung Disease

Alexander

Vasireddy

et al. 2017

J Clin Microbiol

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Bedaquiline (BDQ), a diarylquinoline antibiotic that targets ATP synthase, is effective for the treatment of Mycobacterium tuberculosis infections that no longer respond to conventional drugs. While investigating the off-label use of BDQ as salvage therapy, seven of 13 patients with Mycobacterium intracellulare lung disease had an initial microbiological response and then relapsed. Whole-genome comparison of pretreatment and relapse isolates of M. intracellulare uncovered mutations in a previously uncharacterized locus, mmpT5. Preliminary analysis suggested similarities between mmpT5 and the mmpR5 locus, which is associated with low-level BDQ resistance in M. tuberculosis. Both genes encode transcriptional regulators and are adjacent to orthologs of the mmpS5-mmpL5 drug efflux operon. However, MmpT5 belongs to the TetR superfamily, whereas MmpR5 is a MarR family protein. Targeted sequencing uncovered nonsynonymous mmpT5 mutations in isolates from all seven relapse cases, including two pretreatment isolates. In contrast, only two relapse patient isolates had nonsynonymous changes in ATP synthase subunit c (atpE), the primary target of BDQ. Susceptibility testing indicated that mmpT5 mutations are associated with modest 2-to 8-fold increases in MICs for BDQ and clofazimine, whereas one atpE mutant exhibited a 50-fold increase in MIC for BDQ. Bedaquiline shows potential for the treatment of M. intracellulare lung disease, but optimization of treatment regimens is required to prevent the emergence of mmpT5 variants and microbiological relapse.

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Section: Discussionsupporting

confidence: 80%

mentioning

confidence: 99%

Emergence of mmpT5 Variants during Bedaquiline Treatment of Mycobacterium intracellulare Lung Disease

Alexander

Vasireddy

et al. 2017

J Clin Microbiol

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“…There is interest in evaluating new anti-TB compounds against NTM, which will provide new options for (14), which is significantly lower than the MIC 50 of 0.03 mg/liter from the current study. Although the exact reasons remain unknown, several potential reasons may be responsible for the discrepancy with respect to other studies.…”

Section: Discussionmentioning

confidence: 95%

In Vitro Activity of Bedaquiline against Nontuberculous Mycobacteria in China

Pang

Zheng

Tan

et al. 2017

Antimicrob Agents Chemother

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The main goal of our study was to evaluate the in vitro bedaquiline susceptibility of six prevalent species of pathogenic nontuberculous mycobacteria (NTM) in China. In addition, we investigated the potential molecular mechanisms contributing to bedaquiline resistance in the different NTM species. Among slowly growing mycobacteria (SGM), bedaquiline exhibited the highest activity against 44 (20.2%), 42 (25.8%), and 7 (31.8%), respectively, were resistant to bedaquiline. No significant differences in the proportions of bedaquiline resistance among these species were observed (P Ͼ 0.05). Genetic mutations were observed in 74 isolates (10.8%), with all nucleotide substitutions being synonymous. In conclusion, our data demonstrate that bedaquiline shows moderate in vitro activity against NTM species. Using the proposed ECOFF values, we could distinguish between bedaquiline-resistant and -susceptible strains with the broth dilution method. In addition, no nonsynonymous mutations in the atpE gene that conferred bedaquiline resistance in all six NTM species were identified.

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“…Linezolid is an oxalidinone with broad antimycobacterial activity that has been used to treat multidrug‐resistant tuberculosis as well as NTM. However, the use of the drug has been limited by high rates of adverse reactions including peripheral neuropathy, optic neuritis, and cytopenias . Bedaquiline is a diarylquinoline approved for the treatment of multidrug‐resistant tuberculosis in adults.…”

Section: Treatment Of Ntm Pulmonary Diseasementioning

confidence: 99%

“…However, the use of the drug has been limited by high rates of adverse reactions including peripheral neuropathy, optic neuritis, and cytopenias. 70,71 Bedaquiline is a diarylquinoline approved for the treatment of multidrug-resistant tuberculosis in adults. The drug is an ATP synthase inhibitor with broad antimycobacterial activity with MICs for MAC ranging from 0.008 to .0.03 μg/mL.…”

Section: S31mentioning

confidence: 99%

Nontuberculous mycobacteria in cystic fibrosis: Updates and the path forward

Martiniano

Davidson

Nick

2017

Pediatric Pulmonology

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Nontuberculous mycobacteria (NTM) are troublesome pathogens that can cause significant pulmonary disease in patients with cystic fibrosis (CF). Diagnosis can be difficult in the setting of underlying CF and treatment regimens are burdensome on both patients and providers. Recent consensus guidelines for treatment of NTM in CF have provided a guide for the CF community, however research is lagging regarding accuracy of our diagnostic abilities and treatment efficacy. In this review, we provide new insights into the complexity of NTM from emerging whole genome sequencing data, a summary of current NTM diagnosis and treatment guidelines, highlight new treatment options, and discuss future research projects which aim to better define which patients to treat and timing and duration of treatment.

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In Vitro Susceptibility Testing of Bedaquiline against Mycobacterium avium Complex

Cited by 67 publications

References 16 publications

Emergence of mmpT5 Variants during Bedaquiline Treatment of Mycobacterium intracellulare Lung Disease

Emergence of mmpT5 Variants during Bedaquiline Treatment of Mycobacterium intracellulare Lung Disease

In Vitro Activity of Bedaquiline against Nontuberculous Mycobacteria in China

Nontuberculous mycobacteria in cystic fibrosis: Updates and the path forward

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