Bedaquiline and delamanid in the treatment of multidrug‐resistant tuberculosis: Promising but challenging

Li, Yang; Sun, Feng; Zhang, Wenhong

doi:10.1002/ddr.21498

Cited by 88 publications

(56 citation statements)

References 41 publications

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“…Recently, three new antitubercular drugs, bedaquiline (BDQ) (Janssen, Beerse, Belgium), delamanid (Otsuka, Tokyo, Japan), and pretomanid (TB Alliance) were approved for the treatment of MDR-TB (Li et al, 2019;Nieto Ramirez et al, 2020). Interestingly, several studies demonstrated that patients treated with a BDQ-containing regimen showed a high culture conversion rate (65-100%) (Li et al, 2019;Pontali et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…BDQ is a diarylquinoline that targets atpE gene, coding for the subunit c of the ATP synthase complex ( Andries et al, 2005 ). Its use reduces the mortality when added to treatment for MDR- and XDR-TB ( Li et al, 2019 ; Conradie et al, 2020 ). The potential risk of BDQ of prolonging the QT interval has occurred in only 0.6% of treated patients; consequently, the advantage in its use is uncontested, even if it is still under investigation.…”

Section: Introductionmentioning

confidence: 99%

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In vitro Study of Bedaquiline Resistance in Mycobacterium tuberculosis Multi-Drug Resistant Clinical Isolates

et al. 2020

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Tuberculosis (TB) is one of the major causes of death related to antimicrobial resistance worldwide because of the spread of Mycobacterium tuberculosis multi-and extensively drug resistant (multi-drug resistant (MDR) and extensively drug-resistant (XDR), respectively) clinical isolates. To fight MDR and XDR tuberculosis, three new antitubercular drugs, bedaquiline (BDQ), delamanid, and pretomanid were approved for use in clinical setting. Unfortunately, BDQ quickly acquired two main mechanisms of resistance, consisting in mutations in either atpE gene, encoding the target, or in Rv0678, coding for the repressor of the MmpS5-MmpL5 efflux pump. To better understand the spreading of BDQ resistance in MDR-and XDR-TB, in vitro studies could be a valuable tool. To this aim, in this work an in vitro generation of M. tuberculosis mutants resistant to BDQ was performed starting from two MDR clinical isolates as parental cultures. The two M. tuberculosis MDR clinical isolates were firstly characterized by whole genome sequencing, finding the main mutations responsible for their MDR phenotype. Furthermore, several M. tuberculosis BDQ resistant mutants were isolated by both MDR strains, harboring mutations in both atpE and Rv0678 genes. These BDQ resistant mutants were further characterized by studying their growth rate that could be related to their spreading in clinical settings. Finally, we also constructed a data sheet including the mutations associated with BDQ resistance that could be useful for the early detection of BDQ-resistance in MDR/XDR patients with the purpose of a better management of antibiotic resistance in clinical settings.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In vitro Study of Bedaquiline Resistance in Mycobacterium tuberculosis Multi-Drug Resistant Clinical Isolates

et al. 2020

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“…Although bedaquiline has not been extensively studied in NTM disease, the drug's adverse effects have been investigated in various clinical trials for MDR-TB and it has been safely used for even over 18 months [41][42][43]. However, the long plasma half-life of four to five months and known QTc interval prolongation require careful clinical evaluation [41,44].…”

Section: Discussionmentioning

confidence: 99%

Successful bedaquiline-containing antimycobacterial treatment in post-traumatic skin and soft-tissue infection by Mycobacterium fortuitum complex: a case report

et al. 2020

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Background Mycobacterium fortuitum complex is a group of rapidly growing nontuberculous mycobacteria (NTM) associated with skin and soft-tissue infections after surgery or trauma. Treatment of NTM is challenging, due to resistance to multiple antimycobacterial agents. Bedaquiline is a diarylquinoline that inhibits mycobacterial ATP-synthase. The drug has recently been approved for the treatment of multidrug-resistant tuberculosis and evidence of its in vitro efficacy against NTM, including Mycobacterium fortuitum complex, has been published. Case presentation A 20-year-old Caucasian woman with chronic skin and soft tissue infection in the lower leg following a traffic accident in Vietnam underwent a tedious journey of healthcare visits, hospital admissions, empiric antimicrobial treatments, surgical debridement and plastic reconstruction before definite diagnosis of Mycobacterium fortuitum complex-infection was established by culture from a tissue biopsy and targeted antimycobacterial therapy was administered. Histopathological examination revealed granulomatous purulent inflammation, which strongly supported the diagnosis. Genotypic identification was performed and broth microdilution for susceptibility testing showed macrolide resistance. Five weeks of induction treatment with intravenous amikacin, imipenem / cilastin, and oral levofloxacin was administered, followed by all-oral treatment with bedaquiline combined with levofloxacin for four months, which was well-tolerated and led to persistent healing with scars but without signs of residual infection. Conclusions Bedaquiline is a promising novel agent for NTM treatment, although clinical data are limited and trials evaluating efficacy, safety, and resistance of bedaquiline are required. To our knowledge, this is the first reported case of successful in vivo use of bedaquiline for a skin and soft tissue infection caused by Mycobacterium fortuitum complex.

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“…Bedaquiline (BDQ) and delamanid (DLM) have expanded available treatment options and improved treatment success rates for patients with pulmonary MDR-TB and XDR-TB ( 44, 45, 46, 47 ), including children with MDR-TB ( 48, 49 ). The detection of resistance to BDQ and DLM is critical to ensuring effective treatment and care for DR-TB patients and preventing ongoing transmission.…”

Section: Discussionmentioning

confidence: 99%

Characterization of genomic variants associated with resistance to bedaquiline and delamanid in naïve Mycobacterium tuberculosis clinical strains

Battaglia¹,

Spitaleri

Cabibbe³

et al. 2020

Preprint

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The role of genetic mutations in genes associated to phenotypic resistance to bedaquiline (BDQ) and delamanid (DLM) in Mycobacterium tuberculosis complex (MTBc) strains is poorly understood. However, a clear understanding of the role of each genetic variant is crucial to guide the development of molecular-based drug susceptibility testing (DST). In this work, we analysed all mutations in candidate genomic regions associated with BDQ- and DLM-resistant phenotypes using a whole genome sequencing (WGS) dataset from a collection of 4795 MTBc clinical isolates from six high-burden countries of tuberculosis (TB). From WGS analysis, we identified 61 and 158 unique mutations in genomic regions potentially involved in BDQ- and DLM-resistant phenotypes, respectively. Importantly, all strains were isolated from patients who likely have never been exposed to the medicines. In order to characterize the role of mutations, we performed an energetic in silico analysis to evaluate their effect in the available protein structures Ddn (DLM), Fgd1 (DLM) and Rv0678 (BDQ), and minimum inhibitory concentration (MIC) assays on a subset of MTBc strains carrying mutations to assess their phenotypic effect. The combination of structural protein information and phenotypic data allowed for cataloging the mutations clearly associated with resistance to BDQ (n= 4) and DLM (n= 35), as well as about a hundred genetic variants without any correlation with resistance. Importantly, these results show that both BDQ and DLM resistance-related mutations are diverse and distributed across the entire region of each gene target, which is of critical importance to the development of comprehensive molecular diagnostic tools.ImportancePhenotypic drug susceptibility tests (DST) are too slow to provide an early indication of drug susceptibility status at the time of treatment initiation and very demanding in terms of specimens handling and biosafety. The development of molecular assays to detect resistance to bedaquiline (BDQ) and delamanid (DLM) requires accurate categorization of genetic variants according to their association with phenotypic resistance. We have evaluated a large multi-country set of clinical isolates to identify mutations associated with increased minimum inhibitory concentrations (MICs) and used an in silico protein structure analysis to further unravel the potential role of these mutations in drug resistance mechanisms. The results of this study are an important source of information for the development of molecular diagnostic tests to improve the provision of appropriate treatment and care to TB patients.

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Bedaquiline and delamanid in the treatment of multidrug‐resistant tuberculosis: Promising but challenging

Cited by 88 publications

References 41 publications

In vitro Study of Bedaquiline Resistance in Mycobacterium tuberculosis Multi-Drug Resistant Clinical Isolates

In vitro Study of Bedaquiline Resistance in Mycobacterium tuberculosis Multi-Drug Resistant Clinical Isolates

Successful bedaquiline-containing antimycobacterial treatment in post-traumatic skin and soft-tissue infection by Mycobacterium fortuitum complex: a case report

Characterization of genomic variants associated with resistance to bedaquiline and delamanid in naïve Mycobacterium tuberculosis clinical strains

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