Impact of the CFTR-Potentiator Ivacaftor on Airway Microbiota in Cystic Fibrosis Patients Carrying A G551D Mutation

Bernarde, Cédric; Keravec, Marlène; Mounier, Jérôme; Gouriou, S.; Rault, G.; Férec, Claude; Barbier, Georges; Héry-Arnaud, Geneviève

doi:10.1371/journal.pone.0124124

Cited by 72 publications

(77 citation statements)

References 49 publications

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“…Of interest is that restitution of CFTR function with ivacaftor modified the microbiome, presumably for the better. 32 For idiopathic pulmonary fibrosis (IPF), the most-common mutation in the gene encoding Mucin 5B ( Muc5B ) was found to be associated with the total levels (burden) of bacteria present. 33 More interesting perhaps is the recent study of the Fucosyltransferase 2 ( FUT2 ) genotype in non-CF bronchiectasis and its impact on P. aeruginosa dominance of the microbiota present.…”

Section: Host Factorsmentioning

confidence: 99%

The lung microbiome in health and disease

Moffatt¹,

Cookson²

2017

Clinical Medicine

162

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The Human Microbiome Project began 10 years ago, leading to a signifi cant growth in understanding of the role the human microbiome plays in health and disease. In this article, we explain with an emphasis on the lung, the origins of microbiome research. We discuss how 16S rRNA gene sequencing became the fi rst major molecular tool to examine the bacterial communities present within the human body. We highlight the pitfalls of molecular-based studies, such as false fi ndings resulting from contamination, and the limitations of 16S rRNA gene sequencing. Knowledge about the lung microbiome has evolved from initial scepticism to the realisation that it might have a signifi cant infl uence on many illnesses. We also discuss the lung microbiome in the context of disease by giving examples of important respiratory conditions. In addition, we draw attention to the challenges for metagenomic studies of respiratory samples and the importance of systematic bacterial isolation to enable host-microbiome interactions to be understood. We conclude by discussing how knowledge of the lung microbiome impacts current clinical diagnostics.

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Section: Host Factorsmentioning

confidence: 99%

The lung microbiome in health and disease

Moffatt¹,

Cookson²

2017

Clinical Medicine

162

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“…The drug was recently identified to have potentially beneficial off‐target effects as a weak inhibitor of bacterial DNA gyrase and topoisomerase IV due to its potential chemical similarity with ciprofloxacin (fluoroquinolones) . Simultaneous delivery of ciprofloxacin and ivacaftor may have synergistic bactericidal effects, while also increasing mucociliary clearance (MCC) by promoting Cl ‐ transport . We have shown previously that ivacaftor and ciprofloxacin have synergistic bactericidal activity when used concurrently in vitro .…”

mentioning

confidence: 99%

In‐vitro evaluation of a ciprofloxacin‐ and ivacaftor‐coated sinus stent against Pseudomonas aeruginosa biofilms

Cho

Lim

Mackey

et al. 2019

Int Forum Allergy Rhinol

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Background:We recently developed a novel ciprofloxacincoated sinus stent capable of releasing antibiotics over a sustained period of time. Ivaca or is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that has synergistic bactericidal activity with ciprofloxacin and also enhances sinus mucociliary clearance. The objective of this study was to optimize and evaluate the efficacy of a ciprofloxacin-and ivaca or-releasing biodegradable sinus stent (CISS) in vitro. Methods: A CISS was created by coating ciprofloxacin/ivacaor-embedded nanoparticles with an acrylate and ammonium methacrylate copolymer onto a biodegradable poly-L-lactic acid stent. In-vitro evaluation of the CISS included:(1) assessment of drug stability in nanoparticles by zeta potential, and drug-coating stability within the CISS using scanning electron microscopy (SEM); (2) determination of ciprofloxacin-and ivaca or-release kinetics; and (3) assessment of anti-Pseudomonas aeruginosa biofilm formation by calculating relative optical density units (RODUs) compared with control stents at 590-nm optical density. Results:The presence of drugs and a uniform coating on the stent were confirmed by zeta potential and SEM.Sustained drug release was observed through 21 days without an initial burst release. Anti-biofilm formation was observed a er placing the CISS for 3 days onto a preformed 1-day P aeruginosa biofilm. The CISS significantly reduced biofilm mass compared with bare stents and controls (RO-DUs at 590-nm optical density; CISS, 0.31 ± 0.01; bare stent, 0.78 ± 0.12; control, 1.0 ± 0.00; p = 0.001; n = 3). Conclusion:The CISS maintains a uniform coating and sustained delivery of drugs providing a marked reduction in P aeruginosa biofilm formation. Further studies evaluating the efficacy of CISS in a preclinical model are planned. C 2019 ARS-AAOA, LLC.

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“…98 Although these clinical trials excluded patients with advanced lung disease (FEV 1 <40% predicted), improvements in FEV 1 (absolute 4-6%), weight gain (2-4 kg), and reduced intravenous antibiotic requirements have been seen in those with advanced disease. [99][100][101] Other beneficial effects reported with ivacaftor in patients with G551D mutations include improvements in exhaled nitric oxide levels 102 ; reduced streptococcus sputum bacterial load 103 ; reduced mucus plugging, bronchiectasis, [104][105][106][107] and sinus disease on computed tomography [108][109][110] ; and positive extrapulmonary effects (improved insulin secretion, 111 112 resolution of cystic fibrosis related diabetes, 113 and reduced hepatic steatosis). 114 In addition to targeting class III gating mutations, ivacaftor has been evaluated in patients over 6 years who have at least one class IV R117H mutation, a mutation associated with residual CFTR function.…”

Section: Late Phase Clinical Trials Of Treatments Targeting the Undermentioning

confidence: 99%

New and emerging targeted therapies for cystic fibrosis

Quon

Rowe

2016

BMJ

119

122

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Cystic fibrosis (CF) is a monogenic autosomal recessive disorder that affects about 70,000 people worldwide. The clinical manifestations of the disease are caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The discovery of the CFTR gene in 1989 has led to a sophisticated understanding of how thousands of mutations in the CFTR gene affect the structure and function of the CFTR protein. Much progress has been made over the past decade with the development of orally bioavailable small molecule drugs that target defective CFTR proteins caused by specific mutations. Furthermore, there is considerable optimism about the prospect of gene replacement or editing therapies to correct all mutations in cystic fibrosis. The recent approvals of ivacaftor and lumacaftor represent the genesis of a new era of precision medicine in the treatment of this condition. These drugs are having a positive impact on the lives of people with cystic fibrosis and are potentially disease modifying. This review provides an update on advances in our understanding of the structure and function of the CFTR, with a focus on state of the art targeted drugs that are in development.

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Impact of the CFTR-Potentiator Ivacaftor on Airway Microbiota in Cystic Fibrosis Patients Carrying A G551D Mutation

Cited by 72 publications

References 49 publications

The lung microbiome in health and disease

The lung microbiome in health and disease

In‐vitro evaluation of a ciprofloxacin‐ and ivacaftor‐coated sinus stent against Pseudomonas aeruginosa biofilms

New and emerging targeted therapies for cystic fibrosis

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