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There are a lack of outcome measures with robust clinimetric properties in bronchiectasis.To determine the clinimetric properties (reliability over one year during clinical stability and responsiveness over a course of antibiotics for pulmonary exacerbation) of objective and patient-reported outcome measures.This multi-centre cohort study included adults with bronchiectasis from seven UK hospitals. Participants attended four visits, four months apart over one year while clinically stable and at the beginning/end of exacerbation and completed lung function (spirometry and multiple breath washout), provided a blood sample for C-reactive protein measurement and completed health-related quality of life (HRQoL) questionnaires (Quality of Life-Bronchiectasis (QoL-B), St. George's Respiratory Questionnaire (SGRQ) and EuroQoL (EQ-5D-5L).Participants (n=132) had a mean (SD) age of 66 (11) years, 64% were female. Lung function parameters (forced expiratory volume in one second (FEVThis information on the clinimetric properties of lung function parameters, CRP and HRQoL parameters should be used to inform the choice of outcome measures used in future bronchiectasis trials.

BACKGROUND: Cystic fibrosis (CF) is characterized by neutrophilic inflammation in the airways. Leukotriene B4 (LTB4) is a neutrophil chemoattractant and has been implicated in CF pathogenesis. Acebilustat, a novel, synthetic, small-molecule leukotriene A4 hydrolase inhibitor, reduces LTB4 production. We report findings from a randomized placebo-controlled trial of acebilustat in adult subjects with mild-to-moderate lung disease.METHODS: Subjects were randomized (1:1:1) to once-daily acebilustat 50 mg, 100 mg or placebo for 48 weeks, concomitantly with their current therapeutic regimen. Subjects were stratified by use of concomitant CF transmembrane conductance regulator (CFTR) modulators, baseline percent predicted forced expiratory volume in 1 second (ppFEV1) 50-75 and >75, and number of pulmonary exacerbations in the past year (1 or >1). Primary endpoints were the change from baseline in ppFEV1 and safety. Secondary endpoints included the rate of pulmonary exacerbations.RESULTS: Overall, 199 subjects were randomized and dosed (acebilustat 50 mg, n=67; acebilustat 100 mg, n=66; placebo, n=66). Baseline demographics and disease profile were well balanced among treatment groups. Acebilustat had no statistically significant effect on the primary endpoint of change in ppFEV1 at week 48 or the secondary endpoint pulmonary exacerbations. There was a trend towards reduced pulmonary exacerbations in subjects receiving acebilustat in pre-specified populations with ppFEV1>75 (35% rate reduction) and those on concomitant CFTR modulator therapy (20% rate reduction). Acebilustat was well tolerated.CONCLUSIONS: Acebilustat did not improve lung function. A trend towards reduced pulmonary exacerbations in subjects with an earlier stage of lung disease suggests a potential effect in this population.

Cystic Fibrosis pulmonary exacerbations are critical events in the lives of people with CF that have deleterious effects on lung function, quality of life, and life expectancy. There are significant unmet needs in the management of exacerbations. We review here the associated inflammatory changes that underlie these events and are of interest for the development of biomarkers of exacerbation.Inflammatory responses in CF are abnormal and contribute to a sustained proinflammatory lung microenvironment, abundant in proinflammatory mediators and deficient in counter-regulatory mediators that terminate and resolve inflammation. There is increasing interest in these inflammatory pathways to discover novel biomarkers for pulmonary exacerbation management. In this review, we explore the inflammatory changes occurring during intravenous antibiotic therapy for exacerbation and how they may be applied as biomarkers to guide exacerbation therapy. A literature search was conducted using the PubMed database in February 2020.Heterogeneity in inflammatory responses to treatment of a pulmonary exacerbation, a disease process with complex pathophysiology, limits the clinical utility of individual biomarkers. Biomarker panels may be a more successful strategy to capture informative changes within the CF population to improve pulmonary exacerbation management and outcomes.

BackgroundElexacaftor plus tezacaftor plus ivacaftor is a triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be generally safe and efficacious in people with cystic fibrosis aged 12 years or older with at least one F508del-CFTR allele. We aimed to assess the magnitude and durability of the clinical effects of this triple combination regimen in people with cystic fibrosis homozygous for the F508del-CFTR mutation.MethodsWe conducted a multicentre, randomised, double-blind, active-controlled, phase 3b trial of elexacaftor plus tezacaftor plus ivacaftor at 35 medical centres in Australia, Belgium, Germany, and the UK. Eligible participants were those with cystic fibrosis homozygous for the F508del-CFTR mutation, aged 12 years or older with stable disease, and with a percent predicted FEV1 of 40–90% inclusive. After a 4-week run-in period, in which participants received tezacaftor 100 mg orally once daily and ivacaftor 150 mg orally every 12 h, participants were randomly assigned (1:1) to receive 24 weeks of either elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (elexacaftor plus tezacaftor plus ivacaftor group) or tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (tezacaftor plus ivacaftor group). Randomisation was stratified by percent predicted FEV1, age at screening visit, and whether the participant was receiving CFTR modulators at the time of the screening visit. Patients, investigators, and sponsor's study execution team were masked to treatment assignment. The primary endpoint was the absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline (ie, at the end of the tezacaftor plus ivacaftor run-in period) up to and including week 24. The key secondary endpoint was the absolute change from baseline in percent predicted FEV1 up to and including week 24; other secondary endpoints were the absolute change from baseline in sweat chloride concentrations up to and including week 24, and safety and tolerability. All endpoints were assessed in all randomised patients who had received at least one dose of their assigned regimen. This study is registered with ClinicalTrials.gov, NCT04105972.FindingsBetween Oct 3, 2019, and July 24, 2020, 176 participants were enrolled. Following the 4-week tezacaftor plus ivacaftor run-in period, 175 participants were randomly assigned (87 to the elexacaftor plus tezacaftor plus ivacaftor group and 88 to the tezacaftor plus ivacaftor group) and dosed in the treatment period. From baseline up to and including week 24, the mean CFQ-R respiratory domain score increased by 17·1 points (95% CI 14·1 to 20·1) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·2 points (−1·7 to 4·2) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 15·9 points [95% CI 11·7 to 20·1], pInterpretationThe elexacaftor plus tezacaftor plus ivacaftor regimen was safe and well tolerated, and led to significant and clinically meaningful improvements in respiratory-related quality of life and lung function, as well as improved CFTR function, changes that were durable over 24 weeks and superior to those seen with tezacaftor plus ivacaftor in this patient population.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with cystic fibrosis (pwCF) can lead to severe outcomes.MethodsIn this observational study, the European Cystic Fibrosis Society Patient Registry collected data on pwCF and SARS-CoV-2 infection to estimate incidence, describe clinical presentation and investigate factors associated with severe outcomes using multivariable analysis.ResultsUp to December 31, 2020, 26 countries reported information on 828 pwCF and SARS-CoV-2 infection. Incidence was 17.2 per 1000 pwCF (95% CI: 16.0–18.4). Median age was 24 years, 48.4% were male and 9.4% had lung transplants. SARS-CoV-2 incidence was higher in lung-transplanted (28.6; 95% CI: 22.7–35.5) versus non-lung-transplanted pwCF (16.6; 95% CI: 15.4–17.8) (p≤0.001).SARS-CoV-2 infection caused symptomatic illness in 75.7%. Factors associated with symptomatic SARS-CoV-2 infection were age >40 years, at least one F508del mutation and pancreatic insufficiency.Overall, 23.7% of pwCF were admitted to hospital, 2.5% of those to intensive care, and regretfully 11 (1.4%) died. Hospitalisation, oxygen therapy, intensive care, respiratory support and death were 2- to 6-fold more frequent in lung-transplanted versus non-lung-transplanted pwCF.Factors associated with hospitalisation and oxygen therapy were lung transplantation, cystic fibrosis-related diabetes (CFRD), moderate or severe lung disease and azithromycin use (often considered a surrogate marker for Pseudomonas aeruginosa infection and poorer lung function).ConclusionSARS-CoV-2 infection yielded high morbidity and hospitalisation in pwCF. PwCF with forced expiratory volume in 1 s

Antimicrobial resistance (AMR) has now emerged as a major global public health problem. Certain bacterial pathogens, particularly Gram negative organisms associated with patients with cystic fibrosis (CF), have become resistant to several classes of antibiotics resulting in pan-resistance, which creates a clinical treatment dilemma. This study wished to explore the production of antibacterial extracellular metabolites from plant pathogenic fungi. Fungal Culture Extracts (FCEs) were prepared from 10 fungi (Armillaria gallica, Clitocybe nebularis, Fusarium coeruleum, Fusarium oxysporum, Fusarium poae, Hymenoscyphus fraxineus, Nectria fuckeliana, Phytophthora infestans, Phytophthora ramorum, Postia placenta), which were tested for activity against the CF pathogens, Pseudomonas aeruginosa (PA) (n=8), Burkholderia cenocepacia (n=2) and Stenotrophomonas maltophilia (n=2). In addition, FCE were assessed for their ability to alter antibiotic susceptibility in PA (n=8), with six antipseudomonal antibiotics (ceftazidime, ciprofloxacin, colistin, meropenem, piperacillin/tazobactam, tobramycin). None of the FCEs showed inhibitory activity to the 12 bacterial isolates tested, with the exception of the FCE from Postia placenta, which showed inhibition against all 12 bacteria. An antagonistic interaction was observed, where a statistically significant decrease in mean zone sizes was noted with Armillaria gallica (p=0.03) and Phytophthora infestans (p=0.03) FCEs and their interaction with the fluoroquinolone antibiotic, ciprofloxacin. Given the increase in clinical morbidity and mortality associated with chronic lung infections with Pseudomonas aeruginosa, Burkholderia cenocepacia and Stenotrophomonas maltophilia, coupled with the difficulty in treating such chronic infection due to overwhelming antimicrobial resistance, any novel substance showing inhibition of these organisms merits further investigation as a potential future antimicrobial agent, with potential clinical therapeutic application.

BACKGROUND: Riociguat is a first-in-class soluble guanylate cyclase stimulator for which preclinical data suggested improvements in cystic fibrosis transmembrane conductance regulator (CFTR) function. METHODS: This international, multicenter, two-part, Phase II study of riociguat enrolled adults with cystic fibrosis (CF) homozygous for Phe508del CFTR. Part 1 was a 28-day, randomized, double-blind, placebo-controlled study in participants not receiving CFTR modulator therapy. Twenty-one participants were randomized 1:2 to placebo or oral riociguat (0.5 mg three times daily [tid] for 14 days, increased to 1.0 mg tid for the subsequent 14 days). The primary and secondary efficacy endpoints were change in sweat chloride concentration and percent predicted forced expiratory volume in 1 second (ppFEV1), respectively, from baseline to Day 14 and Day 28 with riociguat compared with placebo. RESULTS: Riociguat did not alter CFTR activity (change in sweat chloride) or lung function (change in ppFEV1) at doses up to 1.0 mg tid after 28 days. The most common drug-related adverse event (AE) was headache occurring in three participants (21%); serious AEs occurred in one participant receiving riociguat (7%) and one participant receiving placebo (14%). This safety profile was consistent with the underlying disease and the known safety of riociguat for its approved indications. CONCLUSIONS: The Rio-CF study was terminated due to lack of efficacy and the changing landscape of CF therapeutic development. The current study⁠, within its limits of a small sample size, did not provide evidence that riociguat could be a valid treatment option for CF. CLINICAL TRIAL REGISTRATION NUMBER: NCT02170025. ispartof: JOURNAL OF CYSTIC FIBROSIS vol:20 issue:6 pages:1018-1025 ispartof: location:Netherlands status: published

The SARS-CoV-2 pandemic has disrupted clinical trials worldwide. The European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) has tracked clinical trial disruption by surveying its 58 trial sites across 17 European countries and collated information on measures to mitigate the impact of the pandemic and ensure trial continuity. Here, we present recommendations on how to reduce the risk of SARS-CoV-2 exposure to patients and trial staff by implementing remote trial visits where possible, using home assessments, video and phone calls, electronic consent, and home delivery of study drugs. We discuss the practicalities of remote source data verification, protocol amendments, changing trial site location, and staff absences and home working. We outline recommendations on how to protect trial outcomes, including home assessments, safety reporting, protocol deviations, and recruitment challenges. Finally, we discuss the importance of continued access to study drugs via extension trials for some patients. This guidance was co-created from the shared knowledge and experience of sites in our network and was re-distributed directly to all ECFS-CTN sites to help mitigate the impact of further waves of the SARS-CoV-2 pandemic. We will also use this guidance to assist companies, academia, and consortia with future protocol design and risk mitigation plans. This guidance can be applied to clinical trials in other diseases and could help sites that are not supported by clinical trial networks. ispartof: TRIALS vol:22 issue:1 ispartof: location:England status: published

Rationale: Sputum biomarkers hold promise as a direct measure of inflammation within the cystic fibrosis (CF) lung, but variability in study design and sampling methodology have limited their use. A full evaluation of the reliability, validity and clinical relevance of individual biomarkers is required to optimise their use within CF clinical research.Objectives: A biomarker Special Interest Working Group was established within the European Cystic Fibrosis Society-Clinical Trials Network Standardisation Committee, to perform a review of the evidence regarding sputum biomarkers in CF. Methods: From the 139 included articles, we identified 71 sputum biomarkers to undergo evaluation of their clinimetric properties, responsiveness, discriminate, concurrent and convergent validity. Results: Current evidence confirms the potential of sputum biomarkers as outcome measures in clinical trials. Inconsistency in responsiveness, concurrent and convergent validity require further research into these markers and processing standardisation before translation into wider use. Of the 71 biomarkers identified Neutrophil Elastase (NE), IL-8, TNF-α and IL-1β, demonstrated validity and responsiveness to be currently considered for use in clinical trials. Other biomarkers show future promise, including IL-6, calprotectin, HMGB-1 and YKL-40. Conclusion: A concerted international effort across the cystic fibrosis community is needed to promote high quality biomarker trial design, establish large population-based biomarker studies, and work together to create standards for collection, storage and analysis of sputum biomarkers.

Summary Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov ( NCT02565914 ). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated.

There are several clinical infection scenarios where the Gram-negative bacterium, Pseudomonas aeruginosa and the yeast, Candida spp. may co-exist in the pathological site of infection. Such co-habi...

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation.METHODS: This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40-90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548.FINDINGS: Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], pINTERPRETATION: Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation.FUNDING: Vertex Pharmaceuticals.

ObjectivesCystic fibrosis (CF) lung disease is characterised by mucus stasis, chronic infection and inflammation, causing progressive structural lung disease and eventual respiratory failure. CF airways are inhabited by an ecologically diverse polymicrobial environment with vast potential for interspecies interactions, which may be a contributing factor to disease progression. Pseudomonas aeruginosa and Aspergillus fumigatus are the most common bacterial and fungal species present in CF airways respectively and coinfection results in a worse disease phenotype.MethodsIn this review we examine existing expert knowledge of chronic co-infection with P. aeruginosa and A. fumigatus in CF patients. We summarise the mechanisms of interaction and evaluate the clinical and inflammatory impacts of this co-infection.ResultsP. aeruginosa inhibits A. fumigatus through multiple mechanisms: phenazine secretion, iron competition, quorum sensing and through diffusible small molecules. A. fumigatus reciprocates inhibition through gliotoxin release and phenotypic adaptations enabling evasion of P. aeruginosa inhibition. Volatile organic compounds secreted by P. aeruginosa stimulate A. fumigatus growth, while A. fumigatus stimulates P. aeruginosa production of cytotoxic elastase.ConclusionA complex bi-directional relationship exists between P. aeruginosa and A. fumigatus, exhibiting both mutually antagonistic and cooperative facets. Cross-sectional data indicate a worsened disease state in coinfected patients; however, robust longitudinal studies are required to derive causality and to determine whether interspecies interaction contributes to disease progression.

The arrival of cystic fibrosis transmembrane conductance regulator (CFTR) modulators as a new class of treatment for cystic fibrosis (CF) in 2012 represented a pivotal advance in disease management, as these small molecules directly target the upstream underlying protein defect. Further advancements in the development and scope of these genotype-specific therapies have been transformative for an increasing number of people with CF (PWCF). Despite clear improvements in CFTR function and clinical endpoints such as lung function, body mass index (BMI), and frequency of pulmonary exacerbations, current evidence suggests that CFTR modulators do not prevent continued decline in lung function, halt disease progression, or ameliorate pathogenic organisms in those with established lung disease. Furthermore, it remains unknown whether their restorative effects extend to dysfunctional CFTR expressed in phagocytes and other immune cells, which could modulate airway inflammation. In this review, we explore the effects of CFTR modulators on airway inflammation, infection, and their influence on the impaired pulmonary host defences associated with CF lung disease. We also consider the role of inflammation-directed therapies in light of the widespread clinical use of CFTR modulators and identify key areas for future research.

As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has disrupted clinical trials worldwide [1]. This could delay the approval of new medicines and reduce access to investigational treatments via clinical trials. This particularly impacts patients with rare diseases such as cystic fibrosis (CF)., Rare disease patients may suffer delayed access to new drugs as SARS-CoV-2 is disrupting clinical trials. Our survey demonstrates that the European cystic fibrosis clinical trials network is ideally placed to track and address such disruption.

Introduction: The microbial landscape of CF is changing, reflecting advances in microbial detection, CF therapies and an increasingly heterogeneous and ageing population. Gram negative organisms are important to clinical trajectory, however, some have unknown implications on disease course.Areas covered: This review covers the evolving landscape of the microbial ecosystem of the CF lung and provides an update on current diagnostic and therapeutic options for management of Gram negative bacteria. Evidence for prevention of acquisition of new organisms, and eradication of Gram negative pathogens is reviewed. There is an increasing range of inhaled antibiotic therapies for chronic suppressive antimicrobial therapy, with an urgent need for research into the efficacy of specific combinations. Intra-venous therapy for pulmonary exacerbations requires optimisation, focusing on greater precision, improved clinical outcomes, whilst reducing anti-microbial resistance and long-term side effects. The future role of CFTR modulators, anti-inflammatory agents and novel anti-infectives is also outlined.Expert opinion: Antimicrobial therapy must evolve to reflect the evolving microbial landscape and the needs of current and future CF populations. With an increasing number of Gram negative organisms, detection methods and therapeutic options, it is critical therapy is targeted appropriately to the organism and the individual.

Cystic fibrosis (CF) lung disease is characterised by mucus stasis, chronic infection and inflammation, causing progressive structural lung disease and eventual respiratory failure. CF airways are inhabited by an ecologically diverse polymicrobial environment with vast potential for interspecies interactions, which may be a contributing factor to disease progression.In this review we examine existing expert knowledge of chronic co-infection withA complex bi-directional relationship exists between

PURPOSE OF REVIEW: The treatment of cystic fibrosis (CF) with CF transmembrane conductance regulator (CFTR) modulators continues to develop at a fast pace. These compounds are potentially disease modifying but are only available to certain patient subsets based on genotype. This review discusses the role of theratyping in CF and the potential to assess all patients' response to current and emerging therapies.RECENT FINDINGS: There are limitations to treatment determined by mutation, as variable clinical response to CFTR modulators has been observed within the same genotype. Patients with rare mutations not currently licensed for CFTR modulator therapy have demonstrated response to these medications. Patient-specific cellular models called organoids can be used to demonstrate response to different CFTR modulators in vitro prior to their clinical application and represent a method of theratyping.SUMMARY: Theratyping charts patients' clinical response to different treatments on an individual basis. This overcomes the limitations of genotype being used to predict response to individual therapies and includes all patients regardless of mutation. The use of organoids in high throughput screening allows numerous compounds to be tested on patient-specific tissue preclinically. This could lead to the extension of theratyping beyond CFTR modulators.

Background Polypharmacy is associated with an increased risk of adverse drug events, inappropriate prescribing and medication errors. People with bronchiectasis have frequent pulmonary exacerbations that require antibiotic therapy. Objective This study aimed to measure polypharmacy and medication regimen complexity in bronchiectasis patients and to explore associations between these factors and oral and intravenous (IV) antibiotic use for suspected pulmonary exacerbations. Setting Patients were sampled from the Regional Bronchiectasis Clinic at the Belfast Health and Social Care Trust, Northern Ireland. Method Data on medicines were collected from patients’ records and used to measure polypharmacy using three thresholds (≥ 4, ≥ 10, and ≥ 15 medicines’). Medication regimen complexity was calculated using the medication regimen complexity index (MRCI). Data analysis investigated differences in outcomes across polypharmacy thresholds and correlations with MRCI. Main outcome measure Primary outcomes were prescriptions for oral antibiotics and IV antibiotics, in the past 6 months and 2 years, respectively. Results Over three-quarters of the sample (N = 95) were prescribed ≥ 4 medicines (n = 74; 77.9%), 31 patients were prescribed ≥ 10 medicines (33.0%), and 12 patients (12.8%) were prescribed ≥ 15 medicines. The median MRCI was 26. Patients prescribed ≥ 10 medicines were over three times more likely to have had an IV antibiotic in the past 2 years (adjusted odd ratio 3.44, 95% confidence intervals 1.15–10.31). Conclusion There were significant differences in all outcomes across the ‘≥ 10 medicines’ threshold. MRCI was positively correlated with oral and IV antibiotic usage. These findings also suggest a possible link between polypharmacy and medicines regimen complexity, and poorer outcomes. Electronic supplementary material The online version of this article (10.1007/s11096-018-0681-1) contains supplementary material, which is available to authorized users.

What is known and objective Ivacaftor is a novel potentiator of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein, which corrects the gating defect and increases ion-function of activated cell-surface CFTR. Bacteria also regulate their physiology through ion channels. However, little is known about the potential effects of ivacaftor on bacterial ion channels, which, in turn, may have a potential effect on transport across the bacterial cell membrane. Therefore, any change in the ability to transport molecules across cell membranes in bacteria could have an important impact on bacterial transport physiology. One area where this could be particularly important is in the movement of antibiotics, both into and out of the bacterial cell. An in vitro study was therefore performed to examine the influence of ivacaftor at therapeutic concentration on antibiotic susceptibility of 11 commonly used anti-pseudomonal antibiotics against a population of clinical Pseudomonas aeruginosa [PA], from CF and non-CF sources. Method Pseudomonas aeruginosa (n = 80; including 70 ivacaftor-naive clinical PA from sputa from adult CF patients and 10 control PA from non-CF clinical blood culture sources) were examined. Antibiotic susceptibility was determined by standard disc diffusion assay using CLSI criteria and measuring zone size (mm), against four classes of anti-pseudomonal antibiotics, including beta-lactams (temocillin, ceftazidime, piperacillin/tazobactam, imipenem, meropenem and aztreonam), aminoglycosides (gentamicin, tobramycin, amikacin), fluoroquinolone (ciprofloxacin) and polymyxin (colistin), in the absence and presence of ivacaftor (5 μmol/L), as previously determined. In addition, all CF and non-CF PA were examined phenotypically in vitro, as previously described, for changes linked to bacterial virulence, including (i) growth density (ii) pigmentation, (iii) presence of adhesins and (iv) change to mucoidy, in the presence/absence of ivacaftor at therapeutic concentration. Results and discussion Antibiotic susceptibility did not decrease significantly with any of the antibiotics examined with CF PA isolates or with non-CF PA control organisms. There was a statistically significant increase in zone size (CF PA and amikacin, gentamicin, temocillin and ciprofloxacin; Non-CF PA and amikacin, gentamicin and aztreonam). However, at a population level, this did not translate into a shift in CLSI category to a more susceptible phenotype. None of the PA isolates examined were susceptible to ivacaftor alone, and additionally, no changes were noted with the four phenotypic parameters examined in the presence of ivacaftor. What is new and conclusion This study showed that antibiotic susceptibility of commonly used anti-pseudomonal antibiotics was not negatively affected by ivacaftor, in a population of ivacaftor-naive P. aeruginosa.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has disrupted clinical trials. The European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) tracked disruption to CF trials via regular surveys to adult and paediatric clinics of member sites throughout 2020. We published preliminary results to May 2020 (doi: 10.1183/13993003.02114-2020). Here we report updated data to the end of 2020. Ongoing trials were heavily impacted up to May. Trial participant visits, new enrollment and monitoring visits were widely banned, with frequent home delivery of study drug (Table 1). From June to December, trial visits, new enrollment and onsite monitoring were mostly allowed, and home delivery of study drug dropped accordingly. The set-up of new trials was heavily impacted in March but recovered substantially from June on. Some sites had reduced staff available to work on CF trials. Table 1 presents how remote visits and measures were used by sites from June to December. Much of the early trial disruption resolved by end 2020;however, challenges remain to protect the progress of clinical research in CF during the pandemic.

Background: Studies are required that evaluate real-world outcomes of inhaled aztreonam lysine in patients with cystic fibrosis (CF). Methods: Our treatment-evaluator tool assessed the effectiveness of inhaled aztreonam in routine practice in 117 CF patients across four time periods (6-12 (P2) and 0-6months (P1) pre-initiation, and 0-6 (T1) and 6-12months (T2) post-initiation). Outcomes were: changes in %-predicted forced expiratory volume in 1s (FEV1), body-mass index (BMI), hospitalisation days and intravenous antibiotic usage. Results: Median FEV1% predicted for each 6-month period was 38.9%, 34.6%, 37.1% and 36.5%; median change was -2.0% between P2 and P1, increasing to +0.6% (p

What is known and objective:The CFTR potentiator, ivacaftor (IVA), has been widely used in the treatment of cystic fibrosis (CF) patients with the G551D mutation. To date, there has been limited information on the microbiological status of patients on this therapy and no data on the effect (if any) on the in vivo antibiotic susceptibility of Pseudomonas aeruginosa isolated from patients on therapy. Although IVA intervention is not designed per se as anti-infective, the effect (if any) of this molecule to CF patients' microbiological status merits careful monitoring. Therefore, it was the aim of this observational study to examine the effect in patients, both before and after commencement of IVA therapy, on several commonly reported microbiological markers in CF patients, including (i) bacterial density, (ii) frequency (rate) of isolation of bacterial pathogens, particularly P. aeruginosa, and (iii) antimicrobial susceptibility of these isolates to commonly prescribed oral and iv antibiotics. In addition, we wished to examine the requirements for these antibiotics in CF patients, before and after commencement of IVA therapy. Methods: Archived data from 15 adult cystic fibrosis patients with the c.1652G>A (G551D) mutation were followed from two years pre-IVA therapy to two years after commencement of IVA therapy. The microbiological parameters examined included (i) oral antibiotic courses taken, (ii) intravenous (iv) antibiotic courses taken, (iii) rate of isolation of non-mucoid Pseudomonas aeruginosa (NM-PA) and mucoid P. aeruginosa (M-PA), (iv) density of NM-PA and M-PA and (v) antimicrobial susceptibility of NM-PA and M-PA to 11 antibiotics [aminoglycosides, beta-lactams, polymyxin and fluoroquinolone]. Results and discussion: Following commencement of IVA therapy, patients required less iv antibiotic courses but no change in number of oral antibiotics courses. There was significant reduction in both the rate of isolation and density of M-PA (P = .02; P = .006, respectively). In contrast, there was no significant reduction in both the rate of isolation and density of NM-PA (P = .90; P = .07, respectively). Antimicrobial susceptibility in NM-PA and M-PA was not significantly reduced within any of the antibiotics classes or individual antibiotics examined. Increased susceptibility was noted in the beta-lactam class for NM-PA and M-PA, in particular with ceftazidime.What is new and conclusion:Overall, (i) the requirement for less iv antibiotic therapy, (ii) a reduction in the rate and density of M-PA and (iii) no reduction in antibiotic susceptibility indicate that microbiological parameters with patients on IVA therapy were not detrimentally affected.

BACKGROUND There is a need to measure antibiotic resistance of Pseudomonas aeruginosa (PA) in cystic fibrosis (CF), either qualitatively or quantitatively, to inform patient management. The aim of this study was to develop a simple method by which resistance can be quantified by calculating a relative resistance index (RRI), and to assess correlation of RRIs with clinical variables.METHODSIn our model, RRIs were calculated based on resistance to aztreonam, ceftazidime, ciprofloxacin, colistin, meropenem, tazocin, temicillin and tobramycin. Eighty-five adults with CF and chronic PA colonisation were identified. For each, all PA cultures were allocated a score of 0 for susceptible, 0.5 for intermediate resistance or 1 for resistance for each antibiotic listed above, and the RRI calculated by dividing the sum of these by the number of antibiotics, giving a maximum score of 1. The mean RRIs for all cultures were correlated with key clinical variables monitored in CF patients (including age, FEV1, IV antibiotic days and BMI).RESULTS RRIs for non-mucoid PA exhibited moderate positive correlation with total number of IV days (r = 0.405; p < 0.001) and moderate negative correlation with FEV1 % predicted (r = -0.437; p < 0.001). RRIs were not significantly correlated with duration of colonisation, typing (clonal vs other strain) or BMI. Median RRIs were significantly higher for females (0.26, IQR 0.13-0.54) than males (0.18, IQR 0.07-0.37) for non-mucoid PA only (p = 0.03).CONCLUSIONSRRI is an easily calculated measure that correlates with other clinical variables in CF patients and enables quantitative monitoring of resistance.

One of the most common and most severe forms of primary antibody deficiency encountered in the clinical setting is a heterogeneous group of syndromes termed common variable immune deficiency (CVID). This disorder is characterized by reduced immunoglobulin production and increased susceptibility to infection, particularly of the respiratory tract. Infection and subsequent immunological/inflammatory processes may contribute to the development of pulmonary complications such as bronchiectasis and interstitial lung disease. Immunoglobulin replacement and/or antibiotic therapy, to prevent infection, are routinely prescribed treatments. However, chronic lung disease, the major cause of morbidity and mortality in this patient cohort, may still progress. This clinical progression suggests that pathogens recalcitrant to currently prescribed treatments and other immunological defects may be contributing to the development of pulmonary disease. This review describes the potential role of microbiological and non-B cell immunological factors, including T-cells, neutrophils, complement, toll like receptors, and antimicrobial peptides, in the pathogenicity of chronic lung disease in patients with CVID.