Changes in Airway Sampling and Pseudomonas Aeruginosa Isolation after the Introduction of Elexacaftor/Tezacaftor/Ivacaftor.

5 Is there an association between Pseudomonas aeruginosa chronic infection and CFTR genotype in adult cystic fibrosis (CF) patients?

104 Antibiotic use in years preceding chronic lung infection with multiresistant Pseudomonas aeruginosa

105 Antibiotic dosing strategies of colistin on biofilm growing Pseudomonas aeruginosa: pharmacokinetic and pharmacodynamic issues

Association of Pseudomonas aeruginosa infection stage with lung function trajectory in children with cystic fibrosis

Longitudinal development of initial, chronic and mucoid Pseudomonas aeruginosa infection in young children with cystic fibrosis

Introduction and ObjectivesPseudomonas aeruginosa (PA) is an important respiratory pathogen resulting in damaging neutrophilic responses. The cytokine IL-17 is important in orchestrating such inflammation. Cells producing IL-17, such as Th17...

Introduction Cystic fibrosis (CF) is a heterogeneous multisystemic disease. Despite considerable improvement in survival, CF remains a life-shortening disease with respiratory failure as the main cause of death. In 2020, elexacaftor/tezacaftor/ivacaftor (ETI) became available as a new highly effective CFTR-modulator therapy targeting the basic protein defect for people with a specific gene variant, and it was shown to improve lung function respiratory symptoms, and other clinical outcomes, including pulmonary exacerbations (PEx) [1]. However, despite the reduced frequency of PEx, these events remain an important driver of morbidity and mortality in people with CF (pwCF) [2]: in 2023, 16% of adults with CF in Europe experienced at least one PEx during the year [3]. The full extent of CFTR modulators effect on chronic airway infections and the recurrent PEx, especially in the long-term, remains uncertain with some studies reporting inconsistent results [4]. Objectives This study aimed to evaluate the real-world effectiveness of ETI therapy on PEx frequency in pwCF followed up between 2018 and 2023, using data from the European Cystic Fibrosis Society Patient Registry (ECFSPR). Specifically, a longitudinal comparison was conducted to evaluate the effectiveness of the new CFTR-modulator therapy on the number of PEx and the prevalence of chronic infections over time. Methods Data were obtained from the ECFSPR, a population-based Registry that collects clinical and demographic data on an annual basis according to agreed definitions of a common set of variables from Centres and national Registries in Europe and neighbouring countries from 2008 to 2023 [9]. To determine the effectiveness of ETI on PEx and chronic infections, a retrospective and longitudinal comparison from 2018 to 2023 was implemented. The analysis included the following variables: total number of days of intravenous antibiotics (IV Abx), including those performed both in hospital and at home (as a proxy for PEx), number of days of IV Abx performed exclusively in hospital, total number of days in hospital for any cause and the presence of chronic infections, including Pseudomonas aeruginosa, Burkholderia Cepacia Complex and Staphylococcus aureus. The first three variables were analysed both as continuous and as categorical (≥1 day vs. 0 days). The chronic infections were instead categorized as the presence of at least one infection versus no infection. To assess whether there were significant differences between the paired periods before and after treatment, the Wilcoxon signed-rank test and McNemar's test for paired data were used, as the same pwCF were evaluated at two time points. All analyses were performed using R software. Results The study included pwCF aged 12-60 years; pwCF who underwent solid organ transplants were excluded. Participants had either an F508del homozygous genotype or were F508del heterozygous with a minimal function variant The analyses were restricted to those who started ETI modulator therapy in 2020 (N= 6,628). Only people with available data on the number of days on IV Abx therapy administered at home and in hospital were considered, resulting in a final study population of 4,602 pwCF. Comparison of two years before and two years after starting ETI showed that the percentage of pwCF with at least one day on IV Abx decreased significantly from 64% to 23% (p<0.001), the percentage of pwCF with at least one day on IV Abx in hospital decreased from 50% to 16% (p<0.001) and, in parallel, that the percentage of pwCF hospitalized dropped from 56% to 24% (p<0.001). Also considering the corresponding variables as continuous, all the differences remain statistically significant. Notably, these improvements measured by total days on IV antibiotics and related variables persisted through three years post-ETI initiation. The prevalence of at least one chronic infection significantly decreased from 67.8% to 36.8% after 2 years of ETI therapy (p<0.001). Number of chronic infections further decreased to 34.5% after 3 years of treatment. Conclusions This analysis of the ECFSPR data demonstrates a marked reduction in PEx after the introduction of the new highly effective CFTR-modulator therapy. The introduction of ETI significantly reduced the clinical burden in pwCF, with decreases of days on IV Abx, hospitalizations and chronic infections. These benefits were observed consistently after 3 years of therapy. Further steps will include the implementation of statistical models to study changes in days on IV Abx as well as in other clinical outcomes before and after ETI.

Rationale: Chronic Pseudomonas aeruginosa (Pa) airway infection is common and a key contributor to diminished lung function and early mortality in persons with cystic fibrosis (PwCF). Risk factors for chronic Pa among PwCF include CFTR (cystic fibrosis transmembrane conductance regulator) genotype, genetic modifiers, and environmental factors. Intensive antibiotic therapy and highly effective modulators do not eradicate Pa in most adolescents and adults with cystic fibrosis. Objectives: To identify new genetic modifiers contributing to the pathophysiology of chronic Pa infection in PwCF. Methods: A total of 4,945 participants in the CF Genome Project with whole-genome sequencing linked to longitudinal clinical data from the 2017 Cystic Fibrosis Foundation Patient Registry were used to conduct a time-to-event genome-wide association study using two definitions of chronic Pa infection. Results: We identified a genome-wide significant association (P = 2.2 × 10-8) between delayed onset of chronic Pa infection and rs194810, a common variant near the gene CHP2, which encodes calcineurin B homolog protein 2 (minor A allele frequency 43%). Survival curves by rs198410 allele dosage show that PwCF homozygous for the A allele are an average of 3 years older when achieving chronic Pa infection compared with G allele homozygotes. Conclusions: Variants near CHP2 are associated with a significant delay in the age of chronic Pa infection among PwCF.

Background:Pseudomonas aeruginosa (Pa) is the predominant pathogen infecting the airways of patients with cystic fibrosis (CF). Initial colonization is usually transient and associated with non-mucoid strains, which can be eradicated if identified early. This strategy can prevent, or at least delay, chronic Pa infection, which eventually develops in the majority of patients by their late teens or early adulthood. This article discusses the management and latest treatment developments of Pa lung infection in patients with CF, with a focus on nebulized antibiotic therapy.Methods:PubMed was searched to identify English language articles published up until August 2011 using combinations of the following key words: ‘antibiotics’, ‘chronic’, ‘cystic fibrosis’, ‘eradication’, ‘exacerbations’, ‘guidelines’, ‘inhaled’, ‘intravenous’, ‘lung infection’, ‘burden’, ‘adherence’, ‘patient segregation’, ‘pseudomonas aeruginosa’ and ‘resistance’.Findings:Antibiotics form a central part of the treatment regimens for chronic Pa lung infection. Current treatment guidelines recommend that patients with chronic pulmonary infection with Pa should receive long-term inhaled anti-pseudomonal therapy to preserve lung function, and to reduce the frequency of pulmonary exacerbations and hospital admissions. While antibiotic resistance seems to increase with frequent antibiotic use, this does not appear to impact on clinical outcome. Negative aspects of therapy include the time needed for drug administration and subsequent cleaning of the equipment. These factors cause a significant treatment burden and impact on adherence. The availability of more convenient formulations and delivery vehicles for anti-pseudomonal antibiotics may help overcome some of these challenges.Conclusions:Current challenges in the management of CF patients with chronic Pa lung infection are numerous. The availability of novel anti-pseudomonal antibiotic formulations/devices is anticipated to improve treatment adherence in patients with CF, and could improve clinical outcomes. Thus, there is hope for improved survival in individuals with CF suffering from chronic pulmonary infection with Pa.

BackgroundLittle is known about risk factors for chronic and mucoid Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) adults, and whether the prevalence is changing.MethodsWe employed a retrospective cohort to analyze data from a single adult CF center (2002 to 2012). Regression models were used to assess independent predictors and change in prevalence of chronic and mucoid Pa infection over time.ResultsThe odds ratio of mucoid Pa infection was significantly less in individuals with better baseline lung function (OR 0.84,95%CI:0.77–0.92) and those diagnosed after the age of 25 (OR 0.21, 95%CI:0.05–0.95). The prevalence of chronic Pa and mucoid Pa decreased during the time interval. After adjusting for confounders, the observed decrease in chronic and mucoid Pa between 2002 and 2012 was no longer significant.ConclusionsThe prevalence of chronic and mucoid Pa is decreasing. Larger studies are needed to confirm these regional trends and their significance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-016-0333-y) contains supplementary material, which is available to authorized users.

BackgroundPseudomonas aeruginosa (Pa) mediates several virulence factors through quorum sensing (QS). Intriguing in vitro data suggests Pa QS molecules are ‘sensed’ by the T2R38 receptor on airway cilia (J Clin...

Introduction: Primary ciliary dyskinesia (PCD) is a genetic disease characterized by anomalies in ciliary structure/function, responsible for chronic pulmonary and rhinosinus disease. To date, no study involving only adults has been published Aims and objectives: to assess the clinical characteristics and respiratory function in adults with PCD Methods: Retrospective study in two French tertiary hospitals, focusing on adults (≥18 yrs) with a diagnosis of PCD based on presence of bronchiectasis with typical ultrastructural defect of cilia and/or situs inversus (SI). We assessed clinical symptoms, respiratory function, extent of bronchiectasis on CT scans, sputum microbiology and molecular analysis. Results: 78 patients (18-77 yrs) were included. Median follow up was 8.1 yrs. 94.8% of patients had chronic rhinosinusitis. Median nasal NO was 18.9 nL/min (IQR 84.7) and half of ultrastructural defects were dynein arm defects. Respiratory function was significantly lower in women (median FEV1=60% pred, IQR=26 vs. 77.5%, IQR=33, p P. aeruginosa (PA, n=21) infection (median FEV 1 =60.5% vs. 75.5%, p 1 (% pred) correlated with age (r=-0.24, p=0.03), chest CT score (r=-0.46, p 1 decline was -11mL/year (IQR=62.3) and was greater in women (−28.3mL/ yr, IQR=43.4, vs -3.8mL/yr in men, IQR=85.7, p=0.01) although age and PA status were similar. FEV 1 decline was not different between patients with or without chronic PA (−22 mL/yr vs -9 mL/yr, p=0.14). Moreover 3 patients had severe chronic respiratory failure Conclusions: PCD in adults is more severe in women and in patients with chronic PA infection.

Background CF is a genetic disease characterized by chronic lung infection, often with Pseudomonas aeruginosa (Pa). It is widely accepted that increasing antibiotic resistance develops in Pa following repeated antibiotic exposure. With the advent of elexacaftor/tezacaftor/ivacaftor (ETI) modulator therapy, we wished to assess Pa antibiotic resistance to beta-lactam and fluoroquinolone (FQ) antibiotics in both children receiving ETI, and those not eligible for ETI (nonETI) who continue to experience recurrent pulmonary exacerbation (PEx) and require repeated antibiotic treatment. Methods We examined current patterns of antibiotic resistance over 3 years for a cohort of 11 children with CF having 5 or more positive sputum cultures for Pa between January 2020-December 2022 obtained from CF clinic and hospital PEx sputum samples. Chart review included: demographic data; dates of PEx/hospitalization; dates of CF clinic visits; dates and results of CF sputum cultures; and antibiotics used and dates for intravenous (IV) and oral (PO) treatment courses. Results Six males and 5 females were reviewed (6/11 [54%] were Hispanic), with 3/11 (27%) on ETI therapy (average age 14.6 yr), and 8/11 (73%) not on ETI therapy (average age 11.6 yr). Average age at acquisition of Pa was 10.2 yrs. The average number of cultures yielding Pa over 3 years was 11 for both ETI and nonETI subjects. Average number of IV antibiotic courses was 6 for nonETI, but 0 for ETI subjects, while the average number of oral (PO) FQ courses with ciprofloxacin/levofloxacin was 6 in nonETI, and only 1 in ETI subjects. No increase in antibiotic resistance was noted against any IV antibiotic over 3 years of observation (Table), but of the 9 subjects (both ETI and nonETI) who received PO FQ, 5 (55%) were documented to have at least one nonsusceptible isolate, as shown for one 16 year old nonETI subject (Figure). Conclusion Current antibiotic/pulmonary management of children with CF was not associated with an increased risk of IV antibiotic resistance over 3 years of observation despite repeated exposure for PEx (mean of 6 IV antibiotic courses per nonETI subject), but susceptibility to FQ decreased in 55% of those treated over 3 years following repeated FQ oral therapy courses. Disclosures All Authors: No reported disclosures

Change in pulmonary pathogens 3 years after elexacaftor/tezacaftor/ivacaftor: an observational study in the Danish cystic fibrosis cohort.

Chronic Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) can be prevented with early eradication treatment. In resource-constrained environments, low-cost, off-label nebulized antibiotics, including intravenous gentamicin solution, are often used for eradication therapy. This study aimed to describe the characteristics and clinical course of children with CF and early Pa infection, treated with a Pa eradication protocol combining inhaled gentamicin and systemic antibiotics. Retrospective descriptive study. All children (0-18 years) attending a CF clinic in South Africa, with early Pa infections between January 2005 and March 2015, who received nebulized gentamicin-based Pa eradication treatment. Data were described and compared between those with successful versus unsuccessful eradication, using descriptive and inferential statistics appropriate to normality of distribution. One hundred and forty-nine children were managed in the CF Clinic over the study period, of whom 44 (29.5%; 28 [63.6%] male) had early Pa infections treated with a gentamicin-based eradication regimen. Thirty-nine (88.6%) patients had successful Pa eradication at 12 months follow-up; of which 28 (71.8%) had Pa reinfection at a median of 37.0 (21.0-101.0) months after initial treatment. Six patients (13%) acquired chronic Pa infection during the median follow-up period of 77 months. Older age was associated with Pa eradication failure and chronic Pa infection. There were no clinically significant adverse events associated with gentamicin inhalational therapy. Nebulized gentamicin solution combined with systemic antibiotics appears to be safe and has comparable efficacy to other strategies in eradicating early Pa infections in children with CF.