for the Macrolide Study Group C YSTIC FIBROSIS (CF) IS CHARacterized by a recurrent cycle of pulmonary infection and inflammation. Pseudomonas aeruginosa is the most common pathogen in patients with CF and by age 18 years, 80% of patients are chronically infected. Neutrophils are the dominant inflammatory cells and much of the airway destruction characteristic of CF is secondary to neutrophil-derived proteases and oxidants. 1 Treatment strategies for CF lung disease have included antibiotics, mucolytics, and antiinflammatory therapies. 2 There is evidence suggesting that macrolide antibiotics may be beneficial for patients with CF. Macrolide antibiotics substantially reduced morbidity and mortality in patients in Japan with diffuse panbronchiolitis. 3,4 Diffuse panbronchiolitis shares many clinical features with CF; patients are often infected with mucoid strains of P aeruginosa and mortality is secondary to chronic pro

BACKGROUND-A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cell-surface CFTR in vitro.

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Rationale: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation.Objectives: To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers.Methods: We conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, b-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV 1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P , 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m 2 ; P , 0.001). Sweat chloride decreased from baseline to 6 months (mean change, 253.8 mmol/L; 95% confidence interval, 257.7 to 249.9; P , 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P , 0.001) and Pseudomonas aeruginosa burden (P , 0.01). Significant improvements in mucociliary clearance (P , 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor.Conclusions: Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology.

Chronic Pseudomonas aeruginosa infections cause significant morbidity in patients with cystic fibrosis (CF). Over years to decades, P. aeruginosa adapts genetically as it establishes chronic lung infections. Nonsynonymous mutations in lasR, the quorum-sensing (QS) master regulator, are common in CF. In laboratory strains of P. aeruginosa, LasR activates transcription of dozens of genes, including that for another QS regulator, RhlR. Despite the frequency with which lasR coding variants have been reported to occur in P. aeruginosa CF isolates, little is known about their consequences for QS. We sequenced lasR from 2,583 P. aeruginosa CF isolates. The lasR sequences of 580 isolates (22%) coded for polypeptides that differed from the conserved LasR polypeptides of well-studied laboratory strains. This collection included 173 unique lasR coding variants, 116 of which were either missense or nonsense mutations. We studied 31 of these variants. About one-sixth of the variant LasR proteins were functional, including 3 with nonsense mutations, and in some LasR-null isolates, genes that are LasR dependent in laboratory strains were nonetheless expressed. Furthermore, about half of the LasR-null isolates retained RhlR activity. Therefore, in some CF isolates the QS hierarchy is altered such that RhlR quorum sensing is independent of LasR regulation. Our analysis challenges the view that QS-silent P. aeruginosa is selected during the course of a chronic CF lung infection. Rather, some lasR sequence variants retain functionality, and many employ an alternate QS strategy involving RhlR.

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clinicaltrials.gov Identifier: NCT00431964.

These data support the role of sputum biomarkers as correlates of disease severity in a diverse CF population.