vx-770 and Pseudomonas-Infections

This paper reviews the most important clinical papers in cystic fibrosis published in 2018, having searched all the literature on Pubmed. Focus is on CFTR modulator therapy, randomised controlled trials, and infection/microbiology issues.

Topics: Administration, Inhalation; Aminophenols; Aminopyridines; Anti-Bacterial Agents; Azithromycin; Benzodioxoles; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Chloride Channel Agonists; Cough; Cross Infection; Cystic Fibrosis; Disease Progression; Drug Combinations; Drug Therapy, Combination; Humans; Indoles; Lung Transplantation; Microbiological Techniques; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Nebulizers and Vaporizers; Proton Pump Inhibitors; Pseudomonas aeruginosa; Pseudomonas Infections; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Randomized Controlled Trials as Topic; Saline Solution, Hypertonic; Specimen Handling; Sputum; Treatment Outcome; Tuberculosis, Pulmonary

Evolving cystic fibrosis 'standards of care' have influenced recent cystic fibrosis clinical trial designs for new therapies; care additions/improvements will require innovative trial designs to maximize feasibility and efficacy detection.. Three cystic fibrosis therapeutic areas (pulmonary exacerbations, Pseudomonas aeruginosa airway infections, and reduced cystic fibrosis transmembrane conductance regulator [CFTR] protein function) differ with respect to the duration for which recognized 'standards of care' have been available. However, developers of new therapies in all the three areas are affected by similar challenges: standards of care have become so strongly entrenched that traditional placebo-controlled studies in cystic fibrosis populations likely to benefit from newer therapies have become less and less feasible. Today, patients/clinicians are more likely to entertain participation in active-comparator trial designs, that have substantial challenges of their own. Foremost among these are the selection of 'valid' active comparator(s), estimation of a comparator's current clinical efficacy (required for testing noninferiority hypotheses), and effective blinding of commercially available comparators.. Recent and future cystic fibrosis clinical trial designs will have to creatively address this collateral result of successful past development of effective cystic fibrosis therapies: patients and clinicians are much less likely to accept simple, placebo-controlled studies to evaluate future therapies.

Topics: Aminophenols; Aminopyridines; Anti-Bacterial Agents; Benzodioxoles; Chloride Channel Agonists; Clinical Trials as Topic; Comparative Effectiveness Research; Cystic Fibrosis; Disease Progression; Drug Combinations; Humans; Pseudomonas Infections; Quinolones; Standard of Care; Treatment Outcome

Cystic fibrosis (CF), especially CF lung disease, is characterized by chronic infection, immune dysfunction including impairment of regulatory T cells (Tregs) and an exaggerated inflammatory response. CF transmembrane conductance regulator (CFTR) modulators have shown to improve clinical outcomes in people with CF (PwCF) with a wide range of CFTR mutations. However, it remains unclear whether CFTR modulator therapy also affects CF-associated inflammation. We aimed to examine the effect of elexacaftor/tezacaftor/ivacaftor therapy on lymphocyte subsets and systemic cytokines in PwCF.. Peripheral blood mononuclear cells and plasma were collected before and at three and six months after the initiation of elexacaftor/tezacaftor/ivacaftor therapy; lymphocyte subsets and systemic cytokines were determined using flow cytometry.. Elexacaftor/tezacaftor/ivacaftor treatment was initiated in 77 PwCF and improved percent predicted FEV1 by 12.5 points (p<0.001) at 3 months. During elexacaftor/tezacaftor/ivacaftor therapy, percentages of Tregs were enhanced (+18.7%, p<0.001), with an increased proportion of Tregs expressing CD39 as a marker of stability (+14.4%, p<0.001). Treg enhancement was more pronounced in PwCF clearing Pseudomonas aeruginosa infection. Only minor, non-significant shifts were observed among Th1-, Th2- and Th17-expressing effector T helper cells. These results were stable at 3- and 6-month follow-up. Cytokine measurements showed a significant decrease in interleukin-6 levels during treatment with elexacaftor/tezacaftor/ivacaftor (-50.2%, p<0.001).. Treatment with elexacaftor/tezacaftor/ivacaftor was associated with an increased percentage of Tregs, especially in PwCF clearing Pseudomonas aeruginosa infection. Targeting Treg homeostasis is a therapeutic option for PwCF with persistent Treg impairment.

Topics: Adult; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytokines; Humans; Leukocytes, Mononuclear; Pseudomonas Infections; T-Lymphocytes, Regulatory

The multi-drug resistance of Pseudomonas aeruginosa is an overwhelming cause of terminal and persistent lung infections in cystic fibrosis (CF) patients. Antimicrobial synergy has been shown for colistin and ivacaftor, and our study designed a relatively high drug-loading dry powder inhaler formulation containing nanoparticles of ivacaftor and colistin. The ivacaftor-colistin nanosuspensions (Iva-Col-NPs) were prepared by the anti-solvent method with different stabilizers. Based on the aggregation data, the formulation 7 (F7) with DSPG-PEG-OMe as the stabilizer was selected for further studies. The F7 consisted of ivacaftor, colistin and DSPG-PEG-OMe with a mass ratio of 1:1:1. The F7 powder formulation was developed using the ultrasonic spray-freeze-drying method and exhibited a rough surface with relatively high fine particle fraction values of 61.4 ± 3.4% for ivacaftor and 63.3 ± 3.3% for colistin, as well as superior emitted dose of 97.8 ± 0.3% for ivacaftor and 97.6 ± 0.5% for colistin. The F7 showed very significant dissolution improvement for poorly water soluble ivacaftor than the physical mixture. Incorporating two drugs in a single microparticle with synchronized dissolution and superior aerosol performance will maximize the synergy and bioactivity of those two drugs. Minimal cytotoxicity in Calu-3 human lung epithelial cells and enhanced antimicrobial activity against colistin-resistant P. aeruginosa suggested that our formulation has potential to improve the treatment of CF patients with lung infections.

Topics: Administration, Inhalation; Aerosols; Aminophenols; Anti-Bacterial Agents; Cell Line; Colistin; Drug Combinations; Dry Powder Inhalers; Humans; Lung; Nanoparticle Drug Delivery System; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones

The cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, ivacaftor, was first approved for people with CF and the G551D CFTR mutation. This study describes the long-term clinical effectiveness of ivacaftor in this population.. We conducted a multicenter, prospective, longitudinal, observational study of people with CF ages ≥6 years with at least one copy of the G551D CFTR mutation. Measurements of lung function, growth, quality of life, and sweat chloride were performed after ivacaftor initiation (baseline, 1 month, 3 months, 6 months, and annually thereafter until 5.5 years).. Ninety-six participants were enrolled, with 81% completing all study measures through 5.5 years. This cohort experienced significant improvements in percent predicted forced expiratory volume in 1 second (ppFEV1) of 4.8 [2.6, 7.1] (p < 0.001) at 1.5 years, that diminished to 0.8 [-2.0, 3.6] (p = 0.57) at 5.5 years. Adults experienced larger improvements in ppFEV1 (7.4 [3.6, 11.3], p < 0.001 at 1.5 years and 4.3 [0.6, 8.1], p = 0.02 at 5.5 years) than children (2.8 [0.1, 5.6], p = 0.04 at 1.5 years and -2.0 [-5.9, 2.0], p = 0.32 at 5.5 years). Rate of lung function decline for the overall study cohort from 1 month after ivacaftor initiation through 5.5 years was estimated to be -1.22 pp/year [-1.70, -0.73]. Significant improvements in growth, quality of life measures, sweat chloride, Pseudomonas aeruginosa detection, and pulmonary exacerbation rates requiring antimicrobial therapy persisted through five years of therapy.. These findings demonstrate the long-term benefits and disease modifying effects of ivacaftor in children and adults with CF and the G551D mutation.

Topics: Adolescent; Adult; Aminophenols; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Genotype; Humans; Longitudinal Studies; Male; Mutant Proteins; Mutation; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Quality of Life; Quinolones; Respiratory Function Tests; United States

Ivacaftor is a CFTR potentiator with demonstrated efficacy in clinical trials and has been rapidly adopted within the CF community. Given the uptake of ivacaftor in eligible people, identifying a comparator group not on modulators to measure effectiveness is difficult. We evaluated health outcomes in individuals with G551D and non-G551D genotypes on ivacaftor using real-world longitudinal data.. This population-based observational study compared clinical trajectories pre-post ivacaftor using the Canadian CF Registry from 2006 to 01-01 through 2018-12-31. Piece-wise linear mixed-effects models were used to compare lung function, nutritional status, pulmonary exacerbations, and Pseudomonas colonization pre- and post-ivacaftor. Multivariable models were used to adjust for confounding factors.. Forced expiratory volume in 1 second (FEV1) increased significantly by 5.7 percent predicted (95% confidence interval (CI) 3.9, 7.5; p<0.001) after initiation of ivacaftor. FEV1 decline rate was attenuated to -0.30% (95% CI -0.9, 0.29; p = 0.32) predicted/year post-ivacaftor, compared with -0.75% (95% CI -1.12, -0.37; p<0.001) predicted/year pre-ivacaftor, although this difference did not reach statistical significance. BMI percentiles also increased post-ivacaftor (6.57 percentiles, 95% CI 3.91, 9.24; p<0.001). Pulmonary exacerbations showed a nonsignificant reduction of 18% (RR 0.82, 95% CI 0.61, 1.11; p = 0.19) and the odds of a positive sputum culture for Pseudomonas aeruginosa decreased in the post-ivacaftor period (odds ratio 0.44, 95% CI 0.30, 0.63; p<0.001).. This real-world, observational study demonstrated improvement in health outcomes in a broad population of people with CF. Additional studies are needed to evaluate the impact of ivacaftor on quality of life and survival.

Topics: Adolescent; Adult; Aminophenols; Canada; Child; Chloride Channel Agonists; Cystic Fibrosis; Female; Humans; Longitudinal Studies; Male; Middle Aged; Pseudomonas Infections; Quinolones; Registries; Retrospective Studies

Topics: Adolescent; Adult; Aminophenols; Biomarkers; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Forced Expiratory Volume; Humans; Longitudinal Studies; Lung; Male; Microbiota; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones; Respiratory System Agents; Sputum; Sweat; Treatment Outcome; Young Adult

Pseudomonas aeruginosa is common in chronic rhinosinusitus (CRS) and frequently resistant to antibiotic treatment. We recently described the ciprofloxacin and ivacaftor-releasing biodegradable sinus stent (CISS)-a drug-delivery system that administers ciprofloxacin and the mucociliary activator (ivacaftor) at high local concentrations with prolonged mucosal contact time and sustained delivery. The objective of this study is to evaluate the efficacy of the CISS in a rabbit model of P aeruginosa (PAO1 strain) sinusitis.. Ciprofloxacin/ivacaftor (double layer) was coated on biodegradable poly-D/L-lactic acid (PLLA). A total of 10 sinus stents (5 bare PLLA stent controls, 5 CISSs) were placed unilaterally in rabbit maxillary sinuses via dorsal sinusotomy after inducing infection for 1 week with PAO1. Animals were assessed 3 weeks after stent insertion with sinus culture, nasal endoscopy, computed tomography scan, histopathology, and in-vivo sinus potential difference (SPD) assay.. Rabbits treated with CISS had significant reductions in computed tomography (∆ Kerschner scale: control, 0.55 ± 0.92; CISS, -5.92 ± 1.69; p = 0.024) and endoscopy (control, 4.0 ± 0.0; CISS, 1.875 ± 0.74; p = 0.003) scores. A 2-log reduction of PAO1 was observed (control, -2.14 ± 0.77; CISS, 1.84 ± 1.52; p = 0.047). SPD revealed significantly increased Cl. The CISS had robust clinical efficacy in treating P aeruginosa rabbit sinusitis. The innovative design of double-layered drug coating on the surface of the biodegradable stent may provide therapeutic advantages over current treatment strategies for P aeruginosa sinusitis.

Topics: Aminophenols; Animals; Chronic Disease; Ciprofloxacin; Maxillary Sinus; Pseudomonas; Pseudomonas Infections; Quinolones; Rabbits; Sinusitis; Stents

Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that has been shown to improve the nutritional status and lung function of cystic fibrosis patients with the G551D mutation in clinical trials. The objective of this study was to describe the real-world progress of children receiving ivacaftor.. We describe the real-world progress of four children with cystic fibrosis and the F508del/G551D genotype comparing data during ivacaftor treatment with baseline and with the year before commencing treatment.. Our sample comprised 4 children aged between 6 and 14 years and including one with a recent diagnosis of CF and other with persistent Mycobacterium abscessus (M. abscessus) and recurrent allergic bronchopulmonary aspergillosis. The baseline FEV1 was 58.5% to 81.8% of the predicted value, and ivacaftor was taken for a mean 24 months (range, 12-30 months). All patients experienced a significant and sustained improvement in lung function. Compared to baseline, the weight z-score improved by 1.53 points, and the BMI z-score by 1.6 points. Compared to the year before starting ivacaftor, the frequency of Pseudomonas aeruginosa (P. aeruginosa) isolates decreased (-0.4/patient/year), as did the number of respiratory exacerbations (-1.8/patient/year). The weight-adjusted dose of lipase per kilogram decreased progressively in all patients. In 1 patient, a previously persistent M. abscessus infection and recurrent allergic bronchopulmonary aspergillosis resolved during treatment.. Children with cystic fibrosis and the F508del/G551D genotype receiving treatment with ivacaftor experienced a real-world improvement in lung function, nutritional status, respiratory exacerbations, isolation of P. aeruginosa, and dose of pancreatic enzymes.

Topics: Adolescent; Aminophenols; Aspergillosis, Allergic Bronchopulmonary; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Genotype; Humans; Male; Mutation; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Nutritional Status; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones; Treatment Outcome

We recently developed a novel ciprofloxacin-coated sinus stent capable of releasing antibiotics over a sustained period of time. Ivacaftor 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 ivacaftor-releasing biodegradable sinus stent (CISS) in vitro.. A CISS was created by coating ciprofloxacin/ivacaftor-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 ivacaftor-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.. 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 after 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 (RODUs 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).. 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.

Topics: Aminophenols; Anti-Bacterial Agents; Biofilms; Chloride Channel Agonists; Ciprofloxacin; Drug Liberation; Drug-Eluting Stents; Nanoparticles; Polylactic Acid-Polyglycolic Acid Copolymer; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones

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.. 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].. 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.. 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.

Topics: Adolescent; Adult; Aminophenols; Anti-Bacterial Agents; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Microbial Sensitivity Tests; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones; Retrospective Studies; Young Adult

Cystic fibrosis patients exhibit chronic Pseudomonas aeruginosa respiratory infections and sustained proinflammatory state favoring lung tissue damage and remodeling, ultimately leading to respiratory failure. Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function is associated with MAPK hyperactivation and increased cytokines expression, such as interleukin-8 [chemoattractant chemokine (C-X-C motif) ligand 8 (CXCL8)]. Recently, new therapeutic strategies directly targeting the basic CFTR defect have been developed, and ORKAMBI (Vx-809/Vx-770 combination) is the only Food and Drug Administration-approved treatment for CF patients homozygous for the F508del mutation. Here we aimed to determine the effect of the Vx-809/Vx-770 combination on the induction of the inflammatory response by fully differentiated primary bronchial epithelial cell cultures from CF patients carrying F508del mutations, following exposure to P. aeruginosa exoproducts. Our data unveiled that CFTR functional rescue with Vx-809/Vx-770 drastically reduces CXCL8 (as well as CXCL1 and CXCL2) transcripts and p38 MAPK phosphorylation in response to P. aeruginosa exposure through a CFTR-dependent mechanism. These results suggest that ORKAMBI has anti-inflammatory properties that could decrease lung inflammation and contribute to the observed beneficial impact of this treatment in CF patients.

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Bronchi; Cells, Cultured; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Interleukin-8; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones

Biofilms may contribute to refractory chronic rhinosinusitis (CRS), as they lead to antibiotic resistance and failure of effective clinical treatment. l-Methionine is an amino acid with reported biofilm-inhibiting properties. Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator with mild antimicrobial activity via inhibition of bacterial DNA gyrase and topoisomerase IV. The objective of this study was to evaluate whether co-treatment with ivacaftor and l-methionine can reduce the formation of Pseudomonas aeruginosa biofilms.. P aeruginosa (PAO-1 strain) biofilms were studied in the presence of l-methionine and/or ivacaftor. For static biofilm assays, PAO-1 was cultured in a 48-well plate for 72 hours with stepwise combinations of these agents. Relative biofilm inhibitions were measured according to optical density of crystal violet stain at 590 nm. Live/dead assays (BacTiter-Glo™ assay, Promega) were imaged with laser scanning confocal microscopy. An agar diffusion test was used to confirm antibacterial effects of the drugs.. l-Methionine (0.5 μM) significantly reduced PAO-1 biofilm mass (32.4 ± 18.0%; n = 4; p < 0.001) compared with controls. Low doses of ivacaftor alone (4, 8, and 12 μg/mL) had no effect on biofilm formation. When combined with ivacaftor (4 μg/mL), a synergistic anti-biofilm effect was noted at 0.05 μM and 0.5 μM of l-methionine (two-way analysis of variane, p = 0.0415) compared with corresponding concentrations of l-methionine alone.. Ivacaftor enhanced the anti-biofilm activity of l-methionine against the PAO-1 strain of P aeruginosa. Further studies evaluating the efficacy of ivacaftor/l-methionine combinations for P aeruginosa sinusitis are planned.

Topics: Aminophenols; Anti-Bacterial Agents; Biofilms; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Progression; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Humans; Methionine; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones; Rhinitis; Sinusitis

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.. Pseudomonas aeruginosa (n = 80; including 70 ivacaftor-naïve 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.. 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.. 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.

Topics: Adult; Aminophenols; Anti-Bacterial Agents; Case-Control Studies; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Interactions; Humans; In Vitro Techniques; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones

Ivacaftor was approved for rarer class-III CFTR mutations including S549N in 2014. Since these mutations are uncommon, ongoing reports of patient experiences with Ivacaftor and these mutations are important. This case series describes the clinical effectiveness (including airway infection status, lung function, and growth) of Ivacaftor therapy in four pediatric Hispanic patients with S549N and F508del over 24 months. In these patients, Ivacaftor was highly efficacious with no further Pseudomonas-positive cultures despite prior chronic colonization in three patients as well as notable improvements in lung function and growth. The remarkable improvements in lung function and growth were similar to G551D patients with more striking changes in airway infection status. Pediatr Pulmonol 2017;52:E37-E39. © 2017 Wiley Periodicals, Inc.

Topics: Adolescent; Adolescent Development; Aminophenols; Child; Child Development; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Hispanic or Latino; Humans; Mutation; Pseudomonas; Pseudomonas Infections; Quinolones; Treatment Outcome

The tumor suppressor PTEN controls cell proliferation by regulating phosphatidylinositol-3-kinase (PI3K) activity, but the participation of PTEN in host defense against bacterial infection is less well understood. Anti-inflammatory PI3K-Akt signaling is suppressed in patients with cystic fibrosis (CF), a disease characterized by hyper-inflammatory responses to airway infection. We found that Ptenl

Topics: Aminophenols; Aminopyridines; Animals; Benzodioxoles; Cell Membrane; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Gene Expression Regulation; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Molecular; Monocytes; Phosphatidylinositol 3-Kinases; Protein Binding; Protein Conformation; Protein Transport; Proto-Oncogene Proteins c-akt; Pseudomonas aeruginosa; Pseudomonas Infections; PTEN Phosphohydrolase; Quinolones; Signal Transduction

Topics: Aminophenols; Aspergillosis, Allergic Bronchopulmonary; Chloride Channel Agonists; Comorbidity; Cystic Fibrosis; Humans; Pseudomonas Infections; Quinolones

Ivacaftor improves outcomes in cystic fibrosis (CF) patients with the G551D mutation; however, effects on respiratory microbiology are largely unknown. This study examines changes in CF respiratory pathogens with ivacaftor and correlates them with baseline characteristics and clinical response.. The G551D Observational Study enrolled a longitudinal observational cohort of US patients with CF aged 6 years and older with at least 1 copy of the G551D mutation. Results were linked with retrospective and prospective culture data in the US Cystic Fibrosis Foundation's National Patient Registry. Pseudomonas aeruginosa infection category in the year before and year after ivacaftor was compared and correlated with clinical findings.. Among 151 participants prescribed ivacaftor, 29% (26/89) who were culture positive for P. aeruginosa the year prior to ivacaftor use were culture negative the year following treatment; 88% (52/59) of those P. aeruginosa free remained uninfected. The odds of P. aeruginosa positivity in the year after ivacaftor compared with the year prior were reduced by 35% (odds ratio [OR], 0.65; P < .001). Ivacaftor was also associated with reduced odds of mucoid P. aeruginosa (OR, 0.77; P = .013) and Aspergillus (OR, 0.47; P = .039), but not Staphylococcus aureus or other common CF pathogens. Patients with intermittent culture positivity and higher forced expiratory volume in 1 second (FEV1) were most likely to turn culture negative. Reduction in P. aeruginosa was not associated with change in FEV1, body mass index, or hospitalizations.. Pseudomonas aeruginosa culture positivity was significantly reduced following ivacaftor treatment. Efficacious CFTR modulation may contribute to lower frequency of culture positivity for P. aeruginosa and other respiratory pathogens, particularly in patients with less established disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amino Acid Substitution; Aminophenols; Aspergillus; Child; Cohort Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Enzyme Activators; Female; Humans; Longitudinal Studies; Male; Middle Aged; Mutant Proteins; Mutation, Missense; Prevalence; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones; Staphylococcus aureus; Treatment Outcome; United States; Young Adult

Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation.. To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers.. 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, β-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. FEV1 % 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, -53.8 mmol/L; 95% confidence interval, -57.7 to -49.9; 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.. 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.

Topics: Adolescent; Adult; Aminophenols; Biomarkers; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Follow-Up Studies; Forced Expiratory Volume; Genetic Markers; Hospitalization; Humans; Hydrogen-Ion Concentration; Intestine, Small; Lung; Male; Microbiota; Mucociliary Clearance; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones; Respiratory System Agents; Sputum; Sweat; Treatment Outcome; Young Adult