Performance evaluation of the βLACTA™ Test for rapid detection of ceftazidime resistance in Pseudomonas aeruginosa isolates from cystic fibrosis patients.

J Microbiol Methods. 2019 Jan 29;:

Authors: Ract P, Dahoumane R, Gallah S, Morand P, Podglajen I, Compain F

Abstract
The chromogenic βLACTA™ test was evaluated to detect ceftazidime resistance in P. aeruginosa isolates from patients with cystic fibrosis. Best results were obtained after one hour of incubation with low sensitivity (64.1%), high specificity (98.3%), and negative and positive predictive values of 80.3% and 96.2%, respectively.

PMID: 30708085 [PubMed - as supplied by publisher]

Nanomedicine for Cystic Fibrosis.

SLAS Technol. 2019 Feb 01;:2472630318824334

Authors: Ong V, Mei V, Cao L, Lee K, Chung EJ

Abstract
Cystic fibrosis is a genetic disease affecting more than 70,000 people worldwide. Caused by a mutation in the CFTR gene, cystic fibrosis can result in difficulty breathing, widespread bacterial infections, edema, malnutrition, pancreatitis, and death. Current drug-based treatments struggle to reach the site of action due to the thick mucus, and only manage symptoms such as blocked airways, lung infections, and limited ability to digest food. Nanotechnology opens up possibilities for improved treatment strategies by focusing on drug penetration through the mucus lining, eliminating resulting bacterial infections, and targeting the underlying genetic cause of the disease. In this review, we present recent nanoparticle developments for cystic fibrosis, challenges in nanomedicine therapeutics, and future research directions in gene editing and nonviral vectors for gene delivery.

PMID: 30707858 [PubMed - as supplied by publisher]

After the Celebrations: Lessons from the New Era of Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy.

Ann Am Thorac Soc. 2019 Feb;16(2):189-190

Authors: Barry PJ, Jones AM

PMID: 30707058 [PubMed - in process]

Macrophage activation syndrome due to Nocardia spp in a pediatric patient with cystic fibrosis.

Pediatr Pulmonol. 2019 Jan 31;:

Authors: Şişmanlar Eyüboğlu T, Aslan AT, Ramaslı Gursoy T, Onay ZR, Kocak U, Aktas Tapısız A

Abstract
Nocardia spp is a gram-positive aerobic filamentous bacteria that causes pulmonary and systemic infections, especially in patients with immunosuppression or chronic lung diseases. It is rarely reported in children with cystic fibrosis. Macrophage activation syndrome is a life-threatening disease with an excessive inflammatory response usually triggered by infections. There are few reports in cystic fibrosis related to macrophage activation syndrome. Herein we report a child with cystic fibrosis who had macrophage activation syndrome due to Nocardia infection.

PMID: 30706673 [PubMed - as supplied by publisher]

Secretory IgA-mediated immune response in saliva and early detection of Pseudomonas aeruginosa in the lower airways of pediatric cystic fibrosis patients.

Med Microbiol Immunol. 2019 Jan 31;:

Authors: Mauch RM, Rossi CL, Nolasco da Silva MT, Bianchi Aiello T, Ribeiro JD, Ribeiro AF, Høiby N, Levy CE

Abstract
Pseudomonas aeruginosa (Pa) detection in the paranasal sinuses may help to prevent or postpone bacterial aspiration to the lower airways (LAW) and chronic lung infection in cystic fibrosis (CF). We assessed the ability of an ELISA test for measurement of specific Pa secretory IgA (sIgA) in saliva (a potential marker of sinus colonization) to early detect changes in the Pa LAW status (indicated by microbiological sputum or cough swab culture and specific serum IgG levels) of 65 patients for three years, in different investigation scenarios. Increased sIgA levels were detected in saliva up to 22 months before changes in culture/serology. Patients who remained Pa-positive had significantly increased sIgA levels than patients who remained Pa-negative, both at the baseline (39.6 U/mL vs. 19.2 U/mL; p = 0.02) and at the end of the follow-up (119.4 U/mL vs. 25.2 U/mL; p < 0.001). No association was found between sIgA levels in saliva and emergence or recurrence of Pa in the LAW. A positive median sIgA result in the first year of follow-up implied up to 12.5-fold increased risk of subsequent Pa exposure in the LAW. Our test detected early changes in the P. aeruginosa LAW status and risk of exposure to P. aeruginosa in the LAW with two years in advance. Comparison with sinus culture is needed to assess the test's ability to identify CF patients in need of a sinus approach for Pa investigation, which could provide opportunities of Pa eradication before its aspiration to the lungs.

PMID: 30706137 [PubMed - as supplied by publisher]

Development of a UHPLC-MS method for inhibitor screening against α-L-1,3-fucosidase.

Anal Bioanal Chem. 2019 Feb 01;:

Authors: Liu T, Liu R, Zhu L, Zou X, Guan H, Xu Z

Abstract
α-L-Fucosidase (AFU) is a promising therapeutic target for the treatment of inflammation, cancer, cystic fibrosis, and fucosidosis. Some of the existing analytical methods for the assessment of AFU activity are lacking in sensitivity and selectivity, since most of them are based on spectrofluorimetric methods. More recently, mass spectrometry (MS) has evolved as a key technology for enzyme assays and inhibitor screening as it enables accurate monitoring of the conversion of substrate to product in enzymatic reactions. In this study, UHPLC-MS has been utilized to develop a simple, sensitive, and accurate assay for enzyme kinetics and inhibition studies of AFU3, a member of the AFU family. A reported method for analyzing saccharide involving a porous graphitic carbon column, combined with reduction by NaBH4/CH3OH, was used to improve sensitivity. The conversion of saccharide into alditol could reach nearly 100% in the NaBH4 reduction reaction. In addition, the bioanalytical quantitative screening method was validated according to US-FDA guidance, including selectivity, linearity, precision, accuracy, stability, and matrix effect. The developed method displayed a good accuracy, high sensitivity (LOD = 0.05 mg L-1), and good reproducibility (RSD < 15%). The assay accurately measured an IC50 value of 0.40 μM for the known AFU inhibitor, deoxyfuconojirimycin, which was consistent with results reported in the literature. Further validation of the assay was achieved through the determination of a high Z'-factor value of 0.89. The assay was applied to screen a marine-derived chemical library against AFU3, which revealed two marine-oriented pyrimidine alkaloids as potential AFU3 inhibitors. Graphical abstract ᅟ.

PMID: 30706074 [PubMed - as supplied by publisher]

Clinical Usefulness of Functional Tests of Leg Muscle Strength and Power in Adults With Cystic Fibrosis.

Respir Care. 2019 Feb;64(2):240-241

Authors: Wu K, Mathur S

PMID: 30705150 [PubMed - in process]

Assessment of Peripheral Muscle Function in Cystic Fibrosis: Why and How?

Respir Care. 2019 Feb;64(2):238-240

Authors: Gruet M, Saynor Z

PMID: 30705149 [PubMed - in process]

CFTR constrains the differentiation from mouse embryonic stem cells to intestine lineage cells.

Biochem Biophys Res Commun. 2019 Jan 28;:

Authors: Li P, Singh J, Sun Y, Ma X, Yuan P

Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR) is a transmembrane Cl- and HCO3- transporter and its malfunction leads to cystic fibrosis (CF) and multiple congenital diseases. The most common mutation in CF patient is DF508 and the patients have increased risk in developing gastrointestinal tumors. To explore the etiology of high cancer risk in DF508-CF patients, we have derived mouse DF508-CFTR embryonic stem (ES) cells and use it as a novel in vitro model to study the role of CFTR from developmental angle. We found the self-renewal properties are intact in DF508-CFTR ES cells. Nevertheless, the differentiation of intestine lineage, the expression of intestine progenitor and major intestine differentiated cell markers is significantly upregulated in DF508-CFTR ES cell differentiated cells. Therefore, CFTR plays an important role in intestine lineage differentiation. Besides, DF508-CFTR ES cells formed teratomas demonstrated enhanced expressions of cell proliferation, migration and epithelial-mesenchymal transition associated marker genes, indicating the tumor suppressive role of CFTR. Taken together, our derived DF508-CFTR ES cells can serve as a new model to study the etiology of CF disease in vitro and malignant teratoma formation in vivo.

PMID: 30704755 [PubMed - as supplied by publisher]

Clinical manifestations and risk factors of arthropathy in cystic fibrosis.

Respir Med. 2019 Feb;147:66-71

Authors: Roehmel JF, Kallinich T, Staab D, Schwarz C

Abstract
BACKGROUND: Recurrent joint pain is frequently observed in patients with CF and can lead to reduced activity and quality of life. We conducted this observational study to assess the clinical manifestations, frequency, and risk factors of CF associated arthropathy.
METHODS: Clinical data were collected using a digital quality management system, medical records, and by conducting structured interviews. Univariate and multivariate statistical analysis were performed for statistical interpretation.
STUDY DESIGN: retrospective observational study including 186 patients.
RESULTS: Of 186 patients (Demographics: Mean age 27 years, female gender 104/186 (57%), CFTR F508del homozygous 82/186 (44%) included in the study, 54/186 (29%) had experienced joint symptoms. Joint pain and swelling were the most frequent symptoms. The joints of the hands (JOH) followed by the joints of the feet were most affected. No specific pattern of autoantibodies was discovered. The level of total serum IgG, age, female gender, and pulmonary exacerbations per year were significant risk factors for arthropathy in the study cohort.
CONCLUSIONS: Joint symptoms in CF are a frequent and clinically relevant phenomenon with a distinct clinical pattern. Pulmonary exacerbations and elevated levels of total serum IgG may reflect chronic inflammation in patients with CF and may lead to a specific arthropathy associated with this condition.

PMID: 30704701 [PubMed - in process]

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

Int Forum Allergy Rhinol. 2019 Jan 31;:

Authors: Cho DY, Lim DJ, Mackey C, Weeks CG, Garcia JAP, Skinner D, Zhang S, McCormick J, Woodworth BA

Abstract
BACKGROUND: 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.
METHODS: 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.
RESULTS: The presence of drugs and a uniform coating on the stent were confirmed by zeta potential and SEM. Sustained drug release was observed through 21 days without an initial burst release. Anti-biofilm formation was observed 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).
CONCLUSION: The CISS maintains a uniform coating and sustained delivery of drugs providing a marked reduction in P aeruginosa biofilm formation. Further studies evaluating the efficacy of CISS in a preclinical model are planned.

PMID: 30702211 [PubMed - as supplied by publisher]

Functional insufficiency of the pancreas and the metabolic activity of the microbiota in cystic fibrosis adults patients.

Ter Arkh. 2018 Nov 22;90(10):84-88

Authors: Vinokurova LV, Baimakanova GE, Krasovsky SA, Silvestrova SY, Dubtsova EA, Varvanina GG, Bordin DS

Abstract
AIM: In order to optimize the therapy, the functional state of the pancreas (P) and the peculiarities of metabolic activity of intestinal microbiota in adults with cystic fibrosis (CF) were assessed.
MATERIALS AND METHODS: 14 CF patients (20-34 years, 7 men, 7 women) were enrolled. In 8 patients, the diagnosis was confirmed in the first year of life on the basis of clinical data, positive sweat test, 5 had genetic confirmation. In 4 patients, the diagnosis was confirmed at the age of 8-13 years and 2 patients aged 18, 27 years. In this group, genetic confirmation was in 4 subjects. In addition to general clinical studies, the level of C-peptide in blood, elastase and the concentration of short chain fatty acids in feces was determined.
RESULTS: Of elastase feces in 9 patients was 5.5±4.7 icg/g, that is revealed severe exocrine insufficiency of the pancreas and in 5 patients the elastase level was normal and amounted to 402±124 icg/g. Deployed the clinical picture of diabetes mellitus was observed in 3 patients. Metabolic activity of the colon microflora as a whole was reduced, the sum of the concentration of short-chain fatty acids (ΣCn) was 6.03±4.11 mg/g at a rate of 10.61±5.11 (p&lt;0.05). At the same time, in some patients (group 1, n=9), who were at the time of the study on antibiotic therapy, the value of ΣCn was 3.32±0.33 mg/g, and in patients receiving probiotic drugs (group 2, n=5), the activity of microflora did not differ from the norm ((ΣCn=11.03±2.01 mg/g). The correlation dependence of the ratio of the total iso-acids fraction in patients with MV to the normal values and the level of fecal elastase (r= -0.46, p=0.049) was revealed.
CONCLUSION: Most patients with CF (64%) diagnosed with exocrine pancreatic insufficiency severe according elastase stool. The activity of faecal elastase correlated with parameters of microbiocenosis, which indicates the necessity of correction is not only functional insufficiency of the pancreas, but also the state of the microbiota.

PMID: 30701801 [PubMed - in process]

Impact of influenza on hospitalization rates in children with a range of chronic lung diseases.

Influenza Other Respir Viruses. 2019 Jan 30;:

Authors: Homaira N, Briggs N, Oei JL, Hilder L, Bajuk B, Snelling T, Chambers GM, Jaffe A

Abstract
BACKGROUND: Data on burden of severe influenza in children with a range of chronic lung diseases (CLDs) remain limited.
METHOD: We performed a cohort study to estimate burden of influenza-associated hospitalization in children with CLDs using population-based linked data. The cohort comprised all children in New South Wales, Australia, born between 2001 and 2010 and was divided into five groups, children with: (a) severe asthma; (b) bronchopulmonary dysplasia (BPD); (c) cystic fibrosis (CF); (d) other congenital/chronic lung conditions; and (e) children without CLDs. Incidence rates and rate ratios for influenza-associated hospitalization were calculated for 2001-2011. Average cost/episode of hospitalization was estimated using public hospital cost weights.
RESULTS: Our cohort comprised 888 157 children; 11 058 (1.2%) had one of the CLDs. The adjusted incidence/1000 child-years of influenza-associated hospitalization in children with CLDs was 3.9 (95% CI: 2.6-5.2) and 0.7 (95% CI: 0.5-0.9) for children without. The rate ratio was 5.4 in children with CLDs compared to children without. The adjusted incidence/1000 child-years (95% CI) in children with severe asthma was 1.1 (0.6-1.6), with BPD was 6.0 (3.7-8.3), with CF was 7.4 (2.6-12.1), and with other congenital/chronic lung conditions was 6.9 (4.9-8.9). The cost/episode (95% CI) of influenza-associated hospitalization was AUD 19 704 (95% CI: 11 715-27 693) for children with CLDs compared to 4557 (95% CI: 4129-4984) for children without.
DISCUSSION: This large population-based study suggests a significant healthcare burden associated with influenza in children with a range of CLDs.

PMID: 30701672 [PubMed - as supplied by publisher]

Predictors of Reduced Survival for Adult-diagnosed Cystic Fibrosis: Older Age at Diagnosis, a Substitute for Older Age?

Ann Am Thorac Soc. 2019 Jan 30;:

Authors: Fieuws S, Hatziagorou E, De Boeck K

PMID: 30698989 [PubMed - as supplied by publisher]

Reply: Predictors of Reduced Survival for Adult-diagnosed Cystic Fibrosis: Older Age at Diagnosis, a Substitute for Older Age?

Ann Am Thorac Soc. 2019 Jan 30;:

Authors: Desai S, Wong H, Sykes J, Stephenson AL, Singer J, Quon BS

PMID: 30698985 [PubMed - as supplied by publisher]

A multi-disciplinary approach to pre and post-transplant management of cystic fibrosis associated liver disease.

Liver Transpl. 2019 Jan 29;:

Authors: Freeman AJ, Sellers ZM, Mazariegos G, Kelly A, Saiman L, Mallory G, Ling SC, Narkewicz MR, Leung DH

Abstract
Approximately 5 to 10% of patients with cystic fibrosis (CF) will develop advanced liver disease with portal hypertension, representing the 3rd leading cause of death among patients with CF. CF liver disease (CFLD) represents the most significant risk to patient mortality second only to pulmonary or lung transplant complications in patients with CF. Currently there is no medical therapy to treat or reverse CFLD. Liver transplantation in patients with CFLD with portal hypertension confers a significant survival advantage over those who do not receive LT, although the timing in which to optimize this benefit is unclear. Despite the value and efficacy of LT in selected patients with CFLD, established clinical criteria outlining indications and timing for LT, as well as disease specific transplant considerations are notably absent. The goal of this comprehensive and multi-disciplinary report is to present recommendations on the unique CF-specific pre- and post-LT management issues clinicians should consider and will face. This article is protected by copyright. All rights reserved.

PMID: 30697907 [PubMed - as supplied by publisher]

Association between HbA1c and the development of cystic fibrosis-related diabetes.

Diabet Med. 2019 Jan 30;:

Authors: Choudhury M, Taylor P, Morgan PH, Duckers J, Lau D, George L, Ketchell RI, Wong FS

Abstract
AIMS: To examine HbA1c as a predictor of risk for future development of cystic fibrosis-related diabetes and to assess the association with the development of retinopathy in people with cystic fibrosis-related diabetes.
METHODS: A 7-year retrospective longitudinal study was conducted in 50 adults with cystic fibrosis, comparing oral glucose tolerance test results with HbA1c values in predicting the development of cystic fibrosis-related diabetes. Retinal screening data were also compared with HbA1c measurements to assess microvascular outcome.
RESULTS: An HbA1c value ≥37 mmol/mol (5.5%; hazard ratio 3.49, CI 1.5-8.1) was significantly associated with the development of dysglycaemia, as defined by the oral glucose tolerance test over a 7-year period. Severity of diabetic retinopathy was associated with a higher HbA1c and longer duration of cystic fibrosis-related diabetes.
CONCLUSION: There is a link between HbA1c level and the future development of dysglycaemia in cystic fibrosis based on oral glucose tolerance test, as well as microvascular outcomes. Although current guidance does not advocate the use of HbA1c as a diagnostic tool in cystic fibrosis-related diabetes, it may be of clinical use in determining individuals at risk of future development of cystic fibrosis-related diabetes. This article is protected by copyright. All rights reserved.

PMID: 30697808 [PubMed - as supplied by publisher]

Competition in Biofilms between Cystic Fibrosis Isolates of Pseudomonas aeruginosa Is Shaped by R-Pyocins.

MBio. 2019 Jan 29;10(1):

Authors: Oluyombo O, Penfold CN, Diggle SP

Abstract
Pseudomonas aeruginosa is an opportunistic pathogen and the leading cause of morbidity and mortality in cystic fibrosis (CF) patients. P. aeruginosa infections are difficult to treat due to a number of antibiotic resistance mechanisms and the organism's propensity to form multicellular biofilms. Epidemic strains of P. aeruginosa often dominate within the lungs of individual CF patients, but how they achieve this is poorly understood. One way that strains of P. aeruginosa can compete is by producing chromosomally encoded bacteriocins, called pyocins. Three major classes of pyocin have been identified in P. aeruginosa: soluble pyocins (S types) and tailocins (R and F types). In this study, we investigated the distribution of S- and R-type pyocins in 24 clinical strains isolated from individual CF patients and then focused on understanding their roles in interstrain competition. We found that (i) each strain produced only one R-pyocin type, but the number of S-pyocins varied between strains, (ii) R-pyocins were generally important for strain dominance during competition assays in planktonic cultures and biofilm communities in strains with both disparate R- and S-pyocin subtypes, and (iii) purified R-pyocins demonstrated significant antimicrobial activity against established biofilms. Our work provides support for a role played by R-pyocins in the competition between P. aeruginosa strains and helps explain why certain strains and lineages of P. aeruginosa dominate and displace others during CF infection. Furthermore, we demonstrate the potential of exploiting R-pyocins for therapeutic gains in an era when antibiotic resistance is a global concern.IMPORTANCE A major clinical problem caused by Pseudomonas aeruginosa, is chronic biofilm infection of the lungs in individuals with cystic fibrosis (CF). Epidemic P. aeruginosa strains dominate and displace others during CF infection, but these intraspecies interactions remain poorly understood. Here we demonstrate that R-pyocins (bacteriocins) are important factors in driving competitive interactions in biofilms between P. aeruginosa strains isolated from different CF patients. In addition, we found that these phage-like pyocins are inhibitory against mature biofilms of susceptible strains. This highlights the potential of R-pyocins as antimicrobial and antibiofilm agents at a time when new antimicrobial therapies are desperately needed.

PMID: 30696740 [PubMed - in process]

The imaging definition of bronchiectasis in children: Is it time for a change?

Pediatr Pulmonol. 2018 01;53(1):6-7

Authors: Brody A, Chang A

PMID: 29136339 [PubMed - indexed for MEDLINE]

Persistence and Microevolution of Pseudomonas aeruginosa in the Cystic Fibrosis Lung: A Single-Patient Longitudinal Genomic Study.

Front Microbiol. 2018;9:3242

Authors: Bianconi I, D'Arcangelo S, Esposito A, Benedet M, Piffer E, Dinnella G, Gualdi P, Schinella M, Baldo E, Donati C, Jousson O

Abstract
Background: During its persistence in cystic fibrosis (CF) airways, P. aeruginosa develops a series of phenotypic changes by the accumulation of pathoadaptive mutations. A better understanding of the role of these mutations in the adaptive process, with particular reference to the development of multidrug resistance (MDR), is essential for future development of novel therapeutic approaches, including the identification of new drug targets and the implementation of more efficient antibiotic therapy. Although several whole-genome sequencing studies on P. aeruginosa CF lineages have been published, the evolutionary trajectories in relation to the development of antimicrobial resistance remain mostly unexplored to date. In this study, we monitored the adaptive changes of P. aeruginosa during its microevolution in the CF airways to provide an innovative, genome-wide picture of mutations and persistent phenotypes and to point out potential novel mechanisms allowing survival in CF patients under antibiotic therapy. Results: We obtained whole genome sequences of 40 P. aeruginosa clinical CF strains isolated at Trentino Regional Support CF Centre (Rovereto, Italy) from a single CF patient over an 8-year period (2007-2014). Genotypic analysis of the P. aeruginosa isolates revealed a clonal population dominated by the Sequence Type 390 and three closely related variants, indicating that all members of the population likely belong to the same clonal lineage and evolved from a common ancestor. While the majority of early isolates were susceptible to most antibiotics tested, over time resistant phenotypes increased in the persistent population. Genomic analyses of the population indicated a correlation between the evolution of antibiotic resistance profiles and phylogenetic relationships, and a number of putative pathoadaptive variations were identified. Conclusion: This study provides valuable insights into the within-host adaptation and microevolution of P. aeruginosa in the CF lung and revealed the emergence of an MDR phenotype over time, which could not be comprehensively explained by the variations found in known resistance genes. Further investigations on uncharacterized variations disclosed in this study should help to increase our understanding of the development of MDR phenotype and the poor outcome of antibiotic therapies in many CF patients.

PMID: 30692969 [PubMed]