Pseudomonas aeruginosa colonization in the upper and lower airways of a child with cystic fibrosis: a father's meticulous approach to successful eradication.
Related ArticlesPseudomonas aeruginosa colonization in the upper and lower airways of a child with cystic fibrosis: a father's meticulous approach to successful eradication. J Bras Pneumol. 2019 Oct 14;45(6):e20190191 Authors: Mainz JG, Baier M, Jaudszus A, Tabori H, Ribeiro JD, Lorenz M PMID: 31618301 [PubMed - in process]
Tedizolid is a promising antimicrobial option for the treatment of Staphylococcus aureus infections in cystic fibrosis patients.
Related ArticlesTedizolid is a promising antimicrobial option for the treatment of Staphylococcus aureus infections in cystic fibrosis patients. J Antimicrob Chemother. 2019 Oct 16;: Authors: Roch M, Varela MC, Taglialegna A, Rosato AE Abstract BACKGROUND: Tedizolid is a protein synthesis inhibitor in clinical use for the treatment of Gram-positive infections. Pulmonary MRSA infections are a growing problem in patients with cystic fibrosis (CF) and the efficacy of tedizolid-based therapy in CF pulmonary infections is unknown. OBJECTIVES: To evaluate the in vitro and in vivo activity of tedizolid and predict the likelihood of tedizolid resistance selection in CF-background Staphylococcus aureus strains. METHODS: A collection of 330 S. aureus strains (from adult and paediatric patients), either of normal or small colony variant (SCV) phenotypes, gathered at three CF centres in the USA was used. Tedizolid activity was assessed by broth microdilution, Etest and time-kill analysis. In vivo tedizolid efficacy was tested in a murine pneumonia model. Tedizolid in vitro mutants were obtained by 40 days of exposure and progressive passages. Whole genome sequencing of clinical S. aureus strains with reduced susceptibility to tedizolid was performed. RESULTS: MRSA strain MIC90s were tedizolid 0.12-0.25 mg/L and linezolid 1-2 mg/L; for MSSA strains, MIC90s were tedizolid 0.12 mg/L and linezolid 1-2 mg/L. Two strains, WIS 441 and Seattle 106, with tedizolid MICs of 2 mg/L and 1 mg/L, respectively, had MICs above the FDA tedizolid breakpoint (0.5 mg/L). Tedizolid at free serum concentrations exhibited a bacteriostatic effect. Mean bacterial burdens in lungs (log10 cfu/g) for WIS 423-infected mice were: control, 11.2 ± 0.5; tedizolid-treated (10 mg/kg), 3.40 ± 1.87; linezolid-treated (40 mg/kg), 4.51 ± 2.1; and vancomycin-treated (30 mg/kg), 5.21 ± 1.93. For WIS 441-infected mice the (log10 cfu/g) values were: control, 9.66 ± 0.8; tedizolid-treated, 3.18 ± 1.35; linezolid-treated 5.94 ± 2.19; and vancomycin-treated, 4.35 ± 1.7. CONCLUSIONS: These results suggest that tedizolid represents a promising therapeutic option for the treatment of CF-associated MRSA/MSSA infections, having potent in vivo activity and low resistance potential.PMID: 31617901 [PubMed - as supplied by publisher]
Quantitative real-time PCR assay for the rapid identification of the intrinsically multidrug-resistant bacterial pathogen Stenotrophomonas maltophilia.
Related ArticlesQuantitative real-time PCR assay for the rapid identification of the intrinsically multidrug-resistant bacterial pathogen Stenotrophomonas maltophilia. Microb Genom. 2019 Oct 16;: Authors: Fraser TA, Bell MG, Harris PNA, Bell SC, Bergh H, Nguyen TK, Kidd TJ, Nimmo GR, Sarovich DS, Price EP Abstract Stenotrophomonas maltophilia is emerging as an important cause of disease in nosocomial and community-acquired settings, including bloodstream, wound and catheter-associated infections. Cystic fibrosis (CF) airways also provide optimal growth conditions for various opportunistic pathogens with high antibiotic tolerance, including S. maltophilia. Currently, there is no rapid, cost-effective and accurate molecular method for detecting this potentially life-threatening pathogen, particularly in polymicrobial specimens, suggesting that its true prevalence is underestimated. Here, we used large-scale comparative genomics to identify a specific genetic target for S. maltophilia, with subsequent development and validation of a real-time PCR assay for its detection. Analysis of 167 Stenotrophomonas spp. genomes identified a conserved 4 kb region in S. maltophilia, which was targeted for Black Hole Quencher assay design. Our assay yielded the positive detection of 89 of 89 (100%) clinical S. maltophilia strains, and no amplification of 23 non-S. maltophilia clinical isolates. S. maltophilia was detected in 10 of 16 CF sputa, demonstrating the assay's utility for direct detection in respiratory specimens. The assay demonstrated good sensitivity, with limits of detection and quantitation on pure culture of ~10 and ~100 genome equivalents, respectively. Our assay provides a highly specific, sensitive and cost-effective method for the accurate identification of S. maltophilia, and will improve the diagnosis and treatment of this under-recognized pathogen by enabling its accurate and rapid detection from polymicrobial clinical and environmental samples.PMID: 31617838 [PubMed - as supplied by publisher]
Factors affecting the growth of infants diagnosed with cystic fibrosis by newborn screening.
Related ArticlesFactors affecting the growth of infants diagnosed with cystic fibrosis by newborn screening. BMC Pediatr. 2019 Oct 15;19(1):356 Authors: Patterson KD, Kyriacou T, Desai M, Carroll WD, Gilchrist FJ Abstract BACKGROUND: Newborn screening (NBS) for cystic fibrosis (CF) improves nutritional outcomes. Despite early dietetic intervention some children fail to grow optimally. We report growth from birth to 2 years in a cohort of children diagnosed with CF by NBS and identify the variables that influence future growth. METHODS: One hundred forty-four children were diagnosed with CF by the West Midlands Regional NBS laboratory between November 2007 and October 2014. All anthropometric measurements and microbiology results from the first 2 years were collated as was demographic and CF screening data. Classification modelling was used to identify the key variables in determining future growth. RESULTS: Complete data were available on 129 children. 113 (88%) were pancreatic insufficient (PI) and 16 (12%) pancreatic sufficient (PS). Mean birth weight (z score) was 3.17 kg (- 0.32). There was no significant difference in birth weight (z score) between PI and PS babies: 3.15 kg (- 0.36) vs 3.28 kg (- 0.05); p = 0.33. By the first clinic visit the difference was significant: 3.42 kg (- 1.39) vs 4.60 kg (- 0.48); p < 0.0001. Weight and height remained lower in PI infants in the first year of life. In the first 2 years of life, 18 (14%) infants failed to regain their birth weight z score. The median time to achieve a weight z score of - 2, - 1 and 0 was 18, 33 and 65 weeks respectively. The median times to reach the same z scores for height were 30, 51 and 90 weeks. Birth weight z score, change in weight z score from birth to first clinic, faecal elastase, isolation of Pseudomonas aeruginosa, isolation of Staphylococcus aureus and sweat chloride were the variables identified by the classification models to predict weight and height in the first and second year of life. CONCLUSIONS: Babies with CF have a lower birth weight than the healthy population. For those diagnosed with CF by NBS, the weight difference between PI and PS babies was not significantly different at birth but became so by the first clinic visit. The presence of certain factors, most already identifiable at the first clinic visit can be used to identify infant at increased risk of poor growth.PMID: 31615474 [PubMed - in process]
Losartan Rescues Inflammation-Related Mucociliary Dysfunction in Relevant Models of Cystic Fibrosis.
Related ArticlesLosartan Rescues Inflammation-Related Mucociliary Dysfunction in Relevant Models of Cystic Fibrosis. Am J Respir Crit Care Med. 2019 Oct 15;: Authors: Kim MD, Baumlin N, Yoshida M, Polineni D, Salathe SF, David JK, Peloquin CA, Wanner A, Dennis JS, Sailland J, Whitney P, Horrigan FT, Sabater JR, Abraham WM, Salathe M Abstract RATIONALE: Despite therapeutic progress in treating cystic fibrosis (CF) airway disease, airway inflammation with associated mucociliary dysfunction remains largely unaddressed. Inflammation reduces the activity of apically expressed large conductance, Ca2+-activated and voltage-dependent K+ channels (BK), critical for mucociliary function in the absence of CFTR. OBJECTIVES AND METHODS: Losartan's anti-inflammatory effectiveness to rescue BK activity and thereby mucociliary function was tested in vitro using primary, fully re-differentiated human airway epithelial cells homozygous for F508del and in vivo using a previously validated, now expanded pharmacological sheep model of CF- and inflammation-associated mucociliary dysfunction. MEASUREMENTS AND MAIN RESULTS: Nasal scrapings from CF patients showed that neutrophilic inflammation correlated with reduced expression of LRRC26, the γ subunit mandatory for BK function in the airways. TGF-β1, downstream of neutrophil elastase, decreased mucociliary parameters in vitro. These were rescued by losartan at concentrations achieved by nebulization in the airway and oral application in the bloodstream: BK dysfunction recovered acutely and over time (the latter via an increase in LRRC26 expression); ciliary beat frequency and airway surface liquid (ASL) volume improved; and mucus hyperconcentration and cellular inflammation decreased. These effects did not depend on angiotensin receptor blockade. Expanding on a validated and published nongenetic sheep model of CF, ewes inhaled CFTRinh172 and neutrophil elastase for three days, which resulted in prolonged tracheal mucus velocity reduction, mucus hyperconcentration and increased TGF-β1. Nebulized losartan rescued both mucus transport and mucus hyperconcentration and reduced TGF-β1. CONCLUSIONS: Losartan effectively reversed CF- and inflammation-associated mucociliary dysfunction, independent of its angiotensin receptor blockade.PMID: 31613648 [PubMed - as supplied by publisher]
Structure of Pseudomonas aeruginosa ribosomes from an aminoglycoside-resistant clinical isolate.
Related ArticlesStructure of Pseudomonas aeruginosa ribosomes from an aminoglycoside-resistant clinical isolate. Proc Natl Acad Sci U S A. 2019 Oct 14;: Authors: Halfon Y, Jimenez-Fernandez A, La Rosa R, Espinosa Portero R, Krogh Johansen H, Matzov D, Eyal Z, Bashan A, Zimmerman E, Belousoff M, Molin S, Yonath A Abstract Resistance to antibiotics has become a major threat to modern medicine. The ribosome plays a fundamental role in cell vitality by the translation of the genetic code into proteins; hence, it is a major target for clinically useful antibiotics. We report here the cryo-electron microscopy structures of the ribosome of a pathogenic aminoglycoside (AG)-resistant Pseudomonas aeruginosa strain, as well as of a nonresistance strain isolated from a cystic fibrosis patient. The structural studies disclosed defective ribosome complex formation due to a conformational change of rRNA helix H69, an essential intersubunit bridge, and a secondary binding site of the AGs. In addition, a stable conformation of nucleotides A1486 and A1487, pointing into helix h44, is created compared to a non-AG-bound ribosome. We suggest that altering the conformations of ribosomal protein uL6 and rRNA helix H69, which interact with initiation-factor IF2, interferes with proper protein synthesis initiation.PMID: 31611393 [PubMed - as supplied by publisher]
In vitro Activities of β-Lactam-β-Lactamase Inhibitor Antimicrobial Agents Against Cystic Fibrosis Respiratory Pathogens.
Related ArticlesIn vitro Activities of β-Lactam-β-Lactamase Inhibitor Antimicrobial Agents Against Cystic Fibrosis Respiratory Pathogens. Antimicrob Agents Chemother. 2019 Oct 14;: Authors: Caverly LJ, Spilker T, Kalikin LM, Stillwell T, Young C, Huang DB, LiPuma JJ Abstract We tested the in vitro activities of ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, piperacillin-tazobactam, and 11 other antimicrobial agents against 420 Burkholderia, Achromobacter, Stenotrophomonas, and Pandoraea strains, 89% of which were cultured from respiratory specimens from persons with cystic fibrosis. Among the β-lactam-β-lactamase inhibitor agents, meropenem-vaborbactam had the greatest activity against Burkholderia and Achromobacter; including multi-drug-resistant and extensively-drug-resistant strains. None of the newer β-lactam-β-lactamase combination drugs showed increased activity compared to older agents against Stenotrophomonas maltophilia or Pandoraea spp.PMID: 31611364 [PubMed - as supplied by publisher]
Improved culture detection of Staphylococcus aureus from sputum of patients with cystic fibrosis (CF).
Related ArticlesImproved culture detection of Staphylococcus aureus from sputum of patients with cystic fibrosis (CF). J Clin Pathol. 2019 Oct 13;: Authors: Wen H, Stirling J, McCaughan J, Schock B, Downey DG, Ennis M, Moore JE PMID: 31611286 [PubMed - as supplied by publisher]
Inflammatory Myofibroblastic Tumor After Lung Transplant-A Rare and Aggressive Complication: A Case Report.
Related ArticlesInflammatory Myofibroblastic Tumor After Lung Transplant-A Rare and Aggressive Complication: A Case Report. Transplant Proc. 2019 Oct 11;: Authors: Poggi C, Pecoraro Y, Carillo C, Anile M, Amore D, Mantovani S, Naldi G, Pagini A, Bassi M, Cagnetti S, Mottola E, D'Agostino F, Vannucci J, Pernazza A, Cimino G, Savi D, Gomellini S, Pugliese F, De Giacomo T, Rendina EA, Venuta F, Diso D Abstract INTRODUCTION: Malignant diseases are well-known complications after lung transplantation (LT). Among these, inflammatory myofibroblastic tumor (IMT) is a rare neoplasm with a not well-known and often aggressive biological behavior. MATERIAL AND METHODS: We hereby describe 2 cases of cystic fibrosis patients who underwent bilateral sequential LT (BSLT) complicated by IMT. RESULTS: A 26-year-old man presented a right endobronchial lesion 6 months after BSLT. Two consecutive fiber bronchoscopic biopsies showed granulation tissue. For the persistent lesion growth, the patient underwent a transthoracic biopsy showing histologic diagnosis of IMT. Therefore, he underwent to right pneumonectomy that was unfortunately complicated after 6 months with a late bronchopleural fistula and empyema with exitus 6 months later. A 31-year-old woman 1 year after BSLT presented with a left voluminous pleural-parenchymal lesion; the histologic examination after biopsy revealed an IMT. She underwent a removal of the lesion with a macroscopic R0 resection. Histologic, immunophenotypic, and cytogenetic examinations showed a strong overexpression of anaplastic lymphoma kinase requiring biological adjuvant therapies; however, the patient refused it. Four years later, she presented a recurrence treated with debulking procedure and adjuvant radiotherapy. At last follow-up, the patient was alive with stable disease and optimal graft function. CONCLUSIONS: Although IMT is a rare complication after lung transplant, to obtain a careful diagnosis, an early and aggressive treatment is mandatory.PMID: 31611127 [PubMed - as supplied by publisher]
Impact of Cold Ischemic Time on Airway Complications After Lung Transplantation: A Single-center Cohort Study.
Related ArticlesImpact of Cold Ischemic Time on Airway Complications After Lung Transplantation: A Single-center Cohort Study. Transplant Proc. 2019 Oct 10;: Authors: Mendogni P, Pieropan S, Rosso L, Tosi D, Carrinola R, Righi I, Damarco F, Musso V, Bonitta G, Morlacchi LC, Rossetti V, Nosotti M Abstract BACKGROUND: Despite significant improvements in lung transplantation procedures, the incidence of airway complications (ACs) remains high (2%-18%); these complications are associated with high costs, great morbidities, and a decreased quality of life. There is general disagreement over potential risk factors determining ACs, including graft cold ischemic time (CIT). The aim of this study was to evaluate the association between CIT and ACs. METHODS: All patients undergoing lung transplantation between January 2011 and December 2017 were evaluated. We excluded retransplantations and patients with 90-day mortality. Demographic and clinical data regarding donors, recipients, and surgical procedures were analyzed using propensity score weighted marginal Cox regression model. RESULTS: Out of the 161 lung transplantations performed in the study timeframe, 147 fulfilled the inclusion criteria and supplied complete data to be analyzed. Median follow-up was 25.5 months (interquartile range = 35.2). Ten patients (6.8%) had late ACs; out of the 260 anastomoses considered, 14 proved to be complicated (5.4%). Median time to event was 5.5 months (range, 3-15). ACs were classified as bronchial stenosis (12) and malacia (2). Mean CIT was 446.6 minutes (range, 117-1200). Without considering time-to-event data, CIT was significantly higher in complicated anastomoses (P = .002). The unweighted marginal univariate Cox model showed a significant association between ACs and CIT (P < .001). The propensity score weighted marginal univariable Cox model confirmed this significant association (P < .001). CONCLUSIONS: The prolonged CIT time seems to be a risk factor for the development of late ACs; we endorse any measure that could limit CIT within 600 minutes.PMID: 31611126 [PubMed - as supplied by publisher]
Frequency of Cystic Fibrosis Transmembrane Conductance Regulator Variants in Individuals Evaluated for Primary Ciliary Dyskinesia.
Related ArticlesFrequency of Cystic Fibrosis Transmembrane Conductance Regulator Variants in Individuals Evaluated for Primary Ciliary Dyskinesia. J Pediatr. 2019 Oct 11;: Authors: Hannah WB, Truty R, Gonzales V, Kithcart GP, Ouyang K, Zeman MK, Li C, Drumm M, Nykamp K, Gaston BM Abstract OBJECTIVE: To evaluate whether cystic fibrosis transmembrane conductance regulator (CFTR) variants are more common among individuals tested for primary ciliary dyskinesia (PCD) compared with controls. STUDY DESIGN: Data were studied from 1021 individuals with commercial genetic testing for suspected PCD and 91 777 controls with genetic testing at the same company (Invitae) for symptoms/diseases unrelated to PCD or CFTR testing. The prevalence of CFTR variants was compared between controls and each of 3 groups of individuals tested for PCD (PCD-positive, -uncertain, and -negative molecular diagnosis). RESULTS: The prevalence of 1 pathogenic CFTR variant was similar among the individual groups. When combining the PCD-uncertain and PCR-negative molecular diagnosis groups, there was a higher prevalence of single pathogenic CFTR variants compared with controls (P = .03). Importantly, >1% of individuals who had negative genetic testing results for PCD had 2 pathogenic CFTR variants (8 of 723), and the incidence of cystic fibrosis (CF) (2 pathogenic variants) is roughly 1 in 3000 individuals of Caucasian ethnicity (∼0.03%). This incidence was also greater than that of 2 pathogenic CFTR variants in the control population (0.09% [84 of 91 777]; P = 9.60 × 10-16). These variants correlate with mild CFTR-related disease. CONCLUSIONS: Our results suggest that a single pathogenic CFTR variant is not likely to be a PCD-mimetic, but ongoing studies are needed in individuals in whom PCD is suspected and genetic testing results are uncertain or negative. Furthermore, CF may be misdiagnosed as PCD, reflecting phenotypic overlap. Among individuals evaluated for PCD, CF should be considered in the differential even in the CF newborn screening era.PMID: 31610925 [PubMed - as supplied by publisher]