Is Intervention in Inositol Phosphate Signaling a Useful Therapeutic Option for Cystic Fibrosis?

2007 ◽  
pp. 103-114
Author(s):  
Stephen B. Shears ◽  
Ling Yang ◽  
Sherif Gabriel ◽  
Carla M. Pedrosa Ribeiro
Keyword(s):  
Cystic Fibrosis ◽  
Inositol Phosphate ◽  
Therapeutic Option

scholarly journals Activity of Telavancin against Staphylococcus aureus Isolates, Including Those with Decreased Susceptibility to Ceftaroline, from Cystic Fibrosis Patients

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Melanie Roch ◽  
Maria Celeste Varela ◽  
Agustina Taglialegna ◽  
Warren E. Rose ◽  
Adriana E. Rosato
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Galleria Mellonella ◽  
Therapeutic Option ◽  
The United States ◽  
Infection Model ◽  
Content Type ◽  
Complicated Skin ◽  
Hospital Acquired

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) acquisition in cystic fibrosis (CF) patients confers a clinical outcome worse than that in non-CF patients with an increased rate of declined lung function. Telavancin, an approved lipoglycopeptide used to treat infections due to S. aureus, has a dual mode of action causing inhibition of peptidoglycan synthesis and membrane depolarization. MRSA infections in CF patients remain an important problem with no foreseeable decline in prevalence rates. Although telavancin is currently in clinical use for the treatment of complicated skin infections and hospital-acquired pneumonia, the activity against S. aureus infections in CF patients has not been investigated. In this work, we studied the activity of telavancin against CF patient-derived S. aureus strains collected from geographically diverse CF centers in the United States. We found that the telavancin MIC90 was 0.06 μg/ml, 8-fold lower than the ceftaroline or daptomycin MIC90 and 25-fold lower than the linezolid and vancomycin MIC90. We demonstrate that telavancin at serum free concentrations has rapid bactericidal activity, with a decrease of more than 3 log10 CFU/ml being achieved during the first 4 to 6 h of treatment, performing better in this assay than vancomycin and ceftaroline, including against S. aureus strains resistant to ceftaroline. Telavancin resistance was infrequent (0.3%), although we found that it can occur in vitro in both CF- and non-CF patient-derived S. aureus strains by progressive passages with subinhibitory concentrations. Genetic analysis of telavancin-resistant in vitro mutants showed gene polymorphisms in cell wall and virulence genes and increased survival in a Galleria mellonella infection model. Thus, we conclude that telavancin represents a promising therapeutic option for infections in CF patients with potent in vitro activity and a low resistance development potential.

Lung transplantation

2010 ◽  
pp. 3476-3485
Author(s):  
P. Hopkins ◽  
K. McNeil
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Cystic Fibrosis ◽  
Lung Transplantation ◽  
Therapeutic Option ◽  
Pulmonary Vascular Disease ◽  
Chronic Obstructive ◽  
Solid Organ ◽  
Obstructive Pulmonary Disease ◽  
Substance Addiction ◽  
Recipient Selection

Lung transplantation offers the only therapeutic option for many patients with a variety of endstage pulmonary and cardiopulmonary diseases, but donors are scarce and the major challenge facing lung transplantation (as with all solid organ transplants) is the critical shortage of donor organs. Recipient selection—emphysema/chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis, and pulmonary vascular disease are the main disease groups referred for lung transplantation. Most patients are listed for transplantation when their survival is estimated to be less than 2 years without a transplant. Exclusion criteria include malignancy (excluding localized skin malignancies) within the last 2 years, inability to cooperate or comply with medical therapy/instruction, recent substance addiction, active or noncurable extrapulmonary infection, significant chest wall/spinal deformity, and significant extrathoracic organ dysfunction....

scholarly journals Rapid Emergence of Resistance to Linezolid and Mutator Phenotypes in Staphylococcus aureus Isolates from an Adult Cystic Fibrosis Patient

2013 ◽  
Vol 57 (10) ◽  
pp. 5186-5188 ◽  
Author(s):  
Asmaa Tazi ◽  
Jeanne Chapron ◽  
Gerald Touak ◽  
Magalie Longo ◽  
Dominique Hubert ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Cystic Fibrosis Patient ◽  
Therapeutic Option ◽  
Clinical Isolates ◽  
23S Rrna ◽  
Mutator Phenotype ◽  
Content Type ◽  
Emergence Of Resistance ◽  
Rapid Emergence

ABSTRACTLinezolid has emerged as an important therapeutic option for the treatment ofStaphylococcus aureusin patients with cystic fibrosis. We report the rapid emergence, upon treatment with linezolid, of linezolid-resistantS. aureusclinical isolates through the accumulation of resistance-associated 23S rRNA mutations, together with acquisition of an altered mutator phenotype.

scholarly journals Comparative evaluation of methods testing in vitro sensitivity to azithromycin in multi-drug resistant Pseudomonas aeruginosa isolated from cystic fibrosis patients

2020 ◽  
Author(s):  
Michael Soerensen ◽  
Dennis Nurjadi ◽  
Bakhodur Khakimov ◽  
Sébastien Boutin ◽  
Alexander H. Dalpke ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Therapeutic Option ◽  
Calf Serum ◽  
Multidrug Resistant ◽  
Term Treatment ◽  
In Vitro Sensitivity ◽  
Mueller Hinton ◽  
Long Term Treatment

Abstract Long-term treatment with azithromycin is a therapeutic option in Cystic Fibrosis (CF) patients chronically infected with P. aeruginosa . It was recently shown that azithromycin has direct antimicrobial activity when P. aeruginosa isolates are tested in Roswell Park Memorial Institute medium supplemented with fetal calf serum (RPMI 1640/FCS) by broth microdilution. We now investigated whether (i) azithromycin might also be active against multidrug resistant (MDR) P. aeruginosa isolated from CF patients and (ii) how in vitro sensitivity assays perform in synthetic cystic fibrosis sputum medium (SCFM), a medium that mimics the particular CF airway environment. In 17 (59%) out of 29 MDR P. aeruginosa CF isolates MICs for azithromycin ranged between 0.25 and 8 µg/ml and 12 isolates (41%) showed a MIC ≥512 µg/ml when measured in RPMI/FCS. In contrast, MICs were ≥256 µg/ml for all P. aeruginosa MDR isolates when tested in either SCFM or in conventional cation-adjusted Mueller Hinton Broth. High MIC values observed in CF adapted medium SCFM for both PAO1 and MDR P. aeruginosa CF isolates, as opposed to findings in RPMI, argue against routine azithromycin MIC testing of CF isolates.

scholarly journals Tedizolid is a promising antimicrobial option for the treatment of Staphylococcus aureus infections in cystic fibrosis patients

2019 ◽  
Vol 75 (1) ◽  
pp. 126-134
Author(s):  
Melanie Roch ◽  
Maria Celeste Varela ◽  
Agustina Taglialegna ◽  
Adriana E Rosato
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Therapeutic Option ◽  
Protein Synthesis Inhibitor ◽  
Synthesis Inhibitor ◽  
Small Colony Variant ◽  
The Usa ◽  
Time Kill

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.

The Effect of TGF-β1 Polymorphisms on Pulmonary Disease Progression in Patients with Cystic Fibrosis

2021 ◽  
Author(s):  
Tobias Trojan ◽  
Maxine von Maessenhausen ◽  
Peter Schneider ◽  
Gregor Fink ◽  
Ernst Rietschel ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Disease Progression ◽  
Pulmonary Disease ◽  
Inflammatory Cytokines ◽  
Transforming Growth Factor ◽  
Therapeutic Option ◽  
Genetic Modifier ◽  
Lung Function Decline ◽  
Tnf Α

Abstract Background: Transforming Growth Factor-β1 (TGF-β1) is a genetic modifier in patients with cystic fibrosis (CF). Several single nucleotide polymorphisms (SNPs) of TGF-β1 are associated with neutrophilic inflammation, lung fibrosis und loss of pulmonary function.Aim: The aim of this study was to assess the relationship between genetic TGF-β1 polymorphisms and pulmonary disease progression in CF patients. Furthermore, the effect of TGF-β1 polymorphisms on inflammatory cytokines in sputum were investigated.Methods: 56 CF-patients and 62 controls were genotyped for three relevant SNPs in their TGF-β1 sequence using the SNaPshot® technique. Individual slopes in forced expiratory volume in 1 second (FEV1) for all patients were calculated by using documented lung function values of the previous five years. The status of Pseudomonas aeruginosa (Pa) infection was determined. Sputum concentrations of the protease elastase, the serine protease inhibitor elafin and the cytokines IL-1β, IL-8, IL-6, TNF-α were measured after a standardized sputum induction and processing.Results: The homozygous TT genotype at codon 10 was associated with a lower rate of chronic Pa infection (p<0.05). The heterozygous GC genotype at codon 25 was associated with lower lung function decline (p<0.05). Patients with homozygous TT genotype at the promotor SNP showed higher levels of TNF-α (p<0,05). Higher levels of TGF-β1 in plasma were associated with a more rapid FEV1 decline over five years (p<0.05). Conclusions: Our results suggest that polymorphisms in the TGF-β1 gene have an effect on lung function decline, Pa infection as well as levels of inflammatory cytokines. Genotyping these polymorphisms could potentially be used to identify CF patients with higher risk of disease progression. TGF-β1 inhibition could potentially be developed as a new therapeutic option to modulate CF lung disease.

scholarly journals Linocin and OmpW Are Involved in Attachment of the Cystic Fibrosis-Associated Pathogen Burkholderia cepacia Complex to Lung Epithelial Cells and Protect Mice against Infection

2016 ◽  
Vol 84 (5) ◽  
pp. 1424-1437 ◽  
Author(s):  
Siobhán McClean ◽  
Marc E. Healy ◽  
Cassandra Collins ◽  
Stephen Carberry ◽  
Luke O'Shaughnessy ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Burkholderia Cepacia ◽  
Therapeutic Option ◽  
Lung Epithelial Cells ◽  
Burkholderia Cenocepacia ◽  
Burkholderia Cepacia Complex ◽  
Content Type ◽  
Lung Epithelial ◽  
Proteomics Approach

Members of theBurkholderia cepaciacomplex (Bcc) cause chronic opportunistic lung infections in people with cystic fibrosis (CF), resulting in a gradual lung function decline and, ultimately, patient death. The Bcc is a complex of 20 species and is rarely eradicated once a patient is colonized; therefore, vaccination may represent a better therapeutic option. We developed a new proteomics approach to identify bacterial proteins that are involved in the attachment of Bcc bacteria to lung epithelial cells. Fourteen proteins were reproducibly identified by two-dimensional gel electrophoresis from four Bcc strains representative of two Bcc species:Burkholderia cenocepacia, the most virulent, andB. multivorans, the most frequently acquired. Seven proteins were identified in both species, but only two were common to all four strains, linocin and OmpW. Both proteins were selected based on previously reported data on these proteins in other species.Escherichia colistrains expressing recombinant linocin and OmpW showed enhanced attachment (4.2- and 3.9-fold) to lung cells compared to the control, confirming that both proteins are involved in host cell attachment. Immunoproteomic analysis using serum from Bcc-colonized CF patients confirmed that both proteins elicit potent humoral responsesin vivo. Mice immunized with either recombinant linocin or OmpW were protected fromB. cenocepaciaandB. multivoranschallenge. Both antigens induced potent antigen-specific antibody responses and stimulated strong cytokine responses. In conclusion, our approach identified adhesins that induced excellent protection against two Bcc species and are promising vaccine candidates for a multisubunit vaccine. Furthermore, this study highlights the potential of our proteomics approach to identify potent antigens against other difficult pathogens.

scholarly journals Revisiting CFTR Interactions: Old Partners and New Players

2021 ◽  
Vol 22 (24) ◽  
pp. 13196
Author(s):  
Carlos M. Farinha ◽  
Martina Gentzsch
Keyword(s):  
Cystic Fibrosis ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Therapeutic Option ◽  
Signal Pathways ◽  
Factors Affecting ◽  
Common System ◽  
Therapeutic Development ◽  
Cftr Mutations ◽  
Development And Differentiation

Remarkable progress in CFTR research has led to the therapeutic development of modulators that rescue the basic defect in cystic fibrosis. There is continuous interest in studying CFTR molecular disease mechanisms as not all cystic fibrosis patients have a therapeutic option available. Addressing the basis of the problem by comprehensively understanding the critical molecular associations of CFTR interactions remains key. With the availability of CFTR modulators, there is interest in comprehending which interactions are critical to rescue CFTR and which are altered by modulators or CFTR mutations. Here, the current knowledge on interactions that govern CFTR folding, processing, and stability is summarized. Furthermore, we describe protein complexes and signal pathways that modulate the CFTR function. Primary epithelial cells display a spatial control of the CFTR interactions and have become a common system for preclinical and personalized medicine studies. Strikingly, the novel roles of CFTR in development and differentiation have been recently uncovered and it has been revealed that specific CFTR gene interactions also play an important role in transcriptional regulation. For a comprehensive understanding of the molecular environment of CFTR, it is important to consider CFTR mutation-dependent interactions as well as factors affecting the CFTR interactome on the cell type, tissue-specific, and transcriptional levels.

Monitoring of lobectomy in cystic fibrosis with electrical impedance tomography – a new diagnostic tool

2014 ◽  
Vol 59 (6) ◽  
Author(s):  
Sylvia Lehmann ◽  
Klaus Tenbrock ◽  
Simone Schrading ◽  
Robert Pikkemaat ◽  
Christoph Hoog Antink ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Electrical Impedance Tomography ◽  
Diagnostic Tool ◽  
Electrical Impedance ◽  
Therapeutic Option ◽  
Middle Lobe ◽  
Voltage Measurement ◽  
Impedance Tomography ◽  
Cross Sectional ◽  
Lung Lobectomy

AbstractElectrical impedance tomography (EIT) is a radiation-free technique generating cross-sectional images of the lung. EIT visualizes global and regional ventilation by illustrating the distribution of electrical bioimpedance. With an electrode belt around the patient’s thorax, rotating injection-couples of a harmless alternating current allow voltage measurement of the remaining electrodes. This enables the reconstruction of a tomogram with highly dynamic changes within ventilation. We report on a female six-year-old patient with cystic fibrosis and complete destruction of the upper and middle lobe of the right lung. Lobectomy, a rare therapeutic option in patients with cystic fibrosis that needs to be considered in cases of severe localized destruction, was performed. We show a pre- and postoperative documentation of static (radiology) and dynamic investigation tools (spirometry) in correlation with EIT as a new non-invasive and radiation-free diagnostic tool for this patient group.

Sign in / Sign up

Export Citation Format

Share Document