scholarly journals Metabolomics of pulmonary exacerbations reveals the personalized nature of cystic fibrosis disease

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2174 ◽  
Author(s):  
Robert A. Quinn ◽  
Yan Wei Lim ◽  
Tytus D. Mak ◽  
Katrine Whiteson ◽  
Mike Furlan ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Platelet Activating Factor ◽  
Clinical State ◽  
Patient Specific ◽  
Rrna Gene ◽  
Chronic Infections ◽  
Metabolomics Data ◽  
Pulmonary Exacerbations ◽  
Personalized Approach ◽  
The Individual

Background.Cystic fibrosis (CF) is a genetic disease that results in chronic infections of the lungs. CF patients experience intermittent pulmonary exacerbations (CFPE) that are associated with poor clinical outcomes. CFPE involves an increase in disease symptoms requiring more aggressive therapy.Methods.Longitudinal sputum samples were collected from 11 patients (n= 44 samples) to assess the effect of exacerbations on the sputum metabolome using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The data was analyzed with MS/MS molecular networking and multivariate statistics.Results.The individual patient source had a larger influence on the metabolome of sputum than the clinical state (exacerbation, treatment, post-treatment, or stable). Of the 4,369 metabolites detected, 12% were unique to CFPE samples; however, the only known metabolites significantly elevated at exacerbation across the dataset were platelet activating factor (PAF) and a related monacylglycerophosphocholine lipid. Due to the personalized nature of the sputum metabolome, a single patient was followed for 4.2 years (capturing four separate exacerbation events) as a case study for the detection of personalized biomarkers with metabolomics. PAF and related lipids were significantly elevated during CFPEs of this patient and ceramide was elevated during CFPE treatment. Correlating the abundance of bacterial 16S rRNA gene amplicons to metabolomics data from the same samples during a CFPE demonstrated that antibiotics were positively correlated toStenotrophomonasandPseudomonas, while ceramides and other lipids were correlated withStreptococcus,Rothia, and anaerobes.Conclusions.This study identified PAF and other inflammatory lipids as potential biomarkers of CFPE, but overall, the metabolome of CF sputum was patient specific, supporting a personalized approach to molecular detection of CFPE onset.

scholarly journals Bioorthogonal non-canonical amino acid tagging reveals translationally active subpopulations of the cystic fibrosis lung microbiota

2019 ◽  
Author(s):  
Talia D. Valentini ◽  
Sarah K. Lucas ◽  
Kelsey A. Binder ◽  
Lydia C. Cameron ◽  
Jason A. Motl ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Amino Acid ◽  
Growth Strategy ◽  
Fluorescent Imaging ◽  
Cystic Fibrosis Lung ◽  
Patient Specific ◽  
Rrna Gene ◽  
Metabolic Labeling ◽  
Bacterial Cells ◽  
Canonical Amino Acid

AbstractCulture-independent studies of cystic fibrosis lung microbiota have provided few mechanistic insights into the polymicrobial basis of disease. Deciphering the specific contributions of individual taxa to CF pathogenesis requires a comprehensive understanding of theirin situecophysiology. We applied bioorthogonal non-canonical amino acid tagging (BONCAT), a ‘click’ chemistry-based metabolic labeling approach, to quantify and visualize translational activity among CF microbiota. Using BONCAT-based fluorescent imaging on sputum collected from stable CF subjects, we reveal that only a subset of bacteria are translationally active. We also combined BONCAT with fluorescent activated cell sorting (FACS) and 16S rRNA gene sequencing to assign taxonomy to the active subpopulation and found that the most dominant taxa are indeed translationally active. On average, only ∼12-18% of bacterial cells were BONCAT labeled, suggesting a heterogeneous growth strategy widely employed by most airway microbiota. Differentiating translationally active populations from those that are dormant adds to our evolving understanding of the polymicrobial basis of CF lung disease and may help guide patient-specific therapeutic strategies targeting active bacterial populations that are most likely to be susceptible.

scholarly journals The Antibacterial and Anti-Biofilm Activity of Metal Complexes Incorporating 3,6,9-Trioxaundecanedioate and 1,10-Phenanthroline Ligands in Clinical Isolates of Pseudomonas aeruginosa from Irish Cystic Fibrosis Patients

Antibiotics ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 674
Author(s):  
Megan O’Shaughnessy ◽  
Pauraic McCarron ◽  
Livia Viganor ◽  
Malachy McCann ◽  
Michael Devereux ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Biofilm Formation ◽  
Post Treatment ◽  
Extracellular Dna ◽  
Clinical Isolates ◽  
Reference Laboratory ◽  
Synergistic Activity ◽  
Chronic Infections ◽  
The Individual

Chronic infections of Pseudomonas aeruginosa in the lungs of cystic fibrosis (CF) patients are problematic in Ireland where inherited CF is prevalent. The bacteria’s capacity to form a biofilm in its pathogenesis is highly virulent and leads to decreased susceptibility to most antibiotic treatments. Herein, we present the activity profiles of the Cu(II), Mn(II) and Ag(I) tdda-phen chelate complexes {[Cu(3,6,9-tdda)(phen)2]·3H2O·EtOH}n (Cu-tdda-phen), {[Mn(3,6,9-tdda)(phen)2]·3H2O·EtOH}n (Mn-tdda-phen) and [Ag2(3,6,9-tdda)(phen)4]·EtOH (Ag-tdda-phen) (tddaH2 = 3,6,9-trioxaundecanedioic acid; phen = 1,10-phenanthroline) towards clinical isolates of P. aeruginosa derived from Irish CF patients in comparison to two reference laboratory strains (ATCC 27853 and PAO1). The effects of the metal-tdda-phen complexes and gentamicin on planktonic growth, biofilm formation (pre-treatment) and mature biofilm (post-treatment) alone and in combination were investigated. The effects of the metal-tdda-phen complexes on the individual biofilm components; exopolysaccharide, extracellular DNA (eDNA), pyocyanin and pyoverdine are also presented. All three metal-tdda-phen complexes showed comparable and often superior activity to gentamicin in the CF strains, compared to their activities in the laboratory strains, with respect to both biofilm formation and established biofilms. Combination studies presented synergistic activity between all three complexes and gentamicin, particularly for the post-treatment of established mature biofilms, and was supported by the reduction of the individual biofilm components examined.

scholarly journals Cystic Fibrosis Rapid Response: Translating Multi-omics Data into Clinically Relevant Information

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Ana Georgina Cobián Güemes ◽  
Yan Wei Lim ◽  
Robert A. Quinn ◽  
Douglas J. Conrad ◽  
Sean Benler ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Cystic Fibrosis ◽  
Microbial Community ◽  
Life Span ◽  
Microbial Community Composition ◽  
Rapid Response ◽  
Metabolomics Data ◽  
Content Type ◽  
Pulmonary Exacerbations

ABSTRACTPulmonary exacerbations are the leading cause of death in cystic fibrosis (CF) patients. To track microbial dynamics during acute exacerbations, a CF rapid response (CFRR) strategy was developed. The CFRR relies on viromics, metagenomics, metatranscriptomics, and metabolomics data to rapidly monitor active members of the viral and microbial community during acute CF exacerbations. To highlight CFRR, a case study of a CF patient is presented, in which an abrupt decline in lung function characterized a fatal exacerbation. The microbial community in the patient’s lungs was closely monitored through the multi-omics strategy, which led to the identification of pathogenic shigatoxigenicEscherichia coli(STEC) expressing Shiga toxin. This case study illustrates the potential for the CFRR to deconstruct complicated disease dynamics and provide clinicians with alternative treatments to improve the outcomes of pulmonary exacerbations and expand the life spans of individuals with CF.IMPORTANCEProper management of polymicrobial infections in patients with cystic fibrosis (CF) has extended their life span. Information about the composition and dynamics of each patient’s microbial community aids in the selection of appropriate treatment of pulmonary exacerbations. We propose the cystic fibrosis rapid response (CFRR) as a fast approach to determine viral and microbial community composition and activity during CF pulmonary exacerbations. The CFRR potential is illustrated with a case study in which a cystic fibrosis fatal exacerbation was characterized by the presence of shigatoxigenicEscherichia coli. The incorporation of the CFRR within the CF clinic could increase the life span and quality of life of CF patients.

scholarly journals A Volatile and Dynamic Longitudinal Microbiome Is Associated With Less Reduction in Lung Function in Adolescents With Cystic Fibrosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Marisa I. Metzger ◽  
Simon Y. Graeber ◽  
Mirjam Stahl ◽  
Olaf Sommerburg ◽  
Marcus A. Mall ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
16S Rrna Gene Sequencing ◽  
Rrna Gene ◽  
Contributing Factors ◽  
Lung Function Decline ◽  
Cross Sectional ◽  
Lung Microbiome ◽  
The Stability ◽  
The Individual

Progressive impairment in lung function caused by chronic polymicrobial airway infection remains the major cause of death in patients with cystic fibrosis (CF). Cross-sectional studies suggest an association between lung function decline and specific lung microbiome ecotypes. However, longitudinal studies on the stability of the airway microbiome are missing for adolescents with CF constituting the age group showing the highest rate of decline in lung function. In this study, we analyzed longitudinal lung function data and sputum samples collected over a period of 3 to 5 years from 12 adolescents with CF. The sputum microbiome was analyzed using 16S rRNA gene sequencing. Our results indicate that the individual course of the lung microbiome is associated with longitudinal lung function. In our cohort, patients with a dynamic, diverse microbiome showed a slower decline of lung function measured by FEV1% predicted, whereas a more stable and less diverse lung microbiome was related to worse outcomes. Specifically, a higher abundance of the phyla Bacteroidetes and Firmicutes was linked to a better clinical outcome, while Proteobacteria were correlated with a decline in FEV1% predicted. Our study indicates that the stability and diversity of the lung microbiome and the abundance of Bacteroidetes and Firmicutes are associated with the lung function decline and are one of the contributing factors to the disease severity.

scholarly journals Personalized Lifestyle Medicine: Relevance for Nutrition and Lifestyle Recommendations

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Deanna M. Minich ◽  
Jeffrey S. Bland
Keyword(s):  
Chronic Disease ◽  
Clinical Medicine ◽  
Lifestyle Modification ◽  
Point Of Care ◽  
Exercise Stress ◽  
Patient Specific ◽  
Lifestyle Medicine ◽  
Genes And Environment ◽  
Personalized Approach ◽  
The Individual

Public health recommendations for lifestyle modification, including diet and physical activity, have been widely disseminated for the prevention and treatment of disease. These guidelines are intended for the overall population without significant consideration for the individual with respect to one’s genes and environment. Personalized lifestyle medicine is a newly developed term that refers to an approach to medicine in which an individual’s health metrics from point-of-care diagnostics are used to develop lifestyle medicine-oriented therapeutic strategies for improving individual health outcomes in managing chronic disease. Examples of the application of personalized lifestyle medicine to patient care include the identification of genetic variants through laboratory tests and/or functional biomarkers for the purpose of designing patient-specific prescriptions for diet, exercise, stress, and environment. Personalized lifestyle medicine can provide solutions to chronic health problems by harnessing innovative and evolving technologies based on recent discoveries in genomics, epigenetics, systems biology, life and behavioral sciences, and diagnostics and clinical medicine. A comprehensive, personalized approach to medicine is required to promote the safety of therapeutics and reduce the cost of chronic disease. Personalized lifestyle medicine may provide a novel means of addressing a patient’s health by empowering them with information they need to regain control of their health.

scholarly journals Pseudomonas aeruginosa PA14 Enhances the Efficacy of Norfloxacin against Staphylococcus aureus Newman Biofilms

2020 ◽  
Vol 202 (18) ◽  
Author(s):  
Giulia Orazi ◽  
Fabrice Jean-Pierre ◽  
George A. O’Toole
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Antimicrobial Agents ◽  
Respiratory Infections ◽  
Multiple Infection ◽  
Bacterial Biofilms ◽  
Interspecies Interactions ◽  
Chronic Infections ◽  
Content Type

ABSTRACT The thick mucus within the airways of individuals with cystic fibrosis (CF) promotes frequent respiratory infections that are often polymicrobial. Pseudomonas aeruginosa and Staphylococcus aureus are two of the most prevalent pathogens that cause CF pulmonary infections, and both are among the most common etiologic agents of chronic wound infections. Furthermore, the ability of P. aeruginosa and S. aureus to form biofilms promotes the establishment of chronic infections that are often difficult to eradicate using antimicrobial agents. In this study, we found that multiple LasR-regulated exoproducts of P. aeruginosa, including 2-heptyl-4-hydroxyquinoline N-oxide (HQNO), siderophores, phenazines, and rhamnolipids, likely contribute to the ability of P. aeruginosa PA14 to shift S. aureus Newman norfloxacin susceptibility profiles. Here, we observe that exposure to P. aeruginosa exoproducts leads to an increase in intracellular norfloxacin accumulation by S. aureus. We previously showed that P. aeruginosa supernatant dissipates the S. aureus membrane potential, and furthermore, depletion of the S. aureus proton motive force recapitulates the effect of the P. aeruginosa PA14 supernatant on shifting norfloxacin sensitivity profiles of biofilm-grown S. aureus Newman. From these results, we hypothesize that exposure to P. aeruginosa PA14 exoproducts leads to increased uptake of the drug and/or an impaired ability of S. aureus Newman to efflux norfloxacin. Surprisingly, the effect observed here of P. aeruginosa PA14 exoproducts on S. aureus Newman susceptibility to norfloxacin seemed to be specific to these strains and this antibiotic. Our results illustrate that microbially derived products can alter the ability of antimicrobial agents to kill bacterial biofilms. IMPORTANCE Pseudomonas aeruginosa and Staphylococcus aureus are frequently coisolated from multiple infection sites, including the lungs of individuals with cystic fibrosis (CF) and nonhealing diabetic foot ulcers. Coinfection with P. aeruginosa and S. aureus has been shown to produce worse outcomes compared to infection with either organism alone. Furthermore, the ability of these pathogens to form biofilms enables them to cause persistent infection and withstand antimicrobial therapy. In this study, we found that P. aeruginosa-secreted products dramatically increase the ability of the antibiotic norfloxacin to kill S. aureus biofilms. Understanding how interspecies interactions alter the antibiotic susceptibility of bacterial biofilms may inform treatment decisions and inspire the development of new therapeutic strategies.

scholarly journals In Vitro Newly Isolated Environmental Phage Activity against Biofilms Preformed by Pseudomonas aeruginosa from Patients with Cystic Fibrosis

2021 ◽  
Vol 9 (3) ◽  
pp. 478
Author(s):  
Ersilia Vita Fiscarelli ◽  
Martina Rossitto ◽  
Paola Rosati ◽  
Nour Essa ◽  
Valentina Crocetta ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Multidrug Resistant ◽  
In Vitro Test ◽  
Chronic Infections ◽  
Hospital Environments ◽  
Vitro Test ◽  
General Reliability ◽  
Phage Activity

As disease worsens in patients with cystic fibrosis (CF), Pseudomonas aeruginosa (PA) colonizes the lungs, causing pulmonary failure and mortality. Progressively, PA forms typical biofilms, and antibiotic treatments determine multidrug-resistant (MDR) PA strains. To advance new therapies against MDR PA, research has reappraised bacteriophages (phages), viruses naturally infecting bacteria. Because few in vitro studies have tested phages on CF PA biofilms, general reliability remains unclear. This study aimed to test in vitro newly isolated environmental phage activity against PA isolates from patients with CF at Bambino Gesù Children’s Hospital (OBG), Rome, Italy. After testing in vitro phage activities, we combined phages with amikacin, meropenem, and tobramycin against CF PA pre-formed biofilms. We also investigated new emerging morphotypes and bacterial regrowth. We obtained 22 newly isolated phages from various environments, including OBG. In about 94% of 32 CF PA isolates tested, these phages showed in vitro PA lysis. Despite poor efficacy against chronic CF PA, five selected-lytic-phages (Φ4_ZP1, Φ9_ZP2, Φ14_OBG, Φ17_OBG, and Φ19_OBG) showed wide host activity. The Φ4_ZP1-meropenem and Φ14_OBG-tobramycin combinations significantly reduced CF PA biofilms (p < 0.001). To advance potential combined phage-antibiotic therapy, we envisage further in vitro test combinations with newly isolated phages, including those from hospital environments, against CF PA biofilms from early and chronic infections.

scholarly journals 1615. Isolation of Lytic Bacteriophages with Broad Host Range Activity Against Pseudomonas aeruginosa Strains Isolated from Respiratory Samples from Cystic Fibrosis Patients Intended for Therapeutic Application

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S801-S801
Author(s):  
Jose Alexander ◽  
Daniel Navas ◽  
Marly Flowers ◽  
Angela Charles ◽  
Amy Carr
Keyword(s):  
Cystic Fibrosis ◽  
Host Range ◽  
Phage Therapy ◽  
Clinical Isolates ◽  
Clinical Samples ◽  
Plaque Morphology ◽  
Broad Host Range ◽  
Chronic Infections ◽  
Clinically Significant ◽  
Host Target

Abstract Background With the rise of the antimicrobial resistance between different genera and species of bacteria, Phage Therapy is becoming a more realistic and accessible option for patients with limited or no antimicrobial options. Being able to have rapid access to a collection of clinical active phages is key for rapid implementation of phage therapy. The Microbiology Department at AdventHealth Orlando is performing routine screening of environmental and patient samples for isolation of phages against non-fermenting Gram negative bacteria to develop a Phage Bank. Methods Protocols for phage isolation from environmental sources such as lakes, rivers and sewers and clinical samples were developed. A series of respiratory, throat, stool and urine samples were processed following an internal protocol that includes centrifugation, filtration and enrichment. Clinical samples were centrifugated for 10 minutes, filtered using 0.45µm centrifugation filters, seeded with targeted host bacteria (clinical isolates) and incubated at 35°C for 24 hours. The enriched samples were centrifugated and filtered for a final phage enriched solution. Screening and isolation were performed using the Gracia method over trypticase soybean agar (TSA) for plaque morphology and quantification. Host range screening of other clinical isolates of P. aeruginosa was performed using the new isolated and purified phages. Results 4 lytic phages against clinical strains of P. aeruginosa from patient with diagnosis of cystic fibrosis (CF), were isolated and purified from 4 different respiratory samples, including sputum and bronchial alveolar lavage. All phages showed phenotypical characteristics of lytic activity. 1 phage was active against 4 strains of P. aeruginosa, 1 phage was active against 2 strains of P. aeruginosa and the remaining 2 phages were active only against the initial host target strain. Conclusion With this study we demonstrated the potential use of clinical samples as source for isolating active bacteriophages against clinically significant bacteria strains. Clinical samples from vulnerable population of patients with chronic infections are part of our routine “phage-hunting” process to stock and grow our Phage Bank project for future clinical use. Disclosures All Authors: No reported disclosures

scholarly journals Variation in treatment preferences of pulmonary exacerbations among Australian and New Zealand cystic fibrosis physicians

2021 ◽  
Vol 8 (1) ◽  
pp. e000956
Author(s):  
Grace Currie ◽  
Anna Tai ◽  
Tom Snelling ◽  
André Schultz
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Trials ◽  
New Zealand ◽  
Treatment Options ◽  
Early Response ◽  
Treatment Preferences ◽  
Dornase Alfa ◽  
Clinical Scenarios ◽  
Professional Opinion ◽  
Pulmonary Exacerbations

BackgroundDespite advances in cystic fibrosis (CF) management and survival, the optimal treatment of pulmonary exacerbations remains unclear. Understanding the variability in treatment approaches among physicians might help prioritise clinical uncertainties to address through clinical trials.MethodsPhysicians from Australia and New Zealand who care for people with CF were invited to participate in a web survey of treatment preferences for CF pulmonary exacerbations. Six typical clinical scenarios were presented; three to paediatric and another three to adult physicians. For each scenario, physicians were asked to choose treatment options and provide reasons for their choices.ResultsForty-nine CF physicians (31 paediatric and 18 adult medicine) participated; more than half reported 10+ years of experience. There was considerable variation in primary antibiotic selection; none was preferred by more than half of respondents in any scenario. For secondary antibiotic therapy, respondents consistently preferred intravenous tobramycin and a third antibiotic was rarely prescribed, except in one scenario describing an adult patient. Hypertonic saline nebulisation and twice daily chest physiotherapy was preferred in most scenarios while dornase alfa use was more variable. Most CF physicians (>80%) preferred to change therapy if there was no early response. Professional opinion was the most common reason for antibiotic choice.ConclusionsVariation exists among CF physicians in their preferred choice of primary antibiotic and use of dornase alfa. These preferences are driven by professional opinion, possibly reflecting a lack of evidence to base policy recommendations. Evidence from high-quality clinical trials is needed to inform physician decision making.

scholarly journals Fully Data-Driven Pseudohealthy Synthesis for Planning Valve-Sparing Aortic Root Reconstruction using Conditional Variational Autoencoders

2020 ◽  
Vol 6 (3) ◽  
pp. 284-287
Author(s):  
Jannis Hagenah ◽  
Mohamad Mehdi ◽  
Floris Ernst
Keyword(s):  
Aortic Root ◽  
Similarity Index ◽  
Ground Truth ◽  
Representation Learning ◽  
Patient Specific ◽  
Ultrasound Images ◽  
Specific Geometry ◽  
The Individual ◽  
Native Root ◽  
Original Information

AbstractAortic root aneurysm is treated by replacing the dilated root by a grafted prosthesis which mimics the native root morphology of the individual patient. The challenge in predicting the optimal prosthesis size rises from the highly patient-specific geometry as well as the absence of the original information on the healthy root. Therefore, the estimation is only possible based on the available pathological data. In this paper, we show that representation learning with Conditional Variational Autoencoders is capable of turning the distorted geometry of the aortic root into smoother shapes while the information on the individual anatomy is preserved. We evaluated this method using ultrasound images of the porcine aortic root alongside their labels. The observed results show highly realistic resemblance in shape and size to the ground truth images. Furthermore, the similarity index has noticeably improved compared to the pathological images. This provides a promising technique in planning individual aortic root replacement.

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