scholarly journals High-Resolution Longitudinal Dynamics of the Cystic Fibrosis Sputum Microbiome and Metabolome through Antibiotic Therapy

mSystems ◽  
2020 ◽  
Vol 5 (3) ◽  
Author(s):  
Ruma Raghuvanshi ◽  
Karla Vasco ◽  
Yoshiki Vázquez-Baeza ◽  
Lingjing Jiang ◽  
James T. Morton ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Antibiotic Therapy ◽  
Pathogenic Bacteria ◽  
Temporal Dynamics ◽  
Alpha Diversity ◽  
Unifrac Distance ◽  
Content Type ◽  
Pulmonary Exacerbations ◽  
Log Ratio ◽  
Clinical Stability

ABSTRACT Microbial diversity in the cystic fibrosis (CF) lung decreases over decades as pathogenic bacteria such as Pseudomonas aeruginosa take over. The dynamics of the CF microbiome and metabolome over shorter time frames, however, remain poorly studied. Here, we analyze paired microbiome and metabolome data from 594 sputum samples collected over 401 days from six adult CF subjects (subject mean = 179 days) through periods of clinical stability and 11 CF pulmonary exacerbations (CFPE). While microbiome profiles were personalized (permutational multivariate analysis of variance [PERMANOVA] r2 = 0.79, P < 0.001), we observed significant intraindividual temporal variation that was highest during clinical stability (linear mixed-effects [LME] model, P = 0.002). This included periods where the microbiomes of different subjects became highly similar (UniFrac distance, <0.05). There was a linear increase in the microbiome alpha-diversity and in the log ratio of anaerobes to pathogens with time (n = 14 days) during the development of a CFPE (LME P = 0.0045 and P = 0.029, respectively). Collectively, comparing samples across disease states showed there was a reduction of these two measures during antibiotic treatment (LME P = 0.0096 and P = 0.014, respectively), but the stability data and CFPE data were not significantly different from each other. Metabolome alpha-diversity was higher during CFPE than during stability (LME P = 0.0085), but no consistent metabolite signatures of CFPE across subjects were identified. Virulence-associated metabolites from P. aeruginosa were temporally dynamic but were not associated with any disease state. One subject died during the collection period, enabling a detailed look at changes in the 194 days prior to death. This subject had over 90% Pseudomonas in the microbiome at the beginning of sampling, and that level gradually increased to over 99% prior to death. This study revealed that the CF microbiome and metabolome of some subjects are dynamic through time. Future work is needed to understand what drives these temporal dynamics and if reduction of anaerobes correlate to clinical response to CFPE therapy. IMPORTANCE Subjects with cystic fibrosis battle polymicrobial lung infections throughout their lifetime. Although antibiotic therapy is a principal treatment for CF lung disease, we have little understanding of how antibiotics affect the CF lung microbiome and metabolome and how much the community changes on daily timescales. By analyzing 594 longitudinal CF sputum samples from six adult subjects, we show that the sputum microbiome and metabolome are dynamic. Significant changes occur during times of stability and also through pulmonary exacerbations (CFPEs). Microbiome alpha-diversity increased as a CFPE developed and then decreased during treatment in a manner corresponding to the reduction in the log ratio of anaerobic bacteria to classic pathogens. Levels of metabolites from the pathogen P. aeruginosa were also highly variable through time and were negatively associated with anaerobes. The microbial dynamics observed in this study may have a significant impact on the outcome of antibiotic therapy for CFPEs and overall subject health.

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 Effect of continuous-infusion antibiotic therapy on pulmonary function of patients with cystic fibrosis: A cross-sectional study

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1766
Author(s):  
Somaya Albhaisi ◽  
Fei-Pi Lin ◽  
Nauman Chaudary
Keyword(s):  
Cystic Fibrosis ◽  
Antibiotic Therapy ◽  
Pulmonary Function ◽  
Continuous Infusion ◽  
Intermittent Infusion ◽  
Cross Sectional Study ◽  
Sectional Study ◽  
Cross Sectional ◽  
Pulmonary Exacerbations ◽  
Infusion Protocol

Background: Cystic fibrosis (CF) is associated with frequent pulmonary exacerbations which increase the mortality risk. Therefore, most CF patients are chronically colonized with respiratory pathogens, the most common being Pseudomonas aeruginosa. Multidrug-resistant organisms are a major problem in CF patients. It’s been hypothesized that continuous-infusion antipseudomonal beta-lactam therapy in CF maintains serum concentrations above the minimum inhibitory concentration of susceptible strains and is more likely than intermittent infusion to achieve optimal pharmacodynamic targets for some intermediate and resistant strains of P. aeruginosa. The most extensively studied antibiotic for continuous-infusion protocol in CF is ceftazidime, which has been shown to improve lung function (forced expiratory volume in 1 second and forced vital capacity) and to increase pulmonary exacerbation free time. There have been no studies to evaluate the cost effectiveness or impact on quality of life of continuous infusion versus intermittent infusion antibiotic therapy in patients with CF. Our study aims to investigate the effect of continuous-infusion antibiotic therapy on pulmonary function. Methods: Cross sectional study of CF patients who were admitted to our hospital with acute pulmonary exacerbations between 1/1/2010 and 12/31/2016 and received parenteral antibiotics. We investigated the effect of use of continuous versus intermittent infusion of intravenous antibiotics on the pulmonary function (FEV1% predicted). Results: Intermittent infusion protocol was found to have a very small advantage over continuous infusion protocol on pulmonary function; however this difference is not statistically significant (p=0.0049). The longer the duration of antibiotics, the slightly better the pulmonary function at the end of the treatment, but the difference was not significant (p=0.2543). Conclusions: Even though we could not draw meaningful conclusions from our data, we would like bring attention to this subject because it carries an important therapeutic value for CF patients.

2-Alkyl-4-quinolone quorum sensing molecules are biomarkers for culture-independent Pseudomonas aeruginosa burden in adults with cystic fibrosis

2021 ◽  
Vol 70 (10) ◽  
Author(s):  
Nur Masirah M. Zain ◽  
Karmel Webb ◽  
Iain Stewart ◽  
Nigel Halliday ◽  
David A. Barrett ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Type Species ◽  
Bacterial Load ◽  
Pulmonary Exacerbation ◽  
Content Type ◽  
Link Type ◽  
Culture Independent ◽  
Clinical Stability

Introduction. Pseudomonas aeruginosa produces quorum sensing signalling molecules including 2-alkyl-4-quinolones (AQs), which regulate virulence factor production in the cystic fibrosis (CF) airways. Hypothesis/Gap statement. Culture can lead to condition-dependent artefacts which may limit the potential insights and applications of AQs as minimally-invasive biomarkers of bacterial load. Aim. We aimed to use culture-independent methods to explore the correlations between AQ levels and live P. aeruginosa load in adults with CF. Methodology. Seventy-five sputum samples at clinical stability and 48 paired sputum samples obtained at the beginning and end of IV antibiotics for a pulmonary exacerbation in adults with CF were processed using a viable cell separation technique followed by quantitative P. aeruginosa polymerase chain reaction (qPCR). Live P. aeruginosa qPCR load was compared with the concentrations of three AQs (HHQ, NHQ and HQNO) detected in sputum, plasma and urine. Results. At clinical stability and the beginning of IV antibiotics for pulmonary exacerbation, HHQ, NHQ and HQNO measured in sputum, plasma and urine were consistently positively correlated with live P. aeruginosa qPCR load in sputum, compared to culture. Following systemic antibiotics live P. aeruginosa qPCR load decreased significantly (P<0.001) and was correlated with a reduction in plasma NHQ (plasma: r=0.463, P=0.003). Conclusion. In adults with CF, AQ concentrations correlated more strongly with live P. aeruginosa bacterial load measured by qPCR compared to traditional culture. Prospective studies are required to assess the potential of systemic AQs as biomarkers of P. aeruginosa bacterial burden.

Serum Bactericidal Test as a Prognostic Indicator in Acute Pulmonary Exacerbations of Cystic Fibrosis

PEDIATRICS ◽  
1993 ◽  
Vol 91 (2) ◽  
pp. 451-455
Author(s):  
Pierre Cahen ◽  
Christine Coustère ◽  
Pascale Nicaise ◽  
Michel Vèron ◽  
Jean-Louis Gaillard ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Antibiotic Therapy ◽  
Predictive Value ◽  
Bacterial Infections ◽  
Statistical Significance ◽  
Age Groups ◽  
Prognostic Indicator ◽  
Trough Serum ◽  
Peak Titer ◽  
Pulmonary Exacerbations

The serum bactericidal test has been used for many years for optimal assessment of the efficacy of antibiotic therapy in patients with infective endocarditis and other bacterial infections. Its capacity to predict the bacteriological outcome of acute pulmonary exacerbations in patients with cystic fibrosis was evaluated. A total of 54 courses of intravenous antibiotic therapy were analyzed in 22 patients, whose ages ranged from 4 months to 24 years (mean age: 10 years). The serum bactericidal activity of blood samples, taken at expected peak and trough antibiotic levels on day 4 of therapy, were determined against the potentially pathogenic strains isolated in sputum at the time of admission. For 104 isolates (64 Pseudomonas aeruginosa, 28 Staphulococcus aureus, and 12 Haemophilus influenzae strains), the peak and trough bactericidal titers were compared to bacteriological outcome. Bacteriological success was defined as a decrease of 2 log10 units or more in the bacterial density in sputum between days 0 and 7 of therapy. At peak antibiotic levels, serum bactericidal titers of 1:128 or more were 96% (all isolates) and 89% (P aeruginosa isolates), predictive of cure, whereas serum bactericidal titers of less than 1:16 were 100% predictive of failure for all infecting bacteria. In patients aged less than 18 years, the best peak titer for predicting success was 1:64, with a predictive value of 96% for titers of 1:64 or greater The peak titer that best predicted success in patients aged 18 years or more was 1:128, with a predictive value of only 83% for titers of 1:128 or greater. No trough serum bactericidal titer achieved statistical significance as a predictor of bacteriological outcome in the two patient age groups. Peak serum bactericidal titers of 1:64 or more (patients aged less than 18 years) and of 1:128 or more (patients aged 18 years or more) are recommended to provide optimal treatment of acute pulmonary exacerbations of cystic fibrosis.

scholarly journals Association of Diverse Staphylococcus aureus Populations with Pseudomonas aeruginosa Coinfection and Inflammation in Cystic Fibrosis Airway Infection

mSphere ◽  
2021 ◽  
Author(s):  
Marie K. Wieneke ◽  
Felix Dach ◽  
Claudia Neumann ◽  
Dennis Görlich ◽  
Lena Kaese ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Antibiotic Therapy ◽  
Content Type ◽  
Airway Infection ◽  
Cystic Fibrosis Airway

Staphylococcus aureus can persist for extended periods in the airways of people with cystic fibrosis (CF) in spite of antibiotic therapy and high numbers of neutrophils, which fail to eradicate this pathogen. Therefore, S. aureus needs to adapt to this hostile niche.

scholarly journals Bacterial Community Dynamics across the Gastrointestinal Tracts of Dairy Calves during Preweaning Development

2018 ◽  
Vol 84 (9) ◽  
pp. e02675-17 ◽  
Author(s):  
Juliana Dias ◽  
Marcos Inácio Marcondes ◽  
Shirley Motta de Souza ◽  
Barbara Cardoso da Mata e Silva ◽  
Melline Fontes Noronha ◽  
...  
Keyword(s):  
Microbial Communities ◽  
Bacterial Communities ◽  
Early Life ◽  
Community Dynamics ◽  
Temporal Dynamics ◽  
Alpha Diversity ◽  
Dairy Calves ◽  
Dairy Calf ◽  
Content Type ◽  
Bacterial Community Dynamics

ABSTRACTMicrobial communities play critical roles in the gastrointestinal tracts (GIT) of preruminant calves by influencing performance and health. However, little is known about the establishment of microbial communities in the calf GIT or their dynamics during development. In this study, next-generation sequencing was used to assess changes in the bacterial communities of the rumen, jejunum, cecum, and colon in 26 crossbred calves at four developmental stages (7, 28, 49, and 63 days old). Alpha diversity differed among GIT regions with the lowest diversity and evenness in the jejunum, whereas no changes in alpha diversity were observed across developmental stage. Beta diversity analysis showed both region and age effects, with low numbers of operational taxonomic units (OTUs) shared between regions within a given age group or between ages in a given region. Taxonomic analysis revealed that several taxa coexisted in the rumen, jejunum, cecum, and colon but that their abundances differed considerably by GIT region and age. As calves aged, we observed lower abundances of taxa such asBacteroides,Parabacteroides, andParaprevotellawith higher abundances ofBulleidiaandSucciniclasticumin the rumen. The jejunum also displayed taxonomic changes with increases inClostridiaceaeandTuricibactertaxa in older calves. In the lower gut, taxa such asLactobacillus,Blautia, andFaecalibacteriumdecreased and S24-7,Paraprevotella, andPrevotellaincreased as calves aged. These data support a model whereby early and successive colonization by bacteria occurs across the GIT of calves and provides insights into the temporal dynamics of the GIT microbiota of dairy calves during preweaning development.IMPORTANCEThe gastrointestinal tracts (GIT) of ruminants, such as dairy cows, house complex microbial communities that contribute to their overall health and support their ability to produce milk. For example, the rumen microbiota converts feed into usable nutrients, while the jejunal microbiota provides access to protein. Thus, establishing a properly functioning GIT microbiota in dairy calves is critical to their productivity as adult cows. However, little is known about the establishment, maintenance, and dynamics of the calf GIT microbiota in early life. In this study, we evaluated the bacterial communities in the rumen, jejunum, cecum, and colon in dairy calves across preweaning development and show that they are highly variable early on in life before transitioning to a stable community. Understanding the dairy calf GIT microbiota has implications for ensuring proper health during early life and will aid in efforts to develop strategies for improving downstream production.

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 VitroActivity of Glucosinolates and Their Degradation Products against Brassica-Pathogenic Bacteria and Fungi

2014 ◽  
Vol 81 (1) ◽  
pp. 432-440 ◽  
Author(s):  
T. Sotelo ◽  
M. Lema ◽  
P. Soengas ◽  
M. E. Cartea ◽  
P. Velasco
Keyword(s):  
Pseudomonas Syringae ◽  
Xanthomonas Campestris ◽  
Pathogenic Bacteria ◽  
Degradation Products ◽  
Allyl Isothiocyanate ◽  
Leaf Extracts ◽  
Soil Pathogens ◽  
Content Type ◽  
Positive Effects

ABSTRACTGlucosinolates (GSLs) are secondary metabolites found inBrassicavegetables that confer on them resistance against pests and diseases. Both GSLs and glucosinolate hydrolysis products (GHPs) have shown positive effects in reducing soil pathogens. Information about theirin vitrobiocide effects is scarce, but previous studies have shown sinigrin GSLs and their associated allyl isothiocyanate (AITC) to be soil biocides. The objective of this work was to evaluate the biocide effects of 17 GSLs and GHPs and of leaf methanolic extracts of different GSL-enrichedBrassicacrops on suppressingin vitrogrowth of two bacterial (Xanthomonas campestrispv. campestris andPseudomonas syringaepv. maculicola) and two fungal (AlternariabrassicaeandSclerotiniascletoriorum)Brassicapathogens. GSLs, GHPs, and methanolic leaf extracts inhibited the development of the pathogens tested compared to the control, and the effect was dose dependent. Furthermore, the biocide effects of the different compounds studied were dependent on the species and race of the pathogen. These results indicate that GSLs and their GHPs, as well as extracts of differentBrassicaspecies, have potential to inhibit pathogen growth and offer new opportunities to study the use ofBrassicacrops in biofumigation for the control of multiple diseases.

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