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• W3100884823 abstract "Pulmonary exacerbations (PExs) are significant life events in people with cystic fibrosis (CF), associated with declining lung function, reduced quality of life, hospitalizations, and decreased survival. The adult CF population is increasing worldwide, with many patients surviving prolonged periods with severe multimorbid disease. In many countries, the number of adults with CF exceeds the number of children, and PExs are particularly burdensome for adults as they tend to require longer courses and more IV treatment than children. The approach to managing PExs is multifactorial and needs to evolve to reflect this changing adult population. This review discusses PEx definitions, precipitants, treatments, and the wider implications to health-care resources. It reviews current management strategies, their relevance in particular to adults with CF, and highlights some of the gaps in our knowledge. A number of studies are underway to try to answer some of the unmet needs, such as the optimal length of treatment and the use of nonantimicrobial agents alongside antibiotics. An overview of these issues is provided, concluding that with the changing landscape of adult CF care, the definitions and management of PExs may need to evolve to enable continued improvements in outcomes across the age spectrum of CF. Pulmonary exacerbations (PExs) are significant life events in people with cystic fibrosis (CF), associated with declining lung function, reduced quality of life, hospitalizations, and decreased survival. The adult CF population is increasing worldwide, with many patients surviving prolonged periods with severe multimorbid disease. In many countries, the number of adults with CF exceeds the number of children, and PExs are particularly burdensome for adults as they tend to require longer courses and more IV treatment than children. The approach to managing PExs is multifactorial and needs to evolve to reflect this changing adult population. This review discusses PEx definitions, precipitants, treatments, and the wider implications to health-care resources. It reviews current management strategies, their relevance in particular to adults with CF, and highlights some of the gaps in our knowledge. A number of studies are underway to try to answer some of the unmet needs, such as the optimal length of treatment and the use of nonantimicrobial agents alongside antibiotics. An overview of these issues is provided, concluding that with the changing landscape of adult CF care, the definitions and management of PExs may need to evolve to enable continued improvements in outcomes across the age spectrum of CF. FOR EDITORIAL COMMENT, SEE PAGE 3Pulmonary exacerbations (PExs) are recognized as important events in the lives of people with cystic fibrosis (pwCF), with prolonged and frequent exacerbations associated with declining lung function, reduced quality of life (QoL), and decreased survival.1Cystic Fibrosis Foundation (CFF). CFF 2018 Patient Registry Annual Data Report. https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2018-Patient-Registry-Annual-Data-Report.pdf. Accessed November 11, 2020.Google Scholar CF demography is changing: national registries containing data on > 90,000 pwCF2Bell S.C. Mall M.A. Gutierrez H. et al.The future of cystic fibrosis care: a global perspective.Lancet Respir Med. 2020; 8: 65-124Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar reveal that in many countries, the adult CF population far outnumbers the pediatric CF population. Although PExs are significant events across all age groups, the prevalence is higher in adulthood, requiring more antibiotic treatments for longer periods compared with treatment of children with CF (Fig 1).1Cystic Fibrosis Foundation (CFF). CFF 2018 Patient Registry Annual Data Report. https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2018-Patient-Registry-Annual-Data-Report.pdf. Accessed November 11, 2020.Google Scholar In 2018, based on US CF registry data, approximately 43% of adults (aged ≥ 18 years) required IV antibiotics for a PEx compared with only 23% of children. In the United Kingdom, median (interquartile range) days of IV antibiotics per year for adults (aged ≤ 16 years) was 28 (14-48) compared with 16 (14-38) for children.3UK Cystic Fibrosis Trust. UK Cystic Fibrosis Registry Annual Data Report 2019. https://www.cysticfibrosis.org.uk/the-work-we-do/uk-cf-registry/reporting-and-resources, 2020.Google Scholar Using western European data, Burgel et al4Burgel P.R. Bellis G. Olesen H.V. et al.Future trends in cystic fibrosis demography in 34 European countries.Eur Respir J. 2015; 46: 133Crossref PubMed Scopus (215) Google Scholar predicted that the number of adults with CF would expand by up to 78% by 2025, while the number of pediatric CF cases would increase by just 20%. An increasing adult CF population (Fig 2), who have increasing multimorbidities,2Bell S.C. Mall M.A. Gutierrez H. et al.The future of cystic fibrosis care: a global perspective.Lancet Respir Med. 2020; 8: 65-124Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar will require the approach to PEx management to evolve to recognize these differences. This review article focuses on PExs specifically in adults with CF to discuss these important emerging issues.Figure 2The increasing percentage of adults with CF. CF = cystic fibrosis. (Reprinted with permission from the Cystic Fibrosis Foundation Patient Registry 2018 Annual Data Report.1Cystic Fibrosis Foundation (CFF). CFF 2018 Patient Registry Annual Data Report. https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2018-Patient-Registry-Annual-Data-Report.pdf. Accessed November 11, 2020.Google Scholar)View Large Image Figure ViewerDownload Hi-res image Download (PPT) FOR EDITORIAL COMMENT, SEE PAGE 3 There remains no universally agreed definition of a PEx, making it difficult to standardize treatments. Historically, a PEx was defined as a deterioration in symptoms and biochemical markers, causing a physician to change treatments. However, by definition, this only accounts for exacerbations that cause management change, excluding those that resolve without antibiotics, and thus carries inherent problems due to variations in practice. Physician-led treatment remains the simplest definition of a PEx and has successfully been used in clinical trials,5Fuchs H.J. Borowitz D.S. Christiansen D.H. et al.Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group.N Engl J Med. 1994; 331: 637-642Crossref PubMed Scopus (1278) Google Scholar although this is unhelpful as a clinical tool to facilitate decision-making regarding antibiotic initiation. Models have been developed to try to standardize this, with the definition by Fuchs et al5Fuchs H.J. Borowitz D.S. Christiansen D.H. et al.Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group.N Engl J Med. 1994; 331: 637-642Crossref PubMed Scopus (1278) Google Scholar being perhaps the most widely recognized; they are not commonly used clinically (Table 1), however, and none of these definitions is exclusively for adult populations.6Bilton D, Canny G, Conway S, et al. Pulmonary exacerbation: towards a definition for use in clinical trials. Report from the EuroCareCF Working Group on outcome parameters in clinical trials. J Cyst Fibros. 2011;10(suppl 2):S79-S81.Google Scholar, 7Rabin H.R. Butler S.M. Wohl M.E.B. et al.Pulmonary exacerbations in cystic fibrosis.Pediatr Pulmonol. 2004; 37: 400-406Crossref PubMed Scopus (145) Google Scholar, 8Rosenfeld M. Emerson J. Williams-Warren J. et al.Defining a pulmonary exacerbation in cystic fibrosis.J Pediatr. 2001; 139: 359-365Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar, 9Ramsey B.W. Pepe M.S. Quan J.M. et al.Intermittent administration of inhaled tobramycin in patients with cystic fibrosis.N Engl J Med. 1999; 340: 23-30Crossref PubMed Scopus (1170) Google ScholarTable 1Summary of the Most Widely Recognized Definitions of a PExDefinitionCriteria to Define a PExDetailEuroCareCF, 20116Bilton D, Canny G, Conway S, et al. Pulmonary exacerbation: towards a definition for use in clinical trials. Report from the EuroCareCF Working Group on outcome parameters in clinical trials. J Cyst Fibros. 2011;10(suppl 2):S79-S81.Google ScholarWhen additional antibiotics are needed due to a recent change in at least 2 items from a predefined listChange in sputum volume or color; increased cough; increased fatigue, malaise, or lethargy; anorexia or weight loss; increased shortness of breath; decrease in pulmonary function by ≥ 10% compared with previous or radiographic changes consistent with a PExRabin et al,7Rabin H.R. Butler S.M. Wohl M.E.B. et al.Pulmonary exacerbations in cystic fibrosis.Pediatr Pulmonol. 2004; 37: 400-406Crossref PubMed Scopus (145) Google Scholar 2004Three or more signs/symptomsIn patients > 6 years old: relative decline in FEV1; increased cough frequency; new crackles; hemoptysisRosenfeld et al,8Rosenfeld M. Emerson J. Williams-Warren J. et al.Defining a pulmonary exacerbation in cystic fibrosis.J Pediatr. 2001; 139: 359-365Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar 2001Combined points system to diagnose a PEx and quantify its severity. Two models proposed, one using FEV1Model 1: decreased exercise tolerance; increased cough; increased sputum/cough clearance; increased sputum/cough congestion; school or work absenteeism; change in lung examination; decreased appetiteModel 2: as per model 1; change in FEV1Ramsey et al,9Ramsey B.W. Pepe M.S. Quan J.M. et al.Intermittent administration of inhaled tobramycin in patients with cystic fibrosis.N Engl J Med. 1999; 340: 23-30Crossref PubMed Scopus (1170) Google Scholar 1999At least 2 signs/symptoms from a predefined list and 1 from a second listList 1: Fever > 38°C; ≥ 50% increase in cough; 50% increase in sputum volume; loss of appetite; weight loss of ≥ 1 kg; absence from school or work for at least 3 of the preceding 7 days due to illness; symptoms of an upper respiratory tract infectionList 2: decrease in FEV1 of at least 10%; increase in respiratory rate of at least 10 breaths/min; peripheral neutrophil count of > 15Fuchs et al,5Fuchs H.J. Borowitz D.S. Christiansen D.H. et al.Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group.N Engl J Med. 1994; 331: 637-642Crossref PubMed Scopus (1278) Google Scholar 1994At least 4 signs/symptoms from a predefined listChange in sputum; new or increased hemoptysis; increased cough; increased shortness of breath; malaise/fatigue/lethargy; temperature > 38°C; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by ≥ 10% compared with previous; radiographic changes consistent with a pulmonary exacerbationPEx = pulmonary exacerbation. Open table in a new tab PEx = pulmonary exacerbation. Antibiotic initiation is often based on a deterioration in FEV1. As a measurable and reproducible marker of lung health, possible for the majority of adults to complete, it remains a driver for guiding clinical decision-making. The Standardized Treatment of Pulmonary Exacerbations (STOP) study highlighted that some pwCF experience PExs without a change in FEV1.10West N.E. Beckett V.V. Jain R. et al.Standardized Treatment of Pulmonary Exacerbations (STOP) study: physician treatment practices and outcomes for individuals with cystic fibrosis with pulmonary exacerbations.J Cyst Fibros. 2017; 16: 600-606Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar In these cases, newer modalities such as the lung clearance index and/or MRI11Wielpütz MO, Mall MA. Imaging modalities in cystic fibrosis: emerging role of MRI. Curr Opin Pulm Med. 2015;21(6):609-616.Google Scholar,12Sonneveld N. Stanojevic S. Amin R. et al.Lung clearance index in cystic fibrosis subjects treated for pulmonary exacerbations.Eur Respir J. 2015; 46: 1055Crossref PubMed Scopus (57) Google Scholar may be helpful, although they have yet to be established in this role, particularly for adults as most of the data are derived from children. In some countries, clinicians rely on C-reactive protein in clinical practice, although this and other biomarkers of inflammation have not yet been effectively incorporated as part of a PEx definition and its associated treatment. Rather than the clinician-led diagnosis of PExs, patient-reported outcome measures are an attractive and promising approach.13Goss C.H. Quittner A.L. Patient-reported outcomes in cystic fibrosis.Proc Am Thorac Soc. 2007; 4: 378-386Crossref PubMed Scopus (109) Google Scholar There have been several attempts to standardize these into scoring systems such as the Chronic Respiratory Infection Symptom Score.14Goss C.H. Edwards T.C. Ramsey B.W. Aitken M.L. Patrick D.L. Patient-reported respiratory symptoms in cystic fibrosis.J Cyst Fibros. 2009; 8: 245-252Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar However, currently, they have largely been used to show the impact of PExs on patients and are mostly used in research studies. The current suggested definitions5Fuchs H.J. Borowitz D.S. Christiansen D.H. et al.Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group.N Engl J Med. 1994; 331: 637-642Crossref PubMed Scopus (1278) Google Scholar, 6Bilton D, Canny G, Conway S, et al. Pulmonary exacerbation: towards a definition for use in clinical trials. Report from the EuroCareCF Working Group on outcome parameters in clinical trials. J Cyst Fibros. 2011;10(suppl 2):S79-S81.Google Scholar, 7Rabin H.R. Butler S.M. Wohl M.E.B. et al.Pulmonary exacerbations in cystic fibrosis.Pediatr Pulmonol. 2004; 37: 400-406Crossref PubMed Scopus (145) Google Scholar,9Ramsey B.W. Pepe M.S. Quan J.M. et al.Intermittent administration of inhaled tobramycin in patients with cystic fibrosis.N Engl J Med. 1999; 340: 23-30Crossref PubMed Scopus (1170) Google Scholar aim to identify a PEx, but none categorizes severity or direct treatment. Importantly, they were all developed in an era predating CF transmembrane conductance regulator modulators, a new class of small molecule drug that treats the basic defect. These drugs have been shown to significantly reduce the rates of PEx15Ramsey B.W. Davies J. McElvaney N.G. et al.A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.N Engl J Med. 2011; 365: 1663-1672Crossref PubMed Scopus (1698) Google Scholar,16Middleton P.G. Mall M.A. Dřevínek P. et al.Elexacaftor–tezacaftor–ivacaftor for cystic fibrosis with a single Phe508del allele.N Engl J Med. 2019; 381: 1809-1819Crossref PubMed Scopus (946) Google Scholar with recent phase III trials of “triple therapy” modulators reducing PEx frequency by 63%.16Middleton P.G. Mall M.A. Dřevínek P. et al.Elexacaftor–tezacaftor–ivacaftor for cystic fibrosis with a single Phe508del allele.N Engl J Med. 2019; 381: 1809-1819Crossref PubMed Scopus (946) Google Scholar The exact etiology of PExs and the underlying biological mechanisms driving disease are poorly understood. Pathogens infecting the pulmonary tract are believed to be the most common cause of PExs, but a variety of insults can change the homeostatic balance. PExs are most frequently caused by bacterial infections precipitating an amplified inflammatory response, leading to progressive and irreversible airway damage.17Ferkol T. Rosenfeld M. Milla C.E. Cystic fibrosis pulmonary exacerbations.J Pediatr. 2006; 148: 259-264Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Chronically infecting pathogens guide antibiotic treatment. Although Staphylococcus aureus and Haemophilus influenzae are most common in pediatrics, Pseudomonas aeruginosa dominates in subjects by 18 years of age. In 2019, 39.4% of UK adults with CF were chronically infected with P aeruginosa, while an additional 16.7% had intermittent P aeruginosa.3UK Cystic Fibrosis Trust. UK Cystic Fibrosis Registry Annual Data Report 2019. https://www.cysticfibrosis.org.uk/the-work-we-do/uk-cf-registry/reporting-and-resources, 2020.Google Scholar In the United States, approximately 70% of adults aged 30 years had at least one positive sputum culture of P aeruginosa in 2018, compared with only 20% of children aged 10 years.1Cystic Fibrosis Foundation (CFF). CFF 2018 Patient Registry Annual Data Report. https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2018-Patient-Registry-Annual-Data-Report.pdf. Accessed November 11, 2020.Google Scholar Other increasingly common bacteria in adults include Stenotrophomonas maltophilia and Achromobacter. Nontuberculous mycobacteria are an increasing issue in CF, although their role in the setting of acute PExs is unclear.18Chmiel J.F. Aksamit T.R. Chotirmall S.H. et al.Antibiotic management of lung infections in cystic fibrosis. II. Nontuberculous mycobacteria, anaerobic bacteria, and fungi.Ann Am Thorac Soc. 2014; 11: 1298-1306Crossref PubMed Scopus (63) Google Scholar Allergic bronchopulmonary aspergillosis affects 8% to 9%3UK Cystic Fibrosis Trust. UK Cystic Fibrosis Registry Annual Data Report 2019. https://www.cysticfibrosis.org.uk/the-work-we-do/uk-cf-registry/reporting-and-resources, 2020.Google Scholar,19Cystic Fibrosis Foundation (CFF)Cystic Fibrosis Foundation Patient Registry 2019 Patient Registry Snapshot.https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2019-Cystic-Fibrosis-Foundation-Patient-Registry-Snapshot/2020Google Scholar of adults with CF and is associated with reduced lung function. Because allergic bronchopulmonary aspergillosis may cause some PExs, it is important to identify and treat this condition. The role of other Aspergillus-associated conditions (eg, Aspergillus bronchitis or sensitization) in PExs is unclear, as is the role of other fungal species, including Scedosporium, Candida families, and Exophiala species.18Chmiel J.F. Aksamit T.R. Chotirmall S.H. et al.Antibiotic management of lung infections in cystic fibrosis. II. Nontuberculous mycobacteria, anaerobic bacteria, and fungi.Ann Am Thorac Soc. 2014; 11: 1298-1306Crossref PubMed Scopus (63) Google Scholar Although respiratory viruses are not found more frequently in pwCF than in people with genetically normal lungs,20Ong E.L. Ellis M.E. Webb A.K. et al.Infective respiratory exacerbations in young adults with cystic fibrosis: role of viruses and atypical microorganisms.Thorax. 1989; 44: 739-742Crossref PubMed Scopus (49) Google Scholar they are believed to increase susceptibility to new bacterial infections or allow chronic bacteria to flare, causing a PEx.21van Ewijk B.E. van der Zalm M.M. Wolfs T.F.W. van der Ent C.K. Viral respiratory infections in cystic fibrosis.J Cyst Fibros. 2005; 4: 31-36Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Data from a small sample of adults with CF highlighted that most PExs were caused by an existing strain of P aeruginosa, not a new bacterial growth.22Aaron S.D. Ramotar K. Ferris W. et al.Adult cystic fibrosis exacerbations and new strains of Pseudomonas aeruginosa.Am J Respir Crit Care Med. 2004; 169: 811Crossref PubMed Google Scholar It remains unclear how much of an impact viruses have on deterioration in adults, whereas this is well established in pediatrics; studies in adults are varied, indicating minimal impact on lung function or rate of exacerbations.20Ong E.L. Ellis M.E. Webb A.K. et al.Infective respiratory exacerbations in young adults with cystic fibrosis: role of viruses and atypical microorganisms.Thorax. 1989; 44: 739-742Crossref PubMed Scopus (49) Google Scholar,23Flight W.G. Bright-Thomas R.J. Tilston P. et al.Incidence and clinical impact of respiratory viruses in adults with cystic fibrosis.Thorax. 2014; 69: 247-253Crossref PubMed Scopus (90) Google Scholar Influenza A and B, respiratory syncytial virus, rhinovirus, parainfluenza, cytomegalovirus, and adenovirus are found in CF, although influenza A is believed to be the most deleterious in adults.23Flight W.G. Bright-Thomas R.J. Tilston P. et al.Incidence and clinical impact of respiratory viruses in adults with cystic fibrosis.Thorax. 2014; 69: 247-253Crossref PubMed Scopus (90) Google Scholar To date, the recent worldwide coronavirus disease 2019 pandemic seems to have had a lower impact on pwCF than predicted. A multinational report of 40 cases (median age, 33 years) concluded that this scenario may be due to effective shielding from exposure, but that the medium- and long-term effects on PwCF from this emerging pathogen are unknown.24Cosgriff R. Ahern S. Bell S.C. et al.A multinational report to characterise SARS-CoV-2 infection in people with cystic fibrosis.J Cyst Fibros. 2020; 19: 355-358Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar Not infrequently, the precise cause of the PEx is unknown, but patients respond to treatments regardless. Particularly relevant to adults is variable treatment adherence due to time constraints from work or family commitments. Reducing treatment burden and strategies to improve adherence were highlighted as research priorities in a survey of the CF community.25Rowbotham N.J. Smith S. Leighton P.A. et al.The top 10 research priorities in cystic fibrosis developed by a partnership between people with CF and healthcare providers.Thorax. 2018; 73: 388-390Crossref PubMed Scopus (150) Google Scholar Self-monitoring is an emerging field in CF: it may be effective to motivate patients to complete therapies and be vigilant for signs of exacerbations, while giving them greater responsibility away from a hospital-based environment. To date, research is scarce on the effectiveness of home monitoring; one large cohort study26Lechtzin N. Mayer-Hamblett N. West N.E. et al.Home monitoring of patients with cystic fibrosis to identify and treat acute pulmonary exacerbations. eICE Study Results.Am J Respir Crit Care Med. 2017; 196: 1144Crossref PubMed Scopus (85) Google Scholar reported increased PEx identification but no difference in FEV1 decline over 52 weeks, which led to early trial termination. The multifactorial presentation of PExs in adults with CF requires a multifaceted approach. Prevention of PExs in pwCF protects against lung injury and reduces rate of lung function decline. A number of pathways are targeted to achieve this goal, including optimizing nutrition and achieving diabetes control. Mucoactive agents are added early in infancy, and airway clearance techniques (ACTs) are used throughout the lives of pwCF. More specific interventions have been developed to eradicate bacteria and suppress chronic infections, including using oral and nebulized antibiotics.27Smyth A.R. Bell S.C. Bojcin S. et al.European Cystic Fibrosis Society Standards of Care: best practice guidelines.J Cyst Fibros. 2014; 13: S23-S42Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar In severe presentations, adjunctive therapies such as noninvasive ventilation (NIV) and oxygen support may be required. Currently, there is no unified consensus for the best treatment or prevention of PEx, and there is a lack of robust evidence to guide clinical practice.28Flume P.A. Mogayzel P.J. Robinson K.A. et al.Cystic fibrosis pulmonary guidelines.Am J Respir Crit Care Med. 2009; 180: 802-808Crossref PubMed Scopus (554) Google Scholar Antibiotics are key to PEx management and can be administered orally, by inhalation, or intravenously. Traditionally, particularly in P aeruginosa treatment,28Flume P.A. Mogayzel P.J. Robinson K.A. et al.Cystic fibrosis pulmonary guidelines.Am J Respir Crit Care Med. 2009; 180: 802-808Crossref PubMed Scopus (554) Google Scholar antibiotic combinations are used, aiming for synergistic antibacterial activity and reducing drug resistance. The STOP study reported that 54% of patients were prescribed two antibiotics, and 35% had three or more.10West N.E. Beckett V.V. Jain R. et al.Standardized Treatment of Pulmonary Exacerbations (STOP) study: physician treatment practices and outcomes for individuals with cystic fibrosis with pulmonary exacerbations.J Cyst Fibros. 2017; 16: 600-606Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar This strategy is currently recommended by European Cystic Fibrosis Society (ECFS)27Smyth A.R. Bell S.C. Bojcin S. et al.European Cystic Fibrosis Society Standards of Care: best practice guidelines.J Cyst Fibros. 2014; 13: S23-S42Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar and US28Flume P.A. Mogayzel P.J. Robinson K.A. et al.Cystic fibrosis pulmonary guidelines.Am J Respir Crit Care Med. 2009; 180: 802-808Crossref PubMed Scopus (554) Google Scholar guidelines, despite a lack of robust evidence.28Flume P.A. Mogayzel P.J. Robinson K.A. et al.Cystic fibrosis pulmonary guidelines.Am J Respir Crit Care Med. 2009; 180: 802-808Crossref PubMed Scopus (554) Google Scholar,29Elphick H.E. Scott A. Single versus combination intravenous anti-pseudomonal antibiotic therapy for people with cystic fibrosis.Cochrane Database Syst Rev. 2016; 12: CD002007PubMed Google Scholar Although a consensus document on antibiotic treatment for CF30UK Cystic Fibrosis Trust Antibiotic Working Group. Antibiotic treatment for cystic fibrosis - 3rd edition. https://www.cysticfibrosis.org.uk/∼/media/documents/the-work-we-do/care/consensus-docs-with-new-address/anitbiotic-treatment.ashx?la=en. Accessed November 11, 2020.Google Scholar identified aminoglycosides, polymyxins, β-lactams, cephalosporins, and carbapenems as potential antibiotics for use, a systematic review concluded that “no specific antibiotic combination can be considered superior to any other.”31Hurley M.N. Prayle A.P. Flume P. Intravenous antibiotics for pulmonary exacerbations in people with cystic fibrosis.Cochrane Database Syst Rev. 2015; 7: CD009730Google Scholar The CF community has highlighted the identification of the most effective/least toxic antibiotics as a research priority,25Rowbotham N.J. Smith S. Leighton P.A. et al.The top 10 research priorities in cystic fibrosis developed by a partnership between people with CF and healthcare providers.Thorax. 2018; 73: 388-390Crossref PubMed Scopus (150) Google Scholar while an international survey on antimicrobial stewardship perceptions found that health-care professionals wanted help with antibiotic choice, dose, and minimizing resistance.32Bullington W. Smyth A. Elborn S. Drevinek P. Hempstead S. Muhlebach M. 1078. Expectations and attitudes toward antimicrobial stewardship among cystic fibrosis care providers.Open Forum Infect Dis. 2019; 6: S382-S383Crossref Google Scholar Most initial isolates of P aeruginosa are susceptible to commonly used antimicrobial therapies; however, resistance develops with repeated courses of antibiotics.33Lechtzin N. John M. Irizarry R. Merlo C. Diette G.B. Boyle M.P. Outcomes of adults with cystic fibrosis infected with antibiotic-resistant Pseudomonas aeruginosa.Respiration. 2006; 73: 27-33Crossref PubMed Scopus (105) Google Scholar Selection of the optimal antibiotic to use is highly debated, and treatments based on results of antibiotic susceptibility tests (ASTs) from traditional sputum cultures do not always predict an optimal clinical response.34Waters V.J. Kidd T.J. Canton R. et al.Reconciling antimicrobial susceptibility testing and clinical response in antimicrobial treatment of chronic cystic fibrosis lung infections.Clin Infect Dis. 2019; 69: 1812-1816Crossref PubMed Scopus (51) Google Scholar,35Zemanick E. Burgel P.R. Taccetti G. et al.Antimicrobial Resistance International Working Group in Cystic Fibrosis. Antimicrobial resistance in cystic fibrosis: a Delphi approach to defining best practices.J Cyst Fibros. 2020; 19: 370-375Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar ASTs have limitations, especially in the context of phenotypic and genotypic diversifications of the CF lung microbiome and CF pathogens,34Waters V.J. Kidd T.J. Canton R. et al.Reconciling antimicrobial susceptibility testing and clinical response in antimicrobial treatment of chronic cystic fibrosis lung infections.Clin Infect Dis. 2019; 69: 1812-1816Crossref PubMed Scopus (51) Google Scholar although research has shown the airway microbiome to be relatively stable except for transient change with antibiotic treatment in PExs.36Einarsson G. Flanagan E. Lee A. Elborn J.S. Tunney M. Plant B.J. WS03.1 Longitudinal airway microbiota profiling in cystic fibrosis patients enrolled in the CFMATTERS clinical trial.J Cyst Fibros. 2017; 16: S4Abstract Full Text PDF Google Scholar The Cystic Fibrosis Microbiome-determined Antibiotic Therapy Trial in Exacerbations: Results Stratified (CFMATTERS) trial compared standard antibiotic therapy vs standard therapy plus an additional antibiotic selected from microbiome analysis of sputum; results showed no significant difference in clincal end points, and the active arm also required more IV days than standard therapy.37Plant B. Final report summary—Cystic fibrosis microbiome-determined antibiotic therapy trial in exacerbations: results stratified.https://cordis.europa.eu/docs/results/603/603038/final1-cfmatters-final-report-draft-v3-mp-31082017.pdfDate accessed: November 11, 2020Google Scholar In the context of AST, a De" @default.
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• W3100884823 title "Pulmonary Exacerbations in Adults With Cystic Fibrosis" @default.
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• W3100884823 doi "https://doi.org/10.1016/j.chest.2020.09.084" @default.
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