Blood eosinophil count, a marker of inhaled corticosteroid effectiveness in preventing COPD exacerbations in post-hoc RCT and observational studies: systematic review and meta-analysis.

BACKGROUND: Blood eosinophil count has been proposed as a predictor of response to inhaled corticosteroid (ICS) in the prevention of acute exacerbations of COPD. An optimal threshold of blood eosinophil count for prescribing ICS has not been agreed. Doubt has been cast on the role by observational studies. The role of inhaled corticosteroids in this relationship, independent of long-acting bronchodilators, has not been examined. METHODS: We conducted a systematic review of post-hoc analyses of randomised controlled trials (RCTs) and observational studies examining three blood eosinophil thresholds and the independent role of ICS. Included studies were categorised by the form (relative or absolute count) and cut point of eosinophil threshold used. Thresholds assessed were relative eosinophil count of 2%, and absolute counts of 150 cells/µL and 300 cells/µL. Three meta-analyses of the effect of ICS use in post-hoc analyses of RCTs based on these counts were carried out. Initial analysis included all studies of ICS vs. any non-ICS regimen. Further analysis examined the effect of ICS, independent of the effect of long-acting bronchodilators. RESULTS: Sixteen studies examined the association between blood eosinophil count and response of exacerbation risk to ICS, in COPD patients. Eleven studies (25,881 patients) were post-hoc analyses of RCTs. Five studies (109,704 patients) were retrospective observational studies. The independent effect of ICS on the reduction of exacerbation risk was 20% at ≥2% blood eosinophil threshold (RR, 0.80; 95% CI, 0.74-0.85), 35% at ≥150 cells/µL blood eosinophil threshold (RR, 0.65; 0.52-0.79), and 39% at ≥300 cells/µL blood eosinophil threshold (RR, 0.61; 0.44-0.78). No association was found in four out of five observational studies. CONCLUSION: This is the first systematic review to assess, in post-hoc analyses of RCTs, the independent effect of ICS in reducing the risk of COPD exacerbation across a range of blood eosinophil thresholds. Association between ICS prescription and reduced exacerbation risk at these thresholds was confirmed. The lack of association found in the observational studies questions the relevance of these observations to a "real world" COPD population. To clarify the clinical utility of this biomarker, the association should be tested in prospective effectiveness studies.

Association between prior antibiotic therapy and subsequent risk of community-acquired infections: a systematic review.

Background: Antibiotic use can have negative unintended consequences including disruption of the human microbiota, which is thought to protect against pathogen overgrowth. We conducted a systematic review to assess whether there is an association between exposure to antibiotics and subsequent risk of community-acquired infections. Methods: We searched MEDLINE, EMBASE and Web of Science for studies published before 30 June 2017, examining the association between antibiotic use and subsequent community-acquired infection. Infections caused by Clostridium difficile and fungal organisms were excluded. Studies focusing exclusively on resistant organism infections were also excluded. Results: Eighteen of 22588 retrieved studies met the inclusion criteria. From these, 16 studies reported a statistically significant association between antibiotic exposure and subsequent risk of community-acquired infection. Infections associated with prior antibiotic use included Campylobacter jejuni infection (one study), recurrent furunculosis (one study), invasive Haemophilus influenzae type b infection (one study), infectious mastitis (one study), meningitis (one study), invasive pneumococcal disease (one study), Staphylococcus aureus skin infection (one study), typhoid fever (two studies), recurrent boils and abscesses (one study), upper respiratory tract infection and urinary tract infection (one study) and Salmonella infection (five studies), although in three studies on Salmonella infection the effect was of marginal statistical significance. Conclusions: We found an association between prior antibiotic use and subsequent risk of a diverse range of community-acquired infections. Gastrointestinal and skin and soft tissue infections were most frequently found to be associated with prior antibiotic exposure. Our findings support the hypothesis that antibiotic use may predispose to future infection risk, including infections caused by both antibiotic-resistant and non-resistant organisms.

National disparities in the relationship between antimicrobial resistance and antimicrobial consumption in Europe: an observational study in 29 countries.

BACKGROUND: Antimicrobial resistance in invasive infections is driven mainly by human antimicrobial consumption. Limited cross-national comparative evidence exists about variation in antimicrobial consumption and effect on resistance. METHODS: We examined the relationship between national community antimicrobial consumption rates (2013) and national hospital antimicrobial resistance rates (2014) across 29 countries in the European Economic Area (EEA). Consumption rates were obtained from the European Surveillance of Antimicrobial Consumption Network (ESAC-Net). Resistance data were obtained from the European Antimicrobial Resistance Surveillance Network (EARS-Net), based on 196480 invasive isolates in 2014. RESULTS: Data availability and consistency were good. Some countries did not report figures for each strain of resistant bacteria. National antimicrobial consumption rates (2013) varied from ≤ 13 DDD (Estonia, the Netherlands and Sweden) to ≥ 30 DDD (France, Greece and Romania) per 1000 inhabitants per day. National antimicrobial resistance rates (hospital isolates, 15 species) also varied from <6.1% (Finland, Iceland and Sweden) to > 37.2% (Bulgaria, Greece, Romania and Slovakia). National antimicrobial consumption rates (2013) showed strong to moderate correlation with national hospital antimicrobial resistance rates (2014) in 19 strains of bacteria (r = 0.84 to r = 0.39). Some countries defied the trend with high consumption and low resistance (France, Belgium and Luxembourg) or low consumption and high resistance (Bulgaria, Hungary and Latvia). CONCLUSIONS: We found associations between national community antimicrobial consumption and national hospital antimicrobial resistance across a wide range of bacteria. These associations were not uniform. Different mechanisms may drive resistance in hospital-based invasive infections. Future research on international variations in antimicrobial resistance should consider environmental factors, agricultural use, vaccination policies and prescribing quality.

Antibiotic prescribing intensity and community UTI resistance: a cross-sectional ecological study.

BACKGROUND: Antibiotic overuse is associated with antimicrobial resistance (AMR). It is unclear whether community AMR is driven by overall antibiotic use or by high levels of repeated (intense) use by individual patients. AIM: To determine the association between high antibiotic prescribing intensity (all antibiotic prescriptions; any indication), and rates of UTI resistance among patients within small communities. DESIGN & SETTING: Repeated cross-sectional ecological analysis of geographical areas (population averaging 1500) from 2012-2015 using anonymised primary care data and urine cultures. METHOD: For each area, we compared the percentage of antibiotic-prescribed patients who received≥5 prescriptions/3 years or≥4 prescriptions/year, with subsequent or same year UTI resistance rates. We also compared 'Average Daily Quantities' of all antibiotics prescribed, with UTI resistance rates, per year, per area. Results were adjusted for co-variates and analysed at area level using mixed effects logistic regression. RESULTS: Of 196,513 patients prescribed antibiotics in 69 areas, 16% were prescribed intensively (≥5 prescriptions in 3 years), receiving almost 30% of prescriptions. Of 12 308 confirmed UTI specimens (80% Escherichia Coli), 65% were resistant to at least one antibiotic (amoxicillin; cefalexin; ciprofloxacin; trimethoprim; nitrofurantoin). We found no significant association between high intensity 'any' antibiotic prescribing (same year/two preceding years) or overall 'any' antibiotic prescribing (same year) and UTI resistance. CONCLUSION: We found no relationship between concurrent high intensity 'any' antibiotic prescribing, and UTI resistance rates in small urban communities, pre-covid. Individual patient use of multiple antibiotics, even at high intensity, may not be an independent risk factor for community UTI resistance.

Association between antibiotics and gut microbiome dysbiosis in children: systematic review and meta-analysis.

Antibiotics in childhood have been linked with diseases including asthma, juvenile arthritis, type 1 diabetes, Crohn's disease and mental illness. The underlying mechanisms are thought related to dysbiosis of the gut microbiome. We conducted a systematic review of the association between antibiotics and disruption of the pediatric gut microbiome. Searches used MEDLINE, EMBASE and Web of Science. Eligible studies: association between antibiotics and gut microbiome dysbiosis; children 0-18 years; molecular techniques of assessment; outcomes of microbiome richness, diversity or composition. Quality assessed by Newcastle-Ottawa Scale or Cochrane Risk of Bias Tool. Meta-analysis where possible. A total of 4,668 publications identified: 12 in final analysis (5 randomized controlled trials (RCTs), 5 cohort studies, 2 cross-sectional studies). Microbiome richness was measured in 3 studies, species diversity in 6, and species composition in 10. Quality of evidence was good or fair. 5 studies found a significant reduction in diversity and 3 a significant reduction in richness. Macrolide exposure was associated with reduced richness for twice as long as penicillin. Significant reductions were seen in Bifidobacteria (5 studies) and Lactobacillus (2 studies), and significant increases in Proteobacteria such as E. coli (4 studies). A meta-analysis of RCTs of the effect of macrolide (azithromycin) exposure on the gut microbiome found a significant reduction in alpha-diversity (Shannon index: mean difference -0.86 (95% CI -1.59, -0.13). Antibiotic exposure was associated with reduced microbiome diversity and richness, and with changes in bacterial abundance. The potential for dysbiosis in the microbiome should be taken into account when prescribing antibiotics for children.Systematic review registration number: CRD42018094188.

Pulmonary rehabilitation and sleep quality: a before and after controlled study of patients with chronic obstructive pulmonary disease.

BACKGROUND: Poor sleep quality is common in chronic obstructive pulmonary disease (COPD). It is associated with poor quality of life. Pulmonary rehabilitation (PR) improves quality of life, exercise capacity, and anxiety and depression. Its effect on sleep quality is uncertain. AIM: To determine whether PR improves sleep quality in COPD. METHODS: A prospective controlled 'before and after' study of sleep quality in COPD patients attending a community PR programme was conducted. Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI). Lung function, disease-specific quality of life (COPD assessment test--CAT), exercise capacity (incremental shuttle walk test--ISWT), and anxiety and depression (Hospital Anxiety and Depression Scale--HADS) were measured. Change in sleep quality was compared with a COPD control group. RESULTS: Twenty-eight participants completed PR. The control group comprised 24 patients. Prevalence of poor sleep quality (PSQI ≥5) was 78%. There were no differences between observation and control groups in sleep quality, age or severity. Quality of life was strongly correlated with quality of sleep (r=0.64, P<0.001). PR improved the quality of life (CAT change 3.0; 95% CI, 0.7-5.3), exercise capacity (ISWT change (metres) 81.0; 15.3-146.6), anxiety (HADS score ≥8: change 2.33; 0.45-4.22), and depression (HADS score ≥8: change 2.90; 1.92-3.88). PR did not improve sleep quality (PSQI mean change 0.79; -0.35 to 1.93). CONCLUSIONS: PR did not improve sleep quality in COPD despite improving quality of life, exercise capacity, anxiety and depression. New strategies, independent of PR, are required to improve sleep quality in COPD.