Determinants of inappropriate antibiotic prescription in primary care in developed countries with general practitioners as gatekeepers: a systematic review and construction of a framework.

OBJECTIVES: This study aimed to identify determinants of inappropriate antibiotic prescription in primary care in developed countries and to construct a framework with the determinants to help understand which actions can best be targeted to counteract development of antimicrobial resistance (AMR). DESIGN: A systematic review of peer-reviewed studies reporting determinants of inappropriate antibiotic prescription published through 9 September 2021 in PubMed, Embase, Web of Science and the Cochrane Library was performed. SETTING: All studies focusing on primary care in developed countries where general practitioners (GPs) act as gatekeepers for referral to medical specialists and hospital care were included. RESULTS: Seventeen studies fulfilled the inclusion criteria and were used for the analysis which identified 45 determinants of inappropriate antibiotic prescription. Important determinants for inappropriate antibiotic prescription were comorbidity, primary care not considered to be responsible for development of AMR and GP perception of patient desire for antibiotics. A framework was constructed with the determinants and provides a broad overview of several domains. The framework can be used to identify several reasons for inappropriate antibiotic prescription in a specific primary care setting and from there, choose the most suitable intervention(s) and assist in implementing them for combatting AMR. CONCLUSIONS: The type of infection, comorbidity and the GPs perception of a patient's desire for antibiotics are consistently identified as factors driving inappropriate antibiotic prescription in primary care. A framework with determinants of inappropriate antibiotic prescription may be useful after validation for effective implementation of interventions for decreasing these inappropriate prescriptions. PROSPERO REGISTRATION NUMBER: CRD42023396225.

Trends in antibiotic selection pressure generated in primary care and their association with sentinel antimicrobial resistance patterns in Europe.

OBJECTIVES: We studied trends in antibiotic prescribing by primary care and assessed the associations between generated antibiotic selection pressure (ASP) and the prevalence of sentinel drug-resistant microorganisms (SDRMs). METHODS: The volume of antibiotic prescribing in primary and hospital care expressed in DDD/1000 inhabitants per day and the prevalences of SDRMs in European countries where GPs act as gatekeepers were obtained from the European Centre for Disease Control ESAC-NET. Associations were tested between (i) DDD and (ii) the Antibiotic Spectrum Index (ASI) as a proxy indicator for ASP, and the prevalences of three SDRMs: MRSA, MDR Escherichia coli and Streptococcus pneumoniae resistant to macrolides. RESULTS: Fourteen European countries were included. Italy, Poland and Spain had the highest prevalence of SDRMs and prescribed the highest volume of antibiotics in primary care (average 17 DDD per 1000 inhabitants per day), approximately twice that of countries with the lowest volumes. Moreover, the ASIs of these high antibiotic volume countries were approximately three times higher than those of the low-volume countries. Cumulative ASI showed the strongest association with a country's prevalence of SDRMs. The cumulative ASI generated from primary care was about four to five times higher than the cumulative ASI generated by hospital care. CONCLUSIONS: Prevalences of SDRMs are associated with the volume of antimicrobial prescribing and in particular broad-spectrum antibiotics in European countries where GPs act as gatekeepers. The impact of ASP generated from primary care on increasing antimicrobial resistance may be much larger than currently assumed.

Comparing antibiotic prescriptions in primary care between SARS-CoV-2 and influenza: a retrospective observational study.

BACKGROUND: Antibiotics are frequently prescribed during viral respiratory infection episodes in primary care. There is limited information about antibiotic prescription during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in primary care and its association with risk factors for an adverse course. AIM: To compare the proportion of antibiotic prescriptions between patients with COVID-19 and influenza or influenza-like symptoms, and to assess the association between antibiotic prescriptions and risk factors for an adverse course of COVID-19. DESIGN & SETTING: An observational cohort study using pseudonymised and coded routine healthcare data extracted from 85 primary care practices in the Netherlands. METHOD: Adult patients with influenza and influenza-like symptoms were included from the 2017 influenza season to the 2020 season. Adult patients with suspected or confirmed COVID-19 were included from the first (15 February 2020-1 August 2020) and second (1 August 2020-1 January 2021) SARS-CoV-2 waves. Proportions of antibiotic prescriptions were calculated for influenza and COVID-19 patients. Odds ratios (ORs) were used to compare the associations of antibiotic prescriptions in COVID-19 patients with risk factors, hospital admission, intensive care unit (ICU) admission, and mortality. RESULTS: The proportion of antibiotic prescriptions during the first SARS-CoV-2 wave was lower than during the 2020 influenza season (9.6% versus 20.7%), difference 11.1% (95% confidence interval [CI] = 8.7 to 13.5). During the second SARS-CoV-2 wave, antibiotic prescriptions were associated with being aged ≥70 years (OR 2.05; 95% CI = 1.43 to 2.93), the number of comorbidities (OR 1.46; 95% CI = 1.18 to 1.82), and admission to hospital (OR 3.19; 95% CI = 2.02 to 5.03) or ICU (OR 4.64; 95% CI = 2.02 to 10.62). CONCLUSION: Antibiotic prescription was less common during the SARS-CoV-2 pandemic than during influenza seasons, and was associated with an adverse course and its risk factors. The findings suggest a relatively targeted prescription policy of antibiotics in primary care during COVID-19.

Optimizing the Acceptability, Adherence, and Inclusiveness of the COVID Radar Surveillance App: Qualitative Study Using Focus Groups, Thematic Content Analysis, and Usability Testing.

BACKGROUND: The COVID Radar app was developed as a population-based surveillance instrument to identify at-risk populations and regions in response to the COVID-19 pandemic. The app boasts of >8.5 million completed questionnaires, with >280,000 unique users. Although the COVID Radar app is a valid tool for population-level surveillance, high user engagement is critical to the success of the COVID Radar app in maintaining validity. OBJECTIVE: This study aimed to identify optimization targets of the COVID Radar app to improve its acceptability, adherence, and inclusiveness. METHODS: The main component of the COVID Radar app is a self-report questionnaire that assesses COVID-19 symptoms and social distancing behaviors. A total of 3 qualitative substudies were conducted. First, 3 semistructured focus group interviews with end users (N=14) of the app were conducted to gather information on user experiences. The output was transcribed and thematically coded using the framework method. Second, a similar qualitative thematic analysis was conducted on 1080 end-user emails. Third, usability testing was conducted in one-on-one sessions with 4 individuals with low literacy levels. RESULTS: All 3 substudies identified optimization targets in terms of design and content. The results of substudy 1 showed that the participants generally evaluated the app positively. They reported the app to be user-friendly and were satisfied with its design and functionalities. Participants' main motivation to use the app was to contribute to science. Participants suggested adding motivational tools to stimulate user engagement. A larger national publicity campaign for the app was considered potentially helpful for increasing the user population. In-app updates informing users about the project and its outputs motivated users to continue using the app. Feedback on the self-report questionnaire, stemming from substudies 1 and 2, mostly concerned the content and phrasing of the questions. Furthermore, the section of the app allowing users to compare their symptoms and behaviors to those of their peers was found to be suboptimal because of difficulties in interpreting the figures presented in the app. Finally, the output of substudy 3 resulted in recommendations primarily related to simplification of the text to render it more accessible and comprehensible for individuals with low literacy levels. CONCLUSIONS: The convenience of app use, enabling personal adjustments of the app experience, and considering motivational factors for continued app use (ie, altruism and collectivism) were found to be crucial to procuring and maintaining a population of active users of the COVID Radar app. Further, there seems to be a need to increase the accessibility of public health tools for individuals with low literacy levels. These results can be used to improve the this and future public health apps and improve the representativeness of their user populations and user engagement, ultimately increasing the validity of the tools.

[Indoor sporting during the COVID-19 pandemic: analysis with data from the COVID RADAR app]. / Binnensporten tijdens de COVID-19-pandemie: analyse met behulp van data uit de COVID RADAR app.

Indoor sporting locations have been forced to stay closed longer than outdoor sporting locations during the lockdowns introduced during the COVID-19 pandemic. This research addresses the question whether exercising indoors does raise one's risk of infection with SARS-CoV­2. This analysis was performed using data from the COVID RADAR app and accounted for user differences in age, vaccine status, sex, other risky behavior, SARS-CoV­2 prevalence and quality of living environment. Analyzing data from 1,353 users, 13.1% of which reported a positive SARS-CoV­2 test, we found that exercising indoors leads to an odds ratio of 1.8 with a positive SARS-CoV­2 test (95%-confidence interval 1.2-2.6, p = 0.003), as compared to users who exercise outdoors. This confirms the justification used in longer closing indoor sporting locations to reduce the number of infections.

Age of red blood cells is not associated with in-hospital mortality in massively transfused patients.

BACKGROUND: Studies comparing mortality following massive transfusion (MT) with fresher versus longer-stored red blood cells (RBCs) have focused on trauma patients. The Australian and New Zealand Massive Transfusion Registry collects data on all adult MT cases (≥5 RBCs within 4 hours, any bleeding context, ≥18 years) at participating hospitals. METHODS: Years 2007 to 2018 data from 29 hospitals were analyzed to quantify the association between mortality and RBC storage time in adult MT cases. We ran three logistic regression models separately on each of seven bleeding contexts, with in-hospital mortality as the outcome and, in turn, (1) mean storage time (STmean) quartiles, (2) proportion of RBCs ≥30 days old (propOLD), and (3) scalar age of blood index as predictors. RESULTS: A total of 8,685 adult MT cases involving transfusion of 126,622 RBCs were analyzed with Australian and New Zealand data analyzed separately. Mean storage times for these cases were (by quartile in ascending order) as follows: Australia, 12.5 days (range, 3.1-15.5 days), 17.7 (15.5-19.9), 22.3 (19.9-24.9), and 29.8 (24.9-41.7); New Zealand, 11.3 days (3.6-13.7), 15.3 (13.7-16.8), 18.7 (16.8-20.7), and 24.5 (20.7-35.6). The odds ratios comparing in-hospital mortality for each quartile with that of the control first quartile (freshest blood), proportion of longer-stored (≥30 days) RBCs, and scalar age of blood index were not statistically significant across all bleeding contexts. CONCLUSION: We find no correlation between in-hospital mortality and storage time of transfused RBCs in a large cohort of adult MT patients representing all bleeding contexts. These results are consistent with those of recent large multicenter trials. LEVEL OF EVIDENCE: Epidemiologic, level III; Therapeutic, level IV.

COVID RADAR app: Description and validation of population surveillance of symptoms and behavior in relation to COVID-19.

BACKGROUND: Monitoring of symptoms and behavior may enable prediction of emerging COVID-19 hotspots. The COVID Radar smartphone app, active in the Netherlands, allows users to self-report symptoms, social distancing behaviors, and COVID-19 status daily. The objective of this study is to describe the validation of the COVID Radar. METHODS: COVID Radar users are asked to complete a daily questionnaire consisting of 20 questions assessing their symptoms, social distancing behavior, and COVID-19 status. We describe the internal and external validation of symptoms, behavior, and both user-reported COVID-19 status and state-reported COVID-19 case numbers. RESULTS: Since April 2nd, 2020, over 6 million observations from over 250,000 users have been collected using the COVID Radar app. Almost 2,000 users reported having tested positive for SARS-CoV-2. Amongst users testing positive for SARS-CoV-2, the proportion of observations reporting symptoms was higher than that of the cohort as a whole in the week prior to a positive SARS-CoV-2 test. Likewise, users who tested positive for SARS-CoV-2 showed above average risk social-distancing behavior. Per-capita user-reported SARS-CoV-2 positive tests closely matched government-reported per-capita case counts in provinces with high user engagement. DISCUSSION: The COVID Radar app allows voluntarily self-reporting of COVID-19 related symptoms and social distancing behaviors. Symptoms and risk behavior increase prior to a positive SARS-CoV-2 test, and user-reported case counts match closely with nationally-reported case counts in regions with high user engagement. These results suggest the COVID Radar may be a valid instrument for future surveillance and potential predictive analytics to identify emerging hotspots.

Transition from fresh frozen plasma to solvent/detergent plasma in the Netherlands: comparing clinical use and transfusion reaction risks.

Plasma transfusion is indicated for replenishment of coagulative proteins to stop or prevent bleeding. In 2014, the Netherlands switched from using ~300mL fresh frozen plasma (FFP) units to using 200mL Omniplasma, a solvent/detergent treated pooled plasma (SD plasma), units. We evaluated the effect of the introduction of SD plasma on clinical plasma use, associated bleeding, and transfusion reaction incidences. Using diagnostic data from six Dutch hospitals, national blood bank data, and national hemovigilance data for 2011 to 2017, we compared the plasma/red blood cell (RBC) units ratio (f) and the mean number of plasma and RBC units transfused for FFP (~300mL) and SD plasma (200mL) for various patient groups, and calculated odds ratios comparing their associated transfusion reaction risks. Analyzing 13,910 transfusion episodes, the difference (Δf = fSD - fFFP) in mean plasma/RBC ratio (f) was negligible (Δfentire_cohort = 0.01 [95% confidence interval (CI): -0.02 - 0.05]; P=0.48). SD plasma was associated with fewer RBC units transfused per episode in gynecological (difference of mean number of units -1.66 [95% CI: -2.72, -0.61]) and aneurysm (-0.97 [-1.59, -0.35]) patients. SD plasma was further associated with fewer anaphylactic reactions than FFP (odds ratio 0.37 [0.18, 0.77; P<0.01]) while the differences for most transfusion reactions were not statistically significant. SD plasma units, despite being one third smaller in volume than FFP units, are not associated with a higher plasma/RBC ratio. SD plasma is associated with fewer anaphylactic reactions than FFP plasma/RBC units ratio.

Comparing transfusion reaction risks for various plasma products - an analysis of 7 years of ISTARE haemovigilance data.

Plasma transfusions may result in transfusion reactions. We used the International Surveillance of Transfusion-Associated Reactions and Events (ISTARE) database, containing yearly reported national annual aggregate data on transfusion reactions from participating countries, to investigate risks of plasma transfusion reactions and compare transfusion reaction risks for different plasma types. We calculated risks for plasma transfusion reactions and compared transfusion reaction risks between plasma types using random effects regression on repeated measures. The ISTARE database contains data from 23 countries, reporting units issued and/or transfused and transfusion reactions observed for some portion of 7 years (2006-2012). Interquartile ranges (IQRs) of plasma transfusion reaction risks were: allergic reactions (5·6-72·2 reactions/105 units transfused); febrile non-haemolytic transfusion reactions (0-9·1); transfusion-associated circulatory overload (0-1·9); transfusion related acute lung injury (TRALI) (0-1·2); and hypotensive reactions (0-0·6). Apheresis plasma was associated with more allergic reactions [odds ratio (OR) = 1·29 (95% confidence interval: 1·19-1·40)] and hypotensive reactions [OR = 2·17 (1·38-3·41)] than whole blood-derived plasma. Pathogen-inactivated plasma was associated with fewer transfusion reactions than untreated plasma.

Comparing transfusion reaction rates for various plasma types: a systematic review and meta-analysis/regression.

BACKGROUND: We estimated rates for common plasma-associated transfusion reactions and compared reported rates for various plasma types. STUDY DESIGN AND METHODS: We performed a systematic review and meta-analysis of peer-reviewed articles that reported plasma transfusion reaction rates. Random-effects pooled rates were calculated and compared between plasma types. Meta-regression was used to compare various plasma types with regard to their reported plasma transfusion reaction rates. RESULTS: Forty-eight studies reported transfusion reaction rates for fresh-frozen plasma (FFP; mixed-sex and male-only), amotosalen INTERCEPT FFP, methylene blue-treated FFP, and solvent/detergent-treated pooled plasma. Random-effects pooled average rates for FFP were: allergic reactions, 92/105 units transfused (95% confidence interval [CI], 46-184/105 units transfused); febrile nonhemolytic transfusion reactions (FNHTRs), 12/105 units transfused (95% CI, 7-22/105 units transfused); transfusion-associated circulatory overload (TACO), 6/105 units transfused (95% CI, 1-30/105 units transfused); transfusion-related acute lung injury (TRALI), 1.8/105 units transfused (95% CI, 1.2-2.7/105 units transfused); and anaphylactic reactions, 0.8/105 units transfused (95% CI, 0-45.7/105 units transfused). Risk differences between plasma types were not significant for allergic reactions, TACO, or anaphylactic reactions. Methylene blue-treated FFP led to fewer FNHTRs than FFP (risk difference = -15.3 FNHTRs/105 units transfused; 95% CI, -24.7 to -7.1 reactions/105 units transfused); and male-only FFP led to fewer cases of TRALI than mixed-sex FFP (risk difference = -0.74 TRALI/105 units transfused; 95% CI, -2.42 to -0.42 injuries/105 units transfused). CONCLUSION: Meta-regression demonstrates that the rate of FNHTRs is lower for methylene blue-treated compared with FFP, and the rate of TRALI is lower for male-only than for mixed-sex FFP; whereas no significant differences are observed between plasma types for allergic reactions, TACO, or anaphylactic reactions. Reported transfusion reaction rates suffer from high heterogeneity.

Effect of solvent/detergent-treated pooled plasma on fibrinolysis in reconstituted whole blood.

BACKGROUND: Hyperfibrinolysis has been observed in patients heavily transfused with solvent/detergent-treated pooled plasma (S/D plasma). We compared coagulation and fibrinolytic variables in blood containing S/D plasma with blood containing fresh-frozen plasma (FFP), with and without α2-antiplasmin or tranexamic acid (TXA) supplementation. STUDY DESIGN AND METHODS: Whole blood samples were reconstituted from red blood cells, platelet (PLT) concentrates, and varying mixtures of FFP and S/D plasma. Hematocrit and PLT count of reconstituted whole blood samples were varied. For a subset of runs, α2-antiplasmin or TXA was added to S/D plasma whole blood samples. Thromboelastography (TEG) analysis was performed to assess 50% clot lysis time (CLT50% ), maximum amplitude (MA), and initial clotting time (R-time). RESULTS: The change in CLT50% of whole blood as the plasma compartment transitions from FFP to S/D plasma was -52% (95% confidence interval [CI], -60% to -45%; p < 0.001). PLT count strengthened the effect, leading to an additional change in CLT50% of -8% (95% CI, -14% to -2%; p = 0.012) as PLT count increased from 10 × 109 to 150 × 109 /L. MA and R-time were not associated with fraction of S/D plasma in whole blood. α2-Antiplasmin and TXA restored clot lysis time in S/D plasma whole blood. CONCLUSION: Whole blood with S/D plasma has shorter clot lysis times in vitro compared to whole blood with FFP. α2-Antiplasmin and TXA restore clot lysis time of S/D plasma whole blood to that of FFP whole blood. Clinicians should be aware of the decreased clot lysis time associated with S/D plasma transfusion.