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Background: Use of antibiotics is the main driver of antimicrobial resistance which is considered one of the biggest threats to human health. In Denmark, most antibiotics are prescribed in general practice. Acute lower respiratory tract infections, including community-acquired pneumonia (CAP), are among the most frequent indications for antibiotic prescribing. Phenoxymethylpenicillin is established as first-line treatment in general practice in Denmark. However, the treatment duration with phenoxymethylpenicillin is mostly based on traditions. Both 5 and 7 days of treatment is recommended in Danish guidelines, and when asking the general practitioners about what treatment duration, they prescribe the variation is even bigger. Several hospital-based studies have proven short course (≤ 6 days) antibiotic treatment non-inferior to long course (≥ 7 days) treatment of CAP. No evidence exists on the optimal treatment duration for CAP in non-hospitalised patients. This randomised controlled trial aim to investigate the optimal treatment duration with phenoxymethylpenicillin for CAP in adults diagnosed in general practice in Denmark., Methods: This is an open-label, pragmatic, randomised controlled, five-arm DURATIONS trial. Participants will be recruited from at least 24 general practices in Denmark. Eligible participants are adults, with no pre-existing lung disease, presenting with symptoms of CAP, and in whom the general practitioner finds it relevant to treat with antibiotics. The study will compare treatment with phenoxymethylpenicillin 1.2 MIE q.i.d. in 3, 4, 5, 6, and 7 days., Discussion: This study will provide evidence for the optimal antibiotic treatment duration of CAP in general practice and inform future guidelines on CAP in all countries using phenoxymethylpenicillin for the treatment of acute respiratory tract infections in adults. The results of this study might also be used to guide treatment recommendations in other countries using phenoxymethylpenicillin. Moreover, a (potential) reduction in antibiotic use might lower the development of antimicrobial resistance, increase patient treatment adherence, reduce risks of adverse events, and lower the economical exp TRIAL REGISTRATION: ClinicalTrials.gov: NCT06295120. Registered 28 February 2024.  The Scientific Ethics Committee for the North Denmark Region: N-20230039., (© 2024. The Author(s).)

Purpose: Older people have the highest use of antibiotics for acute and chronic urinary tract infection (UTI), despite diagnostic uncertainty and the growing problem of antibiotic resistance. We aim to describe use-patterns of UTI antibiotics two years prior to and following care home admission in Denmark., Methods: This was a register-based nationwide drug-utilization study. In a cohort comprising all Danish residents admitted into a care home from 2015 to 2021, we described the use of UTI antibiotics, and examined differences between regions and individual care homes in rates of UTI antibiotic use. Further, we described trends in UTI-related contacts with hospitals in the two years prior to and following care home admission., Results: The cohort comprised 101,297 residents (61% female; median age 84 years). UTI antibiotic use doubled from 7 to 14 treatments/100 residents/month two months prior to care home admission and remained at 10 treatments/100 residents/month the following two years. Prescription of pivmecillinam (55%) was most common. Primary care practitioners prescribed the majority (92%) of UTI antibiotics. UTI-related hospital contacts peaked at two months prior to care home admission, with 6 admissions/100 residents/month, subsequently dropping to 2 admission/100 residents/month. We found considerable variation in UTI antibiotic use, with 10% of care homes responsible for 20% of treatments in 2021., Conclusion: Use of UTI antibiotics increased prior to and remained at a stable high level following care home admission in Denmark. Despite variation in use across regions and individual care homes, an overall decrease was seen throughout the years 2016-2021., (© 2024. The Author(s).)

Background: Oseltamivir is usually not often prescribed (or reimbursed) for non-high-risk patients consulting for influenza-like-illness (ILI) in primary care in Europe. We aimed to evaluate the cost-effectiveness of adding oseltamivir to usual primary care in adults/adolescents (13 years +) and children with ILI during seasonal influenza epidemics, using data collected in an open-label, multi-season, randomised controlled trial of oseltamivir in 15 European countries., Methods: Direct and indirect cost estimates were based on patient reported resource use and official country-specific unit costs. Health-Related Quality of Life was assessed by EQ-5D questionnaires. Costs and quality adjusted life-years (QALY) were bootstrapped (N = 10,000) to estimate incremental cost-effectiveness ratios (ICER), from both the healthcare payers' and the societal perspectives, with uncertainty expressed through probabilistic sensitivity analysis and expected value for perfect information (EVPI) analysis. Additionally, scenario (self-reported spending), comorbidities subgroup and country-specific analyses were performed., Results: The healthcare payers' expected ICERs of oseltamivir were €22,459 per QALY gained in adults/adolescents and €13,001 in children. From the societal perspective, oseltamivir was cost-saving in adults/adolescents, but the ICER is €8,344 in children. Large uncertainties were observed in subgroups with comorbidities, especially for children. The expected ICERs and extent of decision uncertainty varied between countries (EVPI ranged €1-€35 per patient)., Conclusion: Adding oseltamivir to primary usual care in Europe is likely to be cost-effective for treating adults/adolescents and children with ILI from the healthcare payers' perspective (if willingness-to-pay per QALY gained > €22,459) and cost-saving in adults/adolescents from a societal perspective., (© 2022. The Author(s).)

Introduction: While lower respiratory tract infections are the main cause of death for children under 5 globally, only a small proportion of children with respiratory tract infections need antibiotics. Overuse of antibiotics globally is leading to increasing rates of antibiotic resistance. In Kyrgyzstan, healthcare workers regularly prescribe antibiotics when clinical uncertainty is present to err on the side of caution. Targeting antibiotic use with biomarkers of inflammation such as C reactive protein (CRP) testing at the point-of-care test (POCT) has been shown to reduce antibiotic use in general, but only few studies have been done in children and no studies exist from Central Asia. This study aims to assess whether the use of a CRP POCT can safely decrease prescription of antibiotics for children with acute respiratory symptoms in primary level healthcare centres in Kyrgyzstan., Methods and Analysis: Multicentre, open-label, individually randomised, controlled clinical trial with 14 days follow-up (follow-up by phone on days 3, 7 and 14) in rural lowland Chui and highland Naryn regions of Kyrgyzstan. The population are children aged 6 months to 12 years attending the primary level healthcare centres during normal business hours with acute respiratory symptoms. CRP POCT equipment will be supplied to healthcare centres, along with a short training session in CRP use, including the interpretation of results to support the clinical evaluation of the child with acute respiratory infection. The primary outcomes are the proportion of patients prescribed an antibiotic within 14 days of index consultation (superiority analysis) and days to recovery (non-inferiority analysis). Secondary outcomes are antibiotics prescribed at index consultation, reconsultations, hospital admission and vital status within 14 days. Analysis of the first primary outcome, antibiotic use, will be intention to treat using a logistic regression model. Analysis of the second primary outcome, days to recovery, will be per protocol using a linear regression model and a non-inferiority margin of 1 day., Ethics and Dissemination: The study was approved on 18 June 2021 by the Ethics Committee (ref: no. 1) of the National Centre of Maternity and Childhood Care, Bishkek, Kyrgyzstan. The results of the study regardless of the conclusion will be presented at international conferences and published in peer-reviewed scientific medical journals along with policy briefs and technical reports., Trial Registration Number: NCT05195866., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Up to 80% of antibiotics are prescribed in the community. An assessment of prescribing by indication will help to identify areas where improvement can be made. A point prevalence audit study (PPAS) of consecutive respiratory tract infection (RTI) consultations in general practices in 13 European countries was conducted in January-February 2020 (PPAS-1) and again in 2022 (PPAS-4). The European Surveillance of Antibiotic Consumption quality indicators (ESAC-QI) were calculated to identify where improvements can be made. A total of 3618 consultations were recorded for PPAS-1 and 2655 in PPAS-4. Bacterial aetiology was suspected in 26% (PPAS-1) and 12% (PPAS-4), and an antibiotic was prescribed in 30% (PPAS-1) and 16% (PPAS-4) of consultations. The percentage of adult patients with bronchitis who receive an antibiotic should, according to the ESAC-QI, not exceed 30%, which was not met by participating practices in any country except Denmark and Spain. For patients (≥1) with acute upper RTI, less than 20% should be prescribed an antibiotic, which was achieved by general practices in most countries, except Ireland (both PPAS), Croatia (PPAS-1), and Greece (PPAS-4) where prescribing for acute or chronic sinusitis (0-20%) was also exceeded. For pneumonia in adults, prescribing is acceptable for 90-100%, and this is lower in most countries. Prescribing for tonsillitis (≥1) exceeded the ESAC-QI (0-20%) in all countries and was 69% (PPAS-1) and 75% (PPAS-4). In conclusion, ESAC-QI applied to PPAS outcomes allows us to evaluate appropriate antibiotic prescribing by indication and benchmark general practices and countries.

Background: Acute respiratory infections (ARIs) are by far the most common reason for prescribing an antibiotic in primary care, even though the majority of ARIs are of viral or non-severe bacterial aetiology. It follows that in many cases antibiotic use will not be beneficial to a patient's recovery but may expose them to potential side effects. Furthermore, limiting unnecessary antibiotic use is a key factor in controlling antibiotic resistance. One strategy to reduce antibiotic use in primary care is point-of-care biomarkers. A point-of-care biomarker (test) of inflammation identifies part of the acute phase response to tissue injury regardless of the aetiology (infection, trauma, or inflammation) and may be used as a surrogate marker of infection, potentially assisting the physician in the clinical decision whether to use an antibiotic to treat ARIs. Biomarkers may guide antibiotic prescription by ruling out a serious bacterial infection and help identify patients in whom no benefit from antibiotic treatment can be anticipated. This is an update of a Cochrane Review first published in 2014., Objectives: To assess the benefits and harms of point-of-care biomarker tests of inflammation to guide antibiotic treatment in people presenting with symptoms of acute respiratory infections in primary care settings regardless of patient age., Search Methods: We searched CENTRAL (2022, Issue 6), MEDLINE (1946 to 14 June 2022), Embase (1974 to 14 June 2022), CINAHL (1981 to 14 June 2022), Web of Science (1955 to 14 June 2022), and LILACS (1982 to 14 June 2022). We also searched three trial registries (10 December 2021) for completed and ongoing trials., Selection Criteria: We included randomised controlled trials (RCTs) in primary care patients with ARIs that compared the use of point-of-care biomarkers with standard care. We included trials that randomised individual participants, as well as trials that randomised clusters of patients (cluster-RCTs)., Data Collection and Analysis: Two review authors independently extracted data on the following primary outcomes: number of participants given an antibiotic prescription at index consultation and within 28 days follow-up; participant recovery within seven days follow-up; and total mortality within 28 days follow-up. We assessed risk of bias using the Cochrane risk of bias tool and the certainty of the evidence using GRADE. We used random-effects meta-analyses when feasible. We further analysed results with considerable heterogeneity in prespecified subgroups of individual and cluster-RCTs., Main Results: We included seven new trials in this update, for a total of 13 included trials. Twelve trials (10,218 participants in total, 2335 of which were children) evaluated a C-reactive protein point-of-care test, and one trial (317 adult participants) evaluated a procalcitonin point-of-care test. The studies were conducted in Europe, Russia, and Asia. Overall, the included trials had a low or unclear risk of bias. However all studies were open-labelled, thereby introducing high risk of bias due to lack of blinding. The use of C-reactive protein point-of-care tests to guide antibiotic prescription likely reduces the number of participants given an antibiotic prescription, from 516 prescriptions of antibiotics per 1000 participants in the control group to 397 prescriptions of antibiotics per 1000 participants in the intervention group (risk ratio (RR) 0.77, 95% confidence interval (CI) 0.69 to 0.86; 12 trials, 10,218 participants; I² = 79%; moderate-certainty evidence).  Overall, use of C-reactive protein tests also reduce the number of participants given an antibiotic prescription within 28 days follow-up (664 prescriptions of antibiotics per 1000 participants in the control group versus 538 prescriptions of antibiotics per 1000 participants in the intervention group) (RR 0.81, 95% CI 0.76 to 0.86; 7 trials, 5091 participants; I² = 29; high-certainty evidence). The prescription of antibiotics as guided by C-reactive protein tests likely does not reduce the number of participants recovered, within seven or 28 days follow-up (567 participants recovered within seven days follow-up per 1000 participants in the control group versus 584 participants recovered within seven days follow-up per 1000 participants in the intervention group) (recovery within seven days follow-up: RR 1.03, 95% CI 0.96 to 1.12; I² = 0%; moderate-certainty evidence) (recovery within 28 days follow-up: RR 1.02, 95% CI 0.79 to 1.32; I² = 0%; moderate-certainty evidence). The use of C-reactive protein tests may not increase total mortality within 28 days follow-up, from 1 death per 1000 participants in the control group to 0 deaths per 1000 participants in the intervention group (RR 0.53, 95% CI 0.10 to 2.92; I² = 0%; low-certainty evidence). We are uncertain as to whether procalcitonin affects any of the primary or secondary outcomes because there were few participants, thereby limiting the certainty of evidence. We assessed the certainty of the evidence as moderate to high according to GRADE for the primary outcomes for C-reactive protein test, except for mortality, as there were very few deaths, thereby limiting the certainty of the evidence., Authors' Conclusions: The use of C-reactive protein point-of-care tests as an adjunct to standard care likely reduces the number of participants given an antibiotic prescription in primary care patients who present with symptoms of acute respiratory infection. The use of C-reactive protein point-of-care tests likely does not affect recovery rates. It is unlikely that further research will substantially change our conclusion regarding the reduction in number of participants given an antibiotic prescription, although the size of the estimated effect may change.  The use of C-reactive protein point-of-care tests may not increase mortality within 28 days follow-up, but there were very few events. Studies that recorded deaths and hospital admissions were performed in children from low- and middle-income countries and older adults with comorbidities.  Future studies should focus on children, immunocompromised individuals, and people aged 80 years and above with comorbidities. More studies evaluating procalcitonin and potential new biomarkers as point-of-care tests used in primary care to guide antibiotic prescription are needed.  Furthermore, studies are needed to validate C-reactive protein decision algorithms, with a specific focus on potential age group differences., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Between-country differences have been described in antibiotic prescribing for respiratory tract infection (RTI) in primary care, but not yet for diagnostic testing procedures and prescribing confidence., Aim: To describe between-country differences in RTI management, particularly diagnostic testing and antibiotic prescribing, and investigate which factors relate to antibiotic prescribing and GPs' prescribing confidence., Design & Setting: Prospective audit in 18 European countries., Method: An audit of GP-registered patient, clinical, and management characteristics for patients presenting with sore throat and/or lower RTI ( n = 4982), and GPs' confidence in their antibiotic prescribing decision. Factors related to antibiotic prescribing and confidence were analysed using multi-level logistic regression., Results: Antibiotic prescribing proportions varied considerably: <20% in four countries, and >40% in six countries. There was also considerable variation in point-of-care (POC) testing (0% in Croatia, Moldova, and Romania, and >65% in Denmark and Norway, mainly for C-reactive protein [CRP] and group A streptococcal [strep A] infection), and in laboratory or hospital-based testing (<3% in Hungary, the Netherlands, and Spain, and >30% in Croatia, Georgia, Greece, and Moldova, mainly chest X-ray and white blood cell counting). Antibiotic prescribing was related to illness severity, comorbidity, age, fever, and country, but not to having performed a POC test. In nearly 90% of consultations, GPs were confident in their antibiotic prescribing decision., Conclusion: Despite high confidence in decisions about antibiotic prescribing, there is considerable variation in the primary care of RTI in European countries, with GPs prescribing antibiotics overall more often than is considered appropriate. POC testing may enhance the quality of antibiotic prescribing decisions if it can safely reverse decisions confidently made on clinical grounds alone to prescribe antibiotics., (Copyright © 2022, The Authors.)

Background: Clinical findings do not accurately predict laboratory diagnosis of influenza. Early identification of influenza is considered useful for proper management decisions in primary care., Objective: We evaluated the diagnostic value of the presence and the severity of symptoms for the diagnosis of laboratory-confirmed influenza infection among adults presenting with influenza-like illness (ILI) in primary care., Methods: Secondary analysis of patients with ILI who participated in a clinical trial from 2015 to 2018 in 15 European countries. Patients rated signs and symptoms as absent, minor, moderate, or major problem. A nasopharyngeal swab was taken for microbiological identification of influenza and other microorganisms. Models were generated considering (i) the presence of individual symptoms and (ii) the severity rating of symptoms., Results: A total of 2,639 patients aged 18 or older were included in the analysis. The mean age was 41.8 ± 14.7 years, and 1,099 were men (42.1%). Influenza was microbiologically confirmed in 1,337 patients (51.1%). The area under the curve (AUC) of the model for the presence of any of seven symptoms for detecting influenza was 0.66 (95% confidence interval [CI]: 0.65-0.68), whereas the AUC of the symptom severity model, which included eight variables-cough, fever, muscle aches, sweating and/or chills, moderate to severe overall disease, age, abdominal pain, and sore throat-was 0.70 (95% CI: 0.69-0.72)., Conclusion: Clinical prediction of microbiologically confirmed influenza in adults with ILI is slightly more accurate when based on patient reported symptom severity than when based on the presence or absence of symptoms., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Antibiotic resistance is a global health challenge and the close correlation between antibiotic use and the development of resistance makes it essential to maintain a rational use of antibiotics. Most antibiotics are prescribed in general practice against acute respiratory tract infections (ARTI), even though most of these infections are of viral etiology. Thus, a safe method to substantially reduce unnecessary use of antibiotics in general practice is needed. Procalcitonin (PCT) is a precursor protein with very low circulating levels in the blood under physiological conditions. However, in response serious bacterial infection the level of PCT in the blood may increase significantly. Until recently, quantitative analyses of PCT was performed in hospital laboratories, impeding the implementation of PCT in primary care. Our aim is to determine whether it is possible to lower the use of antibiotics in patients presenting with symptoms of ARTI, without significantly prolonging the period of illness, by using a newly released PCT point-of-care test in general practice., Methods: The Procalcitonin-Guided Antibiotics in Respiratory Infections (PARI) study is a randomized, single-blinded, non-inferiority, multi-practice intervention study comparing a PCT-group to a control group. Patients (N = 508) will be randomly assigned 1:1 to standard care or to the PCT group. The primary outcomes the duration of illness and symptoms from ARTI measured with the Acute Respiratory Tract Infection Questionnaire. Secondary outcomes include (1) Number of participants in each trial arm exposed to antibiotic treatment at index consultation (day 1) and within 30 days, (2) Number of participants in each trial arm with side effects from antibiotic treatment within 14 days, (3) Number of participants in each trial arm with re-consultations within 30 days, (4) Number of participants in each trial arm admitted to hospital (including diagnosis and mortality) within 30 days, (5) Characterization of biomarker (CRP and PCT) level at index consultation. Tertiary outcomes include patient and general practitioner satisfaction with the use of the PCT point-of-care test, and long-term follow-up., Discussion: To our knowledge, this is the first study to examine a PCT point-of-care test in general practice with the aim of reducing the use of antibiotics in patients with symptoms of ARTI. Results of this study may prove important in targeting antibiotic treatment only to those patients who need it, thus contributing to limiting the spread of antibiotic resistance., Trial Registration: ClinicalTrials.gov Identifier: NCT04216277 , date of registration: 2. of January 2020., (© 2022. The Author(s).)

Background: There is little evidence about the relationship between aetiology, illness severity, and clinical course of respiratory tract infections (RTIs) in primary care. Understanding these associations would aid in the development of effective management strategies for these infections., Aim: To investigate whether clinical presentation and illness course differ between RTIs where a viral pathogen was detected and those where a potential bacterial pathogen was found., Design and Setting: Post hoc analysis of data from a pragmatic randomised trial on the effects of oseltamivir in patients with flu-like illness in primary care ( n = 3266) in 15 European countries., Method: Patient characteristics and their signs and symptoms of disease were registered at baseline. Nasopharyngeal (adults) or nasal and pharyngeal (children) swabs were taken for polymerase chain reaction analysis. Patients were followed up until 28 days after inclusion. Regression models and Kaplan-Meier curves were used to analyse the relationship between aetiology, clinical presentation at baseline, and course of disease including complications., Results: Except for a less prominent congested nose (odds ratio [OR] 0.55, 95% confidence interval [CI] = 0.35 to 0.86) and acute cough (OR 0.42, 95% CI = 0.27 to 0.65) in patients with flu-like illness in whom a possible bacterial pathogen was isolated, there were no clear clinical differences in presentations between those with a possible bacterial aetiology compared with those with a viral aetiology. Also, course of disease and complications were not related to aetiology., Conclusion: Given current available microbiological tests and antimicrobial treatments, and outside pandemics such as COVID-19, microbiological testing in primary care patients with flu-like illness seems to have limited value. A wait-and-see policy in most of these patients with flu-like illness seems the best option., (© The Authors.)

Background: Most COVID-19 patients experience a mild course of the disease and can be managed in general practice. However, in the early pandemic, most research was conducted in secondary care., Objectives: This scoping review aimed to identify original research published within the first year of the pandemic relevant to general practice regarding symptomatic, non-hospitalised patients with mild to moderate COVID-19 disease to provide an overview of published research., Methods: PubMed was searched for studies written in English, Swedish, Danish, or Norwegian published before 1 April 2021. Two authors screened all titles and abstracts and identified full texts., Results: We screened 1303 titles and abstracts and retrieved 128 full texts. An additional 44 full-texts were obtained from references. After full-text reading, 79 articles were included, six of which were conducted in general practice, 20 in the community, 42 in hospitals, and 11 in other settings. Therapy and harm were investigated in randomised controlled trials in 11 out of 17 studies; the diagnosis was investigated using a diagnostic accuracy design in four out of 26 studies and prognosis in prospective studies in 10 out of 21 studies. The remaining 15 studies had other research questions., Conclusion: Although general practitioners in most countries must have been involved in managing patients with COVID-19, little research has been published from general practice during the first year of the pandemic. General practice research environments must be able to respond quickly in case of future pandemics.

Background and Objective: Influenza-like illness (ILI) leads to a substantial disease burden every winter in Europe; however, oseltamivir is not frequently prescribed to ILI patients in the primary-care setting. An open-label, multi-country, multi-season, randomised controlled trial investigated the effectiveness of oseltamivir for treating ILI in 15 European countries. We aimed to evaluate whether patients presenting with ILI in primary care and being managed with the addition of oseltamivir to usual care had lower average direct and indirect costs compared to patients with usual care alone., Methods: Resource use data were extracted from participants' daily diaries. Itemised country-specific unit costs were collected through official tariffs, pharmacies or literature. Costs were converted to 2018 values. The null hypothesis was tested based on one-sided credible intervals (CrIs) obtained by bootstrapping. Base-case analysis estimated direct cost and productivity losses using itemised costed resource use and the human capital approach. Scenario analyses with self-reported spending rather than itemised costing were also performed., Results: Patients receiving oseltamivir (N = 1306) reported fewer healthcare visits, medication uses, hospital attendances and paid-work hours lost than the other patients (N = 1298). Excluding the oseltamivir cost, the average direct costs were lower in patients treated with oseltamivir from all perspectives, but these differences were not statistically significant (perspective of patient: €17 [0-95% Crl: 16-19] vs. €24 [5-100% Crl: 18-29]; healthcare provider: €37 [28-67] vs. €44 [25-55]; healthcare payers: €54 [45-85] vs. €68 [45-81]; and society: €423 [399-478] vs. €451 [390-478]). Scenario and age-group analyses confirmed these findings, but with some between-country differences., Conclusion: The average direct and indirect costs were consistently lower in patients treated with oseltamivir than in patients without from four perspectives (excluding the oseltamivir cost). However, these differences were not statistically significant., (© 2021. The Author(s).)

Objective: To describe primary health care (consultation characteristics and management) for patients contacting their general practitioner (GP) with a respiratory tract infection (RTI) early on in the COVID-19 pandemic in contrasting European countries, with comparison to prepandemic findings., Setting: Primary care in 16 countries (79 practices), when no routine SARS-CoV-2 testing was generally available., Design and Participants: Before (n=4376) and early in the pandemic (n=3301), patients with RTI symptoms were registered in this prospective audit study., Outcome Measures: Consultation characteristics (type of contact and use of PPE) and management characteristics (clinical assessments, diagnostic testing, prescribing, advice and referral) were registered. Differences in these characteristics between countries and between pandemic and prepandemic care are described., Results: Care for patients with RTIs rapidly switched to telephone/video consultations (10% in Armenia, 91% in Denmark), and when consultations were face-to-face, GPs used PPE during 97% (95% CI 96% to 98%) of contacts. Laboratory testing for SARS-CoV-2 in primary care patients with RTIs was rapidly implemented in Denmark (59%) and Germany (31%), while overall testing for C reactive protein decreased. The proportion of patients prescribed antibiotics varied considerably between countries (3% in Belgium, 48% in UK) and was lower during the pandemic compared with the months before, except for Greece, Poland and UK. GPs provided frequent and varied COVID-related advice and more frequently scheduled a follow-up contact (50%, 95% CI 48% to 52%). GPs reported a slightly higher degree of confidence in the likely effectiveness of their management in face-to-face (73% (very) confident, 95% CI 71% to 76%) than in virtual consultations (69%, 95% CI 67% to 71%)., Conclusions: Despite between-country variation in consultation characteristics, access to SARS-CoV-2 laboratory testing and medication prescribing, GPs reported a high degree of confidence in managing their patients with RTIs in the emerging pandemic. Insight in the highly variable pandemic responses, as measured in this multicountry audit, can aid in fine-tuning national action and in coordinating a pan-European response during future pandemic threats., Competing Interests: Competing interests: AWvdV, CCB, TV, ST-K, SA, EB and HGo received unrestricted funding for studies from the European Commission (IMI2 and H2020). SE is an employee of Abbott Rapid Diagnostics Germany., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials. We aimed to determine whether adding antiviral treatment to usual primary care for patients with influenza-like illness reduces time to recovery overall and in key subgroups., Methods: We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with influenza-like illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921., Findings: Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20-1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74-1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30-1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous illness duration to 3·20 (95% BCrI 1·00-5·50) in patients aged 65 years or older who had more severe illness, comorbidities, and longer previous illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group., Interpretation: Primary care patients with influenza-like illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2-3 days sooner., Funding: European Commission's Seventh Framework Programme., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

To analyze the association between change in HbA1c during the first 6 years after diagnosis of Type 2 diabetes mellitus (Type 2 DM) and incident micro- and macrovascular morbidity and mortality during 13 years thereafter. This is an observational study of the participants in the intervention arm of the randomized controlled trial Diabetes Care in General Practice (DCGP) in Denmark. 494 newly diagnosed persons with Type 2 DM aged 40 years and over with three or more measurements of HbA1c during six years of intervention were included in the analyses. Based on a regression line, fitted through the HbA1c-measurements from 1 to 6 years after diabetes diagnosis, glycaemic control was characterized by the one-year level of HbA1c after diagnosis, and the slope of the regression line. Outcomes were incident diabetes-related morbidity and mortality from 6 to 19 years after diabetes diagnosis. The association between change in HbA1c (the slope of the regression line) and clinical outcomes were assessed in adjusted Cox regression models. The median HbA1c level at year one was 60 (IQR: 52-71) mmol/mol or (7.65 (IQR: 6.91-8.62) %). Higher HbA1c levels one year after diagnosis were associated with a higher risk of later diabetes-related morbidity and mortality. An increase in HbA1c during the first 6 years after diabetes diagnosis was associated with later microvascular complications (HR per 1.1 mmol/mol or 0.1% point increase in HbA1c per year; 95% CI) = 1.14; 1.05-1.24). Change in HbA1c did not predict the aggregate outcome 'any diabetes-related endpoint, all-cause mortality, diabetes-related mortality, myocardial infarction, stroke, or peripheral vascular diseases. We conclude that suboptimal development of glycaemic control during the first 6 years after diabetes diagnosis was an independent risk factor for microvascular complications during the succeeding 13-year follow-up, but not for mortality or macrovascular complications., Competing Interests: Funding was received from the commercial source Novo Nordisk Farmaka Denmark Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.

Genomic medicine holds promise as a potential important novel tool in primary care. However, the current evidence basis regarding pharmogenetics and genetic risk estimates and the trade-off between benefits and harm of introducing genomic medicine in present day primary care is low. More research into this new area is warranted. Also training of general practitioners in correct use and interpretation of genetic testing is needed to ensure successful implementation.

Objective: The aim of this study was to describe and characterize the prescription of antibiotics for urinary tract infection (UTI) in general practice in Denmark and to evaluate compliance with current recommendations., Design: National registry-based study Setting: Danish general practice Patients: 267.539 patients who redeemed a prescription for antibiotics with the clinical indication UTI at community pharmacies between July 1 st 2012 and June 31 st 2013., Main Outcome Measures: Antibiotics prescribed for 1) acute lower UTI, 2) acute upper UTI and 3) recurrent UTI presented as amount of prescriptions, number of treatments per 1000 inhabitants per day (TID) and defined daily doses per 1000 inhabitants per day (DID)., Results: A total of 507.532 prescriptions were issued to 267.539 patients during the one year study period, representing 2.35 DID. Acute lower UTI was the most common reason for prescription of antibiotics (89.5%) followed by recurrent UTI (8.4%). The majority of the prescriptions were issued to people above 60 year old (57.6%). Pivmecillinam was the most commonly prescribed antibiotic in acute lower (45.8%) and acute upper (63.3%) UTI. Trimethroprim was the most commonly prescribed antibiotic in recurrent UTI (45.9%). Prescription of quinolones increased with increasing patient-age (p = <.0001)., Conclusion: Compliance with current Danish recommendations was moderately high. Pivmecillinam is the first line antibiotic for the management of acute lower and upper UTI, and trimethroprim is the first line option of recurrent UTI. A high proportion of the antibiotic prescriptions were issued in the elderly population including a relatively high prescription rate of quinolones. Key points Urinary tract infection (UTI) is a common cause for prescription of antibiotics in general practice Poor compliance in general practice with recommendations for first-line treatment of UTI may increase antibiotic resistance Danish general practitioners are generally compliant with national and regional guidelines for antibiotic treatment of UTI There is high use of antibiotics in the elderly population including a worrisome high use of broad-spectrum antibiotics, such as Quinolones.

Background: In Denmark, the use of amoxicillin is widespread among children, despite phenoxymethylpenicillin being recommended as first-line therapy. The reason for this apparent discrepancy is not fully understood. We aimed at evaluating prescribing patterns of antibiotics among Danish children 0-4 years of age, with emphasis on incidence of treatment episodes, choice of initial antibiotic treatment and switching patterns between different types of antibiotics., Methods: We identified all children ≤4 years of age who filled a prescription of antibiotics from 2000 to 2015 according to the nationwide Danish National Prescription Registry. We estimated the incidence rate of episodes treated with antibiotics and the choice of initial antibiotic treatment over time. Further, we assessed the cumulative risk of switching within 0-3 days after initiating therapy., Results: We identified 3,481,684 antibiotic treatment episodes issued to 0- to 4-year-olds from 2000 to 2015. The incidence rate was stable until 2011 both among children 0-1 years of age (approximately 880/1000) and among children 2-4 years of age (approximately 610/1000), after which it dropped. Phenoxymethylpenicillin and, increasingly, amoxicillin were most frequently used as initial treatments (39% vs. 44%). Few switched from amoxicillin (1%) or phenoxymethylpenicillin (4.7%) within the first 3 days. Of those who switched from phenoxymethylpenicillin, 64% received amoxicillin as second-line treatment., Conclusions: The incidence of episodes treated with antibiotics among Danish children 0-4 years of age has decreased considerably since 2011. In contrast to guideline recommendations, amoxicillin is the most frequently used initial treatment. Early switching between antibiotics is uncommon. Initiatives should address the extensive use of amoxicillin.

Introduction: Effective management of seasonal and pandemic influenza is a high priority internationally. Guidelines in many countries recommend antiviral treatment for older people and individuals with comorbidity at increased risk of complications. However, antivirals are not often prescribed in primary care in Europe, partly because its clinical and cost effectiveness has been insufficiently demonstrated by non-industry funded and pragmatic studies., Methods and Analysis: Antivirals for influenza-Like Illness? An rCt of Clinical and Cost effectiveness in primary CarE is a European multinational, multicentre, open-labelled, non-industry funded, pragmatic, adaptive-platform, randomised controlled trial. Initial trial arms will be best usual primary care and best usual primary care plus treatment with oseltamivir for 5 days. We aim to recruit at least 2500 participants ≥1 year presenting with influenza-like illness (ILI), with symptom duration ≤72 hours in primary care over three consecutive periods of confirmed high influenza incidence. Participant outcomes will be followed up to 28 days by diary and telephone. The primary objective is to determine whether adding antiviral treatment to best usual primary care is effective in reducing time to return to usual daily activity with fever, headache and muscle ache reduced to minor severity or less. Secondary objectives include estimating cost-effectiveness, benefits in subgroups according to age (<12, 12-64 and >64 years), severity of symptoms at presentation (low, medium and high), comorbidity (yes/no), duration of symptoms (≤48 hours/>48-72 hours), complications (hospital admission and pneumonia), use of additional prescribed medication including antibiotics, use of over-the-counter medicines and self-management of ILI symptoms., Ethics and Dissemination: Research ethics committee (REC) approval was granted by the NRES Committee South Central (Oxford B) and Clinical Trial Authority (CTA) approval by The Medicines and Healthcare products Regulatory Agency. All participating countries gained national REC and CTA approval as required. Dissemination of results will be through peer-reviewed scientific journals and conference presentations., Trial Registration Number: ISRCTN27908921; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Prescribing antibiotics for acute respiratory tract infections (RTIs) is common in primary healthcare although most of these infections are of viral origin and antibiotics may not be helpful. Some of these prescriptions will not be associated with a quick recovery, and might be regarded as cases of antibiotic treatment failure (ATF)., Objectives: We studied antibiotic treatment failure in patients with acute RTIs from a general practitioner (GP) perspective, aiming to explore (i) GPs' views of ATF in primary care; (ii) how ATF influences the doctor-patient relationship; and (iii) GPs' understanding of patients' views of ATF., Methods: Qualitative study based on semi-structured, recorded interviews of 18 GPs between August and October 2012. The interviews started with discussion of a unique case of acute RTI involving ATF, followed by a more general reflection of the topic. Interviews were analysed using qualitative content analysis., Results: In patients with acute RTIs, GPs proposed and agreed to a medical definition of antibiotic treatment failure but believed patients' views to differ significantly from this medical definition. GPs thought ATF affected their daily work only marginally. GPs used many communicative tools to maintain trust with patients in cases of ATF, but they did not consider such incidents to affect the doctor-patient relationship adversely., Conclusion: These findings suggest a possible communication gap between doctors and patients, partly due to a narrow medical definition of ATF. Studies describing patients' views are still missing. General practitioners' experiences and views on antibiotic treatment failure in acute respiratory infections or its effects on the doctor-patient relationship have not been studied previously.

A common adverse effect of antibiotic use is diarrhea. Probiotics are living microorganisms, which, upon oral ingestion, may prevent antibiotic-associated diarrhea (AAD) by the normalization of an unbalanced gastrointestinal flora. The objective of this systematic review was to assess the benefits and harms of probiotics used for the prevention of AAD in an outpatient setting. A search of the PubMed database was conducted and yielded a total of 17 RCTs with 3631 participants to be included in the review. A meta-analysis was conducted for the primary outcome: the incidence of AAD. The pooled results found that AAD was present in 8.0% of the probiotic group compared to 17.7% in the control group (RR 0.49, 95% CI 0.36 to 0.66; I² = 58%), and the species-specific results were similar regarding the probiotic strains L. rhamnosus GG and S. boulardii . However, the overall quality of the included studies was moderate. A meta-analysis of the ten trials reporting adverse events demonstrated no statistically significant differences in the incidence of adverse events between the intervention and control group (RD 0.00, 95% CI -0.02 to 0.02, 2.363 participants). The results suggests that probiotic use may be beneficial in the prevention of AAD among outpatients. Furthermore, the use of probiotics appears safe., Competing Interests: The authors declare no conflicts of interest.

Objectives: In Denmark, general practice is responsible for 75% of antibiotic prescribing in the primary care sector. We aimed to identify practice-related factors associated with high prescribers, including prescribers of critically important antibiotics as defined by WHO, after accounting for case mix by practice., Methods: We performed a nationwide register-based survey of antibiotic prescribing in Danish general practice from 2012 to 2013. The unit of analysis was the individual practice. We used multivariable regression analyses and an assessment of relative importance to identify practice-related factors driving high antibiotic prescribing rates., Results: We included 98% of general practices in Denmark ( n  =   1962) and identified a 10% group of high prescribers who accounted for 15% of total antibiotic prescriptions and 18% of critically important antibiotic prescriptions. Once case mix had been accounted for, the following practice-related factors were associated with being a high prescriber: lack of access to diagnostic tests in practice (C-reactive protein and urine culture); high use of diagnostic tests (urine culture and strep A throat test); a low percentage of antibiotic prescriptions issued over the phone compared with all antibiotic prescriptions; and a high number of consultations per 1000 patients. We also found that a low number of consultations per 1000 patients was associated with a reduced likelihood of being a high prescriber of antibiotics., Conclusions: An apparent underuse or overuse of diagnostic tests in general practice as well as organizational factors were associated with high-prescribing practices. Furthermore, the choice of antibiotic type seemed less rational among high prescribers., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To assess the availability and applicability of clinical indications from electronic prescriptions on antibiotic use in Danish general practice., Design: Retrospective cohort register-based study including the Danish National Prescription Register., Setting: Population-based study of routine electronic antibiotic prescriptions from Danish general practice., Subjects: All 975,626 patients who redeemed an antibiotic prescription at outpatient pharmacies during the 1-year study period (July 2012 to June 2013)., Main Outcome Measures: Number of prescriptions per clinical indication. Number of antibiotic prescriptions per 1000 inhabitants by age and gender. Logistic regression analysis estimated the association between patient and provider factors and missing clinical indications on antibiotic prescriptions., Results: A total of 2.381.083 systemic antibiotic prescriptions were issued by Danish general practitioners in the study period. We identified three main clinical entities: urinary tract infections (n = 506.634), respiratory tract infections (n = 456.354) and unspecified infections (n = 416.354). Women were more exposed to antibiotics than men. Antibiotic use was high in children under 5 years and even higher in elderly people. In 32% of the issued prescriptions, the clinical indication was missing. This was mainly associated with antibiotic types. We found that a prescription for a urinary tract agent without a specific clinical indication was uncommon., Conclusion: Clinical indications from electronic prescriptions are accessible and available to provide an overview of drug use, in casu antibiotic prescriptions, in Danish general practice. These clinical indications may be further explored in detail to assess rational drug use and congruence with guidelines, but validation and optimisation of the system is preferable.

Inappropriate use of antibiotics is contributing to the increasing rates of antimicrobial resistance. Several Danish guidelines on antibiotic prescribing for acute respiratory tract infections in general practice have been issued to promote rational prescribing of antibiotics, however it is unclear if these recommendations are followed. We aimed to characterise the pattern of antibiotic prescriptions for patients diagnosed with acute respiratory tract infections, by means of electronic prescriptions, labeled with clinical indications, from Danish general practice. Acute respiratory tract infections accounted for 456,532 antibiotic prescriptions issued between July 2012 and June 2013. Pneumonia was the most common indication with 178,354 prescriptions (39%), followed by acute tonsillitis (21%) and acute otitis media (19%). In total, penicillin V accounted for 58% of all prescriptions, followed by macrolides (18%) and amoxicillin (15%). The use of second-line agents increased with age for all indications, and comprised more than 40% of the prescriptions in patients aged >75 years. Women were more often prescribed antibiotics regardless of clinical indication. This is the first Danish study to characterise antibiotic prescription patterns for acute respiratory tract infections by data linkage of clinical indications. The findings confirm that penicillin V is the most commonly prescribed antibiotic agent for treatment of patients with an acute respiratory tract infection in Danish general practice. However, second-line agents like macrolides and amoxicillin with or without clavulanic acid are overused. Strategies to improve the quality of antibiotic prescribing especially for pneumonia, acute otitis media and acute rhinosinusitis are warranted., Respiratory Tract Infections: TRACKING THE OVERUSE OF ANTIBIOTICS: Better adherence to guidelines for prescribing antibiotics for different respiratory tract infections are warranted in Danish general practice. The over-use of antibiotics, particularly so-called 'second-line' agents such as amoxicillin, increases resistance and may lead to a potentially catastrophic scenario where antibiotics are no longer effective. Exactly how widespread the over-use of antibiotics is for different infections, however, is not clear. Rune Aabenhus at the University of Copenhagen and co-workers analyzed primary care data regarding antibiotic prescriptions for acute respiratory tract infections including pneumonia and ear infections in Denmark. They found that penicillin V-the current recommended first-line drug in Scandinavian countries-accounted for 58 per cent of prescriptions, a figure which should be improved. Amoxicillin and macrolides were over-prescribed, particularly in elderly patients. The team also call for further analysis of prescriptions given by out-of-hours clinics.

Objectives: Antibiotic consumption in the primary care sector is often perceived as synonymous with consumption in general practice despite the fact that few countries stratify the primary care sector by providers' medical specialty. We aimed to characterize and quantify antibiotic use in Danish general practice relative to the entire primary care sector., Methods: This was a registry-based study including all patients who redeemed an antibiotic prescription between July 2004 and June 2013 at a Danish community pharmacy. Antibiotic use was expressed as DDDs and treatments/1000 inhabitants/day (DIDs and TIDs, respectively) and assessed according to antibiotic spectrum (narrow versus broad) and their anatomical therapeutic classification codes in total as well as in six age groups., Results: The contribution of general practice to the entire antibiotic use in the primary care sector declined during the study period (TIDs, 79%-75%; DIDs, 77%-73%). Antibiotic use in general practice increased 8% when expressed as DIDs, while a 9% decrease was observed when expressed as TIDs. The use of broad-spectrum agents increased while narrow-spectrum agents decreased. The decline in antibiotic use was most prominent in children aged <5 years, while elderly patients were increasingly prescribed antibiotics., Conclusions: Using the entire primary care sector as a proxy for general practice prescribing is imprecise. Antibiotic use in general practice is at a stable high level, but DID and TID analyses show different trends and both should be applied when detailing changes in antibiotic consumption. While children are prescribed fewer narrow-spectrum agents, the observed increase in the use of broad-spectrum agents is worrisome and should be addressed in future interventions., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Choice of urine sampling technique in urinary tract infection may impact diagnostic accuracy and thus lead to possible over- or undertreatment. Currently no evidencebased consensus exists regarding correct sampling technique of urine from women with symptoms of urinary tract infection in primary care. The aim of this study was to determine the accuracy of urine culture from different sampling-techniques in symptomatic non-pregnant women in primary care., Methods: A systematic review was conducted by searching Medline and Embase for clinical studies conducted in primary care using a randomized or paired design to compare the result of urine culture obtained with two or more collection techniques in adult, female, non-pregnant patients with symptoms of urinary tract infection. We evaluated quality of the studies and compared accuracy based on dichotomized outcomes., Results: We included seven studies investigating urine sampling technique in 1062 symptomatic patients in primary care. Mid-stream-clean-catch had a positive predictive value of 0.79 to 0.95 and a negative predictive value close to 1 compared to sterile techniques. Two randomized controlled trials found no difference in infection rate between mid-stream-clean-catch, mid-stream-urine and random samples., Conclusions: At present, no evidence suggests that sampling technique affects the accuracy of the microbiological diagnosis in non-pregnant women with symptoms of urinary tract infection in primary care. However, the evidence presented is in-direct and the difference between mid-stream-clean-catch, mid-stream-urine and random samples remains to be investigated in a paired design to verify the present findings.

Background: We aimed to describe the use of systemic antibiotics among children in Denmark., Methods: National data on drug use in Denmark were extracted from the Danish National Prescription Database. We used prescription data for all children in Denmark aged 0 to 11 years from January 1, 2000 to December 31, 2012., Results: We obtained data on 5,884,301 prescriptions for systemic antibiotics issued to 1,206,107 children. The most used single substances were phenoxymethylpenicillin (45%), amoxicillin (34%) and erythromycin (6%). The highest incidence rate of antibiotic treatment episodes was observed among children younger than 2 at 827 per 1000 children in 2012. Incidence rates were relatively stable throughout the study period. One-year prevalences in 2012 were 485, 363 and 190 per 1000 children among children aged 0-1, 2-4 and 5-11, respectively. A gradual shift from narrow-spectrum penicillin V to the broader-spectrum amoxicillin was found among children younger than 5. The use of macrolides decreased slightly, especially among those aged 0-1. Minor regional differences were noted, with somewhat higher use in the Capital Region. Skewness in use was most notable among those aged 0-1. There was little evidence of heavy users., Conclusion: Prescribing rate of antibiotics to children in Denmark remained stable at a high level from 2000 to 2012. An increase in the use of broad-spectrum beta-lactam penicillin was noted, but otherwise the prescribing pattern adhered well to National guidelines with respect to choice of antibiotics.

Background: Variation in prescription of antibiotics in primary care can indicate poor clinical practice that contributes to the increase of resistant strains. General Practitioners (GPs), as a professional group, are expected to have a fairly homogeneous prescribing style. In this paper, we describe variation in prescribing style within and across groups of GPs from six countries., Methods: Cross-sectional study with the inclusion of 457 GPs and 6394 sore throat patients. We describe variation in prescribing antibiotics for sore throat patients across six countries and assess whether variation in "prescribing style"--understood as a subjective tendency to prescribe--has an important effect on variation in prescription of antibiotics by using the concept of prescribing style as a latent variable in a multivariable model. We report variation as a Median Odds Ratio (MOR) which is the transformation of the random effect variance onto an odds ratio; Thus, MOR = 1 means similar odds or strict homogeneity between GPs' prescribing style, while a MOR higher than 1 denotes heterogeneity in prescribing style., Results: In all countries some GPs always prescribed antibiotics to all their patients, while other GPs never did. After adjusting for patient and GP characteristics, prescribing style in the group of GPs from Russia was about three times more heterogeneous than the prescribing style in the group of GPs from Denmark--Median Odds Ratio (6.8, 95% CI 3.1;8.8) and (2.6, 95% CI 2.2;4.4) respectively., Conclusion: Prescribing style is an important source of variation in prescription of antibiotics within and across countries, even after adjusting for patient and GP characteristics. Interventions aimed at influencing the prescribing style of GPs must encompass context-specific actions at the policy-making level alongside GP-targeted interventions to enable GPs to react more objectively to the external demands that are in place when making the decision of prescribing antibiotics or not.

Background Acute respiratory infections (ARIs) are by far the most common reason for prescribing an antibiotic in primary care, even though the majority of ARIs are of viral or non-severe bacterial aetiology. Unnecessary antibiotic use will, in many cases, not be beneficial to the patients' recovery and expose them to potential side effects. Furthermore, as a causal link exists between antibiotic use and antibiotic resistance, reducing unnecessary antibiotic use is a key factor in controlling this important problem. Antibiotic resistance puts increasing burdens on healthcare services and renders patients at risk of future ineffective treatments, in turn increasing morbidity and mortality from infectious diseases. One strategy aiming to reduce antibiotic use in primary care is the guidance of antibiotic treatment by use of a point-of-care biomarker. A point-of-care biomarker of infection forms part of the acute phase response to acute tissue injury regardless of the aetiology (infection, trauma and inflammation) and may in the correct clinical context be used as a surrogate marker of infection,possibly assisting the doctor in the clinical management of ARIs.Objectives To assess the benefits and harms of point-of-care biomarker tests of infection to guide antibiotic treatment in patients presenting with symptoms of acute respiratory infections in primary care settings regardless of age.Search methods We searched CENTRAL (2013, Issue 12), MEDLINE (1946 to January 2014), EMBASE (2010 to January 2014), CINAHL (1981 to January 2014), Web of Science (1955 to January 2014) and LILACS (1982 to January 2014).Selection criteria We included randomised controlled trials (RCTs) in primary care patients with ARIs that compared use of point-of-care biomarkers with standard of care. We included trials that randomised individual patients as well as trials that randomised clusters of patients(cluster-RCTs).Two review authors independently extracted data on the following outcomes: i) impact on antibiotic use; ii) duration of and recovery from infection; iii) complications including the number of re-consultations, hospitalisations and mortality; iv) patient satisfaction. We assessed the risk of bias of all included trials and applied GRADE. We used random-effects meta-analyses when feasible. We further analysed results with a high level of heterogeneity in pre-specified subgroups of individually and cluster-RCTs.Main results The only point-of-care biomarker of infection currently available to primary care identified in this review was C-reactive protein. We included six trials (3284 participants; 139 children) that evaluated a C-reactive protein point-of-care test. The available information was from trials with a low to moderate risk of bias that address the main objectives of this review.Overall a reduction in the use of antibiotic treatments was found in the C-reactive protein group (631/1685) versus standard of care(785/1599). However, the high level of heterogeneity and the statistically significant test for subgroup differences between the three RCTs and three cluster-RCTs suggest that the results of the meta-analysis on antibiotic use should be interpreted with caution and the pooled effect estimate (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.66 to 0.92; I2 statistic = 68%) may not be meaningful.The observed heterogeneity disappeared in our pre planned subgroup analysis based on study design: RR 0.90, 95% CI 0.80 to 1.02; I2 statistic = 5% for RCTs and RR 0.68, 95% CI 0.61 to 0.75; I2 statistic = 0% for cluster-RCTs, suggesting that this was the cause of the observed heterogeneity.There was no difference between using a C-reactive protein point-of-care test and standard care in clinical recovery (defined as at least substantial improvement at day 7 and 28 or need for re-consultations day 28). However, we noted an increase in hospitalisations in the C-reactive protein group in one study, but this was based on few events and may be a chance finding. No deaths were reported in any of the included studies.We classified the quality of the evidence as moderate according to GRADE due to imprecision of the main effect estimate.Authors' conclusions A point-of-care biomarker (e.g. C-reactive protein) to guide antibiotic treatment of ARIs in primary care can reduce antibiotic use,although the degree of reduction remains uncertain. Used as an adjunct to a doctor's clinical examination this reduction in antibiotic use did not affect patient-reported outcomes, including recovery from and duration of illness.However, a possible increase in hospitalisations is of concern. A more precise effect estimate is needed to assess the costs of the intervention and compare the use of a point-of-care biomarker to other antibiotic-saving strategies.

Objective: Patient-reported outcomes are seldom validated measures in clinical trials of acute respiratory tract infections (ARTIs) in primary care. We developed and validated a patient-reported outcome sum-scaling measure to assess the severity and functional impacts of ARTIs., Methods: Qualitative interviews and field testing among adults with an ARTI were conducted to ascertain a high degree of face and content validity of the questionnaire. Subsequently, a draft version of the Acute Respiratory Tract Infection Questionnaire (ARTIQ) was statistically validated by using the partial credit Rasch model to test dimensionality, objectivity, and reliability of items. Test of known groups' validity was conducted by comparing participants with and without an ARTI., Results: The final version of the ARTIQ consisted of 38 items covering five dimensions (Physical-upper, Physical-lower, Psychological, Sleep, and Medicine) and five single items. All final dimensions were confirmed to fit the Rasch model, thus enabling sum-scaling of responses. The ARTIQ scores in participants with an ARTI were significantly higher than in those without ARTI (known groups' validity)., Conclusion: A self-administered, multidimensional, sum-scaling questionnaire with high face and content validity and adequate psychometric properties for assessing severity and functional impacts from ARTIs in adults is available to clinical trials and audits in primary care., (Copyright © 2013, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc.)

Health-care workers may experience uncertainty regarding legal matters when attending to medical needs of undocumented migrants. This paper applies a pragmatic focus when addressing the legal aspects involved in providing health-care services to undocumented migrants with examples from the Danish Health Act and international conventions. The delivery of medical care to vulnerable groups such as pregnant women and children is described.

Bacterial pneumonia has hitherto been considered the key cause of the high respiratory morbidity and mortality in children under five years of age (under-5s) in low-income countries, while asthma has not been stated as a significant reason. This paper explores the definitions and concepts of pneumonia and asthma/wheezing/bronchiolitis and examines whether asthma in under-5s may be confused with pneumonia. Over-diagnosing of bacterial pneumonia can be suspected from the limited association between clinical pneumonia and confirmatory test results such as chest x-ray and microbiological findings and poor treatment results using antibiotics. Moreover, children diagnosed with recurrent pneumonia in infancy were often later diagnosed with asthma. Recent studies showed a 10-15% prevalence of preschool asthma in low-income countries, although under-5s with long-term cough and difficulty breathing remain undiagnosed. New studies demonstrate that approximately 50% of acutely admitted under-5s diagnosed with pneumonia according to Integrated Management of Childhood Illnesses could be re-diagnosed with asthma or wheezing when using re-defined diagnostic criteria and treatment. It is hypothesised that untreated asthma may contribute to respiratory mortality since respiratory syncytial virus (RSV) is an important cause of respiratory death in childhood, and asthma in under-5s is often exacerbated by viral infections, including RSV. Furthermore, acute respiratory treatment failures were predominantly seen in under-5s without fever, which suggests the diagnosis of asthma/wheezing rather than bacterial pneumonia. Ultimately, underlying asthma may have contributed to malnutrition and fatal bacterial pneumonia. In conclusion, preschool asthma in low-income countries may be significantly under-diagnosed and misdiagnosed as pneumonia, and may be the cause of much morbidity and mortality.

Clinical signs of infection do not allow for correct identification of bacterial and viral aetiology in acute respiratory infections. A valid tool to assist the clinician in identifying patients who will benefit from antibiotic therapy, as well as patients with a potentially serious infection, could greatly improve patient care and limit excessive antibiotic prescriptions. Procalcitonin is a new marker of suspected bacterial infection that has shown promise in guiding antibiotic therapy in acute respiratory tract infections in hospitals without compromising patient safety. Procalcitonin concentrations in primary care are low and can be used primarily to rule out serious infection. However, procalcitonin measurement should not be used as the sole basis for clinical decisions; clinical skills are prerequisites for the correct use of this new tool in practice. At present there is no point-of-care test for procalcitonin with acceptable precision, severely hampering its application in primary care. This article reviews the physiology of procalcitonin, describes the assays available for its measurement, evaluates the present evidence from primary care on its use to identify correctly patients who are likely to benefit from antibiotic treatment and to rule out serious infections, and comments on further research to determine a future role for procalcitonin in primary care.

Enterococcus species are common in nosocomial bloodstream infections and their incidence is rising. Although well recognized in several serious bacterial infections, the influence of appropriate antimicrobial therapy in enterococcal bacteraemia has not been fully settled. The aim of the study was to determine whether administration of inappropriate antibiotics in enterococcal bacteraemia is an independent risk factor for mortality, among other known and suspected risk factors. We conducted a cohort study of E. faecalis/faecium bacteraemia during a 3-year period at a single tertiary care hospital in Denmark. Patients with growth of non-enterococcus co-pathogens apart from the enterococcal bacteraemia were also included, as were patients with repeated enterococcal bacteraemia. Time to appropriate antimicrobial therapy was counted from the first episode. Appropriate antibiotic therapy was defined as any therapy with documented clinical effect, in vitro activity and a minimum treatment length of 6 days. Multivariate regression models were built to determine the independent risk factors for mortality. We included 196 patients with enterococcal bacteraemia. Appropriate antibiotics for at least 6 days were administered in 146 of these (74%). Thirty-day mortality was 26%. Multivariate logistic regression identified independent predictors of 30-day all-cause mortality: appropriate antimicrobial therapy for ≥ 6 days (odds ratio for mortality 0.33, 0.14-0.79), ICU admission (4.2, 1.7-10), thrombocytopenia (3.9, 1.6-9.3), chronic liver failure (3.3, 1.1-10) and age ≥ 60 years (2.2, 0.99-5.0). Antibiotics not appropriately covering enterococci are frequently administered empirically in suspected bloodstream infections. Inappropriate antibiotic therapy was an independent risk factor for mortality in enterococcal bacteraemia., (© 2010 The Authors. Clinical Microbiology and Infection © 2010 European Society of Clinical Microbiology and Infectious Diseases.)

Aim: To infect mice with atypical Campylobacter concisus (C. concisus) for the first time., Methods: Three separate experiments were conducted in order to screen the ability of five clinical C. concisus isolates of intestinal origin and the ATCC 33237 type strain of oral origin to colonize and produce infection in immunocompetent BALB/cA mice. The majority of the BALB/cA mice were treated with cyclophosphamide prior to C. concisus inoculation to suppress immune functions. Inoculation of C. concisus was performed by the gastric route., Results: C. concisus was isolated from the liver, ileum and jejunum of cyclophosphamide-treated mice in the first experiment. No C. concisus strains were isolated in the two subsequent experiments. Mice infected with C. concisus showed a significant loss of body weight from day two through to day five of infection but this decreased at the end of the first week. Histopathological examination did not consistently find signs of inflammation in the gut, but occasionally microabscesses were found in the liver of infected animals., Conclusion: Transient colonization with C. concisus was observed in mice with loss of body weight. Future studies should concentrate on the first few days after inoculation and in other strains of mice.

Campylobacter concisus has been as frequently isolated from human diarrhea as the important enteropathogen Campylobacter jejuni, but it also occurs in the feces of healthy individuals. The role of C. concisus in human disease has been difficult to determine, since the species comprises at least two phenotypically indistinguishable but genetically distinct taxa (i.e., genomospecies) that may vary in pathogenicity. We examined 62 C. concisus strains by amplified fragment length polymorphism (AFLP) profiling and correlated the results with clinical data. All C. concisus strains gave unique AFLP profiles, and numerical analysis of these data distributed the strains among four clusters. The clustering was of taxonomic significance: two clusters contained, respectively, the type strain (of oral origin) and a reference strain (from diarrhea) of each of the known genomospecies. Genomospecies 2 strains were more frequently isolated from immunocompetent patients and/or patients without concomitant infections that presented with fever, chronic diarrhea, and gut inflammation than was genomospecies 1, clustering with the type strain of oral origin. Bloody diarrhea was recorded only with C. concisus genomospecies 2 infections. We identified two additional C. concisus genomospecies: genomospecies 3 comprised a single strain from an immunocompetent patient, and genomospecies 4 contained five isolates from severely immunodeficient patients, i.e., organ transplantation recipients or those with hematological malignancies. All genomospecies 4 strains were of the same protein profile group and failed to react with a C. concisus species-specific PCR assay based on 23S rRNA gene sequences: the taxonomic position of this group requires closer investigation. Campylobacter concisus is genetically and taxonomically diverse and contains at least four distinct genomospecies that may exhibit differences in their spectra of virulence potential.

Objective: To characterize and subgroup clinical strains of Campylobacter concisus isolated from patients with gastrointestinal disease., Methods: A total of 109 C. concisus isolates from 98 patients obtained between June 1997 and December 1998 were analysed using protein profiles, conventional biochemical tube tests, ApiCampy, and susceptibility patterns by Neosensitabs and E-test., Results: Two groups were identified by using protein profiles. One resembled the ATCC 33237 type strain of oral origin, and a second group differing from it, particularly in the high molecular weight zone. Considerable diversity exists in the lower molecular range of the gels, also within assigned subgroups. Biochemical testing showed differences between the groups in the ability to reduce nitrate, ApiCampy testing also yielded differences between the two assigned groups, although reactions were highly heterogeneous. Resistance to erythromycin, ciprofloxacin, ampicillin, ceftriaxone and tetracycline occurred in 3%, 13%, 7%, 11% and 0% of the isolates when using Neosensitabs. The E-test yielded comparable results 7%, 5%, 0%, 2% and 3%, respectively., Conclusion: Results indicate that C. concisus can be assigned to two broad groups based on differences in protein profiles. No distinct phenotypic marker was identified. Susceptibility patterns are not suitable for discrimination between the two assigned groups. Further studies using a polyphasic approach including the application of genetic methods are needed to assess the complex taxonomy of this potential pathogen.

The clinical relevance of Campylobacter concisus in gastrointestinal disease has not been determined definitively. This study investigated the phenotypic and genotypic characteristics of 39 C. concisus isolates from Danish patients with diarrhoea, three isolates from healthy individuals and the type strain. A cytolethal distending toxin (CDT)-like effect on Vero cells was observed in 35 (90%) isolates from patients with diarrhoea, in all three isolates from healthy individuals and in the type strain. Analysis of SDS-PAGE protein profiles and PCR amplification of 23S rDNA assigned the isolates into two distinct, but discordant groups. Automated ribotyping (RiboPrinting) identified 34 distinct patterns among the 43 isolates, but cluster analysis did not separate isolates from patients with diarrhoea from isolates from healthy patients. Random amplified polymorphic DNA (RAPD) analysis with three primers identified 37 unique profiles, but requires further evaluation. The isolates obtained from healthy carriers were distinguished by cluster analysis from the isolates obtained from patients with diarrhoea. All the isolates were susceptible to 11 antimicrobial agents tested. Overall, there was considerable variability between the C. concisus isolates, but there were no clear phenotypic or genotypic differences between isolates from patients with diarrhoea and isolates from healthy carriers. Further evidence is needed to support the possible role of C. concisus as a human enteric pathogen.

A total of 44 clinical isolates and the type strain of the putative pathogen Campylobacter concisus were grouped based on their reactions with plant lectins. The optimized lectin typing system used C. concisus strains proteolytically pretreated and subsequently typed by using a panel of four lectins. The system grouped all 45 strains into 13 lectin reaction patterns, leaving no strain untypeable due to autoagglutination. Lectin types were both stable and reproducible.

The importance of Campylobacter species other than C. jejuni/coli in diarrhoeal disease is largely unknown. We wished to determine the prevalence and clinical presentation of C. concisus infection in patients with enteric disease in a tertiary hospital. Stool specimens were routinely tested for the presence of Campylobacter species, by use of the filter isolation method. The medical records of the C. concisus-positive patients were reviewed. Of 224 Campylobacter isolates obtained, 110 were identified as C. concisus. Concomitant infection occurred in only 27% of cases. By means of protein profiling we assigned C. concisus into 2 groups. The predominant C. concisus group 2 was the only strain to infect immunocompetent patients and children: 71% of the infected patients were immunocompromised, the majority being adults (84%). C. concisus may be a frequent cause of diarrhoea in immunocompromised patients. Two groups of C. concisus were found and these groups possibly vary in their pathogenic potential.