Use of antibiotics for urinary tract infections up to and after care home admission in Denmark: a nationwide study.

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.

The Feasibility of C-Reactive Protein Point-of-Care Testing to Reduce Overuse of Antibiotics in Children with Acute Respiratory Tract Infections in Rural Kyrgyzstan: A Pilot Study.

Background: In Kyrgyzstan, the morbidity prevalence of and morbidity from acute respiratory tract infections (ARTI) in children is high. Local healthcare workers (HCW) often prescribe antibiotics that are not indicative due to a mix of professional and societal factors. It is suggested to precede with a decision on antibiotics by a point-of-care test (POCT) on the appropriateness of the treatment, eg, a measurement of C-reactive protein (CRP). CRP-guided antibiotic stewardship in children with ARTI has not previously been studied in Central Asia. Purpose: This pilot study was conducted to examine the feasibility of the methods and procedures to be used in the upcoming randomised controlled COORDINATE clinical trial (NCT05195866) and in daily clinical practice in primary care. Patients and methods: HCWs from three selected rural healthcare facilities were trained in the CRP POCT and in interpretation of results. Children aged 6 months to 12 years attending the primary healthcare facilities with respiratory symptoms were randomly assigned to CRP-guided management or standard care, guided by clinical findings only. Children were followed up for 14 days by scheduled telephone calls to caregivers. Results: Eighty-one children participated in this pilot study. The CRP POCT and the trial procedures were acceptable to the target group as well as to the HCWs. Children from both groups recovered equally well, with an observed significant lower use of antibiotics in the CRP group. HCWs generally adhered to the CRP guidelines, and only once was an antibiotic prescribed despite low CRP results. No safety concerns were observed. Four parents provided wrong phone numbers impeding follow-up. We will collect all mobile phone numbers in the household for the main trial. Conclusion: The pilot provided satisfactory results, suggesting that the COORDINATE trial of CRP POCT is effective, feasible with minor adjustments and without apparent safety concerns for the participants.

C reactive protein-guided prescription of antibiotics for children under 12 years with respiratory symptoms in Kyrgyzstan: protocol for a randomised controlled clinical trial with 14 days follow-up.

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.

Disease-Specific Quality Indicators for Outpatient Antibiotic Prescribing for Respiratory Infections (ESAC Quality Indicators) Applied to Point Prevalence Audit Surveys in General Practices in 13 European Countries.

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.

Cost-effectiveness of adding oseltamivir to primary care for influenza-like-illness: economic evaluation alongside the randomised controlled ALIC4E trial in 15 European countries.

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.

Biomarkers as point-of-care tests to guide prescription of antibiotics in people with acute respiratory infections in primary care.

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.

Sociodemographic characterisation of antibiotic heavy users in the Danish elderly population.

AIMS: The development of effective interventions to reduce inappropriate use of antibiotics in the elderly population requires knowledge on who can benefit from such interventions. Thus, we aimed to identify and characterise antibiotic heavy users among elderly patients in general practice with respect to sociodemographic variables. METHODS: We conducted a retrospective nationwide register-based study on all Danish elderly citizens (⩾65 years) who redeemed an antibiotic prescription in 2017. Heavy users were defined as the 10% with the highest excess use, that is, their recorded use minus the average use for their sex, age group and comorbidity level as estimated from a linear regression model. Comparative analyses of sociodemographic characteristics (civil status, employment status, urbanity, educational level and country of origin) of heavy users and non-heavy users were performed using logistic regression models. RESULTS: The study population consisted of 251,733 elderly individuals, who in total redeemed 573,265 prescriptions of antibiotics. Heavy users accounted for 68% of all excess use of antibiotics. In multivariable analyses, individuals with an educational level above basic schooling, non-retired, residing in an urban municipality and being born in a country outside Scandinavia all had lower odds of being a heavy user. Widowed, divorced or single individuals had higher odds of being a heavy user compared with married individuals. Relative importance analyses showed that civil status and educational level contributed considerably to the explained variance. CONCLUSIONS: This study found an association between sociodemographic characteristics and risk of being a heavy user, indicating that sociodemographic variation exists with regard to antibiotic prescribing.

The Procalcitonin-guided Antibiotics in Respiratory Infections (PARI) project in general practice - a study protocol.

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.

Factors associated with C-reactive protein testing when prescribing antibiotics in general practice: a register-based study.

BACKGROUND: The use of C-reactive protein (CRP) tests has been shown to safely reduce antibiotic prescribing for acute respiratory tract infections (RTIs). The aim of this study was to explore patient and clinical factors associated with the use of CRP testing when prescribing antibiotics recommended for RTIs. METHODS: A nation-wide retrospective cross-sectional register-based study based on first redeemed antibiotic prescriptions issued to adults in Danish general practice between July 2015 and June 2017. Only antibiotics recommended for treatment of RTIs were included in the analysis (penicillin-V, amoxicillin, co-amoxicillin or roxithromycin/clarithromycin). Logistic regression models were used to estimate odds ratios for patient-related and clinical factors on performing a CRP test in relation to antibiotic prescribing. RESULTS: A total of 984,149 patients redeemed at least one antibiotic prescription during the two-year period. About half of these prescriptions (49.6%) had an RTI stated as the indication, and a CRP test was performed in relation to 45.2% of these scripts. Lower odds of having a CRP test performed in relation to an antibiotic prescription was found for patients aged 75 years and above (OR 0.82, 95CI 0.79-0.86), with a Charlson Comorbidity Index of more than one (OR 0.93, 95CI 0.91-0.95), unemployed or on disability pension (OR 0.84, 95CI 0.83-0.85) and immigrants (OR 0.91, 95CI 0.88-0.95) or descendants of immigrants (OR 0.90, 95CI 0.84-0.96). Living with a partner (OR 1.08, 95CI 1.07-1.10), being followed in practice for a chronic condition (OR 1.22, 95CI 1.18-1.26) and having CRP tests performed in the previous year (OR 1.78, 95CI 1.73-1.84) were associated with higher odds of CRP testing in relation to antibiotic prescribing. CONCLUSIONS: Differences were observed in the use of CRP tests among subgroups of patients indicating that both sociodemographic factors and comorbidity influence the decision to use a CRP test in relation to antibiotic prescriptions in general practice. Potentially, this means that the use of CRP tests could be optimised to increase diagnostic certainty and further promote rational prescribing of antibiotics. The rationale behind the observed differences could be further explored in future qualitative studies.

Clinical presentation, microbiological aetiology and disease course in patients with flu-like illness: a post hoc analysis of randomised controlled trial data.

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.

Clinical prediction of laboratory-confirmed influenza in adults with influenza-like illness in primary care. A randomized controlled trial secondary analysis in 15 European countries.

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.

Influenza is usually diagnosed clinically. However, the accuracy of a diagnosis of influenza based on clinical features is limited because symptoms overlap considerably with those caused by other microorganisms. This study examined whether identification of the severity rather than the presence of key signs and symptoms could aid in the diagnosis of influenza, thereby helping clinicians to determine when antiviral agent use is appropriate. The authors used the database of a previous randomized clinical trial on the effectiveness of an antiviral carried out in primary care centers in 15 countries in Europe during three epidemic periods from 2015/2016 to 2017/2018. Participants with influenza symptoms were included and they were asked about the presence and severity of different symptoms during the baseline visit with their doctors and a nasopharyngeal swab was taken for microbiological analysis. Overall, only 51% of the patients aged 18 or older had a confirmed influenza infection. Clinical findings are not particularly useful for confirming or excluding the diagnosis of influenza. However, the results of our study recommend considering how intense the different symptoms are, since key symptoms rated as moderate or severe are slightly better for predicting flu rather than the presence or absence of these symptoms.

Point-of-care testing, antibiotic prescribing, and prescribing confidence for respiratory tract infections in primary care: a prospective audit in 18 European countries.

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.

Prescribing antibiotics: the use of diagnostic tests in general practice. A register-based study.

OBJECTIVE: To assess (i) the pattern of antibiotic prescribing in Danish general practice, (ii) the use of diagnostic tests [point-of-care (POC) and tests analysed at the hospital laboratory (laboratory tests)], and (iii) the frequency of diagnostic testing in relation to antibiotic prescriptions. DESIGN: Retrospective cross-sectional register-based study. SETTING: General practice in a geographical area of Denmark covering 455,956 inhabitants. SUBJECTS: We studied redeemed antibiotic prescriptions and performed diagnostic tests in general practice from 2013 to 2017 among inhabitants in nine selected municipalities. MAIN OUTCOME MEASURES: Frequency of antibiotic courses. Frequency and type of diagnostic testing performed in relation to types of antibiotics. RESULTS: A total of 783,252 antibiotic courses were redeemed from general practice with an overall decrease of 19% during 2013-2017. Diagnostic testing increased by 6% during this period. POC tests comprised the majority of performed diagnostic tests (83%) with C-reactive protein (CRP) as the most frequently used test. A 27% increase in the use of laboratory tests was observed. Tests were performed in relation to 43% of all antibiotic courses; most in relation to prescriptions for sulphonamide and trimethoprim (57%) and rarely when prescribing tetracyclines (10%). Conflicting with national guidelines, Danish GPs prescribed fluoroquinolones without performing any kind of diagnostic testing in 48% of the cases. CONCLUSIONS: This study provides an overview of the use of diagnostic tests in relation to antibiotics and creates basis for further research into the variability between types of antibiotics. The study indicates that there is room for improvement to use diagnostic tests as an aid to promote prudent antibiotic use.KEY POINTSDiagnostic tests (point-of-care or tests analysed at the hospital laboratory), can increase diagnostic certainty and lead to a reduction in antibiotic use in general practice.A decrease in antibiotic courses in general practice in Denmark was observed during 2013-2017, while the use of diagnostic tests increased.A diagnostic test was performed in relation to 43% of antibiotic courses.Only 52% of prescribed fluoroquinolones was related to a diagnostic test, conflicting with national guidelines.

Antibiotic prescribing in Danish general practice in the elderly population from 2010 to 2017.

OBJECTIVE: This study aimed to describe prescription of antibiotics to the elderly population in general practice in Denmark from 2010-2017. DESIGN: This is a national register-based observational study. SETTING: General practice, Denmark. MAIN OUTCOME MEASURE: The main outcome measure was prescriptions/1,000 inhabitants/day (PrID) in relation to year, age and sex, indication, and antibiotic agent. SUBJECTS: In this study, we included inhabitants of Denmark, ≥65 years of age between 01st July 2010-30th June 2017. RESULTS: A total of 5,168,878 prescriptions were included in the study. Antibiotic prescriptions decreased from 2.2 PrID to 1.7 (-26.9%, CI95% [-31.1;-22.4]) PrID during the study. The decrease in PrID was most noticeable among 65-74-year-olds (-25%). The ≥85-year-olds were exposed to twice as many PrID than the 65-74-year-olds, but only accounted for 20% of the total use. Urinary tract infection (UTI) was the most common indication for antibiotic prescription and increased with advancing age. The most commonly prescribed antibiotics were pivmecillinam and phenoxymethylpenicillin. Prescribing with no informative indication was present in one third of all cases. CONCLUSION: The prescription of antibiotics in the elderly population in general practice decreased from 2010 to 2017. The oldest age group was exposed twice as frequently to antibiotic prescriptions as the 65-74-year-olds. The smallest reduction was observed for the ≥85-year-olds, suggesting targeting interventions at this group.Key PointsHigh antibiotic use among elderly is well known and studies indicate mis- and overuse within this population. Our study shows.The prescription rate is decreasing within all age groups of the elderly population.The ≥85-year-olds receive twice as many prescriptions/1000/day as the 65-74-years-olds.

Management of symptomatic patients with suspected mild-moderate COVID-19 in general practice. What was published within the first year of the pandemic? A scoping review.

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.

Direct and Indirect Costs of Influenza-Like Illness Treated with and Without Oseltamivir in 15 European Countries: A Descriptive Analysis Alongside the Randomised Controlled ALIC4E Trial.

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.

Primary care for patients with respiratory tract infection before and early on in the COVID-19 pandemic: an observational study in 16 European countries.

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.

Antimycotic Treatment of Oral Candidiasis in Warfarin Users.

PURPOSE: Azole antimycotics and nystatin oral solution are used to treat oral candidiasis. Azoles inhibit cytochrome (CYP) P450-dependent metabolism of warfarin, which could increase the anticoagulant effect of warfarin. Nystatin is not expected to interfere with warfarin metabolism, but current data are conflicting. With this study, we aimed to explore the potential drug-drug interactions between warfarin and azole antimycotics used in the treatment of oral candidiasis, that is, systemic fluconazole, miconazole oral gel, and nystatin oral solution. METHODS: By linking clinical data on international normalized ratio (INR) measurements with administrative data on filled prescriptions of warfarin and antimycotics during 2000-2015, we explored INR changes in warfarin users relative to initiation of systemic fluconazole (n = 413), miconazole oral gel (n = 330), and nystatin oral solution (n = 399). RESULTS: We found a significant increase in mean INR of 0.83 (95% confidence interval [CI] 0.61-1.04) and 1.27 (95% CI 0.94-1.59) following initiation of systemic fluconazole and miconazole oral gel, respectively. Also, the proportion of patients experiencing an INR-value above 5 was increased after initiation of fluconazole (from 4.3% to 15.3%) and miconazole (from 5.5% to 30.1%). INR was unaffected by initiation of nystatin oral solution (mean change 0.08; 95% CI -0.10 to 0.25). CONCLUSION: Initiation of systemic fluconazole and miconazole oral gel was associated with increased INR in warfarin users. A similar association was not found for nystatin oral solution, which thus appears to be the safest alternative when treating oral candidiasis in warfarin users.

Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial.

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.

Changes in HbA1c during the first six years after the diagnosis of Type 2 diabetes mellitus predict long-term microvascular outcomes.

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.