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.

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.

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.

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.

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.

Prescription of antibiotics for urinary tract infection in general practice in Denmark.

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 1st 2012 and June 31st 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.

Identifying practice-related factors for high-volume prescribers of antibiotics in Danish general practice.

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.

Clinical indications for antibiotic use in Danish general practice: results from a nationwide electronic prescription database.

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.

Antibiotic prescribing in Danish general practice 2004-13.

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.

Urine sampling techniques in symptomatic primary-care patients: a diagnostic accuracy review.

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.

Prescribing style and variation in antibiotic prescriptions for sore throat: cross-sectional study across six countries.

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.

Biomarkers as point-of-care tests to guide prescription of antibiotics in patients 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. 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.

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.

The development and validation of a multidimensional sum-scaling questionnaire to measure patient-reported outcomes in acute respiratory tract infections in primary care: the acute respiratory tract infection questionnaire.

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.

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.

Childhood asthma in low income countries: an invisible killer?

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.