Clinicians' interpretations of point of care urine culture versus laboratory culture results: analysis from the four-country POETIC trial of diagnosis of uncomplicated urinary tract infection in primary care.

Background: Urine culture at the point of care minimises delay between obtaining the sample and agar inoculation in a microbiology laboratory, and quantification and sensitivity results can be available more rapidly in primary care. Objective: To identify the degree to which clinicians' interpretations of a point-of-care-test (POCT) urine culture (Flexicult™ SSI-Urinary Kit) agrees with laboratory culture in women presenting to primary care with symptoms of uncomplicated urinary tract infections (UTI). Methods: Primary care clinicians used the Flexicult™-POCT, recorded their findings and took a photograph of the result, which was interpreted by microbiology laboratory technicians. Urine samples were additionally processed in routine care laboratories. Cross tabulations were used to identify important differences in organism identification, quantification and antibiotic susceptibility between these three sources of data. The influence of various laboratory definitions for UTI on culture were assessed. Results: Primary care clinicians identified 202/289 urine samples (69.9%) as positive for UTI using the Flexicult™-POCT, whereas laboratory culture identified 94-190 (32.5-65.7%) as positive, depending on definition thresholds. 82.9% of samples identified positive for E. coli on laboratory culture were also considered positive for E. coli using the Flexicult™ -POCT, and susceptibilities were reasonably concordant. There were major discrepancies between laboratory staff interpretation of Flexicult™ photographs, clinicians' interpretation of the Flexicult™ test, and laboratory culture results. Conclusion: Flexicult™-POCT overestimated the positivity rate of urine samples for UTI when laboratory culture was used as the reference standard. However, it is unclear whether point-of-care or laboratory based urine culture provides the most valid diagnostic information.

Building an international network for a primary care research program: reflections on challenges and solutions in the set-up and delivery of a prospective observational study of acute cough in 13 European countries.

BACKGROUND: Implementing a primary care clinical research study in several countries can make it possible to recruit sufficient patients in a short period of time that allows important clinical questions to be answered. Large multi-country studies in primary care are unusual and are typically associated with challenges requiring innovative solutions. We conducted a multi-country study and through this paper, we share reflections on the challenges we faced and some of the solutions we developed with a special focus on the study set up, structure and development of Primary Care Networks (PCNs). METHOD: GRACE-01 was a multi-European country, investigator-driven prospective observational study implemented by 14 Primary Care Networks (PCNs) within 13 European Countries. General Practitioners (GPs) recruited consecutive patients with an acute cough. GPs completed a case report form (CRF) and the patient completed a daily symptom diary. After study completion, the coordinating team discussed the phases of the study and identified challenges and solutions that they considered might be interesting and helpful to researchers setting up a comparable study. RESULTS: The main challenges fell within three domains as follows:i) selecting, setting up and maintaining PCNs;ii) designing local context-appropriate data collection tools and efficient data management systems; andiii) gaining commitment and trust from all involved and maintaining enthusiasm.The main solutions for each domain were:i) appointing key individuals (National Network Facilitator and Coordinator) with clearly defined tasks, involving PCNs early in the development of study materials and procedures.ii) rigorous back translations of all study materials and the use of information systems to closely monitor each PCNs progress;iii) providing strong central leadership with high level commitment to the value of the study, frequent multi-method communication, establishing a coherent ethos, celebrating achievements, incorporating social events and prizes within meetings, and providing a framework for exploitation of local data. CONCLUSIONS: Many challenges associated with multi-country primary care research can be overcome by engendering strong, effective communication, commitment and involvement of all local researchers. The practical solutions identified and the lessons learned in implementing the GRACE-01 study may assist in establishing other international primary care clinical research platforms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00353951.

Challenges in managing urinary tract infection and the potential of a point-of-care test guided care in primary care: an international qualitative study.

BACKGROUND: Little is known about clinicians' experiences of using a point-of-care test (POCT) to inform management of urinary tract infection (UTI) in general practice. AIM: To explore experiences of using the Flexicult test to inform management of UTI and views on requirements for an optimal POCT to inform successful implementation. DESIGN & SETTING: Telephone interviews with 35 primary care clinicians and healthcare professionals in Wales, England, Spain, and the Netherlands, who had participated in a trial of the Flexicult POCT for UTI based on urine culture. METHOD: Thematic analysis of semi-structured interviews. RESULTS: Most primary care clinicians interviewed agreed on the need for a POCT in UTI management, and that the Flexicult POCT delivered quicker results than laboratory results used in usual care, reassured patients, boosted their confidence in decision-making, and reminded them about antibiotic stewardship. However, clinicians also reported difficulties in interpreting results, limitations on when the Flexicult could be used, and concerns that testing all patients would strain care delivery and prolong patient discomfort when delaying decisions until a non-rapid POCT result was available. An optimal POCT would produce more rapid results, and be reliable and easy to use. Uptake into routine care would be enhanced by: clear guidance on which patients should be tested; training for interpreting 'grey area' results; reiterating that even 'straightforward' cases might be better managed with a test; clear messages about stopping unnecessary antibiotics versus completing a course; and better self-management strategies to accompany implementation of delayed, or non-prescription of, antibiotics. CONCLUSION: Primary care clinicians believe that POCT tests could play a useful role in the management of UTI and gave clear recommendations for successful implementation.

Point-of-care urine culture for managing urinary tract infection in primary care: a randomised controlled trial of clinical and cost-effectiveness.

BACKGROUND: The effectiveness of using point-of-care (POC) urine culture in primary care on appropriate antibiotic use is unknown. AIM: To assess whether use of the Flexicult™ SSI-Urinary Kit, which quantifies bacterial growth and determines antibiotic susceptibility at the point of care, achieves antibiotic use that is more often concordant with laboratory culture results, when compared with standard care. DESIGN AND SETTING: Individually randomised trial of females with uncomplicated urinary tract infection (UTI) in primary care research networks (PCRNs) in England, the Netherlands, Spain, and Wales. METHOD: Multilevel regression compared outcomes between the two groups while controlling for clustering. RESULTS: In total, 329 participants were randomised to POC testing (POCT) and 325 to standard care, and 324 and 319 analysed. Fewer females randomised to the POCT arm than those who received standard care were prescribed antibiotics at the initial consultation (267/324 [82.4%] versus 282/319 [88.4%], odds ratio [OR] 0.56, 95% confidence interval [CI] = 0.35 to 0.88). Clinicians indicated the POCT result changed their management for 190/301 (63.1%). Despite this, there was no statistically significant difference between study arms in antibiotic use that was concordant with laboratory culture results (primary outcome) at day 3 (39.3% POCT versus 44.1% standard care, OR 0.84, 95% CI = 0.58 to 1.20), and there was no evidence of any differences in recovery, patient enablement, UTI recurrences, re-consultation, antibiotic resistance, and hospitalisations at follow-up. POCT culture was not cost-effective. CONCLUSION: Point-of-care urine culture was not effective when used mainly to adjust immediate antibiotic prescriptions. Further research should evaluate use of the test to guide initiation of 'delayed antibiotics'.

Antivirals for influenza-Like Illness? A randomised Controlled trial of Clinical and Cost effectiveness in primary CarE (ALIC4 E): the ALIC4 E protocol.

INTRODUCTION: Effective management of seasonal and pandemic influenza is a high priority internationally. Guidelines in many countries recommend antiviral treatment for older people and individuals with comorbidity at increased risk of complications. However, antivirals are not often prescribed in primary care in Europe, partly because its clinical and cost effectiveness has been insufficiently demonstrated by non-industry funded and pragmatic studies. METHODS AND ANALYSIS: Antivirals for influenza-Like Illness? An rCt of Clinical and Cost effectiveness in primary CarE is a European multinational, multicentre, open-labelled, non-industry funded, pragmatic, adaptive-platform, randomised controlled trial. Initial trial arms will be best usual primary care and best usual primary care plus treatment with oseltamivir for 5 days. We aim to recruit at least 2500 participants ≥1 year presenting with influenza-like illness (ILI), with symptom duration ≤72 hours in primary care over three consecutive periods of confirmed high influenza incidence. Participant outcomes will be followed up to 28 days by diary and telephone. The primary objective is to determine whether adding antiviral treatment to best usual primary care is effective in reducing time to return to usual daily activity with fever, headache and muscle ache reduced to minor severity or less. Secondary objectives include estimating cost-effectiveness, benefits in subgroups according to age (<12, 12-64 and >64 years), severity of symptoms at presentation (low, medium and high), comorbidity (yes/no), duration of symptoms (≤48 hours/>48-72 hours), complications (hospital admission and pneumonia), use of additional prescribed medication including antibiotics, use of over-the-counter medicines and self-management of ILI symptoms. ETHICS AND DISSEMINATION: Research ethics committee (REC) approval was granted by the NRES Committee South Central (Oxford B) and Clinical Trial Authority (CTA) approval by The Medicines and Healthcare products Regulatory Agency. All participating countries gained national REC and CTA approval as required. Dissemination of results will be through peer-reviewed scientific journals and conference presentations. TRIAL REGISTRATION NUMBER: ISRCTN27908921; Pre-results.

Variations in presentation, management, and patient outcomes of urinary tract infection: a prospective four-country primary care observational cohort study.

BACKGROUND: Regional variations in the presentation of uncomplicated urinary tract infection (UTI) and pathogen sensitivity to antibiotics have been cited as reasons to justify differences in how the infections are managed, which includes the prescription of broad-spectrum antibiotics. AIM: To describe presentation and management of UTI in primary care settings, and explore the association with patient recovery, taking microbiological findings and case mix into account. DESIGN AND SETTING: Prospective observational study of females with symptoms of uncomplicated UTI presenting to primary care networks in England, Wales, the Netherlands, and Spain. METHOD: Clinicians recorded history, symptom severity, management, and requested mid-stream urine culture. Participants recorded, in a diary, symptom severity each day for 14 days. Time to recovery was compared between patient characteristics and between countries using two-level Cox proportional hazards models, with patients nested within practices. RESULTS: In total, 797 females attending primary care networks in England (n = 246, 30.9% of cohort), Wales (n = 213, 26.7%), the Netherlands (n = 133, 16.7%), and Spain (n = 205, 25.7%) were included. In total, 259 (35.8%, 95% confidence interval 32.3 to 39.2) of 726 females for whom there was a result were urine culture positive for UTI. Pathogens and antibiotic sensitivities were similar. Empirical antibiotics were prescribed for 95.1% in England, 92.9% in Wales, 95.1% in Spain, and 59.4% in the Netherlands There were no meaningful differences at a country network level before and after controlling for severity, prior UTIs, and antibiotic prescribing. CONCLUSION: Variation in presentation and management of uncomplicated UTI at a country primary care network level is clinically unwarranted and highlights a lack of consensus concerning optimal symptom control and antibiotic prescribing.

Metagenomic analysis of a sample from a patient with respiratory tract infection reveals the presence of a γ-papillomavirus.

Previously unknown or unexpected pathogens may be responsible for that proportion of respiratory diseases in which a causative agent cannot be identified. The application of broad-spectrum, sequence independent virus discovery techniques may be useful to reduce this proportion and widen our knowledge about respiratory pathogens. Thanks to the availability of high-throughput sequencing (HTS) technology, it became today possible to detect viruses which are present at a very low load, but the clinical relevance of those viruses must be investigated. In this study we used VIDISCA-454, a restriction enzyme based virus discovery method that utilizes Roche 454 HTS system, on a nasal swab collected from a subject with respiratory complaints. A γ-papillomavirus was detected (complete genome: 7142 bp) and its role in disease was investigated. Respiratory samples collected both during the acute phase of the illness and 2 weeks after full recovery contained the virus. The patient presented antibodies directed against the virus but there was no difference between IgG levels in blood samples collected during the acute phase and 2 weeks after full recovery. We therefore concluded that the detected γ-papillomavirus is unlikely to be the causative agent of the respiratory complaints and its presence in the nose of the patient is not related to the disease. Although HTS based virus discovery techniques proved their great potential as a tool to clarify the etiology of some infectious diseases, the obtained information must be subjected to cautious interpretations. This study underlines the crucial importance of performing careful investigations on viruses identified when applying sensitive virus discovery techniques, since the mere identification of a virus and its presence in a clinical sample are not satisfactory proofs to establish a causative link with a disease.

Exploring patients' views of primary care consultations with contrasting interventions for acute cough: a six-country European qualitative study.

BACKGROUND: In a pan-European randomised controlled trial (GRACE INTRO) of two interventions, (i) a point-of-care C-reactive protein test and/or (ii) training in communication skills and use of an interactive patient booklet, both interventions resulted in large reductions in antibiotic prescribing for acute cough. AIMS: This process evaluation explored patients' views of primary care consultations using the two interventions in six European countries. METHODS: Sixty-two interviews were conducted with patients who had participated in the GRACE INTRO trial. Interviews were transcribed verbatim and translated into English where necessary. Analysis used techniques from thematic and framework analysis. RESULTS: Most patients were satisfied with their consultation despite many not receiving an antibiotic. Patients appeared to accept the use of both intervention approaches. A minority, but particularly in the trial arm with both interventions, reported that they would wait longer before consulting for cough in future. CONCLUSIONS: Patients perceived that both interventions supported the general practitioner's (GP's) prescribing decisions by helping them understand when an antibiotic was, and was not, needed. Patients consulting with acute cough had largely positive views about the GP's enhanced communication skills, which included understanding their concerns, and the use of a near-patient test as an additional investigation.

Amoxicillin for acute lower-respiratory-tract infection in primary care when pneumonia is not suspected: a 12-country, randomised, placebo-controlled trial.

BACKGROUND: Lower-respiratory-tract infection is one of the most common acute illnesses managed in primary care. Few placebo-controlled studies of antibiotics have been done, and overall effectiveness (particularly in subgroups such as older people) is debated. We aimed to compare the benefits and harms of amoxicillin for acute lower-respiratory-tract infection with those of placebo both overall and in patients aged 60 years or older. METHODS: Patients older than 18 years with acute lower-respiratory-tract infections (cough of ≤28 days' duration) in whom pneumonia was not suspected were randomly assigned (1:1) to either amoxicillin (1 g three times daily for 7 days) or placebo by computer-generated random numbers. Our primary outcome was duration of symptoms rated "moderately bad" or worse. Secondary outcomes were symptom severity in days 2-4 and new or worsening symptoms. Investigators and patients were masked to treatment allocation. This trial is registered with EudraCT (2007-001586-15), UKCRN Portfolio (ID 4175), ISRCTN (52261229), and FWO (G.0274.08N). FINDINGS: 1038 patients were assigned to the amoxicillin group and 1023 to the placebo group. Neither duration of symptoms rated "moderately bad" or worse (hazard ratio 1.06, 95% CI 0.96-1.18; p=0.229) nor mean symptom severity (1.69 with placebo vs 1.62 with amoxicillin; difference -0.07 [95% CI -0.15 to 0.007]; p=0.074) differed significantly between groups. New or worsening symptoms were significantly less common in the amoxicillin group than in the placebo group (162 [15.9%] of 1021 patients vs 194 [19.3%] of 1006; p=0.043; number needed to treat 30). Cases of nausea, rash, or diarrhoea were significantly more common in the amoxicillin group than in the placebo group (number needed to harm 21, 95% CI 11-174; p=0.025), and one case of anaphylaxis was noted with amoxicillin. Two patients in the placebo group and one in the amoxicillin group needed to be admitted to hospital; no study-related deaths were noted. We noted no evidence of selective benefit in patients aged 60 years or older (n=595). INTERPRETATION: When pneumonia is not suspected clinically, amoxicillin provides little benefit for acute lower-respiratory-tract infection in primary care both overall and in patients aged 60 years or more, and causes slight harms. FUNDING: European Commission Framework Programme 6, UK National Institute for Health Research, Barcelona Ciberde Enfermedades Respiratorias, and Research Foundation Flanders.