Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer.

Antiangiogenic therapy with antibodies against VEGF (bevacizumab) or VEGFR2 (ramucirumab) has been proven efficacious in colorectal cancer (CRC) patients. However, the improvement in overall survival is modest and only in combination with chemotherapy. Thus, there is an urgent need to identify potential underlying mechanisms of resistance specific to antiangiogenic therapy and develop strategies to overcome them. Here we found that anti-VEGFR2 therapy up-regulates both C-X-C chemokine ligand 12 (CXCL12) and C-X-C chemokine receptor 4 (CXCR4) in orthotopic murine CRC models, including SL4 and CT26. Blockade of CXCR4 signaling significantly enhanced treatment efficacy of anti-VEGFR2 treatment in both CRC models. CXCR4 was predominantly expressed in immunosuppressive innate immune cells, which are recruited to CRCs upon anti-VEGFR2 treatment. Blockade of CXCR4 abrogated the recruitment of these innate immune cells. Importantly, these myeloid cells were mostly Ly6Clow monocytes and not Ly6Chigh monocytes. To selectively deplete individual innate immune cell populations, we targeted key pathways in Ly6Clow monocytes (Cx3cr1-/- mice), Ly6Chigh monocytes (CCR2-/- mice), and neutrophils (anti-Ly6G antibody) in combination with CXCR4 blockade in SL4 CRCs. Depletion of Ly6Clow monocytes or neutrophils improved anti-VEGFR2-induced SL4 tumor growth delay similar to the CXCR4 blockade. In CT26 CRCs, highly resistant to anti-VEGFR2 therapy, CXCR4 blockade enhanced anti-VEGFR2-induced tumor growth delay but specific depletion of Ly6G+ neutrophils did not. The discovery of CXCR4-dependent recruitment of Ly6Clow monocytes in tumors unveiled a heretofore unknown mechanism of resistance to anti-VEGF therapies. Our findings also provide a rapidly translatable strategy to enhance the outcome of anti-VEGF cancer therapies.

Antibiotic prescribing for residents in long-term-care facilities across the UK.

BACKGROUND: Antimicrobial resistance (AMR) is a major public health problem. Elderly residents in long-term-care facilities (LTCFs) are frequently prescribed antibiotics, particularly for urinary tract infections. Optimizing appropriate antibiotic use in this vulnerable population requires close collaboration between NHS healthcare providers and LTCF providers. OBJECTIVES: Our aim was to identify and quantify antibiotic prescribing in elderly residents in UK LTCFs. This is part of a wider programme of work to understand opportunities for pharmacy teams in the community to support residents and carers. METHODS: This was a retrospective longitudinal cohort study. Data were extracted from a national pharmacy chain database of prescriptions dispensed for elderly residents in UK LTCFs over 12 months (November 2016-October 2017). RESULTS: Data were analysed for 341536 residents in LTCFs across the four UK nations, from which a total of 544796 antibiotic prescriptions were dispensed for 167002 residents. The proportion of residents prescribed at least one antibiotic over the 12 month period varied by LTCF, by month and by country. CONCLUSIONS: Whilst national data sets on antibiotic prescribing are available for hospitals and primary care, this is the first report on antibiotic prescribing for LTCF residents across all four UK nations, and the largest reported data set in this setting. Half of LTCF residents were prescribed at least one antibiotic over the 12 months, suggesting that there is an opportunity to optimize antibiotic use in this vulnerable population to minimize the risk of AMR and treatment failure. Pharmacy teams are well placed to support prudent antibiotic prescribing and improved antimicrobial stewardship in this population.

Antimicrobial use in UK long-term care facilities: results of a point prevalence survey.

BACKGROUND: The majority of people in long-term care facilities (LTCFs) are aged 65 years and older, and most of their care needs are provided by the LTCF staff. Provision of healthcare services for residents in LTCFs is variable and can result in disjointed care between carers and NHS healthcare professionals. OBJECTIVES: Our aim was to understand the use of antibiotics in LTCFs across the UK and to identify potential gaps in knowledge and support for carers and residents when using antibiotics, in order to determine how community pharmacy teams can provide additional support. METHODS: A point prevalence survey (PPS) was conducted by community pharmacists (n = 57) when they carried out visits to LTCFs across the UK between 13 November and 12 December 2017. Anonymized data were recorded electronically by the individual pharmacists. RESULTS: Data were analysed for 17909 residents in 644 LTCFs across the UK. The mean proportion of residents on antibiotics on the day of the visit was as follows: 6.3% England (536 LTCFs), 7.6% Northern Ireland (35 LTCFs), 8.6% Wales (10 LTCFs) and 9.6% Scotland (63 LTCFs). The percentage of antibiotics prescribed for prophylactic use was 25.3%. Antibiotic-related training was reported as being available for staff in 6.8% of LTCFs and 7.1% of LTCFs reported use of a catheter passport scheme. Pharmacists conducting the PPS intervened during the survey for 9.5% of antibiotic prescription events; 53.4% of interventions were for clinical reasons and 32.2% were for administration reasons. CONCLUSIONS: This survey identified high prophylactic use of antibiotics. There are opportunities for community pharmacy teams to improve antimicrobial stewardship in LTCF settings, including workforce education.

Trends in urine sampling rates of general practice patients with suspected lower urinary tract infections in England, 2015-2022: a population-based study.

OBJECTIVES: Inappropriate prescribing of antibiotics is a key driver of antimicrobial resistance. This study aimed to describe urine sampling rates and antibiotic prescribing for patients with lower urinary tract infections (UTIs) in English general practice. DESIGN: A retrospective population-based study using administrative data. SETTING: IQVIA Medical Research Database (IMRD) data from general practices in England, 2015-2022. PARTICIPANTS: Patients who have consulted with an uncomplicated UTI in England general practices captured in the IMRD. OUTCOME MEASURES: Trends in UTI episodes (episodes were defined as UTI diagnosis codes occurring within 14 days of each other), testing and antibiotic prescribing on the same day as initial UTI consultation were assessed from January 2015 to December 2022. Associations, using univariate and multivariate logistic regressions, were examined between consultation and demographic factors on the odds of a urine test. RESULTS: There were 743 350 UTI episodes; 50.8% had a urine test. Testing rates fluctuated with an upward trend and large decline in 2020. Same-day UTI antibiotic prescribing occurred in 78.2% of episodes. In multivariate modelling, factors found to decrease odds of a urine test included age ≥85 years (0.83, 95% CI 0.82 to 0.84), consultation type (remote vs face to face, 0.45, 95% CI 0.45 to 0.46), episodes in London compared with the South (0.74, 95% CI 0.72 to 0.75) and increasing practice size (0.77, 95% CI 0.76 to 0.78). Odds of urine tests increased in males (OR 1.11, 95% CI 1.10 to 1.13), for those episodes without a same-day UTI antibiotic (1.10, 95% CI 1.04 to 1.16) for episodes for those with higher deprivation status (Indices of Multiple Deprivation 8 vs 1, 1.51, 95% CI 1.48 to 1.54). Compared with 2015, 2016-2019 saw increased odds of testing while 2020 and 2021 saw decreases, with 2022 showing increased odds. CONCLUSION: Urine testing for UTI in general practice in England showed an upward trend, with same-day antibiotic prescribing remaining consistent, suggesting greater alignment to national guidelines. The COVID-19 pandemic impacted testing rates, though as of 2022, they began to recover.

Incidence and treatment of group A streptococcal infections during covid-19 pandemic and 2022 outbreak: retrospective cohort study in England using OpenSAFELY-TPP.

Objective: To investigate the effect of the covid-19 pandemic on the number of patients with group A streptococcal infections and related antibiotic prescriptions. Design: Retrospective cohort study in England using OpenSAFELY-TPP. Setting: Primary care practices in England that used TPP SystmOne software, 1 January 2018 to 31 March 2023, with the approval of NHS England. Participants: Patients registered at a TPP practice at the start of each month of the study period. Patients with missing data for sex or age were excluded, resulting in a population of 23 816 470 in January 2018, increasing to 25 541 940 by March 2023. Main outcome measures: Monthly counts and crude rates of patients with group A streptococcal infections (sore throat or tonsillitis, scarlet fever, and invasive group A streptococcal infections), and recommended firstline, alternative, and reserved antibiotic prescriptions linked with a group A streptococcal infection before (pre-April 2020), during, and after (post-April 2021) covid-19 restrictions. Maximum and minimum count and rate for each infectious season (time from September to August), as well as the rate ratio of the 2022-23 season compared with the last comparably high season (2017-18). Results: The number of patients with group A streptococcal infections, and antibiotic prescriptions linked to an indication of group A streptococcal infection, peaked in December 2022, higher than the peak in 2017-18. The rate ratios for monthly sore throat or tonsillitis (possible group A streptococcal throat infection), scarlet fever, and invasive group A streptococcal infection in 2022-23 relative to 2017-18 were 1.39 (95% confidence interval (CI) 1.38 to 1.40), 2.68 (2.59 to 2.77), and 4.37 (2.94 to 6.48), respectively. The rate ratio for prescriptions of first line, alternative, and reserved antibiotics to patients with group A streptococcal infections in 2022-23 relative to 2017-18 were 1.37 (95% CI 1.35 to 1.38), 2.30 (2.26 to 2.34), and 2.42 (2.24 to 2.61), respectively. For individual antibiotic prescriptions in 2022-23, azithromycin showed the greatest relative increase versus 2017-18, with a rate ratio of 7.37 (6.22 to 8.74). This finding followed a marked decrease in the recording of patients with group A streptococcal infections and associated prescriptions during the period of covid-19 restrictions where the maximum count and rates were lower than any minimum rates before the covid-19 pandemic. Conclusions: Recording of rates of scarlet fever, sore throat or tonsillitis, and invasive group A streptococcal infections, and associated antibiotic prescribing, peaked in December 2022. Primary care data can supplement existing infectious disease surveillance through linkages with relevant prescribing data and detailed analysis of clinical and demographic subgroups.

Multi-faceted intervention to improve management of antibiotics for children presenting to primary care with acute cough and respiratory tract infection (CHICO): efficient cluster randomised controlled trial.

OBJECTIVE: To assess whether an easy-to-use multifaceted intervention for children presenting to primary care with respiratory tract infections would reduce antibiotic dispensing, without increasing hospital admissions for respiratory tract infection. DESIGN: Two arm randomised controlled trial clustered by general practice, using routine outcome data, with qualitative and economic evaluations. SETTING: English primary care practices using the EMIS electronic medical record system. PARTICIPANTS: Children aged 0-9 years presenting with respiratory tract infection at 294 general practices, before and during the covid-19 pandemic. INTERVENTION: Elicitation of parental concerns during consultation; a clinician focused prognostic algorithm to identify children at very low, normal, or elevated 30 day risk of hospital admission accompanied by antibiotic prescribing guidance; and a leaflet for carers including safety netting advice. MAIN OUTCOME MEASURES: Rate of dispensed amoxicillin and macrolide antibiotics (superiority comparison) and hospital admissions for respiratory tract infection (non-inferiority comparison) for children aged 0-9 years over 12 months (same age practice list size as denominator). RESULTS: Of 310 practices needed, 294 (95%) were randomised (144 intervention and 150 controls) representing 5% of all registered 0-9 year olds in England. Of these, 12 (4%) subsequently withdrew (six owing to the pandemic). Median intervention use per practice was 70 (by a median of 9 clinicians). No evidence was found that antibiotic dispensing differed between intervention practices (155 (95% confidence interval 138 to 174) items/year/1000 children) and control practices (157 (140 to 176) items/year/1000 children) (rate ratio 1.011, 95% confidence interval 0.992 to 1.029; P=0.25). Pre-specified subgroup analyses suggested reduced dispensing in intervention practices with fewer prescribing nurses, in single site (compared with multisite) practices, and in practices located in areas of lower socioeconomic deprivation, which may warrant future investigation. Pre-specified sensitivity analysis suggested reduced dispensing among older children in the intervention arm (P=0.03). A post hoc sensitivity analysis suggested less dispensing in intervention practices before the pandemic (rate ratio 0.967, 0.946 to 0.989; P=0.003). The rate of hospital admission for respiratory tract infections in the intervention practices (13 (95% confidence interval 10 to 18) admissions/1000 children) was non-inferior compared with control practices (15 (12 to 20) admissions/1000 children) (rate ratio 0.952, 0.905 to 1.003). CONCLUSIONS: This multifaceted antibiotic stewardship intervention for children with respiratory tract infections did not reduce overall antibiotic dispensing or increase respiratory tract infection related hospital admissions. Evidence suggested that in some subgroups and situations (for example, under non-pandemic conditions) the intervention slightly reduced prescribing rates but not in a clinically relevant way. TRIAL REGISTRATION: ISRCTN11405239ISRCTN registry ISRCTN11405239.

A multifaceted intervention to reduce antibiotic prescribing among CHIldren with acute COugh and respiratory tract infection: the CHICO cluster RCT.

Background: Clinical uncertainty in primary care regarding the prognosis of children with respiratory tract infections contributes to the unnecessary use of antibiotics. Improved identification of children at low risk of future hospitalisation might reduce clinical uncertainty. A National Institute for Health and Care Research-funded 5-year programme (RP-PG-0608-10018) was used to develop and feasibility test an intervention. Objectives: The aim of the children with acute cough randomised controlled trial was to reduce antibiotic prescribing among children presenting with acute cough and respiratory tract infection without increasing hospital admission. Design: An efficient, pragmatic open-label, two-arm trial (with embedded qualitative and health economic analyses) using practice-level randomisation using routinely collected data as the primary outcome. Setting: General practitioner practices in England. Participants: General practitioner practices using the Egton Medical Information Systems® patient-record system for children aged 0-9 years presenting with a cough or upper respiratory tract infection. Recruited by Clinical Research Networks and Clinical Commissioning Groups. Intervention: Comprised: (1) elicitation of parental concerns during consultation; (2) a clinician-focused prognostic algorithm to identify children with acute cough and respiratory tract infection at low, average or elevated risk of hospitalisation in the next 30 days accompanied by prescribing guidance, (3) provision of a printout for carers including safety-netting advice. Main outcome measures: Co-primaries using the practice list-size for children aged 0-9 years as the denominator: rate of dispensed amoxicillin and macrolide items at each practice (superiority comparison) from NHS Business Services Authority ePACT2 and rate of hospital admission for respiratory tract infection (non-inferiority comparison) from Clinical Commissioning Groups, both routinely collected over 12 months. Results: Of the 310 practices required, 294 (95%) were recruited (144 intervention and 150 controls) with 336,496 registered 0-9-year-olds (5% of all 0-9-year-old children in England) from 47 Clinical Commissioning Groups. Included practices were slightly larger than those not included, had slightly lower baseline dispensing rates and were located in more deprived areas (reflecting the distribution for practice postcodes nationally). Twelve practices (4%) subsequently withdrew (six related to the pandemic). The median number of times the intervention was used was 70 per practice (by a median of 9 clinicians) over 12 months. There was no evidence that the antibiotic dispensing rate in the intervention practices [0.155 (95% confidence interval 0.135 to 0.179)] differed to controls [0.154 (95% confidence interval 0.130 to 0.182), relative risk= 1.011 (95% confidence interval 0.992 to 1.029); p = 0.253]. There was, overall, a reduction in dispensing levels and intervention usage during the pandemic. The rate of hospitalisation for respiratory tract infection in the intervention practices [0.019 (95% confidence interval 0.014 to 0.026)] compared to the controls [0.021 (95% confidence interval 0.014 to 0.029)] was non-inferior [relative risk = 0.952 (95% confidence interval 0.905 to 1.003)]. The qualitative evaluation found the clinicians liked the intervention, used it as a supportive aid, especially with borderline cases but that it, did not always integrate well within the consultation flow and was used less over time. The economic evaluation found no evidence of a difference in mean National Health Service costs between arms; mean difference -£1999 (95% confidence interval -£6627 to 2630). Conclusions: The intervention was feasible and subjectively useful to practitioners, with no evidence of harm in terms of hospitalisations, but did not impact on antibiotic prescribing rates. Future work and limitations: Although the intervention does not appear to change prescribing behaviour, elements of the approach may be used in the design of future interventions. Trial registration: This trial is registered as ISRCTN11405239 (date assigned 20 April 2018) at www.controlled-trials.com (accessed 5 September 2022). Version 4.0 of the protocol is available at: https://www.journalslibrary.nihr.ac.uk/ (accessed 5 September 2022). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment (NIHR award ref: 16/31/98) programme and is published in full in Health Technology Assessment; Vol. 27, No. 32. See the NIHR Funding and Awards website for further award information.

Coughs and colds (also known as respiratory tract infections) are the most common reason that children are taken to family doctors and nurses in primary care. These clinicians are not always sure how best to treat them and often use antibiotics 'just in case'. There are now concerns that clinicians are using antibiotics too often, and that this is increasing the number of resistant bugs (bacteria that cannot be killed by antibiotics). We wanted to see if using a scoring system of symptoms and signs of illness to help clinicians identify children very unlikely to need hospital care as well as listening to parents' concerns and giving them a personalised leaflet with care and safety advice, reduced antibiotic use. We recruited practices rather than patients, so did not need individual patient consent. The two main outcomes were the rate of antibiotics dispensed for children and number of children admitted to hospital for respiratory tract infections, using routinely collected data for 0­9-year-olds. We recruited 294 general practitioner practices, which was 95% of the total needed; 144 were asked to use the intervention and 150 to continue providing usual care (controls); only 12 practices subsequently withdrew (6 related to the pandemic). The average number of times the intervention was used was 70 per practice (by an average of 9 clinicians) over 12 months. There was no evidence that the antibiotic dispensing rate in the intervention practices differed from control practices. Further analyses showed an overall reduction in dispensing levels and intervention usage during the pandemic. The rate of hospitalisation for respiratory tract infection in the intervention practices was similar to the control practices. In the interviews, we found that clinicians liked the intervention and used it as a supportive aid during consultations, especially for borderline cases, rather than a tool to change prescribing behaviour.

Can primary care research be conducted more efficiently using routinely reported practice-level data: a cluster randomised controlled trial conducted in England?

OBJECTIVES: Conducting randomised controlled trials (RCTs) in primary care is challenging; recruiting patients during time-limited or remote consultations can increase selection bias and physical access to patients' notes is costly and time-consuming. We investigated barriers and facilitators to running a more efficient design. DESIGN: An RCT aiming to reduce antibiotic prescribing among children presenting with acute cough and a respiratory tract infection (RTI) with a clinician-focused intervention, embedded at the practice level. By using aggregate level, routinely collected data for the coprimary outcomes, we removed the need to recruit individual participants. SETTING: Primary care. PARTICIPANTS: Baseline data from general practitioner practices and interviews with individuals from Clinical Research Networks (CRNs) in England who helped recruit practices and Clinical Commission Groups (CCGs) who collected outcome data. INTERVENTION: The intervention included: (1) explicit elicitation of parental concerns, (2) a prognostic algorithm to identify children at low risk of hospitalisation and (3) provision of a printout for carers including safety-netting advice. COPRIMARY OUTCOMES: For 0-9 years old-(1) Dispensing data for amoxicillin and macrolide antibiotics and (2) hospital admission rate for RTI. RESULTS: We recruited 294 of the intended 310 practices (95%) representing 336 496 registered 0-9 years old (5% of all 0-9 years old children). Included practices were slightly larger, had slightly lower baseline prescribing rates and were located in more deprived areas reflecting the national distribution. Engagement with CCGs and their understanding of their role in this research was variable. Engagement with CRNs and installation of the intervention was straight-forward although the impact of updates to practice IT systems and lack of familiarity required extended support in some practices. Data on the coprimary outcomes were almost 100%. CONCLUSIONS: The infrastructure for trials at the practice level using routinely collected data for primary outcomes is viable in England and should be promoted for primary care research where appropriate. TRIAL REGISTRATION NUMBER: ISRCTN11405239.

Surveillance of Antibacterial Usage during the COVID-19 Pandemic in England, 2020.

Changes in antibacterial prescribing during the COVID-19 pandemic were anticipated given that the clinical features of severe respiratory infection syndrome caused by SARS-CoV-2 mirror bacterial respiratory tract infections. Antibacterial consumption was measured in items/1000 population for primary care and in Defined Daily Doses (DDDs)/1000 admissions for secondary care in England from 2015 to October 2020. Interrupted time-series analyses were conducted to evaluate the effects of the pandemic on antibacterial consumption. In the community, the rate of antibacterial items prescribed decreased further in 2020 (by an extra 1.4% per month, 95% CI: -2.3 to -0.5) compared to before COVID-19. In hospitals, the volume of antibacterial use decreased during COVID-19 overall (-12.1% compared to pre-COVID, 95% CI: -19.1 to -4.4), although the rate of usage in hospitals increased steeply in April 2020. Use of antibacterials prescribed for respiratory infections and broad-spectrum antibacterials (predominately 'Watch' antibacterials in hospitals) increased in both settings. Overall volumes of antibacterial use at the beginning of the COVID-19 pandemic decreased in both primary and secondary settings, although there were increases in the rate of usage in hospitals in April 2020 and in specific antibacterials. This highlights the importance of antimicrobial stewardship during pandemics to ensure appropriate prescribing and avoid negative consequences on patient outcomes and antimicrobial resistance.

Effect of antibiotic stewardship interventions in primary care on antimicrobial resistance of Escherichia coli bacteraemia in England (2013-18): a quasi-experimental, ecological, data linkage study.

BACKGROUND: Antimicrobial resistance is a major global health concern, driven by overuse of antibiotics. We aimed to assess the effectiveness of a national antimicrobial stewardship intervention, the National Health Service (NHS) England Quality Premium implemented in 2015-16, on broad-spectrum antibiotic prescribing and Escherichia coli bacteraemia resistance to broad-spectrum antibiotics in England. METHODS: In this quasi-experimental, ecological, data linkage study, we used longitudinal data on bacteraemia for patients registered with a general practitioner in the English National Health Service and patients with E coli bacteraemia notified to the national mandatory surveillance programme between Jan 1, 2013, and Dec 31, 2018. We linked these data to data on antimicrobial susceptibility testing of E coli from Public Health England's Second-Generation Surveillance System. We did an ecological analysis using interrupted time-series analyses and generalised estimating equations to estimate the change in broad-spectrum antibiotics prescribing over time and the change in the proportion of E coli bacteraemia cases for which the causative bacteria were resistant to each antibiotic individually or to at least one of five broad-spectrum antibiotics (co-amoxiclav, ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin), after implementation of the NHS England Quality Premium intervention in April, 2015. FINDINGS: Before implementation of the Quality Premium, the rate of antibiotic prescribing for all five broad-spectrum antibiotics was increasing at rate of 0·2% per month (incidence rate ratio [IRR] 1·002 [95% CI 1·000-1·004], p=0·046). After implementation of the Quality Premium, an immediate reduction in total broad-spectrum antibiotic prescribing rate was observed (IRR 0·867 [95% CI 0·837-0·898], p<0·0001). This effect was sustained until the end of the study period; a 57% reduction in rate of antibiotic prescribing was observed compared with the counterfactual situation (ie, had the Quality Premium not been implemented). In the same period, the rate of resistance to at least one broad-spectrum antibiotic increased at rate of 0·1% per month (IRR 1·001 [95% CI 0·999-1·003], p=0·346). On implementation of the Quality Premium, an immediate reduction in resistance rate to at least one broad-spectrum antibiotic was observed (IRR 0·947 [95% CI 0·918-0·977], p=0·0007). Although this effect was also sustained until the end of the study period, with a 12·03% reduction in resistance rate compared with the counterfactual situation, the overall trend remained on an upward trajectory. On examination of the long-term effect following implementation of the Quality Premium, there was an increase in the number of isolates resistant to at least one of the five broad-spectrum antibiotics tested (IRR 1·002 [1·000-1·003]; p=0·047). INTERPRETATION: Although interventions targeting antibiotic use can result in changes in resistance over a short period, they might be insufficient alone to curtail antimicrobial resistance. FUNDING: National Institute for Health Research, Economic and Social Research Council, Rosetrees Trust, and The Stoneygate Trust.

Protocol for an 'efficient design' cluster randomised controlled trial to evaluate a complex intervention to improve antibiotic prescribing for CHIldren presenting to primary care with acute COugh and respiratory tract infection: the CHICO study.

INTRODUCTION: Respiratory tract infections (RTIs) in children are common and present major resource implications for primary care. Unnecessary use of antibiotics is associated with the development and proliferation of antimicrobial resistance. In 2016, the National Institute for Health Research (NIHR)-funded 'TARGET' programme developed a prognostic algorithm to identify children with acute cough and RTI at very low risk of 30-day hospitalisation and unlikely to need antibiotics. The intervention includes: (1) explicit elicitation of parental concerns, (2) the results of the prognostic algorithm accompanied by prescribing guidance and (3) provision of a printout for carers including safety netting advice. The CHIldren's COugh feasibility study suggested differential recruitment of healthier patients in control practices. This phase III 'efficiently designed' trial uses routinely collected data at the practice level, thus avoiding individual patient consent. The aim is to assess whether embedding a multifaceted intervention into general practitioner (GP) practice Information Technology (IT) systems will result in reductions of antibiotic prescribing without impacting on hospital attendance for RTI. METHODS AND ANALYSIS: The coprimary outcomes are (1) practice rate of dispensed amoxicillin and macrolide antibiotics, (2) hospital admission rate for RTI using routinely collected data by Clinical Commissioning Groups (CCGs). Data will be collected for children aged 0-9 years registered at 310 practices (155 intervention, 155 usual care) over a 12-month period. Recruitment and randomisation of practices (using the Egton Medical Information Systems web data management system) is conducted via each CCG stratified for children registered and baseline dispensing rates of each practice. Secondary outcomes will explore intervention effect modifiers. Qualitative interviews will explore intervention usage. The economic evaluation will be limited to a between-arm comparison in a cost-consequence analysis. ETHICS AND DISSEMINATION: Research ethics approval was given by London-Camden and Kings Cross Research Ethics Committee (ref:18/LO/0345). This manuscript refers to protocol V.4.0. Results will be disseminated through peer-reviewed journals and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN11405239.

Evaluation of a community pharmacy-led test-and-treat service for women with uncomplicated lower urinary tract infection in England.

BACKGROUND: Uncomplicated lower urinary tract infections (UTIs) are common in women consulting primary healthcare, taking up GP resources. Delayed consultation can increase the risk of serious infections such as pyelonephritis or bacteraemia. OBJECTIVES: To evaluate the effectiveness and uptake of a lower UTI test-and-treat service for women presenting with urinary symptoms within a community pharmacy in supporting self-care and appropriate use of antibiotics and reducing demand on other NHS resources. METHODS: The service was aligned to national guidelines to diagnose and treat lower UTI in women aged 16-64 years and used national resources to provide safety-netting and self-care advice. Consultation included clinical assessment and a urine dipstick test alongside a novel smartphone app, with diagnosis informed by test results. Women were provided with safety-netting advice and either advised on self-care, supplied with antibiotics or referred to their GP. RESULTS: Data were analysed for 764 women who presented to 23 pharmacies during December 2018 to April 2019. Lower UTI was found to be likely in 372/496 (75.0%) women, most of whom purchased antibiotics on the same day. Had the service not been available, approximately three-quarters of women who had completed the service and responded to the question would have visited their GP (214/301) and more than one-third would have used self-care with or without going to see their GP (116/301). CONCLUSIONS: A community pharmacy-led UTI test-and-treat service for women aged 16-64 years presenting with urinary symptoms provided accessible and timely care aligned to national guidance, with 75.0% of consultations requiring antibiotic treatment.

Conceptualising the Integration of Strategies by Clinical Commissioning Groups in England towards the Antibiotic Prescribing Targets for the Quality Premium Financial Incentive Scheme: A Short Report.

Background: In order to tackle the public health threat of antimicrobial resistance, improvement in antibiotic prescribing in primary care was included as one of the priorities of the Quality Premium (QP) financial incentive scheme for Clinical Commissioning Groups (CCGs) in England. This paper briefly reports the outcome of a workshop exploring the experiences of antimicrobial stewardship (AMS) leads within CCGs in selecting and adopting strategies to help achieve the QP antibiotic targets. Methods: We conducted a thematic analysis of the notes on discussions and observations from the workshop to identify key themes. Results: Practice visits, needs assessment, peer feedback and audits were identified as strategies integrated in increasing engagement with practices towards the QP antibiotic targets. The conceptual model developed by AMS leads demonstrated possible pathways for the impact of the QP on antibiotic prescribing. Participants raised a concern that the constant targeting of high prescribing practices for AMS interventions might lead to disengagement by these practices. Most of the participants suggested that the effect of the QP might be less about the financial incentive and more about having national targets and guidelines that promote antibiotic prudency. Conclusions: Our results suggest that national targets, rather than financial incentives are key for engaging stakeholders in quality improvement in antibiotic prescribing.

What antimicrobial stewardship strategies do NHS commissioning organizations implement in primary care in England?

OBJECTIVES: To identify and explore strategies that English NHS commissioning organizations implemented to improve antimicrobial stewardship (AMS) within primary care. METHODS: Questionnaire sent to the medicines management teams (MMTs) of all 209 clinical commissioning groups (CCGs) in England, in 2017. RESULTS: A total of 89% (187/209) of all English CCGs responded to the questionnaire; 74% of responding CCGs (123/167) had a prescribing incentive/engagement scheme, with MMTs representing 88% (90/102) considering incentive schemes successful or very successful for prioritizing AMS in primary care, especially when linked to prescribing NHS Quality Premium indicators. AMS audits were considered successful or very successful by 91% (126/138) of responding CCGs, as they identify reasons for inappropriate prescribing and opportunities for future improvement. All responding MMTs (169/169 CCGs) reported feeding back local/national antimicrobial prescribing data to the general practices they commission, 85% (142/168) to their CCG/Commissioning Support Unit (CSU) board and only 33% (56/169) to out-of-hours services. Benchmarking prescribing data was reported as a powerful tool to engage practices, facilitating an element of competition and peer pressure. CONCLUSIONS: National antimicrobial resistance improvement schemes, in particular the NHS England Quality Premium, have influenced CCG improvement priorities. Most CCGs now report successful improvement strategies including the use of both local and national antibiotic prescribing data to motivate improvements; these should be continued and extended to out-of-hours providers. As local audit data have helped to identify reasons for inappropriate prescribing and inform improvement planning, all organizations should adopt this strategy and include it in local quality improvement schemes, ensuring performance reporting to organizational board level.

What Resources do NHS Commissioning Organisations Use to Support Antimicrobial Stewardship in Primary Care in England?

Professional education and public engagement are fundamental components of any antimicrobial stewardship (AMS) strategy. The National Institute for Health and Care Excellence (NICE), Public Health England (PHE), Health Education England (HEE) and other professional organisations, develop and publish resources to support AMS activity in primary care settings. The aim of this study was to explore the adoption and use of education/training and supporting AMS resources within NHS primary care in England. Questionnaires were sent to the medicines management teams of all 209 Clinical Commissioning Groups (CCGs) in England, in 2017. Primary care practitioners in 168/175 (96%) CCGs received AMS education in the last two years. Respondents in 184/186 (99%) CCGs reported actively promoting the TARGET Toolkit to their primary care practitioners; although 137/176 (78%) did not know what percentage of primary care practitioners used the TARGET toolkit. All respondents were aware of Antibiotic Guardian and 132/167 (79%) reported promoting the campaign. Promotion of AMS resources to general practices is currently excellent, but as evaluation of uptake or effect is poor, this should be encouraged by resource providers and through quality improvement programmes. Trainers should be encouraged to promote and highlight the importance of action planning within their AMS training. AMS resources, such as leaflets and education, should be promoted across the whole health economy, including Out of Hours and care homes. Primary care practitioners should continue to be encouraged to display a signed Antibiotic Guardian poster as well as general AMS posters and videos in practice, as patients find them useful and noticeable.

Content and Mechanism of Action of National Antimicrobial Stewardship Interventions on Management of Respiratory Tract Infections in Primary and Community Care.

A major modifiable factor contributing to antimicrobial resistance (AMR) is inappropriate use and overuse of antimicrobials, such as antibiotics. This study aimed to describe the content and mechanism of action of antimicrobial stewardship (AMS) interventions to improve appropriate antibiotic use for respiratory tract infections (RTI) in primary and community care. This study also aimed to describe who these interventions were aimed at and the specific behaviors targeted for change. Evidence-based guidelines, peer-review publications, and infection experts were consulted to identify behaviors relevant to AMS for RTI in primary care and interventions to target these behaviors. Behavior change tools were used to describe the content of interventions. Theoretical frameworks were used to describe mechanisms of action. A total of 32 behaviors targeting six different groups were identified (patients; prescribers; community pharmacists; providers; commissioners; providers and commissioners). Thirty-nine interventions targeting the behaviors were identified (patients = 15, prescribers = 22, community pharmacy staff = 8, providers = 18, and commissioners = 18). Interventions targeted a mean of 5.8 behaviors (range 1-27). Influences on behavior most frequently targeted by interventions were psychological capability (knowledge and skills); reflective motivation (beliefs about consequences, intentions, social/professional role and identity); and physical opportunity (environmental context and resources). Interventions were most commonly characterized as achieving change by training, enabling, or educating and were delivered mainly through guidelines, service provision, and communications & marketing. Interventions included a mean of four Behavior Change Techniques (BCTs) (range 1-14). We identified little intervention content targeting automatic motivation and social opportunity influences on behavior. The majority of interventions focussed on education and training, which target knowledge and skills though the provision of instructions on how to perform a behavior and information about health consequences. Interventions could be refined with the inclusion of relevant BCTs, such as goal-setting and action planning (identified in only a few interventions), to translate instruction on how to perform a behavior into action. This study provides a platform to refine content and plan evaluation of antimicrobial stewardship interventions.

Optimising antimicrobial stewardship interventions in English primary care: a behavioural analysis of qualitative and intervention studies.

OBJECTIVE: While various interventions have helped reduce antibiotic prescribing, further gains can be made. This study aimed to identify ways to optimise antimicrobial stewardship (AMS) interventions by assessing the extent to which important influences on antibiotic prescribing are addressed (or not) by behavioural content of AMS interventions. SETTINGS: English primary care. INTERVENTIONS: AMS interventions targeting healthcare professionals' antibiotic prescribing for respiratory tract infections. METHODS: We conducted two rapid reviews. The first included qualitative studies with healthcare professionals on self-reported influences on antibiotic prescribing. The influences were inductively coded and categorised using the Theoretical Domains Framework (TDF). Prespecified criteria were used to identify key TDF domains. The second review included studies of AMS interventions. Data on effectiveness were extracted. Components of effective interventions were extracted and coded using the TDF, Behaviour Change Wheel and Behaviour Change Techniques (BCTs) taxonomy. Using prespecified matrices, we assessed the extent to which BCTs and intervention functions addressed the key TDF domains of influences on prescribing. RESULTS: We identified 13 qualitative studies, 41 types of influences on antibiotic prescribing and 6 key TDF domains of influences: 'beliefs about consequences', 'social influences', 'skills', 'environmental context and resources', 'intentions' and 'emotions'. We identified 17 research-tested AMS interventions; nine of them effective and four nationally implemented. Interventions addressed all six key TDF domains of influences. Four of these six key TDF domains were addressed by 50%-67% BCTs that were theoretically congruent with these domains, whereas TDF domain 'skills' was addressed by 24% of congruent BCTs and 'emotions' by none. CONCLUSIONS: Further improvement of antibiotic prescribing could be facilitated by: (1) national implementation of effective research-tested AMS interventions (eg, electronic decision support tools, training in interactive use of leaflets, point-of-care testing); (2) targeting important, less-addressed TDF domains (eg, 'skills', 'emotions'); (3) using relevant, under-used BCTs to target key TDF domains (eg, 'forming/reversing habits', 'reducing negative emotions', 'social support'). These could be incorporated into existing, or developed as new, AMS interventions.

Optimising Interventions for Catheter-Associated Urinary Tract Infections (CAUTI) in Primary, Secondary and Care Home Settings.

Catheter-associated urinary tract infections (CAUTI) are common yet preventable. Healthcare professional behaviours, such as reducing unnecessary catheter use, are key for preventing CAUTI. Previous research has focused on identifying gaps in the national response to CAUTI in multiple settings in England. This study aimed to identify how national interventions could be optimised. We conducted a multi-method study comprising: a rapid review of research on interventions to reduce CAUTI; a behavioural analysis of effective research interventions compared to national interventions; and a stakeholder focus group and survey to identify the most promising options for optimising interventions. We identified 37 effective research interventions, mostly conducted in United States secondary care. A behavioural analysis of these interventions identified 39 intervention components as possible ways to optimise national interventions. Seven intervention components were prioritised by stakeholders. These included: checklists for discharge/admission to wards; information for patients and relatives about the pros/cons of catheters; setting and profession specific guidelines; standardised nationwide computer-based documentation; promotion of alternatives to catheter use; CAUTI champions; and bladder scanners. By combining research evidence, behavioural analysis and stakeholder feedback, we identified how national interventions to reduce CAUTI could be improved. The seven prioritised components should be considered for future implementation.

How Can National Antimicrobial Stewardship Interventions in Primary Care Be Improved? A Stakeholder Consultation.

Many antimicrobial stewardship (AMS) interventions have been implemented in England, facilitating decreases in antibiotic prescribing. Nevertheless, there is substantial variation in antibiotic prescribing across England and some healthcare organizations remain high prescribers of antibiotics. This study aimed to identify ways to improve AMS interventions to further optimize antibiotic prescribing in primary care in England. Stakeholders representing different primary care settings were invited to, and 15 participated in, a focus group or telephone interview to identify ways to improve existing AMS interventions. Forty-five intervention suggestions were generated and 31 were prioritized for inclusion in an online survey. Fifteen stakeholders completed the survey appraising each proposed intervention using the pre-defined APEASE (i.e., Affordability, Practicability, Effectiveness, Acceptability, Safety, and Equity) criteria. The highest-rated nine interventions were prioritized as most promising and feasible, including: quality improvement, multidisciplinary peer learning, appointing AMS leads, auditing individual-level prescribing, developing tools for prescribing audits, improving inductions for new prescribers, ensuring consistent local approaches to antibiotic prescribing, providing online AMS training to all patient-facing staff, and increasing staff time available for AMS work with standardizing AMS-related roles. These prioritized interventions could be incorporated into existing national interventions or developed as stand-alone interventions to help further optimize antibiotic prescribing in primary care in England.

Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice.

Lymph node metastases in cancer patients are associated with tumor aggressiveness, poorer prognoses, and the recommendation for systemic therapy. Whether cancer cells in lymph nodes can seed distant metastases has been a subject of considerable debate. We studied mice implanted with cancer cells (mammary carcinoma, squamous cell carcinoma, or melanoma) expressing the photoconvertible protein Dendra2. This technology allowed us to selectively photoconvert metastatic cells in the lymph node and trace their fate. We found that a fraction of these cells invaded lymph node blood vessels, entered the blood circulation, and colonized the lung. Thus, in mouse models, lymph node metastases can be a source of cancer cells for distant metastases. Whether this mode of dissemination occurs in cancer patients remains to be determined.