Evaluating the role of primary care pharmacy technicians in antimicrobial stewardship (AMS) and acne management using TARGET resources.

Background: Inappropriate antibiotic prescribing is accelerating antimicrobial resistance (AMR) (Antibiotic resistant infections and associated deaths increase  https://www.gov.uk/government/news/antibiotic-resistant-infections-and-associated-deaths-increase). Pharmacy professionals (pharmacists and pharmacy technicians) promote good antibiotic prescribing practice. The traditional role of pharmacy technicians in supporting pharmacists and patients has expanded alongside the clinical expansion of pharmacist roles. (Boughen M, Fenn T. Practice, skill mix and education: the evolving role of pharmacy technicians in Great Britain. Pharmacy (Basel) 2020; 8(2): 50. doi:10.3390/pharmacy8020050) This paper focuses on the opinion of pharmacy technicians and their role in the review of acne management and the evaluation of the UKHSA TARGET acne 'How to…' review resources. Aims and objectives: To explore the impact of the TARGET resources on the capability, opportunity and motivation of pharmacy technicians in general practice in managing patients with acne.To evaluate the usefulness of the acne 'How to…' review resources. Materials and methods: A primarily quantitative study using an electronic survey asking UK-based pharmacy technicians to rate their agreement on a five-point Likert scale with 21 predefined statements, themed on the COM-B model and usefulness of the TARGET resources for acne. Discussion: The survey found that capability and opportunity in managing acne in the group familiar with TARGET resources was higher than the group not familiar with TARGET resources. Scores for motivation in both groups were high; pharmacy technicians have the motivation to undertake infection management roles, whether or not they are familiar with the TARGET toolkit.The acne 'How to…' review resources were overall rated as useful in supporting the review of patients with acne. Conclusion: The TARGET materials are effective resources that helps to upskill pharmacy technicians in the area of AMS, increasing capability and opportunity in the management of acne.

Responding to Urinary Tract Infection Symptoms in England's Community Pharmacies.

Most urinary tract infections (UTIs) are self-limiting and frequently present in primary care; it is common for patients to seek symptom relief. The TARGET Treating Your Infection (TYI) leaflet was used to respond to UTI symptoms for women under 65 years presenting in community pharmacies. The widespread use of these leaflets was incentivised as part of NHS England's Pharmacy Quality Scheme (PQS) 2022-23, between October 2022 and March 2023. The TARGET TYI leaflets are aimed to support appropriate antibiotic use and antimicrobial stewardship (AMS) as well as reducing the opportunity for resistance to develop. A total of 8363 community pharmacies completed the AMS criteria within the PQS and collectively submitted data for 104,142 patients presenting with UTI symptoms. The majority, 77% (75,071), of (non-pregnant) women presented with none or only one of the three strongly predictive symptoms of dysuria, new nocturia, cloudy urine, and/or vaginal discharge and, therefore, were less likely to have a UTI, as outlined in the English UTI diagnostic guidance. Conversely, 23% (22,381) of women presented with two or more symptoms of dysuria, new nocturia, cloudy urine, and with no vaginal discharge and, therefore, they were more likely to have a UTI. The TARGET TYI UTI leaflets support community pharmacy teams to differentiate between symptoms more likely to be associated with UTIs and those that could be managed with self-care. The findings suggest that most women presenting to community pharmacies with urinary symptoms were likely to have self-limiting symptoms, and could be suitably managed with self-care, pain relief, and appropriate safety netting. Approximately one-third of patients were managed by community pharmacy team members without the need for referral to a pharmacist and one in five patients presented with escalation symptoms and were signposted to other healthcare settings. A total of 94% (97,452) of women received self-care advice of which 36% (37,565) were also provided with additional patient information leaflets.

The impact of the COVID-19 pandemic on the treatment of common infections in primary care and the change to antibiotic prescribing in England.

BACKGROUND: There is concern that the COVID-19 pandemic altered the management of common infections in primary care. This study aimed to evaluate infection-coded consultation rates and antibiotic use during the pandemic and how any change may have affected clinical outcomes. METHODS: With the approval of NHS England, a retrospective cohort study using the OpenSAFELY platform analysed routinely collected electronic health data from GP practices in England between January 2019 and December 2021. Infection coded consultations and antibiotic prescriptions were used estimate multiple measures over calendar months, including age-sex adjusted prescribing rates, prescribing by infection and antibiotic type, infection consultation rates, coding quality and rate of same-day antibiotic prescribing for COVID-19 infections. Interrupted time series (ITS) estimated the effect of COVID-19 pandemic on infection-coded consultation rates. The impact of the pandemic on non- COVID-19 infection-related hospitalisations was also estimated. RESULTS: Records from 24 million patients were included. The rate of infection-related consultations fell for all infections (mean reduction of 39% in 2020 compared to 2019 mean rate), except for UTI which remained stable. Modelling infection-related consultation rates highlighted this with an incidence rate ratio of 0.44 (95% CI 0.36-0.53) for incident consultations and 0.43 (95% CI 0.33-0.54) for prevalent consultations. Lower respiratory tract infections (LRTI) saw the largest reduction of 0.11 (95% CI 0.07-0.17). Antibiotic prescribing rates fell with a mean reduction of 118.4 items per 1000 patients in 2020, returning to pre-pandemic rates by summer 2021. Prescribing for LRTI decreased 20% and URTI increased 15.9%. Over 60% of antibiotics were issued without an associated same-day infection code, which increased during the pandemic. Infection-related hospitalisations reduced (by 62%), with the largest reduction observed for pneumonia infections (72.9%). Same-day antibiotic prescribing for COVID-19 infection increased from 1 to 10.5% between the second and third national lockdowns and rose again during 2022. CONCLUSIONS: Changes to consultations and hospital admissions may be driven by reduced transmission of non-COVID-19 infections due to reduced social mixing and lockdowns. Inconsistencies in coding practice emphasises the need for improvement to inform new antibiotic stewardship policies and prevent resistance to novel infections.

Repeated antibiotic exposure and risk of hospitalisation and death following COVID-19 infection (OpenSAFELY): a matched case-control study.

Background: Identifying potential risk factors related to severe COVID-19 outcomes is important. Repeated intermittent antibiotic use is known be associated with adverse outcomes. This study aims to examine whether prior frequent antibiotic exposure is associated with severe COVID-19 outcomes. Methods: With the approval of NHS England, we used the OpenSAFELY platform, which integrated primary and secondary care, COVID-19 test, and death registration data. This matched case-control study included 0.67 million patients (aged 18-110 years) from an eligible 2.47 million patients with incident COVID-19 by matching with replacement. Inclusion criteria included registration within one general practice for at least 3 years and infection with incident COVID-19. Cases were identified according to different severity of COVID-19 outcomes. Cases and eligible controls were 1:6 matched on age, sex, region of GP practice, and index year and month of COVID-19 infection. Five quintile groups, based on the number of previous 3-year antibiotic prescriptions, were created to indicate the frequency of prior antibiotic exposure. Conditional logistic regression used to compare the differences between case and control groups, adjusting for ethnicity, body mass index, comorbidities, vaccination history, deprivation, and care home status. Sensitivity analyses were done to explore potential confounding and the effects of missing data. Findings: Based on our inclusion criteria, between February 1, 2020 and December 31, 2021, 98,420 patients were admitted to hospitals and 22,660 died. 55 unique antibiotics were prescribed. A dose-response relationship between number of antibiotic prescriptions and risk of severe COVID-19 outcome was observed. Patients in the highest quintile with history of prior antibiotic exposure had 1.80 times greater odds of hospitalisation compared to patients without antibiotic exposure (adjusted odds ratio [OR] 1.80, 95% Confidence Interval [CI] 1.75-1.84). Similarly, the adjusted OR for hospitalised patients with death outcomes was 1.34 (95% CI 1.28-1.41). Larger number of prior antibiotic type was also associated with more severe COVID-19 related hospital admission. The adjusted OR of quintile 5 exposure (the most frequent) with more than 3 antibiotic types was around 2 times larger than quintile 1 (only 1 type; OR 1.80, 95% CI 1.75-1.84 vs. OR 1.03, 95% CI 1.01-1.05). Interpretation: Our observational study has provided evidence that antibiotic exposure frequency and diversity may be associated with COVID-19 severity, potentially suggesting adverse effects of repeated intermittent antibiotic use. Future work could work to elucidate causal links and potential mechanisms. Antibiotic stewardship should put more emphasis on long-term antibiotic exposure and its adverse outcome to increase the awareness of appropriate antibiotics use. Funding: Health Data Research UK and National Institute for Health Research.

Impact of COVID-19 on broad-spectrum antibiotic prescribing for common infections in primary care in England: a time-series analyses using OpenSAFELY and effects of predictors including deprivation.

Background: The COVID-19 pandemic impacted the healthcare systems, adding extra pressure to reduce antimicrobial resistance. Therefore, we aimed to evaluate changes in antibiotic prescription patterns after COVID-19 started. Methods: With the approval of NHS England, we used the OpenSAFELY platform to access the TPP SystmOne electronic health record (EHR) system in primary care and selected patients prescribed antibiotics from 2019 to 2021. To evaluate the impact of COVID-19 on broad-spectrum antibiotic prescribing, we evaluated prescribing rates and its predictors and used interrupted time series analysis by fitting binomial logistic regression models. Findings: Over 32 million antibiotic prescriptions were extracted over the study period; 8.7% were broad-spectrum. The study showed increases in broad-spectrum antibiotic prescribing (odds ratio [OR] 1.37; 95% confidence interval [CI] 1.36-1.38) as an immediate impact of the pandemic, followed by a gradual recovery with a 1.1-1.2% decrease in odds of broad-spectrum prescription per month. The same pattern was found within subgroups defined by age, sex, region, ethnicity, and socioeconomic deprivation quintiles. More deprived patients were more likely to receive broad-spectrum antibiotics, which differences remained stable over time. The most significant increase in broad-spectrum prescribing was observed for lower respiratory tract infection (OR 2.33; 95% CI 2.1-2.50) and otitis media (OR 1.96; 95% CI 1.80-2.13). Interpretation: An immediate reduction in antibiotic prescribing and an increase in the proportion of broad-spectrum antibiotic prescribing in primary care was observed. The trends recovered to pre-pandemic levels, but the consequence of the COVID-19 pandemic on AMR needs further investigation. Funding: This work was supported by Health Data Research UK and by National Institute for Health Research.

The impact of COVID-19 on antibiotic prescribing in primary care in England: Evaluation and risk prediction of appropriateness of type and repeat prescribing.

BACKGROUND: This study aimed to predict risks of potentially inappropriate antibiotic type and repeat prescribing and assess changes during COVID-19. METHODS: With the approval of NHS England, we used OpenSAFELY platform to access the TPP SystmOne electronic health record (EHR) system and selected patients prescribed antibiotics from 2019 to 2021. Multinomial logistic regression models predicted patient's probability of receiving inappropriate antibiotic type or repeat antibiotic course for each common infection. RESULTS: The population included 9.1 million patients with 29.2 million antibiotic prescriptions. 29.1% of prescriptions were identified as repeat prescribing. Those with same day incident infection coded in the EHR had considerably lower rates of repeat prescribing (18.0%) and 8.6% had potentially inappropriate type. No major changes in the rates of repeat antibiotic prescribing during COVID-19 were found. In the 10 risk prediction models, good levels of calibration and moderate levels of discrimination were found. CONCLUSIONS: Our study found no evidence of changes in level of inappropriate or repeat antibiotic prescribing after the start of COVID-19. Repeat antibiotic prescribing was frequent and varied according to regional and patient characteristics. There is a need for treatment guidelines to be developed around antibiotic failure and clinicians provided with individualised patient information.

The Use of the TARGET Antibiotic Checklist to Support Antimicrobial Stewardship in England's Community Pharmacies.

Antimicrobial Stewardship (AMS) requires effective teamwork between healthcare professionals, with patients receiving consistent messages from all healthcare professionals on the appropriate antimicrobial use. Patient education may reduce patients' expectations to receive antibiotics for self-limiting conditions and reduce the pressure on primary care clinicians to prescribe antibiotics. The TARGET Antibiotic Checklist is part of the national AMS resources for primary care and aims to support interaction between community pharmacy teams and patients prescribed antibiotics. The Checklist, completed by the pharmacy staff with patients, invites patients to report on their infection, risk factors, allergies, and knowledge of antibiotics. The TARGET antibiotic checklist was part of the AMS criteria of England's Pharmacy Quality Scheme for patients presenting with an antibiotic prescription from September 2021 to May 2022. A total of 9950 community pharmacies claimed for the AMS criteria and 8374 of these collectively submitted data from 213,105 TARGET Antibiotic Checklists. In total, 69,861 patient information leaflets were provided to patients to aid in the knowledge about their condition and treatment. 62,544 (30%) checklists were completed for patients with an RTI; 43,093 (21%) for UTI; and 30,764 (15%) for tooth/dental infections. An additional 16,625 (8%) influenza vaccinations were delivered by community pharmacies prompted by discussions whilst using the antibiotic checklist. Community pharmacy teams promoted AMS using the TARGET Antibiotic Checklist, providing indication-specific education and positively impacting the uptake of influenza vaccinations.

Development of National Antimicrobial Intravenous-to-Oral Switch Criteria and Decision Aid.

INTRODUCTION: Antimicrobial stewardship (AMS) strategies, such as intravenous-to-oral switch (IVOS), promote optimal antimicrobial use, contributing to safer and more effective patient care and tackling antimicrobial resistance (AMR). AIM: This study aimed to achieve nationwide multidisciplinary expert consensus on antimicrobial IVOS criteria for timely switch in hospitalised adult patients and to design an IVOS decision aid to operationalise agreed IVOS criteria in the hospital setting. METHOD: A four-step Delphi process was chosen to achieve expert consensus on IVOS criteria and decision aid; it included (Step One) Pilot/1st round questionnaire, (Step Two) Virtual meeting, (Step Three) 2nd round questionnaire and (Step 4) Workshop. This study follows the Appraisal of Guidelines for Research and Evaluation II instrument checklist. RESULTS: The Step One questionnaire of 42 IVOS criteria had 24 respondents, 15 of whom participated in Step Two, in which 37 criteria were accepted for the next step. Step Three had 242 respondents (England n = 195, Northern Ireland n = 18, Scotland n = 18, Wales n = 11); 27 criteria were accepted. Step Four had 48 survey respondents and 33 workshop participants; consensus was achieved for 24 criteria and comments were received on a proposed IVOS decision aid. Research recommendations include the use of evidence-based standardised IVOS criteria. DISCUSSION AND CONCLUSION: This study achieved nationwide expert consensus on antimicrobial IVOS criteria for timely switch in the hospitalised adult population. For criteria operationalisation, an IVOS decision aid was developed. Further research is required to provide clinical validation of the consensus IVOS criteria and to expand this work into the paediatric and international settings.

Clinical and health inequality risk factors for non-COVID-related sepsis during the global COVID-19 pandemic: a national case-control and cohort study.

Background: Sepsis, characterised by significant morbidity and mortality, is intricately linked to socioeconomic disparities and pre-admission clinical histories. This study aspires to elucidate the association between non-COVID-19 related sepsis and health inequality risk factors amidst the pandemic in England, with a secondary focus on their association with 30-day sepsis mortality. Methods: With the approval of NHS England, we harnessed the OpenSAFELY platform to execute a cohort study and a 1:6 matched case-control study. A sepsis diagnosis was identified from the incident hospital admissions record using ICD-10 codes. This encompassed 248,767 cases with non-COVID-19 sepsis from a cohort of 22.0 million individuals spanning January 1, 2019, to June 31, 2022. Socioeconomic deprivation was gauged using the Index of Multiple Deprivation score, reflecting indicators like income, employment, and education. Hospitalisation-related sepsis diagnoses were categorised as community-acquired or hospital-acquired. Cases were matched to controls who had no recorded diagnosis of sepsis, based on age (stepwise), sex, and calendar month. The eligibility criteria for controls were established primarily on the absence of a recorded sepsis diagnosis. Associations between potential predictors and odds of developing non-COVID-19 sepsis underwent assessment through conditional logistic regression models, with multivariable regression determining odds ratios (ORs) for 30-day mortality. Findings: The study included 224,361 (10.2%) cases with non-COVID-19 sepsis and 1,346,166 matched controls. The most socioeconomic deprived quintile was associated with higher odds of developing non-COVID-19 sepsis than the least deprived quintile (crude OR 1.80 [95% CI 1.77-1.83]). Other risk factors (after adjusting comorbidities) such as learning disability (adjusted OR 3.53 [3.35-3.73]), chronic liver disease (adjusted OR 3.08 [2.97-3.19]), chronic kidney disease (stage 4: adjusted OR 2.62 [2.55-2.70], stage 5: adjusted OR 6.23 [5.81-6.69]), cancer, neurological disease, immunosuppressive conditions were also associated with developing non-COVID-19 sepsis. The incidence rate of non-COVID-19 sepsis decreased during the COVID-19 pandemic and rebounded to pre-pandemic levels (April 2021) after national lockdowns had been lifted. The 30-day mortality risk in cases with non-COVID-19 sepsis was higher for the most deprived quintile across all periods. Interpretation: Socioeconomic deprivation, comorbidity and learning disabilities were associated with an increased odds of developing non-COVID-19 related sepsis and 30-day mortality in England. This study highlights the need to improve the prevention of sepsis, including more precise targeting of antimicrobials to higher-risk patients. Funding: The UK Health Security Agency, Health Data Research UK, and National Institute for Health Research.

Tipping the balance: A systematic review and meta-ethnography to unfold the complexity of surgical antimicrobial prescribing behavior in hospital settings.

Surgical specialties account for a high proportion of antimicrobial use in hospitals, and misuse has been widely reported resulting in unnecessary patient harm and antimicrobial resistance. We aimed to synthesize qualitative studies on surgical antimicrobial prescribing behavior, in hospital settings, to explain how and why contextual factors act and interact to influence practice. Stakeholder engagement was integrated throughout to ensure consideration of varying interpretive repertoires and that the findings were clinically meaningful. The meta-ethnography followed the seven phases outlined by Noblit and Hare. Eight databases were systematically searched without date restrictions. Supplementary searches were performed including forwards and backwards citation chasing and contacting first authors of included papers to highlight further work. Following screening, 14 papers were included in the meta-ethnography. Repeated reading of this work enabled identification of 48 concepts and subsequently eight overarching concepts: hierarchy; fear drives action; deprioritized; convention trumps evidence; complex judgments; discontinuity of care; team dynamics; and practice environment. The overarching concepts interacted to varying degrees but there was no consensus among stakeholders regarding an order of importance. Further abstraction of the overarching concepts led to the development of a conceptual model and a line-of-argument synthesis, which posits that social and structural mediators influence individual complex antimicrobial judgements and currently skew practice towards increased and unnecessary antimicrobial use. Crucially, our model provides insights into how we might 'tip the balance' towards more evidence-based antimicrobial use. Currently, healthcare workers deploy antimicrobials across the surgical pathway as a safety net to allay fears, reduce uncertainty and risk, and to mitigate against personal blame. Our synthesis indicates that prescribing is unlikely to change until the social and structural mediators driving practice are addressed. Furthermore, it suggests that research specifically exploring the context for effective and sustainable quality improvement stewardship initiatives in surgery is now urgent.

An evidence-based surveillance tool to identify and report catheter/cannula bloodstream infection in patients receiving parenteral nutrition.

OBJECTIVE: Catheter/cannula-bloodstream infection (CBI) has been proposed as a marker of the quality of care provided to patients receiving parenteral nutrition (PN). However, surveillance criteria for CBI are variable, inconsistent, and sometimes confusing and impractical. Surveillance criteria were developed to simply and accurately demonstrate the presence or absence of CBI. The aim of this study was to establish a simple and valid surveillance tool, with consideration of changes in vital signs, to identify CBI in patients receiving PN. METHODS: Adult (≥18 y) inpatients prescribed PN at a single large teaching hospital were recruited between October 11, 2017 and November 16, 2018. Common clinical and laboratory criteria, including blood culture, associated with 100 consecutive PN episodes associated with suspected CBI were examined for potential predictive markers of CBI. Using binary logistic regression, criteria were incorporated into an instrument that was validated against a reference classification of CBI established by an expert multidisciplinary group. RESULTS: The reference classification comprised 12 PN episodes with CBI and 88 without. Abnormal vital signs did not significantly predict CBI, but resolution of fever (≥38°C) and low systolic blood pressure (<100 mm Hg) in response to a specific treatment for CBI (line removal/antibiotics) did. Two other criteria were also significant predictors: positive blood culture; and absence of an alternative source that could explain the septic episode other than the catheter/cannula supplying PN. These two criteria together with a positive response to treatment (temperature and/or blood pressure, incorporated into a single binary variable), resulted in 100% correct CBI classification (100% sensitivity, 100% specificity, and 1.000 area under the curve in receiver operating characteristic analysis). All criteria could be retrospectively extracted from the medical records of all PN episodes. CONCLUSION: A CBI tool shows promise as a surveillance instrument for benchmarking and interinstitutional comparisons of the care received by hospitalized patients given PN.

'It makes life so much easier'-experiences of users of the MicroGuide™ smartphone app for improving antibiotic prescribing behaviour in UK hospitals: an interview study.

OBJECTIVES: To understand the impact on prescribing behaviour of an antimicrobial therapy guidelines smartphone app, in widespread use in hospitals in the UK. METHODS: Twenty-eight doctors and five nurse prescribers from four purposively selected hospitals in the UK participated in behavioural theory-informed semi-structured interviews about their experiences of using the MicroGuide™ smartphone app. Data were analysed using a thematic content analysis. RESULTS: Five themes emerged from the interview data: convenience and accessibility; validation of prescribing decisions; trust in app content; promotion of antimicrobial stewardship; and limitations and concerns. Participants appreciated the perceived convenience, accessibility and timesaving attributes of the app, potentially contributing to more prompt treatment of patients with time-critical illness. The interviewees also reported finding it reassuring to use the app to support decision-making and to validate existing knowledge. They trusted the app content authored by local experts and considered it to be evidence-based and up-to-date. This was believed to result in fewer telephone calls to the microbiology department for advice. Participants recognized the value of the app for supporting the goals of antimicrobial stewardship by promoting the responsible and proportionate use of antimicrobials. Finally, a number of limitations of the app were reported, including the risk of de-skilling trainees, cultural problems with using smartphones in clinical environments and software technical problems. CONCLUSIONS: The MicroGuide app was valued as a means of addressing an unmet need for updated, concise, trustworthy specialist information in an accessible format at the bedside to support safe and effective antimicrobial prescribing.

Evaluating Ceftriaxone 80 mg/kg Administration by Rapid Intravenous Infusion-A Clinical Service Evaluation.

In pediatric ambulatory care, the speed of medication infusion can have major impact on healthcare staff workload and the number of children able to be treated by services designed to reduce inpatient length of stay. In many regions of the world, local and supraregional guidelines allow ceftriaxone infusions of ≥50 mg/kg in infants and children up to 12 years of age to be given over 10 minutes. The generic European summary of product characteristics for ceftriaxone does not state a specific infusion time for this dose range, although 1 manufacturers' summary of product characteristics in the United Kingdom states a 30-minute minimum infusion time. We conducted a formal service evaluation of a change in practice at a large UK pediatric children's hospital and demonstrated the clinical feasibility, safety, and high parent satisfaction of 10-minute ceftriaxone infusions for prescribed doses ≥50 mg/kg. This approach can improve patient flow within hospital-based ambulatory services as well as by community nursing teams administering antibiotics at home.

Antibiotic Review Kit for Hospitals (ARK-Hospital): study protocol for a stepped-wedge cluster-randomised controlled trial.

BACKGROUND: To ensure patients continue to get early access to antibiotics at admission, while also safely reducing antibiotic use in hospitals, one needs to target the continued need for antibiotics as more diagnostic information becomes available. UK Department of Health guidance promotes an initiative called 'Start Smart then Focus': early effective antibiotics followed by active 'review and revision' 24-72 h later. However in 2017, < 10% of antibiotic prescriptions were discontinued at review, despite studies suggesting that 20-30% of prescriptions could be stopped safely. METHODS/DESIGN: Antibiotic Review Kit for Hospitals (ARK-Hospital) is a complex 'review and revise' behavioural intervention targeting healthcare professionals involved in antibiotic prescribing or administration in inpatients admitted to acute/general medicine (the largest consumers of non-prophylactic antibiotics in hospitals). The primary study objective is to evaluate whether ARK-Hospital can safely reduce the total antibiotic burden in acute/general medical inpatients by at least 15%. The primary hypotheses are therefore that the introduction of the behavioural intervention will be non-inferior in terms of 30-day mortality post-admission (relative margin 5%) for an acute/general medical inpatient, and superior in terms of defined daily doses of antibiotics per acute/general medical admission (co-primary outcomes). The unit of observation is a hospital organisation, a single hospital or group of hospitals organised with one executive board and governance framework (National Health Service trusts in England; health boards in Northern Ireland, Wales and Scotland). The study comprises a feasibility study in one organisation (phase I), an internal pilot trial in three organisations (phase II) and a cluster (organisation)-randomised stepped-wedge trial (phase III) targeting a minimum of 36 organisations in total. Randomisation will occur over 18 months from November 2017 with a further 12 months follow-up to assess sustainability. The behavioural intervention will be delivered to healthcare professionals involved in antibiotic prescribing or administration in adult inpatients admitted to acute/general medicine. Outcomes will be assessed in adult inpatients admitted to acute/general medicine, collected through routine electronic health records in all patients. DISCUSSION: ARK-Hospital aims to provide a feasible, sustainable and generalisable mechanism for increasing antibiotic stopping in patients who no longer need to receive them at 'review and revise'. TRIAL REGISTRATION: ISRCTN Current Controlled Trials, ISRCTN12674243 . Registered on 10 April 2017.

Adaptation of the WHO Essential Medicines List for national antibiotic stewardship policy in England: being AWaRe.

OBJECTIVES: Appropriate use of and access to antimicrobials are key priorities of global strategies to combat antimicrobial resistance (AMR). The WHO recently classified key antibiotics into three categories (AWaRe) to improve access (Access), monitor important antibiotics (Watch) and preserve effectiveness of 'last resort' antibiotics (Reserve). This classification was assessed for antibiotic stewardship and quality improvement in English hospitals. METHODS: Using an expert elicitation exercise, antibiotics used in England but not included in the WHO AWaRe index were added to an appropriate category following a workshop consensus exercise with national experts. The methodology was tested using national antibiotic prescribing data and presented by primary and secondary care. RESULTS: In 2016, 46/108 antibiotics included within the WHO AWaRe index were routinely used in England and an additional 25 antibiotics also commonly used in England were not included in the WHO AWaRe index. WHO AWaRe-excluded and -included antibiotics were reviewed and reclassified according to the England-adapted AWaRE index with the justification by experts for each addition or alteration. Applying the England-adapted AWaRe index, Access antibiotics accounted for the majority (60.9%) of prescribing, followed by Watch (37.9%) and Reserve (0.8%); 0.4% of antibiotics remained unclassified. There was unexplained 2-fold variation in prescribing between hospitals within each AWaRe category, highlighting the potential for quality improvement. CONCLUSIONS: We have adapted the WHO AWaRe index to create a specific index for England. The AWaRe index provides high-level understanding of antibiotic prescribing. Subsequent to this process the England AWaRe index is now embedded into national antibiotic stewardship policy and incentivized quality improvement schemes.

Measuring Appropriate Antibiotic Prescribing in Acute Hospitals: Development of a National Audit Tool Through a Delphi Consensus.

This study developed a patient-level audit tool to assess the appropriateness of antibiotic prescribing in acute National Health Service (NHS) hospitals in the UK. A modified Delphi process was used to evaluate variables identified from published literature that could be used to support an assessment of appropriateness of antibiotic use. At a national workshop, 22 infection experts reached a consensus to define appropriate prescribing and agree upon an initial draft audit tool. Following this, a national multidisciplinary panel of 19 infection experts, of whom only one was part of the workshop, was convened to evaluate and validate variables using questionnaires to confirm the relevance of each variable in assessing appropriate prescribing. The initial evidence synthesis of published literature identified 25 variables that could be used to support an assessment of appropriateness of antibiotic use. All the panel members reviewed the variables for the first round of the Delphi; the panel accepted 23 out of 25 variables. Following review by the project team, one of the two rejected variables was rephrased, and the second neutral variable was re-scored. The panel accepted both these variables in round two with a 68% response rate. Accepted variables were used to develop an audit tool to determine the extent of appropriateness of antibiotic prescribing at the individual patient level in acute NHS hospitals through infection expert consensus based on the results of a Delphi process.

Opportunities for antimicrobial stewardship in patients with acute bacterial skin and skin structure infections who are unsuitable for beta-lactam antibiotics: a multicenter prospective observational study.

PURPOSE: The objective of this prospective, observational study was to describe the treatment, severity assessment and healthcare resources required for management of patients with acute bacterial skin and skin structure infections who were unsuitable for beta-lactam antibiotic treatments. METHODS: Patients were enrolled across five secondary care National Health Service hospitals. Eligible patients had a diagnosis of acute bacterial skin and skin structure infection and were considered unsuitable for beta-lactam antibiotics (e.g. confirmed/suspected methicillin-resistant Staphylococcus aureus, beta-lactam allergy). Data regarding diagnosis, severity of the infection, antibiotic treatment and patient management were collected. RESULTS: 145 patients with acute bacterial skin and skin structure infection were included; 79% (n = 115) patients received greater than two antibiotic regimens; median length of the first antibiotic regimen was 2 days (interquartile range of 1-5); median time to switch from intravenous to oral antibiotics was 4 days (interquartile range of 3-8, n = 72/107); 25% (n = 10/40) patients with Eron class 1 infection had systemic inflammatory response syndrome, suggesting they were misclassified. A higher proportion of patients with systemic inflammatory response syndrome received treatment in an inpatient setting, and their length of stay was prolonged in comparison with patients without systemic inflammatory response syndrome. CONCLUSION: There exists an urgent need for more focused antimicrobial stewardship strategies and tools for standardised clinical assessment of acute bacterial skin and skin structure infection severity in patients who are unsuitable for beta-lactam antibiotics. This will lead to optimised antimicrobial treatment strategies and ensure effective healthcare resource utilisation.

Isolation and purification of recombinant immunoglobulin light chain variable domains from the periplasmic space of Escherichia coli.

Immunoglobulin light chain amyloidosis is the most common form of systemic amyloidosis. However, very little is known about the underlying mechanisms that initiate and modulate the associated protein aggregation and deposition. Model systems have been established to investigate these disease-associated processes. One of these systems comprises two 114 amino acid light-chain variable domains of the kappa 4 IgG family, SMA and LEN. Despite high sequence identity (93%), SMA is amyloidogenic in vivo, but LEN adopts a stable dimer, displaying amyloidogenic properties only under destabilising conditions in vitro. We present here a refined and reproducible periplasmic expression and purification protocol for SMA and LEN that improves on existing methods and provides high yields of pure protein (10-50mg/L), particularly suitable for structural studies that demand highly concentrated and purified proteins. We confirm that recombinant SMA and LEN proteins have structure and dimerization capabilities consistent with the native proteins and employ fluorescence to probe internalization and cellular localization within cardiomyocytes. We propose periplasmic expression and simplified chromatographic steps outlined here as an optimized method for production of these and other variable light chain domains to investigate the underlying mechanisms of light chain amyloidosis. We show that SMA and LEN can be internalised within cardiomyocytes and were observed to localise to the perinuclear area, assessed by confocal microscopy as a possible mechanism for underlying cytotoxicity and pathogenesis associated with amyloidosis.

Terahertz: dictating the frequency of life. Do macromolecular vibrational modes impose thermal limitations on terrestrial life?

Conditions on exoplanets include elevated temperatures and pressures. The response of carbon-based biological macromolecules to such conditions is then relevant to the viability of life. The capacity of proteins and ribozymes to catalyse reactions or bind receptors, and nucleic acids to convey information, depends on them sampling different conformational states. These are determined by macromolecular vibrational states, or phonon modes, accessible using terahertz (THz: 1012Hz) absorption spectroscopy. THz spectra of biological macromolecules exhibit broad absorption at approximately 6 THz (equating to approx. 280 K) corresponding to dense transitions between phonon modes. There are also troughs at approximately 10 THz (approx. 500 K) implying diminishing numbers of available conformational states at higher temperatures; hence, fewer routes by which biochemical processes can be realized, as equilibrium is approached. Could this conformational bottleneck hinder the operation of biological macromolecules at higher temperatures? We suggest that the troughs at approximately 10 THz in absorbance spectra indicate that the hydrogen bonds, charge interactions and geometry of biological macromolecules associated with terrestrial life impose fundamental vibrational properties that could limit the upper temperature at which they may function.

Effect of amino acid mutations on the conformational dynamics of amyloidogenic immunoglobulin light-chains: A combined NMR and in silico study.

The conformational dynamics of a pathogenic κ4 human immunoglobulin light-chain variable domain, SMA, associated with AL amyloidosis, were investigated by 15N relaxation dispersion NMR spectroscopy. Compared to a homologous light-chain, LEN, which differs from SMA at eight positions but is non-amyloidogenic in vivo, we find that multiple residues in SMA clustered around the N-terminus and CDR loops experience considerable conformational exchange broadening caused by millisecond timescale protein motions, consistent with a destabilized dimer interface. To evaluate the contribution of each amino acid substitution to shaping the dynamic conformational landscape of SMA, NMR studies were performed for each SMA-like point mutant of LEN followed by in silico analysis for a subset of these proteins. These studies show that a combination of only three mutations located within or directly adjacent to CDR3 loop at the dimer interface, which remarkably include both destabilizing (Q89H and Y96Q) and stabilizing (T94H) mutations, largely accounts for the differences in conformational flexibility between LEN and SMA. Collectively, our studies indicate that a correct combination of stabilizing and destabilizing mutations is key for immunoglobulin light-chains populating unfolded intermediates that result in amyloid formation, and underscore the complex nature of correlations between light-chain conformational flexibility, thermodynamic stability and amyloidogenicity.