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Strategies to reduce antibiotic overuse in hospitals depend on prescribers taking decisions to stop unnecessary antibiotic use. There is scarce evidence for how to support these decisions. We evaluated a multifaceted behaviour change intervention (ie, the antibiotic review kit) designed to reduce antibiotic use among adult acute general medical inpatients by increasing appropriate decisions to stop antibiotics at clinical review.We performed a stepped-wedge, cluster (hospital)-randomised controlled trial using computer-generated sequence randomisation of eligible hospitals in seven calendar-time blocks in the UK. Hospitals were eligible for inclusion if they admitted adult non-elective general or medical inpatients, had a local representative to champion the intervention, and could provide the required study data. Hospital clusters were randomised to an implementation date occurring at 1-2 week intervals, and the date was concealed until 12 weeks before implementation, when local preparations were designed to start. The intervention effect was assessed using data from pseudonymised routine electronic health records, ward-level antibiotic dispensing, Clostridioides difficile tests, prescription audits, and an implementation process evaluation. Co-primary outcomes were monthly antibiotic defined daily doses per adult acute general medical admission (hospital-level, superiority) and all-cause mortality within 30 days of admission (patient level, non-inferiority margin of 5%). Outcomes were assessed in the modified intention-to-treat population (ie, excluding sites that withdrew before implementation). Intervention effects were assessed by use of interrupted time series analyses within each site, estimating overall effects through random-effects meta-analysis, with heterogeneity across prespecified potential modifiers assessed by use of meta-regression. This trial is completed and is registered with ISRCTN, ISRCTN12674243.58 hospital organisations expressed an interest in participating. Three pilot sites implemented the intervention between Sept 25 and Nov 20, 2017. 43 further sites were randomised to implement the intervention between Feb 12, 2018, and July 1, 2019, and seven sites withdrew before implementation. 39 sites were followed up for at least 14 months. Adjusted estimates showed reductions in total antibiotic defined daily doses per acute general medical admission (-4·8% per year, 95% CI -9·1 to -0·2) following the intervention. Among 7 160 421 acute general medical admissions, the ARK intervention was associated with an immediate change of -2·7% (95% CI -5·7 to 0·3) and sustained change of 3·0% (-0·1 to 6·2) in adjusted 30-day mortality.The antibiotic review kit intervention resulted in sustained reductions in antibiotic use among adult acute general medical inpatients. The weak, inconsistent intervention effects on mortality are probably explained by the onset of the COVID-19 pandemic. Hospitals should use the antibiotic review kit to reduce antibiotic overuse.UK National Institute for Health and Care Research.

BackgroundStrategies to reduce antibiotic overuse in hospitals depend on clinicians taking decisions to stop unnecessary antibiotics. There is a lack of evidence on how support clinicians do this effectively. We evaluated a multifaceted behaviour change intervention (ARK) which aims to reduce antibiotic consumption in hospitals by increasing decisions to stop antibiotics at clinical review.MethodsWe performed a stepped-wedge, hospital-level, cluster-randomised controlled trial using computer-generated sequence randomisation of 39 acute hospitals to 7 calendar-time blocks (12/February/2018–01/July/2019). Co-primary outcomes were monthly antibiotic defined-daily-doses (DDD) per acute/medical admission (organisation-level, superiority) and all-cause 30-day mortality (patient-level, non-inferiority, margin 5%). Clusters were eligible if they admitted non-elective medical patients, could identify an intervention “champion” and provide pre-intervention data from February/2016. Sites were followed up for a minimum of 14 months. Intervention effects were assessed using interrupted time series analyses in each cluster. Overall effects were derived through random-effects meta-analysis, using meta-regression to assess heterogeneity in effects across prespecified factors. Trial registration was ISRCTN12674243.FindingsAdjusted estimates showed a year-on-year reduction in antibiotic consumption (−4.8%, 95%CI: -9.1%,-0.2%, p=0.042) following the ARK intervention. Among 7,160,421 acute/medical admissions, we observed a -2.7% (95%CI: -5.7%,+0.3%, p=0.079) immediate and +3.0% (95%CI: - 0.1%,+6.2%, p=0.060) sustained change in adjusted 30-day mortality. This mortality trend was not related to the magnitude of antibiotic reduction achieved (Spearman’s ρ=0.011, p=0.949). Whilst 90-day mortality odds appeared to increase over time (+3.9%, 95%CI:+0.5%,+7.4%, p=0.023), this was not observed among admissions before COVID-19 onset (+3.2%, 95%CI:-1.5%,+8.2%, p=0.182). Length of hospital stay was unaffected.InterpretationThe weak, inconsistent effects of the intervention on mortality are likely to be explained by the COVID-19 pandemic onset during the post-implementation phase. We conclude that the ARK-intervention resulted in sustained, safe reductions in hospital antibiotic use.FundingNIHR Programme Grants for Applied Research, RP-PG-0514-20015.Research in contextEvidence before this studyAcutely ill patients often need to receive antibiotics before full diagnostic information is available. Consequently, reducing overuse of antibiotics in hospitals requires clinicians to review and where appropriate, stop unnecessary antibiotic prescriptions. Evidence-based tools to support clinicians stop unnecessary antibiotics do not exist.We searched PubMed, with no language or date restrictions, on 31/January/2022 for clinical studies focused on improving antibiotic use for hospitalised adults using the terms “anti-bacterial agents therapeutic use” AND “antibiotic stewardship”. Among the 427 studies found, the great majority were uncontrolled evaluations of different approaches to education, decision support and feedback. These included one before-after study, which found no impact of unsupported clinician-led prescription review. Three small, hospital-level cluster-randomised trials were identified. One evaluated different approaches to feedback, one compared different hospital specialties and one found intense feedback to be effective. All were small and none considered clinical outcomes or sustainability. There is a need for research to deliver proven interventions ready for implementation into practice.Added value of this studyWe evaluated a multifaceted “Antibiotic Review Kit” (ARK) intervention to support prescribers to appropriately stop antibiotics at clinical review. ARK comprises a prescription decision-aid supported by a brief online training tool, guidance on implementation (including regular data collection and feedback) and a patient information leaflet. We found that the intervention was associated with a sustained reduction in hospital-level antibiotic use overall and of oral and narrow-spectrum antibiotics specifically. Weak trends were observed for 30-day mortality in opposite directions for immediate and sustained impact. Although there was a sustained increase in 90-day mortality after the intervention, this was only seen when analyses included patients admitted after the start of the COVID-19 pandemic. Taken together we conclude that these mortality effects are unrelated to the intervention.Implications of all available evidenceThe ARK intervention is safe and effective in reducing antibiotic use among adult medical hospital admissions. The tools used are now freely available for adoption into practice.

Serious concerns have been raised about a possible increase in cases of Clostridioides difficile infection (CDI) during the COVID-19 pandemic. We conducted a retrospective observational single centre study which revealed that total combined community and hospital-based quarterly rates of CDI decreased during the pandemic compared to the pre-pandemic period.

Background To assess the feasibility of its use in OPAT via continuous infusion, the stability of temocillin solutions at clinically relevant concentrations in two elastomeric infusion devices (B. Braun Medical Ltd Easypump® II LT 270-27- S and Spirit Ltd Medical Dosi-Fuser® L25915-250D1) was evaluated during 14 days of (2°C–8°C) fridge storage followed by 24 h exposure in-use temperature at 32°C, when reconstituted with 0.3% citrate buffer at pH 7. Methods Stability testing was conducted in accordance with the standard protocols for deriving and assessment of stability of small molecule aseptic preparation as per the latest UK National Health Service Pharmaceutical Quality Assurance Committee Yellow Cover Document (YCD) requirements. A stability indicating assay method was developed with an ultra-HPLC (UHPLC) system using photodiode array detector. Temocillin concentrations corresponding to low (500 mg/240 mL), intermediate (4000 mg/240 mL) and high (6000 mg/240 mL) dose in triplicate devices were tested with duplicate samples at 11 timepoints during 14 days of fridge storage followed by 24 h in-use temperature exposure at 32°C. Results A total of 396 samples were collected and assayed. The percentage of temocillin remaining after 14 days of fridge storage was greater than 97% in both devices and at all concentrations tested. During in-use temperature, 95% stability limit was achieved for 12 h for all doses and devices tested except for the high concentration in the Dosi-Fuser® device, which met this criterion for only 10 h of in-use temperature exposure. Conclusions Temocillin reconstituted with 0.3% citrate buffer at pH 7 in elastomeric infusion devices can be stored in a fridge (2°C–8°C) for 2 weeks, meeting the YCD acceptance criteria of

Objectives To investigate the effect of pH control through the use of a citrate-buffered saline diluent pH 7 on the degradation rate of piperacillin/tazobactam solutions for infusion and to determine if an extended shelf-life of up to 13 days fridge 2°C–8°C plus 24 hours ‘in-use’ at 32°C in two elastomeric devices: FOLFusor LV10 (Baxter Healthcare, Thetford, UK) and Easypump II (B. Braun Medical Ltd, Sheffield, UK) can be achieved. Methods Testing was as per the latest National Health Service (NHS) Pharmaceutical Quality Assurance Committee Yellow Cover Document (YCD) requirements. A validated stability indicating high-performance liquid chromatography method was used for assessing the stability of the solutions of piperacillin/tazobactam at a combined concentration of 25 mg/mL and 90 mg/mL respectively. Solutions were tested in two batches in replicate (n=3) at five time points according to the requirements of the YCD. Results Piperacillin/tazobactam stability was significantly improved when 0.3% w/v citrate-buffered saline pH 7 was used as the diluent, compared with using 0.9% w/v saline as diluent. Greater than 95% of the zero-time concentration of both actives remained following storage at 2°C–8°C for up to 13 days plus 24 hours at 32°C in both devices. The data support extended storage of up to 13 days 2°C–8°C plus 24 hours at 32°C ‘in-use’ when using FOLFusor LV10 (Baxter) or Easypump II (B. Braun) pump devices. Conclusions The enhanced stability complies with UK national standards as stated in the YCD for stability testing of aseptically produced small molecules and supports the storage of piperacillin/tazobactam for up to 13 days 2°C–8°C plus 24 hours at 32°C ‘in-use’ within two elastomeric pump devices. The extended shelf-life provides a significant advantage over the stability of piperacillin/tazobactam solutions for infusion when reconstituted and diluted in 0.9% w/v saline as diluent. The data open up the possibility of a continuous infusion of piperacillin/tazobactam delivered by elastomeric pump devices over 24 hours in an outpatient parenteral antimicrobial therapy setting.

Objectives To investigate the stability of ceftolozane/tazobactam 5 mg/mL and 20 mg/mL solutions for infusion in two elastomeric devices: FOLFusor LV10 (Baxter Healthcare) and Easypump® II (B. Braun Medical Ltd) and determine if an extended shelf life of up to 8 days storage at 2–8°C plus 24 h ‘in use’ at 32°C was achievable. Methods Testing was as per the latest NHS Pharmaceutical Quality Assurance Committee Yellow Cover Document (YCD) requirements. A stability-indicating LC method was used for assessing the stability of solutions of ceftolozane/tazobactam at 5 mg/mL and 20 mg/mL (combined concentration of both actives) respectively, tested in two batches in triplicate (n = 3) at five timepoints according to the requirements of the YCD. Results Ceftolozane/tazobactam, diluted in 0.9% w/v sodium chloride at 5 mg/mL and 20 mg/mL, degraded during in-use storage at 32°C with Conclusions Solutions of ceftolozane/tazobactam can be administered in outpatient parenteral antimicrobial therapy (OPAT) services following refrigerated storage for up to 8 days, when limited to a 12 h infusion at in-use temperature of 32°C. For UK OPAT services where twice daily dosing is feasible, our data provides another treatment option for challenging infections. In countries where a 10% loss of ceftolozane/tazobactam is acceptable, a 24 h infusion is supported by the data.

Objectives To investigate the effect of pH and buffers on the degradation rate of flucloxacillin and to determine if flucloxacillin can be stabilised using a buffered diluent for up to 14 days when stored at 2°C–8°C including a 24-hour infusion period at 32°C in two elastomeric devices (Accufuser and INfusor LV) filled to 240 mL. Testing as per the NHS Pharmaceutical Quality Assurance Committee Yellow Cover Document (YCD) requirements. Methods A validated stability indicating high-performance liquid chromatography method was used for assessing the stability of flucloxacillin diluted in 0.3% w/v citrate-buffered saline pH 7.0 when stored at 2°C–8°C in two ambulatory devices (Accufuser and INfusor LV). Flucloxacillin at 10 and 50 mg/mL diluted in 0.3% w/v citrate-buffered saline pH 7.0 to a final volume of 240 mL and stored at 2°C–8°C, including 24 hours at 32°C, was tested from two batches in replicate (n=3) at five time points for up to 14 days according to the requirements of the YCD. Results Greater than 95% of the zero-time concentration of flucloxacillin at 10 and 50 mg/mL remained when stored at 2°C–8°C after 14 days including 24 hours at 32°C in both Accufuser and INfusor LV devices. Conclusions Flucloxacillin sodium stability was improved, and complied with UK national standards, by using a diluent of 0.3% w/v citrate-buffered saline pH 7 in both Accufuser and INfusor LV ambulatory devices when filled to 240 mL. The data support assigning a shelf-life of up to 14 days (13 days stored at 2°C–8°C and 24 hours at 32°C). Flucloxacillin may now be used appropriately as a continuous 24-hour infusion in outpatient parenteral antimicrobial therapy services, providing further opportunity to avoid or shorten patient hospital stays, as well as support ideal antimicrobial stewardship principles.

Objectives To determine the influence of different buffers, pH and meropenem concentrations on the degradation rates of meropenem in aqueous solution during storage at 32°C, with the aim of developing a formulation suitable for 24-hour infusion in an ambulatory elastomeric device, compliant with the latest National Health Service Pharmaceutical Quality Assurance Committee Yellow Cover Document (YCD) requirements. Methods Meropenem was diluted to 6.25 mg/mL and 25 mg/mL in aqueous solutions adjusted to various pH with phosphate or citrate buffer and assessed for stability. Meropenem concentrations were determined using a validated stability-indicating high-performance liquid chromatography method at time 0 and following storage for up to 24 hours at 32°C as per the YCD requirements. Results Degradation was observed to be slowest in citrate buffer around pH 7 and at a meropenem concentration of 6.25 mg/mL; however, losses exceeded 10% after storage for 24 hours at 32°C in all of the diluents tested in the study. Conclusions Meropenem at concentrations between 6.25 mg/mL and 25 mg/mL as tested is not sufficiently stable to administer as a 24-hour infusion in ambulatory device reservoirs. If the YCD 95% minimum content limit is applied, the infusion period must be reduced to less than 6 hours for body-worn devices, especially at the higher concentration studied (25 mg/mL). This limits the possibility of using elastomeric devices to deliver continuous infusions of meropenem as part of a wider outpatient parenteral antimicrobial therapy service.

Objectives We determined the available mechanisms to generate income from outpatient parenteral antimicrobial therapy (OPAT) in the UK and calculated the revenue generated from treatment of an episode of cellulitis. Methods Revenue was calculated for patients receiving treatment for cellulitis as an inpatient and for patients receiving OPAT by a series of different payment pathways. Selected established OPAT services in Northern Ireland, Scotland and Wales, where Payment-by-Results (PbR) does not operate, were contacted to determine individual national funding arrangements. Results In England, a traditional inpatient episode for uncomplicated cellulitis requiring 7 days of treatment generated £1361 of revenue, while OPAT generated revenue ranging from £773 to £2084 for the same length of treatment depending on the payment pathway used. Treatment using OPAT to avoid admission entirely generated £2084, inpatient admission followed by transfer to a virtual OPAT ward at day 2 generated £1361 and inpatient admission followed by discharge from hospital to OPAT at day 2 generated £773. In Northern Ireland, Scotland and Wales block contracts were used and no income was calculable for an individual episode of cellulitis. Conclusions No single funding mechanism supports OPAT across the UK. In England, revenue generated by OPAT providers from treatment of cellulitis varied with the OPAT payment pathway used, but equalled or exceeded the income generated from equivalent inpatient care. Cost savings for OPAT and reuse of released inpatient beds will increase revenue further. A single OPAT tariff is proposed.

Background Outpatient parenteral antimicrobial therapy (OPAT) is an established approach to patient care, the benefits of which are clinical, financial and preferred place of care for patients. In order to maximise these benefits ‘once daily’ antimicrobials should be used. Antimicrobial stewardship principles state that, where possible, narrow spectrum, organism specific agents should be used for infection management. Commercially available narrow spectrum agents frequently require administration 2, 3 or more times each day. A dilemma for OPAT services arises therefore to either: (1) use once daily broad spectrum antimicrobials going against stewardship principles; (2) administer narrow spectrum agents as a continuous infusion via a portable medical device. Purpose Medicines administration via a portable device requires appropriate stability data. The Yellow Covered Document (YCD) stipulates the minimum dataset for assessment of stability. To facilitate OPAT services to adhere to stewardship requirements and access stability data for narrow spectrum agents, a comprehensive literature review was undertaken. This review assessed the published antimicrobial stability literature available and its compliance with the dataset required by the YCD. Material and methods Searches were conducted in Medline, EMBASE, Global Health, International Pharmaceutical Abstracts and Biomedical Research Database in April 2014 and November 2015. Results 420 records were identified, 299 of which were excluded following title and abstract review. Full text review of 121 citations identified no papers that met the dataset requirements of the YCD. Conclusion Access to stability data in administration devices is a barrier to service expansion within the antimicrobial stewardship agenda. This review found no published studies that fully complied with YCD standards for shelf-life extension. References and/or acknowledgements The Yellow Covered Document: A Standard Protocol for Deriving and Assessment of Stability- Part 1. Third Edition, 2015. NHS Pharmaceutical Quality Assurance Committee. Conflict of interest: Corporate sponsored research or other substantive relationships: MG and TH serve on the BSAC UK OPAT Initiative Steering Group receiving reimbursement of travel expenses only from the BSAC for attending and speaking at OPAT related events. MG reports attending advisory boards for Merck, Pfizer, Gilead and receiving educational travel and speaker grants from Merck and Astellas Pharmaceuticals/Sanofi, respectively. MS has attended an advisory board for Baxter. TH has received support to attend conferences from Sanofi, Astellas and Novartis and attended advisory board for Cubist, Astra Zeneca, MSD, Novartis and Ferring Pharmaceuticals Ltd.

Background Outpatient parenteral antimicrobial therapy (OPAT) is an established approach to patient care. A lack of data on antimicrobial stability within administration devices is a barrier to service expansion, and poses an antimicrobial stewardship dilemma. Often broad-spectrum, long half-life agents are used instead of narrow-spectrum agents, which need more frequent administration, but could possibly be used if stability data were available. Objectives To complete a comprehensive literature review of published antimicrobial stability data, and assess these against a nationally recognized minimum dataset for medicines compounded into administration devices. Methods Medline, EMBASE, Global Health, International Pharmaceutical Abstracts and Biomedical Research Database were interrogated in April 2014 and updated in November 2015. Results A total of 420 citations were reviewed with 121 selected for full text review. None of these papers met the inclusion criteria stipulated in the national standards. The most frequent reason for study exclusion was the tolerance limit for the level of the active pharmaceutical ingredient being wider than 95%-105% and absence of 'in-use' testing at 37 °C. Conclusions This review found no published studies that comply with UK national standards for stability testing. We recommend further research and publication of antimicrobial stability data to support OPAT within the antimicrobial stewardship agenda.

To describe the methodology in developing an antimicrobial self-assessment toolkit (ASAT).The ASAT was developed through a National Pharmacy Reference Group using an evidence-based approach of published information and national reports to identify criteria for inclusion. These were subdivided into domains that addressed: 1) Antimicrobial management within the Trust-structures and lines of responsibility and accountability-high-level notification to the Board. 2) Operational delivery of an antimicrobial strategy-operational standards of good antimicrobial stewardship. 3) Risk assessment for antimicrobial chemotherapy. 4) Clinical governance assurance. 5) Education and training-training needs and delivery of education and training for all who issue, prescribe and administer antimicrobials. 6) Antimicrobial pharmacist-systems in place for ensuring their optimum use. 7) Patients, Carers and the Public-information needs of patients, carers and the public.A web-based toolkit was developed using information from national reports and guidance on antimicrobial stewardship. The toolkit offers a checklist for hospitals to self-assess their organizations' levels of antimicrobial stewardship.The ASAT offers a web-enabled, version-controlled instrument for the assessment of antimicrobial stewardship in acute hospitals. It may offer a sensitive instrument to assess longitudinal progress on antimicrobial stewardship in an individual institution or act as a benchmark with similar organizations. Further work is ongoing to evaluate and further refine the ASAT.