Evaluation of the stability of ceftazidime/avibactam in elastomeric infusion devices used for outpatient parenteral antimicrobial therapy utilizing a national stability protocol framework.

Objectives: To evaluate the stability of ceftazidime/avibactam in elastomeric infusers, utilizing the UK's Yellow Cover Document (YCD) stability testing framework, in conditions representative of OPAT practice. Methods: Ceftazidime/avibactam was reconstituted with sodium chloride 0.9% (w/v) in two elastomeric infusers at concentrations (dose) levels of 1500/375, 3000/750 and 6000 mg/1500 mg in 240 mL. The infusers were exposed to a fridge storage (2°C-8°C) for 14 days followed by 24 h in-use temperature (32°C). Results: After 14 days of fridge storage and subsequent 24 h exposure to 32°C, mean ±â€ŠSD of ceftazidime percent remaining was 75.5% ±â€Š1.8%, 79.9% ±â€Š1.1%, 82.4% ±â€Š0.6%, for Easypump, and 81.7% ±â€Š1.2%, 82.5% ±â€Š0.5%, 85.4% ±â€Š1.1% for Dosi-Fuser devices at the high, intermediate and low doses tested, respectively. For avibactam, mean ±â€ŠSD percent remaining was 83.2% ±â€Š1.8%, 87.4% ±â€Š2.0%, 93.1% ±â€Š0.9% for Easypump, and 85.1% ±â€Š2.0%, 86.7% ±â€Š0.1%, 92.5% ±â€Š0.1% for Dosi-Fuser devices. The cumulative amount of pyridine generated in the devices ranged from 10.4 mg at low dose to 76.9 mg at high dose. Regression-based simulation showed that the degradation of both ceftazidime and avibactam was <10% for at least 12 h of the running phase, if stored in a fridge for not more than 72 h prior to in-use temperature exposure. Conclusions: Whilst not meeting the strict UK YCD criteria for ≤5% degradation, ceftazidime/avibactam may be acceptable to administer as a continuous 12 hourly infusion in those territories where degradation of ≤10% is deemed acceptable.

Evaluation of the stability of aciclovir in elastomeric infusion devices used for outpatient parenteral antimicrobial therapy.

OBJECTIVES: To investigate the stability of aciclovir solutions in elastomeric devices used for outpatient parenteral antimicrobial therapy (OPAT). METHODS: Triplicates of two elastomeric devices, Accufuser and Easypump II, were filled with a solution of 200 mg, 2400 mg, and 4500 mg aciclovir in 240 mL 0.9% w/v saline. Devices were stored at room temperature for 14 days, followed by 24 hours storage at 32°C. Assessment using a stability indicating assay, pH and subvisible particle analysis was undertaken at 11 time points throughout the study. RESULTS: Aciclovir solution at 200 mg and 2400 mg in 240 mL was stable for 14 days at room temperature (<20°C) and 24 hours of 32°C 'in-use' temperature exposure, remaining above the 95% limit for NHS stability protocols. The high dose was also stable for 14 days at room temperature, but when stored at 32°C there was precipitation of aciclovir within 4 hours in both devices. The precipitate was confirmed as aciclovir and precipitation was not a sign of chemical degradation. CONCLUSIONS: Aciclovir concentrations above 2400 mg/240 mL are liable to precipitation and cannot be recommended for OPAT services because of heightened risks of nephrotoxicity. Aciclovir solution can be given as a continuous 24-hour infusion for OPAT services at a concentration range of 200-2400 mg in 240 mL in Accufuser and Easypump II elastomeric devices following 14 days storage at room temperature, protected from light.

Retrospective review of medication-related incidents at a major teaching hospital and the potential mitigation of these incidents with electronic prescribing and medicines administration.

OBJECTIVES: To describe the frequency of the different types of medication-related incidents that caused patient harm, or adverse consequences, in a major teaching hospital and investigate whether the likelihood of these incidents occurring would have been reduced by electronic prescribing and medicines administration (EPMA). METHODS: A retrospective review of harmful incidents (n=387) was completed for medication-related reports at the hospital between 1 September 2020 and 31 August 2021. Frequencies of different types of incidents were collated. The potential for EPMA to have prevented these incidents was assessed by reviewing DATIX reports and additional information, including results of any investigations. RESULTS: The largest proportion of harmful medication incidents were administration related (n=215, 55.6%), followed by incidents classified as 'other' and 'prescribing'. Most incidents were classified as low harm (n=321, 83.0%). EPMA could have reduced the likelihood of all incidents which caused harm by 18.6% (n=72) without configuration, and a further 7.5% (n=29) with configuration where configuration refers to adapting the software's functionality without supplier input or development. For 18.4% of the low-harm incidents (n=59) and 20.3% (n=13) of the moderate-harm incidents, EPMA could reduce the likelihood of the incident occurring without configuration. Medication errors most likely to be reduced by EPMA were due to illegibility, multiple drug charts or missing drug charts. CONCLUSION: This study found that administration incidents were the most common type of medication-related incidents. Most of the incidents (n=243, 62.8%) could not be mitigated by EPMA in any circumstance, even with connectivity between technologies. EPMA has the potential to prevent certain types of harmful medication-related incidents, and further improvements could be achieved with configuration and development.

Evaluation of the stability of temocillin in elastomeric infusion devices used for outpatient parenteral antimicrobial therapy in accordance with the requirements of the UK NHS Yellow Cover Document.

OBJECTIVE: To evaluate the stability of temocillin solution in two elastomeric infusion devices - Easypump II LT 270-27- S and Dosi-Fusor L25915-250D1 for OPAT administration during 14 days of 5°C±3°C fridge storage followed by 24 hour exposure at an in-use temperature of 32°C, when reconstituted with 0.3% citrate buffer at pH7. METHODS: Stability testing was conducted in accordance with standard protocols in the UK National Health Service Yellow Cover Document (YCD). A stability indicating assay method was applied using a high-performance liquid chromatography (HPLC) system with a photodiode array detector. Low (500 mg/240 mL), intermediate (4000 mg/240 mL) and high (6000 mg/240 mL) temocillin concentrations were tested in triplicate devices with duplicate samples taken at 11 time points during fridge storage and subsequent in-use temperature exposure. RESULT: The percentage of temocillin remaining after 14 days of fridge storage was greater than 97% in both devices and at all concentrations tested. During subsequent in-use temperature exposure, a 95% stability limit was achieved for 12 hours except for the high concentration (25 mg/mL) in the Dosi-Fusor device. It met this criterion for only 10 hours - the percent of temocillin remaining at 12 hours was 94.5%. However, for all devices and the doses tested, the degradation of temocillin was <9% at the end of 24 hours in-use temperature exposure. CONCLUSION: Temocillin reconstituted with 0.3% citrate buffer at pH7 in elastomeric infusion devices can be stored in a fridge (2°C-8°C) for 14 days meeting the YCD acceptance criteria. Considering <5% degradation, the current data supports twice daily dosing of temocillin within the OPAT setting. In jurisdictions where a <10% degradation limit is acceptable, once daily dosing with 24-hour continuous infusion may be considered. Temocillin is a useful alternative to other broad-spectrum anti-Gram-negative agents currently utilised in the OPAT setting and supports the wider antimicrobial stewardship agenda.

Antibiotic review kit for hospitals (ARK-Hospital): a stepped-wedge cluster-randomised controlled trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: UK National Institute for Health and Care Research.

Assessment of the stability of citrate-buffered piperacillin/tazobactam for continuous infusion when stored in two commercially available elastomeric devices for outpatient parenteral antimicrobial chemotherapy: a study compliant with the NHS Yellow Cover Document requirements.

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.

Impact of COVID-19 pandemic on prevalence of Clostridioides difficile infection in a UK tertiary centre.

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.

Assessment of ceftolozane/tazobactam stability in elastomeric devices and suitability for continuous infusion via outpatient parenteral antimicrobial therapy.

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 <95% remaining after 18 h for some device/concentration combinations and all device/concentration combinations at 24 h, respectively. The data does support extended storage of up to 8 days at 2-8°C plus 12 h at 32°C 'in-use' when using either FOLFusor LV10 or Easypump® II devices and is compliant with YCD. 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.

Investigation of meropenem stability after reconstitution: the influence of buffering and challenges to meet the NHS Yellow Cover Document compliance for continuous infusions in an outpatient setting.

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.

Assessment of the stability of citrate-buffered flucloxacillin for injection when stored in two commercially available ambulatory elastomeric devices: INfusor LV (Baxter) and Accufuser (Woo Young Medical): a study compliant with the NHS Yellow Cover Document (YCD) requirements.

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.

Extended stability of antimicrobial agents in administration devices.

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.

Antimicrobial stewardship: an evidence-based, antimicrobial self-assessment toolkit (ASAT) for acute hospitals.

OBJECTIVES: To describe the methodology in developing an antimicrobial self-assessment toolkit (ASAT). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.