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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 requirementsObjectives: 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.
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Assessment of ceftolozane/tazobactam stability in elastomeric devices and suitability for continuous infusion via outpatient parenteral antimicrobial therapyObjectives 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.
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Widening the net: a literature review of antimicrobial agents with potential suitability for outpatient parenteral antimicrobial therapy services-the importance of storage and stability.Objectives: Outpatient parenteral antimicrobial therapy (OPAT) services using continuous infusions (CIs) of antimicrobial agents in elastomeric devices require evidence of acceptable stability of the agent over the infusion period. A period of refrigerated storage of filled devices, followed by the CI period, is useful for OPAT services but can present a significant challenge to the stability of drugs. The aims of this study were to review fresh-filled stability data on antimicrobials which would be useful for OPAT services and to identify suitable candidates for further assessment. Methods: Searches identified papers relating to stability assessments of antimicrobials for immediate use tested above 31°C using a stability-indicating method. Results: We identified 18 stability studies published in 12 papers between 2015 and 2020, assessing the stability of 10 agents. Aminopenicillins like ampicillin and amoxicillin appear too unstable for CI, while benzylpenicillin may benefit from buffering to improve its stability. Cephalosporins vary in their stability and CI periods of 24 hours may not be achievable. Of the carbapenems, there are insufficient data for doripenem but meropenem has been extensively studied and is unsuitable for CI longer than 6 hours. Voriconazole may be suitable for CI but needs further investigation. Conclusions: Some drugs identified in our review are unlikely to be suitable for continuous infusion in OPAT services due to instability. Using a 'fresh-fill' approach, without refrigerated storage, may make some drugs useful while other agents should be considered for further assessment to Yellow Cover Document standards. The impact of buffering for penicillins should be assessed further.
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Systematic review of the stability of antimicrobial agents in elastomeric devices for outpatient parenteral antimicrobial therapy services based on NHS Yellow Cover Document standards.Background: In order to use aseptically prepared elastomeric infusers, outpatient parenteral antimicrobial therapy (OPAT) services require extended stability data for antimicrobial agents to assign a product shelf-life. In the UK, the relevant standards for stability testing and shelf-life assignment are published in 'A Standard Protocol for Deriving and Assessment of Stability-Part 1 (Aseptic Preparations-Small Molecules), commonly called the Yellow Covered Document (YCD). A previous systematic review published in 2017 failed to identify data on the stability of antimicrobials in elastomeric devices for OPAT services that met YCD requirements in force at the time. The aim of this review was to update that search, following a subsequent change to YCD requirements in 2017 and 2019 and expand that dataset to identify progress made in providing assurance about the stability of antimicrobial agents for OPAT services. Methods: Searches were undertaken for papers relating to extended stability of antimicrobials. Citations were included when antimicrobial shelf-life was assessed using a stability-indicating method and considered a period of storage, either refrigerated or at room temperature, followed by in-use testing at a temperature at or above 32°C. Results: Of 267 initial citations, six met the inclusion criteria and underwent full text review for data extraction. Included antimicrobials were cefazolin, ceftazidime, piperacillin/tazobactam, flucloxacillin and ceftolozane/tazobactam. Of these, only flucloxacillin and piperacillin demonstrated YCD compliant stability over the 24-hour infusion period while cefazolin, ceftazidime and ceftolozane/tazobactam could be infused over 12-hour period. Conclusions: Contrary to the position found in 2017 review, high-quality data are now available to support the use of a number of antimicrobial agents in extended infusion in elastomeric devices for OPAT services. There is a need to expand the dataset, as well as developing international consensus on the ideal parameters for stability assessment of such infusions in elastomeric devices.
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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.