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.

Systematic review of room temperature stability of key beta-lactam antibiotics for extended infusions in inpatient settings.

BACKGROUND: Extended infusion (EI) of beta-lactam antibiotics may offer clinical benefits aligned with improved probability of target attainment for critical pharmacokinetic/pharmacodynamic parameters that correlate with efficacy. There is much research interest in prolonged and continuous infusions (collectively, extended infusions) of beta-lactams to improve patient outcomes, particularly in critically ill patients in intensive care. While definitive clinical trial data demonstrating beneficial outcomes is awaited, there has been limited focus on the stability of the agents given by EI, which may be an equally critical parameter. EI may allow for savings in nursing time due to reduced need for drug reconstitution. We set out to examine the data for stability for EI at room temperature, consistent with the requirements of 'A Standard Protocol for Deriving and Assessment of Stability- Part 1 Aseptic Preparation (Small Molecules)', which allows a 5% loss of active pharmaceutical ingredient (API) applicable for those territories that use the British Pharmacopoeia also for a 10% loss applicable in much of rest of the world. METHODS: Searches using preferred reporting items for systematic reviews and meta-analyses (PRISMA) principles for stability data on freshly prepared beta-lactam antimicrobials for extended administration at room temperature (at or above 23°C) were conducted in November 2021 and updated in December 2022. RESULTS: We found data to support the extension of the shelf life of 12 key beta-lactam antibiotics once reconstituted (aztreonam, amoxicillin, benzylpenicillin, flucloxacillin, piperacillin/tazobactam, cefazolin, cefmetazole, ceftaroline, ceftazidime, ceftriaxone, imipenem and meropenem) compliant with the NHS protocol, and data for five other agents (ticarcillin, cefepime, cefiderocol, cefoxitin and doripenem) which would be acceptable in regions outside the UK beyond that listed in the Summary of Product Characteristics.This review has not been registered under PROSPERO.

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.

Stability of pemetrexed disodium in sodium chloride 0.9% w/v intravenous Viaflo infusion bags.

OBJECTIVES: The aim of this study was to assess the stability of pemetrexed disodium (Alimta), reconstituted in 100 mL sodium chloride 0.9% w/v intravenous infusion bags (Baxter Viaflo) at two target bag concentrations (2.0 and 13.5 mg/mL) during storage at 2-8°C for 28 days (protected from light), followed by 24 hours at 25±2°C with 60±5% relative humidity (RH) (protected from light). This study was commissioned by NHS England and NHS Improvement to generate data to aid shelf life extensions for aseptic products compounded in National Health Service (NHS) hospital aseptic facilities. METHODS: A high performance liquid chromatography (HPLC) assay was developed and validated to monitor pemetrexed concentration and related substance levels in accordance with NHS yellow cover document requirements. This assay and analysis of related substances was used alongside visual inspection, pH monitoring and sub-visible particle count analysis to monitor stability. The stability of three preparations of each concentration of pemetrexed disodium in Viaflo saline bags (0.9% w/v) was assessed at various time points. RESULTS: Pemetrexed assay concentrations remained >97.0% of initial concentration at all points during the study (including the period at elevated temperature). Appearance remained consistent with the Summary of Product Characteristics, particle count data remained within the British Pharmacopoeia limits, and pH remained within 0.43 units of T=0 at all times. The increases in related substance levels during the study were found to be the limiting factor for shelf life assignment. CONCLUSION: The data for appearance, pH, sub-visible particle count analysis and pemetrexed assay would support a shelf life of 28 days stored at 2-8°C (protected from light) followed by 24 hours at 25±2°C with 60±5% RH (protected from light). However, given the increase in related substance levels, a shelf life of 21 days stored at 2-8°C (protected from light) was deemed to be appropriate.

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.

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.

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.

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.