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

Abstract

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.

Keywords: Administration, Intravenous; Drug Compounding; Drug Monitoring; Pharmacology; Quality Assurance, Health Care.

Figure 1

Comparison of percentage of temocillin remaining during fridge storage (5°C±3°C) for 14 days by dose and device type.

Figure 2

Percentage of temocillin remaining during 24 hour in-use temperature exposure (32°C) following 14 days of fridge storage at high (6000 mg/240 mL), intermediate (4000 mg/240 mL) and low (500 mg/240 mL) dose in Easypump II LT 270–27- S elastomeric infusion device. h, hour.

Figure 3

Percentage of temocillin remaining during 24 hour in-use temperature exposure (32°C) following 14 days of fridge storage at high (6000 mg/240 mL), intermediate (4000 mg/240 mL) and low (500 mg/240 mL) dose in Dosi-Fusor L25915-250D1 elastomeric infusion device.

Figure 4

Temocillin chromatogram showing five major degradation peaks A, B, C, D and E.