Stability of Ceftazidime-Avibactam: Changes in Regulatory Information and Implications for Preparation

At our hospital pharmacy service (HPS), the preparation of all individually controlled parenteral antibiotic and antifungal admixtures is centralized. The assignment of beyond-use dates (BUDs) must ensure the stability of the admixture from preparation to administration and depends on the physicochemical properties of the drug, compatibility and stability with diluents, and the preparation risk level. This information is generally provided by the manufacturer, and for newly marketed drugs, alternative sources of information are often limited.

Ceftazidime-avibactam is one of the antibiotics prepared in our HPS. It is a combination of a beta-lactam antibiotic and a beta-lactamase inhibitor indicated for complicated intra-abdominal infection, complicated urinary tract infection, and hospital-acquired pneumonia, as well as infections caused by aerobic gram-negative microorganisms in patients with limited therapeutic options. ¹

According to the Spanish national Guide to Good Practices for the Preparation of Medicinal Products in Hospital Pharmacy Departments, this antibiotic is classified as a low-risk compounded sterile preparation after application of the risk assessment matrix. Consequently, a microbiological BUD of up to 14 days under refrigeration could be assigned, provided that physicochemical stability is maintained and preparation is performed in a laminar airflow cabinet within a controlled environment. ²

Initial European regulatory documents published in 2016, as well as the prescribing information approved by the Food and Drug Administration (FDA), described diluted solutions as stable for up to 24 hours at 2 to 8 °C followed by up to 12 hours at room temperature.^3,4 This BUD was adopted in our HPS.

However, in a subsequent revision of the product information published by the European Medicines Agency (EMA) in 2021, more restrictive limits for stability after dilution were established. In the current European Summary of Product Characteristics, physicochemical stability depends on drug concentration and administration device, with stability described as up to 12 hours at 2 to 8 °C followed by 4 hours at room temperature for solutions of approximately 8 mg/mL in infusion bags, and even shorter times under other preparation conditions. ⁵ This regulatory update represents a substantial reduction in the initially reported BUD.

During a review of available physicochemical stability data for ceftazidime-avibactam, discrepancies were identified among regulatory documents, stability databases, and experimental studies. To facilitate comparison among these sources, Table 1 summarizes the main preparation conditions evaluated and the corresponding reported stability periods.

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Table 1.

Comparison of Ceftazidime-Avibactam Stability According to Regulatory Sources and Experimental Studies.

Source	Studied conditions	Stability
European Summary of Product Characteristics (EMA) 2016 3 Prescribing Information (FDA) 2015 4	Infusion bags in NS and D5W	24 hours at 2 to 8 °C + 12 hours at ≤25 °C
European Summary of Product Characteristics (EMA) 2021 5	Infusion bags, 8 mg/mL in NS and D5W	12 hours at 2 to 8 °C + 4 hours at ≤25 °C
	Infusion bags, >8 mg/mL to 40 mg/mL in NS and D5W	4 hours at ≤25 °C
	Syringes in NS and D5W	6 hours at ≤25 °C
Loeuille et al., 2022 6	Elastomeric devices, 25/6.25 mg/mL in NS	12 hours at 37 °C
	Polypropylene syringes, 125/31.25 mg/mL in NS and D5W	24 hours at 20 to 25 °C
Naicker et al., 2024 7	Elastomeric devices, 25/6.25, 12.5/3.125, and 6.25/1.56 mg/mL in NS	<90% drug concentration after 14 days at 2 to 8 °C followed by 24 hours at 32 °C
Erdmann et al., 2025 8	Elastomeric pumps in NS	>90% drug concentration maintained up to 24 hours at 25 °C, although degradation products were detected after storage at 2 to 8 °C for 7 days

Abbreviations: D5W, 5% dextrose solution; EMA, European Medicines Agency; FDA, Food and Drug Administration; NS, normal saline.

Available experimental evidence shows heterogeneous results. Some studies demonstrated maintenance of drug concentrations above 90% for up to 24 hours under certain conditions, whereas others documented the formation of degradation products, mainly pyridine derived from ceftazidime, which may occur during prolonged storage.^6-8 This may justify the adoption of more conservative physicochemical stability limits in current regulatory documents.

Stability databases such as Stabilis^® also report variable data depending on several factors, including drug concentration, diluent, and administration device. ⁹ The polymeric composition of the container material may also influence stability through adsorption phenomena or the release of leachables, although this information is not consistently specified in regulatory documents or published studies.

Another relevant limitation is the lack of international harmonization regarding the assignment of BUDs for compounded sterile preparations. United States Pharmacopeia chapter <797> (USP <797>) provides standardized recommendations for sterile compounding practices and BUDs, whereas in Europe no equivalent harmonized framework currently exists. ¹⁰ Consequently, several European countries have developed their own national guidance documents, often inspired by USP <797>, which may differ in their criteria and interpretation. ²

The coexistence of outdated and updated regulatory documents may lead to differing interpretations in clinical practice. This situation may have direct implications for HPS, where BUDs are assigned to compounded preparations. The use of outdated stability information may affect both medication-use efficiency and patient safety. Therefore, any modification to stability conditions should be clearly communicated to all HPS.

Sandra Caíña LópezDepartment of Hospital Pharmacy, University Hospital Complex of Pontevedra, Pontevedra, Spain, España Tania González FernándezDepartment of Hospital Pharmacy, Álvaro Cunqueiro Hospital, Vigo (Pontevedra), Spain Alejandro Rodríguez Rodríguez and Carmen Dávila PousaDepartment of Hospital Pharmacy, University Hospital Complex of Pontevedra, Pontevedra, Spain