Preanalytical Stability of Flucloxacillin, Piperacillin, Tazobactam, Meropenem, Cefalexin, Cefazolin, and Ceftazidime in Therapeutic Drug Monitoring: A Structured Review

Abstract

Background: Therapeutic drug monitoring is increasingly being used to optimize beta-lactam antibiotic dosing. Because beta-lactams are inherently unstable, confirming preanalytical sample stability is critical for reporting reliable results. This review aimed to summarize the published literature on the preanalytical stability of selected widely prescribed beta-lactams used in therapeutic drug monitoring.

Methods: The published literature (2010-2020) on the preanalytical stability of flucloxacillin, piperacillin, tazobactam, meropenem, cefalexin, cefazolin, and ceftazidime in human plasma, serum, and whole blood was reviewed. Articles examining preanalytical stability at room temperature, refrigerated, or frozen (-20°C) using liquid chromatography with mass spectrometry or ultraviolet detection were included.

Results: Summarizing the available data allowed for general observations to be made, although data were conflicting in some cases (piperacillin, tazobactam, ceftazidime, and meropenem at room temperature, refrigerated, or -20°C) or limited (cefalexin, cefazolin, and flucloxacillin at -20°C). Overall, with the exception of the more stable cefazolin, preanalytical instability was observed after 6-12 hours at room temperature, 2-3 days when refrigerated, and 1-3 weeks when frozen at -20°C. In all cases, excellent stability was detected at -70°C. Studies focusing on preanalytical stability reported poorer stability than studies investigating stability as part of method validation.

Conclusions: Based on this review, as general guidance, clinical samples for beta-lactam analysis should be refrigerated and analyzed within 2 days or frozen at -20°C and analyzed within 1 week. For longer storage times, freezing at -70°C was required to ensure sample stability. This review highlights the importance of conducting well-designed preanalytical stability studies on beta-lactams and other potentially unstable drugs under clinically relevant conditions.