Simultaneous determination of three β-Lactam/β-lactamase inhibitor combinations in critically ill patients by UPLC-MS/MS.

β-Lactam/β-lactamase inhibitors (BL/BLIs) are widely used in critically ill patients. Recent research has shown the importance of therapeutic drug monitoring (TDM) of BLs, but few studies have highlighted the importance of detecting BLIs in critically ill patients. In our laboratory, we have developed and validated a simple and robust method for the determination of ceftazidime, cefoperazone, piperacillin, avibactam, sulbactam and tazobactam in human plasma by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Sample preparation was by protein precipitation of 100 µL of sample, followed by chromatographic separation on an ACQUITY UPLC® BEH C18 column (2.1 × 50 mm, 1.7 µm) and mass spectrometric detection using a SHIMADZU 8050CL in multiple reaction monitoring (MRM) mode. The method was fully validated for selectivity, carry-over, linearity, lower limit of quantification, matrix effect, extraction recovery, stability and dilution integrity. The results of the TDM could provide feedback to clinicians and allow timely adjustment of dosing regimens in critically ill patients. The method is suitable for routine TDM and has been successfully applied to the clinical determination of 81 plasma concentrations in 44 patients.