The highly variable pharmacokinetics of β-lactam antibiotics and β-lactamase inhibitors poses a significant challenge to clinicians in ensuring appropriate antibiotic doses in critically ill patients. Therefore, routine monitoring of their plasma concentrations is important for individualization of antimicrobial therapy. Accordingly, a simple and robust analytical method for the simultaneous determination of multiple β-lactam antibiotics and β-lactamase inhibitors is highly desirable to ensure quick decisions on dose adjustments. In this study, a sensitive, simple and robust method for the simultaneous quantification of cefepime, meropenem, piperacillin and tazobactam in human plasma was developed and rigorously validated according to the FDA guidance. Sample extraction was accomplished by simple protein precipitation. Chromatographic separation of analytes was achieved using a step-wise gradient elution. Analytes were monitored using MS/MS with a turbo ion spray source in positive multiple reaction monitoring mode. The calibration curve ranged from 0.5-150 μg/mL for cefepime, 0.1-150 μg/mL for meropenem and piperacillin, and 0.25-150 μg/mL for tazobactam. The inter- and intra-day precision and accuracy, sensitivity, selectivity, dilution integrity, matrix effect, extraction recovery and hemolysis effect were investigated for all four analytes and the results met the acceptance criteria. Compared with other reported methods, our method is more robust because of the combination of following features: a) simple sample extraction procedure, b) short sample run time, c) wide dynamic range, and d) small plasma sample volume needed. Since our method already covers β-lactams and a β-lactamase inhibitor with high heterogeneity of physico-chemical properties, further antibiotic candidates could be easily incorporated in this multi-analyte method.
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