Population pharmacokinetics of piperacillin in plasma and subcutaneous tissue in patients on continuous renal replacement therapy

Abstract Objectives Piperacillin is a β-lactam antimicrobial frequently used in critically ill patients with acute kidney injury treated with continuous renal replacement therapy (CRRT). However, data regarding piperacillin tissue concentrations in this patient population is limited. We conducted a prospective observational study of free piperacillin concentrations during a single 8 h dosing interval in plasma (eight samples) and subcutaneous tissue (SCT) (thirteen samples) in 10 patients treated with CRRT following piperacillin 4 g given every 8 h as intermittent administration over 3 min. Methods A population pharmacokinetic (PK) model was developed using NONMEM 7.4.3, to simulate alternative administration modes and dosing regimens. SCT concentrations were obtained using microdialysis. Piperacillin concentrations were compared to the clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/L), with evaluation of the following PK/PD targets: 50% fT>1xMIC, 100% fT>1xMIC and 100% fT>4xMIC. Results SCT concentrations were generally lower than plasma concentrations. For the target of 50% fT>1xMIC and 100% fT>1xMIC, piperacillin 4 g q8h resulted in PTA > 90% in both plasma and SCT. PTA > 90% for the target of 100% fT>4xMIC was only achieved for continuous infusion (CI). Conclusions Piperacillin 4 g q8h is likely to provide sufficient exposure in both plasma and SCT to treat Pseudomonas aeruginosa infections in critically ill patients on CRRT, given that targets of 50% fT>1xMIC or 100% fT>1xMIC are adequate. However, if a more aggressive target of 100% fT>4xMIC is adopted, CI is needed.