Are standard doses of piperacillin sufficient for critically ill patients with augmented creatinine clearance?

Andrew A Udy, Jeffrey Lipman, Paul Jarrett, Kerenaftali Klein, Steven C Wallis, Kashyap Patel, Carl MJ Kirkpatrick, Peter S Kruger, David L Paterson, Michael S Roberts, Jason A Roberts

IntroductionThe aim of this study was to explore the impact of augmented creatinine clearance, and differing minimum inhibitory concentrations (MIC), on piperacillin pharmacokinetic/pharmacodynamic (PK/PD) target attainment (time above MIC - fT>MIC), in critically ill septic patients receiving intermittent dosing.MethodsCritically ill patients with sepsis receiving piperacillin-tazobactam 4.5 g intravenously (IV) by intermittent infusion every 6-hours for presumed or confirmed nosocomial infection, without significant renal impairment (defined by a plasma creatinine concentration >171 ¿mol/L or the need for renal replacement therapy), were eligible for enrolment. Over a single dosing interval, blood samples were drawn to determine unbound plasma piperacillin concentrations. Renal function was assessed by a measured creatinine clearance (CLCR, mL/min). A population PK model was constructed, and the probability of target attainment (PTA) for 50% and 100% fT>MIC calculated for varying MIC and CLCR values.ResultsIn total, 48 patients provided data. Increasing CLCR was associated with lower trough plasma piperacillin concentrations (P <0.01), such that with an MIC of 16 mg/L, 100% fT>MIC would only be achieved in one-third (n¿=¿16) of patients. Mean piperacillin clearance was approximately 1.5 fold higher than in healthy volunteers, and correlated with CLCR (r¿=¿0.58, P <0.01). A reduced PTA for all MIC values, when targeting either 50% or 100% fT>MIC, was noted with increasing CLCR measures.ConclusionsStandard intermittent piperacillin-tazobactam dosing is unlikely to achieve optimal piperacillin exposures in a significant proportion of critically ill patients with sepsis, due to elevated drug clearance. These data suggest CLCR can be employed as a useful tool to determine whether piperacillin PK/PD target attainment is likely with a range of MIC values.