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

INTRODUCTION The 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 patients with sepsis receiving intermittent dosing. METHODS To be eligible for enrolment, critically ill patients with sepsis had to be 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 greater than 171 μmol/L or the need for renal replacement therapy). Over a single dosing interval, blood samples were drawn to determine unbound plasma piperacillin concentrations. Renal function was assessed by measuring creatinine clearance (CLCR). A population PK model was constructed, and the probability of target attainment (PTA) for 50% and 100% fT>MIC was calculated for varying MIC and CLCR values. RESULTS In total, 48 patients provided data. Increasing CLCR values were associated with lower trough plasma piperacillin concentrations (P < 0.01), such that with an MIC of 16 mg/L, 100% fT>MIC would be achieved in only 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. CONCLUSIONS Standard intermittent piperacillin-tazobactam dosing is unlikely to achieve optimal piperacillin exposures in a significant proportion of critically ill patients with sepsis, owing to elevated drug clearance. These data suggest that CLCR can be employed as a useful tool to determine whether piperacillin PK/PD target attainment is likely with a range of MIC values.