Piperacillin Pharmacokinetics in ICU Patients

Sepsis, Septic Shock

Antibiotic dosing in critically ill patients poses a challenge for clinicians due to the pharmacokinetic changes seen in this population. Piperacillin/tazobactam is often used for empirical treatment, and initial appropriate dosing is crucial for reducing mortality. Patients in the Intensive Care Unit (ICU), treated with piperacillin/tazobactam, had their plasma concentration of piperacillin determined 1-3 times weekly. Patients received piperacillin as intermittent bolus infusion 3 times daily or as continuous infusion (this was up to the treating physician). Time above the minimal inhibitory concentration (T\>MIC) estimated for each patient was evaluated against clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/L). Pharmacokinetic-pharmacodynamic (PK-PD) targets evaluated were 100% f T\>MIC (free piperacillin concentration maintained above the MIC throughout the dosing interval) and 50% fT\>4xMIC (free piperacillin concentration maintained at a level fourfold the MIC for at least 50% of the dosing interval).

Early appropriate antimicrobial therapy is of utmost importance for reducing mortality in critically ill patients with sepsis and septic shock. Pathophysiological changes associated with the septic process, such as changes in volume of distribution (Vd), drug clearance (CL), decrease in plasma-protein concentration and organ dysfunction, lead to pharmacokinetic (PK) changes that may alter the efficacy of the antimicrobial given. As a consequence, antibiotic plasma concentrations are variable and hard to predict in these patients, which makes optimal antibiotic exposure a challenge, especially in the early phase of treatment. Piperacillin/tazobactam is a β-lactam - β-lactamase inhibitor combination frequently used for empirical treatment in the critically ill. It is a time-dependent antibiotic where antibacterial activity is related to the time for which the free, unbound concentration of the drug is maintained above the minimal inhibitory concentration (f T\>MIC). Maximizing f T\>MIC both increases the therapeutic impact and reduces the risk of drug resistance development. Because of the PK changes seen in the critically ill, standard dosing of antimicrobials may result in subtherapeutic plasma-concentrations and it has been suggested that current empiric dosing recommendations for Intensive Care Unit (ICU) patients are inadequate and needs to be reconsidered. Piperacillin/tazobactam is generally administered either as 4g/0.5g every 8 hour (h) or as 12g given continuously over 24 hours.The aim of this study is to determine if this dosing results in therapeutic plasma concentrations in septic patients. Patients treated with piperacillin/tazobactam given as intermittent bolus infusion had piperacillin plasma concentrations determined once a week. Patients treated with piperacillin/tazobactam given as continuous infusion had piperacillin plasma concentrations determined three times a week. Time above the minimal inhibitory concentration (T\>MIC) estimated for each patient was evaluated against clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/L). Pharmacokinetic-pharmacodynamic (PK-PD) targets evaluated were 100% f T\>MIC (free piperacillin concentration maintained above the MIC throughout the dosing interval) and 50% fT\>4xMIC (free piperacillin concentration maintained at a level fourfold the MIC for at least 50% of the dosing interval). The unbound piperacillin plasma concentrations were determined using ultra high performance liquid chromatography (UPLC). There was no intervention in the study.

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