Population Pharmacokinetics of Piperacillin in Sepsis Patients: Should Alternative Dosing Strategies Be Considered?

Abstract

Sufficient antibiotic dosing in septic patients is essential for reducing mortality. Piperacillin-tazobactam is often used for empirical treatment, but due to the pharmacokinetic (PK) variability seen in septic patients, optimal dosing may be a challenge. We determined the PK profile for piperacillin given at 4 g every 8 h in 22 septic patients admitted to a medical ward. Piperacillin concentrations were compared to the clinical breakpoint MIC for <i>Pseudomonas aeruginosa</i> (16 mg/liter), and the following PK/pharmacodynamic (PD) targets were evaluated: the percentage of the dosing interval that the free drug concentration is maintained above the MIC (<i>fT</i>_MIC) of 50% and 100%. A two-compartment population PK model described the data well, with clearance being divided into renal and nonrenal components. The renal component was proportional to the estimated creatinine clearance (eCL_CR) and constituted 74% of the total clearance in a typical individual (eCL_CR, 83.9 ml/min). Patients with a high eCL_CR (>130 ml/min) were at risk of subtherapeutic concentrations for the current regimen, with a 90% probability of target attainment being reached at MICs of 2.0 (50% <i>fT</i>_MIC) and 0.125 mg/liter (100% <i>fT</i>_MIC). Simulations of alternative dosing regimens and modes of administration showed that dose increment and prolonged infusion increased the chance of achieving predefined PK/PD targets. Alternative dosing strategies may therefore be needed to optimize piperacillin exposure in septic patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02569086.).