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

<jats:title>ABSTRACT</jats:title> <jats:p> 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 <jats:named-content content-type="genus-species">Pseudomonas aeruginosa</jats:named-content> (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 ( <jats:italic>fT</jats:italic> <jats:sub>MIC</jats:sub> ) 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 <jats:sub>CR</jats:sub> ) and constituted 74% of the total clearance in a typical individual (eCL <jats:sub>CR</jats:sub> , 83.9 ml/min). Patients with a high eCL <jats:sub>CR</jats:sub> (>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% <jats:italic>fT</jats:italic> <jats:sub>MIC</jats:sub> ) and 0.125 mg/liter (100% <jats:italic>fT</jats:italic> <jats:sub>MIC</jats:sub> ). 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.) </jats:p>