Population pharmacokinetics of piperacillin in septic patients - should alternative dosing strategies be considered? [PublishAheadOfPrint]

Sufficient antibiotic dosing in septic patients is essential for reducing mortality. Piperacillin/tazobactam is often used for empiric 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 4g every 8h in 22 septic patients admitted to a medical ward. Piperacillin concentrations were compared to clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/L) and the following PK/PD targets were evaluated: 50% f T>MIC and 100% f T>MIC. A two-compartment population PK model described the data well, with clearance divided into renal and non-renal 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 of 83.9 mL/min). Patients with high eCL_Cr (>130 mL/min) were at risk of sub-therapeutic concentrations for the current regimen, with 90% PTA reached at MICs of 2.0 (50% f T>MIC) and 0.125 mg/L (100% f T>MIC). Simulations of alternative dosing regimens and modes of administration showed that dose increment and prolonged infusion increased the chance of achieving pre-defined PK/PD targets. Alternative dosing strategies may therefore be needed to optimize piperacillin exposure in septic patients.

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