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 (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 () 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) and constituted 74% of the total clearance in a typical individual (eCL, 83.9 ml/min). Patients with a high eCL (>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% ) and 0.125 mg/liter (100%). 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.).

Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Simulation of Piperacillin/Tazobactam for Dosing Optimization in Late Elderly Patients with Pneumonia

“…In this study, the CL values for late elderly patients estimated from the population parameters and mean CL cr values were 4.62 and 5.04 L/h for PIPC and TAZ, respectively. These are lower than the values of PIPC (5.36 to 18.02 L/h) and TAZ (6.95 to 8.03 L/h) in adults including young and elderly patients, which was reported in previous papers [10,[12][13][14][15]17]. This may be due to age-related changes in the elimination process, namely decreased renal function.…”

“…The PK models of PIPC and TAZ have been previously described by both one- [16,18,19] and two-compartment models [10,[12][13][14][15]17]. In our study, plasma-concentration-time data were analyzed by a two-compartment model because the AIC values of the two-compartment model (1040.069, PIPC and 596.955, TAZ) were lower than those of the one-compartment model (1063.038, PIPC and 615.059, TAZ).…”

“…Some population PK studies concerning PIPC/TAZ in adult subjects have been reported [10][11][12][13][14][15][16][17][18][19]. In many antibiotics, including carbapenems and cephems, elderly patients have been reported to have different PK parameters than younger patients [21][22][23].…”

“…Establishing a population PK model is necessary in planning an optimized therapeutic regimen. Population PK models on PIPC/TAZ have been reported in young adult patients with nosocomial infections [10,11], sepsis [12,13], febrile neutropenia [14], acute infections [15], and obesity [16], and those undergoing continuous renal replacement therapy [17]. Additionally, antimicrobial chemotherapy with a combination of a β-lactam/β-lactamase inhibitor requires that there is a sufficient amount of the inhibitor to inactivate β-lactamases, which allows the β-lactam to exhibit its antibacterial activity [18].…”

Piperacillin pharmacokinetics and target attainment in children with cancer and fever: Can we optimize our dosing strategy?

“…The free, non‐protein‐bound fraction of plasma piperacillin was determined using ultra‐high performance liquid chromatography (Agilent 1290, Agilent Technologies, USA), as previously described . The limit of quantification (LOQ) for piperacillin was 0.5 mg/L.…”