Population Pharmacokinetics of Extended-Infusion Piperacillin-Tazobactam in Hospitalized Patients with Nosocomial Infections

Abstract

e While extended infusions of piperacillin-tazobactam (TZP) are increasingly used in practice, the effect of infusion on the pharmacokinetic (PK) profile of TZP has not been widely assessed. To assess its effect on the pharmacokinetic profile of TZP, seven serum samples were collected from 11 hospitalized patients who received 3.375 g TZP intravenously for 4 h every 8 h. Population pharmacokinetic models were fit to the PK data utilizing first-order, Michaelis-Menten (MM), and parallel first-order/MM clearance. A population PK model with first-order clearance was fit to the tazobactam PK data. Monte Carlo simulations (MCSs) were used to determine the most effective administration schedule to ensure that free piperacillin concentrations were above the MIC for at least 50% of the dosing interval (50% fT>MIC) and to quantify the extent of the nonlinear clearance. The model incorporating parallel linear/MM clearance best fit the piperacillin PK data. The MCSs demonstrated that approximately 50% of the administered piperacillin is cleared by the nonlinear clearance mechanism. The results of the MCSs also revealed that more intensive TZP extended infusion dosing schemes (3.375 to 4.5 g intravenously [3-h infusion] every 6 h) than those commonly used in clinical practice were needed to maximize the 50% fT>MIC for MICs of >8 mg/liter. This study suggests that extended infusion of TZP is the most effective method of administration for patients with nosocomial infections. Due to the hyperclearance nature of the hospitalized patient populations studied, more intensive TZP dosing regimens may be needed to maximize fT>MIC in certain hospitalized populations. P iperacillin-tazobactam (TZP) is a combination of an extended-spectrum ␤-lactam antibiotic and a ␤-lactamase inhibitor and is frequently used for nosocomial infections (3, 21). For ␤-lactam antibiotics, the pharmacodynamic index that best links drug exposure with the observed antibacterial effect is the fraction of the dosing interval in which free drug concentrations are above the MIC (9). Near-maximal effect is generally observed when free concentrations exceed the MIC for at least 50% of the dosing interval (fTϾMIC 50%) (12). Although TZP is frequently administered as a rapid infusion, extended infusions of TZP are increasingly used in clinical practice because they facilitate the extension of the fTϾMIC.Although the method is more commonplace than rapid infusions, the impact of prolonging the infusion time of TZP on its pharmacokinetic (PK) profile has not been widely assessed. Here, we describe the population pharmacokinetics for both piperacillin and tazobactam among hospitalized patients receiving an extended infusion regimen. The goal was to identify the model that best explained the observed clearance of both piperacillin and tazobactam. When modeling piperacillin, it is important to consider linear, Michalis-Menten (MM), and parallel first-order/MM models. Piperacillin is cleared via a combination of renal tubular secretion and glomerular filtration (25). Whil...

Developmental Pharmacokinetics of Piperacillin and Tazobactam Using Plasma and Dried Blood Spots from Infants

“…In addition, we did not observe additional therapeutic benefit from prolonging the duration of drug infusion in this population, likely because of the observed slow drug elimination that resulted in therapeutic concentrations for most of the dosing interval. This is in contrast to adult studies that support a prolonged infusion for treatment of highly resistant infections (32)(33)(34). This is an important finding because adult dosing recommendations of anti-infectives are often extrapolated to children and infants without data for this unique patient population.…”

Population Pharmacokinetics of Piperacillin in the Early Phase of Septic Shock: Does Standard Dosing Result in Therapeutic Plasma Concentrations?

“…Furthermore, Felton et al (28) illustrated that piperacillin-tazobactam (4 g/0.5 g) administered as extended infusion (3 h every 6 h) results in a prominently higher PTA than does intermittent bolus infusion. However, the clinical advantages of prolonged infusion remain controversial.…”

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