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. 2023 Jan;62(1):127-139.
doi: 10.1007/s40262-022-01198-z. Epub 2023 Jan 12.

Population Pharmacokinetics of Piperacillin/Tazobactam Across the Adult Lifespan

Marion Hemmersbach-Miller  1   2   3 , Stephen J Balevic  2   4   5 , Patricia L Winokur  6 , Cornelia B Landersdorfer  7 , Kenan Gu  8 , Austin W Chan  1 , Michael Cohen-Wolkowiez  2   4 , Thomas Conrad  9 , Guohua An  10 , Carl M J Kirkpatrick  7 , Geeta K Swamy  11 , Emmanuel B Walter  2   4   12 , Kenneth E Schmader  13   14
Affiliations

Population Pharmacokinetics of Piperacillin/Tazobactam Across the Adult Lifespan

Marion Hemmersbach-Miller et al. Clin Pharmacokinet. 2023 Jan.

Abstract

Background and objective: Piperacillin/tazobactam is one of the most frequently used antimicrobials in older adults. Using an opportunistic study design, we evaluated the pharmacokinetics of piperacillin/tazobactam as a probe drug to evaluate changes in antibacterial drug exposure and dosing requirements, including in older adults.

Methods: A total of 121 adult patients were included. The population pharmacokinetic models that best characterized the observed plasma concentrations of piperacillin and tazobactam were one-compartment structural models with zero-order input and linear elimination.

Results: Among all potential covariates, estimated creatinine clearance had the most substantial impact on the elimination clearance for both piperacillin and tazobactam. After accounting for renal function and body size, there was no remaining impact of frailty on the pharmacokinetics of piperacillin and tazobactam. Monte Carlo simulations indicated that renal function had a greater impact on the therapeutic target attainment than age, although these covariates were highly correlated. Frailty, using the Canadian Study of Health and Aging Clinical Frailty Scale, was assessed in 60 patients who were ≥ 65 years of age.

Conclusions: The simulations suggested that adults ≤ 50 years of age infected with organisms with higher minimum inhibitory concentrations may benefit from continuous piperacillin/tazobactam infusions (12 g/day of piperacillin component) or extended infusions of 4 g every 8 hours. However, for a target of 50% fT + minimum inhibitory concentration, dosing based on renal function is generally preferable to dosing by age, and simulations suggested that patients with creatinine clearance ≥ 120 mL/min may benefit from infusions of 4 g every 8 hours for organisms with higher minimum inhibitory concentrations.

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Conflict of interest statement

Conflicts of Interest

SJB receives support from the National Institutes of Health, the US Food and Drug Administration, the Patient-Centered Outcomes Research Institute, the Rheumatology Research Foundation’s Scientist Development Award, the Childhood Arthritis and Rheumatology Research Alliance, Purdue Pharma, and consulting for UCB.

Figures

Figure 1.
Figure 1.. Prediction-corrected visual predictive check for the final piperacillin model
Prediction-corrected visual predictive check for the final piperacillin model for all patients and all times past start of infusion. Note: Data were very sparse for times past start of infusion >8 hours.
Figure 2.
Figure 2.. Prediction-corrected visual predictive check for the final tazobactam model
Prediction-corrected visual predictive check for the final tazobactam model for all patients and all times past start of infusion. Note: Data were very sparse for times past start of infusion >8 hours.
Figure 3.
Figure 3.. Probability of target attainment for piperacillin by age group and dosing regimen
Probability of target attainment for piperacillin by age group and dosing regimen (target 50% fT>MIC and 100% fT>4xMIC of piperacillin 12 g/day continuous infusion and 3 g q8h 4-hour infusion). MIC, minimum inhibitory concentration
Figure 4.
Figure 4.. Comparison of piperacillin PTA between different renal function groups
Comparison of piperacillin PTA between different renal function groups: less than 60 mL/min, 60 to 119 mL/min, and 120 mL/min and above, for two different dosage regimens. MIC, minimum inhibitory concentration; PTA, probability of target attainment
See this image and copyright information in PMC

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