Utilizing an Opportunistic Clinical Study and Population-Based Pharmacokinetic Models to Identify Rational Empiric Dosing Regimens for Piperacillin-Tazobactam in Critically Ill Patients

Joshua A Reeder; C Buddy Creech; Roger L Nation; Kenan Gu; Demet Nalbant; Nan Wu; Natalia Jimenez-Truque; William Fissell; Stephanie L Rolsma; Nicholas Fishbane; Carl M J Kirkpatrick; Pratish C Patel; Amy Watanabe; Cornelia B Landersdorfer; Patricia Winokur; Guohua An

doi:10.1002/jcph.6161

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Utilizing an Opportunistic Clinical Study and Population-Based Pharmacokinetic Models to Identify Rational Empiric Dosing Regimens for Piperacillin-Tazobactam in Critically Ill Patients

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Utilizing an Opportunistic Clinical Study and Population-Based Pharmacokinetic Models to Identify Rational Empiric Dosing Regimens for Piperacillin-Tazobactam in Critically Ill Patients

Joshua A Reeder, C Buddy Creech, Roger L Nation, Kenan Gu, Demet Nalbant, Nan Wu, Natalia Jimenez-Truque, William Fissell, Stephanie L Rolsma, Nicholas Fishbane, …

Journal of clinical pharmacology, Vol.65(4), pp.452-465

04/2025

DOI: 10.1002/jcph.6161

PMCID: PMC11938006

PMID: 39628093

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Abstract

Determining an effective dosing regimen for piperacillin-tazobactam in critically ill patients is challenging due to substantial pharmacokinetic variability caused by complex pathophysiological changes. To address this need, a prospective clinical study was conducted, which enrolled 112 critically ill patients and employed an opportunistic sampling strategy. Population modeling and simulation were performed to characterize the pharmacokinetics (PK) and probability of target attainment (PTA) of piperacillin-tazobactam under various dosing regimens. Both piperacillin and tazobactam final models were one-compartment models with zero-order input and first-order elimination. Significant covariates included lean body weight for piperacillin and creatinine clearance along with continuous renal replacement therapy (CRRT) for both drugs. Monte Carlo simulations demonstrated that continuous infusion can achieve higher PTA than intermittent and extended infusions. When considering the minimum inhibitory concentration (MIC) of 16 mg/L for Pseudomonas aeruginosa (a frequently encountered bacterial pathogen among critically ill patients) and a PK/PD target of 100% fT >MIC, continuous infusion of 6 g/day is recommended for critically ill patients with a CLcr <60 mL/min, 9 g/day for patients with CLcr in the range of 60 to 129 mL/min, and 12 g/day for patients with a CLcr ≥130 mL/min. In addition, extended infusion represents a good alternative, especially the 3 g q6h or 4 g q6h regimens which can achieve the designated European Committee on Antimicrobial Susceptibility Testing (EUCAST) non-species-related PK/PD breakpoint of 8 mg/L. Our study provided valuable insight into PTA outcomes, which, together with individual renal function of future patients and institution-specific piperacillin susceptibility patterns, may assist physicians when making dosing decisions.

piperacillin–tazobactam

pharmacometric modeling

empiric antibiotic dosing regimen selection

opportunistic clinical study

population pharmacokinetics

UIOWA OA Agreement

Details

Title: Subtitle: Utilizing an Opportunistic Clinical Study and Population-Based Pharmacokinetic Models to Identify Rational Empiric Dosing Regimens for Piperacillin-Tazobactam in Critically Ill Patients
Creators: Joshua A Reeder - University of Iowa
C Buddy Creech - Vanderbilt University Medical Center
Roger L Nation - Monash University
Kenan Gu - National Institute of Allergy and Infectious Diseases
Demet Nalbant - University of Iowa
Nan Wu - University of Iowa
Natalia Jimenez-Truque - Vanderbilt University Medical Center
William Fissell - Vanderbilt University Medical Center
Stephanie L Rolsma - Vanderbilt University Medical Center
Nicholas Fishbane
Carl M J Kirkpatrick - Monash University
Pratish C Patel - Vanderbilt University Medical Center
Amy Watanabe - Emmes
Cornelia B Landersdorfer - Monash University
Patricia Winokur - University of Iowa
Guohua An - University of Iowa
Resource Type: Journal article
Publication Details: Journal of clinical pharmacology, Vol.65(4), pp.452-465
DOI: 10.1002/jcph.6161
PMID: 39628093
PMCID: PMC11938006
NLM abbreviation: J Clin Pharmacol
ISSN: 1552-4604
eISSN: 1552-4604
Publisher: Wiley
Grant note: Division of Microbiology and Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institute of Health through the Vaccine and Treatment Evaluation Unit: HHSN272200800008C University of Iowa VTEU study team
This work was supported by the Division of Microbiology and Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institute of Health through the Vaccine and Treatment Evaluation Unit Contract HHSN272200800008C. Special thanks go to Dr. Baoying Liu who was the clinical project manager, the EMMES, the University of Iowa VTEU study team, and the Vanderbilt University Medical Center VTEU study team for their meticulous and effective oversight of this study.
Language: English
Electronic publication date: 12/03/2024
Date published: 04/2025
Academic Unit: Infectious Diseases; Stead Family Department of Pediatrics; Pharmaceutical Sciences and Experimental Therapeutics; Medicine Administration; Internal Medicine
Record Identifier: 9984757068002771

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