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

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

J Clin Pharmacol. 2024 Dec 3. doi: 10.1002/jcph.6161. Online ahead of print.

Authors

Joshua A Reeder¹, C Buddy Creech², Roger L Nation³, Kenan Gu⁴, Demet Nalbant¹, Nan Wu¹, Natalia Jimenez-Truque², William Fissell⁵, Stephanie L Rolsma², Nicholas Fishbane⁶, Carl M J Kirkpatrick³, Pratish C Patel⁷, Amy Watanabe⁶, Cornelia B Landersdorfer³, Patricia Winokur⁸, Guohua An¹

Affiliations

¹ Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, USA.
² Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
⁴ Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
⁵ Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN, USA.
⁶ The Emmes Company, LLC, Rockville, MD, USA.
⁷ Department of Pharmaceutical Services, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Department of Infectious Diseases, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.

PMID: 39628093
DOI: 10.1002/jcph.6161

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.

Keywords: empiric antibiotic dosing regimen selection; opportunistic clinical study; pharmacometric modeling; piperacillin–tazobactam; population pharmacokinetics.