Individual target pharmacokinetic/pharmacodynamic attainment rates among cefepime-treated patients admitted to the ICU with hospital-acquired pneumonia with and without ECMO
Year: 2025
Type: article
Study design: Observational Study
Abstract: ABSTRACT Cefepime (FEP) is used for hospital- and ventilator-associated pneumonia when Pseudomonas aeruginosa is involved. However, its pharmacokinetics (PK) in severe pneumonia necessitating extracorporeal membrane oxygenation (ECMO) remain unclear. This single-center, prospective study enrolled 70 mechanically ventilated patients with suspected pneumonia ( n = 9 on ECMO), excluding those on renal replacement therapy. Dosing followed institutional renal function-based protocols. Plasma concentrations were quantified by liquid chromatography-tandem mass spectrometry, and a two-compartment PK model was developed using Pmetrics for R, with volume of distribution (Vd) scaled to body weight and ECMO status, and clearance (CL) scaled to renal function. Target attainment was calculated from Bayesian posterior predictions, and Monte Carlo simulations evaluated the cumulative fraction of response (CFR) for regimens of 2 g IV every 8 h, administered as either 0.5 h intermittent or 4 h extended infusion with or without a 2 or 3 g loading dose (LD) (0.5 h). Success was defined as achieving 100% f T >1xMIC within 24 h for 80% of isolates. Seventy patients (60% male, n = 9 ECMO) contributed 114 plasma samples (1–14 per patient). The model fit the data well. ECMO was associated with a 2.8-fold increase in Vd without altering CL. Monte Carlo simulations demonstrated that standard dosing without an LD failed to achieve CFR ≥ 80% in ECMO patients. Incorporating a 3 g but not 2 g LD restored CFR to ≥80% in ECMO. ECMO significantly increased FEP Vd in intensive care unit patients, suggesting sub-optimal target attainment at higher minimum inhibitory concentrations. A 3 g LD appears essential for target attainment, underscoring the need for revised dosing strategies in ECMO.
DOI: 10.1128/aac.00102-25
Authors: Adrian Valadez, Marta Zurawska, Emma Harlan, Marc H. Scheetz, MIchael N. Neely, Paul R. Yarnold, Mengjia Kang, Erin Korth, Francisco Martinez, Bridget Giblin, Helen K. Donnelly, Kay Dedicatoria, Rachel Medernach, Sophia Nozick, Alan R. Hauser, Egon A. Ozer, Estefani Diaz, Alexander V. Misharin, Richard G. Wunderink, Nathaniel J. Rhodes
Institutions: Midwestern University, Midwestern State University, Northwestern Memorial Hospital, University of Southern California, Children's Hospital of Los Angeles, Saban Research Institute, Northwestern University, Rush University Medical Center, Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
Awards: G1005734346, G1382027039, G2229906039, G2621050524, G3241923464, G3692266691, Microglia mediate cognitive dysfunction in elderly survivors of pneumonia, Modeling the Incompleteness and Biases of Health Data, G6150573222, G6233336011, G659096663, G6995442947, G9000033877, G9000054469, G9000126891, G9000136301, G9000143887, G9000211659, G9000244833, G9000246955, G9000313579, Systems-based pharmacologic modelling to elucidate beta-lactam clinical pharmacodynamics and define optimal dosing regimens in severe pneumonia
OpenAlex ID: W4410403226