2. Academic Validation
  3. Individual target pharmacokinetic/pharmacodynamic attainment rates among cefepime-treated patients admitted to the ICU with hospital-acquired pneumonia with and without ECMO

Individual target pharmacokinetic/pharmacodynamic attainment rates among cefepime-treated patients admitted to the ICU with hospital-acquired pneumonia with and without ECMO

  • Antimicrob Agents Chemother. 2025 Jun 4;69(6):e0010225. doi: 10.1128/aac.00102-25.
Adrian Valadez 1 2,  Marta Zurawska 1 2,  Emma Harlan 1 2,  Marc H Scheetz 1 2 3 4,  MIchael N Neely 5 6,  Paul R Yarnold 7,  Mengjia Kang 8,  Erin Korth 8,  Francisco Martinez 8,  Bridget Giblin 8,  Helen K Donnelly 8,  Kay Dedicatoria 1,  Rachel Medernach 9,  Sophia Nozick 10,  Alan R Hauser 10 11,  Egon A Ozer 11 12,  Estefani Diaz 13,  Alexander V Misharin 8,  Richard G Wunderink 8,  Nathaniel J Rhodes 1 2 3
Affiliations

Affiliations

  • 1 Department of Pharmacy Practice, College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA.
  • 2 Pharmacometrics Center of Excellence, Midwestern University, Downers Grove, Illinois, USA.
  • 3 Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois, USA.
  • 4 Department of Pharmacology and Biomedical Sciences, College of Graduate Studies, Midwestern University, Downers Grove, Illinois, USA.
  • 5 Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • 6 Laboratory of Applied Pharmacokinetics and Bioinformatics, The Saban Research Institute, Children's Hospital of Los Angeles, Los Angeles, California, USA.
  • 7 Optimal Data Analysis, LLC, Chicago, Illinois, USA.
  • 8 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  • 9 Division of Infectious Diseases, Department of Internal Medicine, RUSH University Medical Center, Chicago, Illinois, USA.
  • 10 Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  • 11 Division of Infectious Diseases, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  • 12 Center for Pathogen Genomics and Microbial Evolution, Havey Institute for Global Health, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
  • 13 Robert H. Lurie Comprehensive Cancer Research Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
PMID: 40372025 DOI: 10.1128/aac.00102-25
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% fT >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.

Keywords

pharmacokinetics extracorporeal membrane oxygenation.

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