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Peer-reviewedCC BY 4.0Antimicrobial Agents and Chemotherapy

Development and validation of a cefepime population pharmacokinetic model to guide treatment for patients with hospital-acquired pneumonia requiring renal replacement

  • Adrian Valadez1,2
  • Emma Harlan1,2
  • Marc H. Scheetz1,2,3,4,5
  • Michael N. Neely6,7
  • Helen K. Donnelly8
  • Richard G. Wunderink8
  • Nathaniel J. Rhodes1,2,3
8 affiliations
  1. 1Department of Pharmacy Practice, Midwestern University, College of Pharmacy, Downers Grove, Illinois, USA
  2. 2Pharmacometrics Center of Excellence, Midwestern University, Downers Grove, Illinois, USA
  3. 3Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois, USA
  4. 4Department of Pharmacology, College of Graduate Studies, Midwestern University, Downers Grove, Illinois, USA
  5. 5Department of Biomedical Sciences, College of Graduate Studies, Midwestern University, Downers Grove, Illinois, USA
  6. 6Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  7. 7Laboratory of Applied Pharmacokinetics and Bioinformatics, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA
  8. 8Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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Abstract

Cefepime is used in critically ill pneumonia patients, but dosing in renal replacement therapy (RRT) is complicated by altered renal function, extracorporeal removal, and variability in pulmonary epithelial lining fluid (ELF) exposure. We sought to develop an integrated model linking systemic, extracorporeal, and pulmonary cefepime pharmacokinetics in RRT. Pharmacokinetic (PK) data from critically ill adults receiving cefepime and requiring RRT were included. In a dedicated continuous RRT (CRRT) cohort (n = 8), pre- and post-filter plasma and effluent PK data were collected. Additional patients (n = 43) requiring RRT also contributed plasma and ELF samples. A non-parametric population PK model was developed using an 80/20 subject-level development-validation split. Covariate models assessed the impact of residual renal function, effluent flow rate, body size, and fixed intradialytic hemodialysis (HD) clearance. Monte Carlo simulations evaluated plasma and ELF target attainment across dosing strategies, weight strata, and minimum inhibitory concentrations (MICs). The final model jointly described systemic, extracorporeal, and pulmonary cefepime disposition using piecewise central volume, native clearance, linear effluent-flow-dependent CRRT clearance, fixed HD clearance, and ELF distribution. Simulations showed adequate plasma target attainment, whereas ELF attainment was sensitive to MIC, target, regimen, and body weight. Continuous infusions of 4 g/day provided adequate ELF attainment at MICs ≤4 mg/L. Plasma-based cefepime target attainment may overestimate pulmonary exposure during RRT, particularly at higher MICs, body weights, and fT>MIC targets. External validation and prospective studies are needed to refine pulmonary target estimates and determine whether plasma-guided Bayesian dosing can reliably ensure site-of-infection exposure.

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Cite

BibTeXRIS
BibTeX
@article{valadez2026development,
  title = {{Development and validation of a cefepime population pharmacokinetic model to guide treatment for patients with hospital-acquired pneumonia requiring renal replacement}},
  author = {Adrian Valadez and Emma Harlan and Marc H. Scheetz and Michael N. Neely and Helen K. Donnelly and Richard G. Wunderink and Nathaniel J. Rhodes},
  journal = {Antimicrobial Agents and Chemotherapy},
  year = {2026},
  month = oct,
  doi = {10.1128/aac.00900-26},
  url = {https://doi.org/10.1128/aac.00900-26},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Development and validation of a cefepime population pharmacokinetic model to guide treatment for patients with hospital-acquired pneumonia requiring renal replacement
AU  - Adrian Valadez
AU  - Emma Harlan
AU  - Marc H. Scheetz
AU  - Michael N. Neely
AU  - Helen K. Donnelly
AU  - Richard G. Wunderink
AU  - Nathaniel J. Rhodes
PY  - 2026
DA  - 2026/10/08
JO  - Antimicrobial Agents and Chemotherapy
DO  - 10.1128/aac.00900-26
UR  - https://doi.org/10.1128/aac.00900-26
AB  - Cefepime is used in critically ill pneumonia patients, but dosing in renal replacement therapy (RRT) is complicated by altered renal function, extracorporeal removal, and variability in pulmonary epithelial lining fluid (ELF) exposure. We sought to develop an integrated model linking systemic, extracorporeal, and pulmonary cefepime pharmacokinetics in RRT. Pharmacokinetic (PK) data from critically ill adults receiving cefepime and requiring RRT were included. In a dedicated continuous RRT (CRRT) cohort (n = 8), pre- and post-filter plasma and effluent PK data were collected. Additional patients (n = 43) requiring RRT also contributed plasma and ELF samples. A non-parametric population PK model was developed using an 80/20 subject-level development-validation split. Covariate models assessed the impact of residual renal function, effluent flow rate, body size, and fixed intradialytic hemodialysis (HD) clearance. Monte Carlo simulations evaluated plasma and ELF target attainment across dosing strategies, weight strata, and minimum inhibitory concentrations (MICs). The final model jointly described systemic, extracorporeal, and pulmonary cefepime disposition using piecewise central volume, native clearance, linear effluent-flow-dependent CRRT clearance, fixed HD clearance, and ELF distribution. Simulations showed adequate plasma target attainment, whereas ELF attainment was sensitive to MIC, target, regimen, and body weight. Continuous infusions of 4 g/day provided adequate ELF attainment at MICs ≤4 mg/L. Plasma-based cefepime target attainment may overestimate pulmonary exposure during RRT, particularly at higher MICs, body weights, and fT>MIC targets. External validation and prospective studies are needed to refine pulmonary target estimates and determine whether plasma-guided Bayesian dosing can reliably ensure site-of-infection exposure.
SN  - 0066-4804
SN  - 1098-6596
ER  -