Protein Binding Determination of Cefepime, Flucloxacillin, Meropenem, Piperacillin and Tazobactam by Ultrafiltration in Critically Ill Patients: The Choice of Device Matters
Abstract
Background and objective: Therapeutic drug monitoring (TDM) and pharmacokinetic studies of beta-lactam antibiotics in critically ill patients aim to define optimal dosing and require accurate measurement of unbound drug concentrations. This study compared the performance of two ultrafiltration devices, Centrifree and Amicon, for measuring unbound concentrations of cefepime, meropenem, flucloxacillin, piperacillin and tazobactam. Methods: Non-specific binding (NSB) was specifically assessed in phosphate-buffered saline, and unbound concentrations were measured using a chromatographic method in both spiked plasma and plasma samples from critically ill patients, in order to compare the two ultrafiltration devices. Results: Centrifree exhibited no significant NSB for any antibiotics (≤ 15%), while Amicon displayed significant NSB for meropenem (26-61%), flucloxacillin (18-58%) and piperacillin (15-72%), resulting in lower unbound concentrations in both patient and spiked plasma samples compared to Centrifree. Additionally, piperacillin, and to a lesser extent flucloxacillin, demonstrated concentration-dependent NSB with Amicon. The comparative mean ± standard deviation of unbound fractions in intensive care unit (ICU) patients were as follows: cefepime, 0.85 ± 0.12 (Centrifree) versus 0.90 ± 0.10 (Amicon); meropenem, 0.87 ± 0.07 (Centrifree) versus 0.77 ± 0.05 (Amicon); flucloxacillin, 0.25 ± 0.13 (Centrifree) versus 0.18 ± 0.13 (Amicon); piperacillin, 0.91 ± 0.07 (Centrifree) versus 0.67 ± 0.13 (Amicon); and tazobactam, 0.97 ± 0.08 (Centrifree) versus 0.95 ± 0.08 (Amicon). Conclusion: These findings underscore significant differences in results between ultrafiltration devices, depending on the drug, influenced by NSB. Such factors should be considered when developing methods for determining unbound concentrations of beta-lactam antibiotics.
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BibTeX
@article{gregoire2026protein,
title = {{Protein Binding Determination of Cefepime, Flucloxacillin, Meropenem, Piperacillin and Tazobactam by Ultrafiltration in Critically Ill Patients: The Choice of Device Matters}},
author = {Matthieu Gregoire and Steven Wallis and Paul Williams and Hayoung Won and María Patricia Hernández-Mitre and Mohd Abdul-Aziz and Jason A. Roberts},
journal = {Clinical Pharmacokinetics},
year = {2026},
month = aug,
doi = {10.1007/s40262-026-01659-9},
url = {https://hal.science/hal-05825591v1},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Protein Binding Determination of Cefepime, Flucloxacillin, Meropenem, Piperacillin and Tazobactam by Ultrafiltration in Critically Ill Patients: The Choice of Device Matters
AU - Matthieu Gregoire
AU - Steven Wallis
AU - Paul Williams
AU - Hayoung Won
AU - María Patricia Hernández-Mitre
AU - Mohd Abdul-Aziz
AU - Jason A. Roberts
PY - 2026
DA - 2026/08/29
JO - Clinical Pharmacokinetics
DO - 10.1007/s40262-026-01659-9
UR - https://hal.science/hal-05825591v1
AB - Background and objective: Therapeutic drug monitoring (TDM) and pharmacokinetic studies of beta-lactam antibiotics in critically ill patients aim to define optimal dosing and require accurate measurement of unbound drug concentrations. This study compared the performance of two ultrafiltration devices, Centrifree and Amicon, for measuring unbound concentrations of cefepime, meropenem, flucloxacillin, piperacillin and tazobactam. Methods: Non-specific binding (NSB) was specifically assessed in phosphate-buffered saline, and unbound concentrations were measured using a chromatographic method in both spiked plasma and plasma samples from critically ill patients, in order to compare the two ultrafiltration devices. Results: Centrifree exhibited no significant NSB for any antibiotics (≤ 15%), while Amicon displayed significant NSB for meropenem (26-61%), flucloxacillin (18-58%) and piperacillin (15-72%), resulting in lower unbound concentrations in both patient and spiked plasma samples compared to Centrifree. Additionally, piperacillin, and to a lesser extent flucloxacillin, demonstrated concentration-dependent NSB with Amicon. The comparative mean ± standard deviation of unbound fractions in intensive care unit (ICU) patients were as follows: cefepime, 0.85 ± 0.12 (Centrifree) versus 0.90 ± 0.10 (Amicon); meropenem, 0.87 ± 0.07 (Centrifree) versus 0.77 ± 0.05 (Amicon); flucloxacillin, 0.25 ± 0.13 (Centrifree) versus 0.18 ± 0.13 (Amicon); piperacillin, 0.91 ± 0.07 (Centrifree) versus 0.67 ± 0.13 (Amicon); and tazobactam, 0.97 ± 0.08 (Centrifree) versus 0.95 ± 0.08 (Amicon). Conclusion: These findings underscore significant differences in results between ultrafiltration devices, depending on the drug, influenced by NSB. Such factors should be considered when developing methods for determining unbound concentrations of beta-lactam antibiotics.
SN - 0312-5963
SN - 1179-1926
ER -