Binding of temocillin to plasma proteins in vitro and in vivo: the importance of plasma protein levels in different populations and of co-medications

Perrin Ngougni Pokem, Peter Matzneller, Steven Vervaeke, Xavier Wittebole, Lieven Goeman, Marie Coessens, Eleonora Cottone, Arnaud Capron, Beatrix Wulkersdorfer, Pierre Wallemacq, Johan W. Mouton, Anouk E. Muller, Markus Zeitlinger, Pierre-Francois Laterre, Paul M. Tulkens, Francoise Van Bambeke*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background Temocillin plasma protein binding (PPB) in healthy individuals is reported to be similar to 85% but had not been studied in patients. Objectives To obtain normative data on temocillin PPB in patients in relation to infection and impact of co-medications widely used in ICU. Methods Plasma was obtained from healthy individuals (Group #1), non-ICU patients with UTI (Group #2), ICU patients with suspected/confirmed ventriculitis (Group #3) or with sepsis/septic shock (Group #4). Total and unbound temocillin concentrations were measured in spiked samples from temocillin-naive donors (in vitro) or in plasma from temocillin-treated subjects (in vivo). The impact of diluting plasma, using pharmaceutical albumin, or adding drugs potentially competing for PPB was tested in spiked samples. Data were analysed using a modified Hill-Langmuir equation taking ligand depletion into account. Results Temocillin PPB was saturable in all groups, both in vitro and in vivo. Maximal binding capacity (B-max) was 1.2-2-fold lower in patients. At 20 and 200 mg/L (total concentrations), the unbound fraction reached 12%-29%, 23%-42% and 32%-52% in Groups #2, #3, #4. The unbound fraction was inversely correlated with albumin and C-reactive protein concentrations. Binding to albumin was 2-3-fold lower than in plasma and non-saturable. Drugs with high PPB but active at lower molar concentrations than temocillin caused minimal displacement, while fluconazole (low PPB but similar plasma concentrations to temocillin) increased up to 2-fold its unbound fraction. Conclusions Temocillin PPB is saturable, 2-4-fold lowered in infected patients in relation to disease severity (ICU admission, hypoalbuminaemia, inflammation) and only partially reproducible with albumin. Competition with other drugs must be considered for therapeutic concentrations to be meaningful.

Original languageEnglish
Pages (from-to)2742–2753
JournalJournal of Antimicrobial Chemotherapy
Volume77
Issue number10
DOIs
Publication statusPublished - Oct 2022

Bibliographical note

Funding
This study was funded in part by EUMEDICA S.A., Belgium, which also provided useful information for the selection of the Belgian clinical centres
participating in the study. However, the sponsor played no role in launching, performing and ending of the study. It was not involved in data analysis or data interpretation, or in the decision to submit the results for publication. The collection of clinical data, the performance of analytical studies, handling and analysis of the results, and preparation of the present paper were part of the PhD thesis of P.N.P., whose work was supported by the Université catholique de Louvain. No specific funding was set forth or required by the other participants, whose work was supported by the general budget awarded to their clinical or laboratory units by their institutions and considered as being part of their normal academic and/or clinical activities.

© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved.

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