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Prediction of in vivo and in vitro infection model results using a semimechanistic model of avibactam and aztreonam combination against multidrug resistant organisms

The combination of aztreonam‐avibactam is active against multidrug‐resistant Enterobacteriaceae that express metallo‐β‐lactamases. A complex synergistic interaction exists between aztreonam and avibactam bactericidal activities that have not been quantitatively explored. A two‐state semimechanistic...

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Autores principales: Sy, SKB, Zhuang, L, Xia, H, Beaudoin, M‐E, Schuck, VJ, Derendorf, H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351411/
https://www.ncbi.nlm.nih.gov/pubmed/28145085
http://dx.doi.org/10.1002/psp4.12159
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author Sy, SKB
Zhuang, L
Xia, H
Beaudoin, M‐E
Schuck, VJ
Derendorf, H
author_facet Sy, SKB
Zhuang, L
Xia, H
Beaudoin, M‐E
Schuck, VJ
Derendorf, H
author_sort Sy, SKB
collection PubMed
description The combination of aztreonam‐avibactam is active against multidrug‐resistant Enterobacteriaceae that express metallo‐β‐lactamases. A complex synergistic interaction exists between aztreonam and avibactam bactericidal activities that have not been quantitatively explored. A two‐state semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) logistic growth model was developed to account for antimicrobial activities in the combination of bacteria‐mediated degradation of aztreonam and the inhibition of aztreonam degradation by avibactam. The model predicted that changing regimens of 2 g aztreonam plus 0.375 and 0.6 g avibactam as a 1‐hour infusion were qualitatively similar to that observed from in vivo murine thigh infection and hollow‐fiber infection models previously reported in the literature with 24‐hour log kill ≥1. The current approach to characterize the effect of avibactam in enhancing aztreonam activity from time‐kill study was accomplished by shifting the half‐maximal effective concentration (EC(50)) of aztreonam in increasing avibactam concentration using a nonlinear equation as a function of avibactam concentration, providing a framework for translational predictions.
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spelling pubmed-53514112017-03-22 Prediction of in vivo and in vitro infection model results using a semimechanistic model of avibactam and aztreonam combination against multidrug resistant organisms Sy, SKB Zhuang, L Xia, H Beaudoin, M‐E Schuck, VJ Derendorf, H CPT Pharmacometrics Syst Pharmacol Original Articles The combination of aztreonam‐avibactam is active against multidrug‐resistant Enterobacteriaceae that express metallo‐β‐lactamases. A complex synergistic interaction exists between aztreonam and avibactam bactericidal activities that have not been quantitatively explored. A two‐state semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) logistic growth model was developed to account for antimicrobial activities in the combination of bacteria‐mediated degradation of aztreonam and the inhibition of aztreonam degradation by avibactam. The model predicted that changing regimens of 2 g aztreonam plus 0.375 and 0.6 g avibactam as a 1‐hour infusion were qualitatively similar to that observed from in vivo murine thigh infection and hollow‐fiber infection models previously reported in the literature with 24‐hour log kill ≥1. The current approach to characterize the effect of avibactam in enhancing aztreonam activity from time‐kill study was accomplished by shifting the half‐maximal effective concentration (EC(50)) of aztreonam in increasing avibactam concentration using a nonlinear equation as a function of avibactam concentration, providing a framework for translational predictions. John Wiley and Sons Inc. 2017-02-01 2017-03 /pmc/articles/PMC5351411/ /pubmed/28145085 http://dx.doi.org/10.1002/psp4.12159 Text en © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Sy, SKB
Zhuang, L
Xia, H
Beaudoin, M‐E
Schuck, VJ
Derendorf, H
Prediction of in vivo and in vitro infection model results using a semimechanistic model of avibactam and aztreonam combination against multidrug resistant organisms
title Prediction of in vivo and in vitro infection model results using a semimechanistic model of avibactam and aztreonam combination against multidrug resistant organisms
title_full Prediction of in vivo and in vitro infection model results using a semimechanistic model of avibactam and aztreonam combination against multidrug resistant organisms
title_fullStr Prediction of in vivo and in vitro infection model results using a semimechanistic model of avibactam and aztreonam combination against multidrug resistant organisms
title_full_unstemmed Prediction of in vivo and in vitro infection model results using a semimechanistic model of avibactam and aztreonam combination against multidrug resistant organisms
title_short Prediction of in vivo and in vitro infection model results using a semimechanistic model of avibactam and aztreonam combination against multidrug resistant organisms
title_sort prediction of in vivo and in vitro infection model results using a semimechanistic model of avibactam and aztreonam combination against multidrug resistant organisms
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351411/
https://www.ncbi.nlm.nih.gov/pubmed/28145085
http://dx.doi.org/10.1002/psp4.12159
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