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Development of an optimized and practical pharmacokinetics/pharmacodynamics analysis method for aztreonam/nacubactam against carbapenemase-producing K. pneumoniae
BACKGROUND: Nacubactam, a new β-lactamase inhibitor with antibacterial activity, is being developed as a single drug to be co-administered with cefepime or aztreonam. However, determining pharmacokinetics/pharmacodynamics (PK/PD) parameters in β-lactam/β-lactamase inhibitor combinations remains chal...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10068424/ https://www.ncbi.nlm.nih.gov/pubmed/36775998 http://dx.doi.org/10.1093/jac/dkad033 |
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author | Igarashi, Yuki Takemura, Wataru Liu, Xiaoxi Kojima, Nana Morita, Takumi Chuang, Victor Tuan Giam Enoki, Yuki Taguchi, Kazuaki Matsumoto, Kazuaki |
author_facet | Igarashi, Yuki Takemura, Wataru Liu, Xiaoxi Kojima, Nana Morita, Takumi Chuang, Victor Tuan Giam Enoki, Yuki Taguchi, Kazuaki Matsumoto, Kazuaki |
author_sort | Igarashi, Yuki |
collection | PubMed |
description | BACKGROUND: Nacubactam, a new β-lactamase inhibitor with antibacterial activity, is being developed as a single drug to be co-administered with cefepime or aztreonam. However, determining pharmacokinetics/pharmacodynamics (PK/PD) parameters in β-lactam/β-lactamase inhibitor combinations remains challenging. We aimed to establish a practical PK/PD analysis method for aztreonam/nacubactam that incorporates instantaneous MIC (MIC(i)). METHODS: Based on chequerboard MIC measurements, MIC(i) of aztreonam against carbapenemase-producing Klebsiella pneumoniae in the presence of nacubactam was simulated. RESULTS: The mean change in the bacterial count of thigh-infected mice in an in vivo PD study was plotted based on %fT(>MICi) and analysed using the inhibitory effect sigmoid I(max) model. fT(>MICi) calculated from the PK experiments showed a high correlation with the in vivo bactericidal effect, suggesting that fT(>MICi) is the optimal PK/PD parameter for aztreonam/nacubactam. The target values of fT(>MICi) achieving growth inhibition, 1 log(10) kill and 2 log(10) kill, were 22, 38% and 75%, respectively. CONCLUSIONS: The PK/PD analysis method proposed in this study is promising for determining practical PK/PD parameters in combination therapy. In addition, this is the first report of aztreonam/nacubactam showing a potent in vivo therapeutic effect against NDM-producing K. pneumoniae. |
format | Online Article Text |
id | pubmed-10068424 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-100684242023-04-04 Development of an optimized and practical pharmacokinetics/pharmacodynamics analysis method for aztreonam/nacubactam against carbapenemase-producing K. pneumoniae Igarashi, Yuki Takemura, Wataru Liu, Xiaoxi Kojima, Nana Morita, Takumi Chuang, Victor Tuan Giam Enoki, Yuki Taguchi, Kazuaki Matsumoto, Kazuaki J Antimicrob Chemother Original Research BACKGROUND: Nacubactam, a new β-lactamase inhibitor with antibacterial activity, is being developed as a single drug to be co-administered with cefepime or aztreonam. However, determining pharmacokinetics/pharmacodynamics (PK/PD) parameters in β-lactam/β-lactamase inhibitor combinations remains challenging. We aimed to establish a practical PK/PD analysis method for aztreonam/nacubactam that incorporates instantaneous MIC (MIC(i)). METHODS: Based on chequerboard MIC measurements, MIC(i) of aztreonam against carbapenemase-producing Klebsiella pneumoniae in the presence of nacubactam was simulated. RESULTS: The mean change in the bacterial count of thigh-infected mice in an in vivo PD study was plotted based on %fT(>MICi) and analysed using the inhibitory effect sigmoid I(max) model. fT(>MICi) calculated from the PK experiments showed a high correlation with the in vivo bactericidal effect, suggesting that fT(>MICi) is the optimal PK/PD parameter for aztreonam/nacubactam. The target values of fT(>MICi) achieving growth inhibition, 1 log(10) kill and 2 log(10) kill, were 22, 38% and 75%, respectively. CONCLUSIONS: The PK/PD analysis method proposed in this study is promising for determining practical PK/PD parameters in combination therapy. In addition, this is the first report of aztreonam/nacubactam showing a potent in vivo therapeutic effect against NDM-producing K. pneumoniae. Oxford University Press 2023-02-13 /pmc/articles/PMC10068424/ /pubmed/36775998 http://dx.doi.org/10.1093/jac/dkad033 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Research Igarashi, Yuki Takemura, Wataru Liu, Xiaoxi Kojima, Nana Morita, Takumi Chuang, Victor Tuan Giam Enoki, Yuki Taguchi, Kazuaki Matsumoto, Kazuaki Development of an optimized and practical pharmacokinetics/pharmacodynamics analysis method for aztreonam/nacubactam against carbapenemase-producing K. pneumoniae |
title | Development of an optimized and practical pharmacokinetics/pharmacodynamics analysis method for aztreonam/nacubactam against carbapenemase-producing K. pneumoniae |
title_full | Development of an optimized and practical pharmacokinetics/pharmacodynamics analysis method for aztreonam/nacubactam against carbapenemase-producing K. pneumoniae |
title_fullStr | Development of an optimized and practical pharmacokinetics/pharmacodynamics analysis method for aztreonam/nacubactam against carbapenemase-producing K. pneumoniae |
title_full_unstemmed | Development of an optimized and practical pharmacokinetics/pharmacodynamics analysis method for aztreonam/nacubactam against carbapenemase-producing K. pneumoniae |
title_short | Development of an optimized and practical pharmacokinetics/pharmacodynamics analysis method for aztreonam/nacubactam against carbapenemase-producing K. pneumoniae |
title_sort | development of an optimized and practical pharmacokinetics/pharmacodynamics analysis method for aztreonam/nacubactam against carbapenemase-producing k. pneumoniae |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10068424/ https://www.ncbi.nlm.nih.gov/pubmed/36775998 http://dx.doi.org/10.1093/jac/dkad033 |
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