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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...

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Autores principales: Igarashi, Yuki, Takemura, Wataru, Liu, Xiaoxi, Kojima, Nana, Morita, Takumi, Chuang, Victor Tuan Giam, Enoki, Yuki, Taguchi, Kazuaki, Matsumoto, Kazuaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
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.
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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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