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Development of an Optimised Pharmacokinetics/Pharmacodynamics analysis method of β-lactam/nacubactam against Carbapenemase-Producing K. pneumoniae
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  • Yuki Igarashi,
  • Wataru Takemura,
  • Xiaoxi Liu,
  • Nana Kojima,
  • Takumi Morita,
  • Victor Chuang,
  • Yuki Enoki,
  • Kazuaki Taguchi,
  • Kazuaki Matsumoto
Yuki Igarashi
Keio University

Corresponding Author:igarasi05@gmail.com

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Wataru Takemura
Keio University
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Xiaoxi Liu
Keio University
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Nana Kojima
Keio University
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Takumi Morita
Keio University
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Victor Chuang
Curtin University Curtin Medical School
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Yuki Enoki
Keio University
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Kazuaki Taguchi
Keio University
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Kazuaki Matsumoto
Keio University
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Abstract

Background and Purpose: No pharmacokinetics/pharmacodynamics (PK/PD) analysis method has been established for combination therapy that comprehensively reflects the efficacy of both antibiotics. Recently, nacubactam, which is a DBO-type new β-lactamase inhibitor and has antibacterial activity, is being developed as a single drug to be co-administered with cefepime or aztreonam. This study attempted to establish a PK/PD analysis method for β-lactam/β-lactamase inhibitors that incorporates instantaneous MIC (MICi) to determine practical PK/PD parameters for aztreonam/nacubactam. Experimental Approach: Based on Checkerboard MIC measurements, MICi of aztreonam against carbapenemase-producing Klebsiella pneumoniae in the presence of nacubactam was simulated. In vivo PD effect was evaluated by the bacterial count of thigh-infected mice after administered a combination of nacubactam and aztreonam. The mean change in the bacterial count obtained by in vivo PD study was plotted based on %fT>MICi and analysed using the Inhibitory Effect Sigmoid Imax Model. Key Results: fT>MICi calculated from the PK experiments showed a high correlation with the bactericidal effect obtained in the PD experiments, suggesting that fT>MICi is the optimal PK/PD parameter for aztreonam/nacubactam. The target values of fT>MICi achieving growth inhibition, 1 log10-kill and 2 log10-kill, were 22, 38 and 75%, respectively. Conclusion and Implications: The PK/PD analysis method proposed in this study is promising for determining practical PK/PD parameters in a combination antimicrobial therapy. In addition, this is the first report of aztreonam/nacubactam showing a potent in vivo therapeutic effect against carbapenemase-producing K. pneumoniae, particularly NDM-producing K. pneumoniae.