2. Academic Validation
  3. Application of epithelial lining fluid drug concentrations to MICi-Based PK/PD modeling of cefepime/nacubactam in a murine model of CPE pneumonia

Application of epithelial lining fluid drug concentrations to MICi-Based PK/PD modeling of cefepime/nacubactam in a murine model of CPE pneumonia

  • J Infect Chemother. 2026 Jan;32(1):102889. doi: 10.1016/j.jiac.2025.102889.
Yuki Mizukami 1,  Mishu Takahashi 1,  Kenta Suzuki 1,  Shaoqing Duan 1,  Shintaro Ikegami 1,  Takuma Muraishi 1,  Natsuki Satake 1,  Yuko Okamoto 1,  Yuki Igarashi 2,  Yuki Enoki 1,  Kazuaki Taguchi 3,  Kazuaki Matsumoto 1
Affiliations

Affiliations

  • 1 Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan.
  • 2 Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan. Electronic address: [email protected].
  • 3 Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
PMID: 41371496 DOI: 10.1016/j.jiac.2025.102889
Abstract

Introduction: Nacubactam is a novel β-lactamase inhibitor with intrinsic Antibacterial activity that shows therapeutic potential against carbapenemase-producing Enterobacterales when administered with β-lactam Antibiotics. Pharmacokinetics/pharmacodynamics (PK/PD) analyses based on drug concentrations at the site of Infection are recommended to better evaluate Antibiotic efficacy. A new PD index, the instantaneous minimum inhibitory concentration (MICi), which dynamically reflects the changing susceptibility of β-lactams during co-administration with β-lactamase inhibitors, has recently been proposed. This study aimed to assess the efficacy of cefepime combined with nacubactam in a murine model of pneumonia using MICi-based PK/PD analysis in the lung epithelial lining fluid (ELF).

Methods: In vitro pharmacodynamic testing using the checkerboard method was conducted with two β-lactamase-producing Klebsiella pneumoniae strains. In vivo PK and PD studies were performed in neutropenic mice using both β-lactamase-producing and non-producing strains. Drug concentrations in plasma and ELF were measured, and MICi-based PK/PD analysis was conducted.

Results: In vitro, the MIC of cefepime decreased in a concentration-dependent manner with increasing nacubactam. In the murine model of pneumonia, cefepime monotherapy resulted in Bacterial changes of 0.12-4.30 log10 CFU/lung, while the combination therapy reduced Bacterial counts by -5.93 to -0.234 log10 CFU/lung. The percentage of time that free cefepime concentrations exceeded MICi (T > MICi) was highly correlated with Bacterial reduction. The target T > MICi for maximal effect was estimated to be 29.3 %.

Conclusions: These findings support the utility of MICi-based PK/PD analysis for optimizing combination Antibiotic therapy in pneumonia.

Keywords

Carbapenemase-producing enterobacterales; Epithelial lining fluid; Instantaneous MIC; Nacubactam; PK/PD; Pneumonia.

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