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
  • 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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