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

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 (MIC_i), 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 MIC_i-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 MIC_i-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 MIC_i (T > MIC_i) was highly correlated with bacterial reduction. The target T > MIC_i for maximal effect was estimated to be 29.3 %.

Conclusions

These findings support the utility of MIC_i-based PK/PD analysis for optimizing combination antibiotic therapy in pneumonia.