Variability of murine bacterial pneumonia models used to evaluate antimicrobial agents

Abstract

Antimicrobial resistance has become one of the greatest threats to human health, and new antibacterial treatments are urgently needed. As a tool to develop novel therapies, animal models are essential to bridge the gap between preclinical and clinical research. However, despite common usage of in vivo models that mimic clinical infection, translational challenges remain high. Standardization of in vivo models is deemed necessary to improve the robustness and reproducibility of preclinical studies and thus translational research. The European Innovative Medicines Initiative (IMI)-funded "Collaboration for prevention and treatment of MDR bacterial infections" (COMBINE) consortium, aims to develop a standardized, quality-controlled murine pneumonia model for preclinical efficacy testing of novel anti-infective candidates and to improve tools for the translation of preclinical data to the clinic. In this review of murine pneumonia model data published in the last 10 years, we present our findings of considerable variability in the protocols employed for testing the efficacy of antimicrobial compounds using this in vivo model. Based on specific inclusion criteria, fifty-three studies focusing on antimicrobial assessment against Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii were reviewed in detail. The data revealed marked differences in the experimental design of the murine pneumonia models employed in the literature. Notably, several differences were observed in variables that are expected to impact the obtained results, such as the immune status of the animals, the age, infection route and sample processing, highlighting the necessity of a standardized model.

Keywords: Gram-negative; PK/PD; antimicrobial; antimicrobial efficacy studies; lung infection; murine pneumonia model.

FIGURE 1

Flow diagram for the study selection process.

FIGURE 2

Circular dendrogram representing hierarchically structured variables. The area of the nodes represents the number of studies. Hierarchy from inside to outside: bacteria, mouse strain (Inb.: Inbred, Out.: Outbred), mouse immune status (NT: neutropenic, IC: Immunocompetent), study main readout (S: mice survival, B: bacterial load) and infection route (IT: intratracheal, IN: intranasal, ORP: oropharyngeal, IB: intrabronchial, AE: aerosolization).