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.

Longitudinal temperature measurement can determine humane endpoints in BALB/c mouse models of ESKAPEE infection

“…CFU enumeration can demonstrate bacterial burden within pulmonary infection models [ 14 ]. Based on previous work with these models, bacteria colonize and begin infecting the lung tissue about 4 HPI [ 28 ].…”

“…However, clinical scoring remains highly subjective and likely includes variation within and between personnel. While these findings may be useful for pulmonary ESKAPEE pathogen models in BALB/c mice, there are considerations such as mouse strain and bacterial strain differences that will need to be evaluated in order to standardize a mouse pneumonia model [ 14 ].…”

“…weight change, clinical scoring, survival, bacterial burden). Recently, studies have suggested the pulmonary model should be standardized across multiple labs to allow comparisons between different antimicrobials and enable better prediction of efficacy [ 14 ].…”

“…Few survival models exist for ESKAPEE pathogens. This could be related to Institutional Animal Care and Use Committee (IACUC) limitations associated with U.S. Department of Agriculture (USDA) pain and distress Category E animal research protocols [ 14 ]. Non-steroidal anti-inflammatories (NSAID) [ 15 , 16 ] and opioid [ 17 , 18 ] analgesics can produce confounding immunomodulatory effects on mice and may impact bacterial pathogenesis.…”

“…These metrics are often based on clinically observable parameters, such as body weight, body surface temperature, internal body temperature, appearance, behaviour, hydration status, and respiratory effort. However, these parameters are not standardized across laboratory animal medicine [ 14 ].…”