Assessing Animal Models of Bacterial Pneumonia Used in Investigational New Drug Applications for the Treatment of Bacterial Pneumonia

Abstract

Animal models of bacterial infection have been widely used to explore the in vivo activity of antibacterial drugs. These data are often submitted to the U.S. Food and Drug Administration to support human use in an investigational new drug application (IND). To better understand the range and scientific use of animal models in regulatory submissions, a database was created surveying recent pneumonia models submitted as part of IND application packages. The IND studies were compared to animal models of bacterial pneumonia published in the scientific literature over the same period of time. In this review, we analyze the key experimental design elements, such as animal species, immune status, pathogens selected, and route of administration, and study endpoints.

Variability of murine bacterial pneumonia models used to evaluate antimicrobial agents

“…IN infection was mostly employed when working with neutropenic animals, while for immunocompetent animals, IT infection was most common ( Table 3 ). The predominance of the IN route when using neutropenic animals and the IT when employing immunocompetent animals was also observed in a previous report that summarized studies of antibiotic efficacy against seven gram-negative and two gram-positive pneumonia-causing bacterial species ( Waack et al, 2020 ). This variation may reflect the challenge of establishing lung infections in immunocompetent mice, where a more direct inoculation method such as IT route can lead to a greater success.…”

“…In antibacterial research, the length of the study varies between animal species. Murine pneumonia models are mostly used for short term studies, while larger animals usually employ later endpoints ( Waack et al, 2020 ). The vast majority of the studies reviewed here initiated antibiotic therapy at 2 h post infection (h.p.i.).…”

“…was most commonly employed when antibacterial activity against P. aeruginosa , K. pneumoniae and A. baumannii was investigated. Notably, these studies followed a bimodal distribution, having 24- or 48-h endpoints ( Waack et al, 2020 ). The endpoint used for measuring antimicrobial activity could influence the results ( Andes and Craig, 2002 ; Cigana et al, 2020 ); however, the evaluation of antimicrobial treatments for chronic infection requires longer experimental time points ( Cigana et al, 2020 ).…”

“…Several different mammalian species have been used to model human pneumonia including piglets ( Li Bassi et al, 2014 ), rodents ( Mizgerd and Skerrett, 2008 ), non-human primates ( Kraft et al, 2014 ), sheep ( Malachowa et al, 2019 ), and rabbits ( Nguyen et al, 2021 ). Although these models have proven helpful in studies of disease mechanisms and in antibiotic testing, murine models have been the preferred choice in investigational new drug applications for the treatment of bacterial pneumonia ( Waack et al, 2020 ). Despite anatomical and physiological differences, the immune system of mice mimics that of humans and pathology of murine pneumonia resemble features of human pneumonia ( Mizgerd and Skerrett, 2008 ; Metersky and Waterer, 2020 ).…”

Expert workshop summary: Advancing toward a standardized murine model to evaluate treatments for antimicrobial resistance lung infections

“…Preclinical efficacy models play a crucial role in the proof-of-concept efficacy investigations and provide the basis for selection of dosing regimens in clinical applications ( Tängdén et al, 2020 ; Friberg, 2021 ). Differences in the commonly used preclinical models are extensive ( Andes and Craig, 2002 ; Bulitta et al, 2019 ; Waack et al, 2020 ), limiting the results’ comparability and reproducibility and possibly impeding successful translation to the clinic. The pathogenesis of mouse pneumonia may have characteristics with those of human pneumonia despite anatomical and physiological differences ( Mizgerd and Skerrett, 2008 ; Metersky and Waterer, 2020 ).…”