A Robust Pneumonia Model in Immunocompetent Rodents to Evaluate Antibacterial Efficacy against <i>S. pneumoniae</i>, <i>H. influenzae</i>, <i>K. pneumoniae</i>, <em>P. aeruginosa</em> or <em>A. baumannii</em>

Abstract

Efficacy of candidate antibacterial treatments must be demonstrated in animal models of infection as part of the discovery and development process, preferably in models which mimic the intended clinical indication. A method for inducing robust lung infections in immunocompetent rats and mice is described which allows for the assessment of treatments in a model of serious pneumonia caused by S. pneumoniae, H. influenzae, P. aeruginosa, K. pneumoniae or A. baumannii. Animals are anesthetized, and an agar-based inoculum is deposited deep into the lung via nonsurgical intratracheal intubation. The resulting infection is consistent, reproducible, and stable for at least 48 h and up to 96 h for most isolates. Studies with marketed antibacterials have demonstrated good correlation between in vivo efficacy and in vitro susceptibility, and concordance between pharmacokinetic/pharmacodynamic targets determined in this model and clinically accepted targets has been observed. Although there is an initial time investment when learning the technique, it can be performed quickly and efficiently once proficiency is achieved. Benefits of the model include elimination of the neutropenic requirement, increased robustness and reproducibility, ability to study more pathogens and isolates, improved flexibility in study design and establishment of a challenging infection in an immunocompetent host.

Bistable bacterial growth dynamics in the presence of antimicrobial agents

“…Of-course, bacterial infections in-vivo require additional considerations, such as the presence of the immune system, the clearing of the drugs, as well as environmental conditions that are not only subjected to changes by the bacteria but also by the host (e.g., the host may control limiting factors for the bacterial growth, and such factors invoke higher dimensional dynamics, see Figure 2C-D). Nevertheless, studies have shown [14,39] that quite often in-vitro results regarding interaction dynamics between bacteria and antimicrobials are indicative of such dynamics in-vivo and may be used as building blocks for the in-vivo models [30]. If the IE is relevant for application of any antimicrobial agent in-vivo as we show here is the case in-vitro, then the simplest way to avoid its alarming consequences is to treat infections when they are still very small.…”

“…In a therapeutic context, this means that the fate of an initial infection depends on the initial load of bacteriawhile small infections are easily cleared even with no antibiotics, large infections are hazardous, even when antibiotics are administered at high doses. This phenomenon, known as the "inoculum effect" (IE), is well established in-vitro [6][7][8], as well as in-vivo in animal models and in human patients [9][10][11] [7,12] [13] [14] There are several known biological mechanisms that were proposed to account for IE.…”

Animal Models of Pneumococcal pneumonia

“…As summarized by Hoover et al in 2017 [72], another method described to induce lung infection is direct intrabronchial instillation. This technique was first used in rat models and later modified for mice.…”

The Immunobiological Activity of the Complex Preparation Against Haemophilus Influenzae Infection

“…Для изучения влияния комплексного препарата на развитие инфекционного процесса иммунизированных мышей интраназально заражали культурами капсульного и бескапсульного штаммов H.influenzae [6]. Контрольной группе вводили физиологический раствор.…”

“…Развитие инфекционного процесса изучали на легочной модели заражения [6], так как по нашему мнению, она разработана с учетом органотропности H.influenzae к тканям дыхательных путей и легких. После заражения иммунизированных комплексным препаратом животных формирования инфекционного процесса напрямую зависело от развития иммунного ответа на введение комплексного препарата.…”