Abstract
In 2017, the WHO identified Acinetobacter baumannii as the top priority for the development of new antibiotics. Despite the need for new antibiotics, there remains a lack of well validated preclinical tools for A. baumannii. Here, we characterize and validate a mouse model for A. baumannii translational research. Antibiotic sensitivity for meropenem, amikacin, and polymyxin b was determined by the broth microdilution MIC assay. LD100 inoculums, in both blood and lung infection models, were determined in male and female C3HeB/FeJ mice that were challenged with various A. baumannii clinical isolates. Blood (blood infection model) or blood and lung tissue (lung infection model) were collected from infected mice at 2 and 18 hours and the bacterial burden was determined by quantitative culture. Blood chemistry was analyzed using the iStat system. Cytokines (IL-1ß, TNF, IL-6, and IL-10) were measured in the blood and lung homogenate by ELISA assay. Lung sections (H&E stains) were scored by a pathologist. In the blood infection model, the cytokines and physiological data indicate that mice become moribund due to sepsis (low blood pH, falling bicarbonate, and a rising base deficit), whereas mice become moribund due to respiratory failure (low blood pH, rising bicarbonate, and a falling base deficit) in the oral aspiration pneumonia model. We also characterized the timing of changes in various clinical and biomarker endpoints, which can serve as a basis for future interventional studies. Susceptibility was generally similar across gender and infection route. However, we did observe that female mice were approximately 2-fold more sensitive to LAC-4 ColR in the blood infection model. We also observed that female mice were more than 10-fold more resistant to VA-AB41 in the oral aspiration pneumonia model. These results establish parameters to follow in order to assess efficacy of novel preventative and therapeutic approaches for these infections.
Highlights
Sensitivity testing ensured that we used clinical isolates of A. baumannii with broad representation of antibiotic-resistant and antibiotic-susceptible phenotypes, enabling a unique sensitivity profiles for downstream applications (Table 1)
The LAC-4 ColR strain was a spontaneous mutant that was derived from the LAC-4 parent strain by plating a high inoculum of bacteria on agar plates supplemented with 32 μg/mL colistin
In this study we describe the clinical, microbiological, and sepsis characteristics of mice lethally infected via the tail-vein or aspiration pneumonia with a panel of strains of A. baumannii with varying antibiotic susceptibility
Summary
The World Health Organization (WHO) recently released a list of priority pathogens for which new antibiotics are most needed and carbapenem-resistant Acinetobacter baumannii was listed as a “Priority 1: Critical Pathogen.”[1,2] The current pipeline of novel therapeutics is inadequate, and so for A. baumannii.[1,2,3] One potential obstacle that is continuing to hinder drug development efforts are the lack of validated animal models for the preclinical study of A. baumannii infections.Numerous animal studies have previously been published related to A. baumannii, many studies use infection strategies that raise concerns regarding their clinical relevance.[4,5,6,7] For example, many studies use neutropenic mice to increase their susceptibility to infection, [8,9,10] despite the fact that neutropenia is an uncommon risk factor for A. baumannii infection in patients.[2,11,12,13,14] Other studies have used routes of infection (e.g., intraperitoneal) that do not recapitulate clinical disease, and many studies have used A. baumannii strains that are laboratory adapted and/or unable to cause lethal infection at reasonable infectious inocula. [2]Here we extensively characterize the natural history of disease caused by A. baumannii infection, for both bacteremia and aspiration pneumonia, in normal, immune competent mice. The World Health Organization (WHO) recently released a list of priority pathogens for which new antibiotics are most needed and carbapenem-resistant Acinetobacter baumannii was listed as a “Priority 1: Critical Pathogen.”[1,2] The current pipeline of novel therapeutics is inadequate, and so for A. baumannii.[1,2,3] One potential obstacle that is continuing to hinder drug development efforts are the lack of validated animal models for the preclinical study of A. baumannii infections. We describe A. baumannii clinical isolates that are virulent in blood and lung infection model in mice, with different antimicrobial sensitivity profiles including resistance to amikacin, colistin, and/or meropenem. These studies of defined bacteria isolates/mouse model pairings will enable preclinical studies to identify promising new therapeutic candidates for clinical development
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