Natural history of Acinetobacter baumannii infection in mice.

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.

Déclaration de conflit d'intérêts

I have read the journal's policy and the authors of this manuscript have the following competing interests: In the last 12 months, author BL has owned equity in Exbaq. In the last 12 months, author BS has consulted for Shionogi, Alexion, Synthetic Biologics, Paratek, TheoremDx, and Acurx, and has owned equity in Motif, BioAIM, Synthetic Biologics, Mycomed, and Exbaq.In the last 12 months, author RB has consulted for Merck, Allergan, Wockhardt, Shionogi, and Entasis. In the last 12 months, TN has owned equity in Exbaq and BioAim. This does not alter our adherence to PLOS ONE policies on sharing data and materials.