2202. Validation of a Rabbit Model of Pseudomonas aeruginosa Acute Pneumonia

Abstract

BackgroundSeverity and antimicrobial resistance of P. aeruginosa (PA) hospital-acquired pneumonia led the FDA to encourage the development of animal models for preclinical evaluation of new therapeutic strategies. We present here the validation of a rabbit model of PA acute pneumonia.MethodsRabbits were infected by endotracheal instillation of 1.8 mL of a standardized inoculum containing 9 × 107 CFU of PA clinical strain 6206 (predetermined 100% lethal dose). The natural history of the disease was described by the following parameters evaluated at 3, 4, 5, 6, 10 hours post-infection (hpi) and at the time of spontaneous death (6 rabbits/group): lung-to-body weight ratio (LW/BW), pulmonary, splenic and renal bacterial counts, pulmonary histology and blood markers (blood cell counts, blood gas and IL-8). Three groups of 12 rabbits were then treated with saline (controls), tobramycin or meropenem at doses determined by PK/PD analysis to confirm the efficacy of a human-equivalent dosing regimen.ResultsPA strain 6,206 caused fatal pneumonia in 13–23 hours by acute respiratory distress syndrome (pulmonary edema and necrosis with LW/BW > 10, pO2 <40 mmHg) and/or sepsis (hyperlactatemia, hypoglycemia, cytopenias). LW/BW and pulmonary bacterial counts increased significantly over time. The splenic and renal bacterial spread was constant after 6 hpi. Hypoxemia <60 mmHg appeared at 5 hpi for 4/6 rabbits, associated with elevated plasma IL-8 concentration, massive neutrophilic influx into the airspace, lung necrosis, hemorrhage, and pulmonary edema formation. Consequently, 5 hpi appeared as the most appropriate time to trigger a therapeutic intervention. Meropenem (80 mg/kg/q2h) or tobramycin (1 injection of 2.5 mg/kg, then saline/q2h) showed superiority over saline, with a mortality rate of 33% and 17% vs. 100%, and an LW/BW ratio of 8.53 and 8.54 vs. 13.9, respectively. Tobramycin was less effective than meropenem in clearing bacteria, with, respectively, 1 and 9 out of 12 rabbits having sterile samples.ConclusionThis rabbit model of PA acute pneumonia is a reliable evaluation tool for new therapeutic strategies. Our study also provides guidance for the development of animal models by describing the natural history of disease and therapeutic validation. Disclosures All authors: No reported disclosures.