Development and validation of a rabbit model of Pseudomonas aeruginosa hyperdynamic septic shock for preclinical drug development.

Translating preclinical findings into clinical success remains a major barrier in the development of antimicrobials targeting Pseudomonas aeruginosa, particularly for severe infections such as sepsis and septic shock. Rodent models frequently fail to predict therapeutic efficacy in clinical sepsis. To address this gap, we developed and validated a rabbit model of hyperdynamic septic shock incorporating intensive care unit (ICU)-style monitoring and supportive care to better reflect human clinical practice. Rabbits challenged intravenously with P. aeruginosa progressed predictably from hyperdynamic circulation to hypodynamic shock, characterized by progressive metabolic acidosis, leukocyte dysregulation, and acute myocardial injury. A sustained 20% decline in mean arterial pressure reliably marked the onset of cardiovascular decompensation and was prospectively applied in follow-on studies as a predefined hemodynamic trigger for initiating therapeutic interventions. Despite pharmacokinetic studies showing that ciprofloxacin 30 mg/kg infused over 1 h every 8 h achieved human-equivalent exposures and exceeded the AUC0-24h/MIC ≥ 125 efficacy threshold, ciprofloxacin monotherapy improved survival compared to placebo but failed to prevent progression to fatal shock. In contrast, the combination of ciprofloxacin and protocolized supportive care-based on the clinical "VIP" strategy (ventilation, infusion, and pressor)-rescued 75% of animals from lethal septic shock compared with VIP plus placebo, while also stabilizing physiological parameters and markedly reducing bacterial burdens. Together, these findings underscore the importance of VIP supportive care for maintaining hemodynamic stability and establish a clinically relevant platform for evaluating antimicrobial therapies.