Pseudomonas aeruginosa Ventilator-Associated Pneumonia Rabbit Model for Preclinical Drug Development

Abstract

Development and validation of large animal models of Pseudomonas aeruginosa ventilator-associated pneumonia is needed for testing new drug candidates in a manner mimicking how they will be used clinically. We have developed a new model in which rabbits were ventilated with low-tidal volume and challenged with P. aeruginosa to recapitulate hallmark clinical features of acute respiratory distress syndrome (ARDS): acute lung injury and inflammation, progressive decrease in arterial oxygen partial pressure to fractional inspired oxygen PaO2:FiO2, leukopenia, neutropenia, thrombocytopenia, hyperlactatemia, severe hypotension, bacterial dissemination from lung to other organs, multiorgan dysfunction, and ultimately death. We evaluated the predictive power of this rabbit model for antibiotic efficacy testing by determining whether a humanized dosing regimen of meropenem, a potent antipseudomonal β-lactam antibiotic, when administered with or without intensive care unit (ICU)-supportive care (fluid challenge and norepinephrine), could halt or reverse natural disease progression. Our humanized meropenem dosing regimen produced plasma concentration-time profile in the rabbit model similar to those reported in patients with ventilator-associated bacterial pneumonia. In this rabbit model, treatment with humanized meropenem and ICU-supportive care achieved the highest level of survival, halted the worsening of ARDS biomarkers and reversed lethal hypotension, although treatment with humanized meropenem alone also conferred some protection when compared to treatment with placebo (saline) alone or placebo plus ICU-supportive care. In conclusion, this rabbit model could help predict whether an antibiotic will be efficacious for the treatment of human ventilator-associated pneumonia.

Antivirulence Bispecific Monoclonal Antibody-Mediated Protection against Pseudomonas aeruginosa Ventilator-Associated Pneumonia in a Rabbit Model

“…Third, although arterial blood pressure was continuously monitored, it was not recorded due to lack of equipment at that time, resulting in a missed opportunity to better characterize MEDI3902-mediated protection in the rabbit model. Consistent with our recent natural history studies to validate the rabbit model of ventilator-associated pneumonia ( 13 ), we did notice that rabbits pretreated with c-IgG here, but not those pretreated with MEDI3902, all developed severe hypotension in the hours preceding death. Severe hypotension in this rabbit model is nonresponsive to fluid challenge alone, requiring vasopressor to ensure adequate blood pressure and oxygen delivery to prevent multiple organ dysfunction ( 13 ), which was also observed in a subset of rabbits used here (see Fig.…”

“…First, the efficacy of MEDI3902 was evaluated in the present study only as preexposure prophylaxis. However, this rabbit model, which was shown recently to be useful for postexposure treatment studies with ICU supportive care (e.g., fluid challenge and vasopressor) and a humanized dosing regimen of standard-of-care antibiotic, will allow preclinical testing of MEDI3902 in a manner that mimics how this novel molecule could be used clinically to treat ventilator-associated pneumonia ( 13 ). Second, although we used low-tidal-volume mechanical ventilation in the present study, the rabbits were ventilated with nonheated, nonhumidified air, which may contribute to lung injury (data not shown) ( 38 , 39 ).…”

“…Second, although we used low-tidal-volume mechanical ventilation in the present study, the rabbits were ventilated with nonheated, nonhumidified air, which may contribute to lung injury (data not shown) ( 38 , 39 ). Because humidification of inhaled gas is a standard of care, we recently introduced a refinement for this rabbit model to include active heater humidifiers to compensate for the lack of natural humidification mechanisms in the intubated rabbits ( 13 ). Notwithstanding the lack of humidification, MEDI3902 conferred significant protection against P. aeruginosa in our rabbit model of ventilator-associated pneumonia.…”

“…The objective of this study is to compare the protective efficacy of MEDI3902 and an irrelevant isotype-matched control IgG (c-IgG) in a recently described rabbit model of ventilator-associated pneumonia ( 13 ). Although nonventilated mouse and rabbit pneumonia models were used previously to demonstrate the efficacy of MEDI3902 ( 7 , 14 – 16 ), a limitation of those studies is the lack of mechanical ventilation, which is a major predisposing risk factor for P. aeruginosa ventilator-associated pneumonia ( 17 – 19 ).…”

“…Although nonventilated mouse and rabbit pneumonia models were used previously to demonstrate the efficacy of MEDI3902 ( 7 , 14 – 16 ), a limitation of those studies is the lack of mechanical ventilation, which is a major predisposing risk factor for P. aeruginosa ventilator-associated pneumonia ( 17 – 19 ). To better mimic lung-protective mechanical ventilation strategies used clinically ( 20 ), our rabbits were ventilated with a low tidal volume of 6 to 7 mL/kg and positive end-expiratory pressure (PEEP) of 6 cm H 2 O ( 13 ), which were not employed in previous rabbit models of ventilator-associated pneumonia ( 21 , 22 ). In our rabbit model of ventilator-associated pneumonia, MEDI3902 prophylaxis protected against lethal acute lung injury and inflammation.…”