Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
Université François Rabelais, Tours, France.
Antimicrob Agents Chemother. 2021 Jun 17;65(7):e0272420. doi: 10.1128/AAC.02724-20.
Development and validation of large animal models of Pseudomonas aeruginosa ventilator-associated pneumonia are needed for testing new drug candidates in a manner that mimics how they will be used clinically. We 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 PaO:FiO, 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 a 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 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.
需要开发和验证铜绿假单胞菌呼吸机相关性肺炎的大动物模型，以便以模拟它们在临床上的使用方式来测试新的候选药物。我们开发了一种新的模型，其中兔子接受小潮气量通气，并受到铜绿假单胞菌的挑战，以重现急性呼吸窘迫综合征（ARDS）的标志性临床特征：急性肺损伤和炎症、动脉氧分压与吸入氧分数之比（PaO:FiO）逐渐降低、白细胞减少、中性粒细胞减少、血小板减少、高乳酸血症、严重低血压、细菌从肺部扩散到其他器官、多器官功能障碍，最终死亡。我们通过确定是否可以用美罗培南的人源化剂量方案来治疗这种肺炎，这种药物是一种有效的抗假单胞菌β-内酰胺抗生素，并用或不用重症监护病房（ICU）支持性治疗（液体冲击和去甲肾上腺素），来评估这种兔模型在抗生素疗效测试中的预测能力，以确定是否可以阻止或逆转自然疾病进展。我们的人源化美罗培南剂量方案在兔模型中产生的血浆浓度-时间曲线与报告的呼吸机相关性细菌性肺炎患者相似。在这种兔模型中，用美罗培南和 ICU 支持性治疗的人源化治疗方案实现了最高的生存率，阻止了 ARDS 生物标志物的恶化，并逆转了致命性低血压，尽管与单独用安慰剂（生理盐水）或安慰剂加 ICU 支持性治疗相比，单独用人源化美罗培南治疗也提供了一些保护作用。总之，这种兔模型可以帮助预测抗生素是否对治疗人类呼吸机相关性肺炎有效。
