Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Franciscogrid.266102.1, San Francisco, California, USA.
Pathology Program, Fluminense Federal Universitygrid.411173.1, Niterói, Rio de Janeiro, Brazil.
Antimicrob Agents Chemother. 2022 Feb 15;66(2):e0202221. doi: 10.1128/AAC.02022-21. Epub 2021 Dec 13.
Ventilator-associated pneumonia is an important clinical manifestation of the nosocomial pathogen Pseudomonas aeruginosa. We characterized the correlates of protection with MEDI3902, a bispecific human IgG1 monoclonal antibody that targets the P. aeruginosa type 3 secretion system PcrV protein and the Psl exopolysaccharide, in a rabbit model of ventilator-associated pneumonia using lung-protective, low-tidal-volume mechanical ventilation. Rabbits infused with MEDI3902 prophylactically were protected, whereas those pretreated with irrelevant isotype-matched control IgG (c-IgG) succumbed between 12 and 44 h postinfection (100% survival [8/8 rabbits] versus 0% survival [8/8 rabbits]; < 0.01 by log rank test). Lungs from rabbits pretreated with c-IgG, but not those pretreated with MEDI3902, had bilateral, multifocal areas of marked necrosis, hemorrhage, neutrophilic inflammatory infiltrate, and diffuse fibrinous edema in alveolar spaces. All rabbits pretreated with c-IgG developed worsening bacteremia that peaked at the time of death, whereas only 38% of rabbits pretreated with MEDI3902 (3/8 rabbits) developed such high-grade bacteremia (two-sided Fisher's exact test, = 0.026). Biomarkers associated with acute respiratory distress syndrome were evaluated longitudinally in blood samples collected every 2 to 4 h to assess systemic pathophysiological changes in rabbits pretreated with MEDI3902 or c-IgG. Biomarkers were sharply increased or decreased in rabbits pretreated with c-IgG but not those pretreated with MEDI3902, including the ratio of arterial oxygen partial pressure to the fraction of inspired oxygen of <300, hypercapnia or hypocapnia, severe lactic acidosis, leukopenia, and neutropenia. Cytokines and chemokines associated with acute respiratory distress syndrome were significantly downregulated in lungs from rabbits pretreated with MEDI3902, compared with c-IgG. These results suggest that MEDI3902 prophylaxis could have potential clinical utility for decreasing the severity of P. aeruginosa ventilator-associated pneumonia.
呼吸机相关性肺炎是医院获得性铜绿假单胞菌的一种重要临床表现。我们使用肺保护性、小潮气量机械通气，在兔呼吸机相关性肺炎模型中对靶向铜绿假单胞菌 III 型分泌系统 PcrV 蛋白和 Psl 胞外多糖的双特异性人 IgG1 单克隆抗体 MEDI3902 的保护相关性进行了特征描述。预防性输注 MEDI3902 的兔子得到了保护，而用无关的同种型匹配对照 IgG（c-IgG）预处理的兔子在感染后 12 至 44 小时内死亡（100%存活率[8/8 只兔子]与 0%存活率[8/8 只兔子]；对数秩检验<0.01）。用 c-IgG 预处理的兔子的肺，而不是用 MEDI3902 预处理的兔子的肺，有双侧、多灶性明显坏死、出血、中性粒细胞炎症浸润和肺泡空间弥漫性纤维蛋白性水肿。所有用 c-IgG 预处理的兔子都发生了恶化的菌血症，菌血症在死亡时达到高峰，而只有 38%（8 只兔子中的 3 只）用 MEDI3902 预处理的兔子发生了如此高等级的菌血症（双侧 Fisher 确切检验，=0.026）。在每隔 2 至 4 小时采集的血液样本中，纵向评估与急性呼吸窘迫综合征相关的生物标志物，以评估用 MEDI3902 或 c-IgG 预处理的兔子的全身病理生理变化。用 c-IgG 预处理的兔子的生物标志物急剧升高或降低，而用 MEDI3902 预处理的兔子则没有，包括动脉血氧分压与吸入氧分数的比值<300、高碳酸血症或低碳酸血症、严重乳酸酸中毒、白细胞减少和中性粒细胞减少。与急性呼吸窘迫综合征相关的细胞因子和趋化因子在用 MEDI3902 预处理的兔子的肺中显著下调，而在 c-IgG 预处理的兔子中则没有。这些结果表明，MEDI3902 预防治疗可能具有降低铜绿假单胞菌呼吸机相关性肺炎严重程度的潜在临床应用价值。
