PDF(Pubmed)
Abstract：
Patients with septic shock caused by Staphylococcus aureus have mortality rates exceeding 50%, despite appropriate antibiotic therapy. Our objectives were to establish a rabbit model of S. aureus septic shock and to determine whether a novel immunotherapy can prevent or halt its natural disease progression.
Anesthetized rabbits were ventilated with lung-protective low-tidal volume, instrumented for advanced hemodynamic monitoring, and characterized for longitudinal changes in acute myocardial dysfunction by echocardiography and sepsis-associated biomarkers after S. aureus intravenous challenge. To demonstrate the potential utility of this hyperdynamic septic shock model for preclinical drug development, rabbits were randomized for prophylaxis with anti-Hla/Luk/ClfA monoclonal antibody combination that neutralizes alpha-hemolysin (Hla), the bicomponent pore-forming leukocidins (Luk) including Panton-Valentine leukocidin, leukocidin ED, and gamma-hemolysin, and clumping factor A (ClfA), or an irrelevant isotype-matched control IgG (c-IgG), and then challenged with S. aureus.
Rabbits challenged with S. aureus, but not those with saline, developed a hyperdynamic state of septic shock characterized by elevated cardiac output (CO), increased stroke volume (SV) and reduced systemic vascular resistance (SVR), which was followed by a lethal hypodynamic state characterized by rapid decline in mean arterial pressure (MAP), increased central venous pressure, reduced CO, reduced SV, elevated SVR, and reduced left-ventricular ejection fraction, thereby reproducing the hallmark clinical features of human staphylococcal septic shock. In this model, rabbits pretreated with anti-Hla/Luk/ClfA mAb combination had 69% reduction in mortality when compared to those pretreated with c-IgG (P<0.001). USA300-induced acute circulatory failure-defined as >70% decreased in MAP from pre-infection baseline-occurred in only 20% (2/10) of rabbits pretreated with anti-Hla/Luk/ClfA mAb combination compared to 100% (9/9) of those pretreated with c-IgG. Prophylaxis with anti-Hla/Luk/ClfA mAb combination halted progression to lethal hypodynamic shock, as evidenced by significant protection against the development of hyperlactatemia, hypocapnia, hyperkalemia, leukopenia, neutropenia, monocytopenia, lymphopenia, as well as biomarkers associated with acute myocardial injury.
These results demonstrate the potential utility of a mechanically ventilated rabbit model that reproduced hallmark clinical features of hyperdynamic septic shock and the translational potential of immunotherapy targeting S. aureus virulence factors for the prevention of staphylococcal septic shock.
Anesthetized rabbits were ventilated with lung-protective low-tidal volume, instrumented for advanced hemodynamic monitoring, and characterized for longitudinal changes in acute myocardial dysfunction by echocardiography and sepsis-associated biomarkers after S. aureus intravenous challenge. To demonstrate the potential utility of this hyperdynamic septic shock model for preclinical drug development, rabbits were randomized for prophylaxis with anti-Hla/Luk/ClfA monoclonal antibody combination that neutralizes alpha-hemolysin (Hla), the bicomponent pore-forming leukocidins (Luk) including Panton-Valentine leukocidin, leukocidin ED, and gamma-hemolysin, and clumping factor A (ClfA), or an irrelevant isotype-matched control IgG (c-IgG), and then challenged with S. aureus.
Rabbits challenged with S. aureus, but not those with saline, developed a hyperdynamic state of septic shock characterized by elevated cardiac output (CO), increased stroke volume (SV) and reduced systemic vascular resistance (SVR), which was followed by a lethal hypodynamic state characterized by rapid decline in mean arterial pressure (MAP), increased central venous pressure, reduced CO, reduced SV, elevated SVR, and reduced left-ventricular ejection fraction, thereby reproducing the hallmark clinical features of human staphylococcal septic shock. In this model, rabbits pretreated with anti-Hla/Luk/ClfA mAb combination had 69% reduction in mortality when compared to those pretreated with c-IgG (P<0.001). USA300-induced acute circulatory failure-defined as >70% decreased in MAP from pre-infection baseline-occurred in only 20% (2/10) of rabbits pretreated with anti-Hla/Luk/ClfA mAb combination compared to 100% (9/9) of those pretreated with c-IgG. Prophylaxis with anti-Hla/Luk/ClfA mAb combination halted progression to lethal hypodynamic shock, as evidenced by significant protection against the development of hyperlactatemia, hypocapnia, hyperkalemia, leukopenia, neutropenia, monocytopenia, lymphopenia, as well as biomarkers associated with acute myocardial injury.
These results demonstrate the potential utility of a mechanically ventilated rabbit model that reproduced hallmark clinical features of hyperdynamic septic shock and the translational potential of immunotherapy targeting S. aureus virulence factors for the prevention of staphylococcal septic shock.
摘要：
■由金黄色葡萄球菌引起的脓毒性休克患者的死亡率超过50％，尽管有适当的抗生素治疗。我们的目标是建立金黄色葡萄球菌败血性休克的兔模型，并确定新型免疫疗法是否可以预防或阻止其自然疾病进展。
■麻醉的兔子用肺保护性小潮气量通气，先进的血液动力学监测仪器，并通过金黄色葡萄球菌静脉攻击后的超声心动图和脓毒症相关生物标志物表征急性心肌功能障碍的纵向变化。为了证明这种高动力感染性休克模型在临床前药物开发中的潜在实用性，家兔随机接受抗Hla/Luk/ClfA单克隆抗体组合预防，该组合可以中和α-溶血素（Hla），双组分成孔杀白细胞素（Luk），包括Panton-Valentine杀白细胞素，杀白细胞素ED,和γ-溶血素,和结块因子A(ClfA)，或不相关的同种型匹配的对照IgG（c-IgG），然后用金黄色葡萄球菌挑战。
■受到金黄色葡萄球菌挑战的兔子，但不是那些有盐水的人，出现了以心输出量（CO）升高为特征的感染性休克的高动力学状态，每搏量（SV）增加，全身血管阻力（SVR）降低，随后是以平均动脉压（MAP）快速下降为特征的致命低动力状态，中心静脉压升高,减少CO，降低SV,高架SVR,左心室射血分数降低,从而再现人葡萄球菌感染性休克的标志性临床特征。在这个模型中,与用c-IgG预处理的兔相比,用抗-Hla/Luk/ClfAmAb组合预处理的兔死亡率降低69%(P<0.001)。USA300诱导的急性循环衰竭-定义为MAP从感染前基线降低>70%-仅发生在20%(2/10)的用抗Hla/Luk/ClfAmAb组合预处理的兔子中,与100%(9/9)的用c-IgG预处理的那些相比。抗Hla/Luk/ClfAmAb组合的预防阻止了致死性低动力休克的进展，正如对高乳酸盐血症发展的显著保护所证明的那样，低碳酸血症,高钾血症,白细胞减少症,中性粒细胞减少症,单核细胞减少症,淋巴细胞减少,以及与急性心肌损伤相关的生物标志物。
这些结果证明了机械通气兔模型的潜在实用性，该模型再现了高动力感染性休克的标志性临床特征，以及针对金黄色葡萄球菌毒力因子的免疫疗法预防葡萄球菌感染性休克的转化潜力。
■麻醉的兔子用肺保护性小潮气量通气，先进的血液动力学监测仪器，并通过金黄色葡萄球菌静脉攻击后的超声心动图和脓毒症相关生物标志物表征急性心肌功能障碍的纵向变化。为了证明这种高动力感染性休克模型在临床前药物开发中的潜在实用性，家兔随机接受抗Hla/Luk/ClfA单克隆抗体组合预防，该组合可以中和α-溶血素（Hla），双组分成孔杀白细胞素（Luk），包括Panton-Valentine杀白细胞素，杀白细胞素ED,和γ-溶血素,和结块因子A(ClfA)，或不相关的同种型匹配的对照IgG（c-IgG），然后用金黄色葡萄球菌挑战。
■受到金黄色葡萄球菌挑战的兔子，但不是那些有盐水的人，出现了以心输出量（CO）升高为特征的感染性休克的高动力学状态，每搏量（SV）增加，全身血管阻力（SVR）降低，随后是以平均动脉压（MAP）快速下降为特征的致命低动力状态，中心静脉压升高,减少CO，降低SV,高架SVR,左心室射血分数降低,从而再现人葡萄球菌感染性休克的标志性临床特征。在这个模型中,与用c-IgG预处理的兔相比,用抗-Hla/Luk/ClfAmAb组合预处理的兔死亡率降低69%(P<0.001)。USA300诱导的急性循环衰竭-定义为MAP从感染前基线降低>70%-仅发生在20%(2/10)的用抗Hla/Luk/ClfAmAb组合预处理的兔子中,与100%(9/9)的用c-IgG预处理的那些相比。抗Hla/Luk/ClfAmAb组合的预防阻止了致死性低动力休克的进展，正如对高乳酸盐血症发展的显著保护所证明的那样，低碳酸血症,高钾血症,白细胞减少症,中性粒细胞减少症,单核细胞减少症,淋巴细胞减少,以及与急性心肌损伤相关的生物标志物。
这些结果证明了机械通气兔模型的潜在实用性，该模型再现了高动力感染性休克的标志性临床特征，以及针对金黄色葡萄球菌毒力因子的免疫疗法预防葡萄球菌感染性休克的转化潜力。
