Hua L, Cohen T S, Shi Y, Datta V, Hilliard J J, Tkaczyk C, Suzich J, Stover C K, Sellman B R
Department of Infectious Disease, MedImmune, LLC, Gaithersburg, Maryland, USA.
Department of Translational Science, MedImmune, LLC, Gaithersburg, Maryland, USA.
Antimicrob Agents Chemother. 2015 Aug;59(8):4526-32. doi: 10.1128/AAC.00510-15. Epub 2015 May 18.
Immunocompromised individuals are at increased risk of Staphylococcus aureus pneumonia. Neutralization of alpha-toxin (AT) with the monoclonal antibody (MAb) MEDI4893* protects normal mice from S. aureus pneumonia; however, the effects of the MAb in immunocompromised mice have not been reported. In this study, passive immunization with MEDI4893* increased survival rates and reduced bacterial numbers in the lungs in an immunocompromised murine S. aureus pneumonia model. Lungs from infected mice exhibited alveolar epithelial damage, protein leakage, and bacterial overgrowth, whereas lungs from mice passively immunized with MEDI4893* retained a healthy architecture, with an intact epithelial barrier. Adjunctive therapy or prophylaxis with a subtherapeutic MEDI4893* dose combined with subtherapeutic doses of vancomycin or linezolid improved survival rates, compared with the monotherapies. Furthermore, coadministration of MEDI4893* with vancomycin or linezolid extended the antibiotic treatment window. These data suggest that MAb-mediated neutralization of AT holds promise in strategies for prevention and adjunctive therapy among immunocompromised patients.
免疫功能低下的个体患金黄色葡萄球菌肺炎的风险增加。用单克隆抗体（MAb）MEDI4893中和α毒素（AT）可保护正常小鼠免受金黄色葡萄球菌肺炎的侵害；然而，该单克隆抗体在免疫功能低下小鼠中的作用尚未见报道。在本研究中，在免疫功能低下的小鼠金黄色葡萄球菌肺炎模型中，用MEDI4893进行被动免疫可提高存活率并减少肺内细菌数量。感染小鼠的肺表现出肺泡上皮损伤、蛋白质渗漏和细菌过度生长，而用MEDI4893被动免疫的小鼠的肺保持健康结构，上皮屏障完整。与单一疗法相比，用低于治疗剂量的MEDI4893联合低于治疗剂量的万古霉素或利奈唑胺进行辅助治疗或预防可提高存活率。此外，MEDI4893*与万古霉素或利奈唑胺联合给药可延长抗生素治疗窗口。这些数据表明，单克隆抗体介导的AT中和在免疫功能低下患者的预防和辅助治疗策略中具有前景。
