Novel Combination Therapy for Staphylococcus aureus Pneumonia

描述（由申请人提供）：近年来，金黄色葡萄球菌引起的疾病的发病率/严重程度惊人地增加，特别是由社区相关和医院获得的甲氧西林耐药菌株引起的疾病，需要新型有效的抗菌策略。令人不安的发现是，这些菌株产生更多的毒力决定毒素，包括超抗原（SAg），要求使用在葡萄球菌感染的不同阶段起作用的药物组合进行多管齐下的攻击。而抗菌药物 例如抑制细菌毒素产生利奈唑胺是有用的，单独的抑菌剂似乎 不是很有效。这主要有两个原因。(i)抑菌剂不能完全停止体内毒素的产生。(ii)在临床上，几乎总是有一个显着的时间延迟之间的发病S。金黄色葡萄球菌感染和开始抗菌治疗。在这一拖延期间，已经产生了大量的致病性外毒素。不幸的是，抑菌剂对预先形成的外毒素没有活性。因此，可以施用抗体以中和在开始治疗之前产生的毒素以及中和尽管进行了抗菌治疗但仍产生的残留毒素。这样的抗体将与抑菌剂协同作用。由于SAg是S.在金黄色葡萄球菌中，SAg的体内中和可能是优选的方法。此外，SAg具有强烈和非特异性刺激免疫系统的独特能力，随后诱导无反应性或无反应性。SAg，从而转移针对细菌的免疫应答，从而帮助细菌免疫逃避。因此，刺激先天免疫系统也将是有益的，在S。金黄色葡萄球菌感染因此，我们提出了抑菌药物利奈唑胺、超抗原中和抗体和免疫调节剂的联合治疗，这些药物可增强先天免疫，有效控制/消除S。金黄色葡萄球菌感染这种新方法的有效性将使用强大的HLA II类转基因小鼠模型进行测试。在HLA-DR 3转基因小鼠中，用高致病性的S.金黄色葡萄球菌产生大量的SAg，即葡萄球菌肠毒素B（SE B）。为了模拟临床情况，治疗将在感染开始后以2小时为增量延迟。小鼠将不接受治疗或接受利奈唑胺、人-小鼠嵌合中和抗SEB抗体或同种型对照抗体和toll样受体（TLR）-2激动剂Pam 2CSK 4的各种组合治疗。将研究死亡保护。因此，我们将建立一个有效的联合治疗致命的S。金黄色葡萄球菌感染，并确定了联合治疗的治疗窗口。 公共卫生相关性：由产生高致病性毒素的金黄色葡萄球菌的抗生素抗性菌株引起的疾病的发病率和严重程度正在急剧增加。因此，我们建议测试一种新的药物鸡尾酒治疗这种S。金黄色葡萄球菌感染我们的鸡尾酒将包括抗生素，针对致病性葡萄球菌毒素的抗体和刺激免疫力的药物。

DESCRIPTION (provided by applicant): The alarming increase in the incidence/severity of diseases caused by Staphylococcus aureus in recent years, particularly those caused by community-associated and hospital-acquired methicillin resistant strains, call for novel effective antibacterial strategies. The disturbing findings that such strains produce more virulence-determining toxins, including superantigens (SAg), mandate a multipronged attack using a combination of drugs that act at different stages of staphylococcal infection. While antibacterials such as linezolid, which inhibit bacterial toxin production, are useful, bacteriostatics alone seem to be not very effective. This is attributed to two major reasons. (i) Bacteriostatics fail to completely shut down toxin production in vivo. (ii) In the clinical settings, there is almost alway a significant time delay between the onset of S. aureus infection and initiation of antibacterial therapy. During this delay, significant quantities of pathogenic exotoxins have already been produced. Unfortunately, bacteriostatics have no activity on pre-formed exotoxins. Therefore, antibodies could be administered to neutralize toxins that were produced prior to initiation of therapy as well as to inactivate the residual toxins produced in spite of antibacterial therapy. Such antibodies would act synergistically with bacteriostatics. Since SAg are one of the most pathogenic exotoxins of S. aureus, in vivo neutralization of SAg may be the preferred approach. In addition, SAg have the unique ability to robustly and non-specifically stimulate the immune system followed by induction of unresponsiveness or anergy. SAg, thus divert the immune response against the bacterium, thereby helping in bacterial immune evasion. Therefore, stimulating the innate immune system will also be beneficial during S. aureus infections. Hence, we propose a combination therapy with the bacteriostatic drug, linezolid, neutralizing antibodies to superantigens, and immunomodulatory agents that boost innate immunity to effectively control/eliminate S. aureus infections. The effectiveness of this novel approach will be tested using the robust HLA class II transgenic mouse model. Lethal pneumonia will be induced in HLA-DR3 transgenic mice with a highly pathogenic strain of S. aureus that produces large amounts of the SAg, staphylococcal enterotoxin B (SEB). To mimic the clinical scenario, treatment will be delayed in 2-hour increments after initiation of infection. Mice will be left untreated or treated with various combinations of linezolid, human-mouse chimeric neutralizing anti-SEB antibodies or isotype control antibodies and the toll-like receptor (TLR)-2 agonist, Pam2CSK4. Protection from mortality will be studied. Thus, we would have established an effective combination therapy against lethal S. aureus infection and identified the therapeutic window of the combination therapy. PUBLIC HEALTH RELEVANCE: The incidence and severity of diseases caused by antibiotic resistant strains of Staphylococcus aureus, producing highly pathogenic toxins are increasing drastically. Therefore, we propose to test the effectiveness of a new drug cocktail for the treatment of such S. aureus infections. Our cocktail would consist of an antibiotic, antibodies against a pathogenic staphylococcal toxin and a drug to stimulate immunity.