Effect of inhaled Nitric Oxide on bacterial burden and disease outcome in a murine model of Klebsiella pneumonia

吸入一氧化氮对肺炎克雷伯菌小鼠模型中细菌负荷和疾病结果的影响

• 批准号: 434095988
• 负责人: Dr. Steffen Wiegand
• 金额: --
• 依托单位: Department of Anesthesia, Critical Care and Pain Medicine
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/434095988?language=en
• 关键词: Effect; inhaled; Nitric; Oxide; bacterial

Health care-associated infections are an important problem throughout the world and are associated with increased morbidity and mortality, especially in intensive care units. There are various risk factors for health care-associated infections in the intensive care unit, including congestive heart failure, renal dysfunction and immunosuppression. In addition, patients in the intensive care unit may have invasive devices placed, such as an endotracheal tube or a Foley catheter, which further increase the risk of infection. A frequent complication of endotracheal intubation is ventilator-associated pneumonia, which is the most common acquired infection and the leading cause of death from infection in the intensive care unit. Treatment of ventilator-associated pneumonia requires early diagnosis and an initial empiric choice of antibiotics. In the last two decades, bacteria with resistance to different classes of antibiotics have emerged, which complicates antibiotic therapy. These so-called multiple drug resistant organisms contribute to adverse clinical outcomes. There are relatively few antibiotics available for the treatment of these pathogens. The so-called “last line of defense” antibiotics have a limited effect on multiple drug resistant organisms and these drugs are associated with significant side effects including nephro- and neurotoxicity. The ideal new anti-microbial agent would have a completely different mechanism of action, thereby having potential synergistic effects with currently available antibiotics. Nitric oxide, a gas which is used for the treatment of pulmonary hypertension of the newborn and pulmonary hypertension during cardiac surgery, has been shown to have direct and indirect bactericidal effect. In general the cost of administering nitric oxide is very high, but my host’s lab constructed a “mini nitric oxide generator”, which produce nitric oxide from room air. Soon, this less expensive mechanism of delivering will become widely available and use of inhaled nitric oxide will become a feasible option for the cure of patients with difficult to treat pneumonia.In this project, I will study the effect of inhaled nitric oxide on Klebsiella pneumoniae, a frequent cause of ventilator-associated pneumonia. This strain of bacteria often develops drug resistance. I will use in-vitro studies to determine the optimal concentration of nitric oxide to kill Klebsiella pneumoniae. I will then determine the optimal nitric oxide concentration and timing of nitric oxide administration to work in a murine model of Klebsiella pneumonia. As a proof-of-concept experiment, I will further analyze the effect of nitric oxide therapy on multiple drug resistance Klebsiella pneumonia. The proposed studies will increase our knowledge of the potential role of nitric oxide as an adjunctive therapy for lung infection. It is anticipated that the results of this study will permit a novel approach to treat patients with health care-associated pneumonia.

卫生保健相关感染是全世界的一个重要问题，并且与发病率和死亡率的增加有关，特别是在重症监护病房中。重症监护室中存在各种医疗保健相关感染的风险因素，包括充血性心力衰竭、肾功能不全和免疫抑制。此外，重症监护室的患者可能会放置侵入性设备，如气管内导管或Foley导管，这进一步增加了感染的风险。呼吸机相关性肺炎是气管内插管的常见并发症，是重症监护病房中最常见的获得性感染和感染死亡的主要原因。呼吸机相关性肺炎的治疗需要早期诊断和初步经验性选择抗生素。在过去的二十年中，出现了对不同类别抗生素具有耐药性的细菌，这使得抗生素治疗变得复杂。这些所谓的多重耐药微生物导致不良临床结果。有相对较少的抗生素可用于治疗这些病原体。所谓的“最后一道防线”抗生素对多种耐药生物体的作用有限，并且这些药物与显著的副作用相关，包括肾毒性和神经毒性。理想的新型抗菌剂将具有完全不同的作用机制，从而与目前可用的抗生素具有潜在的协同效应。一氧化氮是一种用于治疗新生儿肺动脉高压和心脏手术期间肺动脉高压的气体，已被证明具有直接和间接的杀菌作用。一般来说，管理一氧化氮的成本非常高，但我的主人的实验室建造了一个“迷你一氧化氮发生器”，它从室内空气中产生一氧化氮。不久，这种较便宜的输送机制将被广泛使用，吸入一氧化氮将成为一种可行的选择，用于治疗难以治疗的肺炎患者。在这个项目中，我将研究吸入一氧化氮对肺炎克雷伯氏菌的影响，肺炎克雷伯氏菌是呼吸机相关性肺炎的常见原因。这种细菌菌株通常会产生抗药性。我将使用体外研究来确定一氧化氮杀死肺炎克雷伯菌的最佳浓度。然后，我将确定最佳的一氧化氮浓度和一氧化氮给药的时间，在小鼠模型的克雷伯氏菌肺炎。作为概念验证实验，我将进一步分析一氧化氮治疗对多重耐药克雷伯菌肺炎的影响。拟议的研究将增加我们对一氧化氮作为肺部感染的预防性治疗的潜在作用的认识。预计这项研究的结果将允许一种新的方法来治疗医疗保健相关性肺炎患者。