Antibacterial Perfluorocarbon Ventilation to Treat Severe Respiratory Infections

描述(由申请人提供)：在美国，急性下呼吸道感染导致的疾病和死亡比任何其他感染都多。在大多数情况下，细菌感染是用全身或吸入抗生素治疗的。然而，大量患者仍然患有严重感染，发病率和死亡率很高，可以从改进的治疗技术中受益。对于肺炎、慢性肺部疾病叠加细菌感染和支气管扩张症的严重病例尤其如此。抗生素全氟化碳通气法(APV)如果作为传统的全身或吸入抗生素治疗的辅助手段，可以改善严重细菌感染的治疗。在这种疗法中，肺是 使用含有乳化抗生素的全氟化碳液体(PFC)进行潮汐通风，最长可达几个小时。这项技术可以在几个方面加快标准的抗生素治疗。首先，由于液体剪切和粘液表面张力降低，PFC的潮汐流动能有效地将感染的粘液从气道壁上清除。然后，粘液在浮力的帮助下对流地从肺部输送，并轻松地从PFC呼吸机中清除。其次，抗生素直接输送到感染源，使肺部浓度更高，全身浓度和毒性更低。然而，与吸入抗生素治疗不同，吸入抗生素只能将抗生素输送到有效气体通风的区域，而抗生素在PFC中的对流输送将允许更均匀地向下分布到肺泡水平。主动粘液清除还应使抗生素更容易进入先前堵塞的呼吸道，无论是在APV期间还是之后使用吸入抗生素治疗。最后，PFC具有抗炎特性，可以促进肺愈合和恢复正常的粘液纤毛清除。最终，APV可能会降低严重呼吸道感染的发病率、死亡率和治疗成本。为了确定APV的有效性，我们将用粘液性铜绿假单胞菌感染大鼠。然后，我们将比较这种感染的治疗方法：1)单独吸入妥布霉素，2)全氟碳呼吸机后吸入妥布霉素，3)经氟碳呼吸机加乳化妥布霉素后吸入妥布霉素，或4)经氟碳呼吸机加乳化妥布霉素而不作进一步治疗。我们假设治疗后的细菌负荷和炎症将从最低到最高：组3、组4、组2和组1。这些研究将为未来的研究提供初步数据和指导，这些研究试图通过检查不同的通风设置和乳化液特性来优化治疗。

DESCRIPTION (provided by applicant): Acute lower respiratory infections cause more disease and death than any other infection in the US. In most cases, bacterial infections are treated with systemic or inhaled antibiotics. However, large groups of patients still suffer from severe infections with significant morbidity and mortality and could benefit from improved treatment techniques. This is particularly true for severe cases of pneumonia, bacterial infections superimposed on chronic lung disease states, and bronchiectasis. Antibiotic perfluorocarbon ventilation (APV) could improve treatment of severe bacterial infections if used as an adjunct to traditional systemic or inhaled antibiotic therapy. In this treatment, the lung is tidally ventilated with a perfluorocarbon liquid (PFC) containing emulsified antibiotics for a perid of up to a few hours. This technique could accelerate standard antibiotic therapy in several ways. First, the tidal flow of PFCs actively removes infected mucus from airway walls due to fluid shear and reduced mucus surface tension. The mucus is then convectively transported from the lungs, aided by buoyant force, and removed easily from the PFC ventilator. Second, antibiotic is delivered directly to the source of infection, allowing for higher concentrations in he lung and lower systemic concentrations and toxicity. However, unlike treatment with inhaled antibiotics, which can only deliver antibiotics to areas of effective gas ventilation, convective transport of the antibiotic in PFC will allow much more uniform distribution down to the alveolar level. Active mucus removal should also allow antibiotics to more easily access previously plugged airways, both during APV and treatment with inhaled antibiotics thereafter. Lastly, PFC has anti- inflammatory properties that may promote lung healing and a return towards normal mucociliary clearance. Ultimately, APV may decrease morbidity, mortality, and the cost of treatment from severe respiratory infections. To establish the effectiveness of APV, we will infect rats with mucoid Pseudomonas aeruginosa. We will then compare treatment of this infection with either 1) inhaled tobramycin alone, 2) perfluorocarbon ventilation followed by inhaled tobramycin, 3) perfluorocarbon ventilation with emulsified tobramycin followed by inhaled tobramycin, or 4) perfluorocarbon ventilation with emulsified tobramycin and no further treatment. We hypothesize that bacterial load and inflammation following treatment will be from lowest to highest: group 3, 4, 2, and 1. These studies will provide preliminary data and guidance towards future studies that seek to optimize treatment by examining different ventilation settings and emulsion characteristics.