Antimicrobial Phototherapy of Antibiotic Resistant Chronic Sinusitis

描述(申请人提供)：该研究项目将证明原理，安全性，并确定治疗慢性复发性鼻窦炎(CRS)所需的最佳亚甲蓝(MB)/EDTA药物和光参数，在一个新的解剖学准确的体外人体上颌窦CRS多菌生物膜模型和体外活体人类呼吸道纤毛黏膜模型中。这些结果以及我们已经开发的一次性鼻窦照明系统将立即转化为CRS治疗的人体临床试验，并可能导致这种亟需的治疗方法的迅速采用和商业化。CRS是美国最常见的慢性疾病之一，估计有3700万美国人受到影响。据估计，CRS每年产生1800万至2200万次办公室访问和500 000多万次紧急访问，导致估计7300万个受限活动日，每年的总费用为60亿美元。在临床实践中，有很大一部分CRS患者尽管接受了鼻内窥镜手术、过敏治疗和长期口服、局部或静脉注射抗生素治疗，但仍对治愈感到抵触。已有大量研究报道耐药CRS鼻窦内存在耐药铜绿假单胞菌、流感嗜血杆菌、肺炎链球菌和金黄色葡萄球菌生物膜。微生物生物膜，包括CRS生物膜，对标准的抗生素治疗和宿主免疫防御机制具有众所周知的耐药性，因此导致CRS的治愈率很低，并增加了抗生素耐药性。由于标准疗法未能控制和治愈CRS，医学上对CRS的另一种临床有效、非侵入性、无毒、成本效益高、可重复、无痛、不会导致抗生素耐药性的局部非抗生素治疗方式的需求尚未得到满足。亚甲蓝为基础的抗菌光动力疗法(APDT)具有迅速采用该疗法以及快速商业化的优点，具有成功实现这些目标的巨大潜力。这项拨款提案将确定在一个新的解剖学上准确的上颌窦模型中有效治疗人类CRS多菌生物膜所需的最佳MB药物和光参数。此外，还将对APDT处理后的活体人呼吸道纤毛粘膜进行组织病理学分析，以证明APDT对上颌窦粘膜的安全性。虽然MB APDT已被证明在体外清除生物膜是有效的，但这些研究将是已知的第一次在体外模型中系统地研究MB APDT，包括评估该治疗的有效性和治疗的安全性，如在人副鼻窦发现的生物膜定植的人呼吸道纤毛粘膜。从这项研究中确定的最佳治疗参数然后计划直接转化为治疗CRS的人体临床试验。在更全球的层面上，非抗生素治疗感染控制的好处将被视为一项革命性的医学进步，可用于广泛的医疗应用，并将对世界各地数百万人的生活质量产生积极影响。 公共卫生相关性：慢性复发性鼻窦炎(CRS)是美国最常见的疾病之一。据估计，CRS每年产生1800万至2200万次办公室访问，7300万个受限活动日，每年的总成本为60亿美元。在临床实践中，有很大一部分CRS患者尽管接受了鼻内窥镜手术、过敏治疗和长期口服、局部或静脉注射抗生素治疗，但仍对治愈感到抵触。由于标准疗法无法控制和治愈CRS，迫切需要其他新的非抗生素疗法来摧毁或控制生物膜和耐药细菌。开发这样一种疗法是这项研究和开发工作的具体目标。亚甲蓝为基础的抗菌光动力疗法(APDT)具有迅速采用该疗法以及快速商业化的优点，具有成功实现这些目标的巨大潜力。这项拨款提案将在一种新的解剖学上准确的人上颌窦CRS多菌生物膜模型和体外活体人呼吸道纤毛粘膜模型中确定安全有效地治疗CRS的最佳MB药物和光参数，其结果将直接转化为治疗CRS的人类临床试验。

DESCRIPTION (provided by applicant):This research project will demonstrate proof of principle, safety and determine the optimal methylene blue (MB)/EDTA drug and light parameters necessary for chronic recurrent sinusitis (CRS) treatment in an in vitro novel anatomically accurate human maxillary sinus CRS polymicrobial biofilm model and in an ex vivo live human respiratory ciliated mucosa model. These results along with our already developed disposable sinus illumination system will be immediately translatable to a human clinical trial for CRS treatment and may result in the rapid adoption and commercialization of this much needed therapy. CRS is one of the most common chronic conditions in the United States affecting an estimated 37 million Americans. It is also estimated that CRS results in 18-22 million office visits per year and over 500,000 emergency visits per year resulting in an estimated 73 million restricted activity days with an aggregated cost of six billion dollars annually. In clinical practice there is a significant subpopulation of patients with CRS who remain resistant to cure despite endoscopic sinus surgery, allergy therapy and culture directed long term oral, topical or intravenous antibiotic therapy. Numerous studies have reported the presence of antibiotic resistant Pseudomonas aerugenosa, Hemophilus influenza, Streptococcus pneumoniae and Staphylococcus aureus biofilms in the sinuses of cure resistant CRS. Microbial biofilms, including CRS biofilms, are notoriously resistant to standard antibiotic therapy as well as host immunologic defense mechanisms therefore contributing to the dismal cure rates of CRS and to increased antibiotic resistance. Due to the failure of standard therapies to control and cure CRS, there is an unmet medical need for an alternative clinically effective, non- invasive, non-toxic, cost-effective, repeatable, painless topical non-antibiotic treatment modality for CRS that does not result in antibiotic resistance. MB based antimicrobial photodynamic therapy (aPDT) has the significant potential to successfully achieve these goals with the advantages of rapid adoption of the therapy as well as rapid commercialization. This grant proposal will determine the optimal MB drug and light parameters necessary to effectively treat human CRS polymicrobial biofilms in a novel anatomically accurate maxillary sinus model. In addition, histopathological analysis will be performed on the aPDT treated live human respiratory ciliated mucosa to demonstrate the safety of aPDT on maxillary sinus mucosa. Although MB aPDT has been demonstrated to be effective in eradicating biofilms in vitro, these studies will represent the first known systematic studies of MB aPDT in an ex-vivo model, including evaluating the effectiveness of the therapy and safety of the therapy, on biofilm colonized human respiratory ciliated mucosa as is found in the human paranasal sinuses. The optimal treatment parameters determined from this study are then planned to be directly translated to a human clinical trial for the treatment of CRS. On a more global level, the benefit of a non-antibiotic therapy for infection control would be considered a revolutionary medical advancement that could be used in wide ranging medical applications and would positively affect the quality of life for millions of people worldwide. PUBLIC HEALTH RELEVANCE: Chronic recurrent sinusitis (CRS) is one of the most common diseases in the United States. It is estimated that CRS results in 18-22 million office visits per year, 73 million restricted activity days and an aggregated cost of $6 Billion annually. In clinical practice there is a significant subpopulation of patients with CRS who remain resistant to cure despite endoscopic sinus surgery, allergy therapy and culture directed long term oral, topical or intravenous antibiotic therapy. Due to the failure of standard therapies to control and cure CRS, other novel non-antibiotic therapies are desperately needed that are able to destroy or control biofilms and antibiotic resistant bacteria. Developing such a therapy is the specific objective of this research and development effort. MB based antimicrobial photodynamic therapy (aPDT) has the significant potential to successfully achieve these goals with the advantages of rapid adoption of the therapy as well as rapid commercialization. This grant proposal will determine the optimal MB drug and light parameters for safe and effective CRS treatment in an in vitro novel anatomically accurate human maxillary sinus CRS polymicrobial biofilm model and in an ex vivo live human respiratory ciliated mucosa model, the results of which will be directly translated to a human clinical trial for the treatment of CRS.