Photodynamic therapy for perforated appendicitis

光动力疗法治疗穿孔性阑尾炎

• 批准号: 10722767
• 负责人: Timothy M Baran
• 金额: $ 21.87万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-18 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722767
• 关键词: Abdominal Abscess; Abdominal Infection; Abscess; Acute; Adult; Affect; Alternative Therapies; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Appendectomy; Appendicitis; Bacteria; Biological; Child; Childhood; Clinical; Clinical Trials; Control Animal; Cost Savings; Data; Diagnosis; Dose; Evaluation; Generations; Goals; Greater sac of peritoneum; Healthcare; Hospitalization; Human; In Vitro; Inflammation; Intra-abdominal; Length of Stay; Light; Lighting; Methylene blue; Microbial Biofilms; Modeling; Morbidity - disease rate; Operative Surgical Procedures; Organism; Oryctolagus cuniculus; Outcome; PUVA Photochemotherapy; Pathologic; Patients; Perforated Appendicitis; Perforation; Peritoneal Fluid; Pharmaceutical Preparations; Phase I Clinical Trials; Population; Postoperative Period; Progressive Disease; Prospective Studies; Reactive Oxygen Species; Recovery; Resistance; Resources; Sampling; Specimen; Time; Translating; United States; Variant; antimicrobial; aspirate; bacterial resistance; comparative efficacy; comparison control; cost; design; gut microbiota; high reward; high risk; in vivo; microbial; patient population; pediatric patients; readmission rates; resistant strain; safety and feasibility; standard of care

The primary goal of this proposal is to evaluate the antimicrobial efficacy of photodynamic therapy in the context of perforated appendicitis. This will be accomplished using in vivo rabbit models and in vitro evaluation of human specimens. Appendicitis is the most common general surgical condition affecting children and contributes to more morbidity and health care resource utilization than any other pediatric general surgical condition. Approximately ⅓ of pediatric cases in the United States present with perforated appendicitis (PA), with these perforated cases associated with higher costs, longer hospitalizations, higher hospital readmission rates, and worse postoperative outcomes. Prolonged antibiotic therapy after appendectomy remains the mainstay for treatment for intra-abdominal infection. This results in long hospital stays and may not be effective against antibiotic resistant strains, highlighting the need for alternative therapies. Photodynamic therapy (PDT), which exerts antimicrobial activity through photochemical generation of reactive oxygen species, is broad spectrum and fast acting, efficacious against antibiotic-resistant strains, and does not result in acquired resistance. Given that the intra-abdominal infection associated with PA is polymicrobial and often complicated by bacterial resistance to common antibiotics, PDT is an appealing adjunct to the treatment of intra-abdominal infection in perforated appendicitis and could further be used to treat abscess formation post-appendectomy. The objective of this study is to demonstrate proof-of-concept of antimicrobial PDT as a treatment of intra-abdominal infection in perforated appendicitis in a rabbit model, as well as efficacy against bacteria isolated from human samples. This high risk, high reward study could revolutionize management of PA, and drastically reduce hospital stay and complications. Aim 1 – Demonstrate feasibility and efficacy of photodynamic therapy in a rabbit model of perforated appendicitis. Using an established rabbit model of PA, a prospective study will be performed to assess reduction of bacterial burden in the peritoneal cavity following methylene blue photodynamic therapy (MB- PDT). Bacterial load will be quantified pre- and post-PDT, and compared to control animals that receive illumination without MB. It is hypothesized that MB-PDT will result in a reduction of ≥99.9% in total bacterial population, with potential variation in killing of specific bacterial species found in the intestinal flora. Aim 2 – Demonstrate efficacy of photodynamic therapy in vitro for bacteria isolated from patients with perforated appendicitis. Bacteria isolated from aspirated peritoneal fluid captured from pediatric patients undergoing appendectomy for PA will be characterized. MB-PDT will then be performed on both planktonic cultures and biofilms. It is hypothesized that PDT will significantly reduce bacterial burden, with biofilms potentially requiring larger drug/light doses for comparable efficacy.

本提案的主要目标是评估光动力疗法在治疗慢性乙型肝炎中的抗菌功效。 阑尾炎穿孔的背景下。这将使用体内兔模型和体外评价来完成 人类标本。阑尾炎是影响儿童的最常见的一般外科疾病， 与其他儿科普通外科相比， 条件在美国，大约有%的儿科病例表现为穿孔性阑尾炎（PA）， 这些穿孔病例与更高的费用、更长的住院时间、更高的再入院率相关 率和更差的术后结局。阑尾切除术后延长抗生素治疗仍然是 腹腔内感染治疗的支柱。这导致住院时间长， 对抗生素耐药菌株有效，突出了替代疗法的必要性。 光动力疗法（PDT），其通过光化学产生反应性的抗微生物活性来发挥抗微生物活性。 氧物种，是广谱和快速作用的，对耐药菌株有效，并且不 导致获得性抵抗。鉴于与PA相关的腹腔内感染是多种微生物感染， 通常由于细菌对普通抗生素的耐药性而变得复杂，PDT是一种有吸引力的辅助治疗方法， 治疗穿孔性阑尾炎腹腔内感染，并可进一步用于治疗 阑尾切除术后脓肿形成。 本研究的目的是证明抗微生物PDT作为治疗 穿孔性阑尾炎腹腔内感染的实验研究 从人体样本中分离出的细菌。这项高风险、高回报的研究可能会彻底改变 PA，并大大减少住院时间和并发症。 目的1 -证明光动力学疗法在穿孔的兔模型中的可行性和有效性 阑尾炎使用已建立的PA兔模型，将进行前瞻性研究以评估 亚甲蓝光动力疗法（MB-1）后腹膜腔中细菌负荷的减少 PDT）。将在PDT前后定量细菌负荷，并与接受PDT的对照动物进行比较。 没有MB的照明。假设MB-PDT将导致细菌总数减少≥99.9%。 群体，在杀死肠道植物群中发现的特定细菌物种方面存在潜在变异。 目的2 -证明体外光动力疗法对分离自患有以下疾病的患者的细菌的功效： 穿孔性阑尾炎从儿科患者抽吸的腹膜液中分离出的细菌 将对因PA接受阑尾切除术的患者进行表征。然后，将对两种血管紧张素转换酶进行MB-PDT。 培养物和生物膜。假设PDT将显著降低细菌负荷，生物膜 潜在地需要较大的药物/光剂量以获得相当的功效。