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.

该提案的主要目的是评估光动力疗法的抗菌效率 穿孔阑尾炎的背景。这将使用体内兔模型和体外评估来实现 人类标本。阑尾炎是影响儿童和 比任何其他儿科一般手术都有更多的发病率和医疗资源利用 健康）状况。在美国大约有阑尾炎（PA）的小儿病例， 这些穿孔案件与较高的成本，更长的住院和更高的医院再入院有关 速率和术后结果较差。阑尾切除术后长时间的抗生素疗法仍然是 用于治疗腹内感染的主要治疗。这导致长期住院，可能不是 有效防止抗生素抗性菌株，突出了对替代疗法的需求。 光动力疗法（PDT），该疗法通过光化学的活性导出抗菌活性 氧气，具有广泛的频谱和快速起作用，对抗生素抗性菌株有效，并且不会 导致获得的阻力。鉴于与PA相关的腹腔内感染是多数型的， PDT通常会因对普通抗生素的抗性耐药性而复杂，是对 在穿孔的阑尾炎中治疗腹腔内感染，可以进一步治疗 腹肌后切除术后脓肿形成。 这项研究的目的是证明抗菌PDT的概念证明是对 兔模型中穿孔阑尾炎的腹内感染，以及针对的效率 从人类样品中分离出来的细菌。这种高风险，高奖励研究可以彻底改变 PA，并大大减少住院和并发症。 目标1 - 在兔子模型中证明光动力疗法的可行性和效率 阑尾炎。使用已建立的兔子模型，将进行一项前瞻性研究以评估 甲基蓝光光动力疗法后，腹膜腔中细菌燃烧的减少（MB- 太平洋夏令时）。细菌载荷将被量化PDT前后，并将其与接受的动物进行比较 没有MB的照明。假设MB-PDT将导致总细菌降低≥99.9％ 人口，在肠道菌群中发现的特定细菌物种的杀死潜在变化。 AIM 2 - 在体外表现出对从患者分离的细菌的体外光动力疗法的效率 穿孔阑尾炎。从小儿患者捕获的吸气腹膜液中分离出的细菌 进行PA的阑尾切除术将被表征。然后将在两个浮游生物上进行MB-PDT 培养和生物膜。假设PDT将显着减少细菌燃烧，并使用生物膜燃烧 有可能需要更大的药物/轻剂量才能达到可比的效率。