Combination Antibotics as a Treatment for Chlamydia-Induced Reactive Arthritis

联合抗生素治疗衣原体引起的反应性关节炎

• 批准号: 7084906
• 负责人: John Dillon Carter
• 金额: $ 20.13万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-22 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7084906
• 关键词: Chlamydia trachomatis; Chlamydiaceae; antibiotics; arthritis; chlamydial disease; clinical research; clinical trials; infection; placebos; rifamycins

DESCRIPTION (provided by applicant): Reactive Arthritis (ReA) is an inflammatory arthritis that arises after certain genitourinary and gastrointestinal infections. Chlamydia trachomatis (Ct) is a known trigger for ReA. Ct has been proven to exist in a persistent metabolically active state that is very different than the active infection. Paramount in this persistence is the up-regulation of certain Ct heat shock protein 60 (HSP-60) paralog genes. Persistent Ct has been demonstrated by polymerase chain reaction (PCR) in the synovial tissue of patients with ReA years after their initial exposure. Our long-term objective is to establish definitive proof that Ct-induced ReA can be cured with prolonged combined antimicrobial therapy. It is our hypothesis that treatment with a combination of antibiotics, which also inhibits Ct HSP-60 production, can eradicate this persistent Chlamydial state; thereby curing chronic Ct-induced ReA. Rifampin has been shown to attenuate Ct HSP production; it also displays synergistic effect with azithromycin in Ct infections. Our proposal has two aims that will be accomplished with 1) an in vivo therapeutic clinical trial, and 2) a concurrent in vivo study. 1. In the therapeutic clinical trial, we expect to establish proof that significantly more patients respond to prolonged, combined antimicrobial therapy compared to placebo. Patients with probable Ct-induced ReA will be screened with a peripheral blood mononuclear cell (PBMC) and synovial biopsy PCR for Chlamydia. If either PCR is positive, they will be enrolled in this double-blind trial and randomized to one of three treatment groups: doxycydine and rifampin, azithromycin and rifampin, or placebo. All patients will be treated for 9 months and followed regularly with clinical assessments to determine if they are responders. 2. Our in vitro study aims to prove that PBMC's infected with persistent Ct can be cleared of their infection with the same combination of antibiotics. The PBMC's will be obtained from normal controls (infected in vitro) and patients in our therapeutic trial. We will also show that infected PBMC's from symptomatic patients respond to the antimicrobials exactly as the normal controls that are infected in vitro. This project will be a critical pathway in discovering a cure for persistent Chlamydia infections in the joint and at other anatomic sites. Chronic Chlamydia infections have also been linked to trachoma, tubal infertility, coronary artery disease, asthma, certain types of cervical cancer, and possibly other diseases.

描述（由申请人提供）：反应性关节炎（ReA）是一种在某些泌尿生殖系统和胃肠道感染后出现的炎性关节炎。沙眼衣原体 (Ct) 是 ReA 的已知触发因素。 Ct 已被证明以持续的代谢活跃状态存在，这与活动性感染有很大不同。这种持久性中最重要的是某些 Ct 热休克蛋白 60 (HSP-60) 旁系同源基因的上调。聚合酶链反应 (PCR) 已证实 ReA 患者初次接触数年后其滑膜组织中存在持续 Ct。我们的长期目标是建立明确的证据，证明 Ct 诱导的 ReA 可以通过长期联合抗菌治疗来治愈。我们的假设是，抗生素组合治疗（同时抑制 Ct HSP-60 的产生）可以根除这种持续的衣原体状态；从而治愈慢性 Ct 诱导的 ReA。利福平已被证明可以减弱 Ct HSP 的产生；它还与阿奇霉素在 Ct 感染中表现出协同作用。我们的提案有两个目标，将通过 1) 体内治疗临床试验和 2) 同步体内研究来实现。 1. 在治疗性临床试验中，我们希望找到证据表明，与安慰剂相比，更多的患者对长期联合抗菌治疗有反应。可能患有 Ct 诱导 ReA 的患者将通过外周血单核细胞 (PBMC) 和滑膜活检 PCR 进行衣原体筛查。如果任一 PCR 呈阳性，他们将参加这项双盲试验，并随机分配到三个治疗组之一：强力霉素和利福平、阿奇霉素和利福平或安慰剂。所有患者将接受 9 个月的治疗，并定期进行临床评估，以确定他们是否有反应。 2. 我们的体外研究旨在证明感染持续性Ct的PBMC可以使用相同的抗生素组合来清除其感染。 PBMC 将从正常对照（体外感染）和我们治疗试验中的患者获得。我们还将证明，来自有症状患者的受感染 PBMC 对抗菌药物的反应与体外感染的正常对照完全相同。该项目将成为寻找治疗关节和其他解剖部位持续性衣原体感染的方法的关键途径。慢性衣原体感染还与沙眼、输卵管性不孕、冠状动脉疾病、哮喘、某些类型的宫颈癌以及可能的其他疾病有关。