Microbiologic impact of medical therapies for recurrent Clostridium difficile infection

药物治疗对复发性艰难梭菌感染的微生物学影响

• 批准号: 10427235
• 负责人: Curtis Donskey
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427235
• 关键词: Address; Aftercare; Antibiotic Therapy; Bacteria; Bacteroides; Bifidobacterium; Clinical; Clostridium difficile; Collaborations; Colon; Communities; Complication; Data; Dose; Drug Exposure; Feces; Healthcare Systems; Hospital Nursing; Indigenous; Infection; Intestines; Laboratories; Length of Stay; Medical; Microbiology; Morbidity - disease rate; Nursing Homes; Participant; Patients; Physiologic pulse; Principal Investigator; Quality of life; Recovery; Recurrence; Regimen; Reproduction spores; Research; Research Personnel; Risk; Testing; Treatment Protocols; Vancomycin; colonization resistance; cooperative study; cost; effective therapy; experience; gut microbiota; microbiota; mortality; mouse model; programs; randomized trial; recurrent infection; standard care; stool sample; success; transmission process; treatment duration; treatment group; trial comparing

Approximately 25% of patients responding to treatment for initial cases of Clostridium difficile infection (CDI) develop a recurrence of the infection, and many develop multiple recurrences. Unfortunately, the optimal medical management of recurrent CDI is unclear. In particular, vancomycin taper and pulse regimens are commonly used, but have not been compared to other medical treatments in randomized trials. To address this deficiency, the VA Cooperative Studies Program (CSP) is conducting a randomized trial, CSP596, to compare a standard 10-day course of vancomycin versus 10 days of fidaxomicin versus 10 days of vancomycin followed by a vancomycin taper and pulse regimen for first or second recurrences of CDI. We propose to conduct a sub-study of the CSP trial to develop a better understanding of the microbiologic impact of the treatment regimens. The central hypothesis of the proposal is that taper and pulse treatment regimens facilitate clearance of spores from the colon while allowing recovery of intestinal microbiota that provide colonization resistance to C. difficile. Our first specific aim is to compare the composition of the indigenous intestinal microbiota and clearance of C. difficile in patients receiving treatment with vancomycin taper and pulse regimens versus standard vancomycin or fidaxomicin regimens for recurrent CDI. To accomplish this aim, we will collect stool specimens before, during, and after treatment for a subset of 120 participants in the VA CSP trial (~40 per treatment group). We will compare the composition of the microbiota and the presence and concentration of C. difficile in stool of patients in each treatment group. Our second specific aim is to determine if pulse dosing of vancomycin and fidaxomicin enhances clearance of C. difficile spores. To accomplish this aim, we will use a mouse model of C. difficile colonization to compare clearance of C. difficile spores and recovery of the microbiota with every 2 or 3-day pulse dosing of vancomycin or fidaxomicin in comparison to daily dosing for the same treatment duration and to the standard 10-day treatment regimens used in the CSP# 596 trial. The results will be significant because recurrent CDI is an important clinical challenge and there is an urgent need for effective management approaches.

大约 25% 的患者对艰难梭菌初始病例的治疗有反应 感染（CDI）会导致感染复发，并且许多会出现多次复发。 不幸的是，复发性 CDI 的最佳医疗治疗尚不清楚。尤其， 万古霉素逐渐减量和脉冲治疗方案很常用，但尚未与其他方案进行比较 随机试验中的药物治疗。为了解决这一缺陷，VA 合作研究 计划 (CSP) 正在进行一项随机试验 CSP596，以比较标准的 10 天课程 万古霉素与非达霉素 10 天对比万古霉素 10 天，然后 万古霉素逐渐减量和脉冲方案用于 CDI 第一次或第二次复发。我们建议 对 CSP 试验进行子研究，以更好地了解微生物影响 的治疗方案。该提案的中心假设是锥度和脉冲 治疗方案促进孢子从结肠中的清除，同时允许恢复 肠道微生物群对艰难梭菌具有定植抗性。我们的第一个具体目标是 比较本地肠道微生物群的组成和艰难梭菌的清除率 接受万古霉素逐渐减量和脉冲方案治疗的患者与标准方案的比较 万古霉素或非达霉素治疗复发性 CDI 的方案。为了实现这一目标，我们将收集 VA CSP 中 120 名参与者在治疗前、治疗期间和治疗后的粪便样本 试验（每个治疗组约 40 人）。我们将比较微生物群的组成和 每个治疗组患者粪便中艰难梭菌的存在和浓度。我们的第二个 具体目的是确定万古霉素和非达霉素的脉冲给药是否可以增强清除率 艰难梭菌孢子。为了实现这一目标，我们将使用艰难梭菌定植的小鼠模型 每 2 或 3 天比较艰难梭菌孢子的清除率和微生物群的恢复情况 万古霉素或非达霉素的脉冲剂量与相同治疗的每日剂量相比 持续时间以及 CSP# 596 试验中使用的标准 10 天治疗方案。结果 将会很重要，因为复发性 CDI 是一个重要的临床挑战，并且有一个紧迫的任务 需要有效的管理方法。