Microbiologic impact of medical therapies for recurrent Clostridium difficile infection

约25%的患者对艰难梭菌首发病例的治疗有反应 感染(CDI)会导致感染的复发，许多患者会多次复发。 不幸的是，复发性CDI的最佳医疗处理尚不清楚。特别是， 万古霉素锥形和脉冲方案是常用的方案，但尚未与其他方案进行比较 随机试验中的医疗治疗。为了解决这一不足，退伍军人事务部合作研究 项目(CSP)正在进行一项随机试验，CSP596，以比较标准的10天疗程 万古霉素与10天的非达克索米星和10天的万古霉素 万古霉素锥形和脉冲方案治疗CDI首次或第二次复发。我们建议 进行CSP试验的子研究，以更好地了解微生物的影响 治疗方案的一部分。该提案的中心假设是，缩减和脉冲 治疗方案有助于清除结肠中的孢子，同时允许恢复 对艰难梭菌提供定植抗性的肠道微生物区系。我们的第一个具体目标是 艰难梭菌本土肠道微生物区系组成和清除能力的比较 接受万古霉素锥形和脉冲方案治疗的患者与标准方案相比 万古霉素或非达克索米星方案治疗复发性CDI。为了实现这一目标，我们将收集 退伍军人CSP的120名参与者在治疗前、治疗中和治疗后的粪便标本 试验(每个治疗组约40人)。我们将比较微生物区系的组成和 各治疗组患者粪便中艰难梭菌的存在和浓度。我们的第二个 具体目的是确定脉冲剂量的万古霉素和非达克索米星是否能增强清除 艰难梭菌孢子。为了实现这一目标，我们将使用艰难梭菌的小鼠模型 比较每隔2天或3天艰难梭菌孢子的清除和微生物区系的恢复情况 脉冲剂量万古霉素或非达克索米星与每日剂量相同治疗的比较 持续时间和CSP#596试验中使用的标准10天治疗方案。结果是 将具有重大意义，因为复发的CDI是一个重要的临床挑战，而且有一个紧急的 需要有效的管理方法。

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.