Microbiologic impact of medical therapies for recurrent Clostridium difficile infection

大约25%的患者对艰难梭菌初始病例的治疗有反应 感染（CDI）的患者会出现感染复发，许多患者会出现多次复发。 不幸的是，复发性CDI的最佳医疗管理尚不清楚。特别是， 万古霉素逐渐减少和脉冲方案是常用的，但尚未与其他方案进行比较。 随机试验中的药物治疗。为了解决这个问题，合作研究。 CSP计划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vs非达霉素10天vs万古霉素10天， 万古霉素减量和冲击方案治疗首次或二次复发的CDI。我们建议 开展CSP试验的子研究，以更好地了解微生物学影响 治疗方案。该提案的中心假设是， 治疗方案有利于从结肠清除孢子， 提供对C.很难我们的首要目标是 比较固有肠道微生物群的组成和C.中艰难 接受万古霉素减量和脉冲方案与标准方案治疗的患者 万古霉素或非达霉素方案治疗复发性CDI。为了实现这一目标，我们将收集 VA CSP中120例受试者的治疗前、治疗期间和治疗后粪便标本 试验（每个治疗组约40例）。我们将比较微生物群的组成和 C的存在和浓度。各治疗组患者粪便中的艰难梭菌。我们的第二 具体目的是确定万古霉素和非达霉素的脉冲给药是否增强清除 梭艰难孢子为了实现这一目标，我们将使用C.艰难定植 比较C.艰难梭菌孢子和恢复的微生物群与每2或3天 万古霉素或非达霉素的脉冲给药与相同治疗的每日给药相比 持续时间和CSP# 596试验中使用的标准10天治疗方案。结果 因为复发性CDI是一个重要的临床挑战， 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.