Differences in infecting and colonizing Enterobacteriaceae from short-course vs s

描述(由申请人提供)：这份R21申请提出了一项详细的细菌分离的分子分析，作为童子军研究(“儿童尿路感染的短程疗法”)的一部分。父母研究是降低抗菌素耐药性风险的定向临床试验之一，是一项针对确诊为尿路疾病的儿童的多中心、随机、双盲、安慰剂对照的非劣势临床试验 呼吸道感染(UTI)。受试者将随机接受三种抗生素方案之一的标准(10天)或短期(5天)治疗：甲氧苄啶-磺胺甲恶唑(TMP-SMX)；阿莫西林-克拉维酸(AMC)；或头孢克新(CFX)/头孢地尼(CFD)。这项研究的主要目的是确定短程疗法对儿童尿路感染的治疗是否与标准疗程疗法一样有效；次要目标是确定这两种疗法是否导致耐药大肠埃希菌和/或肺炎克雷伯菌在胃肠道定植的儿童比例相似。因此，受试者将在登记访问(#1；第4-6天)和两次后续访问(第12-14天(#2)和第24-26天(#3))时获得用于细菌培养的粪便样本。在这项建议中，我们假设抗生素制剂和治疗时间都会影响患者的本土菌群。 从而影响从粪便中回收大肠杆菌和/或肺炎克雷伯菌的可能性和回收的分离株的耐药性表型。我们将利用聚合酶链式反应和基于序列的方法来鉴定回收的分离株的系统发育和抗性特性。我们假设(1)从2个或3个粪便培养中恢复的大肠杆菌和肺炎克雷伯菌更有可能是其各自物种内与疾病相关的亚组的成员(大肠杆菌系统群B2和D，肺炎克雷伯氏菌簇KPI)；(2)从治疗期间从培养物中恢复的治疗敏感菌株(5天组的培养#1；培养#1或#2，10天组)更有可能是疾病相关亚组的成员；(3A)在治疗期间，两个物种的抗药株比从培养物中恢复的治疗敏感株更有可能；与TMP/SMX或CFX/CFD组相比，在AMC组治疗期间，任何一种的治疗敏感菌株都更有可能从培养中恢复。如果Scout证明短程疗法与标准疗法一样安全有效，并且这项建议表明短程疗法不太可能选择肠道携带耐药大肠杆菌或肺炎克雷伯菌，这些发现将对处方行为产生重大影响，从而减少儿科抗生素的暴露，从而选择耐药性。

DESCRIPTION (provided by applicant): This R21 application proposes a detailed molecular analysis of bacterial isolates recovered as part of the SCOUT Study ("Short Course Therapy for Urinary Tract Infections in Children"). The parent study, one of the Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance, is a multicenter, randomized, double-blind, placebo-controlled non-inferiority clinical trial of children with a confirmed diagnosis of urinary tract infection (UTI). Subjects will be randomized to receive either standard (10-day) or short-course (5-day) therapy with one of three antibiotic regimens: trimethoprim-sulfamethoxazole (TMP-SMX); amoxicillin-clavulanate (AMC); or cefixime (CFX)/cefdinir (CFD). The primary objective of the study is to determine whether short- course therapy is as effective as standard course therapy for treatment of UTI in children; a secondary objective seeks to determine whether the two therapy arms result in similar proportions of children with gastrointestinal colonization by antibiotic-resistant Escherichia coli and/or Klebsiella pneumoniae. Thus, subjects will have stool samples obtained for bacterial culture at enrollment visit (#1; day 4-6) and two follow-up visits, on day 12-14 (#2) and day 24- 26 (#3). In this proposal, we hypothesize that both the antibiotic agent and the length of therapy will affect the patients' indigenous flora and thus affect both the likelihood of recovering E. coli and/or K. pneumoniae from stool and the resistance phenotypes of the recovered isolates. We will utilize PCR- and sequence-based methods to characterize phylogenetic and resistance properties of the recovered isolates. We hypothesize that (1) E. coli and K. pneumoniae recovered from 2 or 3 stool cultures are more likely to be members of disease-associated subgroups within their respective species (E. coli phylogroups B2 and D, K. pneumoniae cluster KpI); (2) treatment-susceptible strains recovered from cultures during treatment (culture #1 for 5-day arm; cultures #1 or #2, 10-day arm) are more likely to be members of disease-associated subgroups; (3A) treatment-resistant strains of either species are more likely than treatment- susceptible strains to be recovered from cultures during treatment; and (3B) treatment- susceptible strains of either species are more likely to be recovered from cultures during treatment in the AMC arm than in the TMP/SMX or CFX/CFD arms. If SCOUT demonstrates that short-course therapy is as safe and effective as standard therapy, and this proposal demonstrates that short-course therapy is less likely to select for intestinal carriage of resistant E. coli or K. pneumoniae, these findings would make a significant impact on prescribing behavior, toward reducing pediatric antibiotic exposure and thus the selection for resistance.