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

描述（由申请人提供）：该R21申请提出了对作为SCOUT研究（“儿童尿路感染短程治疗”）一部分回收的细菌分离株进行详细的分子分析。母研究是降低抗生素耐药性风险的靶向临床试验之一，是一项多中心、随机、双盲、安慰剂对照的非劣效性临床试验，在确诊为泌尿系感染的儿童中进行。 尿路感染（UTI）。受试者将随机接受标准（10天）或短期（5天）治疗，采用三种抗生素方案之一：甲氧苄啶-磺胺甲恶唑（TMP-SMX）;阿莫西林-克拉维汀（AMC）;或头孢克肟（CFX）/头孢地尼（CFD）。本研究的主要目的是确定短期治疗是否与标准疗程治疗儿童UTI一样有效;次要目的是确定两个治疗组是否导致相似比例的儿童胃肠道定植耐药大肠埃希菌和/或肺炎克雷伯菌。因此，受试者将在入组访视（#1;第4-6天）和两次随访访视（第12-14天（#2）和第24- 26天（#3））时采集粪便样本进行细菌培养。在这个建议中，我们假设抗生素和治疗时间都会影响患者的本地植物群 从而影响恢复E. coli和/或K.从粪便中分离的肺炎和回收的分离株的耐药表型。我们将利用PCR和基于序列的方法来表征回收的分离株的系统发育和抗性特性。我们假设（1）E.埃希菌和从2或3个粪便培养物中回收的肺炎链球菌更可能是其各自物种内疾病相关亚组的成员（E.大肠杆菌B2、D、K. pneumoniae cluster KpI）;（2）处理期间从培养物中回收的处理敏感菌株（3A）任一物种的治疗抗性菌株比治疗敏感菌株更可能在治疗期间从培养物中回收;和（3B）在AMC组治疗期间，任一种属的治疗敏感菌株比TMP/SMX或CFX/CFD组更可能从培养物中回收。如果SCOUT证明短程治疗与标准治疗一样安全有效，并且该建议表明短程治疗不太可能选择耐药大肠杆菌的肠道携带。coli或K.肺炎，这些发现将对处方行为产生重大影响，减少儿科抗生素暴露，从而减少耐药性的选择。

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.