National surveillance of emerging MDR in pediatric Enterobacteriaceae infections

描述（由申请人提供）：日益严重的抗菌素耐药性问题已得到充分认识。多重耐药生物感染的治疗具有挑战性，并且与发病率、死亡率和医疗资源支出增加有关。虽然很多注意力都集中在了解革兰氏阳性菌，特别是耐甲氧西林金黄色葡萄球菌耐药的流行病学上，但对革兰氏阴性菌，特别是儿科多药耐药的流行病学知之甚少。我们的初步数据显示，在我们的儿科中心，肠杆菌科质粒传播的广谱2-内酰胺耐药（PBLR）的增加具有统计学意义，并且非常令人担忧。这种类型的耐药性包括质粒携带的AmpC-、ESBL-和碳青霉烯酶型决定因子，它令人担忧，因为它限制了可用于治疗感染的抗菌剂，而且因为质粒很容易在生物体之间转移，造成耐药性快速传播的威胁。我们提出了一个多中心试点项目，以描述儿童肠杆菌科PBLR的国家分子和流行病学趋势。目的1。估计质粒传播的广谱2-内酰胺耐药（PBLR）的患病率，并描述各分子决定因素和质粒类型的频率分布，这些分布在美国4个医疗中心的临床儿科肠杆菌科分离物中。2. 目的：确定显示PBLR的大肠杆菌分离株与无PBLR的对照大肠杆菌分离株的克隆背景和毒力特性。3. 定义儿童肠杆菌科感染中与PBLR相关的人口学、临床和细菌因素。方法。一个由4家儿科医院组成的联盟参与了这个项目。通过常规临床护理，每个站点将确定具有可能指示PBLR的耐药模式的肠杆菌科。这些分离株（以及非pblr对照分离株）以及感染患者的人口统计学和临床数据将被发送到西雅图儿童医院，在那里将进行进一步的生物特征和数据分析。项目的预期成果。该项目将在全国范围内确定儿科PBLR耐药的范围。这一信息有可能为儿童严重细菌感染的治疗提供信息，特别是经验性治疗。它还将提供来自人类宿主的临床数据、菌株背景和细菌宿主的毒力以及耐药性的分子决定因素的综合分析的新信息。这将为未来设计旨在预防PBLR耐药的介入性研究提供必要的信息。

DESCRIPTION (provided by applicant): The growing problem of antimicrobial resistance is well recognized. Infections with multi-drug resistant organisms are challenging to treat, and are associated with increased morbidity, mortality, and expenditure of healthcare resources. While much attention has been directed at understanding the epidemiology of resistance in Gram-positive organisms, especially methicillin-resistant Staphylococcus aureus, much less is known about the epidemiology of multi-drug resistance in Gram-negative organisms, particularly in pediatrics. Our preliminary data demonstrate statistically significant and very worrisome increases in plasmid-borne, broad-spectrum 2-lactam resistance (PBLR) in Enterobacteriaceae at our pediatric center. This type of resistance includes plasmid-borne AmpC-, ESBL-, and carbapenemase-type determinants, and is concerning both because it limits the antimicrobials available to treat infections and because plasmids are readily transferable between organisms, creating a threat for rapid spread of resistance. We propose a multicenter pilot project to describe national molecular and epidemiological trends in pediatric PBLR in Enterobacteriaceae . Aims 1. To estimate the prevalence of plasmid-borne, broad-spectrum 2-lactam resistance (PBLR), and to describe frequency distributions of the respective molecular determinants and plasmid types, among clinical pediatric Enterobacteriaceae isolates from 4 medical centers across the U.S. over time. 2. To define the clonal background and virulence properties of E. coli isolates demonstrating PBLR versus control E. coli isolates without PBLR. 3. To define the demographic, clinical, and bacterial factors associated with PBLR in Enterobacteriaceae infections in pediatric patients. Methods. A consortium of 4 pediatric hospitals is involved in this project. Each site, through routine clinical care, will identify Enterobacteriaceae with resistance patterns potentially indicative of PBLR. These isolates (along with non-PBLR control isolates) and demographic and clinical data from the infected patients will be sent to Seattle Children's, where further characterization of the organisms and data analyses will take place. Expected Outcomes of the Project. This project will define the scope of PBLR resistance in pediatrics on a national scale. This information has the potential to inform treatment, especially empiric treatment, of serious bacterial infections in children. It will also provide novel information from integrated analyses of clinical data from the human host, strain background and virulence of the bacterial host, and the molecular determinants of resistance. This will provide needed information for the design of future interventional studies aimed at preventing PBLR resistance. PUBLIC HEALTH RELEVANCE: We propose to study antibiotic resistance in Enterobacteriaceae bacteria (such as Escherichia coli and Klebsiella pneumoniae) that produce urinary tract and bloodstream infections in children, by analyzing clinical isolates from 4 children's hospitals across the country. Having already demonstrated a statistically significant increase in the frequency of specific resistance genes among clinical isolates at our medical center, we describe an expanded approach that features geographically broader sampling as well as a powerful set of molecular tools that can highlight key epidemiologic differences between resistant strains and still-susceptible strains. This data will fill a critical gap in the pediatric literature, and provide the foundation for design of intervention studies to reduce the spread of this resistance, and guide changes in treatment to reduce the morbidity and mortality of such infections.