National surveillance of emerging MDR in pediatric Enterobacteriaceae infections

描述（由申请人提供）：抗菌素耐药性问题日益严重，这一点已得到充分认识。多重耐药微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相关。虽然很多注意力都集中在了解革兰氏阳性微生物，特别是耐甲氧西林金黄色葡萄球菌的耐药性的流行病学，但对革兰氏阴性微生物，特别是儿科的多重耐药的流行病学知之甚少。我们的初步数据表明，在我们的儿科中心，肠杆菌科中质粒传播的广谱2-内酰胺耐药（PBLR）增加具有统计学显著性，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簇，并且由于其限制了可用于治疗感染的抗菌药物，并且由于质粒易于在生物体之间转移，从而造成耐药性快速传播的威胁，因此受到关注。我们提出了一个多中心的试点项目，以描述国家的分子和流行病学的趋势，在儿科PBLR肠杆菌科。目标1.在美国4个医疗中心的临床儿科肠杆菌科分离株中，估计质粒传播的广谱2-内酰胺耐药（PBLR）的患病率，并描述各分子决定簇和质粒类型随时间推移的频率分布。2.明确大肠杆菌的克隆背景和毒力特性。与对照E. coli分离株相比，不含PBLR的大肠杆菌菌株。3.明确与儿科患者肠杆菌科感染中PBLR相关的人口统计学、临床和细菌因素。方法.一个由4家儿科医院组成的联合体参与了该项目。每个研究中心将通过常规临床护理，识别具有潜在指示PBLR的耐药模式的肠杆菌科。这些分离株（沿着非PBLR对照分离株）以及感染患者的人口统计学和临床数据将发送至西雅图儿童医院，在那里将进行微生物的进一步表征和数据分析。项目的预期成果。该项目将在全国范围内确定儿科中PBLR耐药的范围。这些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。它还将从人类宿主的临床数据、细菌宿主的菌株背景和毒力以及耐药性的分子决定因素的综合分析中提供新的信息。这将为未来旨在预防PBLR耐药的干预性研究的设计提供所需的信息。 公共卫生相关性：我们建议通过分析来自全国4家儿童医院的临床分离株，研究引起儿童尿路和血液感染的肠杆菌科细菌（如大肠杆菌和肺炎克雷伯菌）的抗生素耐药性。在我们的医学中心已经证明了临床分离株中特定耐药基因频率的统计学显着增加之后，我们描述了一种扩展方法，该方法具有地理上更广泛的采样以及一套强大的分子工具，可以突出耐药菌株和仍然敏感菌株之间的关键流行病学差异。这些数据将填补儿科文献中的一个关键空白，并为干预研究的设计提供基础，以减少这种耐药性的传播，并指导治疗的变化，以减少此类感染的发病率和死亡率。

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.