The rates and routes of transmission of multidrug resistant Klebsiella clones and genes into the clinic from environmental sources.

近年来，由于对多种抗生素具有广泛耐药性，在全球范围内对卫生保健机构构成高风险的细菌菌株急剧增加。我们的研究项目将集中于肺炎克雷伯菌（Klebsiella pneumoniae），这是全球多药耐药医院获得性感染的主要原因，特别是在新生儿、老年人和免疫抑制患者中，据报道死亡率高达50%以上。由于社区获得性侵袭性感染，它也造成越来越大的负担，可导致化脓性肝脓肿、肺炎和脑膜炎。除了引起疾病外，克雷伯氏菌是一种生态多发病菌，可在健康个体的肠道、皮肤、鼻子和喉咙中无症状携带，并可在一系列节肢动物、鸟类或植物宿主（包括作物和树木）以及水和土壤等环境生态位中繁殖。它还能在一些动物物种中引起侵袭性疾病，是奶牛群中乳腺炎的常见原因。为了通过有针对性的监测和干预政策控制克雷伯氏菌的传播，有必要从包括“环境”在内的相互关联和不同的小生境中确定突发社区和保健相关感染的来源。环境流行率数据提供了一个关键的基线，但并不总是足以为公共卫生政策提供信息。例如，观察到海鸥经常携带克雷伯氏菌本身不足以指导管理海鸥种群的政策，因为直接传播给人类仍然很难证明。然而，如果水被确定为克雷伯氏菌的主要储存库，并且经常进出诊所，这可能反过来影响废水处理程序。同样，如果发现蟑螂与克雷伯氏菌有关，这应该导致在医院和社区加强害虫控制。为了解决这个问题，我们将采集样本，以便从多个临床、社区、农业、兽医和环境环境中识别克雷伯菌。然后，我们将使用一种基于全基因组测序的新方法来提供一种更有效的方法来了解细菌的生态适应，抗性和毒力基因的分布，并确定这些克雷伯氏菌克隆产生的关键环境。这种方法将涉及同时对多个菌落进行测序，以便在给定样本中检测更广泛的基因样本。我们将建立一个全面的、数据驱动的模型，在所有相关的生态和临床部门之间建立适应、多样化、基因流动和传播动态。这将为制定有针对性的疾病管理战略铺平道路。

Recent years have seen a dramatic global increase of strains of bacteria that pose a high risk in health care settings due to broad resistance to a wide range of antibiotics.Our research project will concentrate on Klebsiella pneumoniae (Klebsiella), a leading cause of multidrug resistant hospital-acquired infections globally, particularly among neonates, the elderly and immunosuppressed patients, with reported mortality rates upwards of 50%. It is also responsible for an increasing burden due to community-acquired invasive infections, which can lead to pyogenic liver abscess, pneumonia, and meningitis. In addition to causing disease, Klebsiella is an ecological generalist and can be carried asymptomatically in the intestinal tract, skin, nose, and throat of healthy individuals, and can thrive in a range of arthropod, bird or plant hosts (including crops and trees) and environmental niches such as water and soil. It can also cause invasive disease in several animal species, and it is a common cause of mastitis in dairy herds.In order to control the spread of Klebsiella through targeted surveillance and intervention policies it is necessary to identify the sources of emergent community and health-care associated infection from the interlinked and varied niches encompassing "the environment". Environmental prevalence data provides a critical baseline, but is not always sufficient to inform on public health policy. For instance, the observation that gulls frequently harbour Klebsiella is, by itself, insufficient to guide policy on managing gull populations, as direct transmission to humans remains very difficult to demonstrate. However, if, say, water were to be identified as a major Klebsiella reservoir with frequent transmission to and from the clinic, this might in turn impact on waste water treatment procedures. Similarly, if cockroaches are found to be associated with Klebsiella this should lead to increased pest control both in hospitals and in the community. To address this, we will take samples in order to identify Klebsiella from multiple clinical, community, agricultural, veterinary and environmental settings. Then we will use a novel approach based on whole genome sequencing to provide a much more efficient means to understand ecological adaptation, the distribution of resistance and virulence genes in the bacteria, and to identify key environmental settings from which these Klebsiella bacterial clones emerge. This approach will involve sequencing multiple colonies of bacteria simultaneously in order to detect a wider sample of genes present within a given sample. We will build a comprehensive, data-driven, model of adaptation, diversification, gene flow and transmission dynamics between all relevant ecological and clinical compartments. This will then pave the way for the development of targeted disease management strategies.