Determining the clinical and environmental impact, burden and cost of Extensively Drug Resistant Enterobacteriaceae in China (DETER-XDRE-CHINA-HUB)

抗菌素耐药性(AMR)现在被认为是21世纪人类面临的最大全球威胁。AMR已成为全球卫生问题的焦点，但大多数非专家并不知道AMR将对全球人口产生的影响，以及它将感染治疗带回“黑暗时代”的潜力。因此，根据“同一个世界卫生”的一般概念，各国之间显然需要更好地协调思维，密切合作，协同开展活动、知识和技能，以更好地了解和预防AMR。到目前为止，世界各地研究AMR影响的大多数研究都是小规模、一维的，而且往往存在偏见--过于集中于AMR细菌，而不是研究整个细菌种群。两年前，我们与我们的中国同事一起发表了一篇文章，预示着最后一种抗生素Colisitin的问世，这种抗生素被用来治疗由已经具有耐药性的细菌引起的非常严重的感染，如大肠杆菌(俗称大肠杆菌)。这一新发现的不同之处在于，粘菌素耐药机制(名为MCR-1)是可移动的，即可以很容易地从一种细菌传播到另一种细菌--甚至在远亲细菌之间。这篇文章获得了全球的好评，被引用1000多次，反映了其广泛的影响。在这一发现的基础上，利用中国同事、医院、农业和环境部门的相同网络，我们打算使用耐甲氧西林杆菌(MCRPE)和耐碳青霉烯肠杆菌科(大肠杆菌和类大肠杆菌)(Cre)作为标记，了解AMR是如何在中国人和动物群体中传播的(中国将粘菌素用于动物饲料)。首先，我们有一个全面的采样平台：工作包(WP)1，正常菌群运输；WP2，初级和二级护理感染；WP3，鸡、鸭和猪，包括屠宰场；WP4，苍蝇和野鸟；WP5，水、土壤和废物；WP6，水产养殖；WP7，家畜。在样本类型确定之前，我们将每3/6个月分析至少百份样本，以检验季节性变化，并从山东、广东和江苏三个不同省份抽取样本；此外，我们还将选择青海作为对照地区。将通过基本的微生物学技术对细菌进行分析，并选择对其进行全基因组测序，在那里我们可以询问细菌的整个DNA，并将其与其他细菌进行比较，以确定它们是否从一个部门(例如苍蝇)传播到另一个部门(例如人类)。这项研究还将对人类肠道中的细菌(称为微生物组)进行测序，以了解AMR细菌种群的动态。我们还将在养鸡场进行对照实验，以监测CRE和MRCPE上的传播，并使用数学模型来了解AMR如何在动物中传播。重要的是，中国政府最近(2017)停用了抗生素粘菌素，因此这项研究在衡量这种影响方面是非常及时的，即停用粘菌素是否会影响环境中的MCRPE率、人体肠道水平以及导致人类感染的MCRPE？与以前的研究不同，这项研究故意采用整体性的方法，以了解AMR在广泛的环境和人类部门的动态和传播。这项研究将让我们了解CRE和MCRPE对人类人口的影响以及对中国卫生系统的负担和成本。它还将帮助我们通过数学模型了解AMR对鸡、鸭和猪贸易的影响。这项研究的影响将对中国的动物、人类和经济部门产生巨大的影响。我们的网络建立得很好，非常成功，并且有在中国一起工作的良好记录和专业知识来承担这项令人兴奋和具有挑战性的计划。

Antimicrobial resistance (AMR) is now deemed to be the biggest global threat facing humanity in the 21C. AMR has taken center stage as a global health issue yet most non-specialists are unaware the impact AMR will have on global populations and the potential it has of taking the treatment of infections back to the "dark ages". Therefore, in keeping with the general notion of "One World Health", there clearly needs to a better alignment of thinking and closer co-operation between countries synergizing activities, knowledge and skills to better understand and prevent AMR. Hitherto, most studies around the world studying the impact of AMR have been small, one dimensional and often biased - too focused on AMR bacteria as oppose to studying the whole bacterial population. Two years ago, we published an article with our Chinese colleagues heralding the breech of the last antibiotic, colisitin, that is used to treat the very serious infections caused by already resistant bacteria such as Escherichia coli (commonly known as E. coli). The difference with this new discovery is that the mechanism of colistin resistance (named MCR-1) is mobile i.e. can be readily passed around from one bacteria to another - even between distantly related bacteria. This article reached global acclaim and has been cited over 1000 times reflecting its broad impact. Following on from this discovery and using the same network of Chinese colleagues, hospitals, farming and environmental sectors, we intend to use MCR (MCRPE) and carbapenem-resistant Enterobacteriaceae (E. coli and E. coli-like bacteria)(CRE) as markers to understand how AMR has spread throughout the Chinese human and animal populations (colistin is used in animal feed in China). Firstly, we have a comprehensive sampling platform: work package (WP) 1, normal flora carriage; WP2, primary and secondary care infections; WP3, chicken, duck and pigs including slaughter houses; WP4, flies and wild birds; WP5, Water, soil and waste; WP6, Aquaculture; and WP7, Domestic animals. Pending the type of sample, we will analyze at least 100 samples every 3/6 months to examine seasonal variation and sample from three distinct provinces in China: Shandong, Guangdong and Jiangsu; additionally, we will also chose Qinghai as a control region. Bacteria will be analyzed by basic microbiology techniques and selected to be whole genome sequenced where we can interrogate the bacteria's whole DNA and compare it to other bacteria to see if they have spread from one sector (e.g. flies) to another (e.g. humans). This study will also sequence bacteria in the human gut (called the microbiome) to understand the dynamics of AMR bacterial populations. We will also undertake controlled experiments in chicken farms to monitor the spread on CRE and MRCPE and use mathematical models to understand how AMR spreads in animals. Importantly, the Chinese government has recently (2017) withdrawn the antibiotic colistin so this study is very timely in measuring that effect i.e. will withdrawing colistin impact on MCRPE rates in the environment, human gut levels and MCRPE causing human infections? Unlike previous studies, this study is deliberately holistic in its approach to understand the dynamics and transmission of AMR across a broad range of environmental and human sectors. This study will let us understand the impact of CRE and MCRPE on human populations and the burden and cost to the Chinese health system. It will also help us understand the impact AMR on the chicken, duck and pig trade by using mathematical models. The impact of this study will have immense consequences for the animal, human and economic sectors in China. Our network is well established, high successful and has a proven track record of working together in China and expertise to undertake this exciting and challenging proposal.