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。抗菌素耐药性已成为全球健康问题的中心，但大多数非专业人士都不知道抗菌素耐药性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”的总体概念，显然需要更好地协调各国之间的思想和更密切的合作，将活动、知识和技能协同起来，以更好地了解和预防抗微生物药物耐药性。迄今为止，世界上大多数研究抗菌素耐药性影响的研究都是小规模的、一维的，而且往往是有偏见的——过于关注抗菌素耐药性细菌，而不是研究整个细菌种群。两年前，我们与中国同事发表了一篇文章，宣布最后一种抗生素粘菌素问世。粘菌素用于治疗由大肠杆菌（俗称大肠杆菌）等已经具有耐药性的细菌引起的非常严重的感染。这一新发现的不同之处在于，粘菌素耐药性（被称为MCR-1）的机制是可移动的，即可以很容易地从一个细菌传递到另一个细菌，甚至在远亲细菌之间。这篇文章获得了全球的好评，被引用了1000多次，反映了它的广泛影响。根据这一发现，并利用中国同事、医院、农业和环境部门的相同网络，我们打算使用MCR （MCRPE）和耐碳青霉烯类肠杆菌科（大肠杆菌和大肠杆菌样细菌）（CRE）作为标记，了解AMR如何在中国人类和动物群体中传播（粘菌素在中国用于动物饲料）。首先，我们有完善的采样平台：工作包（WP） 1，正常菌群携带；WP2，初级和二级保健感染；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100个样本，以检查中国三个不同省份的季节性变化和样本：山东、广东和江苏；此外，我们还将选择青海作为控制区。细菌将通过基本的微生物学技术进行分析，并选择全基因组测序，我们可以询问细菌的整个DNA，并将其与其他细菌进行比较，以查看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，以了解抗菌素耐药性细菌种群的动态。我们亦会在养鸡场进行对照实验，以监测CRE和MRCPE的传播情况，并使用数学模型了解抗微生物药物耐药性如何在动物中传播。重要的是，中国政府最近（2017年）撤回了抗生素粘菌素，因此本研究非常及时地测量了这种影响，即撤回粘菌素会对环境中的MCRPE率、人体肠道水平和MCRPE引起人类感染产生影响吗？与以往的研究不同，本研究有意采用整体的方法来了解抗菌素耐药性在广泛的环境和人类部门中的动态和传播。本研究将使我们了解CRE和MCRPE对人口的影响以及中国卫生系统的负担和成本。它还将通过使用数学模型帮助我们了解抗菌素耐药性对鸡、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影响。我们的网络建立良好，非常成功，在中国有着良好的合作记录和专业知识来承担这一令人兴奋和具有挑战性的项目。

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.