Determining the clinical and environmental impact, burden and cost of extensively drug resistant Enterobacteriaceae in China (DETER-XDRE-CHINA)

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。抗菌素耐药性已经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，以及它将人类带回“黑暗时代”的潜力。英国首相戴维•卡梅伦（David Cameron）、英国首席医疗官（Sally Davies教授）和美国总统巴拉克•奥巴马（barack Obama）最近的声明清楚地表明，我们正在失去一种宝贵的药物资源。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。就在最近，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。根据这一发现，并利用中国同事、医院和农业部门的相同网络，我们打算使用MCR-1 （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，以了解它如何在中国动物种群中传播（粘菌素在中国用于动物饲料）。首先，我们有一个全面的抽样平台：工作包（WP） 1，初级和二级保健感染；WP2，正常菌群携带；WP3，养鸡场和屠宰场；WP4，零售肉类；WP5环境采样。我们将每3个月分析至少100个样本，以检查季节变化和来自中国三个不同省份的样本：山东、浙江和广东。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所有细菌进行测序，以了解AMR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，中国政府可能会从动物饲料中撤出粘菌素，所以这项研究非常及时地测量了这种影响，即，撤出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，本研究的方法是整体性的，以便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生素耐药性对鸡和猪贸易的影响。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，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 centre 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 humanity back to the "dark ages". Recent announcements from Prime Minister David Cameron, the UK Chief Medical Officer (Professor Sally Davies), and the US president, Barak Obama, is clear evidence that we are loosing one of medicines precious resources. 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. Very recently, 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. Following on from this discovery and using the same network of Chinese colleagues, hospitals and faming sectors, we intend to use MCR-1 (MCRPE) and carbapenem-resistant Enterobacteriaceae (E. coli and E. coli-like bacteria)(CRE) as markers to understand how it has spread throughout the Chinese animal population (colistin is used in animal feed in China). Firstly, we have a comprehensive sampling platform: work package (WP) 1, primary and secondary care infections; WP2, normal flora carriage; WP3, chicken farms and slaughter houses; WP4, retail meat; WP5 Environmental sampling. We will analyze at least 100 samples every 3 months to examine seasonal variation and sample from three distinct provinces in China: Shandong, Zhejiang and Guangdong. 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 all the bacteria in the human gut 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 is likely to withdraw colistin from animal feed 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 so as 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 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, has a proven track record of working together in China and expertise to undertake this exciting and challenging proposal.