Acquisition and Selection of Antibiotic Resistance in Companion and Farmed Animals and Implications for Transmission to Humans

如果没有抗微生物药物，细菌感染的风险将使许多常见的医疗程序过于危险，因为“机会性细菌”引起的感染风险。它们可以生活在病人的皮肤上，或者在他们的肠道里，当细菌进入正常无菌的身体部位时，就会发生感染。一个很好的例子是由粪便细菌引起的尿路感染（UTI）。E.大肠杆菌在人类粪便中特别丰富，因此是引起机会性感染的最佳场所。它是英国医疗保健肺炎、手术部位感染、血液感染和尿路感染的最常见原因之一。为了预防和治疗机会性感染，患者需要服用抗菌药物。几乎所有的抗菌药物都是“抗生素”，这意味着它们来自环境中发现的微生物产生的天然化学物质。天然抗生素已经在环境中存在了数百万年，因此生活在它们存在下的细菌有时间进化出可以抵抗它们的作用的机制，由“抗性基因”编码。寄生菌如E.大肠杆菌可以随机获得这些预先进化的抗性基因，并且在一个步骤中，它们变得对特定的抗菌剂不敏感。如果那个不敏感的E.大肠杆菌在人体内定植，然后引起机会性感染，这种感染不能用这种特定的抗菌剂治疗。我们称之为“抗菌素耐药性”（AMR）;然而AMR细菌不仅能抵抗临床抗菌治疗，而且还能战胜它。大肠杆菌，经常用抗菌剂治疗。这可以选择用于AMR E的获取。大肠杆菌，然后可以直接或通过粪便污染环境传给另一种动物。理论上，AMR E.大肠杆菌也可以传染给人，关于这种“人畜共患病的传播”是否在任何显著程度上发生，还有很多争论。这是一个重要的争论，因为它导致一些人呼吁大幅减少给予动物的抗菌药物的量，认为这将降低动物体内的AMR水平，从而降低人畜共患病传播给人类的可能性。但是对福利和食品生产的潜在影响意味着只有在有证据表明它有效的情况下才应该这样做。大肠杆菌为例菌，奶牛和狗为例养殖和伴侣动物。我们将测试动物在与环境相互作用时遇到的AMR细菌是否影响其粪便中的AMR特征，和/或早期使用抗菌剂是否在动物中选择AMR细菌中发挥作用。我们还将测试减少奶牛抗菌药物的使用是否真的会减少被奶牛粪便污染的农场附近环境中的AMR。我们将测试在这些受污染的农场附近环境中锻炼是否会影响狗体内AMR细菌的丰度，以及是否有任何直接获得AMR E的证据。最后，我们将调查人类UTI E中AMR丰度是否高于人类UTI E。大肠杆菌减少抗菌药物处方减少在初级保健;是否生活在农场附近会影响UTI E中AMR丰度。大肠杆菌;是否有直接证据表明大肠杆菌。这些交叉研究将提供有关可能减少动物和人类AMR的管理变化的急需数据，并旨在解决以下基本问题：相对于医生使用的抗菌药物，人畜共患病传播是否是人类AMR的驱动因素。

Without antimicrobial drugs, the risk of bacterial infection would render many common medical procedures too dangerous to contemplate because of the risk of infections caused by "opportunistic bacteria". They can live on the patient's skin, or in their intestines, and infection occurs when bacteria get into parts of the body that are normally sterile. A perfect example is urinary tract infection (UTI) caused by faecal bacteria. E. coli is particularly abundant in human faeces so is perfectly placed to cause opportunistic infections. It is one of the most common causes of healthcare pneumonia, surgical site infection, bloodstream infection and UTI in the UK. In order to prevent against and treat opportunistic infections, patients are given antimicrobials.Almost all antimicrobials are "antibiotics", which means they are derived from natural chemicals produced by microbes found in the environment. Natural antibiotics have been present in the environment for millions of years, and so bacteria living in their presence have had time to evolve mechanisms that can resist their actions, encoded by "resistance genes". Opportunistic bacteria like E. coli can randomly acquire these pre-evolved resistance genes and in a single step, they become insusceptible to a particular antimicrobial. If that insusceptible E. coli colonises a person and then causes an opportunistic infection, the infection will not be treatable with that particular antimicrobial. We refer to this as "antimicrobial resistance" (AMR); however AMR bacteria don't just resist clinical antimicrobial therapy, they beat it.Animals also carry an abundance of E. coli in their intestines and are frequently treated with antimicrobials. This can select for the acquisition of AMR E. coli which can then be passed on to another animals, directly, or via contamination of the environment with faeces. Theoretically, the AMR E. coli could also be passed on to people, and there is much debate about whether such "zoonotic transmission" happens to any significant degree. This is an important debate because it has led to calls from some to dramatically reduce the amount of antimicrobials that are given to animals with the view that it will reduce the level of AMR in animals, and so the possibility of zoonotic transmission to people. But the potential impact on welfare and food production means this should only be done if there is evidence that it will work.In this project we will identify what drives acquisition of AMR in animals using E. coli as the exemplar bacterium and dairy cows and dogs as exemplar farmed and companion animals. We will test whether AMR bacteria encountered by an animal as it interacts with the environment influence the AMR profile in its faeces, and/or whether early life antimicrobial use plays a part in selection of AMR bacteria in animals. We will also test whether reducing antimicrobial use in dairy cows actually does reduce AMR in the near-farm environment that is contaminated with their faeces. We will test whether exercising in these contaminated near-farm environments influences the abundance of AMR bacteria in dogs, and whether there is any evidence of direct acquisition of AMR E. coli by dogs from near-farm environments, which might be brought into the home.Finally, we will investigate whether AMR abundance in human UTI E. coli reduces as antimicrobial drug prescribing reduces in primary care; whether living close to a farm affects AMR abundance in UTI E. coli; whether there is direct evidence for E. coli carried by dogs or found in near-farm environments contaminated by cattle faeces also causing UTIs in humans.These interlaced studies will provide much needed data about the management changes that might reduce AMR in animals and in humans, and are designed to address the fundamental question of whether zoonotic transmission is particularly significant as a driver of AMR in people relative to antimicrobial drug use by doctors.