Canada_IPAP - Impacts of antibiotic usage reduction in farmed animals

抗生素用于预防和治疗人类和动物的细菌感染。抗生素是微生物的天然产物，已经在环境中少量存在了数百万年。因此，一些环境细菌有时间进化出对这些抗生素的耐药性。一旦我们开始使用抗生素治疗感染，我们就引发了一系列事件，导致预先进化的耐药性从环境起源转移到引起疾病的细菌中。这种“流动的”耐药性可以通过细菌种群传播，当这些细菌引起感染时，会导致长期后果。一个例子是CTX-M酶，它使第三代头孢菌素（3GC）抗生素产生耐药性。CTX-M是在30年前被发现的，但现在在英国，它被发现存在于导致约5%人类尿路和血液感染的细菌中。3gcs用于治疗人类和动物的感染。然而，由于它们被认为是人类使用的最高优先级极其重要的抗菌素，因此在英国，它们在农场动物中的使用现在几乎已经停止。这是因为红色拖拉机农场保证计划（95%的英国农场都遵循该计划）在2018年年中引入了关于抗生素使用的新规定。其中一个目标是减少农场动物中3GC耐药细菌的数量，这些细菌可能会传播给人类并导致耐药感染。相比之下，一些抗生素用于治疗农场动物的感染，但从未用于人类（在英国）。大观霉素就是一个例子，它在英国已经被广泛用于治疗绵羊几十年了。目前还没有专门禁止使用大观霉素等“养殖动物专用”抗生素的规定，但在许多国家，养殖中抗生素的使用普遍呈下降趋势。此外，自2021年底以来，大霉素在英国已不再用于治疗绵羊，因为其制造商已将其从销售中撤出。这可能会降低英国羊群中大观霉素耐药性的比率。我们还在引起人类感染的细菌中发现了大观霉素——以及其他养殖动物特有的抗生素耐药性——这表明有一种耐药细菌从养殖动物流向人类。也许现在会开始减少？许多国家正在采取行动减少农业中抗生素的使用。该项目旨在建立英国（布里斯托尔大学）研究人员与加拿大（蒙特利尔大学、圭尔夫大学、卡尔加里大学和爱德华王子岛大学）研究人员之间的伙伴关系，这些研究人员是养殖动物和/或人类抗生素使用和耐药性方面的专家。在加拿大，在省级农业中，监管和行业主导的抗生素使用变化有所不同，但总体而言，使用量下降的轨迹开始晚于英国。我们的伙伴关系将通过各种活动建立，但主要是通过合作研究，旨在了解农业中抗生素使用的减少是否会降低农场的抗生素耐药性水平，以及人类感染。为了做到这一点，我们将利用英国和加拿大的自然实验，这是我们唯一可能进行的，因为我们正在参与大规模的纵向农场抗生素使用和耐药性监测项目，事实上，抗生素的使用在这两个国家正在以不同的速度和微妙的方式减少。很难有效地证明农业中抗生素使用量的减少与农场中细菌的抗生素耐药性之间存在显著关联，更难以证明其对人类的影响。这是因为所有潜在的混杂因素同时发生，也可能降低耐药性。我们合作伙伴关系的价值在于，我们可以汇集尖端的技术专长，从而使这些分析成为可能。

Antibiotics are used to prevent and treat bacterial infections in humans and animals. Antibiotics are natural products of microbes and have been present in the environment in small amounts for millions of years. Some environmental bacteria have therefore had time to evolve resistance to these antibiotics. Once we started using antibiotics to treat infections, we set off a chain of events that has led to pre-evolved resistance moving from its environmental origins into bacteria that cause disease. This "mobile" resistance can spread through bacterial populations, leading to long-term consequences when these bacteria cause infections. One example is the CTX-M enzyme, which gives resistance to 3rd generation cephalosporin (3GC) antibiotics. CTX-M was discovered 30 years ago, but it is now found in bacteria causing about 5% of urinary tract and bloodstream infections in humans in the UK.3GCs are used to treat infections in humans and animals. However, because they are considered Highest Priority Critically Important Antimicrobials for use in humans, their use in farm animals in the UK has now almost stopped. This is because the Red Tractor farm assurance scheme, which is followed by 95% of UK farms, introduced new regulations around antibiotic use in mid 2018. One aim is to reduce the number of 3GC resistant bacteria in farm animals, which might spread to humans and cause resistant infections.Some antibiotics, in contrast, are used to treat infections in farmed animals but never in humans (in the UK). One example is spectinomycin, which has been extensively used to treat sheep in the UK for decades. There are no rules specifically preventing the use of "farmed animal specific" antibiotics like spectinomycin, but in many countries, there is a general downward trend in antibiotic usage in farming. Furthermore, since late 2021, spectinomycin has no longer been available in the UK for treatment of sheep because its manufacturers have withdrawn it from sale. This might be expected to reduce rates of spectinomycin resistance in the UK sheep flock. We also see spectinomycin - and other farmed animal specific antibiotic resistance - in bacteria causing human infections, suggesting that there is a flow of resistant bacteria from farmed animals to humans. Maybe this will now start to reduce?Moves to reduce antibiotic usage in farming are ongoing in many countries. This project aims to build a partnership between UK (University of Bristol) researchers and those in Canada (Universities of Montreal, Guelph, Calgary and Prince Edward Island) who are experts in antibiotic use and resistance in farmed animals, and/or in humans. In Canada, there has been variation in regulatory and industry-led changes to antibiotic usage in farming at provincial level, but generally, a downward trajectory in usage started later than it did in the UK.Our partnership will be built though a variety of activities, but predominantly by collaborative research aiming to understand whether antibiotic usage reduction in farming is driving down antibiotic resistance levels on farms, and also in human infections. To do this, we will take advantage of natural experiments in the UK and Canada that are uniquely possibly for us to undertake, become of our ongoing involvement in large-scale longitudinal farm antibiotic usage and resistance surveillance projects, and the fact that antibiotic usage is being reduced in both countries at different rates and in subtly different ways.It is very difficult to validly demonstrate a significant association between antibiotic usage reduction in farming on antibiotic resistance in bacteria on farms, and even more difficult to show and effect on human populations. This is because of all the potential confounding factors occurring in parallel that might also be driving down resistance. The value of our partnership is that we can pool our cutting edge technical expertise and so make these analysis possible.