The use of next generation sequencing to measure the effects of antibiotics on resistance in the host microbiota

使用下一代测序来测量抗生素对宿主微生物群耐药性的影响

• 批准号: MR/M003736/1
• 负责人: Nicola Fawcett
• 金额: $ 29.81万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM003736%2F1
• 关键词: use; next; generation; sequencing; measure

Antimicrobial resistance is increasing worldwide, causing more serious and difficult to treat infections, and is of sufficient severity that the Chief Medical Officer has tabled it to be added to the national risk register. We face a future where infections become untreatable and previously routine procedures such as hip replacements and chemotherapy become too high risk to perform. Resistance is increasing both in the bacteria causing serious infection, but also in the 'good' bacteria in our gut which form part of our 'microbiome' - the community of microorganisms which share our body and are essential for daily function. The gut microbiome forms a reservoir of resistance genes which can be transmitted between different species of bacteria - including disease-causing strains, and cause them to become resistant too. It has been shown that resistance in the gut bacteria is associated with an increased likelihood of developing a resistant infection. Resistant bacteria can be acquired- from food sources (where there is high antibiotic use in farmed meat and aquaculture) from countries of high resistance prevalence (predominantly low-resource countries), and from healthcare institutions. By using antibiotics to treat infection, we are selecting for resistant organisms and increasing antimicrobial resistance.It has been shown that antibiotic use correlates with resistance on a population level, and based on this it is thought that by reducing overall antibiotic use we can reduce resistance. However reduction in antibiotic use has to be achieved safely and without putting patients at undue risk from undertreated infection, and there is not yet robust evidence that a reduction in antibiotic use in this way can provide a reduction in resistance.The long term aim of the project is to develop antibiotic treatment strategies able to reduce the development of resistance. To do this, we need to be able to measure and compare how much a particular antibiotic increases resistance. We also need to be able to understand what other factors lead to resistance. The bacteria colonising the gut are present in large numbers in faecal samples. Due to rapid advances in DNA sequencing technology we are able to measure resistance genes these bacteria by extracting bacterial DNA from faecal samples, and sequencing it in days, rather than months. I propose to pioneer and develop this Next-Generation Sequencing (NGS) technology to detect antibiotic resistance genes in faecal samples (measuring the gut ' resistome'). It has already been used to detect resistance in samples from the Human Microbiome Project, and the pattern of resistance was shown to follow country-wide antibiotic use. I will use it to assess the factors which lead to increased resistance in the gut bacteria, to try and find out where this resistance is being acquired from (food, travel, healthcare institutions). I will also use it to study the association between prior antibiotic use and resistance, including mode of delivery - there is evidence in mouse models that giving antibiotics orally may increase resistance in the gut compared to giving the same dose intravenously. I will then look at the dynamic effect of antibiotics by recruiting patients who will receive antibiotic therapy and analysing multiple faecal samples to see whether resistance returns to prior levels or is maintained. In this project I aim to identify which antibiotic strategies cause the least selection for antimicrobial resistance in the gut. This information will be used by clinicians to choose antibiotic strategies to take to clinical trials to show a reduction in resistance without risking undertreating infection, and to help decide which antibiotics to use to minimise the risk of future resistant infection to patients.

抗菌素耐药性在世界范围内日益增加，导致更严重和更难治疗的感染，其严重性足以使首席医疗官将其列入国家风险登记册。我们面临的未来是，感染变得无法治愈，以前的常规手术，如髋关节置换和化疗变得风险太高，无法进行。耐药性正在增加，不仅在导致严重感染的细菌中，而且在我们肠道中的“好”细菌中也是如此，这些细菌构成了我们的“微生物群”的一部分--微生物群落与我们的身体共享，对日常功能至关重要。肠道微生物组形成了一个耐药性基因储存库，这些基因可以在不同种类的细菌之间传播--包括致病菌株，并导致它们也产生抗药性。已有研究表明，肠道细菌的耐药性与发生耐药性感染的可能性增加有关。抗药性细菌可以从食物来源(在养殖肉类和水产养殖中抗生素使用率高)、来自高耐药性流行国家(主要是低资源国家)以及从卫生保健机构获得。通过使用抗生素治疗感染，我们正在选择耐药微生物并增加抗菌素耐药性。已有研究表明，抗生素的使用与种群水平上的耐药性相关，基于此，人们认为通过减少抗生素的总体使用，我们可以减少耐药性。然而，减少抗生素的使用必须安全地实现，并且不会使患者面临未得到充分治疗的感染的不适当风险，而且目前还没有强有力的证据表明，以这种方式减少抗生素的使用可以减少耐药性的产生。该项目的长期目标是开发能够减少耐药性发展的抗生素治疗策略。要做到这一点，我们需要能够测量和比较一种特定的抗生素增加了多少耐药性。我们还需要能够理解哪些其他因素会导致阻力。肠道中的细菌大量存在于粪便样本中。由于DNA测序技术的快速进步，我们能够通过从粪便样本中提取细菌DNA，并在几天而不是几个月内对其进行测序，来测量这些细菌的耐药性基因。我建议开创和开发这项下一代测序(NGS)技术，以检测粪便样本中的抗生素耐药基因(测量肠道‘抵抗组’)。它已经被用于检测来自人类微生物组计划的样本中的耐药性，并显示出耐药性模式遵循全国范围内使用抗生素的情况。我将用它来评估导致肠道细菌耐药性增加的因素，试图找出这种耐药性是从哪里获得的(食品、旅游、医疗机构)。我还将用它来研究以前使用抗生素和耐药性之间的联系，包括给药方式-在小鼠模型中有证据表明，与静脉注射相同剂量的抗生素相比，口服抗生素可能会增加肠道中的耐药性。然后，我将通过招募将接受抗生素治疗的患者并分析多个粪便样本来观察抗生素的动态效果，以确定抗药性是否恢复到以前的水平或保持下去。在这个项目中，我的目标是确定哪些抗生素策略对肠道中的抗菌素耐药性造成的选择最少。这些信息将被临床医生用来选择用于临床试验的抗生素策略，以在不存在治疗不足的感染风险的情况下显示耐药性的减少，并帮助决定使用哪些抗生素来将患者未来耐药感染的风险降至最低。

项目成果

Additional file 1: of â Caveat emptorâ : the cautionary tale of endocarditis and the potential pitfalls of clinical coding dataâ an electronic health records study

附加文件 1：“买者自负”：心内膜炎的警示故事和临床编码数据的潜在陷阱“电子健康记录研究”

• DOI: 10.6084/m9.figshare.9766277
• 发表时间: 2019
• 作者: Fawcett N

Reducing carbapenem prescribing in high-use settings: it is possible, and it is good to talk.

减少高使用环境中碳青霉烯类药物的处方：这是可能的，而且值得讨论。

• DOI: 10.1007/s11739-018-1959-y
• 发表时间: 2018
• 期刊: Internal and emergency medicine
• 影响因子: 4.6
• 作者: Fawcett NJ

Additional file 2 of Investigation of the impact of the NICE guidelines regarding antibiotic prophylaxis during invasive dental procedures on the incidence of infective endocarditis in England: an electronic health records study

附加文件 2：调查 NICE 指南关于侵入性牙科手术期间抗生素预防对英格兰感染性心内膜炎发病率的影响：一项电子健康记录研究

• DOI: 10.6084/m9.figshare.12062190
• 发表时间: 2020
• 作者: Quan T

Increasing burden of community-acquired pneumonia leading to hospitalisation, 1998-2014.

• DOI: 10.1136/thoraxjnl-2015-207688
• 发表时间: 2016-06
• 期刊: Thorax
• 影响因子: 10
• 作者: Quan TP;Fawcett NJ;Wrightson JM;Finney J;Wyllie D;Jeffery K;Jones N;Shine B;Clarke L;Crook D;Walker AS;Peto TE;Infections in Oxfordshire Research Database (IORD)
• 通讯作者: Infections in Oxfordshire Research Database (IORD)

Bacteria on display-can we, and should we? Artistically exploring the ethics of public engagement with science in microbiology.

• DOI: 10.1093/femsle/fny101
• 发表时间: 2018-06-01
• 期刊: FEMS microbiology letters
• 影响因子: 2.1
• 作者: Fawcett NJ;Dumitriu A
• 通讯作者: Dumitriu A