Antimicrobial resistant E. coli before and after California Senate bill 27 (ARES): a natural experiment

摘要 过度使用抗生素会导致抗菌素耐药性（AMR），对人类健康构成日益严重的威胁。 国际吧在美国，工业化食用动物生产（IFAP）是抗生素使用的强大驱动力。七十 %的抗生素用于牲畜，包括四环素，庆大霉素和第三代抗生素。 头孢菌素（3GC）。为了减少AMR和人口健康影响，从1月1日开始， 2018年，加州参议院第27号法案（SB 27）将禁止在牲畜中使用所有非治疗性抗菌剂（包括 生长促进和常规疾病预防），并需要兽医处方进行治疗 迹象。我们将量化该立法对AMR E的影响。杆菌 E.大肠杆菌是评估抗菌药物使用变化的理想病原体， AMR与畜牧生产有关，因为（1）E.在牲畜和人类中传播的大肠杆菌 （2）肠外致病性E.大肠杆菌是导致人类UTI的主要原因， 每年10 - 20亿美元。我们计划在自然实验中使用从分子到种群水平的数据- 我们要实现三个具体目标。在目标1中，我们将使用全基因组测序和抗菌素- 敏感性测试，以表征抗性基因、表型和E.从零售店分离的大肠杆菌种群 鸡肉和UTI。我们假设，受污染的零售肉类产品有助于负担， AMR E.大肠杆菌UTI。在目标2中，我们将利用纵向（2015-2021）电子健康记录 零售鸡肉和人体E. 大肠杆菌尿路感染（UTIs）。 （EHR）对700多万名门诊患者进行了10万次E.加州两个主要的健康中心 系统来估计四环素，庆大霉素，和3GC耐药的比例的纵向变化。 从零售鸡肉中分离的大肠杆菌和实验室确认的大肠杆菌。大肠杆菌UTI实施前后 的SB 27。我们还将采用综合控制统计分析来估计SB 27对以下方面的因果影响： 零售鸡肉和大肠杆菌的AMR趋势。coli UTI。我们预计，SB 27的颁布将与 降低E.从零售鸡肉及人类泌尿道感染个案中分离的大肠杆菌。在目标3中，我们 利用电子健康记录中的患者地址和全民信息计划位置数据进行空间分析。我们假设- 或SB 27，居民接近IFAP将是四环素，庆大霉素和3GC耐药E. coli UTI; SB 27后，这种风险将降低。这种方法是创新的，因为它使用了一种准实验性的方法。 设计围绕着美国第一个政策规定的减少牲畜抗菌剂使用。成果 这项工作将为连接食品系统和UTI的证据基础做出重大贡献，并将 确定这种州一级的立法干预是否会影响零售肉类和人类UTI的AMR趋势， 在美国各地实施类似政策的决策。

ABSTRACT Overuse of antibiotics contributes to antimicrobial resistance (AMR) and is a growing threat to human health worldwide. In the U.S., industrial food animal production (IFAP) is a powerful driver of antibiotic use. Seventy percent of antibiotics are sold for use in livestock, including tetracycline, gentamicin, and third-generation cephalosporins (3GC). In an attempt to reduce AMR and population health impacts, beginning January 1, 2018, California's Senate Bill 27 (SB27) will ban all non-therapeutic uses of antimicrobials in livestock (includ- ing growth promotion and routine disease prevention) and require a veterinarian's prescription for therapeutic indications. We will quantify the effect of this legislation on AMR E. coli E. coli is an ideal pathogen for evaluating changes in antimicrobial use and AMR related to livestock production because (1) AMR profiles of E. coli circulating in livestock and humans overlap; and (2) extraintestinal pathogenic E. coli are a leading cause of human UTI, which cost Americans $1-2 billion annually. We plan to use data ranging from the molecular to the population level in a natural exper- iment to address three specific aims. In Aim 1, we will use whole genome sequencing and antimicrobial sus- ceptibility testing to characterize resistance genes, phenotypes, and E. coli populations isolated from retail chicken meat and UTI. We hypothesize that contaminated retail meat products contribute to the burden of AMR E. coli UTI in humans. In Aim 2, we will leverage longitudinal (2015-2021) electronic health records on retail chicken meat and human E. coli urinary tract infections (UTIs). (EHRs) on more than 7 million outpatients with 100,000 E. coli UTIs per year from two major California health systems to estimate longitudinal changes in the proportion of tetracycline-, gentamicin-, and 3GC-resistant E. coli isolated from retail chicken meat and laboratory-confirmed E. coli UTI before and after the implementation of SB27. We will also employ synthetic control statistical analyses to estimate the causal effect of SB27 on AMR trends in retail chicken meat and E. coli UTI. We anticipate that the enactment of SB27 will be associated with reductions in AMR of E. coli isolated from retail chicken meat and human UTI cases. In Aim 3, we will conduct spatial analyses using patient addresses from EHRs and IFAP location data. We hypothesize that pri- or to SB27, residential proximity to IFAP will be a risk factor for tetracycline-, gentamicin-, and 3GC-resistant E. coli UTI; after SB27, this risk will be reduced. The approach is innovative because it uses a quasi-experimental design built around a first-in-the U.S. policy-mandated reduction in livestock antimicrobial use. Results of this work will make a significant contribution to the evidence base connecting food systems and UTI and will de- termine if this state-level legislative intervention affects AMR trends in retail meat and human UTIs, informing decision-making about implementation of similar policies across the U.S.