Big Data- Epidemiology of Antimicrobial Resistance

共耐药导致需要使用疗效较低或毒性相对较强的储备抗生素（氨基糖苷类、替加环素和粘菌素/多粘菌素B）可能会使生存率恶化。我们使用美国医院的大型临床数据库，研究了革兰氏阴性血流感染（GNBSI）中的难治性耐药（DTR），定义为对所有一线药物（碳青霉烯类、β-内酰胺类和氟喹诺酮类（FQ））均不敏感。我们发现，抗微生物耐药GNBSI患者的生存率高度依赖于是否存在活性一线药物选择; DTR将治疗选择限制在储备药物，包括氨基糖苷类药物，这些药物远非普遍有效。DTR在GNBSI中仍然不常见（1%），但在接受检查的一半医院和美国所有地区都发生了DTR。这项工作已经在美国传染病学会和重症监护医学学会的年会上发表。我们继续使用Cerner Health电子健康记录事实库验证我们的发现。 作为NIH抗菌素耐药性成果研究计划（NIH-ARORI）的一部分，我们还继续研究了新兴抗生素的前景，以了解它们的实际使用和需求。我们发现，头孢他啶-阿维巴坦的使用增加了数倍，取代了粘菌素的使用，但总体使用仍然适度。作为FDA资助的一项计划的一部分，我们确定美国医院中难以治疗的抗生素耐药病原体的治疗机会仍然很小，这表明可能需要非收入策略来维持抗生素开发。 作为部分由FDA资助的工作的一部分，我们对两种关键病原体抗生素组合的最低抑菌浓度和结果之间的关系进行了分析，以确定标准制定组织为这些组合设定的现有断点是否值得修订。我们还进行了一项研究，以确定针对DTR病原体的新型抗生素的住院使用情况，并了解其他未来新型抗生素的当前剩余市场规模。这份手稿正在一家期刊上接受审查。我们相信这项工作将为正在进行的努力提供信息，以证实非收入为基础的战略，以维持抗生素开发行业。 作为美国国立卫生研究院抗菌药物耐药性结果研究计划（NIH-ARORI）的一部分，我们确定，在美国医院中，每五名血流感染患者中就有一名接受与体外耐药性不一致的经验性抗生素治疗。这种做法很普遍，在不同类型的医院中也很相似。菌血症患者接受体外不一致的经验性治疗显示出较高的死亡风险比接受一致的治疗。S.金黄色葡萄球菌和肠球菌目的病原体及其耐药表型是体外不一致疗法的绝大多数负担和影响，阻碍了有效的快速床旁诊断的开发和广泛实施，特别是那些靶向这些病原体及其耐药表型的诊断。我们还进行了一项研究，比较甲氧苄啶磺胺甲恶唑与左氧氟沙星对嗜麦芽窄食单胞菌感染的临床有效性，发现两者的表现相对稳定，这表明未来的试验比较这些药物是平衡的。我们还研究了ICU发病BSI的患病率、病原体的分布及其抗生素耐药表型，并确定了获得这些感染的风险因素。我们发现，ICU发病的BSI代表严重感染，显示出独特的病原体和耐药谱相比，BSI，需要入住ICU。 我们与哈佛人口医学系的研究人员合作，使用了来自100多家美国医院的更大的电子健康记录数据，并确定尽管广泛使用广谱经验性抗生素治疗社区发病的脓毒症，但抗生素耐药病原体的患病率很小。针对耐药表型的快速诊断可能在增强脓毒症的抗生素管理方面发挥作用。

Co-resistance necessitating use of less effective or relatively toxic reserve antibiotics (aminoglycosides, tigecycline and colistin/polymyxin B) may worsen survival. We investigated difficult-to-treat resistance (DTR) in gram-negative bloodstream infections (GNBSIs) defined by absence of susceptibility to all first-line agents (carbapenems, beta-lactams and fluoroquinolones (FQ) using a large clinical database of US hospitals. We found that survival in antimicrobial-resistant GNBSI is highly contingent on presence of active first-line option(s); DTR limits treatment options to reserve agents, including aminoglycosides, which are far from universally active. DTR remained infrequent (1%) among GNBSI, but occurred at half of the hospitals examined and across all US regions. This work has been presented at the Annual Meetings of the Infectious Diseases Society of America and Society of Critical Care Medicine.We went on to validate our findings using the Cerner Health facts repository of electronic health records. As part of the NIH Antimicrobial Resistance Outcomes Research Initiative (NIH-ARORI), we also went on to study the landscape of emerging antibiotics to understand their real-world use and demand. We found that ceftazidime-avibactam use increased several fold replacing colistin use, however overall use was still modest. As part of an FDA-funded initiative, we determined that treatment opportunities for difficult-to-treat antibiotic resistant pathogens in US hospitals remain small, suggesting that non-revenue based strategies might be necessary to sustain antibiotic development. As part of work that is funded in part by the FDA, we conducted analyses on the relationship between minimum inhibitory concentration and outcomes for two key pathogen antibiotic combinations to determine whether existing breakpoints for those combinations set by standards development organizations warrant revision. We also conducted a study to determine the inpatient utilization of novel antibiotics against DTR pathogens as well as understand the current residual market size for other future novel antibiotics. This manuscript is under review at a journal. We believe this work will inform ongoing efforts to substantiate non revenue based strategies to sustain the antibiotic development industry. As part of the NIH Antimicrobial Resistance Outcomes Research Initiative (NIH-ARORI), we determined that one in every five patients with bloodstream infection in US hospitals receives empiric antibiotic therapy that is discordant with in vitro susceptibilities. This practice was prevalent and similar across hospital types. Bacteremic patients who received in vitro-discordant empiric therapy displayed a higher mortality risk than recipients of concordant therapy. S. aureus and Enterobacterales and their resistance phenotypes account for the overwhelming majority of burden and impact of in vitro-discordant therapy, warranting development and wide implementation of effective rapid point-of-care diagnostics, especially those targeting these pathogens and their resistance phenotypes. We also conducted a study to compare the clinical effectiveness of trimethoprim sulfamethoxazole versus levofloxacin for Stenotrophomonas maltophilia infections and found that both performed relatively comparably, suggesting there is equipoise for a future trial comparing these agents. We also studied the prevalence of ICU-onset BSI, the distribution of pathogens and their antibiotic resistance phenotypes and determined risk factors for the acquisition of these infections. We found that ICU-onset BSI represent serious infection that display a unique pathogen and resistance profile compared to BSI that necessitates admission to the ICU. In collaboration with the investigators at the Harvard Department of Population Medicine, we used larger electronic health record data from over a hundred U.S. hospitals and determined that despite the extensive use of broad-spectrum empiric antibiotic therapy for community-onset sepsis, the prevalence of antibiotic resistant pathogens warranting such therapy is small. Rapid diagnostics targeting resistance phenotypes may have a role in enhancing antibiotic stewardship in sepsis.