Big Data- Epidemiology of Antimicrobial Resistance

共同耐药需要使用效果较差或相对毒性较高的备用抗生素(氨基糖苷类、替加环素和粘菌素/多粘菌素B)，可能会恶化存活率。我们使用美国医院的大型临床数据库调查了革兰氏阴性血流感染(GNBSI)中的难治耐药性(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))不敏感。我们发现，耐药GNBSI的存活率高度取决于是否存在有效的一线选择(S)；DTR将治疗选择限制为储备药物，包括氨基糖苷类药物，这些药物远未普遍有效。DTR在GNBSI中仍然很少见(1%)，但在接受检查的一半医院和美国所有地区发生。这项工作已经在美国传染病学会和重症护理医学会的年度会议上发表。我们继续使用Cerner健康事实电子健康记录储存库来验证我们的发现。 作为NIH抗菌素耐药性结果研究倡议(NIH-ARORI)的一部分，我们还继续研究了新兴抗生素的情况，以了解它们在现实世界中的使用和需求。我们发现，头孢他啶-阿巴坦的使用量比粘菌素的使用量增加了几倍，但总体使用量仍然不大。作为FDA资助的一项倡议的一部分，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，这表明可能有必要采取非营收战略来维持抗生素的开发。 作为FDA部分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与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需要修改。我们还进行了一项研究，以确定住院患者对DTR病原体的新型抗生素的使用情况，并了解其他未来新型抗生素目前的剩余市场规模。这份手稿正在一家期刊上审阅。我们相信，这项工作将为正在进行的努力提供信息，以证实维持抗生素开发行业的非营收战略。 作为NIH抗菌素耐药性结果研究倡议(NIH-ARORI)的一部分，我们确定，美国医院每五名血液感染患者中就有一人接受与体外敏感性不一致的经验性抗生素治疗。这种做法在不同类型的医院中很普遍，也很相似。接受体外非协调性经验性治疗的菌血症患者显示出比接受协调性治疗的患者更高的死亡风险。金黄色葡萄球菌和肠杆菌属及其耐药表型是体外非协调性治疗的绝大多数负担和影响因素，需要开发和广泛实施有效的快速医疗点诊断方法，特别是针对这些病原体及其耐药表型的诊断方法。我们还进行了一项研究，比较了甲氧嘧啶磺胺甲恶唑和左氧氟沙星治疗嗜麦芽窄食单胞菌感染的临床疗效，发现两者的表现相对相似，这表明未来可以进行一项比较这两种药物的试验。我们还研究了ICU发病的BSI的患病率、病原体的分布及其耐药性表型，并确定了这些感染的危险因素。我们发现，与需要进入ICU的BSI相比，ICU发病的BSI代表严重感染，表现出独特的病原体和耐药性特征。 与哈佛大学人口医学部的研究人员合作，我们使用了来自100多家美国医院的更大的电子健康记录数据，并确定尽管广谱经验性抗生素疗法被广泛用于社区发作性脓毒症，但需要这种疗法的抗生素耐药病原体的流行率很低。针对耐药表型的快速诊断可能在加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.