美国医院新型革兰氏阴性抗生素需求评估：一项回顾性队列研究。
Needs assessment for novel Gram-negative antibiotics in US hospitals: a retrospective cohort study.
机构信息
Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD, USA; United States Public Health Service Commissioned Corps, Frederick, MD, USA.
Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD, USA.
出版信息
Lancet Infect Dis. 2020 Oct;20(10):1172-1181. doi: 10.1016/S1473-3099(20)30153-5. Epub 2020 Jun 4.
BACKGROUND
Evidence-based needs assessments for novel antibiotics against highly-resistant Gram-negative infections (GNIs) are scarce. We aimed to use real-world data from an electronic health record repository to identify treatment opportunities in US hospitals for GNIs resistant to all first-line drugs.
METHODS
For this retrospective cohort study, population estimates with an unmet need for novel Gram-negative antibiotics were quantified using the Cerner Health Facts database (2009-15), aggregating episodes of infection in US hospitals with pathogens displaying difficult-to-treat resistance (DTR; resistance to carbapenems, other β-lactams, and fluoroquinolones) and episodes involving empirical coverage with reserve drugs (colistin or polymyxin B and aminoglycosides). Episodes displaying extended-spectrum cephalosporin resistance (ECR) were also estimated. Episodes were multiplied by site-specific and fixed 14-day treatment durations for conservative and liberal days-of-therapy (DOT) estimates and stratified by site and taxon. Hospital type-specific DOT rates were reliability adjusted to account for random variation; cluster analyses quantified contribution from outbreaks.
FINDINGS
Across 2 996 271 inpatient encounters and 134 hospitals, there were 1352 DTR-GNI episodes, 1765 episodes involving empirical therapy with colistin or polymyxin B, and 16 632 episodes involving aminoglycosides. Collectively, these yielded 39·0 (conservative estimate) to 138·2 (liberal estimate) DOT per 10 000 encounters for a novel DTR-GNI-targeted drug, whereas greater treatment opportunities were identified for ECR (six times greater) and β-lactam susceptible GNIs (70 times greater). The most common DTR-GNI site and pathogen was lower respiratory (14·3 [43·3%] of 33 DOT per 10 000 encounters) and Pseudomonas aeruginosa (522 [38·1%] of 1371 episodes), whereas Enterobacteriaceae urinary-tract infections dominated the ECR or carbapenem-sparing niche (59·0% [5589 of 9535 episodes]) equating to 210·7 DOT per 10 000 encounters. DTR Stenotrophomonas maltophilia, Burkholderia spp, and Achromobacter spp represented less than 1 DOT per 10 000 encounters each. The estimated need for DTR-GNI-targeted antibiotics saw minor contributions by outbreaks and varied from 0·5 to 73·1 DOT per 10 000 encounters by hospital type.
INTERPRETATION
Suspected or documented GNIs with no or suboptimal treatment options are relatively infrequent. Non-revenue-based strategies and innovative trial designs are probably essential to the development of antibiotics with improved effectiveness for these GNIs.
FUNDING
Center for Drug Evaluation and Research, US Food and Drug Administration; Intramural Research Program, National Institutes of Health Clinical Center and the National Institute of Allergy and Infectious Diseases and the National Cancer Institute.
背景
针对高度耐药革兰氏阴性感染（GNIs）的新型抗生素的循证需求评估很少。我们旨在使用电子健康记录库中的真实世界数据，来确定美国医院中针对所有一线药物耐药的 GNIs 的治疗机会。
方法
在这项回顾性队列研究中，使用 Cerner Health Facts 数据库（2009-15 年）量化了对新型革兰氏阴性抗生素有未满足需求的人群估计数，将美国医院中显示出难以治疗的耐药性（对碳青霉烯类、其他β-内酰胺类和氟喹诺酮类耐药）的感染发作和涉及经验性使用储备药物（粘菌素或多粘菌素 B 和氨基糖苷类）的发作进行了汇总。还估计了具有扩展谱头孢菌素耐药性（ECR）的发作。根据特定地点和固定的 14 天治疗持续时间，对保守和宽松的治疗日（DOT）估计值进行了乘法运算，并按地点和分类群进行了分层。根据医院类型对特定的 DOT 率进行了可靠性调整，以考虑随机变异；聚类分析量化了暴发的贡献。
结果
在 2996271 例住院患者就诊和 134 家医院中，有 1352 例 DTR-GNI 发作、1765 例涉及粘菌素或多粘菌素 B 的经验性治疗以及 16632 例涉及氨基糖苷类药物的发作。总的来说，对于一种新型 DTR-GNI 靶向药物，每 10000 例就诊中产生了 39.0（保守估计）至 138.2（宽松估计）的 DOT，而 ECR（高出 6 倍）和β-内酰胺敏感的 GNIs（高出 70 倍）则有更多的治疗机会。最常见的 DTR-GNI 部位和病原体是下呼吸道（33 个 DOT 中的 14.3 [43.3%]，每 10000 例就诊）和铜绿假单胞菌（333 [38.1%]例），而肠杆菌科尿路感染则主导着 ECR 或碳青霉烯类节约的利基市场（59.0% [5589 例]），相当于每 10000 例就诊中有 210.7 个 DOT。DTR 嗜麦芽窄食单胞菌、伯克霍尔德菌属和产碱杆菌属的每个 DOT 不到 1。对 DTR-GNI 靶向抗生素的需求估计数，由暴发产生的贡献较小，每家医院的 DOT 数量从 0.5 到 73.1 不等。
结论
疑似或确诊的 GNIs 治疗选择不足或不理想的情况相对较少。基于非收入的策略和创新的试验设计可能是为这些 GNIs 开发具有更高疗效的抗生素的必要条件。
资助
美国食品和药物管理局药物评价和研究中心；国立卫生研究院临床中心和国家过敏和传染病研究所及国家癌症研究所的内部研究计划。
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