本文由小咖机器人翻译整理

期刊来源：Ann Intern Med

原文链接：https://doi.org/10.7326/M23-2309

摘要内容如下：

背景

美国抗生素市场的失败已经威胁到未来的创新和供应。了解临床医生何时以及为何未充分利用最近批准的革兰氏阴性抗生素，可能有助于在未来的抗生素开发和潜在的市场进入回报中优先考虑患者。

客观

确定最近美国食品和药物管理局（FDA）批准的革兰氏阴性抗生素（头孢他啶-阿维巴坦、头孢洛嗪-他唑巴坦、美罗培南-瓦博巴坦、普拉佐米星、依拉环素、亚胺培南-雷利巴坦-西司他丁和头孢地考尔）的使用模式，并确定与其在革兰氏阴性感染患者中优先使用（相对于传统仿制药）相关的因素，这些感染是由于病原体表现出难以治疗的耐药性（DTR；即对所有一线抗生素耐药）。

设计

回顾性队列。

设置

619家美国医院。

参与者

成人住院患者。

测量

使用加权线性回归计算抗生素使用的季度百分比变化。机器学习选择了候选变量，混合模型确定了与DTR感染中新（与传统）抗生素使用相关的因素。

结果

2016年第1季度至2021年第2季度，头孢洛嗪-他唑巴坦（2014年批准）和头孢他啶-阿维巴坦（2015年）在新抗生素使用中占主导地位，而随后批准的革兰氏阴性抗生素的使用相对缓慢。在革兰氏阴性菌感染住院患者中，0.7%（362142例中的2551例[2631次]）显示DTR病原体。在2631例DTR事件中，有1091例（41.5%）仅使用传统药物治疗，其中865例（79.3%）使用“储备”抗生素，如多粘菌素、氨基糖苷类和替加环素。患有菌血症和慢性疾病的患者有较高的校正概率，而患有不复苏状态、急性肝衰竭、鲍曼不动杆菌复合群和其他非假单胞菌非发酵菌病原体的患者分别接受较新（相对于传统）抗生素治疗DTR感染的校正概率较低。新抗生素药敏试验的可用性增加了使用的可能性。

局限性

残余混杂。

结论

尽管FDA在2014年至2019年间批准了7种新一代革兰氏阴性菌抗生素，但临床医生仍经常使用安全性和疗效欠佳的较老的非专利抗生素来治疗耐药的革兰氏阴性菌感染。未来的抗生素具有针对未开发的病原体小生境的创新机制、广泛可用的药敏试验以及证明耐药感染结果改善的证据，可能会提高利用率。

主要资金来源

美国食品和药物管理局；NIH内部研究计划。

英文原文如下：

Abstracts

BACKGROUND  The U.S. antibiotic market failure has threatened future innovation and supply. Understanding when and why clinicians underutilize recently approved gram-negative antibiotics might help prioritize the patient in future antibiotic development and potential market entry rewards.

OBJECTIVE  To determine use patterns of recently U.S. Food and Drug Administration (FDA)-approved gram-negative antibiotics (ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, plazomicin, eravacycline, imipenem-relebactam-cilastatin, and cefiderocol) and identify factors associated with their preferential use (over traditional generic agents) in patients with gram-negative infections due to pathogens displaying difficult-to-treat resistance (DTR; that is, resistance to all first-line antibiotics).

DESIGN  Retrospective cohort.

SETTING  619 U.S. hospitals.

PARTICIPANTS  Adult inpatients.

MEASUREMENTS  Quarterly percentage change in antibiotic use was calculated using weighted linear regression. Machine learning selected candidate variables, and mixed models identified factors associated with new (vs. traditional) antibiotic use in DTR infections.

RESULTS  Between quarter 1 of 2016 and quarter 2 of 2021, ceftolozane-tazobactam (approved 2014) and ceftazidime-avibactam (2015) predominated new antibiotic usage whereas subsequently approved gram-negative antibiotics saw relatively sluggish uptake. Among gram-negative infection hospitalizations, 0.7% (2551 [2631 episodes] of 362 142) displayed DTR pathogens. Patients were treated exclusively using traditional agents in 1091 of 2631 DTR episodes (41.5%), including "reserve" antibiotics such as polymyxins, aminoglycosides, and tigecycline in 865 of 1091 episodes (79.3%). Patients with bacteremia and chronic diseases had greater adjusted probabilities and those with do-not-resuscitate status, acute liver failure, and Acinetobacter baumannii complex and other nonpseudomonal nonfermenter pathogens had lower adjusted probabilities of receiving newer (vs. traditional) antibiotics for DTR infections, respectively. Availability of susceptibility testing for new antibiotics increased probability of usage.

LIMITATION  Residual confounding.

CONCLUSION  Despite FDA approval of 7 next-generation gram-negative antibiotics between 2014 and 2019, clinicians still frequently treat resistant gram-negative infections with older, generic antibiotics with suboptimal safety-efficacy profiles. Future antibiotics with innovative mechanisms targeting untapped pathogen niches, widely available susceptibility testing, and evidence demonstrating improved outcomes in resistant infections might enhance utilization.

PRIMARY FUNDING SOURCE  U.S. Food and Drug Administration; NIH Intramural Research Program.

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