Office of Biodefense, Research Resources and Translational Research , Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, Rockville, Maryland, USA.
Office of Regulatory Affairs, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, Rockville, Maryland, USA.
Clin Infect Dis. 2020 May 21;70(70 Suppl 1):S51-S59. doi: 10.1093/cid/ciz1233.
Additional treatment options for pneumonic plague, the most severe form of infection by Yersinia pestis, are needed, as past US Food and Drug Administration (FDA) approvals were not based on clinical trials that meet today's standards, and multiple drugs are sought to counter resistance or use in special populations. Due to the sporadic nature of outbreaks and the low number of pneumonic cases of disease, we sought FDA approval of antimicrobials for treatment under the Animal Efficacy Rule, where efficacy can be demonstrated in 1 or more well-characterized animal models that sufficiently represent human disease.
A model was developed in African green monkeys (AGMs) after challenge with a lethal dose of Y. pestis delivered as an aerosol, in 4 independent studies in 3 laboratories. The primary data points were bacteremia (daily), body temperature and heart rate (continuously monitored by telemetry), and survival. In antimicrobial efficacy studies, human-equivalent doses of gentamicin, ciprofloxacin, levofloxacin, and doxycycline were administered upon fever onset for 10 days.
Disease in AGMs was similar to case reports of human disease. Fever was determined to be a reliable sign of disease and selected as a treatment trigger. Gentamicin was 60%-80% effective depending on the dose given to animals. Ciprofloxacin and levofloxacin were found to be >90% efficacious. These data were submitted to FDA and plague indications were approved. Doxycycline was less effective.
The AGM model of pneumonic plague is reproducible, well-characterized, and mimics human disease. It has been used to support plague indications for fluoroquinolones and to test the efficacy of additional antimicrobials.
需要为肺鼠疫（鼠疫耶尔森菌感染的最严重形式）提供额外的治疗选择，因为过去美国食品和药物管理局（FDA）的批准并非基于符合当今标准的临床试验，并且需要多种药物来对抗耐药性或用于特殊人群。由于暴发的偶发性和疾病的肺鼠疫病例数量较少，我们根据《动物疗效法规》寻求 FDA 批准用于治疗的抗菌药物，其中可以在 1 个或多个充分代表人类疾病的特征明确的动物模型中证明疗效。
在 3 个实验室的 4 项独立研究中，用气溶胶方式向非洲绿猴（AGM）中接种致死剂量的鼠疫耶尔森菌后，建立了一个模型。主要数据点是菌血症（每日）、体温和心率（通过遥测连续监测）以及存活率。在抗菌药物疗效研究中，在发热时给予相当于人体剂量的庆大霉素、环丙沙星、左氧氟沙星和多西环素，持续 10 天。
AGM 中的疾病与人类疾病的病例报告相似。发热被确定为疾病的可靠迹象，并被选为治疗触发因素。庆大霉素的有效率为 60%-80%，具体取决于给予动物的剂量。环丙沙星和左氧氟沙星的有效率均>90%。这些数据已提交给 FDA，并批准了鼠疫的适应证。多西环素的疗效较差。
肺鼠疫的 AGM 模型是可重复的、特征明确的，并且模拟了人类疾病。它已被用于支持氟喹诺酮类药物的鼠疫适应证，并测试了其他抗菌药物的疗效。
