抗菌素耐药性(AMR)是一个世界性的问题,这推动了更多的临床前研究,以寻找耐药细菌的新治疗方法和对策。然而,临床前空间的转化模型多年来一直保持不变。为了提高动物使用的伦理考虑,我们评估了评估ESKAPEE病原体致死性感染后生存率的新方法(屎肠球菌,金黄色葡萄球菌,肺炎克雷伯菌,鲍曼不动杆菌,铜绿假单胞菌,阴沟肠杆菌,和大肠杆菌)在肺部感染模型中。与经常用于新型抗菌药物开发的已发表的肺部感染模型一致,用环磷酰胺对BALB/c小鼠进行免疫抑制,并用个别ESKAPEE病原体或无菌盐水鼻内接种。以频繁的间隔记录观察结果,以确定人道终点决策的预测阈值。通过植入的IPTT300微芯片测量内部温度,外部温度是使用非接触式测量的,红外测温仪.此外,根据动物外观评估临床评分,行为,水合状态,呼吸,和体重。对于屎肠球菌,幸存者和非幸存者之间的内部温度差异具有统计学意义。金黄色葡萄球菌,肺炎克雷伯菌,A.鲍曼尼,阴沟,和大肠杆菌,金黄色葡萄球菌的外部温度差异具有统计学意义,肺炎克雷伯菌,阴沟,和大肠杆菌。与外部温度相比,内部温度更准确地预测死亡率,这表明85ºF(29.4ºC)的阈值对死亡率的预测率为86.0%,对生存的预测率为98.7%。根据我们的发现,我们建议未来涉及BALB/c小鼠ESKAPEE病原体感染的研究使用体温监测作为人道终点阈值.
Antimicrobial resistance (AMR) is a worldwide problem, which is driving more preclinical research to find new treatments and countermeasures for drug-resistant bacteria. However, translational models in the preclinical space have remained static for years. To improve animal use ethical considerations, we assessed novel methods to evaluate survival after lethal infection with ESKAPEE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter cloacae, and Escherichia coli) in pulmonary models of infection. Consistent with published lung infection models often used for novel antimicrobial development, BALB/c mice were immunosuppressed with cyclophosphamide and inoculated intranasally with individual ESKAPEE pathogens or sterile saline. Observations were recorded at frequent intervals to determine predictive thresholds for humane endpoint decision-making. Internal temperature was measured via implanted IPTT300 microchips, and external temperature was measured using a non-contact, infrared thermometer. Additionally, clinical scores were evaluated based on animal appearance, behaviour, hydration status, respiration, and body weight. Internal temperature differences between survivors and non-survivors were statistically significant for E. faecium, S. aureus, K. pneumoniae, A. baumannii, E. cloacae, and E. coli, and external temperature differences were statistically significant for S. aureus, K. pneumoniae, E. cloacae, and E. coli. Internal temperature more precisely predicted mortality compared to external temperature, indicating that a threshold of 85ºF (29.4ºC) was 86.0% predictive of mortality and 98.7% predictive of survival. Based on our findings, we recommend future studies involving BALB/c mice ESKAPEE pathogen infection use temperature monitoring as a humane endpoint threshold.