Antibiotic efficacy varies based on the infection model and treatment regimen for Pseudomonas aeruginosa
Antibiotic efficacy varies based on the infection model and treatment regimen for Pseudomonas aeruginosa
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DOI：
10.1183/13993003.02456-2018
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发表时间：
2020-03-01
影响因子：
24.3
通讯作者：
Bragonzi, Alessandra
中科院分区：
文献类型：
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作者：
Cigana, Cristina;Ranucci, Serena;Bragonzi, Alessandra
需要抗生素的发现和临床前的测试来对抗铜绿假单胞菌的健康威胁。最常见的是，抗生素的有效性是在急性呼吸道感染的模型中测试的，而慢性肺炎在很大程度上仍未被探索。这种方法引起了对慢性感染患者的治疗评估的严重关注，并强调了模拟人类疾病过程的动物模型的必要性。在本研究中，市场上销售的抗菌药物妥布霉素(TOB)和粘菌素(COL)在急性和慢性铜绿假单胞菌肺部感染的小鼠模型上进行了疗效测试。不同的给药途径(鼻腔、气雾剂或皮下注射)和治疗方案(感染后不久或7天)进行了测试。在急性感染模型中，TOB气雾剂和皮下给药减少了细菌负荷和炎症反应，而鼻内治疗效果不佳。COL降低细菌负担的效果较差，但抑制了炎症。在慢性感染后不久的7天内，每天使用气雾剂或皮下注射TOB的小鼠比使用赋形剂的小鼠表现出更高、更快的体重恢复，并减少了细菌负荷和炎症。接受COL治疗的小鼠体重没有改善，炎症也没有变化。只有使用气雾剂Col时，细菌负荷才有适度的减少。当慢性感染的治疗在感染后7天开始时，TOB和COL都不能减轻铜绿假单胞菌的负担和炎症，也不能帮助体重恢复。我们的研究结果表明，应该根据感染的类型仔细选择动物模型和治疗方案来评估抗生素的疗效。
Antibiotic discovery and preclinical testing are needed to combat the Pseudomonas aeruginosa health threat. Most frequently, antibiotic efficacy is tested in models of acute respiratory infection, with chronic pneumonia remaining largely unexplored. This approach generates serious concerns about the evaluation of treatment for chronically infected patients, and highlights the need for animal models that mimic the course of human disease.In this study, the efficacy of the marketed antibacterial drugs tobramycin (TOB) and colistin (COL) was tested in murine models of acute and chronic P. aeruginosa pulmonary infection. Different administration routes (intranasal, aerosol or subcutaneous) and treatment schedules (soon or 7 days post-infection) were tested.In the acute infection model, aerosol and subcutaneous administration of TOB reduced the bacterial burden and inflammatory response, while intranasal treatment showed modest efficacy. COL reduced the bacterial burden less effectively but dampened inflammation. Mice treated soon after chronic infection for 7 days with daily aerosol or subcutaneous administration of TOB showed higher and more rapid body weight recovery and reduced bacterial burden and inflammation than vehicle-treated mice. COL-treated mice showed no improvement in body weight or change in inflammation. Modest bacterial burden reduction was recorded only with aerosol COL administration. When treatment for chronic infection was commenced 7 days after infection, both TOB and COL failed to reduce P. aeruginosa burden and inflammation, or aid in recovery of body weight.Our findings suggest that the animal model and treatment regimen should be carefully chosen based on the type of infection to assess antibiotic efficacy.