Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, 751 85, Uppsala, SE, Sweden.
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
Crit Care. 2020 Nov 14;24(1):646. doi: 10.1186/s13054-020-03303-9.
Sepsis is often treated with penicillin-binding protein 3 (PBP-3) acting β-lactam antibiotics, such as piperacillin-tazobactam, cefotaxime, and meropenem. They cause considerable bacterial structural changes and have in vitro been associated with an increased inflammatory response. In a clinically relevant large animal sepsis model, our primary aim was to investigate whether bacteria killed by a PBP-3-active antibiotic has a greater effect on the early inflammatory response and organ dysfunction compared with corresponding amounts of live or heat-killed bacteria. A secondary aim was to determine whether the addition of an aminoglycoside could mitigate the cefuroxime-induced response.
Killed or live Escherichia coli were administrated as a 3-h infusion to 16 healthy pigs in a prospective, randomized controlled interventional experimental study. Cefuroxime was chosen as the PBP-3-active antibiotic and tobramycin represented the aminoglycosides. The animals were randomized to receive (I) bacteria killed by cefuroxime, (II) live bacteria, (III) bacteria killed by heat, or (IV) bacteria killed by the combination of cefuroxime and tobramycin. Plasma endotoxin, tumor necrosis factor alpha, interleukin-6, interleukin-10, leukocytes, and organ function were recorded at the start of the experiment and then hourly for 6 h.
Differences in dynamics of concentration over time between the four treatment groups were found for the three cytokines (p < 0.001). Animals receiving cefuroxime-killed bacteria demonstrated higher responses than those receiving live (p < 0.05) or heat-killed bacteria (p < 0.01). The addition of tobramycin reduced the cefuroxime-induced responses (p < 0.001). The cytokine responses were associated with leucocyte activation that was further associated with pulmonary dysfunction and increases in lactate (p < 0.01).
In comparison with live or heat-killed bacteria, bacteria killed by a PBP-3-active antibiotic induced an increased inflammatory response that appears to be associated with deteriorated organ and cellular function. The addition of an aminoglycoside to the PBP-3-active antibiotic reduced that response.
脓毒症常使用青霉素结合蛋白 3（PBP-3）作用的β-内酰胺类抗生素进行治疗，如哌拉西林他唑巴坦、头孢噻肟和美罗培南。这些抗生素会导致细菌发生显著的结构变化，并与体外的炎症反应增强相关。在一个具有临床相关性的大型动物脓毒症模型中，我们的主要目标是研究与相应数量的活菌或热死菌相比，被 PBP-3 作用的抗生素杀死的细菌是否对早期炎症反应和器官功能障碍产生更大的影响。次要目标是确定是否可以添加氨基糖苷类药物来减轻头孢呋辛引起的反应。
在一项前瞻性、随机对照的干预性实验研究中，16 头健康猪接受了 3 小时的肠内输注已死亡或存活的大肠杆菌。头孢呋辛被选为作用于 PBP-3 的抗生素，而妥布霉素则代表氨基糖苷类药物。动物随机分为四组，分别接受（I）头孢呋辛杀死的细菌、（II）活菌、（III）热死菌或（IV）头孢呋辛联合妥布霉素杀死的细菌。在实验开始时和随后的 6 小时内，每小时记录一次血浆内毒素、肿瘤坏死因子-α、白细胞介素-6、白细胞介素-10、白细胞和器官功能。
在四个治疗组中，三种细胞因子的浓度随时间的变化存在差异（p<0.001）。接受头孢呋辛杀死的细菌的动物比接受活菌（p<0.05）或热死菌（p<0.01）的动物产生更高的反应。添加妥布霉素可降低头孢呋辛诱导的反应（p<0.001）。细胞因子反应与白细胞激活有关，白细胞激活进一步与肺功能障碍和乳酸增加有关（p<0.01）。
与活菌或热死菌相比，被 PBP-3 作用的抗生素杀死的细菌诱导了炎症反应的增强，这似乎与器官和细胞功能的恶化有关。在 PBP-3 作用的抗生素中添加氨基糖苷类药物可减轻这种反应。
