Abstract
Empiric broad-spectrum antimicrobials therapy is suggested to be started immediately for sepsis patients. Empiric antimicrobial therapy should be narrowed once pathogen identification and sensitivities are established. However, the detailed mechanisms of de-escalation strategy are still unclear. Here we hypothesized neutrophil extracellular traps (NETs) played an essential role and de-escalation strategy might alleviate organs injury through regulation of NETs formation in sepsis. We evaluated the effect of imipenem and ceftriaxone on NETs formation in vitro and examined the role of reactive oxygen species (ROS). Next, we designed de-escalation and escalation strategy in cecum ligation and puncture (CLP) models. Organ injury, inflammatory cytokines, NETs levels were compared and evaluated. In CLP models, de-escalation therapy resulted in an increased serum MPO-DNA level during the early stage and decreased MPO-DNA level during late stage, which exerted the reverse effects in escalation therapy. Inflammatory response and organ injury exacerbated when eliminated NETs with DNAse I during the early stage of sepsis (p < 0.01). Histopathological analysis showed decreased injury in lung, liver, and intestine in de-escalation therapy compared with escalation therapy (p < 0.01). De-escalation therapy results in the highest 6-day survival rate compared with the control group (p < 0.01), however, no significant difference was found between de-escalation and escalation group (p = 0.051). The in vitro study showed that the imipenem could promote, while the ceftriaxone could inhibit the formation of NETs in PMA-activated PMNs through a ROS-dependent manner. We firstly demonstrate that de-escalation, not escalation, therapy reduces organ injury, decreases inflammatory response by promoting NETs formation in the early stage, and inhibiting NETs formation in the late stage of sepsis.
Highlights
Sepsis remains a distressing public health care problem and ranks among the top ten causes of death worldwide
De-escalation antibiotic therapy alleviates organ injury and inflammation in the cecum ligation and puncture (CLP) model In order to compare the therapeutic effects of different antibiotic therapy methods on sepsis, mice were divided into four groups: the de-escalation group, the escalation group, the sham group, and the control group
Antibiotic administration was more effective, but de-escalation therapy in the CLP mice did not lead to significantly higher survival than escalation therapy (p = 0.051, Fig. 1A)
Summary
Sepsis remains a distressing public health care problem and ranks among the top ten causes of death worldwide. It is characterized by organ dysfunction and caused by a dysregulated host response to infection [1]. The link between early administration of antibiotics for suspected infection and antibiotic stewardship remains an essential aspect of high-quality sepsis management [4] Both de-escalation and escalation antibiotic therapy kill bacteria during sepsis [5], it is unclear why de-escalation, not escalation, therapy reduces mortality, and the detailed mechanism by which these changes in the sequence of antibiotic drug administration or the changes in the drugs themselves affect clinical outcomes are unknown
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