De-escalation Antibiotic Therapy Alleviates Organ Injury through
Modulation of NET Formation during Sepsis
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 detail mechanisms of de-escalation strategy are still
unclear. Here we hypothesized neutrophil extracellular trap (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 based on their effects on
NETs formation in CLP model. Organ injury, inflammatory cytokines, NETs
levels were compared and evaluated. The in vitro study showed that
imipenem and ceftriaxone had opposite effects on NETs formation in
activated neutrophils. De-escalation therapy resulted in an evaluated
MPO-DNA during early stage and decreased MPO-DNA during late stage,
which exerted the reverse effects in escalation therapy sepsis animal
model. Inflammatory response and organ injury exacerbated when
eliminated NETs with DNAseI during 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). We 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.