Late Therapeutic Intervention with Antibiotics and Fluid Resuscitation Allows for a Prolonged Disease Course with High Survival in a Severe Murine Model of Sepsis.

ABSTRACT

Current animal models of sepsis often incorporate antibiotics to be consistent with clinical standards for treatment of patients in the intensive care unit. However, such experimental intervention is commonly initiated very early after infectious insult, which likely blunts the progression of systemic inflammation and downstream pathology. The objective of this study was to establish an animal model of sepsis with delayed therapeutic intervention, allowing a longer disease course and downstream pathology, but still resulting in a high survival rate. Severe lethal abdominal infection was initiated in young adult (17-18-week-old) C57BL/6 mice by cecal slurry (CS) injection. When initiated early (1- or 6-h post-CS injection), antibiotic treatment (imipenem, 1.5 mg/mouse i.p., twice/day for 5 days) rescued the majority of mice; however, few of these mice showed evidence of bacteremia, cytokinemia, or organ injury. When antibiotic treatment was delayed until late time-points (12- or 24-h post-CS injection) the majority of animals did not survive beyond 48 h. When fluid resuscitation (physiological saline, s.c.) was performed in combination with antibiotic treatment (twice daily) beginning at these late time-points, the majority of mice survived (75%) and showed bacteremia, cytokinemia, organ dysfunction, and prolonged body weight loss (<90% for 4 weeks). We recommend that this new repeated combination treatment with antibiotics and fluids resuscitation be initiated at a late time point after bacteremia becomes evident because this model more closely mimics the downstream pathological characteristics of severe clinical sepsis yet maintains a high survival rate. This model would be advantageous for studies on severe sepsis and postintensive care illness.