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 ICU. 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-hours post-CS injection), antibiotic treatment (imipenem, 1.5mg/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-hours post-CS injection) the majority of animals did not survive beyond 48 hours. 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 post intensive care illness.

Chronic muscle weakness and mitochondrial dysfunction in the absence of sustained atrophy in a preclinical sepsis model

“…We adapted our recently reported ICU-like model of sepsis to late middle-aged C57BL/6 mice (Steele et al, 2017) (16 months; equivalent to ~50-year-old human [Flurkey K et al, 2007]). Sepsis was induced by bolus injection of cecal slurry (CS) and therapeutic resuscitation with antibiotics and fluids was initiated at 12h and continued twice daily for five days (schematic provided in Figure 1A).…”

“…In an effort to better model the clinical course of sepsis by addressing the above four factors, we induced sepsis by CS injection in late middle-aged mice, and used our ICU-like severe model of sepsis (Steele et al, 2017) which resulted in ~75% survival after an otherwise lethal insult. In the current study, using ex vivo force analysis, we found that middle-aged sepsis surviving mice exhibit a ~ 20% reduction of muscle force compared to non-sepsis controls up to 1 month after sepsis.…”

“…To overcome this issue, we recently refined a non-surgical murine model of polymicrobial sepsis whereby infection is initiated by injection of cecal slurry (CS) (Starr et al, 2014; Starr et al, 2016). Therapeutic intervention with a broad-spectrum antibiotic and fluids is provided, but initiated after bacteremia is evident (Steele et al, 2017). This delayed ICU-like resuscitation protocol allows for the development of sepsis with organ damage, yet rescues the majority of mice from an otherwise completely lethal condition, thereby allowing the study of survivors.…”

Romo1-Derived Antimicrobial Peptide Is a New Antimicrobial Agent against Multidrug-Resistant Bacteria in a Murine Model of Sepsis

“…4D) (32). Imipenem was intraperitoneally administered four times every 12 h (q12h) as previously described, with minor modifications (33). Interestingly, a single dose (10 mg/kg) of AMPR-11, which was a 10-fold lower concentration when tested for in vivo toxicity, increased the survival rate by Ͼ60% in both Gram-positive bacteria (S. aureus) and Gram-negative bacteria (P. aeruginosa, K. pneumoniae, and A. baumannii) ( Fig.…”

Recombinant human thrombomodulin attenuated sepsis severity in a non-surgical preterm mouse model

“…Because most Veh-treated controls (71.4%) died within 48 h post-sepsis induction, it was difficult to collect specimens for histological analysis. To further elucidate the pathophysiology, we plan to conduct a study that includes histologic examination using a newly established murine model of sepsis with a prolonged disease course and high survival rate 42 . Although we utilised decapitation for blood collection in our study, this procedure is not ideal.…”