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Objective: While broad-spectrum antimicrobial therapy in sepsis has beneficial effects, its prolonged use is associated with resistant microorganisms, increased cost, and secondary infections such as clostridium difficile colitis. It is unclear whether a shorter course of antibiotics in the murine model of cecal ligation and puncture (CLP) will influence outcomes. We investigated whether 3 days of imipenem-cilastatin post-CLP, rather than the traditional 5 days, will alter physiological parameters, inflammatory biomarkers, and survival. Design: Prospective, controlled animal trial. Setting: University research laboratory. Patients: Female ICR(CD-1) mice. Interventions: Polymicrobial sepsis was induced by CLP in mice using a 16-gauge needle for double puncture. The mice were randomized to receive imipenem-cilastatin(25mg/kg) in dextrose 5% in Lactated Ringer’s solution every 12 hours for either the first three or five days (control) after injury. Daily monitoring included body weight, temperature, and facial vein sampling. Main Outcome Measures: Inflammatory cytokine profile and 21-day mortality. Results: Initial work in our lab demonstrated that 5 day treatment post-CLP with imipenem-cilastatin and fluid resuscitation compared to fluids alone doubled murine survival(p=0.004). Interestingly, shortening the course of antibiotics from 5 days to 3 days did not increase mortality(p=0.17). The change in body weight and temperature remained consistent between the groups when stratified by mice that lived versus died. Pro-inflammatory plasma cytokines on post-operative day 5 were comparable between the 3 day and 5 day(control) treatment groups for IL-6(180pg/mL vs 252pg/mL for control), IL-1β(137pg/mL vs 112pg/mL), MIP-2(357 pg/mL vs 332 pg/mL) and anti-inflammatory cytokines IL-10(170 pg/mL vs 263 pg/mL), TNF sr1(88 pg/mL vs 118 pg/mL). Conclusions: Our results indicate that reducing the duration of broad-spectrum antibiotics post-CLP in sepsis does not increase inflammatory cytokines or mortality.