Azithromycin in combination with ceftriaxone reduces systemic inflammation and provides survival benefit in murine model of polymicrobial sepsis [PublishAheadOfPrint]

Sepsis is a life threatening systemic inflammatory condition triggered as a result of excessive host immune response to infection. In the past, immunomodulators have demonstrated protective effect in sepsis. Azithromycin (macrolide antibiotic) having immunomodulatory activity was therefore evaluated in combination with ceftriaxone in a clinically relevant murine model of sepsis induced by caecal ligation and puncture (CLP). First, mice underwent CLP and 3 h later were administered with vehicle or sub-protective dose of ceftriaxone (100 mg/kg, subcutaneous) alone or in combination with immunomodulatory dose of azithromycin (100 mg/kg, intraperitoneal). Survival was monitored for 5 days. In order to assess the immunomodulatory activity, parameters such as plasma and lung cytokines concentrations (interleukin IL-6, IL-1β, tumor necrosis factor-α), plasma glutathione (GSH), plasma and lung myeloperoxidase (MPO), body temperature, blood glucose, total white blood cell count, along with bacterial load in blood, peritoneal fluid and lung homogenate were measured 18 h after CLP challenge. Azithromycin in presence of ceftriaxone significantly improved the survival of CLP challenged mice. Further, the combination attenuated the elevated levels of inflammatory cytokines and MPO in plasma and lung tissue and increased the body temperature, blood glucose and GSH which were otherwise markedly decreased in CLP mice. Ceftriaxone exhibited significant reduction in bacterial load, while co-administration of azithromycin did not show further reduction. Therefore, the survival benefit by azithromycin was due to immunomodulation and not by its antibacterial action. Findings of this study indicate that azithromycin could provide clinical benefits in sepsis in conjunction with appropriate antibacterial agents.

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