Azithromycin reduces systemic inflammation and provides survival benefit in murine model of polymicrobial sepsis

Abstract

27Sepsis is a life threatening systemic inflammatory condition triggered as a result of excessive 28 host immune response to infection. In the past, drugs modulating immune reactions have 29 demonstrated protective effect in sepsis. Azithromycin (macrolide antibiotic) with 30 immunomodulatory activity was therefore evaluated in combination with ceftriaxone in a 31 more clinically relevant murine model of sepsis induced by caecal ligation and puncture 32 (CLP). First, mice underwent CLP and 3 h later were administered with vehicle, sub-effective 33 dose of ceftriaxone (100 mg/kg, subcutaneous) alone or in combination with 34 immunomodulatory dose of azithromycin (100 mg/kg, intraperitoneal). Survival was then 35 monitored for 5 days. Parameters like body temperature, blood glucose, total white blood cell 36 count, plasma glutathione (GSH), plasma and lung myeloperoxidase (MPO) as well as 37 cytokine (interleukin IL-6, IL-1β, tumor necrosis factor-α) levels along with bacterial load in 38 blood, peritoneal fluid and lung homogenate were measured 18 h after CLP challenge. 39Combination group significantly improved the survival of CLP mice. It attenuated the 40 elevated levels of inflammatory cytokines and MPO in plasma and lung tissue and increased 41 the body temperature, blood glucose and GSH which were otherwise markedly decreased in 42 CLP mice. Ceftriaxone exhibited significant reduction of bacterial count in blood, peritoneal 43 fluid and lung homogenate, while co-administration of azithromycin did not further reduce it. 44This confirms that survival benefit by azithromycin was due to immunomodulation and not 45 by its antibacterial action. Findings of this study indicate that azithromycin in combination 46 with ceftriaxone could exhibit clinical benefit in sepsis. 47 Abstract word count: 245 48 49 50 51 52 53Sepsis is a generalized systemic inflammatory condition elicited by pro-inflammatory 54 cytokines released by host immune cell in response to exotoxin or endotoxins secreted by 55 bacteria. Overproduction of these cytokines is associated with multiple organ failure which is 56 the major cause of death in critically ill and elderly patients. Despite recent advances in our 57 understanding of the pathophysiological mechanism of sepsis and improved antimicrobial 58 therapy, the mortality rate from sepsis remains frustratingly high. Unfortunately many of the 59 therapeutic options proposed over the years for the management of sepsis and its 60 complication have either failed to meet their initial expectations or remained unproved. 61Strategies are currently being developed to minimize the inflammatory response associated 62 with sepsis through immunotherapy (1). 63Several reports have provided evidence of immunomodulatory activity of macrolide 64 antibiotics (2, 3, 4). As a result, macrolides have proved beneficial in chronic pulmonary 65 inflammatory conditions like diffuse panbronchiolitis, cystic fibrosis, asthma and 66 bronchiectasis (5, 6). Due to this behaviour, they have earlier demonstrated clinical b...