Abstract
Sepsis is a life-threatening organ dysfunction resulting from inflammatory responses instigated by toxins secreted by bacteria. Immunomodulatory effect of clindamycin is earlier reported in a murine lipopolysaccharide (LPS)-induced sepsis model. There are no studies demonstrating the immunomodulatory effect of clindamycin in combination with ceftriaxone in a clinically relevant murine polymicrobial sepsis model induced by cecal ligation and puncture (CLP). Ceftriaxone is combined to control the bacterial growth. Following 3 h of CLP challenge, Swiss albino mice were administered vehicle, ceftriaxone alone (100 mg/kg, subcutaneously), and in combination with clindamycin at immunomodulatory dose (200 mg/kg, intraperitoneally). Survival was assessed for 5 days, and bacterial count and biochemical and physiological parameters were measured after 18 h of CLP challenge. Ceftriaxone alone caused significant reduction in bacterial count in blood, peritoneal fluid, lung, liver, and kidney homogenate which was not further substantially reduced by ceftriaxone and clindamycin combination. Day 5 survival was greatly improved by combination compared with ceftriaxone alone which was also evident through marked drop in blood glucose, total white blood cell (WBC) count, and body temperature. The combination group significantly mitigated the cytokine (tumor necrosis factor (TNF)-α and interleukin (IL)-6) and myeloperoxidase (MPO) levels in plasma, lung, liver, and kidney of CLP-challenged mice, which further helped in significantly suppressing the elevated levels of liver and kidney function parameters. Clindamycin at immunomodulatory dose in combination with ceftriaxone attenuated organ damage and improved survival of septic mice by suppressing infection, inflammatory responses, and oxidative stress.
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Acknowledgments
We thank the Wockhardt Research Centre, India, and Dr. Mahesh Patel for granting permission for performing these studies. We also thank Mr. Satish Damle and Mr. Bhushan Choudhari for assisting in sample analysis.
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This work was self-funded.
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AP and SM conceived and designed the research. AP and HP conducted experiments. AP analyzed the data. AP and SM wrote the manuscript. All authors read and approved the manuscript.
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Study protocols were approved by Institutional Animal Ethics Committee of Wockhardt Research Centre, India, registered under Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), India.
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Patel, A.M., Periasamy, H. & Mokale, S.N. Immunomodulatory dose of clindamycin in combination with ceftriaxone improves survival and prevents organ damage in murine polymicrobial sepsis. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1671–1679 (2020). https://doi.org/10.1007/s00210-020-01876-4
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DOI: https://doi.org/10.1007/s00210-020-01876-4