Combination of imipenem and TAK-242, a Toll-like receptor 4 signal transduction inhibitor, improves survival in a murine model of polymicrobial sepsis.

Sepsis is characterized by an excessive host response to infection. Toll-like receptors (TLRs) are essential for triggering this type of host immune response. Toll-like receptor 4 mediates recognition of LPS from gram-negative bacteria and is an important initiator of sepsis. In the present study, we evaluated the efficacy of TAK-242, a novel TLR4 signal transduction inhibitor, in a murine cecal ligation and puncture (CLP) model. Treatment with TAK-242 (10 mg/kg i.v.) in combination with imipenem (1 mg/kg s.c.) 1 h after CLP significantly increased the survival rates of mice from 17% to 50% (P ≤ 0.01) and suppressed CLP-induced increases in serum levels of IL-1[beta], IL-6, IL-10, and macrophage inflammatory protein 2 by 64%, 73%, 79%, and 81%, respectively (P ≤ 0.025). Additionally, coadministration of TAK-242 with imipenem after CLP significantly inhibited CLP-induced decreases in blood platelet counts by 37% (P ≤ 0.025) and increases in serum levels of alanine aminotransferase by 32% (P ≤ 0.025) and blood urea nitrogen by 43% (P ≤ 0.025). TAK-242 at a dose of 10 mg/kg had no effect on bacterial counts in blood, suggesting that it does not affect blood bacteria spread. These results indicate that TAK-242 shows therapeutic effects in murine polymicrobial sepsis, and it may be a potential therapeutic agent for the treatment of sepsis.