Efficacy of the combination of tachyplesin III and clarithromycin in rat models of Escherichia coli sepsis

Abstract

We investigated the efficacy of tachyplesin III and clarithromycin in two experimental rat models of severe gram-negative bacterial infections. Adult male Wistar rats were given either (i) an intraperitoneal injection of 1 mg/kg Escherichia coli 0111:B4 lipopolysaccharide or (ii) 2 x 10(10) CFU of E. coli ATCC 25922. For each model, the animals received isotonic sodium chloride solution, 1 mg/kg tachyplesin III, 50 mg/kg clarithromycin, or 1 mg/kg tachyplesin III combined with 50 mg/kg clarithromycin intraperitoneally. Lethality, bacterial growth in the blood and peritoneum, and the concentrations of endotoxin and tumor necrosis factor alpha (TNF-alpha) in plasma were evaluated. All the compounds reduced the lethality of the infections compared to that for the controls. Tachyplesin III exerted a strong antimicrobial activity and achieved a significant reduction of endotoxin and TNF-alpha concentrations in plasma compared to those of the control and clarithromycin-treated groups. Clarithromycin exhibited no antimicrobial activity but had a good impact on endotoxin and TNF-alpha plasma concentrations. A combination of tachyplesin III and clarithromycin resulted in significant reductions in bacterial counts and proved to be the most-effective treatment in reducing all variables measured.

FIG. 1.

Endotoxin and TNF-α plasma levels after intraperitoneal administration of 1.0 mg E. coli serotype 0111:B4 LPS. EU, endotoxin unit(s).

FIG. 2.

Effects on endotoxin plasma levels of 1 mg/kg tachyplesin III, 50 mg/kg clarithromycin, and 1 mg/kg tachyplesin III plus 50 mg/kg clarithromycin administered intravenously after intraperitoneal injection of 1 × 10⁹ CFU of E. coli ATCC 25922. EU, endotoxin unit(s).

FIG. 3.

Effects on TNF-α plasma levels of 1 mg/kg tachyplesin III, 50 mg/kg clarithromycin, and 1 mg/kg tachyplesin III plus 50 mg/kg clarithromycin administered intravenously at 0 and 360 min after intraperitoneal injection of 1 × 10⁹ CFU of E. coli ATCC 25922.