Effects of pexiganan alone and combined with betalactams in experimental endotoxic shock

Andrea Giacometti, Oscar Cirioni, Roberto Ghiselli, Fiorenza Orlando, Wojciech Kamysz, Marco Rocchi, Giuseppina D'Amato, Federico Mocchegiani, Carmela Silvestri, Jerzy Łukasiak, Vittorio Saba, Giorgio Scalise

Research output: Contribution to journalArticlepeer-review

Abstract

To investigate the efficacy of pexiganan, a 22-residue magainin analog, alone and combined with betalactmas antibiotics in three experimental rat models of Gram-negative septic shock. Adult male Wistar rats were given (i) an intraperitoneal injection of 1 mg Escherichia coli 0111:B4 LPS; (ii) 2 × 10 10 CFU of E. coli ATCC 25922; and (iii) intra-abdominal sepsis induced via cecal ligation and puncture. For each model, all animals were randomized to receive intraperitoneally isotonic sodium chloride solution, 1 mg/kg pexiganan, 1 mg/kg polymyxin B, 20 mg/kg imipenem, 60 mg/kg piperacillin alone and combined with 1 mg/kg pexiganan. Each group included 15 animals. Lethality, bacterial growth in blood or intra-abdominal fluid, endotoxin and TNF-α concentrations in plasma. All compounds reduced the lethality when compared to controls. Piperacillin and imipenem significantly reduced the lethality and the number of E. coli in abdominal fluid compared with saline treatment. Pexiganan showed a slightly lower antimicrobial activity than betalactams even though it achieved a substantial higher decrease in endotoxin and TNF-α plasma concentrations than imipenem and piperacillin. No statistically significant differences were noted for antimicrobial and antiendotoxin activities between pexiganan and polymyxin B. Combination between pexiganan and betalactams showed to be the most effective treatment in reducing all variables measured. The use of a novel antimicrobial compound able to bind to LPS associated to potent antibiotics such as betalactams may become an important future consideration for sepsis treatment.

Original languageEnglish
Pages (from-to)207-216
Number of pages10
JournalPeptides
Volume26
Issue number2
DOIs
Publication statusPublished - Feb 2005

Keywords

  • Antimicrobial peptides
  • Endotoxin
  • Lipopolysaccharide
  • Pexiganan
  • Sepsis

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Physiology
  • Cellular and Molecular Neuroscience

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