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JAC Advance Access published online on August 4, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh390
© 2004 by The British Society for Antimicrobial Chemotherapy
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Received April 1, 2004
Revised June 28, 2004
Accepted July 1, 2004

Original article

Therapeutic efficacy of the magainin analogue MSI-78 in different intra-abdominal sepsis rat models

Andrea Giacometti 1*, Roberto Ghiselli 2, Oscar Cirioni 1, Federico Mocchegiani 2, Giuseppina D'Amato 1, Fiorenza Orlando 3, Valerio Sisti 1, Wojciech Kamysz 4, Carmela Silvestri 2, Piotr Naldoski 4, Jerzy Lukasiak 4, Vittorio Saba 2, Giorgio Scalise 1

1 Institute of Infectious Diseases and Public Health, Università Politecnica delle Marche, Ancona, Italy
2 Department of General Surgery, I.N.R.C.A.--I.R.R.C.S., Università Politecnica delle Marche, Ancona, Italy
3 Biotechnology Centre, Research Department, I.N.R.C.A.--I.R.R.C.S., Ancona, Italy
4 Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland

* To whom correspondence should be addressed. E-mail: anconacmi{at}interfree.it.


  Abstract

Objectives: This study was designed to investigate the antimicrobial and anti-endotoxin activity of MSI-78, a synthetic cationic peptide analogue of magainin 2.

Methods: The in vitro antimicrobial activity of MSI-78 was investigated against the commercially available quality control strain Escherichia coli ATCC 25922. In addition, three rat models of septic shock were investigated: (i) rats were injected intraperitoneally with 1 mg Escherichia coli 0111:B4 LPS; (ii) rats were given an intraperitoneal injection of 2 x 1010 cfu of Escherichia coli ATCC 25922; (iii) intra-abdominal sepsis was induced via caecal ligation and puncture. All animals were randomized to receive after 360 min intravenously isotonic sodium chloride solution, 1 mg/kg MSI-78, or 60 mg/kg piperacillin. Main outcome measures were: abdominal exudate and plasma bacterial growth, plasma endotoxin and tumour necrosis factor {alpha} (TNF-{alpha}) concentrations, and lethality.

Results: Our in vitro data showed that MSI-78 possesses a strong activity against Escherichia coli. The in vivo studies showed that all compounds reduced the lethality when compared to controls. MSI-78 showed a slightly higher antimicrobial activity than piperacillin and achieved a substantial decrease in endotoxin and TNF-{alpha} plasma concentrations than the {beta}-lactam.

Conclusions: Because of its strong double anti-endotoxin and antimicrobial activities MSI-78 could be an interesting compound for Gram-negative septic shock treatment.

Keywords: septic shock; endotoxin; peptides.
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