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JAC Advance Access published online on September 16, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn393
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Protective effects of the combination of {alpha}-helical antimicrobial peptides and rifampicin in three rat models of Pseudomonas aeruginosa infection

Oscar Cirioni1,*, Carmela Silvestri1, Roberto Ghiselli2, Fiorenza Orlando3, Alessandra Riva1, Federico Mocchegiani2, Leonardo Chiodi2, Sefora Castelletti1, Eleonora Gabrielli1, Vittorio Saba2, Giorgio Scalise1 and Andrea Giacometti1

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 Experimental Animal Models for Aging Units, Research Department, I.N.R.C.A. I.R.R.C.S., Ancona, Italy

Received 16 May 2008; returned 2 July 2008; revised 19 August 2008; accepted 25 August 2008

* Corresponding author. Tel: +39-071-5963715; Fax: +39-071-5963468; E-mail: o.cirioni{at}univpm.it or anconacmi{at}interfree.it

Introduction: An experimental study has been performed to compare the in vitro activity and the in vivo efficacy of magainin II and cecropin A with or without rifampicin against control and multidrug-resistant Pseudomonas aeruginosa strains.

Methods: In vitro experiments included MIC determinations and synergy studies. For in vivo studies, animals were given an intraperitoneal injection of P. aeruginosa lipopolysaccharide, P. aeruginosa ATCC 27853 and one clinical multiresistant P. aeruginosa strain. Groups of animals received intravenously isotonic sodium chloride solution, 10 mg/kg rifampicin, 1 mg/kg magainin II or 1 mg/kg cecropin A. Two groups of animals received a combined treatment with magainin II + rifampicin or cecropin A + rifampicin at the same dosages as the singly treated groups. In addition, a further group was treated with tazobactam/piperacillin (120 mg/kg). Lethality, bacterial growth in blood and peritoneum, and endotoxin and TNF-{alpha} concentrations in plasma were evaluated.

Results: Combinations of {alpha}-helical antimicrobial peptides showed in vitro synergistic interaction. Magainin II and cecropin A exerted strong antimicrobial activity and achieved a significant reduction in plasma endotoxin and TNF-{alpha} concentrations when compared with control and rifampicin-treated groups. Rifampicin exhibited no anti-P. aeruginosa activity and good substantial impact on endotoxin and TNF-{alpha} plasma concentrations. Combined treatment groups had significant reductions in bacterial count, positive blood cultures and mortality rates when compared with singly treated and control groups.

Conclusions: Our results highlight the potential usefulness of these combinations that provide future therapeutic alternatives in P. aeruginosa infections.

Key Words: sepsis , multiresistant organisms , P. aeruginosa , synergy , animal model


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