Protective effects of the combination of alpha-helical antimicrobial peptides and rifampicin in three rat models of Pseudomonas aeruginosa infection.
BACKGROUND
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.
Cirioni
Oscar
O
Institute of Infectious Diseases and Public Health, Università Politecnica delle Marche, Ancona, Italy. o.cirioni@univpm.it
Silvestri
Carmela
C
Ghiselli
Roberto
R
Orlando
Fiorenza
F
Riva
Alessandra
A
Mocchegiani
Federico
F
Chiodi
Leonardo
L
Castelletti
Sefora
S
Gabrielli
Eleonora
E
Saba
Vittorio
V
Scalise
Giorgio
G
Giacometti
Andrea
A
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001769:Blood / Q000382:microbiology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004731:Endotoxins / Q000097:blood; D007275:Injections, Intravenous; D054806:Magainins; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D010537:Peritoneum / Q000382:microbiology; D010878:Piperacillin / Q000627:therapeutic use; D000077725:Piperacillin, Tazobactam Drug Combination; D010949:Plasma / Q000737:chemistry; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D029867:Xenopus Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D004731:Endotoxins; D054806:Magainins; D014409:Tumor Necrosis Factor-alpha; D029867:Xenopus Proteins; C053301:magainin 2 peptide, Xenopus; D000077725:Piperacillin, Tazobactam Drug Combination; C031161:cecropin A; D010397:Penicillanic Acid; D012293:Rifampin; D010878:Piperacillin