RESUMO
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.
Assuntos
Antibacterianos , Peptídeos Catiônicos Antimicrobianos , Claritromicina , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Infecções por Escherichia coli/tratamento farmacológico , Escherichia coli/efeitos dos fármacos , Peptídeos Cíclicos , Sepse/tratamento farmacológico , Animais , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/administração & dosagem , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Claritromicina/administração & dosagem , Claritromicina/uso terapêutico , Proteínas de Ligação a DNA/administração & dosagem , Proteínas de Ligação a DNA/uso terapêutico , Quimioterapia Combinada , Endotoxinas/sangue , Infecções por Escherichia coli/microbiologia , Humanos , Masculino , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/uso terapêutico , Ratos , Ratos Wistar , Sepse/microbiologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangueRESUMO
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.