The cathelicidin-derived tritrpticin enhances the efficacy of ertapenem in experimental rat models of septic shock.
Sepsis remains a serious clinical problem despite intense efforts to improve survival. In this study, the efficacy of ertapenem combined with the cathelicidin tritrpticin was investigated in two rat models of septic shock. Main outcome measures were bacterial growth in blood, peritoneum, spleen, liver, and mesenteric lymph nodes; endotoxin, interleukin 6, and tumor necrosis factor alpha concentrations in plasma; and lethality. Adult male Wistar rats were given (1) an intraperitoneal injection of 1 mg Escherichia coli serotype 0111:B4 LPS or (2) 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 tritrpticin, 15 mg/kg ertapenem, and 1 mg/kg tritrpticin combined with 15 mg/kg ertapenem. Each group included 20 animals. All compounds significantly reduced bacterial growth and lethality as compared with saline treatment. Treatment with tritrpticin resulted in significant decrease in plasma endotoxin and cytokine levels, whereas ertapenem exerted opposite effect. The combination between tritrpticin and ertapenem proved to be the most effective treatment in reducing all variables measured. In conclusion, tritrpticin enhances ertapenem efficacy in gram-negative septic shock rat models.
Ghiselli
Roberto
R
Department of General Surgery, I.N.R.C.A. I.R.R.C.S., Università Politecnica delle Marche, Ancona, Italy.
Cirioni
Oscar
O
Giacometti
Andrea
A
Mocchegiani
Federico
F
Orlando
Fiorenza
F
Silvestri
Carmela
C
Licci
Alberto
A
Della Vittoria
Agnese
A
Scalise
Giorgio
G
Saba
Vittorio
V
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry; D002432:Cecum / Q000601:surgery; D004195:Disease Models, Animal; D004357:Drug Synergism; D004731:Endotoxins / Q000097:blood; D013293:Enterococcus faecalis / Q000187:drug effects; D000077727:Ertapenem; D004926:Escherichia coli / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy*; D015850:Interleukin-6 / Q000097:blood; D008026:Ligation; D008297:Male; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D047090:beta-Lactams / Q000494:pharmacology*; D054804:Cathelicidins
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D004731:Endotoxins; D015850:Interleukin-6; D009842:Oligopeptides; D014409:Tumor Necrosis Factor-alpha; D047090:beta-Lactams; C402895:tritrpticin; D000077727:Ertapenem; D054804:Cathelicidins