Effects of pexiganan alone and combined with betalactams in experimental endotoxic shock.
To investigate the efficacy of pexiganan, a 22-residue magainin analog, alone and combined with betalactmas antibiotics in three experimental rat models of Gram-negative septic shock. Adult male Wistar rats were given (i) an intraperitoneal injection of 1 mg Escherichia coli 0111:B4 LPS; (ii) 2x10(10)CFU of E. coli ATCC 25922; and (iii) 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 pexiganan, 1 mg/kg polymyxin B, 20 mg/kg imipenem, 60 mg/kg piperacillin alone and combined with 1 mg/kg pexiganan. Each group included 15 animals. Lethality, bacterial growth in blood or intra-abdominal fluid, endotoxin and TNF-alpha concentrations in plasma. All compounds reduced the lethality when compared to controls. Piperacillin and imipenem significantly reduced the lethality and the number of E. coli in abdominal fluid compared with saline treatment. Pexiganan showed a slightly lower antimicrobial activity than betalactams even though it achieved a substantial higher decrease in endotoxin and TNF-alpha plasma concentrations than imipenem and piperacillin. No statistically significant differences were noted for antimicrobial and antiendotoxin activities between pexiganan and polymyxin B. Combination between pexiganan and betalactams showed to be the most effective treatment in reducing all variables measured. The use of a novel antimicrobial compound able to bind to LPS associated to potent antibiotics such as betalactams may become an important future consideration for sepsis treatment.
Giacometti
Andrea
A
Institute of Infectious Diseases and Public Health, Università Politecnica delle Marche, Ancona, Italy. anconacmi@interfree.it
Cirioni
Oscar
O
Ghiselli
Roberto
R
Orlando
Fiorenza
F
Kamysz
Wojciech
W
Rocchi
Marco
M
D'Amato
Giuseppina
G
Mocchegiani
Federico
F
Silvestri
Carmela
C
Łukasiak
Jerzy
J
Saba
Vittorio
V
Scalise
Giorgio
G
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D002432:Cecum / Q000382:microbiology; D004359:Drug Therapy, Combination; D004731:Endotoxins / Q000097:blood; D004926:Escherichia coli / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D015378:Imipenem / Q000008:administration & dosage* / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D008033:Limulus Test; D008070:Lipopolysaccharides; D008297:Male; D010878:Piperacillin / Q000008:administration & dosage*; D011112:Polymyxin B / Q000008:administration & dosage* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000188:drug therapy* / Q000382:microbiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000187:drug effects
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D004731:Endotoxins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D015378:Imipenem; D011112:Polymyxin B; C093828:pexiganan; D010878:Piperacillin