Efficacy of a recombinant endotoxin neutralizing protein in rabbits with Escherichia coli sepsis.
Gram-negative bacterial sepsis is associated with endotoxemia and a high mortality rate. In previous studies, we demonstrated the therapeutic benefit of an anti-lipopolysaccharide factor isolated from amebocytes of Limulus polyphemus, and of a recombinant version of this protein, termed endotoxin neutralizing protein (ENP), in rabbits challenged with purified lipopolysaccharides. To assess the benefit of ENP in treating a live bacterial infection, we established a rabbit model of Escherichia coli (E. coli) peritonitis and bacteremia with high mortality despite gentamicin treatment. Twenty-four pairs of New Zealand white rabbits were challenged intraperitoneally (IP) with E. coli O18ac K1 in 5% porcine mucin (mean bacteria per dose = 2.5 x 10(8)). The animals were treated with intravenous (i.v.) gentamicin (2.5 mg/kg), and with either ENP (5 mg/kg) or saline i.v. at 1 hr after E. coli challenge. All rabbits were bacteremic 1 hr after challenge (geometric mean 4.1 +/- 1.2 x 10(4) cfu/mL). Peak geometric mean serum endotoxin (2.62 v 10.54 EU/mL, P = .013) and tumor necrosis factor (TNF) (2540 v 6438 TNF units/mL, P = .046) concentrations were lower in ENP-treated animals as compared to control animals. Seven of 24 animals treated with ENP survived 24 hr compared with 4 of 24 controls (Kaplan-Meier analysis, P = .19). However, in the subgroup of 13 paired animals in whom bacteremia was eliminated by gentamicin treatment, 5 of 13 ENP-treated animals survived 24 hr, compared with 1 of 13 controls (Kaplan-Meier analysis, P = .032).(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Medicine (Division of Emergency Medicine), Children's Hospital, Boston, Massachusetts 02115.
R
R
Saladino
C
C
Garcia
C
C
Thompson
B
B
Hammer
J
J
Parsonnet
T
T
Novitsky
G
G
Siber
G
G
Fleisher
D000818:Animals; D016470:Bacteremia / Q000188:drug therapy* / Q000401:mortality; D004731:Endotoxins / Q000097:blood; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000401:mortality; D005839:Gentamicins / Q000627:therapeutic use; D008297:Male; D010538:Peritonitis / Q000188:drug therapy / Q000382:microbiology; D011506:Proteins / Q000627:therapeutic use*; D011817:Rabbits; D011994:Recombinant Proteins / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004731:Endotoxins; D005839:Gentamicins; D011506:Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha