Lipid X protects mice against fatal Escherichia coli infection.
Lipid X, the major monosaccharide precursor of lipid A, is nontoxic and has previously been shown to protect mice and sheep from the harmful effects of endotoxin. To test the hypothesis that lipid X could be therapeutic against infections with gram-negative organisms, neutropenic ICR mice were infected by intramuscular inoculation of Escherichia coli and subsequently treated with lipid X alone or in combination with the antibiotic ticarcillin. Lipid X slightly prolonged survival; treated mice had a significantly improved rate of survival 18 h after intramuscular inoculation as compared with controls (P less than 0.025). By 24 h, however, this difference disappeared. When lipid X was combined with ticarcillin, survival differences were both significant and prolonged. Treatment of mice with one to two doses of lipid X for a total dose of 1 mg intravenously and with 1,200 mg of ticarcillin per kg every 6 h improved survival over a 48-h treatment period from 5 to 23% (P less than 0.0025). Treatment with lipid X and ticarcillin over a broad range of antibiotic dosages in 362 mice demonstrated improved survival of two- to fourfold (P less than 0.0001 at 24 h after inoculation, P less than or equal to 0.0005 at 48 h, and P less than or equal to 0.0001 at 5 days). Lipid X enabled the dose of ticarcillin necessary to protect 50% of mice from death to be reduced by two- to fivefold. Pretreatment with lipid X was not necessary to improve survival: 16 of 17 (94%) infected and visibly ill animals that received lipid X and ticarcillin 6 h after thigh inoculation survived versus 30 of 44 (68%) control animals treated with ticarcillin alone (P less than 0.0001). Lipid X had no antimicrobial activity in vitro. Lipid X is a novel agent that enhances survival in an animal model of severe infection with gram-negative organisms.
Golenbock
D T
DT
Department of Medicine, University of Wisconsin-Madison.
Leggett
J E
JE
Rasmussen
P
P
Craig
W A
WA
Raetz
C R
CR
Proctor
R A
RA
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004927:Escherichia coli Infections / Q000188:drug therapy*; D006017:Glycolipids / Q000008:administration & dosage*; D051379:Mice; D010406:Penicillins / Q000008:administration & dosage*; D018805:Sepsis / Q000188:drug therapy; D013982:Ticarcillin / Q000008:administration & dosage*
D006017:Glycolipids; D010406:Penicillins; C044283:lipid X; D013982:Ticarcillin