Effect of SDZ MRL 953 on the survival of mice with advanced sepsis that cannot be cured by antibiotics alone

Abstract

Stimulation of nonspecific immunity as an additional modality for therapy of sepsis that cannot be cured by antibiotics alone was investigated. SDZ MRL 953, a novel monosaccharidic lipid A analog as a prototype immunostimulant, and cefotaxime or gentamicin were administered to normal or myelosuppressed mice in a state of advanced sepsis caused by Escherichia coli or Staphylococcus aureus. In this novel model, antibiotic therapy was initiated when the infected mice appeared moribund. At this stage, neither pretreatment with the immunostimulant nor therapy with high doses of cefotaxime or gentamicin was effective in protecting the animals from fatal sepsis. However, pretreatment with a single dose of SDZ MRL 953 1 day prior to microbial inoculation dramatically improved the curative effects of the antibiotics. Hence, long-term survival was significantly enhanced with increasing doses of the immunostimulant in the combined therapy. Peritoneal macrophages from SDZ MRL 953-pretreated animals were primed for enhanced production of microbicidal reactive oxygen metabolites in vitro. In conclusion, the results of the present study indicate that SDZ MRL 953 is a potential candidate for use in a clinical setting as an adjunct to antimicrobial therapy for infections that cannot be treated successfully with appropriate antibiotics alone.