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.