Lipopolyamines as a therapeutic strategy in experimental Gram-negative bacterial sepsis

Lipopolyamines are a class of polycationic amphiphilic compounds that have been shown to bind with high affinity to polyanionic macromolecules, includ ing both DNA and bacterial lipopolysaccharide (LPS). One of these compounds , termed DOSPER (1,3-di-oleoyloxy-2-(6-carboxylspermyl)-propylamide), is no n-cytotoxic and has been shown to inhibit LPS-mediated cytokine release and lethality in endotoxin challenge models. In the study reported here, the a ctivity of DOSPER was tested in neutropenic rats with invasive Gram-negativ e bacteremia caused by Pseudomonas aeruginosa. DOSPER alone was ineffective (0/8) at influencing mortality, but provided a significant survival advant age if administered in combination with a bactericidal antibiotic, ceftazid ime (10/12; P <0.05). Ceftazidime alone was partially protective (6/12) whi le the control group had no survivors (0/8). DOSPER administration markedly reduced circulating endotoxin levels (P <0.01) and interleukin-6 levels (P <0.05) but had no significant effect on bacteremia and bacterial concentra tions of P. aeruginosa in liver or spleen tissue. Lipopolyamines may be pot entially valuable as a therapeutic adjunct in treatment of Gram-negative ba cterial sepsis.