SYNERGISTIC EFFECT OF A RECOMBINANT N-TERMINAL FRAGMENT OF BACTERICIDAL PERMEABILITY-INCREASING PROTEIN AND CEFAMANDOLE IN TREATMENT OF RABBIT GRAM-NEGATIVE SEPSIS

As a consequence of their bactericidal actions, many antibiotics cause the release of endotoxin, a primary mediator of gram-negative sepsis, Bactericidal/permeability-increasing protein (BPI) has bactericidal a ctivity and neutralizes endotoxin in vitro and in vivo. We sought to e xamine the effect of a recombinant N-terminal fragment of BPI (rBPI(21 )) in conjunction with cefamandole, a cephalosporin antibiotic, in the treatment of Escherichia coli bacteremia and septic shock in rabbits, Cefamandole (100 mg/kg of body weight) was injected intravenously. Th is was followed by simultaneous 10-min infusions of E. coli O7:K1 (9 x 10(9) CFU/kg) and rBPI(21) (10 mg/kg), rBPI(21) was continuously infu sed for an additional 110 min at 10 mg/kg/h. The administration of rBP I(21) in conjunction with the administration of cefamandole prevented the cefamandole-induced increase of free endotoxin in plasma, accelera ted bacterial clearance, ameliorated cardiopulmonary dysfunction, and thereby, prevented death, whereas neither agent alone was protective i n this animal model, The efficacy of the combined treatment with rBPI( 21) and cefamandole suggests a synergistic interaction between the two agents. The data indicate that rBPI(21) may be useful in conjunction with traditional antibiotic therapy.