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 activity and neutralizes endotoxin in vitro and in vivo. We sought to examine 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. This 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 infused for an additional 110 min at 10 mg/kg/h. The administration of rBPI(21) in conjunction with the administration of cefamandole prevented the cefamandole-induced increase of free endotoxin in plasma, accelerated bacterial clearance, ameliorated cardiopulmonary dysfunction, and thereby, prevented death, whereas neither agent alone was protective in 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.