title: Synergistic effect of a recombinant N-terminal fragment of bactericidal/permeability-increasing protein and cefamandole in treatment of rabbit gram-negative sepsis.
abstract: 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 (rBPI21) 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 rBPI21 (10 mg/kg). rBPI21 was continuously infused for an additional 110 min at 10 mg/kg/h. The administration of rBPI21 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 rBPI21 and cefamandole suggests a synergistic interaction between the two agents. The data indicate that rBPI21 may be useful in conjunction with traditional antibiotic therapy.
authors.affiliation: Department of Pharmacology, Xoma Corporation, Berkeley, California 94710, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.forename: W J
authors.initials: WJ
authors.lastname: Leach
authors.forename: W S
authors.initials: WS
authors.lastname: Ammons
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use* / Q000633:toxicity; D023181:Antimicrobial Cationic Peptides; D001784:Blood Gas Analysis; D001786:Blood Glucose / Q000378:metabolism; D001798:Blood Proteins / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D002435:Cefamandole / Q000627:therapeutic use* / Q000633:toxicity; D002511:Cephalosporins / Q000627:therapeutic use* / Q000633:toxicity; D015169:Colony Count, Microbial; D004357:Drug Synergism; D004731:Endotoxins / Q000097:blood; D004927:Escherichia coli Infections / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007773:Lactates / Q000097:blood; D008297:Male; D008565:Membrane Proteins; D011817:Rabbits; D011994:Recombinant Proteins / Q000627:therapeutic use* / Q000633:toxicity; D012772:Shock, Septic / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D001786:Blood Glucose; D001798:Blood Proteins; D002511:Cephalosporins; D004731:Endotoxins; D007773:Lactates; D008565:Membrane Proteins; D011994:Recombinant Proteins; C021623:bactericidal permeability increasing protein; D002435:Cefamandole; C044101:endotoxin, Escherichia coli