Preliminary evaluation of recombinant amino-terminal fragment of human bactericidal/permeability-increasing protein in children with severe meningococcal sepsis.
BACKGROUND
Meningococcal sepsis remains an important cause of morbidity and mortality. We hypothesised that children with severe meningococcaemia might benefit from inhibition of the inflammatory processes thought responsible for fulminant disease. rBPI21 is a recombinant, N-terminal fragment of human bactericidal/permeability-increasing protein, which kills meningococci and binds to and clears bacterial endotoxin, these being the primary inducers of the systemic inflammation. The aim of this study was to determine the safety and kinetics of rBPI21 in children with severe meningococcaemia and to make a preliminary assessment of clinical outcome.


METHODS
In this open-label, dose-escalation, phase I/II trial in severe meningococcaemia (Glasgow meningococcal prognostic septicaemia score [GMSPS] > or = 8), 26 patients aged 1-18 years, who had received their first dose of antibiotics no more than 8 hours earlier were given rBPI21 by infusion at total doses of 1.0, 2.0, and 4.0 mg/kg.


RESULTS
The patients had significantly raised plasma concentrations of bacterial endotoxin and cytokines. Peak and steady state BPI concentrations were comparable with pharmacokinetic data in healthy adults. All complications were compatible with the expected pattern for severe meningococcal sepsis. Only one patient died. This outcome was found to compare favourably with a predicted mortality of > or = 30% by GMSPS, > or = 15% by plasma endotoxin values, > or = 28% by plasma interleukin-6 concentrations, 29-49% by severity of coagulopathy, and 20% (11/54) by comparison with recent historical patients consecutively treated in participating centres before this study.


CONCLUSIONS
This, the first clinical trial or rBPI21, shows that rBPI21 can be safely administered to children with severe meningococcaemia and that the pharmacokinetics are consistent with patterns seen in healthy adults. Predicted mortality, on the basis of GMSPS, laboratory indices of inflammation and coagulopathy, and historical controls, was for between four and eight deaths. These findings have prompted a phase III randomised trial.
Giroir
B P
BP
Department of Pediatrics, University of Texas Southwesten Medical Centre, Dallas 75235-9063, USA. bgiroi@mednet.swmed.edu
Quint
P A
PA
Barton
P
P
Kirsch
E A
EA
Kitchen
L
L
Goldstein
B
B
Nelson
B J
BJ
Wedel
N J
NJ
Carroll
S F
SF
Scannon
P J
PJ
D000328:Adult; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D023181:Antimicrobial Cationic Peptides; D016470:Bacteremia / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D001770:Blood Bactericidal Activity; D001798:Blood Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008589:Meningococcal Infections / Q000188:drug therapy* / Q000401:mortality; D011994:Recombinant Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D008565:Membrane Proteins; D011994:Recombinant Proteins; C021623:bactericidal permeability increasing protein