Late treatment with a protective antigen-directed monoclonal antibody improves hemodynamic function and survival in a lethal toxin-infused rat model of anthrax sepsis.
BACKGROUND
In animal models, treatment with 5H3, a fully human protective antigen-directed monoclonal antibody (PA-MAb), improved survival when administered close to the time of Bacillus anthracis lethal toxin (LeTx) bolus or live bacterial challenge. However, treatment with PA-MAb would be most valuable clinically if it were beneficial even when administered after the onset of shock and lethality due to LeTx.


METHODS
We investigated the effects of PA-MAb versus placebo administered in rats (n=324) at the time of or 3, 6, 9, or 12 h after the initiation of a 24-h LeTx infusion.


RESULTS
In rats receiving placebo, mean arterial blood pressure (MBP) and heart rate (HR) were decreased in nonsurvivors, compared with those in survivors, at 6 h and then worsened further, with lethality first evident at 8 h (median, 16 h; range, 8-152 h). At each treatment time, survival rates were greater for PA-MAb than for placebo, although improvement was decreased at later treatment times (P=.001, for the effect of time). Compared with placebo, PA-MAb significantly increased MBP during the 12 h after the initiation of treatment, but the increase was greatest for treatment at 3 h; similarly, PA-MAb significantly increased HR at all treatment times.


CONCLUSIONS
In this rat model, improvements in outcome due to PA-MAb were significant when it was administered up to 6 h (and approached significance when administered up to 12 h) after initial exposure to LeTx. Clinically, PA-MAb may be beneficial even when administered after the onset of shock and lethality due to LeTx.
Cui
Xizhong
X
Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA. cxizhong@mail.cc.nih.gov
Li
Yan
Y
Moayeri
Mahtab
M
Choi
Gil H
GH
Subramanian
G M
GM
Li
Xuemei
X
Haley
Michael
M
Fitz
Yvonne
Y
Feng
Jing
J
Banks
Steven M
SM
Leppla
Stephen H
SH
Eichacker
Peter Q
PQ
D000818:Animals; D000881:Anthrax / Q000401:mortality / Q000628:therapy*; D000907:Antibodies, Bacterial / Q000008:administration & dosage* / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000276:immunology / Q000633:toxicity*; D001408:Bacillus anthracis / Q000378:metabolism / Q000472:pathogenicity; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000276:immunology / Q000633:toxicity*; D001794:Blood Pressure; D006339:Heart Rate; D006439:Hemodynamics / Q000187:drug effects*; D007262:Infusions, Intravenous; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000401:mortality / Q000628:therapy*; D013997:Time Factors
D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin