TY - JOUR
T1 - Anthrax lethal and edema toxins produce different patterns of cardiovascular and renal dysfunction and synergistically decrease survival in canines
AU - Sweeney, Daniel A.
AU - Cui, Xizhong
AU - Solomon, Steven B.
AU - Vitberg, David A.
AU - Migone, Thi S.
AU - Scher, Dara
AU - Danner, Robert L.
AU - Natanson, Charles
AU - Subramanian, G. Mani
AU - Eichacker, Peter Q.
N1 - Funding Information:
Received 10 March 2010; accepted 14 July 2010; electronically published 10 November 2010. Potential conflicts of interest: Recombinant anthrax toxins were provided by Human Genome Sciences (Rockville, Maryland). Financial support: National Institutes of Health (NIH) Clinical Center; Trans NIH– Food and Drug Administration Biodefense grant. Reprints or correspondence: Dr Peter Q. Eichacker, Critical Care Medicine Dept, National Institutes of Health, Bldg 10, Rm 2C145, Bethesda, MD 20892 (peichacker@ mail.cc.nih.gov).
PY - 2010/12/15
Y1 - 2010/12/15
N2 - Background: High mortality in the 2001 US and recent European anthrax outbreaks suggests that better understanding of the effects of the toxins produced by this bacterium is needed to improve treatment. Methods and results. Here, 24-h edema (ETx) and lethal (LeTx) toxin infusions were investigated for 96 h in sedated canines receiving mechanical ventilation. The initial study compared similarly lethal doses of ETx (n=8) or LeTx (n=15) alone. ETx was 24 times less lethal than LeTx, and the median time to death in nonsurvivors (n=6 and n=9, respectively) was shorter with ETx (42 vs 67 h; P=.04). Compared with controls (n=9), both toxins decreased arterial and central venous pressures and systemic vascular resistance and increased heart rate, cardiac index, blood urea nitrogen (BUN) level, creatinine (Cr) concentration, BUN:Cr ratio, and hepatic transaminase levels (P ≤ .05 for toxin effect or time interaction). However, ETx stimulated early diuresis, reduced serum sodium levels, and had more pronounced vasodilatory effects, compared with LeTx, as reflected by greater or earlier central venous pressures, systemic vascular resistance, and changes in the BUN:Cr ratio (P ≤ .01). LeTx progressively decreased the left ventricular ejection fraction (P ≤ .002). In a subsequent study, a lethal dose of LeTx with an equimolar nonlethal ETx dose (n=8) increased mortality, compared with LeTx alone (n=8; P=.05). Conclusions: Shock with ETx or LeTx may require differing supportive therapies, whereas toxin antagonists should likely target both toxins.
AB - Background: High mortality in the 2001 US and recent European anthrax outbreaks suggests that better understanding of the effects of the toxins produced by this bacterium is needed to improve treatment. Methods and results. Here, 24-h edema (ETx) and lethal (LeTx) toxin infusions were investigated for 96 h in sedated canines receiving mechanical ventilation. The initial study compared similarly lethal doses of ETx (n=8) or LeTx (n=15) alone. ETx was 24 times less lethal than LeTx, and the median time to death in nonsurvivors (n=6 and n=9, respectively) was shorter with ETx (42 vs 67 h; P=.04). Compared with controls (n=9), both toxins decreased arterial and central venous pressures and systemic vascular resistance and increased heart rate, cardiac index, blood urea nitrogen (BUN) level, creatinine (Cr) concentration, BUN:Cr ratio, and hepatic transaminase levels (P ≤ .05 for toxin effect or time interaction). However, ETx stimulated early diuresis, reduced serum sodium levels, and had more pronounced vasodilatory effects, compared with LeTx, as reflected by greater or earlier central venous pressures, systemic vascular resistance, and changes in the BUN:Cr ratio (P ≤ .01). LeTx progressively decreased the left ventricular ejection fraction (P ≤ .002). In a subsequent study, a lethal dose of LeTx with an equimolar nonlethal ETx dose (n=8) increased mortality, compared with LeTx alone (n=8; P=.05). Conclusions: Shock with ETx or LeTx may require differing supportive therapies, whereas toxin antagonists should likely target both toxins.
UR - http://www.scopus.com/inward/record.url?scp=78650395903&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78650395903&partnerID=8YFLogxK
U2 - 10.1086/657408
DO - 10.1086/657408
M3 - Article
C2 - 21067373
AN - SCOPUS:78650395903
VL - 202
SP - 1885
EP - 1896
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
SN - 0022-1899
IS - 12
ER -