Protective Antigen Antibody Augments Hemodynamic Support in Anthrax Lethal Toxin Shock in Canines

Barochia, Amisha V.; Cui, Xizhong; Sun, Junfeng; Li, Yan; Solomon, Steven B.; Migone, Thi Sau; Subramanian, G. Mani; Bolmer, Sally D.; Eichacker, Peter Q.

doi:10.1093/infdis/jir834

Cited by 13 publications

(32 citation statements)

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“…Circulating ET in these patients could have contributed to this shock by causing arterial relaxation directly as well as by inhibiting the vasoconstrictor action of endogenous or therapeutically administered catecholamines. Possibly consistent with this, in a sedated and mechanically ventilated canine model, a regimen of fluid and norepinephrine support, which improved survival in LT-challenged animals, was ineffective with a similarly lethal ET challenge (3,34).…”

Section: Discussionmentioning

confidence: 71%

“…In initial experiments, pretreatment with ET but not LT inhibited the contractile response of aortic rings to phenylephrine (PE) stimulation. In subsequent experiments directed at ET, we examined whether PA-directed monoclonal antibody (mAb) or adefovir, a nucleoside that selectively blocks EF-stimulated cAMP production, inhibited the effects of the toxin and whether ET's relaxant effects required an intact arterial endothelium (3,36,37). Also, to determine whether ET reverses catecholamine-induced arterial contraction, we measured its relaxant effects on aortic rings precontracted with PE.…”

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confidence: 99%

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B. anthracisedema toxin increases cAMP levels and inhibits phenylephrine-stimulated contraction in a rat aortic ring model

Cui

Solomon

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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B. anthracis edema toxin (ET) and lethal toxin (LT) are each composed of protective antigen (PA), necessary for toxin uptake by host cells, and their respective toxic moieties, edema factor (EF) and lethal factor (LF). Although both toxins likely contribute to shock during infection, their mechanisms are unclear. To test whether ET and LT produce arterial relaxation, their effects on phenylephrine (PE)-stimulated contraction in a Sprague-Dawley rat aortic ring model were measured. Rings were prepared and connected to pressure transducers. Their viability was confirmed, and peak contraction with 60 mM KCl was determined. Compared with PA pretreatment (control, 60 min), ET pretreatment at concentrations similar to those noted in vivo decreased the mean (±SE) maximum contractile force (MCF; percent peak contraction) in rings generated during stimulation with increasing PE concentrations (96.2 ± 7.0 vs. 57.3 ± 9.1) and increased the estimated PE concentration producing half the MCF (EC50; 10(-7) M, 1.1 ± 0.3 vs. 3.7 ± 0.8, P ≤ 0.002). ET inhibition with PA-directed monoclonal antibodies, selective EF inhibition with adefovir, or removal of the ring endothelium inhibited the effects of ET on MCF and EC50 (P ≤ 0.02). Consistent with its adenyl cyclase activity, ET increased tissue cAMP in endothelium-intact but not endothelium-denuded rings (P < 0.0001 and 0.25, respectively). LT pretreatment, even in high concentrations, did not significantly decrease MCF or increase EC50 (all P > 0.05). In rings precontracted with PE compared with posttreatment with PA (90 min), ET posttreatment produced progressive reductions in contractile force and increases in relaxation in endothelium-intact rings (P < 0.0001) but not endothelium-denuded rings (P = 0.51). Thus, ET may contribute to shock by producing arterial relaxation.

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Section: Discussionmentioning

confidence: 71%

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confidence: 99%

B. anthracisedema toxin increases cAMP levels and inhibits phenylephrine-stimulated contraction in a rat aortic ring model

Cui

Solomon

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…27,42 While antimicrobials prevent bacterial replication, they do not prevent the uptake of toxin and the subsequent formation of toxin complexes. 18,46,48,52 There is a biologically plausible conceptual basis to support antitoxin use in addition to antimicrobial therapy—to prevent intracellular uptake of circulating toxin. Antitoxin appears safe and well tolerated, 18,32,52 and thus the benefits appear to outweigh the risks.…”

Section: Discussionmentioning

confidence: 99%

Antitoxin Treatment of Inhalation Anthrax: A Systematic Review

Huang¹,

Pillai²,

Bower³

et al. 2015

Health Security

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Concern about use of anthrax as a bioweapon prompted development of novel anthrax antitoxins for treatment. Clinical guidelines for the treatment of anthrax recommend antitoxin therapy in combination with intravenous antimicrobials; however, a large-scale or mass anthrax incident may exceed antitoxin availability and create a need for judicious antitoxin use. We conducted a systematic review of antitoxin treatment of inhalation anthrax in humans and experimental animals to inform antitoxin recommendations during a large-scale or mass anthrax incident. A comprehensive search of 11 databases and the FDA website was conducted to identify relevant animal studies and human reports: 28 animal studies and 3 human cases were identified. Antitoxin monotherapy at or shortly after symptom onset demonstrates increased survival compared to no treatment in animals. With early treatment, survival did not differ between antimicrobial monotherapy and antimicrobial-antitoxin therapy in nonhuman primates and rabbits. With delayed treatment, antitoxin-antimicrobial treatment increased rabbit survival. Among human cases, addition of antitoxin to combination antimicrobial treatment was associated with survival in 2 of the 3 cases treated. Despite the paucity of human data, limited animal data suggest that adjunctive antitoxin therapy may improve survival. Delayed treatment studies suggest improved survival with combined antitoxin-antimicrobial therapy, although a survival difference compared with antimicrobial therapy alone was not demonstrated statistically. In a mass anthrax incident with limited antitoxin supplies, antitoxin treatment of individuals who have not demonstrated a clinical benefit from antimicrobials, or those who present with more severe illness, may be warranted. Additional pathophysiology studies are needed, and a point-of-care assay correlating toxin levels with clinical status may provide important information to guide antitoxin use during a large-scale anthrax incident.

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“…A more recent study investigating the efficacy of norepinephrine treatment also showed that while norepinephrine improved survival of rats challenged with LPS and increased blood pressure before the onset of lethality with LT, it did not improve survival with the latter [87]. In contrast to these rat studies, however, in a mechanically ventilated canine model, conventional hemodynamic support (i.e., fluids and norepinephrine titrated on the basis of intravascular hemodynamic measures) did improve outcome [88]. Interestingly, the protective effects of hemodynamic support were enhanced when combined with anti-PA directed monoclonal antibody.…”

Section: Managementmentioning

confidence: 99%

An overview of anthrax infection including the recently identified form of disease in injection drug users

et al. 2012

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Purpose Bacillus anthracis infection (anthrax) can be highly lethal. Two recent outbreaks related to contaminated mail in the USA and heroin in the UK and Europe and its potential as a bioterrorist weapon have greatly increased concerns over anthrax in the developed world. Methods This review summarizes the microbiology, pathogenesis, diagnosis, and management of anthrax. Results and conclusions Anthrax, a gram-positive bacterium, has typically been associated with three forms of infection: cutaneous, gastrointestinal, and inhalational. However, the anthrax outbreak among injection drug users has emphasized the importance of what is now considered a fourth disease form (i.e., injectional anthrax) that is characterized by severe soft tissue infection. While cutaneous anthrax is most common, its early stages are distinct and prompt appropriate treatment commonly produces a good outcome. However, early symptoms with the other three disease forms can be nonspecific and mistaken for less lethal conditions. As a result, patients with gastrointestinal, inhalational, or injectional anthrax may have advanced infection at presentation that can be highly lethal. Once anthrax is suspected, the diagnosis can usually be made with gram stain and culture from blood or tissue followed by confirmatory testing (e.g., PCR). While antibiotics are the mainstay of anthrax treatment, use of adjunctive therapies such as anthrax toxin antagonists are a consideration. Prompt surgical therapy appears to be important for successful management of injectional anthrax.

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Protective Antigen Antibody Augments Hemodynamic Support in Anthrax Lethal Toxin Shock in Canines

Abstract: PA-mAb may augment conventional hemodynamic support during anthrax LT-associated shock.

Cited by 13 publications

References 40 publications

B. anthracisedema toxin increases cAMP levels and inhibits phenylephrine-stimulated contraction in a rat aortic ring model

B. anthracisedema toxin increases cAMP levels and inhibits phenylephrine-stimulated contraction in a rat aortic ring model

Antitoxin Treatment of Inhalation Anthrax: A Systematic Review

An overview of anthrax infection including the recently identified form of disease in injection drug users

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