Anthrax is a toxin-mediated zoonotic disease caused by Bacillus anthracis, with a worldwide distribution recognized for millennia. Bacillus anthracis is considered a potential biowarfare agent.
We completed a systematic review for clinical and demographic characteristics of adults and children hospitalized with anthrax (cutaneous, inhalation, ingestion, injection [from contaminated heroin], primary meningitis) abstracted from published case reports, case series, and line lists in English from 1880 through 2018, assessing treatment impact by type and severity of disease. We analyzed geographic distribution, route of infection, exposure to anthrax, and incubation period.
Data on 764 adults and 167 children were reviewed. Most cases reported for 1880 through 1915 were from Europe; those for 1916 through 1950 were from North America; and from 1951 on, cases were from Asia. Cutaneous was the most common form of anthrax for all populations. Since 1960, adult anthrax mortality has ranged from 31% for cutaneous to 90% for primary meningitis. Median incubation periods ranged from 1 day (interquartile range [IQR], 0-4) for injection to 7 days (IQR, 4-9) for inhalation anthrax. Most patients with inhalation anthrax developed pleural effusions and more than half with ingestion anthrax developed ascites. Treatment and critical care advances have improved survival for those with systemic symptoms, from approximately 30% in those untreated to approximately 70% in those receiving antimicrobials or antiserum/antitoxin.
This review provides an improved evidence base for both clinical care of individual anthrax patients and public health planning for wide-area aerosol releases of B. anthracis spores.

Bacillus anthracis is a high-priority threat agent because of its widespread availability, easy dissemination, and ability to cause substantial morbidity and mortality. Although timely and appropriate antimicrobial therapy can reduce morbidity and mortality, the role of adjunctive therapies continues to be explored.
We searched 11 databases for articles that report use of anthrax antitoxins in treatment or prevention of systemic anthrax disease published through July 2019. We identified other data sources through reference search and communication with experts. We included English-language studies on antitoxin products with approval by the US Food and Drug Administration (FDA) for anthrax in humans, nonhuman primates, and rabbits. Two researchers independently reviewed studies for inclusion and abstracted relevant data.
We abstracted data from 12 publications and 2 case reports. All 3 FDA-approved anthrax antitoxins demonstrated significant improvement in survival as monotherapy over placebo in rabbits and nonhuman primates. No study found significant improvement in survival with combination antitoxin and antimicrobial therapy compared to antimicrobial monotherapy. Case reports and case series described 25 patients with systemic anthrax disease treated with antitoxins; 17 survived. Animal studies that used antitoxin monotherapy as postexposure prophylaxis (PEP) demonstrated significant improvement in survival over placebo, with greatest improvements coming with early administration.
Limited human and animal evidence indicates that adjunctive antitoxin treatment may improve survival from systemic anthrax infection. Antitoxins may also provide an alternative therapy to antimicrobials for treatment or PEP during an intentional anthrax incident that could involve a multidrug-resistant B. anthracis strain.

Bacillus anthracis can cause anthrax and is a potential bioterrorism agent. The 2014 Centers for Disease Control and Prevention recommendations for medical countermeasures against anthrax were based on in vitro data and expert opinion. However, a century of previously uncompiled observational human data that often includes treatment and outcomes is available in the literature for analysis.
We reviewed treatment outcomes for patients hospitalized with anthrax. We stratified patients by meningitis status, route of infection, and systemic criteria, then analyzed survival by treatment type, including antimicrobials, antitoxin/antiserum, and steroids. Using logistic regression, we calculated odds ratios and 95% confidence intervals to compare survival between treatments. We also calculated hospital length of stay. Finally, we evaluated antimicrobial postexposure prophylaxis (PEPAbx) using data from a 1970 Russian-language article.
We identified 965 anthrax patients reported from 1880 through 2018. After exclusions, 605 remained: 430 adults, 145 children, and 30 missing age. Survival was low for untreated patients and meningitis patients, regardless of treatment. Most patients with localized cutaneous or nonmeningitis systemic anthrax survived with 1 or more antimicrobials; patients with inhalation anthrax without meningitis fared better with at least 2. Bactericidal antimicrobials were effective for systemic anthrax; addition of a protein synthesis inhibitor(s) (PSI) to a bactericidal antimicrobial(s) did not improve survival. Likewise, addition of antitoxin/antiserum to antimicrobials did not improve survival. Mannitol improved survival for meningitis patients, but steroids did not. PEPAbx reduced risk of anthrax following exposure to B. anthracis.
Combination therapy appeared to be superior to monotherapy for inhalation anthrax without meningitis. For anthrax meningitis, neither monotherapy nor combination therapy were particularly effective; however, numbers were small. For localized cutaneous anthrax, monotherapy was sufficient. For B. anthracis exposures, PEPAbx was effective.

Anti-toxin agents for severe B. anthracis infection will only be effective if they add to the benefit of the two mainstays of septic shock management, antibiotic therapy and titrated hemodynamic support. Both of these standard therapies could negate benefits related to anti-toxin treatment. At present, three anthrax anti-toxin antibody preparations have received US Food and Drug Administration (FDA) approval: Raxibacumab, Anthrax Immune Globulin Intravenous (AIGIV) and ETI-204. Each agent is directed at the protective antigen component of lethal and edema toxin. All three agents were compared to placebo in antibiotic-treated animal models of live B. anthracis infection, and Raxibacumab and AIGIV were compared to placebo when combined with standard hemodynamic support in a 96 h canine model of anthrax toxin-associated shock. However, only AIG has actually been administered to a group of infected patients, and this experience was not controlled and offers little insight into the efficacy of the agents. To provide a broader view of the potential effectiveness of these agents, this review examines the controlled preclinical experience either in antibiotic-treated B. anthracis models or in titrated hemodynamic-supported toxin-challenged canines. The strength and weaknesses of these preclinical experiences are discussed.

Clostridium difficile is the most commonly reported pathogen to cause nosocomial infections in the United States with a high burden affecting morbidity, mortality and healthcare expenditure. The use of Fecal Microbiota Transplantation (FMT) is one of the current standard therapies for recurrent C. difficile infection (CDIr). One emerging promising approach is the use of monoclonal antibodies that bind to and neutralize C. difficile toxins such as Bezlotoxumab. We present the first case report on combining the third FMT with bezlotoxumab after the failure of standard-of-care antibiotics and two trials of FMT alone, with subsequent success in preventing the recurrence of refractory CDI for 12 weeks following treatment. This case highlights the need for further studies and guidelines to recommend the best combination among different treatment options and modalities.

B. anthracis anti-toxin agents are approved and included in the Strategic National Stockpile based primarily on animal infection trials. However, in the only anthrax outbreak an approved anti-toxin agent was administered in, survival did not differ comparing recipients and non-recipients, although recipients appeared sicker.
Employ a systematic review and meta-analysis to investigate preclinical studies supporting anthrax anti-toxin agents.
PubMed, EMBASE, and Scopus.
Compared survival with an anti-toxin agent versus control in B. anthracis challenged, antibiotic treated animals.
Examine model and study design and the effect of anti-toxin agents on relative risk of death(95%CI) (RR).
From 9 studies, 29 experiments were analyzed which included 4 species (748 animals) and 5 agents; LFI, AIG, AVP-21D9, Raxibacumab, and ETI-204. Only five experiments were blinded and no experiment included the cardiopulmonary support sick B. anthracis patients receive. Only one agent in a single un-blinded experiment reduced RR significantly [0.45(0.22,0.940]. However, in six studies testing an agent in more than one experiment in the same species, agents had consistent survival effects across experiments [I2 = 0, p≥0.55 in five and I2 = 42%, p = 0.16 in one]. Within each species, agents had effects on the side of benefit; in one study testing AVP-21D9 in mice [0.11(0.01,1.82)] or guinea pigs [0.70(0.48,1.03)]; across eight rabbit studies testing LFI, Raxibacumab, AIG or ETI-204 [0.62(0.45,0.87); I2 = 17.4%, p = 0.29]; and across three monkey studies testing Raxibacumab, AIG or ETI-204 [0.66(0.34,1.27); I2 = 25.3%, p = 0.26]. Across all agents and species, agents decreased RR [0.64(0.52,0.79); I2 = 5.3%, p = 0.39].
Incidence of selective reporting not identifiable.
Although overall significant, individually anti-toxin agents had weak beneficial effects. Lack of study blinding and relevant clinical therapies further weakened studies. Although difficult, preclinical studies with more robust designs and results are warranted to justify the resources necessary to maintain anti-toxin agents in national stockpiles.

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.

Systemic anthrax is associated with high mortality. Current national guidelines, developed for the individualized treatment of systemic anthrax, outline the use of combination intravenous antimicrobials for a minimum of 2 weeks, bactericidal and protein synthesis inhibitor antimicrobials for all cases of systemic anthrax, and at least 3 antimicrobials with good blood-brain barrier penetration for anthrax meningitis. However, in an anthrax mass casualty incident, large numbers of anthrax cases may create challenges in meeting antimicrobial needs. To further inform our understanding of the role of antimicrobials in treating systemic anthrax, a systematic review of the English-language literature was conducted to identify cases of systemic anthrax treated with antimicrobials for which a clinical outcome was recorded. A total of 149 cases of systemic anthrax were identified. Among the identified 59 cases of cutaneous anthrax, 33 were complicated by meningitis (76% mortality), while 26 simply had evidence of the systemic inflammatory response syndrome (4% mortality); 21 of 26 (81%) of this latter group received monotherapy. Subsequent analysis regarding combination antimicrobial therapy was restricted to the remaining 123 cases of more severe anthrax (overall 67% mortality). Recipients of combination bactericidal and protein synthesis inhibitor therapy had a 45% survival versus 28% in the absence of combination therapy (p = 0.07). For meningitis cases (n = 77), survival was greater for those receiving 3 or more antimicrobials over the course of treatment (3 of 4; 75%), compared to receipt of 1 or 2 antimicrobials (12 of 73; 16%) (p = 0.02). Median parenteral antimicrobial duration was 14 days. Combination bactericidal and protein synthesis inhibitor therapy may be appropriate in severe anthrax disease, particularly anthrax meningitis, in a mass casualty incident.

There is a need to develop food-compatible conditions to alter the structures of fungal, bacterial, and plant toxins, thus transforming toxins to nontoxic molecules. The term \'chemical genetics\' has been used to describe this approach. This overview attempts to survey and consolidate the widely scattered literature on the inhibition by natural compounds and plant extracts of the biological (toxicological) activity of the following food-related toxins: aflatoxin B1, fumonisins, and ochratoxin A produced by fungi; cholera toxin produced by Vibrio cholerae bacteria; Shiga toxins produced by E. coli bacteria; staphylococcal enterotoxins produced by Staphylococcus aureus bacteria; ricin produced by seeds of the castor plant Ricinus communis; and the glycoalkaloid α-chaconine synthesized in potato tubers and leaves. The reduction of biological activity has been achieved by one or more of the following approaches: inhibition of the release of the toxin into the environment, especially food; an alteration of the structural integrity of the toxin molecules; changes in the optimum microenvironment, especially pH, for toxin activity; and protection against adverse effects of the toxins in cells, animals, and humans (chemoprevention). The results show that food-compatible and safe compounds with anti-toxin properties can be used to reduce the toxic potential of these toxins. Practical applications and research needs are suggested that may further facilitate reducing the toxic burden of the diet. Researchers are challenged to (a) apply the available methods without adversely affecting the nutritional quality, safety, and sensory attributes of animal feed and human food and (b) educate food producers and processors and the public about available approaches to mitigating the undesirable effects of natural toxins that may present in the diet.

暂无摘要。