(See also the Centers for Disease Control and Prevention’s Emergency Preparedness regarding anthrax.)
Etiology of Anthrax
Anthrax is an important domestic animal disease, occurring in goats, cattle, sheep, and horses. Anthrax also occurs in wildlife, such as hippos, elephants, and Cape buffalo. It is rare in humans and occurs mainly in countries that do not prevent industrial or agricultural exposure to infected animals or their products (eg, hides, carcasses, hair). The incidence of natural infection has decreased, particularly in the developed world.
However, the potential use of anthrax as a biological weapon has increased fear of this pathogen. Spores have been prepared in very finely powdered form (weaponized) to be used as agents of warfare and bioterrorism Biological Agents as Weapons Biological warfare (BW) is the use of microbiological agents for hostile purposes. Such use is contrary to international law and has rarely taken place during formal warfare in modern history... read more ; in anthrax bioattacks of 2001, spores were spread in envelopes delivered via the United States Postal Service.
Pathophysiology of Anthrax
Bacillus anthracis readily form spores when they dry—an environmental condition unfavorable for growth. Spores resist destruction and can remain viable in soil, wool, and animal hair and hides for decades. Spores germinate and begin multiplying rapidly when they enter an environment rich in amino acids and glucose (eg, tissue, blood).
Human infection can be acquired by
Cutaneous contact (most common)
Cutaneous infection is usually acquired by contact with infected animals, spore-contaminated animal products, or soil-containing spores or rarely by injection from contaminated heroin in injection drug users. Open wounds or abrasions increase susceptibility, but infection may occur when skin is intact. Cutaneous anthrax is typically not contagious, but in very rare instances skin infection may be transmitted from person to person by direct contact or fomites.
Gastrointestinal (including oropharyngeal) infection may occur after ingestion of inadequately cooked meat containing the vegetative forms of the organism, usually when a break in the pharyngeal or intestinal mucosa facilitates invasion. Ingested anthrax can cause lesions from the oral cavity to the cecum. Released toxin causes hemorrhagic necrotic ulcers and mesenteric lymphadenitis, which may lead to intestinal hemorrhage, obstruction, or perforation.
Pulmonary infection (inhalation anthrax), caused by inhaling spores, is almost always due to occupational exposure to contaminated animal products (eg, hides) and is often fatal.
Gastrointestinal anthrax and inhalation anthrax are not transmitted from person to person.
After entering the body, spores germinate inside macrophages, which migrate to regional lymph nodes where the bacteria multiply. In inhalation anthrax, spores are deposited in alveolar spaces, where they are ingested by macrophages, which migrate to mediastinal lymph nodes, usually causing a hemorrhagic mediastinitis.
Bacteremia Bacteremia Bacteremia is the presence of bacteria in the bloodstream. It can occur spontaneously, during certain tissue infections, with use of indwelling genitourinary or IV catheters, or after dental... read more may occur in any form of anthrax and occurs in nearly all fatal cases; meningeal involvement is common.
The virulence of B. anthracis is due to its
Rapid replication capability
The predominant toxins are edema toxin and lethal toxin. A cell-binding protein, called protective antigen (PA), binds to target cells and facilitates cellular entry of edema toxin and lethal toxin. Edema toxin causes massive local edema. Lethal toxin triggers a massive release of cytokines from macrophages, which is responsible for the sudden death common in anthrax infections.
Symptoms and Signs of Anthrax
Most patients with anthrax present within 1 to 6 days of exposure, but for inhalation anthrax, the incubation period can be > 6 weeks.
Cutaneous anthrax begins as a painless, pruritic, red-brown papule 1 to 10 days after exposure to infective spores. The papule enlarges with a surrounding zone of brawny erythema and marked edema. Vesiculation and induration are present. Central ulceration follows, with serosanguineous exudation and formation of a black eschar (the malignant pustule). Local lymphadenopathy is common, occasionally with malaise, myalgia, headache, fever, nausea, and vomiting. It may take several weeks for the wound to heal and the edema to resolve.
Gastrointestinal anthrax ranges from asymptomatic to fatal. Fever, nausea, vomiting, abdominal pain, and bloody diarrhea are common. Ascites may be present. Intestinal necrosis and septicemia with potentially lethal toxicity ensue.
Oropharyngeal anthrax manifests as edematous lesions with central necrotic ulcers on the tonsils, posterior pharyngeal wall, or hard palate. Soft-tissue swelling in the neck is marked, and cervical lymph nodes are enlarged. Symptoms include hoarseness, sore throat, fever, and dysphagia. Airway obstruction may occur.
Inhalation anthrax begins insidiously as a flu-like illness. Within a few days, fever worsens, and chest pain and severe respiratory distress develop, followed by cyanosis, shock, and coma. Severe hemorrhagic necrotizing lymphadenitis develops and spreads to adjacent mediastinal structures. Serosanguineous transudation, pulmonary edema, and bloody pleural effusion occur. Typical bronchopneumonia does not occur. Hemorrhagic meningoencephalitis or gastrointestinal anthrax may develop.
Diagnosis of Anthrax
Gram stain and culture
Direct fluorescent antibody (DFA) test and polymerase chain reaction (PCR) assay
Occupational and exposure history is important.
Cultures and Gram stain of samples from clinically identified sites, including cutaneous or mucosal lesions, blood, pleural fluid, cerebrospinal fluid, ascites, or stool, should be done. Sputum examination and Gram stain are unlikely to identify inhalation anthrax because airspace disease is frequently absent. A PCR test and immunohistochemical methods (eg, DFA) can help.
Nasal swab testing for spores in people potentially exposed to inhalation anthrax is not recommended because the negative predictive value is unknown. Although a positive nasal swab culture indicates exposure, a negative nasal swab does not mean that exposure has not occurred.
Pearls & Pitfalls
Chest x-ray (or CT) should be done if pulmonary symptoms are present. It typically shows widening of the mediastinum (because of enlarged hemorrhagic lymph nodes) and pleural effusion. Pneumonic infiltrates are uncommon.
Lumbar puncture Lumbar Puncture (Spinal Tap) Lumbar puncture is used to do the following: Evaluate intracranial pressure and cerebrospinal fluid (CSF) composition (see table Cerebrospinal Fluid Abnormalities in Various Disorders) Therapeutically... read more should be done if patients have meningeal signs or a change in mental status.
An enzyme-linked immunosorbent assay (ELISA) can detect antibody in serum, but confirmation requires a 4-fold change in antibody titer from acute to convalescent specimens.
Prognosis for Anthrax
Case fatality rates in untreated anthrax vary depending on infection type:
Inhalation and meningeal anthrax: 100%
Cutaneous anthrax: 10 to 20%
Gastrointestinal anthrax: About 40%
Oropharyngeal anthrax: 12 to 50%
With early diagnosis, treatment, and intensive support, including mechanical ventilation, fluids, and vasopressors, mortality of inhalation anthrax may be reduced to less than the rate in previously documented cases (45% in the US 2001 anthrax attacks and 90% in cases before these attacks).
Treatment of Anthrax
If treatment of anthrax is delayed (usually because the diagnosis is missed), death is more likely.
Cutaneous anthrax without significant edema or systemic symptoms is treated with one of the following antibiotics:
Ciprofloxacin 500 mg (10 to 15 mg/kg for children) orally every 12 hours
Levofloxacin 500 mg orally every 24 hours
Moxifloxacin 400 mg orally every 24 hours
Doxycycline 100 mg (2.5 mg/kg for children) orally every 12 hours
Amoxicillin 1 g every 8 hours may still be used if the infection is thought to have been naturally acquired.
Cutaneous anthrax without significant edema, systemic symptoms, or risk of inhalation exposure is treated with antibiotics for 7 to 10 days. Treatment is extended to 60 days if concomitant inhalation exposure was possible.
Children and pregnant or breastfeeding women, who typically should not be given ciprofloxacin or doxycycline, should nonetheless be given one of these drugs; however, if prolonged treatment is needed, they may be switched to amoxicillin 500 mg (15 to 30 mg/kg for children) 3 times a day after 14 to 21 days if the organism is shown to be susceptible to penicillin. Mortality is rare with treatment, but the lesion will progress through the eschar phase.
Inhalation and other forms of anthrax, including cutaneous anthrax with significant edema or systemic symptoms, require therapy with 3 antibiotics. Antibiotic therapy should include ≥ 2 antibiotics with bactericidal activity, and ≥ 1 should be a protein synthesis inhibitor, which may block toxin production (eg, ciprofloxacin plus clindamycin).
Appropriate antibiotics with bactericidal activity include
Ciprofloxacin 400 mg (10 to 15 mg/kg for children) IV every 12 hours
Levofloxacin 750 mg IV every 24 hours
Moxifloxacin 400 mg IV every 24 hours
Meropenem 2 g IV every 8 hours
Imipenem 1 g IV every 6 hours
Vancomycin IV dosing to maintain serum trough concentration of 15 to 20 mcg/mL (10.4 to 13.8 micromol/L)
Penicillin G 4 million units IV every 4 hours (for penicillin-susceptible strains)
Ampicillin 3 g IV every 4 hours (for penicillin-susceptible stains)
Appropriate antibiotics that inhibit protein synthesis include
Linezolid 600 mg IV every 12 hours
Clindamycin 900 mg IV every 8 hours
Rifampin 600 mg every 12 hours
Chloramphenicol 1 g IV every 6 to 8 hours
Linezolid should be used with caution in patients with myelosuppression; it cannot be used for long periods because of its neurologic side effects.
Chloramphenicol has good central nervous system penetration and has been used to successfully treat anthrax (1 Treatment reference Anthrax is caused by the gram-positive Bacillus anthracis, which are toxin-producing, encapsulated, facultative anaerobic organisms. Anthrax, an often fatal disease of animals, is transmitted... read more ).
Rifampin, although not a protein synthesis inhibitor, may be used in this capacity because it has a synergistic effect with the primary antibiotic.
If meningitis is suspected, meropenem should be used with other antibiotics because it has good central nervous system penetration. If meropenem is not available, imipenem/cilastatin is an equivalent alternative. The initial IV combination therapy should be given for ≥ 2 weeks or until patients are clinically stable, whichever is longer. If patients have been exposed to aerosolized spores, treatment should be continued for 60 days to prevent relapse due to any ungerminated spores that may have survived in their lungs after the initial exposure.
Once IV combination therapy is completed, therapy should be switched to a single oral antibiotic.
Corticosteroids may be useful for meningitis and severe mediastinal edema but have not been evaluated adequately.
Raxibacumab, obiltoxaximab, and Valortim® (MDX-1303) are monoclonal antibodies that bind to the protective antigen protein and can be used in combination with antibiotics to treat inhalation anthrax. Both monoclonal antibodies have shown efficacy in animal models of inhalation anthrax, particularly when given early.
IV anthrax human immune globulin also can be used in combination with antibiotics to treat inhalation anthrax.
Drug resistance is a theoretical concern. Although normally sensitive to penicillin, B. anthracis manifests inducible beta-lactamases, so single-drug therapy with a penicillin or a cephalosporin is generally not recommended.
Biological warfare researchers may have created strains of anthrax that are resistant to multiple antibiotics, but these strains have not yet been encountered in a clinical situation.
1. Hendricks KA, Wright ME, Shadomy SV, et al: Centers for Disease Control and Prevention Expert Panel meetings on prevention and treatment of anthrax in adults. Emerg Infect Dis 20(2), 2014. doi: 10.3201/eid2002.130687
Prevention of Anthrax
An anthrax vaccine, composed of a cell-free culture filtrate, is available for people at high risk (eg, military personnel, veterinarians, laboratory technicians, employees of textile mills processing imported goat hair). Repeated preexposure vaccination with a 5-dose intramuscular series is required to ensure protection. Local reactions from vaccine can occur. A separate veterinary vaccine is also available.
Limited data suggest that cutaneous anthrax does not result in acquired immunity, particularly if early effective antimicrobial therapy was used. Inhalation anthrax may provide some immunity in patients who survive, but data are very limited.
Postexposure measures include
Asymptomatic people (including pregnant women and children) exposed to inhaled anthrax require prophylaxis with one of the following oral antibiotics, given for 60 days:
Ciprofloxacin 500 mg (10 to 15 mg/kg for children) every 12 hours
Doxycycline 100 mg (2.5 mg/kg for children) every 12 hours
Levofloxacin 750 mg every 24 hours
Moxifloxacin 400 mg every 24 hours
Clindamycin 600 mg every 8 hours
If the organism has been shown to be susceptible to penicillin, amoxicillin 500 mg (25 to 30 mg/kg for children) 3 times a day is an option when ciprofloxacin and doxycycline are contraindicated.
Viable spores have been detected in the lungs for ≥ 60 days after aerosol exposure. Because people exposed to aerosolized B. anthracis spores are presumed to be at risk of inhalation anthrax due to ungerminated spores remaining in their lungs after the initial exposure, antibiotic therapy is continued for 60 days to clear germinating organisms.
The Centers for Disease Control and Prevention (CDC) recommend that the anthrax vaccine be administered with antibiotic prophylaxis to patients exposed to anthrax spores. The CDC recommends a 3-dose vaccine series given subcutaneously at 0, 2, and 4 weeks with antimicrobial therapy for at least 60 days. During an emergency (eg, a bioterrorism attack), the only people who should not be given the vaccine after exposure are those who have had a serious allergic reaction to a previous dose of anthrax vaccine (1 Prevention reference Anthrax is caused by the gram-positive Bacillus anthracis, which are toxin-producing, encapsulated, facultative anaerobic organisms. Anthrax, an often fatal disease of animals, is transmitted... read more ).
Raxibacumab, obiltoxaximab, and Valortim® (MDX-1301) are monoclonal antibodies indicated for prophylaxis of inhalation anthrax when alternative therapies are not available or are not appropriate.
Anthrax is typically acquired from infected animals but has been used as a biological weapon.
Potent toxins, including edema toxin and lethal toxin, are responsible for the most severe manifestations.
The main clinical forms of anthrax are cutaneous (most common), oropharyngeal, gastrointestinal, meningeal, and inhalation (most lethal).
Gastrointestinal and inhalation anthrax are not transmitted from person to person.
Treat with ciprofloxacin, levofloxacin, or moxifloxacin plus, for inhalation anthrax, a monoclonal antibody to protective antigen or anthrax immune globulin.
Give postexposure prophylaxis with ciprofloxacin, levofloxacin, moxifloxacin, doxycycline, or clindamycin, anthrax vaccine, and sometimes monoclonal antibodies to people exposed to inhalation anthrax.
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