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Anthrax

By Larry M. Bush, MD, Maria T. Perez, MD

Anthrax is caused by Bacillus anthracis, toxin-producing, encapsulated, facultative anaerobic organisms. Anthrax, an often fatal disease of animals, is transmitted to humans by contact with infected animals or their products. In humans, infection is typically acquired through the skin. Inhalation infection is less common; oropharyngeal, meningeal, and GI infections are rare. For inhalation and GI infections, nonspecific local symptoms are typically followed in several days by severe systemic illness, shock, and often death. Empiric treatment is with ciprofloxacin or doxycycline. A vaccine is available.

(See also the Centers for Disease Control and Prevention’s Emergency Preparedness regarding anthrax.)

Etiology

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; in anthrax bioattacks of 2001, spores were spread in envelopes delivered via the United States Postal Service.

Pathophysiology

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)

  • Ingestion

  • Inhalation

Cutaneous infection is usually acquired by contact with infected animals or spore-contaminated animal products. Open wounds or abrasions increase susceptibility, but infection may occur when skin is intact. Skin infection may be transmitted from person to person by direct contact or fomites.

GI (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 spores 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.

GI 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 may occur in any form of anthrax and occurs in nearly all fatal cases; meningeal involvement is common.

Virulence factors

The virulence of B. anthracis is due to its

  • Antiphagocytic capsule

  • Toxins (factors)

  • 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

Most patients present within 1 to 6 days of exposure, but for inhalation anthrax, the incubation period can be > 6 wk.

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.

GI 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 GI anthrax may develop.

Diagnosis

  • Gram stain and culture

Occupational and exposure history is important.

Cultures and Gram stain of samples from clinically identified sites, including cutaneous or mucosal lesions, pleural fluid, CSF, 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 can help.

Nasal swab testing for spores in people potentially exposed to inhalation anthrax is not recommended because the predictive value is unknown.

Pearls & Pitfalls

  • Sputum examination and Gram stain are unlikely to identify inhalation anthrax because airspace disease is frequently absent.

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 should be done if patients have meningeal signs or a change in mental status.

An enzyme-linked immunosorbent assay (ELISA) is available, but confirmation requires a 4-fold change in antibody titer from acute to convalescent specimens.

Prognosis

Mortality in untreated anthrax varies depending on infection type:

  • Inhalation and meningeal anthrax: 100%

  • Cutaneous anthrax: 10 to 20%

  • GI anthrax: About 50%

  • Oropharyngeal anthrax: 12 to 50%

Treatment

  • Antibiotics

With early diagnosis, treatment, and intensive support, including mechanical ventilation, fluids, and vasopressors, mortality 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). If treatment is delayed (usually because the diagnosis is missed), death is likely.

Antibiotics

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) po q 12 h

  • Levofloxacin 500 mg po q 24 h

  • Doxycycline 100 mg (2.5 mg/kg for children) po q 12 h

Amoxicillin 500 mg q 8 h 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) tid 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 2 or 3 antibiotics. Antibiotic therapy should include ≥1 antibiotic with bactericidal activity, and ≥1 should be a protein synthesis inhibitor, which may block toxin production (eg, ciprofloxacin plus clindamycin).

Antibiotics with bactericidal activity include

  • Ciprofloxacin 400 mg (10 to 15 mg/kg for children) IV q 12 h

  • Levofloxacin 750 mg IV q 24 h

  • Moxifloxacin 400 mg IV q 24 h

  • Meropenem 2 g IV q 8 h

  • Imipenem 1 g IV q 6 h

  • Vancomycin IV dosing to maintain serum trough concentration of 15 to 20 mcg/mL

  • Penicillin G 4 million units IV q 4 h (for penicillin-susceptible strains)

  • Ampicillin 3 g IV q 4 h (for penicillin-susceptible stains)

Antibiotics that inhibit protein synthesis include

  • Linezolid 600 mg IV q 12 h

  • Clindamycin 900 mg IV q 8 h

  • Doxycycline 200 mg IV initially, then 100 mg q 12 h

  • Chloramphenicol 1 g IV q 6 to 8 h

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 CNS penetration and has been used to successfully treat anthrax1.

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 CNS penetration. If meropenem is not available, imipenem/cilastatin is an equivalent alternative. The initial IV combination therapy should be given for ≥ 2 wk 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.

Other drugs

Corticosteroids may be useful for meningitis and severe mediastinal edema but have not been evaluated adequately.

Ca channel blockers and ACE inhibitors may be considered.

Raxibacumab is a monoclonal antibody that can be used to treat effects of toxins already present and can be combined with antibacterial therapy. Raxibacumab has shown efficacy in animal models of inhalation anthrax, particularly when given early.

Drug resistance

Drug resistance is a theoretical concern. Although normally sensitive to penicillin, B. anthracis manifests inducible β-lactamases, so single-drug therapy with a penicillin or a cephalosporin is 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.

Prevention

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). A separate veterinary vaccine is also available. Repeated vaccination is required to ensure protection. Local reactions from vaccine can occur.

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 prophylaxis

Postexposure measures include

  • Antibiotics

  • Vaccination

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) q 12 h

  • Doxycycline 100 mg (2.5 mg/kg for children) q 12 h

  • Levofloxacin 750 mg q 24 h

  • Moxifloxacin 400 mg q 24 h

If the organism has been shown to be susceptible to penicillin, amoxicillin 500 mg (25 to 30 mg/kg for children) tid 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) recommends that the anthrax vaccine be administered with antibiotic prophylaxis to patients exposed to anthrax spores. Postexposure antibiotic treatment is extended to 100 days in patients who are vaccinated.

Key Points

  • 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, GI, and inhalation (most lethal).

  • GI and inhalation anthrax are not transmitted from person to person.

  • Treat with ciprofloxacin or doxycycline plus an additional drug for inhalation anthrax.

  • Give postexposure prophylaxis with ciprofloxacin, levofloxacin, or doxycycline and anthrax vaccine to people exposed to inhaled anthrax.

More Information

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Brand Names
  • PERIOSTAT, VIBRAMYCIN
  • CILOXAN, CIPRO
  • RIFADIN, RIMACTANE
  • IQUIX, LEVAQUIN, QUIXIN
  • AMOXIL
  • CLEOCIN
  • AVELOX
  • VANCOCIN
  • MERREM
  • No US brand name
  • ZYVOX
  • RAXIBACUMAB

* This is the Professional Version. *