• Anthrax is a highly infectious disease of animals, especially ruminants (hooved animals such as cows, goats, and sheep) that is caused by the bacteria Bacillus anthracis. Cutaneous (95% of US cases), inhalational, and GI forms can be transmitted to humans by contact with the animals or their products (typically hair or hides).
• Synonym(s) for cutaneous anthrax: Charbon; malignant pustule; Siberian ulcer; malignant edema; splenic fever; milzbrand
• Synonym(s) for inhalational anthrax: Ragpicker disease; woolsorter disease

• Total of 235 anthrax cases (224 cutaneous and 11 inhalational) occurred in the US between 1955 and 1994, resulting in 20 fatalities.
• Cutaneous: 95% of cases in the US; cases of cutaneous anthrax without occupational risk should raise concern for bioterrorism.
  • ~5–20% of untreated cases result in death; case fatality rate is <1% with antibiotic therapy.
• GI: Very rare in the US (no documented case in the 20th century).
• Inhalational anthrax is rare in the US; must be considered a bioterrorist event in US until proven otherwise (the last US occupational case occurred in 1976):
  • Death results in 99% of untreated cases and in 45–80% of patients with severe symptoms who are treated in a state-of-the-art facility.
• Anthrax is most common in agricultural regions, where it occurs in animals. These regions include the Middle East, Asia, Southern and Eastern Europe, Africa, South and Central America, and the Caribbean.

• Contact with infected animals or their products
• Bioterrorist event

• Anthrax vaccine protects against all forms of anthrax and is as safe as other vaccines, according to the FDA, CDC, and the National Academy of Sciences.
• A 2009 review by the Cochrane Infectious Disease Group concluded that the anthrax vaccine is effective in reducing the risk of contracting anthrax and has a low rate of adverse effects (1)[A].
• Anthrax vaccine should be effective against all known strains of B. anthracis as well as against any strains that might be bioengineered by terrorists or others.
• Vaccine schedule and route changed in late 2008: Route is now IM (previously SC) and schedule is decreased from 6 doses to 5 doses (0 and 4 weeks, and 6, 12, and 18 months) plus annual boosters. IM versus SC injection greatly reduces the incidence of injection-site adverse events (2)[A]:
  • Anthrax vaccine adsorbed (trade name BioThrax) is FDA approved for ages 18 through 65 and is pregnancy category D.
  • If you get behind schedule, do not start the series over; begin where you left off (delays do not reduce the resulting protection).
  • Individuals are not considered protected until they have completed the full vaccination series.
  • The most common (>10%) local (injection-site) adverse reactions observed in clinical studies were tenderness, pain, erythema, and arm motion limitation. The most common (>5%) systemic adverse reactions were muscle aches, fatigue, and headache.
  • The Advisory Committee on Immunization Practices recommends vaccination for the following groups:
    • Persons who work directly with the organism in the laboratory
    • Persons who work with imported animal hides or furs in areas where standards are insufficient to prevent exposure to anthrax spores
    • Persons who handle potentially infected animal products in high-incidence areas
    • Military personnel deployed to areas with high risk for exposure to organisms (when used as a biologic warfare weapon)
    • Pregnant women should be vaccinated for anthrax only if absolutely necessary.
• Patients with a likely inhalational exposure history but no symptoms are candidates for postexposure prophylaxis with either ciprofloxacin 500 mg PO b.i.d. or doxycycline 100 mg PO b.i.d. for 60 days. Levofloxacin is also FDA approved for patients age 18 or older. CDC guidelines state patients should also receive 3 doses of anthrax vaccine (0, 2 weeks, 4 weeks), but since BioThrax is not licensed for postexposure prophylaxis or for a 3-dose series, this would need to be conducted under an Investigational New Drug application. Prophylactic medications are not indicated for prevention of cutaneous anthrax.

• B. anthracis is a spore-forming, gram-positive bacterium found in the soil worldwide. The word anthracis is derived from a Greek word meaning “coal,” which is used to describe the cutaneous form of the disease that leads to a characteristic black lesion.
• B. anthracis has 3 known virulence factors: An antiphagocytic capsule and 2 protein toxins (known as edema factor and lethal factor):
  • The capsule provides resistance to phagocytosis.
  • Lethal factor and edema factor are named for the effects they induce when injected into experimental animals.
  • A protein called protective antigen binds to the host cell’s surface; when cleaved by a protease on the cell surface it creates a site to which the lethal factor and edema factor can bind; protective antigen is required for the action of the 2 protein toxins.
• B. anthracis spores introduced into the host are ingested at the exposed site by macrophages and then germinate into vegetative forms that produce the virulence factors.

• Cutaneous: Occurs when B. anthracis enters the skin through a cut or abrasion during the handling of animal products (e.g., meat, wool, or hides infected with B. anthracis)
• GI: Ingestion of bacillus-contaminated meat
• Inhalational: Inhalation of aerosolized B. anthracis spores

• Cutaneous: Incubation period is usually immediate up to 1 day. Begins as a pruritic spot, followed by a red-brown papule that enlarges with peripheral erythema, vesiculation, and induration, followed by black eschar formation within 7–10 days of the initial lesion:
  • The papule, blister, and eschar are painless, and cutaneous symptoms may be accompanied by fever, malaise, and headache.
  • A black eschar with massive edema is nearly pathognomonic for cutaneous anthrax.
• GI: Incubation period is usually 1–7 days. Presents as 1 of 2 distinct syndromes—oropharyngeal and abdominal:
  • Oropharyngeal syndrome presentation can include fever, edema, ulcer, severe sore throat, and lymphadenopathy, resulting in marked unilateral or bilateral neck swelling.
  • Abdominal syndrome may present with fever, malaise, hematemesis, anorexia, severe abdominal pain, and hematochezia or melena. 2–4 days after onset of symptoms, pain begins to subside and ascites develops, with shock and death within just a few days.
• Inhalational: Incubation period is usually <1 week, but may be up to 60 days. Biphasic presentation, with initial phase featuring nonspecific influenzalike symptoms (e.g., low-grade fever, chills, headache, nonproductive cough, diaphoresis, malaise, chest discomfort, nausea, vomiting, diarrhea, abdominal pain):
  • This initial phase is followed by a 2nd fulminant phase that begins 1–5 days after onset of the initial phase symptoms. Signs and symptoms of the fulminant phase include abrupt onset of high fever, severe dyspnea, hypoxia, hypotension, and death within 24–36 hours.

• Cutaneous: Crucial clinical clues are rapid evolution of symptoms, lack of pain, occasional massive edema, and the near pathognomonic black eschar. Incubation period is usually immediate but may last up to 1 day.
• GI: Incubation period usually 1–7 days; 2–4 days after onset of symptoms, ascites develops as abdominal pain decreases. Shock and death occur within 2–5 days after onset of symptoms.
• Inhalational: Incubation period is usually <1 week but may be as long as 2 months. 2nd portion of the biphasic presentation begins 1–5 days after onset of initial symptoms. There may be a 1–3 day period of improvement after the 1st phase and before the 2nd phase begins. Shock and death occur within 24–36 hours after onset of the 2nd phase.

• Cutaneous: Red-brown papule, vesicles, or black eschar
• GI: Acute abdomen with rebound tenderness may occur. Ascites presents later in course.
• Inhalational: Rhonchi may be present.

Lab Gram stain and culture. Obtain specimens for culture before initiating antimicrobial therapy. B. anthracis is easily isolated from blood cultures in <24 hours. A presumptive diagnosis can be made if gram-positive rods are present that are nonmotile, nonhemolytic, and encapsulated (usually seen with India ink). If antibiotics have been given for >24 hours, perform immunohistochemical staining and/or PCR.

Imaging

• Inhalational: Widened mediastinum on chest x-ray (CXR) may be present; pleural effusions frequently present; infiltrates are rare.
• CXR is indicated for suspected inhalational anthrax (3)[A].
• CT chest for patients with suspected anthrax but normal CXR (3)[A]
• GI: Mesenteric adenopathy on CT scan is likely.

• Skin cellulitis
• Brown recluse spider bite
• Cat-scratch disease
• Rat bite fever
• Rickettsial spotted fever
• Carbuncle
• Cowpox
• Bullous erysipelas
• Tularemia vasculitides
• Ecthyma gangrenosum
• Orf (a transmissible viral disease of goats and sheep)

First Line

• Cutaneous: Ciprofloxacin 500 mg PO b.i.d. or doxycycline 100 mg PO b.i.d. for 7–10 days for localized or uncomplicated cases of naturally acquired cutaneous anthrax. Treat for 7–10 days with IV instead for severe cases of naturally acquired cutaneous anthrax with signs of systemic involvement, extensive edema, or lesions of the head and neck.
  • If cutaneous case is localized or uncomplicated but is bioterrorism-related, the patient must be treated for 60 days with PO ciprofloxacin or doxycycline because they are at risk for inhalational anthrax.
  • Patients with bioterrorism-related cutaneous anthrax who show signs of systemic involvement, massive edema, or lesions on the head or neck should be treated per inhalational anthrax recommendation (below) (4,5)[C].
• Inhalational and GI: IV ciprofloxacin 400 mg q12h (1st line) or doxycycline 100 mg q12h (2nd line) and 1 or 2 additional antimicrobials such as rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, and clarithromycin
  • May switch to PO when clinically appropriate.
  • Must complete 60-day course (combined PO and IV) (4)[C].
  • Early and aggressive pleural fluid drainage is recommended for all inhalational anthrax patients (5)[C].

Second Line Patients being treated for anthrax may also benefit from vaccination as part of their regimen.

General Measures

• Inhalational and GI anthrax are not known to spread from person to person, so communicability concerns are not an issue during management of the patient.
• Although cutaneous anthrax is also considered noncontagious, avoidance of contact with the wound or wound drainage seems prudent.

Patient Monitoring Must monitor patient for 60 days to ensure completion of the treatment course.

• Cutaneous: Death in 5–20% of untreated cases, but the case fatality rate is <1% with antibiotic therapy
• GI: Mortality rates as high as 50% reported
• Inhalational: Death in 45–80% of patients with severe symptoms who are treated in a state-of-the-art facility; case fatality rate approaches 99% in untreated cases.

• Centers for Disease Control and Prevention, Emergency Preparedness and Response. http://www.bt.cdc.gov/agent/anthrax/
• Durning SJ, Roy MJ. Anthrax. In: Roy MJ, ed. Physician’s Guide to Terrorist Attack. Totowa, NJ: Humana, 2003.
• Marano N, Plikaytis BD, Martin SW, et al. Effects of a reduced dose schedule and intramuscular administration of anthrax vaccine adsorbed on immunogenicity and safety at 7 months: A randomized trial. JAMA. 2008;300:1532–43.
• Schwartz MN. Recognition and management of anthrax—an update. N Engl J Med. 2001;345:1621–1626.
• The anthrax vaccine immunization program. http://www.anthrax.mil

• 022.0 Cutaneous anthrax
• 022.1 Pulmonary anthrax
• 022.9 Anthrax, unspecified
• 022.2 Gastrointestinal anthrax
• 022.3 Anthrax septicemia

• A22.9 Anthrax, unspecified
• A22.0 Cutaneous anthrax
• A22.1 Pulmonary anthrax
• A22.2 Gastrointestinal anthrax
• A22.7 Anthrax sepsis

• 409498004 Anthrax (disorder)
• 84980006 cutaneous anthrax (disorder)
• 11389007 inhalational anthrax (disorder)
• 111798006 gastrointestinal anthrax (disorder)
• 14972006 anthrax septicemia (disorder)

• Anthrax vaccine (only recommended for high-risk groups) protects against all forms of anthrax and is as safe as other vaccines, according to the FDA, CDC, and the National Academy of Sciences.
• Inhalational anthrax is rare in US; must be considered a bioterrorist event until proven otherwise (last US occupational case occurred in 1976):
  • Death results in 99% of untreated cases and in 45–80% of patients with severe symptoms who are treated in a state-of-the-art facility.
• Widened mediastinum on CXR may be present; pleural effusions frequently present; infiltrates are rare.

Gregory D. Gutke, MD, MPH
Richard J. Thomas, MD, MPH
Jill A. Grimes, MD

1. Donegan S, Bellamy R, Gamble CL. Vaccines for preventing anthrax. Cochrane Database Syst Rev. 2009;2:CD006403.
2. Wright JG, Quinn CP, Shadomy S, et al. Use of anthrax vaccine in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep. 2010;59:1–30.  [PMID:20651644]
3. Kirsch J, Ramirez J, Mohammed TL, et al. ACR Appropriateness Criteria® acute respiratory illness in immunocompetent patients. J Thorac Imaging. 2011;26:W42–4.  [PMID:21508726]
4. Centers for Disease Control and Prevention. Update: Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR Morb Mortal Wkly Rep. 2001;50:909–19.  [PMID:11699843]
5. Stern EJ, Uhde KB, Shadomy SV, et al. Conference report on public health and clinical guidelines for anthrax. Emerg Infect Dis. 2008;14.  [PMID:18394267]

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