Anthrax 

Updated: Apr 05, 2021
Author: David J Cennimo, MD, FAAP, FACP, AAHIVS; Chief Editor: Michael Stuart Bronze, MD 

Overview

Practice Essentials

Anthrax is a zoonotic infection caused by the gram-positive rod Bacillus anthracis. Most cases of anthrax are cutaneous (95%); the remaining cases are inhalational (5%) and gastrointestinal (< 1%). Anthrax caused by inhalation is usually fatal, and symptoms usually begin days after exposure. Bioterrorism must be suspected in any case of inhalational anthrax.

Skin lesion of anthrax on face. Image courtesy of Skin lesion of anthrax on face. Image courtesy of the Public Health Image Library, US Centers for Disease Control and Prevention, Atlanta, Georgia.

See Clues on the Skin: Acute Poisonings, a Critical Images slideshow, to help diagnose patients based on their dermatologic presentations.

Signs and symptoms

Depending on the route of exposure to B anthracis spores, patients may present with cutaneous, respiratory, or GI complaints. Exposure may be via handling of sick animals or contaminated wool, hair, or hides; inhalation; or ingestion of contaminated meat.

Cutaneous anthrax

  • Cutaneous anthrax develops 2-5 days (range, 1-7 days) postexposure.
  • Lesions most commonly develop at lacerations, abrasions, or insect bites on exposed areas of skin; most commonly affects upper extremities but may arise anywhere on the body.
  • Infection begins as a pruritic papule that enlarges within 24-48 hours to form a 1-cm vesicle; this then becomes an ulcer surrounded by an edematous halo. [1]
  • Resultant lesions are usually 2-3 cm in diameter with a round, regular, raised edge.
  • Lesions may become edematous and necrotic but are usually not purulent.
  • They are painless but on occasion are slightly pruritic.
  • Regional lymphadenopathy may occur and may be painful.
  • The ulcer and edema evolve into a black eschar within 7-10 days and then last for 7-14 days before separating and leaving a scar.
  • Lymphadenopathy may be persistent.
  • With neck lesions, edema and lymphadenopathy may impinge on the airway and cause stridor and respiratory compromise.

Oropharyngeal anthrax

  • Oropharyngeal anthrax develops 2-7 days after ingestion.
  • Presents as neck swelling and fever in the presence of an oral lesion
  • The lesion starts as an edematous area that becomes necrotic and forms a pseudomembrane within 2 weeks.
  • Sore throat, dysphagia, respiratory distress, and oral bleeding may also occur, depending on the lesion site.
  • Soft-tissue edema and dramatic cervical lymph node enlargement usually follow.

Intestinal anthrax

  • Intestinal anthrax develops 2-5 days after ingestion.
  • Commonly presents as nonspecific abdominal pain with fever; may be associated with nausea, vomiting, malaise, anorexia, hematemesis, dysentery, and/or diarrhea
  • Distributive or hypovolemic shock may develop depending on the severity of illness.

Inhalational anthrax

  • Inhalational anthrax begins abruptly 1-3 days (range, hours to 60 days) postexposure and follows a biphasic course
  • Typically begins as fever with nonproductive cough and may feature myalgia, fatigue, or retrosternal chest pain
  • Transient clinical improvement may occur after the first few days, followed by rapid progression and clinical deterioration including the following:
    • High-grade fever
    • Symptoms of respiratory failure: severe dyspnea, tachypnea, hypoxemia
    • Hematemesis or hemoptysis
    • Chest pain, which may be severe enough to mimic acute coronary syndrome
    • Decreased level of consciousness, meningismus, and coma (with meningeal involvement)

See Clinical Presentation for more detail.

Diagnosis

B anthracis is present in high numbers in appropriate specimens and can be demonstrated by staining or culture. Laboratory personnel should take biosafety level 2 precautions.

Diagnostic studies may include the following:

  • Staining of cutaneous ulcer exudate with methylene blue or Giemsa stain
  • Punch biopsy at the edge of the lesion, examined by silver staining and immunohistochemical testing (for patients with prior antibiotic treatment)
  • Blood culture and Gram stain (for patients with systemic symptoms)
  • ELISA serology for B anthracis toxins or IgG response to B anthracis protective antigen
  • Chest radiography – In inhalational anthrax, typically shows widening of the mediastinum and pleural effusions, whereas the parenchyma may appear normal
  • Chest CT – In inhalational anthrax, detects hemorrhagic mediastinal and hilar lymph nodes and edema, peribronchial thickening, and pleural effusions
  • Lumbar puncture (for patients with meningeal symptoms) – CSF is grossly hemorrhagic, with grossly hemorrhagic with few polymorphonuclear neutrophils (PMNs) and numerous gram-positive bacilli

See Workup for more detail.

Management

Treatment of anthrax varies. See Treatment and Medication for more detail.

Background

Anthrax is a zoonotic infection caused by Bacillus anthracis. Most anthrax is cutaneous (95%). The remaining cases of the disease are inhalational (5%) and gastrointestinal (< 1%). Cutaneous anthrax results from exposure to the spores of B anthracis while handling sick animals or contaminated wool, hair, or animal hides. Pulmonary anthrax results from inhaling anthrax spores. GI anthrax results from ingesting meat products that contain anthrax. Anthrax is present in areas where animals, particularly herbivores, graze. Anthrax caused by inhalation is usually fatal, and symptoms usually begin days after exposure. This delay makes the initial exposure to B anthracis difficult to track.

Polychrome methylene blue stain of Bacillus anthra Polychrome methylene blue stain of Bacillus anthracis. Image courtesy of Anthrax Vaccine Immunization Program Agency, Office of the Army Surgeon General, United States.

Anthrax was described in the early literature of the Greeks, Romans, Egyptians, and Hindus. The term anthrakis means coal in Greek, and the disease is named after the black appearance of its cutaneous form.[2] The fifth plague described in the Old Testament book of Genesis may be among the earliest descriptions of anthrax. At the end of the 19th century, Robert Koch's experiments with anthrax led to the original theory of bacteria and disease. John Bell's work in inhalational anthrax led to wool disinfection processes and the term woolsorter's disease.

A modern concern is use of anthrax as a biologic warfare agent. During the first Gulf War, Iraq reportedly produced 8500 L of anthrax. A total of 150,000 US troops were vaccinated with anthrax toxoid. In the weeks following the terrorist attacks of September 11, 2001, 22 confirmed or suspected cases of anthrax infection were disseminated via the US postal system; the spores mailed in these letters were ultimately traced to a US army medical research institute. Since there have been no cases of naturally occurring inhalational anthrax in the US since 1976, alarm should be raised for the occurrence of even a single infection.

For patient education information, see the Bioterrorism and Disaster Medicine Center, as well as Biological Warfare, Anthrax, and Personal Protective Equipment.

Pathophysiology

Anthrax is primarily a disease of herbivores (eg, cattle, sheep, goats, horses). Pigs are not immune, but they are more resistant, as are dogs and cats. Birds are usually naturally resistant to anthrax. Buzzards and vultures are naturally resistant to anthrax but may transmit the spores on their talons and beaks.

Anthrax (B anthracis) is a large, spore-forming, gram-positive rod. Persistence of spores is aided by nitrogen and organic soil content, environmental pH greater than 6, and ambient temperature greater than 15°C. Spores can exist indefinitely in the environment. Optimal growth conditions result in a vegetative phase and bacterial multiplication. Drought or rainfall can trigger anthrax spore germination, while flies and vultures spread the spores.

Virulence depends on the bacterial capsule and the toxin complex. The capsule is a poly-D-glutamic acid that protects against leukocytic phagocytosis and lysis. Experiments by Sterne demonstrated that the capsule is vital for pathogenicity.

Anthrax toxins

Anthrax toxins are composed of 3 entities: a protective antigen, a lethal factor, and an edema factor. The protective antigen is an 83-kd protein that binds to cell receptors within a target tissue. Once it is bound, a fragment is cleaved free to expose an additional binding site. The binding of edema factor at this site results in the formation of edema toxin; the binding of lethal factor results in the formation of lethal toxin.

Edema toxin acts by converting adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Cellular cAMP levels are increased, leading to cellular edema within the target tissue. Lethal factor is not well understood; it may inhibit neutrophil phagocytosis, lyse macrophages, and cause release of tumor necrosis factor and interleukin-1. Death from anthrax occurs as a result of the effects of lethal toxin. Near death or just after death, animals bleed from all body orifices.

Cutaneous anthrax

Humans are relatively resistant to cutaneous invasion by B anthracis, but the organisms may gain access through microscopic or gross breaks in the skin. In cutaneous anthrax, a malignant pustule develops at the infection site. This pustule is a central area of coagulation necrosis (ulcer) surrounded by a rim of vesicles filled with bloody or clear fluid. A black eschar forms at the ulcer site. Extensive edema surrounds the lesion.

The organisms multiply locally and may spread to the bloodstream or other organs (eg, spleen) via the efferent lymphatics. B anthracis remains in the capillaries of invaded organs, and the local and fatal effects of the infection are due, in large part, to the toxins elaborated by B anthracis. Dissemination from the liver, spleen, and kidneys back into the bloodstream may result in bacteremia. Secondary hemorrhagic intestinal foci of anthrax result from B anthracis bacteremia.

Intestinal anthrax

Primary intestinal anthrax predominantly affects the cecum and produces a local lesion similar to the lesion produced in the cutaneous form. In this illness, spores invade the GI mucosa. In some cases, necrosis and ulceration at the site of infection produce GI hemorrhage.

Histopathology of large intestine showing marked h Histopathology of large intestine showing marked hemorrhage in the mucosa and submucosa. Image courtesy of Marshall Fox, MD, Public Health Image Library, US Centers for Disease Control and Prevention, Atlanta, Georgia.

As spores are transported to mesenteric lymph nodes, replication and bacteremia begin. Ascites and ileus follow as the lymphatic system becomes occluded with the large number of bacilli. Peritoneal fluid is turbid with the presence of leukocytes and red blood cells from hemorrhagic adenitis. Vascular stasis occurs, and the stomach and intestine become edematous.

Oropharyngeal anthrax

Oropharyngeal anthrax is a variant of intestinal anthrax and occurs in the oropharynx after ingestion of meat products contaminated by anthrax. Oropharyngeal anthrax is characterized by throat pain and difficulty in swallowing. The lesion at the site of entry into the oropharynx resembles the cutaneous ulcer.

Inhalational anthrax

Inhalational anthrax occurs after a person inhales spores into the lungs. Primate studies suggest that the minimum infective dose ranges from 4000-8000 inhaled spores. Inhaled spores are ingested by pulmonary macrophages and then carried to hilar and mediastinal lymph nodes. The incubation period is 1-6 days.

Histopathology of mediastinal lymph node showing a Histopathology of mediastinal lymph node showing a microcolony of Bacillus anthracis on Giemsa stain. Image courtesy of Marshall Fox, MD, Public Health Image Library, US Centers for Disease Control and Prevention, Atlanta, Georgia.

The spores undergo germination and multiplication and begin to elaborate toxins. Anthrax in the lungs does not cause pneumonia, but it does cause hemorrhagic mediastinitis and pulmonary edema. Hemorrhagic pleural effusions frequently accompany inhalational anthrax. After the lymph nodes become overwhelmed, bacteremia and death quickly ensue. Without treatment, the mortality rate of inhalational anthrax is approximately 95%.

Bacteremic anthrax with hematogenous spread most commonly follows inhalational anthrax. In bacteremic anthrax, hemorrhagic lesions may develop anywhere on the body. Septicemic anthrax refers to overwhelming infection resulting from bloodstream invasion secondary to inhalation or intestinal anthrax.

Anthrax meningitis

Anthrax meningitis may complicate any form of anthrax, with bacteremia and hematogenous spread to the CNS. It also has occurred without a primary focus. The meninges are characteristically hemorrhagic and edematous. The mortality rate is near 100%.

Anthrax infection. Histopathology of hemorrhagic m Anthrax infection. Histopathology of hemorrhagic meningitis in anthrax. Image courtesy of Marshall Fox, MD, Public Health Image Library, US Centers for Disease Control and Prevention, Atlanta, Georgia.

Etiology

Anthrax is caused by B anthracis, a gram-positive bacillus. B anthracis has a diameter of 1-1.5 µm and a length of 3-10 µm. It is usually straight but may be slightly curved. The ends of the bacilli are truncated, not rounded. Anthrax bacilli tend to form into long chains and may appear similar to streptobacilli on cultures.

B anthracis produces a capsule that is easily visualized using a methylene blue or India ink stain. Ground-glass–appearing colonies are adherent and appear gray or white on blood agar. Colonies measure 4-5 mm in diameter and have characteristic comma-shaped protrusions.

Polychrome methylene blue stain of Bacillus anthra Polychrome methylene blue stain of Bacillus anthracis. Image courtesy of Anthrax Vaccine Immunization Program Agency, Office of the Army Surgeon General, United States.

Bacilli grow optimally in enhanced carbon dioxide and are nonmotile. The organism shows preferential growth on phenylethyl alcohol blood agar with characteristic gelatin hydrolysis and salicin fermentation. B anthracis is catalase positive. Capsule formation may help differentiate B anthracis from other nonpathogenic bacilli. Anthrax is differentiated from other gram-positive rods on culture by lack of motility in broth and lack of hemolysis on blood agar. 

Table 1. Microbiological Differences Between B anthracis and Non– B anthracis Bacilli (Open Table in a new window)

B anthracis

Non–B anthracis bacilli (pseudoanthrax bacilli)

Nonmotile long chains

Generally motile short chains

Capsule formation on bicarbonate agar

No capsule formation in bicarbonate

No growth on penicillin agar

(10 mcg/mL)

Usually good growth on penicillin agar

Growth in gelatin resembles inverted fir tree

Growth in gelatin absent or resembles atypical fir tree

Gelatin liquefaction slow

Gelatin liquefaction usually rapid

No hemolysis of sheep RBCs

Hemolysis of sheep RBCs

Ferments salicin slowly or not at all

Usually ferments salicin rapidly

Pathogenic to laboratory animals

Nonpathogenic to laboratory animals

Adapted from Cunha CB. Anthrax: Ancient Plague, Persistent Problem. Infect Dis Pract. 1999;23(4):35-9.

Anthrax toxins

Anthrax exotoxins are produced in the vegetative phase and are composed of proteins (see Table 2 below). Lethal toxin is the single most important virulence factor and is the primary cause of death. Lethal toxin is a combination of protective antigen and lethal factor. Edema factor and lethal toxin inhibit phagocytosis and polymorphonuclear neutrophil (PMN) function. The other major anthrax virulence factor is its antiphagocytic poly-D-glutamic acid capsule.

Table 2. Toxins and Protein Toxins of Bacillus anthracis (Open Table in a new window)

Edema factor (EF) + lethal factor (LF) = Host cell penetration by B anthracis

EF + protective antigen (PA) = Edema toxin

LF + PA = Lethal toxin (primary virulence factor of B anthracis)

Edema toxin + lethal toxin = Inhibited PMN function and phagocytosis

Risk factors

Studies of inhalational anthrax based on several cases in patients with no known exposure in the October 2001 postal anthrax release found the following determinants of risk:

  • Bacterial virulence factors

  • Balance between infectious aerosol production and removal

  • Pulmonary ventilation rate

  • Duration of exposure

  • Host susceptibility factors

Dilution ventilation of the indoor environment is an important determinant of the risk for infection. Enhanced room ventilation, germicidal irradiation with ultraviolet light, and other engineering control measures may be used to decrease the risk for infection.

Important host susceptibility risk factors for inhalational anthrax include the following:

  • Prior exposure to radiation

  • Alcoholism

  • Underlying pulmonary disease

Epidemiology

United States statistics

Natural incidence is rare, but infection is an occupational hazard among veterinarians, farmers, and individuals who handle animal wool, hair, hides, or bone meal products. During the last 30 years, the indigenous US incidence of any anthrax infection has been less than 1 case per year. From 1955–1994, US cases totaled 235, with 224 cases of cutaneous anthrax, 11 cases of inhalational anthrax, and 20 fatalities. The last fatal case during this period occurred in 1976, when a home craftsman died of inhalational anthrax after working with yarn imported from Pakistan.

Before October 2001, the Centers for Disease Control and Prevention (CDC) investigated several threats in the United States, including Indiana, Kentucky, Tennessee, and California. In October 2001, 22 confirmed or suspected cases of anthrax infection were identified. Cases were reported from Florida, New York, New Jersey, the District of Columbia, and Connecticut. There were 11 confirmed cases of inhalational anthrax (5 deaths) and 7 confirmed and 4 suspected cases of cutaneous anthrax (no deaths).

Seven cases were associated with occupational exposures in the postal service, and 2 cases had documented exposures to contaminated mail in the business office of a media company. No sources of exposure were identified for 2 women who were presumably exposed to secondarily contaminated mail. No reports in the literature have documented direct human-to-human transmission.

International statistics

Anthrax is uncommon in Western Europe, but the disease is not uncommon in the Middle East, the Indian subcontinent,[3] Africa, Asia, and Latin America. In 1958, approximately 100,000 cases of anthrax occurred worldwide. Exact figures do not exist because of reporting difficulties in Africa. Anthrax is endemic in Africa and Asia despite vaccination programs.

Sporadic outbreaks have occurred as a result of both agricultural and military disruptions. During the 1978 Rhodesian civil war, failure of veterinary vaccination programs led to a human epidemic, causing 6500 anthrax cases and 100 fatalities. A mishap at a military microbiology facility in Sverdlovsk in the former Soviet Union in 1979 resulted in at least 66 deaths.[2] Human anthrax often is associated with agricultural or industrial workers who come in contact with infected animal tissue.

Race-, sex-, and age-related differences in incidence

There is no racial, sexual, or age predilection for anthrax. However, because anthrax is often related to industrial exposure and farming, the disease most often affects young and middle-aged adults. Persons of any age can of course be affected if anthrax is used as a bioterrorist weapon.

Prognosis

Most cases of anthrax are the cutaneous type, are mild, and resolve with or without treatment. If treated early with appropriate antibiotics, the mortality rate of cutaneous anthrax is less than 1%-2%.[4]

However, other forms of anthrax are potentially fatal, with inhalational anthrax carrying the worst prognosis. Inhalational anthrax and its subsequent systemic infection (eg, septicemia, hemorrhagic leptomeningitis) have a mortality rate approaching 100%. Even with present-day critical care capabilities and modern medical technology, the mortality rates of GI and inhalational anthrax remain 40% and 45%, respectively.[5] If treatment is initiated during the incubation period of 1-6 days and before the manifestation of symptoms, mortality can decrease to 1%.

Oropharyngeal or intestinal anthrax carries a less favorable prognosis than cutaneous anthrax but a more favorable prognosis than inhalational anthrax. Patients with oropharyngeal anthrax may develop airway obstruction (as may those with inhalational anthrax or cutaneous anthrax involving the neck). Intestinal anthrax is more difficult to diagnose given its initial nonspecific syndrome and is associated with higher morbidity and mortality rates.[5]

 

Presentation

History

Anthrax is primarily zoonotic. No reports of direct human-to-human transmission exist in the literature, but laboratory personnel may contract the disease from specimens. Exposure to Bacillus anthracis may occur by contact with animals or animal products. Military personnel and civilians may become exposed in biologic warfare situations.

Exposure may be through agriculture or industry. Those at highest risk are shepherds, farmers, and workers in facilities that use animal products, especially previously contaminated goat hair, wool, or bone. Consumers may be exposed through contact with contaminated products (eg, hides in African export shops).

Cutaneous anthrax

Cutaneous anthrax develops 1-7 days (usually 2-5 days) after skin exposure and penetration of B anthracis spores[1] In the most common cutaneous form of anthrax, spores inoculate a host through skin lacerations, abrasions, or biting flies. This form most commonly affects the exposed areas of the upper extremities and, to a lesser extent, the head and neck. Hematogenous dissemination occurs in 5-10% of untreated cases.

Cutaneous anthrax. Image courtesy of Anthrax Vacci Cutaneous anthrax. Image courtesy of Anthrax Vaccine Immunization Program Agency, Office of the Army Surgeon General, United States.
Skin lesions of anthrax on neck. Cutaneous anthrax Skin lesions of anthrax on neck. Cutaneous anthrax showing the typical black eschar. Image courtesy of the Public Health Image Library, US Centers for Disease Control and Prevention, Atlanta, Georgia.
Skin lesion of anthrax on face. Image courtesy of Skin lesion of anthrax on face. Image courtesy of the Public Health Image Library, US Centers for Disease Control and Prevention, Atlanta, Georgia.
Seven-month-old infant with anthrax. In this infan Seven-month-old infant with anthrax. In this infant, the infection progressed rapidly with significant edema developing the day after exposure. This large hemorrhagic lesion developed within 3 more days. The infant was febrile and was admitted to the hospital on the second day after the symptoms appeared.On September 28, 2001, the infant had visited the mother's workplace. On September 29, nontender massive edema and a weeping erosion developed. On September 30, a 2-cm sore developed over the edematous area. (Note that edema preceded the primary lesion.) On October 2, an ulcer or eschar formed, and the lesion was diagnosed as a spider bite. Hemolytic anemia and thrombocytopenia developed, and the patient was hospitalized. Serum was drawn on October 2; the polymerase chain reaction results were positive for Bacillus anthracis. On October 13, skin biopsy results were positive with immunohistochemical testing for the cell wall antigen.Note that the initial working diagnosis was a Loxosceles reclusa spider bite with superimposed cellulitis. Courtesy of American Academy of Dermatology with permission of NEJM.
Fourth patient with cutaneous anthrax in New York Fourth patient with cutaneous anthrax in New York City, October 2001. This dry ulcer was present. Photo used with permission of the patient. Courtesy of American Academy of Dermatology. Courtesy of Sharon Balter of the New York City Department of Health.
Note the hemorrhage that is associated with cutane Note the hemorrhage that is associated with cutaneous anthrax lesions. The early ulcer has a moist base. Courtesy of American Academy of Dermatology.
Note the central ulcer and eschar. Courtesy of Ame Note the central ulcer and eschar. Courtesy of American Academy of Dermatology.
An example of a central ulcer and eschar with surr An example of a central ulcer and eschar with surrounding edema. Courtesy of American Academy of Dermatology with permission from Boni Elewski, MD.
Note the black eschar. Courtesy of American Academ Note the black eschar. Courtesy of American Academy of Dermatology. Courtesy of Gorgas Course in Clinical Tropical Medicine.
Anthrax with facial edema. Courtesy of American Ac Anthrax with facial edema. Courtesy of American Academy of Dermatology.

Oropharyngeal anthrax

Oropharyngeal anthrax is a more common form of GI anthrax and has occurred in epidemic settings. For example, ingestion of contaminated water buffalo meat caused an outbreak of 24 cases, concurrently with 52 cases of cutaneous anthrax, in Thailand in 1982.

Ingestion of B anthracis spores may result in oropharyngeal anthrax 2-7 days after exposure. Typically, 2 days after ingestion of contaminated meat, fever and neck swelling occur in the presence of an oral cavity lesion. The lesion starts as an edematous area that becomes necrotic and forms a pseudomembrane within 2 weeks. Sore throat, dysphagia, respiratory distress, and oral bleeding also occur. Soft-issue edema and dramatic cervical lymph node enlargement follow. Recovery usually takes 3 weeks with antibiotic therapy. The reason the disease limits itself to the oropharyngeal area is unknown.

Intestinal anthrax

Intestinal anthrax is a rare form of infection. It occurs from eating infected, undercooked meat. Only 11 cases have been reported, all in underdeveloped countries. Ingesting B anthracis spores may cause intestinal anthrax 2-5 days following ingestion. Abdominal pain and fever occur first, followed by nausea, vomiting, malaise, anorexia, hematemesis, bloody diarrhea, and, less often, watery diarrhea.

Shock may occur from interstitial and intraperitoneal volume losses. Anthrax toxin further causes intrinsic renal failure independent of prerenal azotemia. Death is rapid without antibiotic therapy and aggressive volume resuscitation. The mortality rate is 50%.

Inhalational anthrax

Inhalational anthrax usually occurs in textile and tanning industries among workers handling contaminated animal wool, hair, and hides. Inhalational anthrax begins abruptly, usually 1-3 days (range, 1-60 days) after inhaling anthrax spores, which are 1-5 µm in diameter. The number of spores needed to cause inhalational anthrax varies. As evidenced by anthrax cases in the United States in 2001, fewer spores of weapon-grade anthrax may be required to cause inhalational anthrax.

Patients with inhalational anthrax present initially with nonspecific symptoms, including a low-grade fever and a nonproductive cough. They may report substernal discomfort early in the illness. After initial improvement, inhalational anthrax progresses rapidly, causing hemorrhagic mediastinitis and rapid clinical deterioration. The following symptoms may be present:

  • High fever

  • Severe shortness of breath

  • Tachypnea

  • Cyanosis

  • Profuse diaphoresis

  • Hematemesis

  • Chest pain, which may be severe enough to mimic acute myocardial infarction

Septicemic anthrax

Septicemic anthrax refers to overwhelming infection by anthrax bacilli. This form of anthrax may complicate inhalational anthrax. The anthrax bacilli multiply in the blood and proliferate to outnumber red blood cells. Another name for anthrax is black blood, which refers to the very dark color of the blood of animals or humans with overwhelming septicemic anthrax.

Because humans are relatively resistant to invasion by B anthracis, most cases of septicemic anthrax occur following inhalational anthrax. The number of organisms released from the liver or spleen into the bloodstream overwhelms host defenses and produces massive amounts of lethal toxin that cause shock and death.

Physical Examination

Physical findings are nonspecific. The incubation period for all clinical manifestations is 1-6 days following exposure. The prodrome includes fever, malaise, and adenopathy. Inhalational anthrax, the most deadly form, can be mistaken for influenza-like illness, especially during the winter season. Unlike patients with influenza or other viral respiratory illness, adults with inhalational anthrax are not contagious; they will have shortness of breath and vomiting; and they do not have sore throat or rhinorrhea. Subcutaneous anthrax is a subset of cutaneous anthrax that is being recognized more frequently in intravenous drug users. It may also present as necrotizing fasciitis.[6]

Cutaneous anthrax begins as a pruritic papule that enlarges within 24-48 hours to form a 1-cm vesicle and subsequently becomes an ulcer surrounded by an edematous halo.[1] Occasionally, surrounding edema is severe. The cutaneous anthrax lesion is usually approximately 2-3 cm in diameter and has a round, regular, and raised edge.

The skin in infected areas may become edematous and necrotic but not purulent. Such skin lesions have been described as "malignant pustules" after their characteristic appearance, despite being neither malignant nor pustular. The membrane/exudate of the ulcer contains numerous anthrax bacilli. Lesions are painless but on occasion are slightly pruritic. Regional lymphadenopathy of the nodes draining the infected area may occur. The adenopathy associated with cutaneous anthrax may be painful.

The anthrax ulcer and surrounding edema evolve into a black eschar within 7-10 days and last for 7-14 days before separating and leaving a permanent scar. The edema surrounding the ulcer may persist through the eschar stage. Lymphadenopathy associated with cutaneous anthrax may persist long after disappearance of the ulcer/eschar. If the lesions of cutaneous anthrax affect the neck, neck swelling due to edema and enlarged cervical lymph nodes may impinge on the trachea and cause stridor and respiratory distress. Severe cases may result in asphyxiation.

Cutaneous anthrax usually remains localized, but without treatment it disseminates systemically in up to one fifth of cases. Antibiotic therapy prevents dissemination but does not affect the natural history of the lesion.

Oropharyngeal anthrax

Oropharyngeal anthrax is the proximal GI manifestation of intestinal anthrax. Mouth lesions may affect the hard palate or pharyngeal walls. The anthrax ulcer in the oropharynx may be accompanied by a membrane and is associated with local edema and cervical adenopathy. Death may result from asphyxiation due to neck edema or toxemia.

Intestinal anthrax

Patients with intestinal anthrax may have severe abdominal pain, hematemesis, and/or bloody diarrhea. Multiple anthrax ulcerative lesions are found throughout the GI tract secondary to hematogenous spread. Primary intestinal anthrax causes a local lesion that resembles the ulcer of oropharyngeal anthrax. Intestinal anthrax is difficult to recognize, and shock and death may occur 2-5 days after onset.

Inhalational anthrax

The clinical presentation is usually biphasic in nature. The initial stage begins with the onset of myalgia, malaise, fatigue, nonproductive cough, an occasional sensation of retrosternal pressure, and fever. A transient clinical improvement may occur after the first few days.

The second stage, lasting 24 hours and often culminating in death, develops suddenly with the onset of acute respiratory distress, hypoxemia, and cyanosis. The patient may have mild fever; alternatively, the patient may have hypothermia and develop shock.

Diaphoresis often is present; enlarged mediastinal lymph nodes may lead to partial tracheal compression and alarming stridor. Auscultation of the lungs is remarkable for crackles and signs of pleural effusions. Meningeal involvement may be present in up to 50% of cases; it usually is bloody and may be associated with subarachnoid hemorrhage. Decreased level of consciousness, meningismus, and coma may be present. Inhalational anthrax is usually fatal; the patient often succumbs to shock and to the effects of lethal toxin.

 

DDx

Diagnostic Considerations

Early diagnosis is difficult, and a high index of suspicion is required. The differential diagnosis varies among cutaneous, inhalational, and intestinal anthrax. A triage checklist has been developed in case of a mass exposure event.[7]

Cutaneous anthrax

Physicians must differentiate cutaneous anthrax from bubonic plague or lymphocutaneous tularemia. Patients with plague have painful adenopathy, usually in the groin or axilla. No ulcer is present, and ulcer edema and eschar characteristic of anthrax are absent. Patients with bubonic plague appear more toxemic than patients with uncomplicated cutaneous anthrax.

Patients with anthrax have an appropriate history of contact with animal products. In contrast, patients with bubonic plague may have a history of contact with infected cats that may have been in contact with sylvatic rodents in plague-endemic areas. Patients with bubonic plague may also provide a history of contact with armadillos or infected prairie dogs in the western United States.

Inhalational anthrax

Do not confuse inhalational anthrax with the zoonotic atypical pneumonias. Pulmonary tularemia usually presents as a community-acquired pneumonia with bilateral hilar adenopathy and bloody pleural effusion. The primary clinical manifestation of inhalational anthrax is hemorrhagic mediastinitis with bloody pleural effusions. No pulmonary infiltrate is present, and a widened mediastinum is observed on early chest CT scans. Mediastinitis very closely resembles inhalational anthrax on chest radiographs, but their clinical presentations are different.

The initial phase of inhalational anthrax may resemble bacterial mediastinitis, but it is associated with hemoptysis, severe substernal chest pain, and shock, which is very different from bacterial mediastinitis. Patients with bacterial mediastinitis have a history of previous esophageal tear or recent thoracic surgery. Patients with inhalational anthrax have a history of exposure to sources of anthrax spores.

Intestinal anthrax

Intestinal anthrax is a difficult diagnosis that must be distinguished from dysentery. Dysentery may manifest as bloody diarrhea, as does intestinal anthrax, and may be accompanied by abdominal pain (eg, in cases of Shigella or amebic dysentery). A history of ingesting meat possibly contaminated with anthrax is helpful in suspected cases of intestinal anthrax.

In tropical areas where bacillary and amebic dysentery are common, clinically differentiating intestinal anthrax from these endemic causes of dysentery is very difficult unless a cluster of dysentery cases or an outbreak is known to exist. Stool examination provides rapid confirmation of bacillary or amebic dysentery. Stools negative for amebic cysts or trophs and for Shigella suggest the possibility of intestinal anthrax in patients residing near areas where anthrax is endemic (ie, in pastures where herbivores graze) or after ingestion of spores from hand/food contact.

Ulceroglandular tularemia is characterized by purple ulcerative lesions that are painful, not pruritic, and not surrounded by a gelatinous edematous halo. Patients with anthrax, tularemia, or plague may report headache and have fever associated with shaking chills.

The chancre of primary syphilis may also be confused with cutaneous anthrax. The chancre of primary syphilis is painless, as is the lesion of cutaneous anthrax, but the syphilitic chancre is not pruritic and is not surrounded by an edematous halo. Generalized rather than local adenopathy accompanies syphilis, which is the opposite of what is expected with cutaneous anthrax.

Exudates from the ulcers of both ulceroglandular tularemia and cutaneous anthrax reveal organisms when properly stained. The ulcer of syphilis does not reveal organisms, but Treponema pallidum may be visualized using dark-field examination.

Other problems to be considered include the following:

  • Ecthyma (Pseudomonas aeruginosa and staphylococcal infections)

  • Glanders (Pseudomonas pseudomallei)

  • Histoplasmosis

  • Leprosy

  • Orf (Rickettsia akari)

  • Psittacosis

  • Rat-bite fever (Streptococcus moniliformis, Spirillum minus)

  • Rickettsia

  • Tularemia

  • Typhoid

Differential Diagnoses

 

Workup

Approach Considerations

Bacillus anthracis is present in high numbers in the ulcer/eschar of cutaneous anthrax, in bloody pleural fluid in inhalational anthrax, in the cerebrospinal fluid (CSF) in anthrax meningitis, and in the blood in septicemic anthrax. Specimens may be stained or cultured to demonstrate the organism. Culture is performed on sheep blood or peptone agar. In persons exposed to antibiotics, immunohistochemical examination of the suspected fluid (eg pleural fluid, CSF, cutaneous biopsy) is performed using antibodies to B anthracis cell wall and capsule.

The diagnosis of cutaneous anthrax is usually suggested by the characteristic appearance of skin lesions. As spore germination occurs within macrophages at the site of inoculation, anthrax bacilli are isolated easily from the vesicular lesions and can be observed on Gram stain. If prior treatment with antibiotics has occurred, the best way to determine infection is to perform serologic testing and punch biopsy at the edge of the lesion and examine by silver staining and immunohistochemical testing.

In patients with inhalational anthrax, a chest radiograph typically shows widening of the mediastinum and pleural effusions, whereas the parenchyma may appear normal. In a review of the 11 patients infected by anthrax in October 2001, chest radiographs from the initial examination showed mediastinal widening, paratracheal and hilar fullness, and pleural effusions or infiltrates. In some patients, the initial findings were subtle and not detected immediately.

Gram Stain and Blood Culture

The preferred diagnostic procedure for cutaneous anthrax is staining the ulcer exudate with methylene blue or Giemsa stain. B anthracis readily grows on blood agar, and staining microbiologically differentiates the organism from non– B anthracis bacilli. Warn laboratory personnel that contracting anthrax from specimens is possible and that they must take appropriate biohazard (level II) precautions.

Polychrome methylene blue stain of Bacillus anthra Polychrome methylene blue stain of Bacillus anthracis. Image courtesy of Anthrax Vaccine Immunization Program Agency, Office of the Army Surgeon General, United States.

In patients with cutaneous anthrax who have fever and systemic symptoms that suggest extracutaneous spread, blood culture may be indicated. Treat blood cultures as biohazard II specimens. Blood culture and Gram stain are high-yield tests in infected persons who have not taken antibiotics. Sputum from patients seldom yields positive smears or cultures. A Gram stain is the easiest means of initially identifying suggested cases. Anthrax appears as a large, gram-positive rod.

In October 2001, blood cultures were positive for anthrax in all 8 patients who did not receive antibiotics. Serologic diagnosis of anthrax can be made using a microhemagglutination test specific for the protective antigen (PA) component of the toxin. Any Gram stain results suggestive of anthrax should be reported to the CDC.

Several biochemical tests aid in differentiating B anthracis from other members of the species (chief among them is Bacillus cereus, which has been associated with outbreaks of human food poisoning). B anthracis is characterized by the absence of hemolysis on sheep blood agar, lack of motility, absence of salicin fermentation, gelatin hydrolysis, and lack of growth on phenylethyl alcohol medium.

Enzyme-Linked Immunosorbent Assay

Enzyme-linked immunosorbent assay (ELISA) serologic diagnosis is also available. The ELISA for edema and lethal toxins is positive if a single acute-phase titer is highly elevated or if a fourfold greater rise in the titer is observed between acute and convalescent specimens.

ELISA to detect immunoglobulin G (IgG) response to B anthracis protective antigen (PA) is 98.6% sensitive and 80% specific. Protective antigen–competitive inhibition ELISA is used as a second confirmatory step to improve specificity. Specific IgG anti-PA antibody can be detected as early as 10 days after onset of symptoms, but peak IgG levels may not be observed until 40 days of symptom onset.

Chest Radiography and Computed Tomography

If inhalational anthrax is suspected, obtain a chest radiograph or computed tomography (CT) scan. The appearance on chest radiograph or CT scan may suggest the diagnosis, especially if other predisposing disorders that might result in a widening mediastinum (eg, dissecting aortic aneurysm, bacterial mediastinitis) are absent.

Inhalation anthrax. Chest radiograph with widened Inhalation anthrax. Chest radiograph with widened mediastinum 22 hours before death. Image courtesy of P.S. Brachman, MD, Public Health Image Library, US Centers for Disease Control and Prevention, Atlanta, Georgia.

Inhalational anthrax often does not appear on chest radiographs as a typical pneumonia; pulmonary densities often are absent. A prominent mediastinum with pleural effusions may be present. The prominent mediastinum is caused by hilar lymphadenopathy. In the 11 cases of inhalational anthrax, initial examination was often subtle but showed mediastinal widening, paratracheal and hilar fullness, and pleural effusions and/or infiltrates.

CT of the chest detects hemorrhagic mediastinal and hilar lymph nodes and edema, peribronchial thickening, and pleural effusions. It also may help differentiate inhalational anthrax from histoplasmosis, sarcoidosis, tuberculosis, and lymphoma.

Lumbar Puncture

If anthrax meningitis is suspected, perform a lumbar puncture to obtain CSF for stain and culture. The CSF in patients with anthrax meningitis is grossly hemorrhagic with few polymorphonuclear neutrophils (PMNs) and numerous gram-positive bacilli. As with other specimens from patients with possible anthrax, advise laboratory personnel to handle specimens with biohazard level II precautions.

Histologic Findings

The characteristic finding in anthrax is the presence of the organisms in the capillaries at the infection site; therefore, if a patient is infected, expect B anthracis in the capillaries of the skin, intestines, liver, spleen, lungs, or leptomeninges. Pathological findings are not in proportion to the numbers of bacilli present, which is best explained by the effects of one or more of the toxins associated with B anthracis. Hemorrhage may be evident. 

Histopathology of mediastinal lymph node showing a Histopathology of mediastinal lymph node showing a microcolony of Bacillus anthracis on Giemsa stain. Image courtesy of Marshall Fox, MD, Public Health Image Library, US Centers for Disease Control and Prevention, Atlanta, Georgia.
Histopathology of large intestine showing marked h Histopathology of large intestine showing marked hemorrhage in the mucosa and submucosa. Image courtesy of Marshall Fox, MD, Public Health Image Library, US Centers for Disease Control and Prevention, Atlanta, Georgia.
Histopathology of the large intestine showing subm Histopathology of the large intestine showing submucosal thrombosis and edema. Image courtesy of Marshall Fox, MD, Public Health Image Library, US Centers for Disease Control and Prevention, Atlanta, Georgia.
Histopathology of mediastinal lymph node showing m Histopathology of mediastinal lymph node showing mediastinal necrosis. Image courtesy of Marshall Fox, MD, Public Health Image Library, US Centers for Disease Control and Prevention, Atlanta, Georgia.
Anthrax infection. Histopathology of hemorrhagic m Anthrax infection. Histopathology of hemorrhagic meningitis in anthrax. Image courtesy of Marshall Fox, MD, Public Health Image Library, US Centers for Disease Control and Prevention, Atlanta, Georgia.
 

Treatment

Approach Considerations

With doxycycline, a loading regimen should be used (200 mg PO/IV every 12 hours for 72 hours). In severely ill patients, 200 mg IV/PO every 12 hours may be continued (without toxicity) for the duration of therapy. Oral doxycycline and quinolones have excellent bioavailability; the same blood/tissue levels are obtained with PO and IV therapy. Use any quinolone in patients who are unable to take penicillin or doxycycline.

The preferred agent used to treat nonbioterrorist anthrax is penicillin. Penicillin is the preferred agent to treat inhalational anthrax and anthrax meningitis. Use meningeal doses for inhalational anthrax because meningitis is often also present.

For bioterrorist anthrax, use any quinolone or doxycycline for 1-2 weeks. Clindamycin may be added for its anti-exotoxin effect. Use doxycycline or any quinolone (eg, ciprofloxacin, levofloxacin) for postexposure prophylaxis (PEP) to prevent inhalational anthrax. PEP to prevent inhalational anthrax should be continued for 60 days.

Raxibacumab is a human IgG1 gamma monoclonal antibody directed at the protective antigen of Bacillus anthracis. It is produced by recombinant DNA technology in a murine cell expression system. This agent was approved by the FDA in December 2012 for treatment of inhalational anthrax or for prevention when alternative therapies are not available or appropriate. It is used as part of a combination regimen with appropriate antibiotic drugs.[8] The efficacy of raxibacumab as a prophylactic agent and after disease onset was assessed in 4 randomized controlled animal model trials to provide surrogate endpoints applicable to human use.[9]

Obiltoxaximab is another monoclonal antibody directed at the protective antigen of B anthracis that was approved by the FDA in March 2016. It is a chimeric IgG1 kappa monoclonal antibody.[10]

Human anthrax immune globulin (Anthrasil) is indicated for treatment of inhalational anthrax in adults and children in combination with antibiotic therapy.[11]

The indication for anthrax vaccine adsorbed (BioThrax) was expanded in November 2015 to include postexposure use following suspected or confirmed B anthracis exposure in combination with antimicrobial therapy. It was originally approved for pre-exposure prophylaxis in high-risk individuals.[12]

Antimicrobial therapy renders lesions culture-negative within hours, but the lethal effects of anthrax are related to the effects of the organism's toxin. Patients with septic and hemorrhagic shock, which is the final common pathway for end-stage anthrax infection, should be admitted to the intensive care unit for hemodynamic monitoring and management. In addition, progressive respiratory insufficiency may necessitate the use of ventilatory support.

Despite early treatment, persons infected with inhalational, gastrointestinal, or meningeal anthrax have a very poor prognosis. Although prophylaxis and vaccinations confer almost complete protection, adequately providing immunity to a potentially exposed community is extremely difficult.

The Infectious Diseases Society of America (IDSA) published guidelines for the treatment of both naturally acquired and bioterrorism-related cases of cutaneous anthrax (see Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America).[13]

The CDC has issued updated guidelines on anthrax postexposure prophylaxis (PEP) and treatment in nonpregnant and pregnant adults. Recommendations include the following:[14, 15]

  • All individuals exposed to aerosolized B anthracis spores should receive a full 60 days of PEP antimicrobial drugs, regardless of their vaccination status
  • Compared with monotherapy, antimicrobial combination therapy is more likely to result in a cure; combined bactericidal and protein synthesis inhibitor agents may be beneficial
  • Ciprofloxacin, levofloxacin, and doxycycline are approved by the FDA for PEP for inhalation anthrax in adults aged 18 years or older; ciprofloxacin and doxycycline are first-line treatments
  • Treatment for anthrax meningitis should include at least 3 antimicrobial drugs with activity against B anthracis, at least 1 of which should have bactericidal activity, and at least 1 of which should be a protein synthesis inhibitor
  • For patients suspected to have systemic anthrax, antitoxin should be added to combination antimicrobial drug treatment
  • Uncomplicated cutaneous anthrax can be treated with a single oral agent; fluoroquinolones (ciprofloxacin, levofloxacin, and moxifloxacin) and doxycycline are equivalent first-line drugs
  • Treatments for pregnant, postpartum, and lactating women are generally the same as those for nonpregnant patients

Cutaneous Anthrax

Patients with isolated cutaneous anthrax without systemic involvement (ie, without edema, fever, cough, headache, etc) or complications may be treated on an outpatient basis with antibiotic monotherapy. The treatment of choice has been outlined as recommended by the CDC, IDSA, and AAP.

Table 3. CDC Expert Panel Recommendations for Treatment of Cutaneous Anthrax (Open Table in a new window)

Nonpregnant adults

Pregnant/lactating women

Children

Recommended therapy[15] : Treatment duration, 7-10 days

Ciprofloxacin 500 mg every 12 hours

Ciprofloxacin 500 mg every 12 hours

Ciprofloxacin 30 mg/kg/day divided every 12 hours (max dose, 500 mg/dose)

Doxycycline 100 mg every 12 hours

 

Amoxicillin 75 mg/kg/day divided every 8 hours (max dose, 1 g/dose)

Levofloxacin 750 mg every 12 hours

   

Moxifloxacin 400 mg every 24 hours

   

Alternative therapy

Clindamycin 600 mg every 8 hours

Levofloxacin 750 mg every 12 hours

Doxycycline

< 45 kg: 4.4 mg/kg/day divided every 12 hours (max dose, 100 mg/dose)

>45 kg: 100 mg every 12 hours

Amoxicillin 1 g every 8 hours (susceptible strain only)

Amoxicillin 1 g every 8 hours (susceptible strain only)

Clindamycin 30 mg/kg/day divided every 8 hours (max dose, 600 mg/dose)

   

Levofloxacin

< 50 kg: 16 mg/kg/day divided every 12 hours (max dose, 250 mg/dose)

>50 kg: 500 mg every 24 hours

Systemic Anthrax Without Meningitis

All patients with suspected systemic anthrax should be begun immediately on IV antibiotics with co-administration of an antitoxin (raxibacumab or anthrax IgG) and should receive aggressive supportive care. All patients with suspected systemic illness should be admitted to inpatient for treatment. Early diagnosis and clinical suspicion are critical to improving outcomes. Workup should include standard fever workup pending the clinical situation, often including blood cultures and urine samples.

For adults with systemic anthrax (inhalational, intestinal, meningitis, injection), the CDC expert panel recommends the following:

Table 4. CDC Expert Panel Recommendations for Treatment of Systemic Anthrax Without Meningitis [15] (Open Table in a new window)

Adults

Children

1. Bactericidal agent

Ciprofloxacin 400 mg every 8 hours

Ciprofloxacin 30 mg/kg/day divided every 8 hours (max dose, 400 mg/dose)

Alternative

Levofloxacin 750 mg every 24 hours

-OR-

Meropenem 60 mg/kg/day divided every 8 hours (max dose, 2 g/dose)

-OR-

Moxifloxacin 400 mg every 24 hours

-OR-

Levofloxacin

< 50 kg: 20 mg/kg/day divided every 12 hours (max dose, 250 mg/dose)

>50 kg: 500 mg every 24 hours

-OR-

Meropenem 2 g every 8 hours

-OR-

Imipenem 100 mg/kg/day divided every 6 hours (max dose, 1 g/dose)

-OR-

Imipenem 1 g every 6 hours

-OR-

Vancomycin 60 mg/kg/day divided every 8 hours (max dose, 2 g/dose); trough target, 15-20 mcg/mL

Doripenem 500 mg every 8 hours

-OR-

 

Vancomycin 60 mg/kg/day divided every 8 hours (max dose, 2 g/dose); trough target, 15-20 mcg/mL

 

PLUS

2. Protein synthesis inhibitor

Clindamycin 900 mg every 8 hours

-OR-

Clindamycin 40 mg/kg/day divided every 8 hours (max dose, 900 mg/dose)

Linezolid 600 mg every 12 hours

 

Alternative

Doxycycline 200-mg loading dose followed by 100 mg every 12 hours

-OR-

Linezolid

< 12 years: 30 mg/kg/day divided every 8 hours

>12 years: 30 mg/kg/day divided every 12 hours (max dose, 600 mg/dose)

-OR-

Rifampin 600 mg every 12 hours

Doxycycline

< 45 kg: 4.4 mg/kg loading dose (max 200 mg) followed by 4.4 mg/kg/day divided every 12 hours (max 100 mg/dose)

>45 kg: 200 mg loading dose followed by 100 mg every 12 hours

-OR-

 

Rifampin 20 mg/kg/day divided every 12 hours (max dose, 300 mg/dose)

Anthrax Meningitis, Suspected or Confirmed

In patients with suspected or confirmed anthrax meningitis, if not already done, a lumbar puncture should be performed for CSF analysis. Immediate antibiotics are warranted, and lumbar puncture should never delay therapy. Two bactericidal agents plus a protein synthesis inhibitor are indicated. All must be dosed for CSF penetration.

Table 5. CDC Expert Panel Recommendations for Treatment of Anthrax Meningitis [15] (Open Table in a new window)

Adults

Children

1. Bactericidal agent

Ciprofloxacin 400 mg every 8 hours

Ciprofloxacin 30 mg/kg/day divided every 8 hours (max 400 mg/dose)

Alternative

Levofloxacin 750 mg every 24 hours

-OR-

Levofloxacin

< 50 kg: 16 mg/kg/day divided every 12 hours (max 250 mg/dose)

≥50 kg: 500 mg every 24 hours

-OR-

Moxifloxacin 400 mg every 24 hours

Moxifloxacin

Age 3 months to < 2 years: 12 mg/kg/day divided every 12 hours

Age 2-5 years: 10 mg/kg/day divided every 12 hours

Age 6-11 years: 8 mg/kg/day divided every 12 hours

Age 12-17 years, < 45 kg: 8 mg/kg/day divided every 12 hours

(Max 200 mg/dose)

Age 12-17 years, ≥45 kg: 400 mg every 24 hours

PLUS

2. Second bactericidal agent

Meropenem 2 g every 8 hours

Meropenem 120 mg/kg/dose divided every 8 hours (max 2 g/dose)

Alternative

Imipenem 1 g every 6 hours

-OR-

Imipenem 100 mg/kg/day divided every 6 hours (max 1 g/dose)

-OR-

Doripenem 500 mg every 8 hours

-OR-

Doripenem 120 mg/kg/day divided every 8 hours (max 1 g/dose)

-OR-

Ampicillin 3 g every 6 hours

-OR-

Vancomycin 60 mg/kg/day divided every 8 hours (max 2 g/dose); target trough, 15-20 mcg/mL

-OR-

 

Ampicillin 400 mg/kg/day divided every 6 hours (max 3 g/dose)

PLUS

3. Protein synthesis inhibitor

Linezolid 600 mg every 12 hours

Linezolid

< 12 years old: 30 mg/kg/day divided every 8 hours

≥12 years old: 30 mg/kg/day divided every 12 hours

(Max 600 mg/dose)

Alternative

Clindamycin 900 mg every 8 hours

-OR-

Clindamycin 40 mg/kg/day divided every 8 hours (max 900 mg/dose)

-OR-

Rifampin 600 mg every 12 hours

-OR-

Rifampin 20 mg/kg per day divided every 12 hours (max 300 mg/dose)

-OR-

Chloramphenicol 1 g every 6-8 hours

Chloramphenicol 100 mg/kg per day divided every 6 hours (max 1 g/dose)

Anticipate a therapy duration of at least three weeks or until clinical improvement, whichever comes last, as clinical improvement may take several weeks. Thereafter, patients should complete a 60-day course of antibiotics with oral monotherapy to prevent relapse involving dormant endospores. Oral antibiotic should be dosed according to guidelines for postexposure prophylaxis.

Prehospital Care

All suspected cases of inhalational anthrax should be considered a bioterror event until proven to be otherwise. As with any potential epidemic biologic exposure, patients should be decontaminated in the field when possible, and paramedical health care workers should wear masks and gloves. If protection is needed from exposure, responders are advised to use splash protection, gloves, and a full-face respirator with high-efficiency particulate air (HEPA) filters (level C) or self-contained breathing apparatus (SCBA) (level B).

Persons who are potentially contaminated should wash with soap and water, not bleach solutions. Clothing and evidence/materials should be placed in plastic bags (triple). If the contamination is confirmed, then a 1:10 dilution of household beach may be used to decontaminate any materials and surfaces not sufficiently cleaned by soap and water.

Chemoprophylaxis with antibiotics should be instituted only if exposure is confirmed. For persons not at risk for repeated exposures to aerosolized B. anthracis spores through their occupation, preexposure vaccination with anthrax vaccine is not recommended.

Emergency Department Care

The emergency department workup includes rapid initiation of intravenous antibiotic therapy. If risk of exposure is considerable, initiate PEP.

During the 2001 bioterrorist attacks in the United States, the Centers for Disease Control and Prevention (CDC) recommendations for antimicrobial PEP included ciprofloxacin or doxycycline; the CDC recommended amoxicillin for children and pregnant or breastfeeding women exposed to strains susceptible to penicillin. The duration of postexposure antimicrobial prophylaxis should be 60 days if used alone for PEP of unvaccinated exposed persons.

There is a potential preventive benefit of using anthrax vaccine along with an antimicrobial drug for PEP, and the vaccine was made available for this use during the 2001 bioterrorism attacks; however, anthrax vaccine is not licensed for use in PEP.

Raxibacumab and obiltoxaximab are monoclonal antibodies available from the CDC for treatment of inhalational anthrax or as prophylaxis when other therapies are not available or appropriate. These monoclonal antibodies are used as part of a combination regimen with appropriate antibiotic drugs.[9, 10, 16]

Human anthrax immune globulin was approved by the FDA in March 2015. It provides passive immunity to adults and children exposed to inhalational anthrax. It is used in conjunction with appropriate antibiotic therapy.[11]

The indication for anthrax vaccine adsorbed (BioThrax) was expanded in November 2015 to include postexposure use following suspected or confirmed B anthracis exposure in combination with antimicrobial therapy. It was originally approved for pre-exposure prophylaxis in high-risk individuals.[12]

Patients can be admitted to a normal hospital room with barrier nursing procedures (ie, gown, gloves, mask) and secretion precautions (ie, special handing of potentially infectious dressings, drainage, and excretions).

Consultations

Anthrax is a reportable disease; notify local health care authorities and the Centers for Disease Control and Prevention of suspected cases. In addition, consultation with an infectious disease specialist may be warranted, although treatment of patients in whom anthrax is suspected is straightforward. If biologic terrorism is a threat, consider contacting the Federal Bureau of Investigation (FBI) through the local police department.

Deterrence/Prevention

For PEP in adults, the CDC recommends vaccination and the use of oral fluoroquinolones (ciprofloxacin, 500 mg bid; levofloxacin, 500 mg qd; or ofloxacin, 400 mg bid). Doxycycline is an acceptable alternative. Prophylaxis should continue until exposure to B anthracis is excluded or for a period of 4 weeks if exposure is confirmed.

The monoclonal antibodies raxibacumab and obiltoxaximab are indicated for prophylaxis of inhalational anthrax when alternative therapies are not available or not appropriate. They should be used as part of a combination regimen with appropriate antibiotic drugs.[9, 10, 16]

Three doses of vaccine should be administered during the 4-week period (at 0, 2, and 4 weeks post exposure). If a vaccine is not available, the antibiotic treatment should continue for at least 60 days. A second option is treatment for 100 days. A third option is 100 days of antibiotic prophylaxis with vaccine.

Anthrax vaccine

A vaccine exists but is not readily available. Preexposure vaccination is recommended only for populations at high risk of exposure to aerosolized B anthracis spores, according to the CDC's Advisory Committee on Immunization Practices (ACIP). The populations at high risk are the following:

  • Those who work directly with the organism in the laboratory
  • Those who work with imported animal hides or furs in areas where standards are insufficient to prevent exposure to anthrax spores
  • Those who handle potentially infected animal products in high-incidence areas; while incidence is low in the United States, veterinarians who travel to work in other countries where incidence is higher should consider being vaccinated
  • Those who work in the military and are deployed to areas with high risk for exposure to the organism

The anthrax vaccine adsorbed pre-exposure prophylaxis regimen is as follows:

  • Three-dose primary series: 0.5 mL IM at 0, 1, and 6 months
  • Booster series: 0.5 mL IM at 6 and 12 months after primary series initiation and then at 1-year intervals thereafter for persons who remain at risk
  • In persons who are at risk for hematoma formation following IM injection, the vaccine may be administer SC as a 4-dose primary series at 0, 2, 4 weeks and at 6 months
  • Note: Individuals are not considered protected until completion of the primary series
  • Administer in deltoid region

Anthrax vaccine adsorbed is also approved for postexposure prophylaxis following suspected or confirmed B anthracis exposure.

The anthrax vaccine adsorbed postexposure prophylaxis regimen is as follows:

  • 0.5 mL SC at 0, 2, and 4 weeks postexposure combined with antimicrobial therapy
  • Administer over deltoid region

Better protection, more extensive testing, more rigorous FDA approval, reduction of adverse effects, and a simpler dosing schedule are needed for anthrax vaccine. No human studies are available that document efficacy of available vaccines.

 

Medication

Medication Summary

Before October 2001, the first-line treatment of anthrax infection and prophylaxis was penicillin; however, this is not the case for bioterrorism-related cases because of the concern for genetically engineered penicillin-resistant anthrax strains. The Centers for Disease Control and Prevention (CDC) recommends ciprofloxacin or doxycycline. Doxycycline should not be used in suspected meningitis because it has poor penetration of the central nervous system.

Quinolones are not routinely indicated for pediatric patients because of the risk of musculoskeletal disorders. However, in 2008, the US Food and Drug Administration (FDA) approved use of levofloxacin in children as young as 6 months for the treatment of inhalational (and inhalational exposure to) anthrax.[17] Treatment duration is 60 days, but safety has not been evaluated beyond 14 days.

Women who are pregnant or breastfeeding can use amoxicillin. Resistance exists to third-generation cephalosporins, trimethoprim, and sulfisoxazole. For patients with severe anthrax, therapy with corticosteroids and intravenous antibiotics is recommended.

Individuals with inhalational anthrax should receive a multidrug regimen of either ciprofloxacin or doxycycline along with at least one more agent, including a quinolone, rifampin, tetracycline, vancomycin, imipenem, meropenem, chloramphenicol, clindamycin, or an aminoglycoside. After susceptibility testing and clinical improvement, the regimen may be altered.

Raxibacumab, a monoclonal antibody directed at the protective antigen of Bacillus anthracis, is available from the CDC for treatment of inhalational anthrax in adults and children. It is used as part of a combination regimen with appropriate antibiotic drugs. It is also approved for prophylaxis of inhalational anthrax when alternative therapies are not available or not appropriate.[16]

Human anthrax immune globulin (Anthrasil) is indicated for treatment of inhalational anthrax in adults and children in combination with antibiotic therapy.[11]

Cases of gastrointestinal and cutaneous anthrax can be treated with ciprofloxacin or doxycycline for 60 days. Penicillin such as amoxicillin or amoxicillin-clavulanate may be used to complete the course if the strain is susceptible.

Measures to prevent anthrax infection after exposure include vaccination, decontamination, and prophylactic treatment. For people who have been exposed to anthrax but do not have symptoms, 60 days of ciprofloxacin, a tetracycline (including doxycycline), or penicillin is given to reduce the risk or progression of disease due to inhaled anthrax.

A vaccine (anthrax vaccin adsorbed) is also available. It is indicated for pre-exposure prophylaxis in persons at high risk of exposure and for postexposure prophylaxis following suspected or confirmed B anthracis exposure.

Antibiotics, Other

Class Summary

Empirical antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Penicillin G (Pfizerpen)

Penicillin interferes with the synthesis of bacterial cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms. Penicillin is the drug of choice for nonbioterrorism-related anthrax. Treatment should begin with intravenous dosing.

Penicillin VK (Pen Vee K, Penicillin V, Veetids)

Penicillin interferes with the synthesis of bacterial cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms. Penicillin is the drug of choice for nonbioterrorism-related anthrax. Treatment should begin with intravenous dosing.

Penicillin G procaine

Penicillin reduces the incidence or progression of anthrax following exposure to aerosolized B anthracis. Available safety data for penicillin G procaine best support a duration of therapy of 2 weeks or less. Treatment for inhalational anthrax (postexposure) must be continued for a total of 60 days. Physicians must consider risks and benefits of continuing administration of penicillin G procaine for more than 2 weeks or switching to an effective alternative treatment.

In adults, administer by deep IM injection only into the upper outer quadrant of a buttock. In infants and small children, the midlateral aspect of the thigh may be a better site for administration.

Doxycycline (Adoxa, Doryx, Vibramycin)

Doxycycline is a second-generation tetracycline that is more active than tetracycline against many pathogens and is not hepatotoxic. Its adverse-effect profile and pharmacokinetics are different than those of tetracycline. Doxycycline reduces the incidence or progression of anthrax, including inhalational anthrax (postexposure) following exposure to aerosolized B anthracis.

Doxycycline inhibits protein synthesis and, thus, bacterial growth by binding with 30S and, possibly, 50S ribosomal subunits of susceptible bacteria. Although tetracyclines have an adverse effect on teeth in children younger than 8 years, the delay in bone development is apparently reversible; balancing these risks against the lethality of inhalational anthrax, the US Food and Drug Administration recommends a pediatric dosing regimen for inhalational anthrax (postexposure).

Administer IV therapy only when oral administration is not indicated, and do not give over a prolonged period (may increase the risk of thrombophlebitis and other complications). Switch to oral doxycycline or another antimicrobial drug product as soon as possible to complete a 60-day course of therapy.

Amoxicillin (Moxatag)

Amoxicillin interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.

Ampicillin

Ampicillin has bactericidal activity against susceptible organisms. It is an alternative to amoxicillin for patients who are unable to take medication orally.

Ciprofloxacin (Cipro, Proquin XR)

Ciprofloxacin is the drug of choice for anthrax when mutant strains are suspected (as in biological warfare). It is indicated for inhalational anthrax post exposure. Ciprofloxacin inhibits bacterial DNA synthesis and, consequently, growth by inhibiting DNA gyrase in susceptible organisms. It has high resistance potential. Initiate treatment immediately following suspected or confirmed anthrax exposure.

Levofloxacin (Levaquin)

Levofloxacin is a second-generation quinolone that acts by interfering with DNA gyrase in bacterial cells and promoting breakage of DNA strands. It is highly active against gram-negative and gram-positive organisms. It has low resistance potential.

Chloramphenicol

Chloramphenicol binds to 50 S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. It is effective against gram-negative and gram-positive bacteria.

Streptomycin

Streptomycin is an aminoglycoside antibiotic recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated.

Tetracycline

Tetracycline treats susceptible infections caused by gram-positive and gram-negative bacteria and infections caused by Mycoplasma, Chlamydia, and Rickettsia species. It inhibits bacterial protein synthesis by binding with 30S and, possibly, 50S ribosomal subunits of susceptible bacteria.

Corticosteroids

Class Summary

These agents are used for severe edema, meningitis, or swelling in the head and neck region.

Dexamethasone (Baycadron)

This agent is used in various inflammatory diseases. Dexamethasone may decrease inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Prednisone

Prednisone is useful in inflammatory and allergic reactions. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity.

Antidotes, Other

Class Summary

A monoclonal antibody (raxibacumab) and human anthrax immune globulin have been approved by the FDA using the animal efficacy rule for inhalational anthrax.[8, 11]

Anthrax immune globulin (Anthrasil)

Human anthrax immune globulin is indicated to provide passive immunization for inhalational anthrax in combination with appropriate antibacterial drugs for adults and children. Its effectiveness is based solely on efficacy studies conducted in animal models of inhalational anthrax. It does not cross the blood-brain barrier and does not prevent or treatment meningitis associated with anthrax. It is prepared using plasma collected from healthy, screened donors who have been immunized with anthrax vaccine adsorbed (BioThrax).

Raxibacumab

Raxibacumab is a recombinant human IgG1-gamma monoclonal antibody directed at the protective antigen of Bacillus anthracis. It is indicated for treatment of inhalational anthrax in adults and children and used in combination with appropriate antibacterial drugs. It is also indicated for prophylaxis of inhalational anthrax when alternative therapies are not available or are not appropriate.

Obiltoxaximab (Anthim, Anthrax antitoxin)

Monoclonal antibody that binds to the protective antigen of B anthracis and prevents the formation of the anthrax toxin that directly damages cell. It is indicated in adult and pediatric patients for the treatment of inhalational anthrax due to B anthracis in combination with appropriate antibacterial drugs. It is also indicated for prophylaxis of inhalational anthrax when alternative therapies are not available or not appropriate.

Vaccines

Class Summary

The FDA approved a standard anthrax vaccine designated "anthrax vaccine adsorbed" (AVA), which is a sterile filtrate of cultures of an avirulent strain that elaborates protective antigen. No human controlled trials are available. It is the first vaccine approved utilizing the animal rule by the FDA. The efficacy of this vaccine in inhalation (biowarfare) anthrax is questionable.

 

Anthrax vaccine adsorbed (BioThrax)

The vaccine is prepared from a cell-free filtrate of B anthracis, but contains no dead or live bacteria. The virulent components of Bacillus anthracis include an antiphagocytic polypeptide capsule and 3 proteins, including protective antigen (PA), lethal factor (LF), and edema factor (EF). They are not cytotoxic individually, but the combination of PA with LF or EF forms cytotoxic lethal toxin and edema toxin, respectively. The immune mechanism of AVA is unknown but, theoretically, antibodies to PA may provide protection by neutralizing the activities of these toxins. It is indicated for pre-exposure prophylaxis in persons at high risk of exposure and for postexposure prophylaxis following suspected or confirmed B anthracis exposure.

 

Questions & Answers

Overview

What are the signs and symptoms of inhalational anthrax?

What is anthrax?

What are the routes of exposure to anthrax?

What are the signs and symptoms of cutaneous anthrax?

What are the signs and symptoms of oropharyngeal anthrax?

What are the signs and symptoms of intestinal anthrax?

How is anthrax diagnosed?

What is anthrax?

What is the pathophysiology of anthrax meningitis?

What is the pathophysiology of anthrax?

What is the pathophysiology of cutaneous anthrax?

What is the pathophysiology of intestinal anthrax?

What is the pathophysiology of inhalational anthrax?

What causes anthrax?

Which factors increase the risk for inhalation anthrax?

What is the prevalence of anthrax in the US?

What is the global prevalence of anthrax?

Which patient groups are at highest risk for anthrax?

What is the prognosis of anthrax?

Presentation

Which clinical history findings are characteristic of cutaneous anthrax?

Which clinical history findings are characteristic of anthrax?

Which clinical history findings are characteristic of oropharyngeal anthrax?

Which clinical history findings are characteristic of intestinal anthrax?

Which clinical history findings are characteristic of inhalational anthrax?

What are the signs and symptoms of inhalational anthrax?

Which clinical history findings are characteristic of septicemic anthrax?

Which physical findings are characteristic of anthrax?

Which physical findings are characteristic of cutaneous anthrax?

Which physical findings are characteristic of oropharyngeal anthrax?

Which physical findings are characteristic of intestinal anthrax?

Which physical findings are characteristic of inhalational anthrax?

DDX

How is cutaneous anthrax differentiated from bubonic plague?

How is inhalational anthrax differentiated from zoonotic atypical pneumonias?

How is intestinal anthrax differentiated from dysentery?

How is anthrax differentiated from ulceroglandular tularemia?

How is cutaneous anthrax differentiated from syphilis?

Which conditions should be included in the differential diagnoses of anthrax?

What are the differential diagnoses for Anthrax?

Workup

How is anthrax diagnosed?

What is the role of gram stain and blood culture in the diagnosis of anthrax?

What is the role of enzyme-linked immunosorbent assay (ELISA) in the diagnosis of anthrax?

What is the role of imaging in the diagnosis of anthrax?

What is the role of lumbar puncture in the diagnosis of anthrax?

Which histologic findings are characteristic of anthrax?

Treatment

How is anthrax treated?

What guidelines have been published for the treatment of cutaneous anthrax?

What are the CDC guidelines for anthrax postexposure prophylaxis (PEP)?

How is cutaneous anthrax treated?

How is systemic anthrax without meningitis treated?

How is anthrax meningitis treated?

What is included in prehospital care for anthrax?

What is included in emergency department (ED) care for anthrax?

Which specialist consultations are beneficial to patients with anthrax?

What is included in postexposure prophylaxis (PEP) against anthrax?

Which high-risk groups should be vaccinated against anthrax?

How is the anthrax vaccine administered for pre-exposure prophylaxis?

How is the anthrax vaccine administered for postexposure prophylaxis?

Medications

What is the role of medications in the treatment of anthrax?

Which medications in the drug class Vaccines are used in the treatment of Anthrax?

Which medications in the drug class Antidotes, Other are used in the treatment of Anthrax?

Which medications in the drug class Corticosteroids are used in the treatment of Anthrax?

Which medications in the drug class Antibiotics, Other are used in the treatment of Anthrax?