Bacillus anthracis

I. Organism Information

A. Taxonomy Information
  1. Species:
    1. Bacillus anthracis (Shafazand et al., 1999, Website 15):
      1. GenBank Taxonomy No.: 1392
      2. Description: The anthrax bacterium is named Bacillus anthracis because it is rod-shaped when viewed under a microscope. The name "Bacillus" comes from the Latin word "baculus," meaning "rod." Anthrax is derived from the Greek word for coal, the characteristic color and appearance of the eschar in cutaneous anthrax. Anthrax is also known as charbon (pronounced shar-bawn), which is French for coal. Pulmonary anthrax is also known as woolsorter's disease. This is because people who sorted the wool of animals had contracted it in this way (Shafazand et al., 1999).
      3. Variant(s):
        • Sterne Strain (Cummings et al., 2002, Read et al., 2002):
          • Description: Recently, using mutiple-locus variable number tandem repeat (VNTR) analysis bioterror strain was identified as the veterinary vaccine strain, Sterne 34F2. Geographic region is in China. Sequencing is being considered and may be sequenced in the future (Cummings et al., 2002).
        • Strain V770 (Cummings et al., 2002):
          • Description: Geographic region is in Turkey, South Africa, Argentina, and the United States of America. Sequencing is being considered and may be sequenced in the future (Cummings et al., 2002).
        • Strain Kruger A (Cummings et al., 2002):
          • Description: The Kruger A strain of Bacillus anthracis is similar to Ames but of a lower virulence. Geographic region is South Africa. In Kruger National Park (South Africa), Kruger A isolates have a wider geographic range and greater genetic diversity than Kruger B isolates. Sequencing is being considered and may be sequenced in the future (Website 14, Cummings et al., 2002, Smith et al., 2000).
        • Strain Kruger B (Cummings et al., 2002, Website 14):
          • Description: The Kruger B strain of Bacillus anthracis is more virulent than Kruger A and has the greatest phylogenetic diversity relative to Ames. Geographic region is South Africa. Sequencing is being drafted (shotgun sequence with eightfold coverage is available) (Website 14, Cummings et al., 2002).
        • Strain Vollum 1b (Cummings et al., 2002):
          • Description: Vollum-1b is a low virulence strain that has been used for many research studies. Geographic region is in the United Kingdom, Spain, and Zimbabwe. Sequencing is underway (Website 14, Cummings et al., 2002).
        • Strain CNEVA 9066 (Cummings et al., 2002):
          • Description: CNEVA 9066 is a phylogenetically diverse strain from France, There is little data available on virulence. Geographic region is in Slovenia, France, and Croatia. Sequencing is underway (Cummings et al., 2002, Website 34).
B. Lifecycle Information :
  1. Stage Information:
    1. Vegetative Phase: :
      1. Size: The non-flagellated vegetative cell is large (1-8 micrometers long, 1-1.5 micrometers wide). Spore size is approximately 1 micrometer (Inglesby et al., 2002).
      1. Shape: Vegetative cells are rod-shaped. The chains of virulent forms of the bacteria are usually surrounded by a capsule (Mock et al., 2001).
      1. Picture(s):
        • SEM Images of Vegetative and Spore Stages (Website 37):



          Description: Scanning Electron Micrograph of Bacillus anthracis spore and vegetative stages. Bacillus anthracis is a Gram-positive, encapsulated, spore-forming, zoonotic, rod prokaryote. Magnification: x700.
      1. Description: Spores ingested by herbivores germinate within the host to produce the vegetative forms; these multiply and express their virulence factors, killing the host (ref76, Figure 1). The vegetative form is square ended and capsulated. Sporulating cells carry elliptic, centrally located spores. Bacilli shed by the dying or dead animal will sporulate on contact with air. Sporulation requires the presence of free oxygen, and the efficiency of the process is influenced by the environmental conditions. The proportion of cells that reach the ultimate stage, a dormant spore, is variable. The various steps of this cycle and current knowledge of the molecular mechanisms they involve are reviewed (Mock and Fouet, 2001).
    2. Intense Growth Phase: :
      1. Description: This is the phase where the bacteria have intense growth (Website 36).
    3. Stationary Phase: :
      1. Description: The growth of B. anthracis is stationary (Website 36).
    4. Sporulation Phase: :
      1. Size: Endospores are 1 micrometer by 1.5 micrometers in size and are able to reach the alveoli (ie, less than 5 micrometers) (Website 2).
      1. Shape: Endospores are nonswelling and oval-shaped (Website 2). Endospore is located central-to-subterminal and does not usually swell; carbon dioxide levels within the body inhibit sporulation. Forms long chains in vitro giving them a bamboo appearance; single cells or short chains in direct clinical samples (Mock et al., 2001, Website 2, Shafazand et al., 1999).
      1. Picture(s):
        • Scanning Electron Micrograph of Spores in Lung (Website 37):



          Description: Photocomposite of Bacillus anthracis spores in lung bronchiole.Magnification: x43(lung), x1,410(bacteria).
      1. Description: The SPORE is a particular stage in the life cycle of the ANTHRAX organism; during this stage it goes into STASIS and remains dormant until something happens in its natural environment (Website 35). Dormant spores are highly resistant to adverse environmental conditions including heat, ultraviolet and ionizing radiation, pressure, and chemical agents. They are able to survive for long periods in contaminated soils and thus account for the ecological cycle of the organism. In a suitable environment, spores reestablish vegetative growth. However the bacilli are poor survivors, and it is unclear whether existence of a complete cycle, from germination to resporulation, occurs outside the host. Indeed the particular properties of B. anthracis, compared with those of other Bacillus cereus-group bacilli sharing the same ecological niche, are consistent with a life cycle that almost exclusively takes place in the mammalian host (Mock and Fouet, 2001).

  2. Progression Information:
    1. From stage: Vegetative Phase , To stage: Intense Growth Phase:
      1. Description: The bacteria at the vegetative phase begin to replicate very quickly with the appropriate growth condition (Website 35).
    2. From stage: Intense Growth Phase , To stage: Stationary Phase:
      1. Description: The intensively grown active bacteria eventually kill the host and the stationary phase forms (Website 36, Turnbull et al., 2002).
    3. From stage: Stationary Phase , To stage: Sporulation Phase:
      1. Description: The rate of sporulation by the shed vegetative cells and the proportion which succeed in sporulating are influenced in a complex manner by the environmental conditions into which they fall. Temperature, pH, water, oxygen availability, sunlight, organic matter and the presence of certain cations such as Mn++ are among the many influcencing factors. The spore forms are highly resistant ot adverse environmental conditions (Turnbull et al., 2002).
    4. From stage: Sporulation Phase , To stage: Vegetative Phase:
      1. Description: Within the infected host the spores germinate to produce the vegetative forms (Website 35, Turnbull et al., 2002).

  3. Description: Bacillus anthracis is Gram-positive, non-motile, aerobic, facultative anaerobic, spore-forming, bacterium (Mock et al., 2001, Website 2, Shafazand et al., 1999).
C. Genome Summary:
  1. Genome of Ames Strain (Website 38, Read et al., 2002):
    1. Chromosome Information:
      1. GenBank Accession Number: NC_003997
      2. Size: 5227293 bp (Website 19)
      3. Description: Bacillus anthracis strain Ames, complete genome (Website 19).

  2. Genome of Pasteur Strain (Read et al., 2002):
    1. Description: Plasmid pXO2 from the Pasteur strain has been sequenced
    2. Plasmid pX02 (Mock et al., 2001, Website 1, Okinaka et al., 1999, Dixon et al., 2000, Website 27):
      1. GenBank Accession Number: NC_002146
      2. Size: 96,231 bp in length (Mock et al., 2001)
      3. Gene Count: 85 open reading frames (Mock et al., 2001)
      4. Description: Plasmid pXO2 (60Mda) carries genes required for the synthesis of an antiphagocytic poly-gamma-D-glutamic acid capsule which inhibits phagocytosis of vegetative cells. Plasmid pXO2 carries: three genes required for capsule synthesis (capB, capC, and capA), a gene associated with capsule degradation (dep), and a trans-acting regulatory gene (acpA) (Pannucci et al., 2002, Mock et al., 2001, Website 1, Okinaka et al., 1999, Dixon et al., 2000).

  3. Genome of Sterne Strain (Read et al., 2002):
    1. Description: Plasmid pXO1 has been isolated from the Sterne strain (Read et al. 2002).
    2. Plasmid pXO1 (Mock et al., 2001, Website 1, Okinaka et al., 1999, Leppla et al., 1995, Dixon et al., 2000, Pannucci et al., 2002, Bradley et al., 2001, Website 28):
      1. GenBank Accession Number: NC_001496
      2. Size: 181,654 bp in length (Okinaka et al., 1999)
      3. Description: Plasmid pX01 contains 143 ORFs, covering ~61% of the DNA. Plasmid pXO1 (110-Mda) contains genes required for synthesis of the anthrax toxin proteins: cya which encodes edema factor (EF), lef which encodes lethal factor (LF), and pagA which encodes protective antigen (PA). Plasmid pXO1 also harbors two trans-acting regulatory genes [atxA the toxin gene transactivator], pagR [the negative regulator of pagA], a gene encoding a type I topoisomerase (topA); a resolvase and a transposase, an operon containing three genes (gerXC, -A and -B) whose functions appear to affect germination. The virulence genes of pXO1 are organized in a manner similar to pathogenicity islands (PAIs) located on the chromosomes of other bacterial pathogens (Mock et al., 2001) (Mock et al., 2001, Website 1, Okinaka et al., 1999, Dixon et al., 2000).

  4. Genome of Florida isolate of Ames Strain (Read et al., 2002):
    1. Chromosome Information (Website 21):
      1. GenBank Accession Number: NC_003995
      2. Size: 5093554 bp (Website 21)
      3. Description: Bacillus anthracis A2012, unfinished sequence, whole genome shotgun sequencing project (Read et al., 2002).
    2. Plasmid pXO1 (Website 29):
      1. GenBank Accession Number: NC_003980
      2. Size: 181677 bp (Read et al., 2002)
      3. Description: Bacillus anthracis str. A2012 plasmid pXO1, complete sequence (Website 29).
    3. Plasmid pXO2 (Website 30):
      1. GenBank Accession Number: NC_003981
      2. Size: 94829 bp (Read et al., 2002)
      3. Description: Bacillus anthracis str. A2012 plasmid pXO2, complete sequence (Website 30).

II. Epidemiology Information

A. Outbreak Locations:
  1. Anthrax in animals is hyperendemic or endemic in the following areas of the world: most areas of the Middle East, most areas of equatorial Africa, Mexico, Central Africa, Chile, Argentina, Peru, Bolivia, certain Southeast Asian countries (e.g. Burma (Myanmar), Vietnam, Cambodia, Thailand), Papua New Guinea, China, and some Mediterranean countries. In most of the rest of the world, anthrax occurs only sporadically. In the United States (US), outbreaks in animals have occurred since 1990 in the Midwest (Kansas, Nebraska, North Dakota, South Dakota, Missouri); in the West (California, Nevada); and in Texas and Oklahoma. In the US, the microorganism remains endemic in the soil of Texas, Oklahoma, and the lower Mississippi valley (Website 2, Shafazand et al., 1999).
  2. An estimated 2,000 to 20,000 human cases of anthrax occur globally each year (Website 2).
  3. Early descriptions of anthrax date to 3,500 years ago; anthrax may have been responsible for two of the plagues that afflicted Egypt in 1491 BC (Shafazand et al., 1999).
  4. A major outbreak involving nearly 10,000 cases (most of them cutaneous infection) occurred in Zimbabwe during the late 1970s and early 1980s. An epizootic outbreak in cattle occurred at that time in the same area (Website 2).
  5. An outbreak involving nine cases (five inhalational and four cutaneous) occurred in 1957 in the United States in a New Hampshire goat-hair processing plant. This was the last recognized outbreak of naturally occurring infection in this country (Website 2).
  6. An outbreak of oropharyngeal anthrax involving 24 cases occurred in Thailand in 1982 following consumption of contaminated meat. Oropharyngeal disease is an unusual manisfestation of infection, which makes this outbreak of particular interest (Website 2).
  7. In 1941, the British conducted limited experiments by realeasing spores of anthrax on Gruinard Island near Scotland. During 1943 and 1944, an estimated 4 x 10e14 anthrax spores were dispersed on the island through explosive means. Spores were still detectable more than 40 years later. The viable anthrax spores persisted until the island was decontaminated with formaldehyde and seawater in 1986 (Shafazand et al., 1999, Website 2).
  8. The US experimented with biological weapons including anthrax spores in 1950s and 1960s (Shafazand et al., 1999).
  9. In 1979, a large epidemic of anthrax occurred in the former Soviet Union at Sverdlosk, an industrial city of 1.2 million people just east of the Ural Mountains. The accidental release of Bacillus anthracis spores from a nearby military facility was responsible for the epidemic, which caused at least 77 clinical cases and 66 deaths (Shafazand et al., 1999, Website 2, Website 31).
  10. Between 1984 and 1993, only three cases of cutaneous anthrax were reported to the Centers for Disease Control. A fatal case occurred in 1976; when a home craftsman died of inhalational anthrax after working with yarn imported form Pakistan. Approximately 130 cases occurred annually in the US in early 1900s. The incidence has gradually declined over time, with less than 10 cases reported each year since the early 1960s (Shafazand et al., 1999, Website 2).
  11. About 95% of naturally occurring cases in the United States (US) are cutaneous and 5% are inhalational. Gastrointestinal infection has not been recognized in the country. Only 18 cases of naturally occurring inhalational anthrax were reported in the US during the 20th century, with the most recent case in 1976. All but three were associated with industrial exposures; two of the remaining cases were laboratory-acquired and the source of exposure for the third case remains unknown. Since 1990, only two cases of naturally occurring infection have been reported in the US (one in 1992 and one in 2000); both patients had cutaneous disease. The latter case occurred in North Dakota and resulted from agricultural exposure (Website 2).
  12. In 2001, an outbreak in the United States involved direct exposure to mail that was deliberately contaminated with anthrax spores. At least five contaminated letters were sent and one was reported to contain 2g of powder, with 100 billion to 1 trillion anthrax spores per gram. Twenty-two confirmed or suspect cases of anthrax infection resulted. Eleven of these were inhalational cases, of whom 5 died; 11 were cutaneous cases (7 confirmed, 4 suspected) (Website 2, Inglesby et al., 2002).
B. Transmission Information:
  1. From: Grazing Herbivores (at lifecycle stage: Vegetative Phase, Intense Growth Phase), To: Homo sapiens (at lifecycle stage: Vegetative Phase, Intense Growth Phase) (Dixon et al., 1999, Website 2, Website 7):
    Mechanism: Exposure to infected animals or contaminated animal products. Anthrax is predominantly a disease of animals. Contact with infected tissues of dead animals (e.g. butchering, preparing contaminated meat), which generally leads to cutaneous anthrax, consumption of contaminated undercooked meat, which can lead to gastrointestinal or oropharyngeal anthrax, contact with contaminated hair, wool, or hides (particularly during processing) or contact with products made from them, which can lead to either inhalational or cutaneous anthrax (Website 2).

  2. From: Homo sapiens (at lifecycle stage: Vegetative Phase, Intense Growth Phase), To: Homo sapiens (at lifecycle stage: Vegetative Phase, Intense Growth Phase) (Website 2):
    Mechanism: The agent may be present in blood, skin lesion exudates, cerebrospinal fluid, pleural fluid, sputum, and rarely, in urine and feces. Reported rarely with cutaneous anthrax, but has not been recognized with gastrointestinal or inhalational disease (Website 2, Dixon et al., 1999, Website 3).

C. Environmental Reservoir:
  1. Contaminated environment (Website 35, Website 7, Inglesby et al., 2002, Website 2, Shafazand et al., 1999):
    1. Description: Contaminated environment reservoir includes soil, air, or animal carcass. B. anthracis spores remain prevalent in soil samples throughout the world and cause anthrax cases among herbivores annually. Ecologic factors (such as abundant rainfall following a period of drought may enhance spore density in soil, although the exact influence of such factors remains poorly understood (Inglesby et al., 2002; Shafazand et al., 1999; Website 2).
    2. Survival Information: The results of studies of agricultural outbreaks have suggested that conditions for multiplication are favorable when the soil pH is >6.0 and rich in organic matter. Major changes in the soil microenvironment, such as drought or rainfall, enhance the sporulation. Spores germinate and form vegetative cells in environments rich in nutrients (e.g. glucose, amino acids, nucleosides). Vegetative bacteria have poor survival outside of an animal or human host; colony counts decline to being undetectable within 24 hours following inoculation into water. Conversely, vegetative cells form spores when nutrients in the environment are exhausted. Spores have been shown to survive in the environment for decades (more than 40 years). The environmentally hardy properties of the spore allow it to survive for decades in ambient conditions. Endospores are resistant to drying, heat, ultraviolet light, gamma radiation, and some disinfectants (Inglesby et al., 2002; Website 2).
D. Intentional Releases:
  1. Intentional Release information (Website 2):
    1. Description: Aerosol release of weaponized spores is the most likely mechanism for use of anthrax as a biological weapon. Although there is no formal definition of weaponized anthrax, weaponization generally involves: small particle size, high concentration of spores, treatment to reduce clumping, neutralization of the electrical charge, and use of antimicrobial-resistant strains by genetic modification of the organism to increase virulence or escape vaccine protection (Website 2).
    2. Emergency contact: Anthrax is a notifiable disease in all 50 states and is Federally reportable. According to bioterrorism guidelines put forth by Centers for Disease Control (CDC), any case of inhalational (pulmonary) anthrax in the United States should also be reported to the Federal Bureau of Investigation, as it is assumed that inhalational anthrax is so rare in the United States that any case must be due an intentional release. Immediately notify the local or state public health department, local hospital epidemiologist, and local or state public health laboratory. If you are at home, then report the incident to local police. If you are at work, then report the incident to local police, and notify your building security official or an available supervisor. The Laboratory Response Network (LRN) has been developed in the United States to coordinate clinical diagnostic testing for bioterrorism events. LRN has been established through a collaboration of the Association of Public Health Laboratories and the CDC. The network is organized into four laboratory levels (A, B, C, and D). The LRN can be accessed by contacting state public health laboratories. Level A laboratories can perform standard initial tests to rule out (but not definitively identify) B. anthracis, and include Clinical Laboratory Improvement Act (CLIA)-certified clinical laboratories with BSL-2 safety practices. Level B laboratories have core capacity for agent isolation and confirmatory testing and include most state public health laboratories. Level C laboratories have advanced capacity for rapid identification and include selected public health, federal, and academic laboratories. Level D laboratories have the highest level of containment (BSL-4) and expertise in the diagnosis of rare and dangerous biologic agents and include specialized Federal laboratories (Website 5, Inglesby et al., 2002, Website 2, Website 10, Website 23).
    3. Delivery mechanism: Aerosolized spores may be delivered by missiles, bomblets, artillery fires, point release, or airborne line release. Contamination of food and water may be used. Mail can also be an effective vehicle for disseminating anthrax spores (Pannucci et al., 2002, Website 2, Website 7).
    4. Containment: A suspicious, unopened letter or package should be marked with a threatening message such as "anthrax": Do not shake or empty the contents of any suspicious envelope or package. PLACE the envelope or package in a plastic bag or some other type of container to prevent leakage of contents. If you do not have any container, then COVER the envelope or package with anything (e.g., clothing, paper, trash can, etc.) and do not remove this cover. Then LEAVE the room and CLOSE the door, or section off the area to prevent others from entering (i.e., keep others away). WASH your hands with soap and water to prevent spreading any powder to your face. Envelope with powder and powder spills out onto surface: DO NOT try to CLEAN UP the powder. COVER the spilled contents immediately with anything (e.g., clothing, paper, trash can, etc.) and do not remove this cover! Then LEAVE the room and CLOSE the door, or section off the area to prevent others from entering (i.e., keep others away). WASH your hands with soap and water to prevent spreading any powder to your face. REMOVE heavily contaminated clothing as soon as possible and place in a plastic bag, or some other container that can be sealed. This clothing bag should be given to the emergency responders for proper handling. SHOWER with soap and water as soon as possible. Do Not Use Bleach Or Other Disinfectant On Your Skin. Question of room contamination by aerosolization: for example: small device triggered, warning that air handling system is contaminated, or warning that a biological agent released in a public space. Turn off local fans or ventilation units in the area. LEAVE area immediately. CLOSE the door, or section off the area to prevent others from entering (i.e., keep others away). SHUT down air handling system in the building, if possible. If possible, list all people who were in the room or area, especially those who had actual contact with the powder. Give this list to both the local public health authorities so that proper instructions can be given for medical follow-up, and to law enforcement officials for further investigation (Website 23, Website 2).

III. Infected Hosts

  1. Humans:
    1. Taxonomy Information:
      1. Species:
        1. Humans:
          • GenBank Taxonomy No.: 9606
          • Scientific Name: Homo sapiens

    2. Infection Process:
      1. Infectious Dose: The infective dose for cutaneous anthrax is not known (Website 2). Extrapolations from animal data suggest that the human LD50 (dose sufficient to kill 50% of persons exposed to it) is 2500 to 55000 inhaled spores. On the basis of experimental studies involving primates, the United States Department of Defense has estimated that the LD50 for inhalational anthrax in humans from weapons-grade anthrax is 2,500 to 55,000 spores. The United States Department of Defense estimates that the LD50 for humans is between 8,000 and 10,000 spores. The LD10 (dose sufficient to kill 10% of persons exposed to it) was as low as 100 spores and data suggest that as few as 1 to 3 spores may cause infection. Extrapolation of dose-response curves involving cynomolgous monkeys suggest that the LD10 in humans following exposure to airborne anthrax spores may be as low as 50 to 98 spores, the LD5 (dose sufficient to kill 5% of persons exposed to it) may be only 14 to 28 spores, and the LD1 (dose sufficient to kill 1% of persons exposed to it) may be only 1 to 3 spores. From data available (1979 accidental release of aerosol in Sverdlovsk, Russia), estimates were made that the median lethal dose of spore-bearing particles less than 5 micrometers in size was 4,100. The minimum infectious inhaled dose in chimpanzees is 40,000 to 65,000 spores. A review of previous outbreaks suggests that prior exposure to radiation, alcoholism, and underlying pulmonary disease are important risk factors for inhalational anthrax. In experimental animals, once toxin production has reached a critical threshold, death occurs even if sterility of the bloodstream is achieved with antibiotics (Inglesby et al., 2002, Website 2, Brachman, 2002, Shafazand et al., 1999). The infective dose for gastrointestinal anthrax is not known (Website 2).
      2. Description: B. anthracis is able to form spores. These spores are the infectious agents and can enter the human body through skin lesions, ingestion or inhalation. Most commonly, spores enter via a skin lesion and germinate locally. The bacteria multiply quickly and secrete a toxin that causes a lesion characterized by edema and necrosis, which develops into a black eschar. Although the lesion usually heals spontaneously, in rare instances the bacteria enter the systemic circulation and replicate to high densities. In these circumstances, the large amount of toxin released by the bacteria can cause shock, respiratory failure and death. When the spores are ingested or inhaled, they are engulfed by macrophages, germinate in central lymph nodes and usually spread systemically. Thus, gastrointestinal and inhalation anthrax are often fatal (Mourez et al., 2002). Humans usually do not contract anthrax directly from the soil, unless they work with fertilizers (bonemeal) prepared from infected animals. Also, humans can contract spores from inhalation of aerosolized spores released during a biological weapons attack (Website 2, Website 7).

    3. Disease Information:
      1. Cutaneous anthrax (Website 2):
        1. Pathogenesis Mechanism: Disease results when Bacillus anthracis spores are introduced into the skin via inoculation of small cuts/abrasions or inapparent skin lesions. Endospores often are phagocytosed by macrophages and carried to regional lymph nodes, causing painful lymphadenopathy and lymphangitis. Low-level germination at the site of introduction leads to localized necrosis with eschar formation and soft-tissue or mucosal edema (which can be massive in some cases). Hematogenous spread with resultant toxemia can occur, although such spread is not common with appropriate antibiotic therapy (Website 7, Website 2).

          • Pathogenesis of B. anthracis (Prince, 2003):



            Description: How anthrax toxins cause pathology. Fully virulent B. anthracis produce an antiphagocytic capsule as well as toxins. The protective antigen (PA) of the anthrax toxin binds to the ATR on the host cell surface. The 83-kDa form of PA is cleaved by the cell surface protease furin and produces a 63-kDa monomer. Heptamerization of PA induces clustering of the ATRs, association of the complex with lipid rafts, and exposure of binding domains to the edema factor (EF) or the lethal factor (LF). The heptamer, and bound EF or LF, are then endocytosed. EF, an adenylate cyclase, and LF, a Zn2+ metalloprotease, translocate to the cytosol through a pore created in the membrane and act on host cytosolic targets to induce edema, necrosis, and hypoxia. Modified with permission from Annual Reviews (4). CaM, calmodulin. Reproduced with permission from Journal of Clinical Investigation (Prince, 2003).


        2. Incubation Period: 1-7 days (may be as long as 12 days). Data from 21 patients infected in October 2001 indicate a 1-10 day (mean of 5 days) incubation period for cutaneous anthrax. Signs and symptoms become apparent within 5 days of exposure (Website 2, Shafazand et al., 1999).


        3. Prognosis: Case-fatality rate is currently less than 1% (most people recover with appropriate antimicrobial therapy). In preantibiotic era, case-fatality rates of about 20% were reported. The case fatality rate for untreated cutaneous anthrax is up to 20%, but with early, effective therapy is reduced to less than 5% (Website 2, Website 7, Little et al., 1999).


        4. Diagnosis Overview: Differential diagnosis. Two key features that distinguish cutaneous anthrax from other conditions in the differential diagnosis are the painlessness of the lesion and the relatively large extent of the associated edema (Website 2).


        5. Symptom Information :
          • Lymphangitis and painful lymphadenopathy:
            • Description: Lymphangitis and painful lymphadenopathy may occur. Regional adenopathy is often an associated feature (Website 2, Shafazand et al., 1999).
            • Observed: One outbreak in Thailand demonstrated the following cutaneous finding for 13 patients with cutaneous anthrax: Lymphadenopathy (100%) (Website 2).
          • Edema and necrosis:
            • Description: Edema and necrosis ensues with little purulence noted, which is likely due to the inhibitory function of edema toxin on leukocytes. Edema out of proportion to vesicular size surrounds the lesion. Painless, localized, nonpitting edema surrounds ulcerated area. Malignant edema is rare complication and is characterized by severe edema, multiple bullae, and shock (Shafazand et al., 1999, Website 7, Website 2).


              • Edema and lesions (Website 26):



                Description: Cutaneous anthrax vesicle development. Day 4: Notice the edema and typical lesions. Copyright: CDC.
            • Observed: One outbreak in Thailand demonstrated the following cutaneous finding for 13 patients with cutaneous anthrax: Edema around lesion (77%) (Website 2).
          • Fever:
          • Malaise:
          • Lesion:
            • Description: Initial lesion is small papule or vesicle (small, painless, often puritic papules). Evolving skin lesion (face, hands, neck, arms) generally ruptures near the end of the first week (Shafazand et al., 1999, Website 7, Website 2).
            • Observed: One outbreak in Thailand demonstrated the following cutaneous finding for 13 patients with cutaneous anthrax: Blister (92%) (Website 2).
          • Ulcer:
            • Description: Within 24 to 48 hours, the papules enlarge and become vesicular (usually, 1 to 2 cm in diameter). By the second day, the papule ulcerates with central necrosis and drying. Fine vesicles may encircle ulcer; these enlarge over next 1- 2 days and may discharge serosanguinous fluid (Shafazand et al., 1999, Website 7, Website 2).
            • Observed: One outbreak in Thailand demonstrated the following cutaneous finding for 13 patients with cutaneous anthrax: Ulcer (23%) (Website 2).
          • Anthrax eschar:
            • Description: The remaining ulcer progresses to a black eschar. The eschar sloughs off in 2 to 3 weeks. After 1 to 2 days, painless black eschar forms over ulcerated area. Eschar sloughs off after 12-14 days (Shafazand et al., 1999, Website 7, Website 2).


              • Black eschar and redness (Website 26):



                Description: Cutaneous anthrax vesicle development. Day 4: Black eschar, redness remains. Copyright: CDC.
            • Observed: Lesions resolve without complications or scarring in 80%-90% of patients. One outbreak in Thailand demonstrated the following cutaneous finding for 13 patients with cutaneous anthrax: Eschar (85%) (Website 2).

        6. Treatment Information:
          • Antibiotic (Website 2): These treatment recommendations were made during the US 2001 anthrax outbreak. In other settings, antimicrobial susceptibility testing should be used to guide therapy decisions. Adults: Ciprofloxacin, 500 mg PO twice daily or Doxycycline, 100 mg PO twice daily for 60 days. Children: Ciprofloxacin, 10-15 mg/kg PO every 12 hr, not to exceed 1 g/day or Doxycycline: >8 yr and >45 kg: 100 mg PO every 12 hr; >8 yr and <45 kg: 2.2 mg/kg PO every 12 hr <8 yr: 2.2 mg/kg PO every 12 hr for 60 days (Website 2). American Academy of Pediatrics recommends treatment of young children with tetracyclines for serious infections. Pregnant women: Same as for nonpregnant adults (high death rate from the infection outweighs risk posed by antimicrobial agent). Treat for 60 days. Although tetracyclines and ciprofloxacin are not recommended for pregnant women, their use may be indicated for life-threatening illness. Adverse effects on developing teeth and bones are dose-related; therefore, doxycycline might be used for a short time (7-14 days) before 6 mo of gestation. Immunocompromised persons: Same as for nonimmunocompromised persons and children for 60 days. Initial therapy is oral although, cutaneous anthrax cases with signs of systemic involvement, extensive edema, or lesions on the head or neck require intravenous therapy, and a multidrug approach is recommended. Ciprofloxacin or doxycycline should be considered first-line therapy. Amoxicillin (500 mg orally 3 times daily for adults or 80 mg/kg/day divided every 8 hr for children) is an option for completion of therapy after clinical improvement. Oral amoxicillin dose is based on need to achieve appropriate minimum inhibitory concentration. Treatment of cutaneous anthrax does not prevent the evolution of the skin lesions; however, it usually will prevent progression to systemic disease. In cases of naturally occurring cutaneous anthrax, previous recommendations have indicated that treatment for 7 to 10 days is adequate; however, in the setting where inhalational exposure is also likely, treatment should be continued for 60 days (Website 2).
            • Applicable: Cutaneous anthrax

        7. Other Information:
          • Occurrence of cutaneous anthrax: Cutaneous anthrax is the most common naturally occurring form accounting for more than 90 percent of all anthrax cases worldwide (Website 7, Inglesby et al., 2002).
          • Children: Naturally occurring cutaneous anthrax is uncommon in children, probably because children have less opportunity for exposure to infected animals. Other modes of transmission (such and person-to-person or transmission via fomites) may be more common for young children who acquire cutaneous anthrax. The clinical presentation of cutaneous anthrax in children usually is similar to the presentation in adults. Progression to severe systemic disease can occur (Website 2).

      2. Inhalational anthrax :
        1. Pathogenesis Mechanism: Occurs when individuals working with animal hides, wool, or bonemeal, inhale the spores. Also, inhalation anthrax may occur from inhalation of aerosolized spores released during a biological weapon attack. Spore-bearing particles deposit in the alveolar spaces. Aerosolized anthrax spores >5 micrometer in size are deposited in the upper airways (pharynx, larynx, and trachea) and effectively trapped or cleared by the mucociliary system. Spores between 2 and 5 micrometer in size are able to reach the alveolar ducts and alveoli. Endospores are introduced into the body via inhalation. Endospores are 1 micrometer by 1.5 micrometer in size. Endospores are phagocytosed by macrophages and carried to regional lymph nodes. Spores then germinate inside macrophages and become vegetative cells, which leave the macrophages and multiply in the lymphatic system. Bacteria enter the bloodstream and lead to septic shock and toxemia; hematogenous spread can lead to hemorrhagic meningitis (Website 7, Inglesby et al., 2002, Shafazand et al., 1999, Website 2).


        2. Incubation Period: 2-43 days (may be longer). Data from 21 patients infected in October 2001 indicate a 5-11 day (mean of 7 days) incubation period for inhalational anthrax is 1-5 days, and possibly, up to 60 days. Initial incubation period of ~11 days. The incubation for anthrax is hours to 7 days. Most cases present within 48 hours post-exposure (Website 2, Maynard et al., 2002, Website 7).


        3. Prognosis: Inhalational anthrax is expected to account for most serious morbidity and mortality. Illness may be biphasic, with an initial prodrome (that includes symptoms such as fever, malaise, fatigue, anorexia) followed by sudden increase in fever, severe respiratory distress, diaphoresis and shock, if left untreated. Case-fatality rate in Sverdlovsk outbreak: 86%, US outbreak: 45% (lower observed case-fatality rate in US outbreak likely due to early diagnosis and aggressive therapy). Almost all inhalation anthrax cases in which treatment was begun after onset of significantly severe symptoms have been fatal, regardless of treatment. Despite medical therapy, most patients with inhalation anthrax die within 24 hours of the onset of the acute phase of the illness. However, in nonhuman primate trials, animals have responded to aggressive therapy. Whereas the case-fatality of the previous 18 cases of inhalational anthrax in the US was 88%, the current rate among the current cases (11 cases) was 45%. This may reflect differences in dose or in the infecting strain or the institution of prompt and aggressive treatment for the recent cases. Once respiratory distress develops, mortality rates may approach 90%. Begin treatment when inhalational anthrax is suspected, do not wait for confirmatory testing. Limited data from the October 2001 infections indicate that early treatment significantly decreases the mortality rate (Inglesby et al., 2002, Website 2, Website 7, Brachman, 2002).


        4. Diagnosis Overview: Features that distinguish inhalational anthrax from other conditions in the differential diagnosis include the presence of a widened mediastinum and pleural effusions on chest radiograph or CT with minimal evidence of pneumonia. Several features can be used to distinguish inhalational anthrax from influenza-like illness (ILI): Most patients with ILI have rhinorrhea, which is uncommon among patients with inhalational anthrax. Most patients with inhalational anthrax have shortness of breath, which is uncommon among patients with ILI. Nausea and vomiting are more common among patients with inhalational anthrax. Patients with inhalational anthrax are likely to have abnormalities on chest radiographs at the time of initial presentation, including mediastinal widening, infiltrates, and pleural effusion (Website 2).


        5. Symptom Information (Inglesby et al., 2002, Website 2, Shafazand et al., 1999):

        6. Treatment Information:
          • Antibiotic (Website 2): These treatment recommendations were made during the US 2001 anthrax outbreak. In other settings, antimicrobial susceptibility testing should be used to guide therapy decisions. Ciprofloxacin or doxycycline should be considered an essential part of first-line therapy for inhalational anthrax. Steroids may be considered an adjunct therapy for patients with severe edema and for meningitis based on experience with bacterial meningitis of other etiologies. Initial therapy may be altered based on clinical course of patient; one or two antimicrobial agents (eg, ciprofloxacin or doxycycline) may be adequate as patient improves. Initial IV Therapy: Adults: Ciprofloxacin, 400 mg every 12 hr or Doxycycline, 100 mg every 12 hr and One or two additional antimicrobials (agents with in vitro activity include rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, and clarithromycin). Children: Ciprofloxacin, 10-15 mg/kg every 12 hr, not to exceed 1 g/day or Doxycycline: >8 yr and >45 kg: 100 mg PO every 12 hr >8 yr and <45 kg: 2.2 mg/kg PO every 12 hr <8 yr: 2.2 mg/kg PO every 12 hr And One or two additional antimicrobials (see agents listed under therapy for adults). If intravenous ciprofloxacin is not available, oral ciprofloxacin may be acceptable because it is rapidly and well absorbed from gastrointestinal tract with no substantial loss by first-pass metabolism. Maximum serum concentrations are attained 1-2 hours after oral dosing but may not be achieved if vomiting or ileus is present. American Academy of Pediatrics recommends treatment of young children with tetracyclines for serious infections. Pregnant women: Same as for nonpregnant adults (high death rate from the infection outweighs risk posed by antimicrobial agent). Although tetracyclines are not recommended for pregnant women, their use may be indicated for life-threatening illness. Adverse effects on developing teeth and bones are dose-related; therefore, doxycycline might be used for a short time (7-14 days) before 6 months of gestation. Immunocompromised persons: Same as for nonimmunocompromised persons and children. Oral Regimens (continue therapy for 60 days [IV and PO combined]): Adults: Patients should be treated with IV therapy initially. Treatment can be switched to oral therapy when clinically appropriate: Ciprofloxacin, 500 mg PO twice daily or Doxycycline, 100 mg PO twice daily. Children: Patients should be treated with IV therapy initially. Treatment can be switched to oral therapy when clinically appropriate: Ciprofloxacin, 10-15 mg/kg PO every 12 hr, not to exceed 1 g/day or Doxycycline: >8 yr and >45 kg: 100 mg PO every 12 hr >8 yr and <45 kg: 2.2 mg/kg PO every 12 hr <8 yr: 2.2 mg/kg PO every 12 hr Pregnant women: Patients should be treated with IV therapy initially. Treatment can be switched to PO when clinically appropriate. Oral therapy regimens are the same as for nonpregnant adults. Immunocompromised persons: Same as for nonimmunocompromised persons and children (Website 2).
            • Applicable: Inhalational anthrax
            • Contraindicator: If meningitis is suspected, doxycycline may be less optimal because of poor central nervous system penetration. Because of concerns of constitutive and inducible beta-lactamases in Bacillus anthracis isolates, penicillin and ampicillin should not be used alone. Consultation with an infectious disease specialist is advised. Other agents with in vitro activity include tetracycline, linezolid, macrolides, aminoglycosides, and cefazolin. B anthracis strains are naturally resistant to sulfamethoxazole, trimethoprim, cefuroxime, cefotaxime sodium, aztreonam, and ceftazidime (Website 2).

        7. Other Information:
          • Children: Inhalational anthrax is uncommon in children. For example, none of the cases in the Sverdlovsk inhalational anthrax outbreak occurred in children and reports of inhalational disease among children are rare (Website 2).
          • Recommendations for postexposure prophylaxis for prevention of inhalational anthrax following exposure to Bacillus anthracis: Adults (including immunocompromised patients): Ciprofloxacin, 500 mg PO twice daily or Doxycycline, 100 mg PO twice daily. Duration for 60 days. Pregnant women and breastfeeding mothers: Ciprofloxacin, 500 mg PO twice daily or Doxycycline, 100 mg PO twice daily [Amoxicillin, 500 mg orally three times daily, may be used if isolate involved in exposure is determined to be susceptible to penicillin]. Duration for 60 days. Children (including immunocompromised patients): Ciprofloxacin, 10-15 mg/kg PO every 12 hr, not to exceed 1 gm/day or Doxycycline: >8 yr and >45 kg: 100 mg PO every 12 hr >8 yr and <45 kg: 2.2 mg/kg PO every 12 hr <8 yr: 2.2 mg/kg PO every 12 hr for 60 days [Note: Amoxicillin, 80 mg/kg/day divided every 8 hr, not to exceed 500 mg/dose, may be used if the isolate involved in exposure is determined to be susceptible to penicillin]. Duration for 60 days (Website 2).

      3. Oropharyngeal and Gastrointestinal anthrax :
        1. Pathogenesis Mechanism: Pathogenesis of gastrointestinal anthrax is not clear, since this condition is relatively rare. After intestinal absorption, bacteria are transported to mesenteric and other regional lymph nodes where there is multiplication and dissemination, development of hemorrhagic adenitis, ascites, and bacteremia. Like cutaneous anthrax, the gastrointestinal form of the disease presents within 5 days of ingestion of contaminated meat (Website 2, Shafazand et al., 1999).


        2. Incubation Period: 1-7 days (usually 2-5 days) (Website 2)


        3. Prognosis: The case fatality rate for gastrointestinal anthrax is between 25% and 60%. The effect of early antibiotic treatment on outcome has not be studied. In the Thailand outbreak of oropharyngeal disease, the case fatality rate was 13%. In another report of 6 cases of pharyngeal anthrax, the case fatality rate was 50%. The prognosis for oropharyngeal and GI anthrax is poor, with case fatality rates 50 to 100 percent, even with aggressive therapy. Lethality approaches 100% if untreated but data is limited. Rapid, aggressive treatment may reduce mortality. If the patient survives, symptoms last about 2 wk (Website 2, Website 7).


        4. Symptom Information :
          • Nausea:
          • Headache:
            • Description: Headache (Website 2)
            • Observed: Observed in 100% of 143 patients in an outbreak in Uganda (Website 2).
          • Vomiting:
            • Description: Vomiting (may be coffee-ground or blood-tinged) (Website 7, Website 2).
            • Observed: Observed in 90% of 143 patients in an outbreak in Uganda.
          • Diarrhea:
            • Description: Watery or bloody diarrhea (Shafazand et al., 1999, Website 7).
            • Observed: Observed in 80%; bloody in only 5% of 143 patients in an outbreak in Uganda. Observed in 4% of 24 patients in an outbreak of oropharyngeal anthrax in Thailand. Diarrhea (4%) (Website 2).
          • Abdominal swelling:
            • Description: Massive abdominal swelling (ascites) may develop 2-4 days after onset (fluid may be clear or purulent). Hematogenous spread with resultant toxemia can occur (Website 7, Website 2).
          • Abdominal pain or tenderness:
          • Hematemesis, hematochezia:
          • Fever:
            • Description: Fever may be low-grade (Website 7, Website 2)
            • Observed: Observed in 70% of 143 patients in an outbreak in Uganda. Observed in 96% of 24 patients in an outbreak of oropharyngeal anthrax in Thailand (Website 2).
          • Necrotic ulcer or eschar:
            • Description: Necrotic ulcer or eschar involving the hard palate, tonsils, or posterior oropharyngeal wall and/or intestinal lesions (Website 7, Website 2).
            • Observed: Acute Phase. Observed mouth or pharyngeal ulcerative or necrotic lesions in 100% of 24 patients in an outbreak of oropharyngeal anthrax in Thailand (pseudomembranes also were noted in some patients). Observed bleeding from the mouth in 4% of 24 patients in an outbreak of oropharyngeal anthrax in Thailand (Website 7).
          • Sore throat:
            • Description: Sore throat or difficulty swallowing (dysphagia), hoarseness, sensation of a "lump in throat" (Website 7, Website 2).
            • Observed: Acute Phase. Observed sore throat, dysphagia in 63% of 24 patients in an outbreak of oropharyngeal anthrax in Thailand. Observed hoarseness in 8% of 24 patients in an outbreak of oropharyngeal anthrax in Thailand. Observed Sensation of a "lump in throat" in 8% of 24 patients in an outbreak of oropharyngeal anthrax in Thailand (Website 7, Website 2).
          • Edema of cervical tissues:
            • Description: Edema of cervical tissues (possibly resulting in upper airway obstruction) (Website 7, Website 2).
            • Observed: Acute Phase. Observed pharyngeal edema in 10% of 143 patients in an outbreak in Uganda. Observed neck swelling in 100% of 24 patients in an outbreak of oropharyngeal anthrax in Thailand. Observed respiratory distress in 25% of 24 patients in an outbreak of oropharyngeal anthrax in Thailand (Website 7, Website 2).
          • Cervical or regional lymphadenopathy:
          • Septic shock and death: