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

Akbayram S, Dogan M, Akgün C, et al. Clinical findings in children with cutaneous anthrax in eastern Turkey. Pediatr Dermatol. 2010 Nov-Dec. 27(6):600-6. [QxMD MEDLINE Link].
Inglesby TV, O'Toole T, Henderson DA, et al. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA. 2002 May 1. 287(17):2236-52. [QxMD MEDLINE Link].
John TJ, Dandona L, Sharma VP, Kakkar M. Continuing challenge of infectious diseases in India. Lancet. 2011 Jan 15. 377(9761):252-69. [QxMD MEDLINE Link].
Doganay M, Metan G, Alp E. A review of cutaneous anthrax and its outcome. J Infect Public Health. 2010. 3 (3):98-105. [QxMD MEDLINE Link].
Beatty ME, Ashford DA, Griffin PM, Tauxe RV, Sobel J. Gastrointestinal anthrax: review of the literature. Arch Intern Med. 2003 Nov 10. 163 (20):2527-31. [QxMD MEDLINE Link].
Knox D, Murray G, Millar M, et al. Subcutaneous anthrax in three intravenous drug users: a new clinical diagnosis. J Bone Joint Surg Br. 2011 Mar. 93(3):414-7. [QxMD MEDLINE Link].
Hupert N, Person M, Hanfling D, Traxler RM, Bower WA, Hendricks K. Development and Performance of a Checklist for Initial Triage After an Anthrax Mass Exposure Event. Ann Intern Med. 2019 Apr 16. 170 (8):521-530. [QxMD MEDLINE Link].
US Food and Drug Administration (FDA). FDA approves raxibacumab to treat inhalational anthrax. December 14, 2012 (press announcement). Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm332341.htm.
Migone TS, Subramanian GM, Zhong J, Healey LM, Corey A, Devalaraja M, et al. Raxibacumab for the treatment of inhalational anthrax. N Engl J Med. 2009 Jul 9. 361(2):135-44. [QxMD MEDLINE Link]. [Full Text].
Anthim (obiltoxaximab) [package insert]. Pine Brook, NJ: Elusys Therapeutics, Inc. March 2016. Available at [Full Text].
Anthrasil (anthrax immune globulin intravenous [human]) [package insert]. Winnipeg, MB; Canada: Cangene Corp (Emergent BioSolutions). March 24, 2015. Available at [Full Text].
BioThrax (anthrax vaccine adsorbed) [package insert]. Lansing, MI: Emergent BioSolutions. November, 2015. Available at [Full Text].
[Guideline] Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ, Gorbach SL, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of america. Clin Infect Dis. 2014 Jul 15. 59(2):e10-52. [QxMD MEDLINE Link].
Barclay L. Anthrax Guidelines Address Nonpregnant, Pregnant Adults. Available at http://www.medscape.com/viewarticle/819274. Accessed: January 19, 2014.
[Guideline] Hendricks KA, Wright ME, Shadomy SV, et al. Centers for Disease Control and Prevention expert panel meetings on prevention and treatment of anthrax in adults. Emerg Infect Dis 2014. Available at https://read.qxmd.com/doi/10.3201/eid2002.130687.
Raxibacumab [package insert]. Research Triangle Park, NC: GlaxoSmithKline. December, 2012. Available at [Full Text].
Food and Drug Administration. 17.5 FDA-Approved Medication Guide. Levaquin (levofloxacin). [Full Text].

Media Gallery

Polychrome methylene blue stain of Bacillus anthracis. Image courtesy of Anthrax Vaccine Immunization Program Agency, Office of the Army Surgeon General, United States.
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.
Cutaneous anthrax. Image courtesy of Anthrax Vaccine Immunization Program Agency, Office of the Army Surgeon General, United States.
Skin lesion of anthrax on face. Image courtesy of the Public Health Image Library, US Centers for Disease Control and Prevention, Atlanta, Georgia.
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.
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 submucosal thrombosis and edema. Image courtesy of Marshall Fox, MD, Public Health Image Library, US Centers for Disease Control and Prevention, Atlanta, Georgia.
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.
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.
Hemorrhagic meningitis resulting from inhalation anthrax. Image courtesy of the Public Health Image Library, US Centers for Disease Control and Prevention, Atlanta, Georgia.
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.
Microscopic picture of anthrax showing gram-positive rods. Image courtesy of Ramon E. Moncada, MD.
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 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 cutaneous anthrax lesions. The early ulcer has a moist base. Courtesy of American Academy of Dermatology.
Note the central ulcer and eschar. Courtesy of American Academy of Dermatology.
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 Academy of Dermatology. Courtesy of Gorgas Course in Clinical Tropical Medicine.
Anthrax with facial edema. Courtesy of American Academy of Dermatology.

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Table 1. Microbiological Differences Between B anthracis and Non– B anthracis Bacilli

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.

Table 2. Toxins and Protein Toxins of Bacillus anthracis

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

Table 3. CDC Expert Panel Recommendations for Treatment of Cutaneous Anthrax

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

Table 4. CDC Expert Panel Recommendations for Treatment of Systemic Anthrax Without Meningitis ^[15]

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)

Table 5. CDC Expert Panel Recommendations for Treatment of Anthrax Meningitis ^[15]

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)

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Author

David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS Associate Professor of Medicine and Pediatrics, Adult and Pediatric Infectious Diseases, Rutgers New Jersey Medical School

David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS is a member of the following medical societies: American Academy of HIV Medicine, American Academy of Pediatrics, American College of Physicians, American Medical Association, HIV Medicine Association, Infectious Diseases Society of America, Medical Society of New Jersey, Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Coauthor(s)

Justin R Hofmann, MD Resident Physician, Departments of Internal Medicine and Pediatrics, Rutgers New Jersey Medical School

Justin R Hofmann, MD is a member of the following medical societies: American Medical Association, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, Association of Professors of Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

Burke A Cunha, MD Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Acknowledgements

Hilarie Cranmer, MD, MPH, FACEP Director, Global Women's Health Fellowship, Associate Director, Harvard International Emergency Medicine Fellowship, Department of Emergency Medicine, Brigham and Women's Hospital; Director, Humanitarian Studies Program, Harvard Humanitarian Initiative; Assistant Professor, Harvard University School of Medicine

Hilarie Cranmer, MD, MPH, FACEP is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, Massachusetts Medical Society, Physicians for Human Rights, and Society for Academic Emergency Medicine