ANTHRAX

ANTHRAX

Current diagnosis

Cutaneous Anthrax

• Incubation period of 1 to 7 days from exposure to cattle

•   Painless or pruritic lesion progresses to ulcer and eschar

•   Significant swelling

•   Gram stain and culture of lesion

Gastrointestinal

• Incubation period of 1 to 6 days after consumption of raw or undercooked meat

•   Nonspecific symptoms followed by abdominal pain, ascites

•   Diarrhea uncommon

•   Obtain blood culture and ascitic fluid for culture and Gram stain

Inhalational

•   Incubation period of 1 to 7 days (up to 43 days)

•   Biphasic: fever, malaise, myalgia followed by dyspnea

• Widened mediastinum seen on chest x-ray and computed tomography (CT) of chest

•   Blood cultures turn positive in most

Injection

•   Injection drug use

•   Significant swelling seen; eschar rare

Current therapy

Systemic Anthrax With Possible/Confirmed  Meningitis

• Ciprofloxacin (Cipro) 400 mg IV every 8 hours or levofloxacin (Levaquin) 750 mg IV every 24 hours or moxifloxacin (Avelox)1 400 mg IV every 24 hours

plus

• Meropenem (Merrem)1 2 g IV every 8 hours or imipenem/cilastatin (Primaxin)1 1 g IV every 6 hours or doripenem (Doribax)1 500 mg IV every 8 hours

• If penicillin-susceptible strains, then penicillin G 4 million units IV every 4 hours or ampicillin1 3 g IV every 6 hours could be an alternative to carbapenems

plus

• Linezolid (Zyvox)1 600 mg IV every 12 hours or clindamycin (Cleocin) 900 mg IV every 8 hours or rifampin (Rifadin) 600 mg IV every 12 hours or chloramphenicol 1 g every 6 to 8 hours

Systemic Anthrax When Meningitis Has Been  Excluded

• Ciprofloxacin 400 mg IV every 8 hours or levofloxacin 750 mg IV every 24 hours or moxifloxacin1 400 mg IV every 24 hours

or

• Meropenem1 2 g IV every 8 hours or imipenem/cilastatin1 1 g IV every 6 hours or doripenem1 500 mg IV every 8 hours

or

• Vancomycin (Vancocin)1 60 mg/kg/day IV divided every 8 hours (goal trough 15–20 µg/mL)

or

• If penicillin-susceptible strains, then penicillin G 4 million units IV every 4 hours or ampicillin1 3 g IV every 6 hours

plus

• Clindamycin1 900 mg IV every 8 hours or linezolid1 600 mg IV every 12 hours

or

• Doxycycline 200 mg IV × 1, then 100 mg IV every 12 hours, or rifampin1 600 mg IV every 12 hours

Oral Treatment for Cutaneous Anthrax Without Systemic Involvement

• One of the agents below for 7 to 10 days in naturally-acquired cases and for 60 days in bioterrorism-associated cases

•   Ciprofloxacin 500 mg PO every 12 hours

•   Doxycycline 100 mg PO every 12 hours

•   Levofloxacin 750 mg PO daily

•   Moxifloxacin1 400 mg PO daily

•   Clindamycin1 600 mg PO every 8 hours

•   If penicillin-susceptible strain

•   Amoxicillin1 1 g PO every 8 hours

•   Penicillin VK 500 mg PO every 6 hours

1 Not FDA approved for this  indication.

Anthrax has been described for centuries and the name is derived from Greek for “burnt coal” owing to eschar formation from cutaneous anthrax. Anthrax is rarely seen in developed countries, including the United States, but it is important to be aware of this condition because of its potential as a bioterrorism agent. When anthrax is suspected, the clinician needs to contact the local or state health department immediately. Anthrax has historical significance because it was the agent utilized in Koch’s postulate during the 19th century when Koch proved that Bacillus anthracis is responsible for anthrax in cattle.

Background

B. anthracis is the bacterium responsible for anthrax. It forms spores which can survive in soil for years. It is hyperendemic in the Middle East and in sub-Saharan Africa. Systemic anthrax is primarily a disease of grazing animals. In naturally-acquired anthrax, humans are accidentally infected from exposure to the animal or its products.

Epidemiology

Since the mid-20th century, there has been a precipitous decline in anthrax owing to animal and human vaccines, improvement in factory hygiene, sterilization procedures for imported animal products, and increased use of alternatives to animal hides or hair. Cutaneous anthrax comprises over 95% of naturally-acquired human anthrax and there are an estimated 2000 cases annually. Between 1900 and 2001 there were 18 cases of inhalational anthrax in the United States, of which 16 were fatal. Over the last decade, there have been several cases of inhalational and cutaneous anthrax related to African drum makers. In late 2001, there were 22 cases of anthrax in the United States from spores delivered in the mail, of which five were fatal. In 1979, accidental release of dried anthrax spores from a biologic weapons facility in Sverdlovsk in the former Soviet Union resulted in 68 deaths from inhalation anthrax.

Pathophysiology

B. anthracis is a gram positive, encapsulated, spore forming, nonhemolytic, nonmotile rod shaped bacterium. Infection with anthrax requires three components: the edema factor, the lethal factor, and protective antigen. The edema factor combines with protective antigen and becomes edema toxin, which causes edema and impairment of the immune system. The lethal factor combines with protective antigen and becomes lethal toxin, which causes lysis of macrophages. For cutaneous anthrax, these exotoxins result in extensive edema and tissue necrosis locally. In inhalation anthrax, spores that reach the alveoli or alveolar ducts are phagocytized by the alveolar macrophage and transported to the mediastinal lymph nodes where they replicate and cause hemorrhagic mediastinitis. With gastrointestinal tract infection, B. anthracis is transported from the gastrointestinal tract to mesenteric lymph nodes where they multiply and cause mesenteric lymphadenitis, ascites, and sepsis.

Clinical Manifestations

There are four distinct clinical presentations: cutaneous, inhalation, gastrointestinal tract, and injection anthrax, depending on the site of entry. Meningitis is a devastating complication which could occur with any of the four infections.

Cutaneous Anthrax

Cutaneous anthrax is the most common form and seen in developing countries as a result of contact with infected animals or animal products such as wool, hair, or hides. Spores invade through either skin abrasions or hair follicles. Subsequently, they germinate and multiply. The incubation period is commonly 5 to 7 days with range of 1 to 19 days. The lesions appear in exposed areas such as head, neck, forearms, and hands and begin as a small, painless papule. They are pruritic at times and form blisters. Subsequently, they evolve into painless necrotic ulcers with a black, depressed eschar with extensive edema and lymphadenopathy.

Inhalation Anthrax

Inhalation anthrax occurs when spores are aerosolized while working with contaminated animal products or when they are released intentionally in bioterrorism. The incubation period is 1 to 7 days, but could be as long as 43 days. The course of disease is usually biphasic. Initially, nonspecific symptoms such as fever, malaise, and myalgia are present, resembling influenza. These symptoms last for several days before the bacteremic phase starts. The manifestations include rapidly, fulminant progressive respiratory symptoms such as severe dyspnea, as well as hypoxemia and shock. Once in this phase, the patient dies within a few days despite support in the intensive care unit. Therefore, it is important to suspect anthrax in the prodromal phase which is difficult owing to its rarity and lack of specific symptoms. Widening of the mediastinum on a chest x-ray may be helpful in establishing the diagnosis. This finding was seen in 7 out of 10 cases of inhalation anthrax from 2001. Hilar abnormalities, pulmonary infiltrates, or consolidation and pleural effusion may be seen.

Gastrointestinal Tract Anthrax

Gastrointestinal tract anthrax occurs after ingestion of raw or undercooked meat from an animal infected with anthrax.

Gastrointestinal infection is relatively common and has been reported from mouth to ascending colon. The incubation period is 1 to 6 days. Initially, nonspecific symptoms such as asthenia, headache, low grade fever, facial flushing and conjunctival injection occur. They are followed by abdominal pain, abdominal distention from ascites, nausea, and vomiting. Diarrhea occurs less frequently. As the disease progresses, abdominal pain becomes severe and findings of hypotension and intravascular depletion are seen. When the infection occurs in the oropharynx, necrotic ulcers with pseudomembranes cause pain and edema.

Injection Anthrax

An outbreak of injection anthrax was described in 2009. It was reported in Scotland among injection heroin users. Among the 47 confirmed cases, typical eschar formation seen in cutaneous anthrax was not seen in all but one case. Prominent edema was seen in most patients and some developed compartment syndrome.

Meningitis

Meningitis is a complication seen with all forms of anthrax. About half of patients with inhalation anthrax develop hemorrhagic meningitis.

Symptoms such as altered mental status, seizures, cranial nerve palsies, and myoclonus may be seen. When anthrax is suspected, lumbar puncture should be done on presentation unless there are contraindications.

Diagnosis

When diagnosis of anthrax is suspected, the provider must notify the local department of health and the clinical microbiology laboratory.

There has been reported transmission of anthrax to laboratory personnel handling B. anthracis and specimen handling in biosafety level 3 facilities is recommended. As the genus Bacillus is part of the normal skin flora, it is crucial for the microbiology laboratory to distinguish B. anthracis from other non-anthracis species of Bacillus. Conventional culture and staining are used for distinction. B. anthracis is nonmotile and nonhemolytic and those characteristics are used to distinguish it from non-anthracis species of Bacillus. Most microbiology laboratories have the ability to make a presumptive identification of an organism, and the identification is confirmed by a reference laboratory.

Specimen Collection

When collecting clinical specimens for suspected anthrax, proper personal protective equipment such as disposable gloves, disposable aprons, and boots, should be used. When there is any potential of aerosolization of spores, then face shields and respirators are recommended. Hand washing with soap and water will reduce the endospore contamination of the skin but alcohol handrubs are not effective against these endospores. For cutaneous anthrax, the edge of the eschar should be lifted and two specimens of vesicular fluid should be collected by rotating a swab. One swab will be used for culture and Gram stain while the other would be used for polymerase chain reaction (PCR). Punch biopsy of the cutaneous lesion is an alternative. When inhalational anthrax is suspected, blood cultures must be obtained prior to use of antibiotics. If pleural fluid is present, then thoracentesis should be performed for Gram stain, culture and PCR. For alimentary tract anthrax, blood cultures must be obtained. If there are oral lesions, then specimens could be collected with swabs similar to a cutaneous lesion. If ascites is present, then paracentesis should be performed for Gram stain, culture and PCR. For meningitis, cerebrospinal fluid (CSF) should be collected for culture, Gram stain and PCR.

There are unique findings observed in routine laboratories with systemic anthrax. Marked hemoconcentration may be seen in the complete blood count and the initial white blood cell count is frequently within normal limits. In chemistry, decreased sodium, increased blood urea nitrogen, mild transaminitis and hypoalbuminemia are seen. Inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein are elevated in most cases except in cases of injection anthrax, when C-reactive protein is low.

Treatment

Supportive Care

Hospitalization is required for all patients with systemic infections. Only uncomplicated cutaneous anthrax could be treated on an outpatient basis. Close monitoring is warranted because the patient status may deteriorate rapidly. Hemodynamic support should be given, including fluids, vasopressors, blood products, and invasive hemodynamic monitoring. Mechanical ventilation may be needed because of respiratory distress, airway protection for altered mental status, or for airway edema. Adjunctive corticosteroids may be indicated in four situations: patients with history of endocrine or corticosteroid therapy; edema of head or neck; anthrax meningitis; or vasopressor-resistant shock. Pleural fluid and ascites should be drained aggressively. Surgery is indicated in certain situations.

Surgery for cutaneous anthrax has led to dissemination and poor outcome. Therefore, in cutaneous anthrax, indication for surgery is limited to tracheotomy for airway obstruction and surgery for compartment syndrome. In gastrointestinal anthrax, surgery might be considered for complications such as bowel ischemia or infarct and perforation. In injection anthrax, removal of necrotic nidus would help reduce the toxin and spore reservoir.

Antimicrobial Treatment for Systemic Disease with Possible Meningitis

At least three intravenous antibiotics with good penetration to the central nervous system are recommended. At least one drug should have bactericidal activity and at least one drug should inhibit protein synthesis. These should be continued for at least 2 weeks or until clinically stable, whichever is longer. The fluoroquinolone class is bactericidal, has good penetration to the central nervous system, and has no reported resistance by B. anthracis. Intravenous ciprofloxacin (Cipro) is the primary bactericidal component in the treatment of systemic disease. Levofloxacin (Levaquin) and moxifloxacin (Avelox)1 are considered to be alternatives. The carbapenem class has good central nervous system penetration and meropenem (Merrem)1 is the preferred second antibiotic in treatment of systemic disease with possible meningitis. Imipenem/cilastatin (Primaxin)1 and doripenem (Doribax)1  are considered alternatives. Penicillin G or ampicillin1 could be used in place of carbapenems when the isolate is known to have a minimum inhibitory concentration (MIC) of less than 1.125 µg/mL. As for protein synthesis inhibitor, linezolid (Zyvox)1 is preferred because it provides good central nervous system penetration. If there is contraindication to linezolid use such as drug– drug interaction or myelosuppression, then clindamycin (Cleocin)1 is the alternative. When both linezolid and clindamycin cannot be used, rifampin (Rifadin)1 could be used for synergistic effect in combination with the bactericidal drugs. Chloramphenicol is another antibiotic which is a protein synthesis inhibitor. It could be used if linezolid, clindamycin, and rifampin are unavailable. Doxycycline (Vibramycin) is an inhibitor of protein synthesis but does not adequately penetrate the central nervous system. Therefore, doxycycline should not be used when meningitis is not ruled out. If the patient had been exposed to aerosolized spores, then the patient should be transitioned to oral antibiotics after completion of initial intravenous combination therapy to prevent relapse from

Antimicrobial Treatment for Systemic Disease when Meningitis is Ruled Out

At least two antimicrobial agents are recommended for systemic anthrax without meningitis. At least one should be bactericidal and at least one should be a protein synthesis inhibitor. This combination should be administered intravenously for at least 2 weeks or until clinically stable, whichever is longer. For penicillin-susceptible strains, penicillin G is considered equivalent to ciprofloxacin. Vancomycin (Vancocin)1  is an acceptable alternative bactericidal agent.

Clindamycin1 and linezolid1 are equivalent first choices for protein synthesis inhibitors. Doxycycline is an alternative agent. If the patient had been exposed to aerosolized spores, then the patient should be transitioned to oral antibiotics after completion of initial intravenous combination therapy to prevent relapse from spores.

Treatment for Cutaneous Anthrax without Systemic Involvement

A single oral antibiotic is adequate to treat cutaneous anthrax without systemic involvement. Fluoroquinolones and doxycycline are considered first-line agents. Clindamycin1 is a second line agent when first-line agents are unavailable or contraindicated. Penicillin or amoxicillin1 may be used if the isolate is found to be sensitive in vitro. It is important to give an adequate dose because resistance may develop when underdosed.

Antitoxins

There are two antitoxins in the Centers for Disease Control and Prevention (CDC) Strategic National stockpile: raxibacumab and anthrax immune globulin intravenous (AIGIV). These agents are not readily available to the public. They inhibit binding of protective antigen to the anthrax toxin receptor and translocation of lethal factor and edema factor into cells. There are human and animal data from the pre-antibiotic era which suggest that there is lower mortality in those who received the antitoxin in cutaneous anthrax compared with those who did not. Whether this agent should be given for systemic anthrax is controversial owing to lack of data. Because the mortality rate with systemic anthrax is high while the complication of antitoxin treatment is low, the potential benefit from antitoxins outweighs the potential risk from the antitoxins in systemic anthrax. This agent should be given in addition to appropriate antibiotics when systemic anthrax is suspected.

Pregnancy

Overall management is similar to the nonpregnant patient. In pregnancy, ciprofloxacin is preferred over doxycycline for both treatment and prevention. Newer fluoroquinolones such as levofloxacin and moxifloxacin1 are not preferred because embryo toxicity has been observed in animal studies. This was not seen with ciprofloxacin. Transplacental transmission of anthrax is known to occur. Ciprofloxacin, levofloxacin, meropenem,1 ampicillin,1 penicillin, clindamycin,1  and rifampin1  are known to have adequate concentration in the placenta and at least one agent should be used with treatment.

Prognosis

Uncomplicated cutaneous anthrax has a mortality rate of less than 2% with treatment. Injection anthrax has a mortality rate of 28% and gastrointestinal anthrax has a mortality rate of 40%. Inhalational anthrax has mortality of 45% despite antibiotics and modern intensive care. Meningitis from anthrax is almost always fatal.

Prevention

Postexposure prophylaxis should be started as soon as possible after exposure. Sixty days of antibiotics for immediate protection and a three-dose series of Anthrax Vaccine Adsorbed (AVA, BioThrax) for long-term protection are recommended by the United States Advisory Committee on Immunization Practices. Ciprofloxacin and doxycycline are recommended as first-line antibiotic therapy for postexposure prophylaxis and are FDA-approved for this indication. Alternative agents include levofloxacin, moxifloxacin, amoxicillin, or penicillin VK (if sensitive); and clindamycin. AVA should be administered at diagnosis and at 2 and 4 weeks. AVA is not FDA-approved for postexposure prophylaxis.

References

1.     Anthrax. Available at http://www.cdc.gov/anthrax/ [accessed 31.01.15].

2.    Hendricks K.A., Wright M.E., Shadomy S.V., et al. Centers for disease control and prevention expert panel meetings on prevention and treatment of anthrax in adults. Emerg Infect Dis. 2014;20:doi:10.3201/eid2002.130687.

3.     Knox D., Murray G., Millar M., et al. Subcutaneous anthrax in three intravenous drug users. J Bone Joint Surg. 2011;93:414– 417.

4.    Logan N.A., Hoffmaster A.R., Shadomy S.V., Stauffer K.E. In: Versalovic J., ed. Manual of clinical microbiology. 10th ed. Washington DC: ASM Press; 2011:381–402.

5.     Meaney-Delman D., Zotti M.E., Creanga A.A., et al. Special considerations for prophylaxis for and treatment of anthrax in pregnant and postpartum women. Emerg Infect Dis. 2014;20:doi:10.3201/eid2002.130611.

6.      Ruoff K.L., Clarridge J., Bernard K. In: Garcia L.S., ed. Clinical microbiology procedures handbook. ed 3rd Washington DC: ASM Press; 2010 3.18.1.

7.    Singh K. Laboratory-acquired infections. Clin Infect Dis. 2009;49:142–147.

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