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Anthrax

From the May ACP Observer, copyright 2004 by the American College of Physicians.

Anthrax is caused by a gram-positive, spore-forming bacteria, Bacillus anthracis. Humans can become infected through skin contact, ingestion or inhalation of spores from infected animals or animal products. "Woolsorter's disease," for instance, is anthrax caused by exposure to animal hair and wool.

Depending on how they infiltrate the body, anthrax bacteria can cause cutaneous, respiratory or gastrointestinal infections. Although cutaneous infections are the most common in nature, bioterrorism-related anthrax would most likely occur as either a cutaneous infection, a more lethal respiratory infection or both. Gastrointestinal infection is very rare and has never been diagnosed in the United States.


Bacillus anthracis from an agar culture, demonstrating spores.


Clinical presentation and diagnosis

The primary lesion of cutaneous anthrax is a painless, pruritic papule that appears one to seven days after inoculation. Within one to two days, small vesicles or a larger, 1- to 2-cm vesicle forms that is filled with clear or serosanguineous fluid. As the vesicle enlarges, satellite vesicles may form. Fluid within the vesicles may contain numerous, large gram-positive bacilli. As the lesion matures, a prominent, non-pitting edema surrounds it. Eventually, the vesicle ruptures, undergoes necrosis and enlarges, forming a painless ulcer covered by the characteristic black eschar. Symptoms include low-grade fever and malaise. Regional lymphadenopathy is present early on.

Presumptive diagnosis is based upon the direct Gram-stained smear of a skin lesion (vesicular fluid or eschar) showing encapsulated, broad, gram-positive bacilli. A presumptive diagnosis can also be based on growth on sheep's blood-agar cultures consisting of nonhemoltyic colonies and large, nonmotile, nonencapsulated gram-positive, spore-forming rods. Confirmatory tests include positive cultures from blood, vesicles and tissue biopsies.

Notify your local department of health of patients with suspected anthrax before doing diagnostic tests. For detailed instructions on how to collect diagnostic materials for cutaneous anthrax, go to the diagnosis section of the American Academy of Dermatology's here. (Your health department can also give you additional instructions on testing materials.)

Differential diagnosis

Cutaneous anthrax. The necrotic ulcer of cutaneous anthrax is rarely painful, unlike that of a brown recluse spider bite. Pustules are rarely present in anthrax lesions, which can distinguish the disease from more common skin disorders, such as a staphylococcal furuncle. Lymphadenopathy is almost always present early on and helps distinguish cutaneous anthrax from conditions of lesser importance.

The list of cutaneous anthrax mimics is long and includes conditions not always familiar to internal medicine physicians. For a description of cutaneous anthrax and its mimics, and to view clinical images, go to the ACP Bioterrorism Resource Center here.

Inhalation anthrax. Inhalation anthrax is more difficult to diagnose because patients initially present with nonspecific symptoms such as a low-grade fever, nonproductive cough, malaise, fatigue, headache and chest discomfort. Patients may improve after a few days but then rapidly deteriorate, developing a high fever accompanied by abrupt onset of respiratory failure, hemodynamic collapse, delirium and shock that is often fatal. In 1979 in Sverdlovsk (now Yekaterinburg), Russia—where aerosolized anthrax was accidentally released from a Soviet military compound—50% of those infected developed hemorrhagic meningitis.

Chest X-rays of patients with inhalation anthrax usually reveal mediastinal widening or pleural effusion. Any patient with suspicious chest radiograph findings should have a follow-up CT scan of the chest, which may show hyperattenuation of mediastinal or hilar lymphadenopathy, or mediastinal hemorrhage.


Chest X-ray showing widened mediastinum due to inhalation anthrax.


Prominent influenza-like symptoms of recent origin in a patient with a widened mediastinum suggest anthrax, particularly if there is more than one case. (Tuleremia may produce a similar clinical picture.) Radiographic findings of air space disease, pleural effusions and a widened mediastinum are common with inhalation anthrax, but they do not occur in uncomplicated influenza.

Anthrax lacks the nasal congestion, pharyngitis and rhinorrhea that typically accompany a cold or the flu. Anthrax is also not spread by person-to-person contact. If a patient's family members and co-workers have recently recovered from a respiratory tract infection, the patient most likely does not have anthrax, but a more common respiratory infection.

Rapid tests for influenza and respiratory syncytial virus, if positive, can also rule out the possibility of inhalation anthrax. However, the sensitivities of many of these tests are relatively low, and they do not test for other infections that cause flu-like symptoms. Consequently, a negative test does not indicate that inhalation anthrax is more likely.

After symptom onset, a presumptive diagnosis can be based upon direct Gram-stained smears of sputum, blood and cerebrospinal fluid, as well as on initial growth of a compatible organism on appropriate cultures. In some anthrax cases, Gram-positive bacilli were visible in a peripheral blood smear during the bactermic phase of the illness. Diagnosis may be confirmed by blood or sputum cultures, which are frequently positive in less than 12 hours if antibiotics have not been administered prior to their collection.

All specimens for B. anthracis culture should be collected before initiating antimicrobial therapy, but specimen collection should not unduly delay treatment. Immediately report any patients suspected of having anthrax or of being exposed to the microbe to local or state public health departments, and coordinate all aspects of collecting, packaging and transporting specimens with public health officials and laboratories.

Treatment

Because survival is related to the time from symptom onset to antibiotic administration, empiric therapy should be started as soon as an anthrax diagnosis is suspected and specimens have been collected. Historically, the case fatality rate has been 80% to 100%—although the rate was 45% during the 2001 attacks, presumably because of rapid diagnosis and treatment.

Naturally occurring anthrax strains are susceptible to many antibiotics, including penicillins, tetracyclines and fluoroquinolones. In patients with significant symptoms, ciprofloxacin or doxycycline should be combined with clindamycin, which is a potent inhibitor of toxin production. Other antibiotics may be added to cover central nervous system infections.

All strains are resistant to cephalosporins, and some strains produce an inducible penicillinase. Consequently, do not use extended-spectrum cephalosporins or trimethoprim/sulfamethoxazole. Because bioweapons may be genetically altered and have unusual drug susceptibilities, specific antibiotic therapy should be based on antibiotic susceptibility testing when available.

For more detailed anthrax treatment information see the anthrax treatment protocols.

Prevention

Pre-exposure vaccination against anthrax is not recommended for the general public. The CDC recommends that groups at risk for repeated exposures to B. anthracis spores be given priority for pre-exposure vaccination. Groups at risk for repeated exposure include the following:

  • laboratory personnel handling environmental specimens (especially powders) and performing confirmatory testing for B. anthracis in the U.S. Laboratory Response Network for Bioterrorism level B (or above) laboratories;
  • workers who will be making repeated entries into areas known to be contaminated with B. anthracis spores after a terrorist attack;
  • workers in other settings where repeated exposure to aerosolized B. anthracis spores might occur; and
  • military personnel likely to encounter anthrax.

Post-exposure containment

The incubation period for anthrax varies according to the exposure route and dose. For cutaneous anthrax, the incubation period is usually two to three days (range one to seven). For intestinal anthrax, it is one to seven days.

The incubation period following inhalation of anthrax spores is typically six days, but it may vary according to the level of exposure. In animal studies and during the human outbreak in Sverdlovsk, the incubation period was as long as 100 days.

Physicians should maintain universal precautions when evaluating patients with suspected cutaneous anthrax. Direct exposure to vesicle secretions of cutaneous anthrax lesions may result in secondary cutaneous infections.


A patient with a cutaneous anthrax lesion, showing the characteristic black eschar.


With suspected inhalation anthrax, however, a mask is not required. Inhalation anthrax is acquired through contact with anthrax spores and not viable bacteria. Because direct person-to-person spread of inhalational anthrax has not been reported, there is no need to immunize or treat contacts of patients with anthrax.

For persons known to be exposed to anthrax, however, try to prevent infection with early antibiotic treatment. Treatment delays reduce patients' chances for survival.

The following overview of prophylactic treatment strategies has been adapted from the Center for Civilian Biodefense Studies, Johns Hopkins University Schools of Medicine.

It should be noted that since the release of these recommendations, the CDC has reported that, to date, all anthrax isolates from bioterrorism-related incidents have been susceptible to ciprofloxacin, doxycycline and other agents. However, the use of doxycycline may be preferable to prevent development of ciprofloxacin resistance in more common bacteria. When no information is available about the antimicrobial susceptibility of the implicated strain of anthrax, initial therapy with ciprofloxacin or doxycycline is recommended for adults and children.

The use of tetracyclines and fluoroquinolones in children has adverse effects. The risk for these adverse effects must be weighed carefully against the risk of developing life-threatening disease. As soon as the susceptibility of the organism has been confirmed, prophylactic therapy for children should be changed to amoxicillin.

Adults and immunocompromised hosts

  • Ciprofloxacin 500 mg po BID for 60 days
  • Doxycycline 100 mg po BID OR amoxicillin 500 mg po TID, either antibiotic for 60 days

Pregnant women

  • Ciprofloxacin 500 mg po BID
  • Amoxicillin 500 mg po TID for 60 days

Children

  • Ciprofloxacin 15 mg/kg po q 12 hrs but not to exceed 500 mg/dose for 60 days
  • If greater than or equal to 20 kg, amoxicillin 500 mg po TID for 60 days; if < 20 kg, amoxicillin 80 mg/kg po TID for 60 days

Patients should be followed closely after completing a post-exposure antibiotic prophylaxis course because there is little experience with this treatment regimen. However, no cases of anthrax surfaced among those recommended to take antimicrobial prophylaxis after the 2001 terrorist attacks.

A six-dose anthrax vaccine can prevent infection, while animal studies suggest that a three-dose vaccine regimen combined with antibiotic administration for 30 days is also effective for post-exposure prophylaxis. Because of the potential preventive benefit of combining antibiotics with the anthrax vaccine, the CDC—under an FDA investigational new drug application—will make anthrax vaccine available in a three-dose regimen (0, 2, 4 weeks) in combination with antimicrobial prophylaxis for unvaccinated persons at risk for inhalation anthrax. However, anthrax vaccine is not licensed for post-exposure use to prevent anthrax.

Use of anthrax vaccine for post-exposure prophylaxis could have additional benefits, including reducing the need for long-term antimicrobial therapy with its associated problems of noncompliance and possible adverse events. After the 2001 anthrax attacks, approximately 10,000 persons were recommended to receive a 60-day regimen of antimicrobial prophylaxis for suspected or confirmed exposure. However, as few as 42% adhered to the prescribed regimen.

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Cutaneous anthrax treatment protocol

Adults, pregnant women and immunocompromised hosts

  • Ciprofloxacin 500 mg po BID OR doxycycline 100 mg po BID for 60 days
  • Cutaneous anthrax with signs of systemic involvement, extensive edema or lesion on the head or neck requires IV therapy, and a multi-drug approach is recommended.
  • While ciprofloxacin and doxycycline are first line agents, amoxicillin 500 mg po TID may be substituted for adults who cannot take these drugs.
  • While tetracyclines are not recommended during pregnancy, their use may be indicated for life-threatening infections.

Children

  • Ciprofloxacin 15 mg/kg po q 12 hrs (maximum of 500 mg/dose) OR doxycycline if > 45 kg, 100 mg po BID; if less than or equal to 45 kg, 2.2 mg/kg po BID for 60 days
  • Cutaneous anthrax with signs of systemic involvement, extensive edema or lesion on the head or neck requires IV therapy, and a multi-drug approach is recommended.
  • For children, amoxicillin may be an option for completion of therapy after clinical improvement; weight less than or equal to 20 kg, 500 mg po TID; weight < 20 kg, 80 mg/kg po TID to complete 60 days of therapy.
  • The American Academy of Pediatrics recommends treating young children with tetracyclines for serious infections.

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Treatment protocols for inhalational, gastrointestinal and oropharyngeal anthrax

Adults, pregnant women and immunocompromised hosts

  • Ciprofloxacin 400 mg q 12 hrs IV OR doxycycline 100 mg q 12 hrs IV
  • If meningitis is suspected, doxycycline may be less optimal due to poor CNS penetration.

And

  • One or two additional antibiotics: rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin and clarithromycin. Penicillin or ampicillin should not be used alone.
  • If intravenous ciprofloxacin is not available, and there is no vomiting or ileus, the postexposure use of the prophylaxis oral therapy program described above may be the only reasonable alternative to intravenous ciprofloxacin.
  • While tetracyclines are not recommended during pregnancy, their use may be indicated for life-threatening infections.
  • Switch to oral antibiotics when clinically appropriate: Ciprofloxacin 500 mg po BID OR doxycycline 100 mg po BID for 60 days (IV and po combined)
  • Steroids may be considered as an adjunct for patients with severe edema and for meningitis.

Children

  • Ciprofloxacin 10 mg/kg q 12 hrs IV (maximum 400 mg/dose) OR doxycycline if > 45 kg, 100 mg q 12 hrs IV; if < 45 kg, 2.2 mg/kg q 12 hrs IV
  • If meningitis is suspected, doxycycline may be less optimal due to poor CNS penetration.

And

  • One or two additional antibiotics: rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin andclarithromycin. Penicillin or ampicillin should not be used alone.
  • If intravenous ciprofloxacin is not available, and there is no vomiting or ileus, the postexposure prophylaxis oral therapy program described above may be the only reasonable alternative
  • Switch to oral antibiotics when clinically appropriate: Ciprofloxacin 15 mg/kg po q 12 hrs (not to exceed 500 mg/dose) OR doxycycline if > 45 kg, 100 mg po BID; if less than or equal to 45 kg, 2.2 mg/kg po BID for 60 days (IV and po combined)
  • Steroids may be considered as an adjunct for patients with severe edema and for meningitis.
  • The American Academy of Pediatrics recommends treating young children with tetracyclines for serious infections.

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