The term anthrax is derived from the Greek word anthrakis meaning coal, because of the classic black eschar lesions caused by the cutaneous form of anthrax.23 Anthrax was first described in the early biblical era of Moses and the fifth Egyptian plague in Exodus 9, and in the last three decades, numerous human cases have been reported. Poor veterinary vaccination programs in Zimbabwe lead to 6,500 human anthrax cases and 200 deaths in 1979 and 1980. An accidental exposure at a research center in what is now Ekateringburg, Russia, caused the death of 66 adults in 1979. In the fall of 2001, several envelopes containing anthrax were discovered in the United States, which led to 22 confirmed and suspected cases and five deaths.24,25
B. anthracis is a gram-positive, spore-forming rod found endemically in the soil of many regions worldwide. Domesticated and wild herbivores (e.g., sheep, camels, elephants, horses, cattle, goats) commonly acquire anthrax; humans usually become infected through contact with infected animal tissue or, more recently, exposure as a result of an intentional release. One characteristic that separates anthrax from most other agents in category A is its ability to produce spores under adverse conditions. Endospores produced by the bacterium are resistant to most forms of sanitization and are thus capable of persisting for several years in contaminated environments; waiting for entry into the blood or tissue of an animal where they then germinate and cause disease.
Three clinical manifestations of anthrax exist: cutaneous (the most common, but least severe), inhalational (main bioterrorism concern), and gastrointestinal (very rare). Rare, but life-threatening neurologic complications, such as cerebral edema and hemorrhagic meningitis, are possible sequelae of all primary forms of anthrax infections.26 Anthrax spores deposited into pulmonary alveoli may not germinate until taken up by alveoli macrophages and transported to regional lymph nodes, potentially taking weeks or months, which necessitates extended durations of antibiotic coverage. Replicating bacteria, once in a host, achieve their virulence via production of two main toxins, named lethal toxin and edema toxin. Edema toxin, as its name implies, causes extensive systemic edema as the result of disruptions of electrolyte and water transport across cellular membranes, whereas lethal toxin is thought to be responsible for the tissue damage, shock, and high probability of death associated with infection.26 Although anthrax is extremely virulent and pathogenic, there is no documented human-to-human transmission.
Naturally occurring anthrax is nearly always attributable to cutaneous infection. Bacterium (acquired via handling of contaminated animal products) enters the body via abrasions on the skin and causes localized edema progressing to a small, pruritic papule 1 to 12 days after infection. Within 1 to 2 days, the papule enlarges to a round ulcer and then the characteristic painless, black eschar follows. One to 2 weeks after infection the eschar dries and sloughs away (Fig. 15–1). Subsequent lesions near the initial papule may occur. Once anthrax is suspected, a Gram stain of the vesicular fluid should yield gram-positive bacteria and, ideally, the stain is confirmed with culture.18 Mortality rates from the cutaneous form are relatively low at approximately 5% to 20% in untreated cases and <1% in antibiotic-treated cases, with most deaths associated with disseminated disease or progression to sepsis.23
Acquiring the gastrointestinal form of anthrax is rare and usually occurs as a result of ingestion of contaminated meat. The incubation period is similar to the inhalation form and ranges from 1 to 7 days. Oropharyngeal ulcerations are common, along with sore throat and fever. Initially nausea, loss of appetite, and vomiting will predominate, transitioning into severe abdominal pain and bloody diarrhea after acute inflammation of the bowel. These typical symptoms often closely mimic other gastrointestinal maladies, making a definitive diagnosis difficult. Obtaining a thorough history and culturing ulcerations may be helpful. Mortality rates are higher, estimated at 25% to 60%, due to the difficulty in early diagnosis.23 Treatment protocols should involve antibiotics and surgical intervention of the affected intestine may be indicated.26
Inhalational anthrax is the most likely form of infection encountered after intentional dispersal. The initial symptoms strongly resemble those of influenza infection; fever, nonproductive cough, myalgia, and fatigue after a short incubational period of 1 to 6 days (potentially extending out to 43 days because of endospores). One component of the prodrome not described before the bioterrorist attack in the United States in 2001 was the occurrence of profuse drenching sweats, which may prove beneficial in differentiating inhalation anthrax from viral illness. Chest radiographs often reveal mediastinal widening or pleural effusions, both hallmarks of anthrax exposure (Fig. 15–2). The CDC recommends obtaining blood, pleural fluid, and cerebrospinal fluid, if available, for culture, Gram stain, and polymerase chain reaction (PCR). Sputum cultures are not recommended initially because of the lack of actual lung involvement. Without prompt antibiotic initiation, the mortality rate may be as high as 85% within 24 to 36 hours after symptom onset.6 Prompt medical attention and initiation of antibiotic treatment is imperative; alarmingly, data from the outbreak in 2001 demonstrated that victims waited an average of 3.5 days to seek medical advice.24 This lends high importance to the development of a strong clinical knowledge base regarding detection, diagnosis, and treatment.
Anthrax chest radiograph. (Courtesy of the CDC and Arthur E. Kaye. “This posteroanterior (PA) chest x-ray was taken 4 months after the onset of anthrax in a 46-year-old male, revealing bilateral pulmonary effusion, and a widened mediastinum, which are hallmarks of the disease process.” CDC Public Health Image Library. http://phil.cdc.gov/phil/home.asp.)
Sidebar: Clinical Presentation of Anthrax
- Depending on route of exposure to anthrax, persons can present with some or all of the constellation of symptoms described below.
- Inhalational prodrome normally consists of fever, malaise, dry cough, and shortness of breath.
- Cutaneous forms produce the distinctive painless, black-crusted ulcer.
- Gastrointestinal anthrax is distinguished by abdominal pain, fever, and bloody diarrhea or emesis.
- Rhinorrhea is rarely reported with anthrax, thus assisting in differentiation from other influenza-like illnesses.
- Complaints of drenching sweats were reported in the 2001 anthrax outbreak in the United States.
- Standard, routine blood cultures before antibiotic administration.
- Gram stain (from blood, cerebrospinal fluid, ulcer, pleural fluid).
- Confirmatory assays (PCR, enzyme-linked immunosorbent assay, or immunohistochemistry).
- Chest radiography will often demonstrate pleural effusions or mediastinal widening.
- Sputum cultures are rarely beneficial early in the course of inhalational cases.
- Leukocyte counts are normal or only mildly elevated.
Management of Potential Exposure
Once a suspected or confirmed exposure case is known, identifying at-risk individuals becomes the highest priority. Persons with exposure to an item or environment thought or known to be contaminated with B. anthracis should be offered antibiotic therapy, irrespective of laboratory test results. Nasal swabs can be used to help detect anthrax spores, but cannot rule out exposure. Based on in vitro and animal data, the CDC has published treatment guidelines to assist healthcare professionals.1,25 For PEP of inhalation anthrax (in adults, pregnant women, the immunocompromised, and children), oral doxycycline or ciprofloxacin is recommended as a first-line agent. Because spores may persist in lung tissue after aerosol exposure, antibiotic therapy must be continued for 60 days (Table 15–3).1,26
Table 15–3 Treatment and Prophylaxis for Anthrax (Bacillus anthracis) |Favorite Table|Download (.pdf)
Table 15–3 Treatment and Prophylaxis for Anthrax (Bacillus anthracis)
|Treatment (Symptomatic)||Postexposure Prophylaxis (Prevention)||Vaccination||Comments|
Duration: 60 days
Life-threatening (inhalational, systemic or serious cutaneous)
Adults: Ciprofloxacin 400 mg IV q 12 h or
Doxycycline 200 mg IV, then 100 mg IV q 12 h or
Levofloxacin 750 mg IV daily
Children: Ciprofloxacin 10–15 mg/kg IV q 12 h (maximum 400 mg/dose) or
Doxycycline IV (maximum 100 mg/dose):
>8 y and >45 kg: 100 mg q 12 h
>8 y and ≤45 kg: 2.2 mg/kg q 12 h
≤8 years: 2.2 mg/kg q 12 h
plus 1–2 additional: ampicillin, chloramphenicol, clindamycin, imipenem, linezolid, meropenem, macrolide (erythro-/clarithro-/azithromycin), penicillin, rifampin, vancomycin
Supportive therapy: aggressive and early) for shock, fluid volume deficit, and adequacy of airway may be indicated
Duration: minimum of 60 days after last exposure
Adults: Ciprofloxacin 500 mg PO q 12 h or
Doxycycline 100 mg PO q 12 h or
Levofloxacin 500–750 mg PO daily
Children: Ciprofloxacin 10–15 mg/kg PO q 12 h (maximum 500 mg/dose) or
Doxycycline PO (maximum 100 mg/dose):
>8 y and >45 kg: 100 mg q 12 h
>8 y and ≤45 kg: 2.2 mg/kg q12h
≤8 y: 2.2 mg/kg q 12 h
Pre-exposure prophylaxis: BioThrax (Anthrax Vaccine Adsorbed) 0.5 mL IM at 0 and 4 weeks; 6, 12, 18 mo with annual booster, as indicated
Postexposure prophylaxis: BioThrax (Anthrax Vaccine Adsorbed) 0.5 mL SC at 0, 2, 4 wk postexposure (IND) along with 60-day course of appropriate antimicrobials
Vaccine is not readily available to general public and mass vaccination is not practical
Pregnancy and immunocompromised: same recommendations
Cutaneousanthrax treatment (intentional release): Fluoroquinolonea or doxycycline for 60 days (10–14 days for contact with contaminated animal products)
Modify antimicrobials (treatment and postexposure prophylaxis) as indicated by susceptibility testing
Change from IV to PO when clinically appropriate
Consultation with infectious disease specialist advised
Sidebar: Clinical Controversy
Some clinicians recommend fluoroquinolones as first-line agents in mass PEP after suspected or confirmed anthrax exposure. Others recommend doxycycline, because they are concerned about development of fluoroquinolone antimicrobial resistance.
Although no controlled studies using PEP after suspected cutaneous or gastrointestinal exposures exist, doxycycline, ciprofloxacin, penicillin, and amoxicillin all have reasonably predictable activity against B. anthracis and could be used for shorter durations (7–14 days).23 Pre-exposure vaccination regimens are available, but are usually reserved for military personnel and select groups of people with potential exposure to anthrax. The vaccination schedule is laborious, requiring five injections over 18 months, in addition to annual boosters, and it is important to note that the vaccine itself is not without side effects. Data from various nonhuman studies show that vaccination alone is not protective postexposure and the Food and Drug Administration (FDA) has not approved a vaccination schedule for postexposure treatment, as of yet.23,28
Treatment of Confirmed Cases
Intravenous doxycycline or ciprofloxacin are indicated for use in treatment of inhalation anthrax and gastrointestinal anthrax. In addition, one to two other antibiotics with documented activity against B. anthracis (see Table 15–3) should be added to the therapy. This combination should be continued for 60 days (conversion to oral antibiotics is recommended once the patient becomes clinically stable).1 Treatment of cutaneous cases differs in that only one antibiotic (doxycycline or ciprofloxacin) is necessary and oral products may be used if cases do not include extensive edema or lesions of the head or neck. These clinically severe cases require intravenous antibiotics. Regardless of whether the cutaneous infection is deemed severe or not, the selected antibiotic should be continued for 60 days, just like treatment for inhalation or gastrointestinal anthrax. The extended duration is a result of the possibility of cutaneous infections being caused by intentional release and the potential inhalational exposure.1 Those treated during the outbreak of 2001 all received combination therapy (at least two antibiotics with activity against B. anthracis) and their fatality rate of 45% was slightly lower than previous observations reported in the literature.23,24 In addition to antibiotic therapy, aggressive supportive care should also be pursued. Drainage of pleural effusions, correction of electrolyte imbalances, and early mechanical ventilation all appear to positively affect survival rates. Several humanized monoclonal antibodies are in various stages of development to augment our treatment options with several close to addition into the SNS.30
One monoclonal antibody, raxibacumab, specifically directed at a component of the anthrax toxin demonstrates the impressive potential of these antibodies. When doses of raxibacumab were given in animals before aerosolized exposure to B. anthracis spores, 14- and 28-day survival rates were about 80% versus 0% in placebo groups. Fourteen- and 28-day survival rates of 50% were recorded when administration of raxibacumab was delayed until serum testing confirmed anthrax toxin exposure.31 Raxibacumab could potentially have a role in confirmed exposure cases or when initial antibiotic therapy response is perceived to be inadequate.
Treatment options generally remain similar across population groups and scenarios. Conversion from ciprofloxacin or doxycycline to penicillin or amoxicillin is recommended when antibiotic susceptibilities are known because of potential adverse effects associated with tetracycline and fluoroquinolone use in children. Children 2 years old or younger should always be initially treated with intravenous antibiotics because of limited experience in this age group.32 The risks and benefits of antibiotic administration need to be discussed with pregnant women exposed to anthrax, as these medications are not normally recommended for these patients; rarely, however, do the risks of treatment exceed the risks associated with foregoing antibiotic treatment. Dosages do not necessarily need to be adjusted in the elderly population, but considerations with regard to renal function for all populations may be necessary (see Chap. 57).