ANTHRAX
INTRODUCTION
Bacillus anthracis is a large, aerobic, gram-positive, spore forming, nonmotile bacillus. The bacterium ordinarily produces a zoonotic disease in domesticated and wild animals such as goats, sheep, cattle, horses, and swine. Humans become infected by contact with infected animals or contaminated animal products. Infection occurs predominantly through the cutaneous route and only rarely via the respiratory or gastrointestinal (GI) route.
Anthrax occurs worldwide. The organism exists in the soil as a spore. The form of the organism in infected animals is the bacillus. Sporulation occurs only when the organism in the carcass is exposed to air.
The true incidence of human anthrax is unknown. Reporting of illness has been unreliable. In 1958, an estimated 20,000-100,000 cases occurred worldwide. In the US, the annual incidence of human anthrax has declined steadily from approximately 127 cases in the early years of this century to approximately 1 per year for the past 10 years.
PATHOPHYSIOLOGY - ANTHRAX
B anthracis possesses 3 known virulence factors, an antiphagocytic capsule and 2 protein exotoxins (lethal and edema toxin). The role of the capsule in pathogenesis was demonstrated in the early 1900s when anthrax strains, lacking a capsule, were demonstrated to be virulent. In more recent years, the genes encoding synthesis of the capsule were found to be encoded on a 110-kilobase plasmid. The capsule is composed of a polymer of poly-D-glutamic acid, which confers resistance to phagocytosis and may contribute to the resistance of anthrax to lysis by serum cationic proteins.
The anthrax toxins, like many bacterial and plant toxins, possess the following 2 components: a cell binding B-domain and an active A-domain. The A-domain confers enzymatic activity and toxicity. Edema toxin, which consists of the same protective antigen together with a third protein, edema factor, causes edema when injected into the skin of experimental animals.
Infection begins when the spores are inoculated through skin or mucosa. It is believed that spores are ingested locally by tissue macrophages. Subsequently, spores germinate within macrophages to the vegetative bacilli, which produce capsules and toxins. Bacteria proliferate at these tissue sites and produce the edema and lethal toxins that impair host leukocyte function and lead to the following distinctive and pathologic findings: edema, hemorrhage, tissue necrosis, and a relative lack of leukocytes. In inhalation anthrax, the spores are ingested by alveolar macrophages, which transport them to the regional tracheobronchial lymph nodes, where germination occurs.
Once in the tracheobronchial lymph nodes, the local production of toxins by extracellular bacilli gives rise to the characteristic pathologic picture of massive hemorrhagic, edematous, and necrotizing lymphadenitis and mediastinitis. The bacillus then can spread to the blood, leading to septicemia and frequently causing hemorrhagic meningitis. Death results from respiratory failure, overwhelming bacteremia, septic shock, and meningitis.
CLINICAL FEATURES - ANTHRAX
Cutaneous: More than 95% of cases of anthrax are cutaneous. After inoculation, the incubation period is 1-5 days. The disease first appears as a small papule that progresses over 1-2 days to a vesicle containing serosanguinous fluid with many organisms and a paucity of leukocytes. This often has been referred to as a malignant pustule; however, this is a misnomer because no pustular lesions are found in anthrax patients. The vesicle ruptures, leaving a necrotic ulcer. The lesion usually is painless, and varying degrees of edema may be present around it. The edema occasionally may be massive, encompassing the entire face or limb, and is described as malignant edema. Patients generally experience fever, malaise, and headache, which may be severe in those with extensive edema. Local lymphadenitis also may be present. The ulcerbase develops a characteristic 1-5 cm black eschar. (The black appearance of the eschar gives anthrax its name [Greek anthrakos = coal].) After a period of 2-3 weeks, the eschar separates, often leaving a scar. Septicemia is rare. Mortality should be less than 1% with adequate treatment.
Inhalation: Also known as woolsorter's disease, inhalation anthrax has a typical incubation period of 1-6 days, but a latent period as long as 60 days has been described. Initial manifestations are nonspecific and include headache, malaise, fatigue, myalgia, and fever. Associated nonproductive cough and mild chest discomfort may occur. These symptoms usually persist for 2-3 days, and in some patients a short period of improvement may occur. This is followed by the sudden onset of increasing respiratory distress with dyspnea, stridor, cyanosis, increased chest pain, and diaphoresis. Associated edema of the chest and neck may be present. Chest x-ray usually shows the characteristic widening of the mediastinum and often, pleural effusion. Pneumonia is an uncommon finding. The onset of respiratory distress is followed by the rapid onset of shock and death within 24-36 hours. Mortality is nearly 100% despite appropriate treatment. Inhalation anthrax is the most likely form of disease to follow military or terrorist attack. Such an attack likely will involve the aerosolized delivery of anthrax spores.
Oropharyngeal and gastrointestinal: These result from the ingestion of infected meat that has not been cooked sufficiently. After an incubation period of 2-5 days, patients with oropharyngeal disease present with severe sore throat or a local oral or tonsillar ulcer, usually associated with fever, toxicity, and swelling of the neck due to cervical or submandibular lymphadenitis or edema. Dysphagia and respiratory distress also may be present. GI anthrax begins with nonspecific symptoms of nausea, vomiting, and fever. These are followed in most patients by severe abdominal pain. The presenting sign may be an acute abdomen, which may be associated with hematemesis, massive ascites, and diarrhea. Mortality in both forms may be as high as 50%, especially in the GI form.
Meningitis: This may occur following bacteremia as a complication of any of the other clinical forms. Meningitis also may occur, rarely, without any of the other clinical forms of the disease. It often is hemorrhagic and almost invariably fatal.
DIAGNOSIS - ANTHRAX
The most critical aspect in making a diagnosis is a high index of suspicion associated with a compatible history of exposure. Consider cutaneous anthrax following the development of a painless, pruritic papule, vesicle, or ulcer. This area often is associated with surrounding edema that develops into a black eschar. With extensive or massive edema, such a lesion is almost pathognomonic. Gram stain or culture of the lesion confirms the diagnosis. The differential diagnosis should include tularemia and staphylococcal or streptococcal species.
The diagnosis of inhalation anthrax is extremely difficult, but suspect the disease with a history of exposure to a B anthracis-containing aerosol. Early symptoms are entirely nonspecific. The development of respiratory distress in association with radiographic evidence of a widened mediastinum due to hemorrhagic mediastinitis and the presence of hemorrhagic pleural effusions or hemorrhagic meningitis should suggest the diagnosis. Sputum Gram stain and culture usually are not helpful, since pneumonia is an uncommon feature of illness. Gram stain of peripheral blood may be positive for gram-positive bacilli and should be performed. GI anthrax also is exceedingly difficult to diagnose because of the rarity of the disease and nonspecific symptoms. Diagnosis usually is confirmed only with a history of ingesting contaminated meat in the setting of an outbreak. Once again, cultures generally are not helpful in making the diagnosis.
Meningitis from anthrax is clinically indistinguishable from meningitis due to other etiologies. A distinguishing feature is that the spinal fluid is hemorrhagic in as many as 50% of patients. The diagnosis can be confirmed by identifying the organism in the spinal fluid by microscopy, culture, or both.
Serology can be used to make a retrospective diagnosis. Antibody develops in 68-93% of reported cases of cutaneous anthrax and 67-94% of reported cases of oropharyngeal anthrax. A positive skin test to anthracin also has been used to make a retrospective diagnosis of anthrax.
The most useful microbiologic test is the standard blood culture, which is almost always positive in patients with systemic illness. Blood cultures should show growth in 6-24 hours. If the laboratory has been alerted to the possibility of anthrax, biochemical testing and review of colonial morphology should provide a preliminary diagnosis 12-24 hours later. However, if the laboratory has not been alerted to the possibility of anthrax, B anthracis may not be identified correctly.
New rapid diagnostic tests for B anthracis and its proteins include polymerase chain reaction (PCR), enzyme-linked immunoassay (ELISA), and direct fluorescent antibody (DFA) testing. Currently, these tests are only available at national reference laboratories.
TREATMENT - ANTHRAX
A number of possible therapeutic strategies have yet to be fully explored experimentally or submitted for approval to the Food and Drug Administration (FDA). The recommendations provided do not represent uses currently approved by the FDA but are a consensus based on best available information of recent studies.
Given the fulminant course of inhalation anthrax, early antibiotic administration is essential to maximize patient survival. Given the difficulty in achieving timely microbiologic diagnosis of anthrax, all persons with fever or evidence of systemic disease in an area where anthrax cases are occurring should be treated empirically for anthrax until the disease is excluded.
No clinical studies exist of the treatment of inhalation anthrax in humans. Most naturally occurring strains of anthrax are sensitive to penicillin, and penicillin historically has been the preferred therapy for the treatment of anthrax. Penicillin and doxycycline are FDA-approved antibiotics for anthrax. Doxycycline is the preferred option from the tetracycline class of antibiotics because of its proven efficacy in monkey studies. Experts currently recommend initiation of ciprofloxacin or other fluoroquinolones in adults with presumed inhalation anthrax infection. Following a terrorist attack, assume resistance to penicillin and tetracycline class antibiotics until laboratory testing demonstrates otherwise.
In a contained casualty setting (a situation in which a modest number of patients require therapy), initiate intravenous antibiotics for symptomatic patients. In adults, ciprofloxacin 400 mg IV q12h is recommended. Traditionally, ciprofloxacin and other fluoroquinolones are not recommended for use in children younger than 16-18 years because of a link to permanent arthropathy in adolescent animals and transient arthropathy in a small number of children. Balancing these small risks against the real risk of death and resistant strains of B anthracis, experts recommend that ciprofloxacin be given to a pediatric population for initial therapy or postexposure prophylaxis following anthrax attack. In children, ciprofloxacin at 20-30 mg/kg/d IV in 2 daily doses (not to exceed 10 g/d) is recommended. If antibiotic susceptibility testing allows, substitute intravenous penicillin for the fluoroquinolones. For adults and children older than 12 years, penicillin G at 4 million U IV q4h is recommended for 60 days. Doxycycline at 100 mg IV q12h for 60 days is an acceptable alternative for adults. For children younger than 12 years, penicillin G is dosed 50,000 U/kg IV q6h for 60 days. In experimental models, antibiotic therapy during anthrax infection has prevented development of an immune response. This suggests that even if the antibiotic-treated patient survives anthrax infection, risk of recurrence remains for at least 60 days. Oral therapy should replace intravenous therapy as soon as a patient's clinical condition improves.
Historically, the treatment of cutaneous anthrax has been oral penicillin. Recent recommendations suggest that oral fluoroquinolones or tetracycline antibiotics, as well as amoxicillin, are suitable alternatives if antibiotic susceptibility is proven. Although previous guidelines have suggested treating cutaneous anthrax with 7-10 days of therapy, recent recommendations suggest treatment for 60 days in the setting of bioterrorism, given the presumed exposure to the primary aerosol. Treatment of cutaneous anthrax generally prevents progression to systemic disease, although it does not prevent the formation and evolution of the eschar.
Other antibiotics effective against B anthracis in vitro include chloramphenicol, erythromycin, clindamycin, extended spectrum penicillins, macrolides, aminoglycosides, vancomycin, cefazolin, and other first-generation cephalosporins.
In pregnant women, experts recommend that ciprofloxacin be given for therapy and postexposure prophylaxis following anthrax attack. Substitute intravenous penicillin for the fluoroquinolones if microbiologic testing confirms penicillin susceptibility.
PREVENTION/PROPHYLAXIS-ANTHRAX
No FDA-approved chemoprophylactic regimens are available following exposure to an anthrax aerosol. For postexposure prophylaxis, experts recommend the same oral regimen as that recommended for treatment of mass casualties. For adults, administer ciprofloxacin 500 mg PO bid for 60 days. Ciprofloxacin may be changed to amoxicillin at 500 mg PO tid or doxycycline 100 mg PO bid for 60 days if microbiologic testing confirms such antibiotic susceptibility. In children, administer ciprofloxacin at 20-30 mg/kg/d PO taken twice daily (not to exceed 1 g/d) for 60 days. If the strain is susceptible to penicillins and patient weight is greater than 20 kg, amoxicillin may be given at 500 mg PO tid. For a child who weighs less than 20 kg, amoxicillin is administered at 40 mg/kg/d divided tid for 60 days.
A licensed vaccine, an aluminum hydroxide-absorbed preparation, is derived from culture fluid supernatant taken from an attenuated strain. The vaccination series consists of 6 subcutaneous doses at 0, 2, and 4 weeks, then at 6, 12, and 18 months, followed by annual boosters. Insufficient data are available regarding efficacy against inhalation anthrax in humans, although studies in rhesus monkeys indicate that it is protective. If information indicates that a BW attack is imminent or may have occurred, prophylaxis of unimmunized individuals with ciprofloxacin (500 mg PO bid) or doxycycline (100 mg PO bid) is recommended. Initiate the vaccination series for unimmunized individuals. Should an anthrax attack be confirmed, continue chemoprophylaxis for at least 4 weeks and until all those exposed receive 3 doses of vaccine (at 0, 2, and 4 wk). |
