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Bio-Terrorism | Anthrax
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Anthrax is an uncommon illness in the United States, although currently it is in the news. Fifteen confirmed or suspected cases have been reported from the Centers for Disease Control and Prevention (CDC) from Florida, the District of Columbia, New York City, New Jersey, Maryland, Pennsylvania, and Virginia . Seven of these cases were inhalational and eight cutaneous; all have resulted from probable exposure to Bacillus anthracis in powder which had been sent through the mail. From 1984 through 1997, only three cases of cutaneous anthrax were reported to the CDC. Before the recent cluster of cases, the last prior fatal case of anthrax in the United States occurred in 1976 when a weaver who was a home craftsman died of inhalation anthrax after working with yarn imported from Pakistan. The dramatic reduction in the incidence of anthrax infection is due to decreased use of imported, contaminated raw material and to a successful immunization program among textile workers who are at risk. (See "Pathogenesis and epidemiology of anthrax";).
Spores can persist in the soil for long periods of time. Surface decontamination is not practical except in very unusual circumstances; thus, epizootic anthrax will continue to occur in highly endemic areas, such as Iran, Iraq, Turkey, Pakistan, and sub-Saharan Africa, where the use of animal anthrax vaccine is not comprehensive. In addition, a large epidemic occurred in Sverdlovsk in the former Soviet Union due to accidental release from a military microbiologic facility .
CLINICAL MANIFESTATIONS AND DIAGNOSIS There are three major anthrax syndromes: cutaneous; inhalation; and pharyngeal and gastrointestinal anthrax [3, 4]. The symptoms that occur are due to the actions of three exotoxins produced by B. anthracis: edema factor; lethal factor; and protective antigen. Edema factor causes edema and lethal factor causes death through an unknown mechanism when injected into susceptible animals. Neither edema factor nor lethal factor is toxic alone; they produce their deleterious effects only when they are combined with protective antigen, which is required for cell entry by binding to a cell surface receptor. (See "Pathogenesis and epidemiology of anthrax";).
Diagnosis B. anthracis is a sporulating Gram positive rod that can often be identified on Gram stain of cutaneous lesions or peritoneal fluid. Cultures of appropriate specimens in the absence of prior antibiotic therapy are usually positive. B. anthracis is nonmotile and grows well on blood agar plates. Individual colonies are nonhemolytic and sticky. A gamma bacteriophage can confirm the identity of the organism, and newly developed polymerase chain reaction techniques can identify as few as three spores of B. anthracis in a specimen. Serologic diagnosis is possible using a sensitive and specific indirect microhemagglutination test.
Although not widely available, anthrax skin testing also may be a helpful diagnostic tool. In one study of patients with cutaneous anthrax, the skin test was positive in the first three days in 82 percent, a time at which only 42 percent had positive cultures . In patients with a past history of cutaneous anthrax, the skin test was positive in 98.5 percent at 29 to 45 days after infection and in 73 percent at 16 to 31 years. Thus, a positive test cannot be used to indicate acute infection.
Cutaneous anthrax Spores of virulent B. anthracis can be introduced subcutaneously. They multiply and their antiphagocytic poly-D-glutamic acid capsule facilitates local spread. The release of exotoxin results in edema and tissue necrosis.
The clinical manifestations of cutaneous anthrax are usually quite striking (show picture 1) . Over 90 percent of the lesions occur in exposed areas such as the face, neck, arms, and hands. The disease begins as a small, painless, but often pruritic papule. The lesion progresses with initial enlargement of the papule followed by vesiculation and rapid (within two days) ulceration with eschar formation. Regional lymphadenopathy is often present.
Gram stain of the vesicular fluid shows rare to absent polymorphonuclear leukocytes and sporulating Gram positive rods. In an appropriate epidemiologic setting, there are three clinical characteristics, in addition to the presence of Gram positive rods, that are strongly suggestive of cutaneous anthrax:
The presence of edema out of proportion to the size of the lesion
The absence of pain
The relative rarity of polymorphonuclear leukocytes on Gram stain
Once entertained, the diagnosis of cutaneous anthrax is relatively easy to make.
Inhalation anthrax Inhalation anthrax, or woolsorters' disease, follows the inhalation of anthrax spores generated during the early cleaning of contaminated goat hair. Airborne anthrax spores which are greater than 5 microns in size pose no threat to the lung since they are either physically trapped in the nasopharynx or cleared by the mucociliary escalator system. In comparison, spores between 2 to 5 microns in size are deposited on alveolar ducts or alveoli. They are phagocytosed by alveolar macrophages and transported to mediastinal lymph nodes. There they multiply and cause hemorrhagic necrosis of the thoracic lymph nodes draining the lungs, a hemorrhagic mediastinitis, and, in occasional cases, a necrotizing pneumonia at the portal of entry . The organisms then become blood-borne, causing bacteremia and meningitis.
Early clinical diagnosis of inhalation anthrax is almost impossible [3, 8]. Initial symptoms, such as myalgia, fever, and malaise mimic those of influenza. Two to three days later, infected patients become dramatically sicker with the development of respiratory symptoms, including severe dyspnea and hypoxemia. An important diagnostic finding is widening of the mediastinum on chest x-ray, reflecting the mediastinitis. Pleural effusions are also common. The organism can be recovered from sputum and from nasal swab specimens.
Patients soon become hypotensive, and about one-half will also have a hemorrhagic meningitis with positive spinal fluid Gram stain and culture. Inhalation anthrax is virtually always fatal.
Pharyngeal and gastrointestinal anthrax Pharyngeal and gastrointestinal anthrax follow the consumption of tainted meat and tend to occur in family clusters. The bacilli can multiply in the oropharynx. Once they are absorbed in the intestine, they are transported to the mesenteric lymph nodes .
Patients with pharyngeal anthrax present with fever, pharyngitis, and neck swelling. One or more eschars are typically seen in the pharynx. Gastrointestinal anthrax is characterized by severe abdominal pain and the rapid development of hemorrhagic ascites. Gram stain of pharyngeal lesion or paracentesis fluid reveals Gram positive bacilli and cultures are positive.
TREATMENT B. anthracis is highly susceptible to a variety of antibiotics including penicillin, chloramphenicol, tetracycline, erythromycin, streptomycin, and the fluoroquinolones [9, 10]. Testing of the 11 isolates from the confirmed bioterrorism-related cases in the United States showed that the organisms were susceptible in vitro to rifampin, vancomycin, chloramphenicol, imipenem, clindamycin, and clarithromycin . Although sensitive to penicillin and ampicillin, the presence of inducible beta-lactamases led the CDC to advise against the use of either of these drugs alone for therapy of anthrax. The CDC has issued interim treatment recommendations for cases and exposure related to this bioterrorism attack; the agency cautions that there are no clinical trials on which to base these recommendations .
Cutaneous anthrax Penicillin has been used most extensively for the treatment of cutaneous anthrax. Organisms are rapidly cleared from skin lesions. In one study, for example, 25 patients with cutaneous anthrax and positive initial cultures of blister fluid were given 2 million units of penicillin G intravenously with hourly subsequent blister fluid cultures . All cultures were negative within five hours of initiation of therapy. However, prompt treatment does not prevent progression to the eschar phase.
Case fatality rates as high as 20 percent have been reported for untreated cutaneous anthrax but fatalities are now unusual with appropriate antibiotic treatment. Surgical excision of the cutaneous lesions is not recommended.
The length of therapy with penicillin is not well established; in the absence of controlled observations, penicillin G (2 million units every three hours intravenously for five to seven days) is generally recommended. Erythromycin (500 mg IV every six hours) and ciprofloxacin (400 mg IV every 12 hours) are alternative drugs for penicillin-sensitive patients [6, 9, 10].
Another regimen that may be effective is single dose oral therapy with doxycycline. In one series, 33 patients with cutaneous anthrax were treated with a single oral dose of doxycycline, and all patients were observed in a hospital setting for three days . There was dramatic clinical improvement, and all cases were bacteriologically negative by the fourth day. Based on this study, it is proposed that cutaneous anthrax can be safely treated with a single 500 mg oral dose of doxycycline in adults and 100 to 300 mg in children and adolescents. This regimen is recommended for unusual situations such as occasionally found in developing countries where access to medical care may be limited.
Treatment recommendations for the current United States cutaneous bioterrorism cases Ciprofloxacin or doxycycline are recommended by the CDC for treatment of cutaneous anthrax in association with the recent bioterrorism attack (show table 1) . Penicillin is not recommended based upon the presence of inducible beta-lactamases in the B. anthracis isolates, as noted above. Children and pregnant women are recommended for treatment with these drugs because of the seriousness of the disease despite usual prohibitions against their use. The CDC recommends continuation of therapy for 60 days based upon the possibility of additional aerosol exposure in these individuals. Treatment with the same regimens as for inhalational anthrax is suggested for patients with cutaneous disease and signs of systemic involvement, extensive edema, or involvement of the head and neck (show table 2).
Inhalation anthrax Because patients with pulmonary anthrax present late in the course of their illness, virtually all cases are fatal even if they receive antibiotic therapy. However, in an accidental outbreak from a biologic weapons laboratory in Sverdlovsk, 11 survivors (with more than 60 deaths) were reported, indicating that this is not a universally fatal disease . Thus, treatment should be initiated in any patient with suspected inhalation anthrax. Penicillin G (2 million units every three hours intravenously for five to seven days) is the treatment of choice.
Treatment recommendations for the current United States inhalational bioterrorism cases The CDC recommends multidrug therapy for inhalational anthrax associated with this bioterrorism attack (show table 2) . The multidrug recommendation is based upon the seriousness of the illness and successes in some cases treated early. There are no clinical trials of multidrug therapy in this disease. The regimens which were used in the nonfatal cases included ciprofloxacin, rifampin, and vancomycin or ciprofloxacin, rifampin, and clindamycin. Cephalosporins and trimethoprim-sulfamethoxazole should not be used.
Corticosteroids have been recommended as adjunctive therapy for some patients with inhalational anthrax because of toxin-related morbidity. Such patients might include those with extensive edema, respiratory failure, and meningitis .
Pharyngeal and gastrointestinal anthrax There are so few well studied cases of gastrointestinal and pharyngeal anthrax that specific recommendations about antibiotic treatment other than intravenous penicillin G (2 million units IV every three hours) cannot be made at this time.
PREVENTION Vaccination against anthrax is the major means of preventing the illness. A vaccine has been licensed for use in the United States but is not available to the general public. In 1999 a decision was made to immunize all United States military personnel against anthrax because of the threat of inhalation anthrax as a biological warfare agent. (See "Identifying and managing casualties of biological terrorism";). In 2000, because of vaccine shortages, the vaccination program was limited to troops designated to be at greater risk (Middle East and Korea). Postexposure antibiotic prophylaxis can also be used to prevent clinical illness and has been the approach used in 2001 in South Florida, Washington, DC, New York City, and New Jersey.
Anthrax vaccine Prevention of anthrax has largely depended upon the use of vaccines, since widespread decontamination of infected soil is impractical. Sterne vaccine is a live, toxigenic, unencapsulated, avirulent animal strain that is widely used as a veterinary vaccine. This vaccine has not been used widely in humans because of development of necrosis at the inoculation site. Due to these safety concerns, spore vaccines have generally not been used as human vaccines except in Russia where a live spore vaccine has been developed for human use and is considered to be highly effective.
Anthrax Vaccine Adsorbed (AVA) is the only licensed human anthrax vaccine in the United States . The vaccine has been field tested and shown to be highly effective . The recommended vaccination schedule with AVA is complex; primary vaccination consists of three subcutaneous injections at zero, two, and four weeks and three booster vaccinations at 6, 12, and 18 months. In addition, to maintain immunity the manufacturer (BioPort, Lansing) recommends an annual booster injection. Studies are currently underway to evaluate the immunogenicity of a reduced number of doses and the intramuscular route .
Postexposure prophylaxis The extensive epidemic of inhalation anthrax that occurred in Sverdlovsk increased interest in postexposure prophylaxis . Earlier studies in experimental animals had shown that treatment with penicillin beginning one day after aerosol exposure to anthrax spores was protective during the 5 to 10 days of drug therapy; however, the animals died when penicillin was discontinued .
In a more recent study of experimental inhalation anthrax, monkeys were challenged with aerosolized anthrax spores; 24 hours later three groups of animals were treated with either penicillin, ciprofloxacin, or doxycycline for 30 days, and a fourth group received the combination of doxycycline and immunization with anthrax vaccine (see below) . All of the 30-day antibiotic regimens completely protected animals while they were on therapy, and provided better long-term protection than the shorter 5 and 10-day treatment protocols in the previous study. All animals that were immunized and treated with doxycycline survived.
When the monkeys were rechallenged with airborne anthrax spores, all succumbed except for the animals which had been immunized . These data offer convincing proof that postexposure prophylaxis is effective, particularly when combined with active immunization.
Two agents have been recommended for postexposure prophylaxis: ciprofloxacin (500 mg PO BID) or doxycycline (100 mg PO BID) (show table 3). An advisory panel of the United States Food and Drug Administration (FDA) recently recommended expanding the approval of ciprofloxacin for this use . Penicillin V (500 mg PO QID), according to the CDC, should be reserved for cases in which one of the other drugs is contraindicated . The recommended duration of prophylaxis is 60 days.
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1 Update: Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR Morb Mortal Wkly Rep 2001; 50(42):909.
2 Meselson, M, Guillemin, J, Hugh-Jones, M, et al. The Sverdlovsk anthrax outbreak of 1979. Science 1994; 266:1202.
3 LaForce, FM. Anthrax. Clin Infect Dis 1994; 19:1009.
4 Dixon, TC, Meselson, M, Guillemin, J, Hanna, PC. Anthrax. N Engl J Med 1999; 341:815.
5 Shlyakhov, E, Rubenstein, E. Evaluation of the anthraxin skin test for the diagnosis of acute and past anthrax. Eur J Clin Microbiol Infect Dis 1996; 15:242.
6 Gold, H. Anthrax: A report of one hundred seventeen cases. Arch Intern Med 1955; 96:387.
7 Abramova, FA, Grinberg, LM, Yampolskaya, OV, et al. Pathology of inhalational anthrax in 42 cases from the Sverdlovsk outbreak of 1979. Proc Natl Acad Sci U S A 1993; 90:2291.
8 Plotkin, SA, Brachman, PS, Utell, M, et al. An epidemic of inhalation anthrax, the first in the twentieth century. Am J Med 1960; 29:992.
9 Lightfoot, NF, Scott, RJD, Turnbull, BCB. Antimicrobial susceptibility of Bacillus anthracis. Salisbury Med Bull Suppl 1990; 68:95.
10 Doganay, M, Aydin, N. Antimicrobial susceptibility of Bacillus anthracis. Scand J Infect Dis 1991; 23:333.
11 Ronaghy, HA, Azadeh, B, Kohout, E, Dutz, W. Penicillin therapy of human cutaneous anthrax. Curr Ther Res 1972; 14:721.
12 Saggar, SN, Joseph, MM, Bell, WJ. Treatment of cutaneous anthrax with a single oral dose of doxycycline. East Afr Med J 1974; 51:889.
13 Centers for Disease Control and Prevention. Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2000; 49(No. RR-15):1.
14 Brachman, PS, Gold, H, Plotkin, SA, et al. Field evaluation of a human anthrax vaccine. Am J Public Health 1962; 52:632.
15 Gochenour, WS, Gleiser, CA, Tigertt, WD. Observations on penicillin prophylaxis of experimental inhalation anthrax in the monkey. J Hyg (London) 1962; 60:29.
16 Friedlander, AM, Welkos, SL, Pitt, MLM, et al. Postexposure prophylaxis against experimental inhalation anthrax. J Infect Dis 1993; 167:1239.
17 Bayer cipro for anthrax prophylaxis would be alternative to penicillin FDA. In: "The Pink Sheet. Vol 62, No 32, F-D-C Reports, Chevy Chase, Maryland 2000. p.26.
18 Update: Investigation of anthrax associated with intentional exposure and interim public health guidelines, October 2001. MMWR Morb Mortal Wkly Rep 2001; 50(41):889.