Anthrax exposure—stay alert, act swiftly

Kevin Lohenry, MPAS, PA-C

Mr. Lohenry is Associate Director and Assistant Professor at Midwestern University Physician Assistant Program, Downers Grove, Ill. The author has indicated no relationships to disclose relating to the content of this article.

Initiating appropriate antibiotic therapy as soon as anthrax infection is suspected is not only acceptable but is also justified by the outcomes of the 2001 anthrax cases.

Bacillus anthracis, the bacterium that causes anthrax, is listed by the CDC as a category A biological weapon, owing to its ability to cause public panic and its potential impact on public health.¹ In 2001, 23 cases of confirmed or suspected anthrax infection—accounting for five deaths²—awakened public health officials and health care providers to the importance of timely recognition and treatment of anthrax infection and of understanding protocols for antibiotic prophylaxis following a suspected exposure to B anthracis. The organism is a large, aerobic, gram-positive, spore-forming bacillus that measures 1 to 1.5 µm by 3 to 10 µm. It is nonmotile, grows readily at a temperature of 37°C, and forms large colonies with an irregularly shaped outgrowth.

There are four clinical forms of anthrax: inhalational, cutaneous, gastrointestinal, and oropharyngeal. The inhalational form is the deadliest of the four, while the cutaneous form is the most common and typically results from occupational exposure, such as to infected livestock.³ The cutaneous form is thought to have been the cause of the fifth and sixth plagues described in the book of Exodus.⁴

Anthrax as a weapon

The CDC estimates that a terrorist attack using B anthracis could cost at least $26.2 billion per 100,000 persons exposed.⁵ Although the Biological Weapons Convention terminated research on B anthracis more than 30 years ago in the United States, research using the agent as a weapon has continued in some countries, among them Iraq, which in 1995 acknowledged production and weaponization of the bacterium to the United Nations Special Commission. The former Soviet Union has also acknowledged B anthracis production as part of its bioweapons program following the first large-scale accidental release in 1979 of B anthracis spores from a bioweapons factory in Sverdlovsk, Russia. The organism killed 68 of 79 persons who developed inhalational anthrax. In the United States, 18 cases of occupational exposure that caused inhalational anthrax occurred during the 20th century and were typically associated with wool sorters,⁶ and 224 cases of cutaneous anthrax were reported between 1944 and 1994. The largest epidemic occurred in Zimbabwe between 1978 and 1980, when more than 10,000 human cases of cutaneous anthrax were reported.^4,7 Anthrax may be contracted by skinning, butchering, or eating contaminated meat.

The course of four forms

The deadliest form—inhalational anthrax The inhalational form develops after a person is exposed to the bacillus, and those spores that are not ingested by macrophages are transported to the mediastinal lymph nodes. Dormancy follows germination, which can occur as many as 60 days after exposure and accounts for the recommended length of antibiotic prophylaxis after exposure. Clinical symptoms begin as B anthracis replicates, resulting in a release of toxins that lead to hemorrhage, edema, and necrosis. Animal studies have shown that death occurs when toxin production reaches a critical threshold. Although the number of spores necessary to cause infection in humans is not known, published extrapolations from primate data suggest that as few as one to three spores can cause infection.^4,8

The first phase of inhalational anthrax is characterized by a nonspecific illness with mild fever, malaise, myalgia, nonproductive cough, and some chest or abdominal pain. The second phase of the illness begins with an abrupt onset of fever, acute dyspnea, cyanosis, and diaphoresis. Stridor may develop secondary to lymphadenopathy, mediastinal widening, and subcutaneous edema in the chest and neck, and anthrax meningoencephalitis may result in obtundation and nuchal rigidity. This phase progresses rapidly, and shock and death typically occur within 24 to 36 hours.⁹ Early lumbar puncture should be considered because of the high case fatality rate (94%) associated with anthrax meningoencephalitis.¹⁰ Common findings from the lumbar puncture sample in anthrax infection include a cloudy or bloody fluid, elevated opening pressure, increased protein concentration, and a decreased glucose concentration. Gram's staining reveals the large gram-positive bacilli.¹¹

Most common, less deadly—cutaneous anthrax The cutaneous form of anthrax accounts for more than 95% of naturally occurring anthrax cases. The spore enters the body through a cut or abrasion, typically on the arms, face, or neck. Toxin production results in localized edema following the germination in the tissue. The first sign of infection is a painless, pruritic papule or macule that appears 1 to 7 days after the spore is deposited; several small vesicles may surround the lesion. The lesion enlarges to a round ulcer by day 2 and is then surrounded by a nonpitting, gelatinous edema. Low-grade fever and malaise are typical. Necrosis follows rupture of the vesicle, resulting in the black eschar that characterizes cutaneous anthrax (see Figure 1). This eschar dries and sloughs off, usually within 2 weeks, and scarring is minimal.

Click here to view full-size graphic

Lymphangitis, local pain, purulent drainage, and fever suggest the presence of Staphylococcus aureus or streptococci, although secondary infection is uncommon.^4,9 Anthrax meningoencephalitis has also been reported as a complication in 5% of patients with cutaneous anthrax.¹⁰

Gastrointestinal anthrax This form causes symptoms 2 to 5 days after ingestion of undercooked meat containing spores or large numbers of vegetative bacilli. Nausea, vomiting, fever, and abdominal pain progress rapidly to severe, bloody diarrhea and signs of an acute abdomen. Patients may develop esophageal, gastric, or intestinal ulcerations. Hemorrhagic mesenteric lymphadenitis with marked ascites may also occur. Mortality associated with gastrointestinal anthrax is greater than 50%.

Oropharyngeal anthrax Although it is rarely seen, an oropharyngeal form of anthrax may also occur. Symptoms include severe sore throat, fever, dysphagia, and possibly respiratory distress secondary to lymphadenopathy or edema. Oral or pharyngeal ulcers may also be seen.^4,9

Alertness the key to diagnosis

The sudden appearance of several cases of acute-onset febrile illness and fulminant death—particularly febrile illness among postal workers, military personnel, or members of the media—should trigger suspicion of anthrax followed by immediate notification of the local or state public health department to begin tracking the spread and to help confirm the diagnosis. Special reference laboratories should be utilized for diagnostic testing. A Laboratory Response Network (LRN) has been established through a collaboration of the Association of Public Health Laboratories and the CDC. Confirmatory tests include polymerase chain reaction (PCR) assays, immunohistochemical staining, and gamma phage testing. In inhalational anthrax, chest radiographic findings classically include mediastinal widening. Other findings may include massive pleural effusions, consolidation, and air bronchograms. Chest CT may show mediastinal lymphadenopathy or edema, infiltrates, or pleural effusions. A review of the cases during 2001 showed that 10 patients had abnormal chest radiographs, and 8 of the 10 had abnormal chest CT scans. The abnormalities included a widened mediastinum and effusions.

A peripheral blood smear may show gram-positive bacilli with preliminary identification of Bacillus species. A standard blood culture may also show growth in 6 to 24 hours. Eight of the patients during the 2001 crisis had positive blood cultures, and all eight received antibiotic therapy immediately following the collection of samples.^4,12-16 Blood cultures appear to be sterilized after one or two doses of antibiotics, underscoring the importance of obtaining cultures before initiating therapy. Because some laboratories do not further identify species unless specifically requested to do so, it is important to communicate the suspicion of anthrax infection to the laboratory personnel. The CDC's 2002 management update suggests modified clinical laboratory procedures to specifically exclude B anthracis in any culture that identifies a Bacillus species.¹

Note that the collection of nasal swabs among the cases in 2001 was not found to be helpful; one patient who died from inhalational anthrax had a negative nasal swab.¹² Although nasal swab samples may be used for epidemiologic studies, they are not recommended for clinical diagnosis.⁴

Maximizing the vaccine's effectiveness

Anthrax vaccine is available as a cell-free filtrate of a nonencapsulated attenuated strain of B anthracis that is given in six doses. Preexposure vaccination has shown some effectiveness in some animal studies.^17-19 Postexposure studies with monkeys have shown that those monkeys who received only vaccine died. Five of 29 monkeys who received antibiotic therapy for 30 days without vaccination died after treatment ended, and the remaining 24 died after reexposure to B anthracis. Nine monkeys who received doxycycline for 30 days plus the vaccination at baseline and on day 14 following exposure survived, even after reexposure.^4,20

Reported adverse effects of the vaccine are rare and include headache (the most frequently reported problem), malaise, myalgia, fever, nausea, vomiting, dizziness, chills, diarrhea, hives, anorexia, arthralgias, diaphoresis, blurred vision, generalized itching, or sore throat. Local or injection site reactions have also been reported. Since 1997, several hundred thousand military personnel have received more than 1.5 million doses of the vaccine, with no pattern of unexpected local or systemic adverse effects noted.²¹

The vaccine has no apparent effect on pregnancy, birth rates, or birth outcomes.²² The CDC Working Group consensus recommendation is to administer the vaccine in conjunction with an antibiotic that is taken for 60 days following exposure. According to the Working Group, no cases of anthrax infection were reported among those who were exposed to B anthracis during the 2001 outbreak despite failure by some persons to complete the 60-day course of antibiotic therapy.⁴

Swift and decisive treatment

The CDC Working Group consensus recommendation on treatment of anthrax infection is based on a few human cases of anthrax infection and may run counter to FDA indications, and some of the recommendations—such as those for pregnant women and children—are described in the literature as ill advised. In determining the risk-benefit ratio, however, the Working Group noted that the risk of death from anthrax infection was greater than the risk of adverse effects from the antibiotic therapy.

Inhalational anthrax Rapid initiation of antibiotics is essential for patient survival in inhalational anthrax, and antibiotic therapy should be initiated as soon as anthrax is suspected.^3,22,23 The Working Group's consensus recommendation is to use IV ciprofloxacin or doxycycline for inhalational anthrax in adults, children, pregnant women, and immunocompromised patients (see Table 1).

 

TABLE 1 Inhalational anthrax treatment protocol used in 2001 cases
Initial therapy, IV	Duration
ADULTS
Ciprofloxacin, 400 mg q12h OR Doxycycline, 100 mg q12h AND One or two additional antimicrobials	IV treatment initially;* switch to oral antimicrobial therapy when clinically appropriate: Ciprofloxacin, 500 mg po bid OR Doxycycline, 100 mg po bid Continue for 60 days (IV and po combined)
CHILDREN
Ciprofloxacin, 10-15 mg/kg q12h (not to exceed 1 g/d) OR Doxycycline >8 y and >45 kg, 100 mg q12h >8 y and <45 kg, 2.2 mg/kg q12h <8 y, 2.2 mg/kg q12h AND One or two additional antimicrobial agents	IV treatment initially;* switch to oral antimicrobial therapy when clinically appropriate: Ciprofloxacin, 10-15 mg/kg po q12h (not to exceed 1 g/d) OR Doxycycline >8 y and >45 kg, 100 mg po bid >8 y and <45 kg, 2.2 mg/kg po bid <8 y, 2.2 mg/kg po bid Continue for 60 days (IV and po combined)
PREGNANT WOMEN†
Same as for nonpregnant adults (high death rate from anthrax infection outweighs the risk posed by the antimicrobial agent)	IV treatment initially; switch to oral antimicrobial therapy when clinically appropriate. Oral therapy regimens same as for nonpregnant adults
IMMUNOCOMPROMISED PERSONS
Same as for adults and children	Same as for adults and children
Note: Regimen also is recommended for GI and oropharyngeal anthrax. Ciprofloxacin and doxycycline should be considered an essential part of first-line therapy for inhalational anthrax. Corticosteroids may be considered as an adjunct therapy for patients with severe edema or meningitis; if meningitis is suspected, doxycycline may be less optimal. *Initial therapy may be altered based on the clinical course of the patient; one or two antimicrobial agents (eg, ciprofloxacin or doxycycline) may be adequate as the patient improves. †Although tetracyclines are not recommended during pregnancy, their use may be indicated for life-threatening illness. Adverse effects on developing teeth and bones are dose related; consider doxycycline for 7-14 days before 6 months’ gestation.
Adapted from Update: Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR Morb Mortal Wkly Rep. 2001;50:909-919. Available at: www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm. Accessed June 20, 2004.

Doxycycline has been proven effective in monkey studies and is the preferred option among the tetracyclines, although other tetracyclines are suitable alternatives.²⁴ Ciprofloxacin has proven efficacy in animal models but has not been studied in humans.^20,24,25 Other fluoroquinolones likely have equivalent efficacy, but no published data are available using a primate model.⁴

The FDA has approved penicillin and doxycycline for the treatment of inhalational anthrax in children.⁴ This treatment is controversial because it carries a risk of permanent arthropathy.²⁶ Although this risk should also be considered when fluoroquinolones are considered for treatment of other diseases, their use in inhalational anthrax in children and adolescents is warranted by the risk posed by the disease. The CDC recommends that ciprofloxacin be used in this population.⁴

Fluoroquinolones are generally not recommended in pregnancy, and the tetracycline class of antibiotics has been associated with toxic effects on the liver in pregnant women and on the fetus, including retarded skeletal growth.²⁶ Ciprofloxacin is, however, the drug of choice in the treatment of inhalational anthrax in pregnant women because the benefits of administration outweigh the risks of withholding treatment. Doxycycline may be used as an alternative to ciprofloxacin as part of combination therapy in pregnant women. Periodic liver function testing should be done to monitor a patient's response to doxycycline.⁴

Cutaneous anthrax Although oral penicillin has long been the treatment of choice in cutaneous anthrax, current recommendations include a 60-day course of an oral fluoroquinolone or doxycycline (see Table 2). Lesions with extensive edema around the head and neck may require more aggressive clinical management, including IV antibiotics.⁴

 

TABLE 2 Cutaneous anthrax treatment protocol* used in the 2001 cases
Initial oral therapy†	Duration
ADULTS‡
Ciprofloxacin, 500 mg bid OR Doxycycline, 100 mg bid	60 d
CHILDREN‡
Ciprofloxacin, 10-15 mg/kg q12h (not to exceed 1 g/d) OR Doxycycline >8 y and >45 kg, 100 mg q12h >8 y and <45 kg, 2.2 mg/kg q12h <8 y, 2.2 mg/kg q12h	60 d
*Cutaneous anthrax with signs of systemic involvement, extensive edema, or lesions on the head or neck requires IV therapy, and a multidrug regimen is recommended. †Ciprofloxacin or doxycycline should be considered first-line therapy. Amoxicillin, 500 mg po tid for adults or 80 mg/kg/d in divided doses q8h for children, is an option for completion of therapy after clinical improvement. The oral amoxicillin dose is based on the need to achieve appropriate minimum inhibitory concentration levels. Includes pregnant women and immunocompromised patients.
Adapted from Update: Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR Morb Mortal Wkly Rep. 2001;50:909-919. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm. Accessed June 20, 2004.

Gastrointestinal anthrax Rapid initiation of antibiotic therapy has not been shown to have an effect on the case fatality rate in gastrointestinal anthrax.²⁷ Although there is little clinical experience in treating gastrointestinal anthrax, a patient who may have it should receive aggressive treatment utilizing the same standards for inhalational anthrax.²⁸

Postexposure prophylaxis

The decision to initiate postexposure prophylaxis is made by public health officials and is based on the timing, location, and conditions of the exposure.²⁹ The CDC Working Group recommendation for postexposure prophylaxis is the same antibiotic regimen recommended for the treatment of inhalational anthrax, continuing for at least 60 days postexposure.⁴ Doxycycline may be used as an alternative to ciprofloxacin. The B anthracis in the 2001 cases was found to be susceptible to penicillin, and amoxicillin was used in women who were pregnant or breast-feeding.

Conclusion

The heightened awareness of biological and chemical threats has increased the need for provider education in diagnosing and treating the illness and injury caused by these agents. B anthracis, the spore responsible for anthrax infection, is a potentially serious public health risk. Rapid diagnosis and appropriate treatment of suspected anthrax infection made a substantial difference in the patient outcomes during the 2001 outbreak.

 

KEY POINTS in this article Among the four forms of anthrax—inhalational, cutaneous, gastrointestinal, and oropharyngeal—the inhalational form is the deadliest and the cutaneous form is the most common, typically resulting from occupational exposure, such as to infected livestock. A high degree of suspicion is essential to early recognition, swift, appropriate treatment, and timely antibiotic prophylaxis following a suspected exposure to Bacillus anthracis. Blood cultures appear to be sterilized after one or two doses of antibiotics, underscoring the importance of obtaining cultures before beginning antimicrobial therapy.

REFERENCES

1. Centers for Disease Control. Emergency Preparedness and Response. Biological agents/diseases. Available at: http://www.bt.cdc.gov/Agent/agentlist.asp. Accessed June 21, 2004.

2. Mina B, Dym JP, Kuepper F, et al. Fatal inhalational anthrax with unknown source of exposure in a 61-year-old woman in New York City. JAMA. 2002;287:858-862.

3. Inglesby TV, O'Toole T, Henderson DA, et al. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA. 2002;287:2236-2252.

4. Sidell FR, Takafuji ET, Franz DR. The Textbook of Military Medicine: Medical Aspects of Chemical and Biological Warfare. Falls Church, Va: Office of the Surgeon General; 1997.

5. Leger MM, McNellis R, Davis R, et al. Biological and chemical terrorism: are we clinicians ready? [monograph]. Alexandria Va: American Academy of Physician Assistants; October 2001. Available at: http://www.aapa.org/clinissues/BTtext.htm. Accessed June 21, 2004.

6. Plotkin SA, Brachman PS, Utell M, et al. An epidemic of inhalation anthrax, the first in the twentieth century: I. Clinical features. 1960. Am J Med. January 2002;112:4-12.

7. Mwenye KS, Siziya S, Peterson D. Factors associated with human anthrax outbreak in the Chikupo and Ngandu villages of Murewa district in Mashonaland East Province, Zimbabwe. Cent Afr J Med. 1996;42:312-315.

8. Peters CJ, Hartley DM. Anthrax inhalation and lethal human infection. Lancet. 2002;359:710-711.

9. Swartz MN. Recognition and management of anthrax—an update. N Engl J Med. 2001;345:1621-1626.

10. Lanska DJ. Anthrax meningoencephalitis. Neurology. 2002;59:327-334.

11. Roos KL. Medusa's head in bloody CSF. Neurology. 2002;59:300,301.

12. Borio L, Frank D, Mani V, et al. Death due to bioterrorism-related inhalational anthrax: report of 2 patients. JAMA. 2001;286:2554-2559.

13. Jernigan JA, Stephens DS, Ashford DA, et al. Bioterrorism-related inhalational anthrax: the first 10 cases reported in the United States. Emerg Infect Dis. 2001;7:933-944.

14. Barakat LA, Quentzel HL, Jernigan JA, et al. Fatal inhalational anthrax in a 94-year-old Connecticut woman. JAMA. 2002;287:863-868.

15. Freedman A, Afonja O, Chang MW, et al. Cutaneous anthrax associated with microangiopathic hemolytic anemia and coagulopathy in a 7-month-old infant. JAMA. 2002;287:869-874.

16. Mina B, Dym JP, Kuepper F, et al. Fatal inhalational anthrax with unknown source of exposure in a 61-year-old woman in New York City. JAMA. 2002;287:858-862.

17. Pitt ML, Little S, Ivins BE, et al. In vitro correlate of immunity in an animal model of inhalational anthrax. J Appl Microbiol. 1999;87:304.

18. Ivins BE, Fellows PF, Pitt ML, et al. Efficacy of a standard human anthrax vaccine against Bacillus anthracis aerosol spore challenge in rhesus monkeys. Salisbury Med Bull. 1996;87(suppl):125,126.

19. Fellows PF, Linscott MK, Ivins BE, et al. Efficacy of a human anthrax vaccine in guinea pigs, rabbits, and rhesus macaques against challenge by Bacillus anthracis isolates of diverse geographical origin. Vaccine. 2001;19:3241-3247.

20. Friedlander AM, Welkos SL, Pitt ML, et al. Postexposure prophylaxis against experimental inhalation anthrax. J Infect Dis. 1993;167:1239-1243.

21. Pittman PR, Gibbs PH, Cannon TL, Friedlander AM. Anthrax vaccine: short-term safety experience in humans. Vaccine. 2001;20:972-978.

22. Barnes JM. Penicillin and B. anthracis. J Pathol Bacteriol. 1947;194:113-125.

23. Lincoln RE, Klein F, Walker JS, et al. Successful treatment of monkeys for septicemic anthrax. In: Antimicrobial Agents and Chemotherapy—1964. Washington DC: American Society for Microbiology; 1965:759-763.

24. Franz DR, Jahrling PB, Friedlander AM, et al. Clinical recognition and management of patients exposed to biological warfare agents. JAMA. 1997;278:399-411.

25. Kelly DJ, Chulay JD, Mikesell P, Friedlander AM. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis. 1992;166:1184-1187.

26. American Society of Hospital Pharmacists. AHFS drug information. Bethesda, Md: Board of Directors of the American Society of Hospital Pharmacists;1996.

27. Ressel G; Centers for Disease Control and Prevention. CDC issues guidelines on illnesses associated with intentional release of biologic agents. Am Fam Physician. 2001;64:1761,1762,1764.

28. Lew D. Bacillus anthracis (Anthrax). In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. New York, NY: Churchill Livingstone;1995:1885-1889.

29. Perkins WA, Vaughan LM. Public health implications of airborne infection: physical aspects. Bacteriol Rev. 1961;25:347-355.

 

Kevin Lohenry. Anthrax exposure--stay alert, act swiftly. JAAPA August 2004;17:29-33.

Copyright © 2004, Advanstar Medical Economics Healthcare Communications at Montvale, NJ 07645-1742. All rights reserved.

© 2007 Haymarket Media, Inc. and the American Academy of Physician Assistants. All rights reserved.
Use of jaapa.com subject to License agreement. Please read our Disclaimer and Privacy policy.