Cutaneous Anthrax Management Algorithm
Version 11/14/01 11:30 p.m. EST
- Suspicious Lesions
- The highest suspicion should be given to those lesions where the patient had a known or highly suspected exposure to anthrax. However, as some of the recent cases have demonstrated, no known exposure had occurred when the patients presented for care.
- After an incubation period of approximately 7 days (range = 1 to 12 days), cutaneous anthrax begins as a papule, usually on an exposed area, such as the head, neck, or an upper extremity. The papule may resemble an insect or spider bite and may itch.
- The papule enlarges and develops a central vesicle or bulla with surrounding brawny, non-pitting edema.
- The central vesicle becomes hemorrhagic, depressed, and necrotic, and it may become surrounded by satellite vesicles.
- A central black eschar forms, and the surrounding erythema and edema increase. The necrotic ulcer is usually painless, which is an important differentiating feature from a brown recluse spider bite.
- Pustules are rarely present in anthrax lesions, and a primary pustular lesion is unlikely to be cutaneous anthrax. Primary lesions presenting as cloudy vesicles may occur.
- Lesions progress from papule to vesicle to ulcer to eschar with or without antibiotic therapy as the progression is based on toxin production.
- Lesions may be solitary or multiple, and if multiple, they are usually found on the same part of the body.
- Tender regional lymphadenopathy, fatigue, fever, and/or chills may accompany cutaneous findings (ulceroglandular disease).
- The highest suspicion should be given to those lesions where the patient had a known or highly suspected exposure to anthrax. However, as some of the recent cases have demonstrated, no known exposure had occurred when the patients presented for care.
Differential Diagnosis of Eschar and Ulceration
A common initial diagnosis is that of a pruritic and papular ‘insect bite' by the vast majority of patients.
Anti-phospholipid antibody syndrome ulcers
Leprosy
Aspergillosis
Mucormycosis
Brown recluse spider bite
Orf/Milker's nodule
Coumadin necrosis
Plague
Cutaneous leishmaniasis
Rat bite fever
Cutaneous tuberculosis
Rickettsialpox
Ecthyma gangrenosum
Staphylococcal/Streptococcal ecthyma
Glanders
Tropical ulcer
Heparin necrosis
Tularemia
Typhus, Scrub and Tick
Differential Diagnosis for Ulceroglandular Syndromes
Cat scratch disease
Melioidosis
Chancroid
Plague
Glanders
Staphylococcal/Streptococcal adenitis
Herpes simplex infection
Tuberculosis
Lymphogranuloma venereum
Tularemia
2. Notify your local Department of Health to inform them of the patient with suspected anthrax and to obtain any additional instructions before doing diagnostic tests. (A list of state Department of Health Contacts can be found at www.cdc.gov/phppo by clicking on "State Public Health Locator".)
Notify your local laboratory regarding suspected anthrax and inform them that samples will be sent shortly.
3. Diagnosis: Physicians should maintain universal precautions when evaluating patients with suspected cutaneous anthrax (mask is not required). Although contact with exudate should be avoided (as should contact with any blood or body fluid), physicians evaluating patients with suspected cutaneous anthrax are not considered at risk for contracting pulmonary anthrax, because the disease is acquired through contact with anthrax spores, not active bacteria. The laboratory work-up should include the following.
a. Swab exudates for gram stain and culture. The organism is best demonstrated in the vesicular stage. When vesicles are present, soak two, dry, sterile Dacron or Rayon (not cotton) tipped swabs in vesicular fluid from a previously unopened vesicle. During the eschar stage, gently lift an edge of the eschar and rotate two swabs beneath the edge without removing the eschar. If no vesicle or eschar is present, swab the base of the ulcer with a sterile moist synthetic (Dacron or Rayon) swab. (Lesions usually become sterile within 24-48 hours with antibiotics with efficacy against B. anthracis. Therefore, culture of lesions in patients on antibiotics may not yield bacterial growth.)
b. Obtain a full-thickness (through the entire dermis) 4-mm punch biopsy for permanent sections (formalin-fixed) for histologic evaluation, immunohistochemistry (IHC) studies and PCR. A second sterile punch biopsy specimen can be obtained for gram stain and bacterial culture and fungal and atypical mycobacterial stains and cultures if indicated (bacterial culturette or sterile non-bacteriostatic saline). Dividing a single biopsy specimen is not recommended.
i. If a vesicle is present, biopsy the edge of the vesicle and include adjacent non-vesicular skin.
ii. If an eschar is present, biopsy the erythematous area immediately adjacent to the edge of the eschar. If possible, a second biopsy from the center of the eschar is useful.
iii. If both a vesicle and eschar are present, a biopsy of each lesion is indicated.
iv. Specimens submitted should be accompanied by information such as a brief clinical history, description and chronology of the lesion(s), treatment, and date of biopsy in relation to antibiotic treatment. A photograph, digital image or diagram indicating the site of each biopsy in relation to the lesion, and descriptive details of the lesion would be extremely valuable.
v. The sample for permanent sections should be placed in formalin and shipped at room temperature. After preparing hematoxylin and eosin stained slides,** the fixed tissue block should be saved by the dermatopathology laboratory for potential transfer to the CDC (Centers for Disease Control and Prevention) for histologic evaluation, IHC, and PCR.
vi. The sample for culture should be transported immediately to the microbiology laboratory fresh in a sterile container or in a bacterial culture tube (e.g. a culturette) for immediate processing for Gram stain and bacterial culture, and fungal and atypical mycobacterial stains and cultures if indicated. (One may add sterile non-bacteriostatic saline to the container.)
vii. Note: Because the skin lesions of anthrax are caused by toxins, cutaneous anthrax is not ruled out by a biopsy that demonstrates no Bacillus anthracis organisms.
c. Draw one 5-ml tube of blood into a red-topped or serum separator tube and transfer it to the laboratory for isolation of serum and subsequent storage of serum at -70°C. Label the tube: "Anthrax serology. Store serum at -70°C for special pickup." A similar convalescent sample should also be drawn 3-4 weeks later.
d. Draw one 5-ml tube of blood into a purple-topped tube. This tube should be refrigerated and held for pick-up for potential PCR diagnostic tests by the CDC. Blood-based assays are currently in a state of development by the CDC. During your contact with your local laboratory or Department of Health office, ask them about the up-to-date blood-testing recommendations.
d. Obtain blood cultures for febrile or hospitalized patients.
There is no need to perform nasal swabs unless directed by the public health authorities as part of an epidemiologic investigation.
4. Treatment: If you have a patient that you suspect may have anthrax, start them on the appropriate treatment regimen as listed below, unless the State Department of Health has notified you to do otherwise.
Table 1.
Treatment for cutaneous anthrax patients without systemic symptoms and not located on the head or neck and not with extensive edema5 and not in children younger than two years of age8
Category
Initial Oral Therapy
Duration
Adultsa
Ciprofloxacin 500 mg BID
OR
Doxycycline 100 mg BID
60 daysb
Childrena
Ciprofloxacin 15 mg/kg every 12 hours (not to exceed 1g/day)c
OR
Doxycycline:d
>8 years and >45 kg: 100 mg every 12 hours
All other children: 2.2 mg/kg every 12 hours
60 daysb
Pregnant womena,e
Ciprofloxacin 500 mg BID (preferred)
OR
Doxycycline 100 mg BID
Current recommendations favor ciprofloxacin over doxycycline in pregnant women when susceptibilities are unknown.
60 daysb
Immuno - compromised personsa
Same as for immunocompetent persons and children
60 daysb
a
Cutaneous anthrax with signs of systemic involvement, extensive edema, or lesions on the head or neck require intravenous therapy, and a multidrug approach is recommended (see Table 2)
b
Previous guidelines have suggested treating cutaneous anthrax for 7-14 days, but 60 days is recommended in the setting of this attack, given the likelihood of simultaneous exposure to aerosolized B. anthracis.
c
Ciprofloxacin or doxycycline should be considered first-line therapy. Amoxicillin 500 mg po TID for adults or 80 mg/kg/day divided every 8 hours for children is an option for completion of therapy after clinical improvement. Oral amoxicillin dose is based on the need to achieve appropriate minimum inhibitory concentration levels.
d
The American Academy of Pediatrics recommends treatment of young children with tetracyclines for serious infections (e.g., Rocky Mountain spotted fever)
e
Although tetracyclines or ciprofloxacin are not recommended during pregnancy, their use may be indicated for life-threatening illness. Adverse effects on developing teeth and bones are dose-related; therefore, doxycycline might be used for a short time (7-14 days) before 6 months of gestation.
Table 2.
Treatment of cutaneous anthrax patients with systemic symptoms or extensive edema or involving the head or neck or children younger than two years of age (same as for inhalational anthrax exposure)5
Category
Intravenous Therapyf,g
Duration
Adults
Ciprofloxacin 400 mg every 12 hours
OR
Doxycycline 100 mg every 12 hours
AND One or two additional antimicrobialsg
IV treatment initiallyh. Switch to oral antimicrobial therapy when clinically appropriate (see previous table for oral therapy). Continue for 60 days (IV and po combined)i
Children
Ciprofloxacin 10 mg/kg every 12 hours (not to exceed 1g/day)j
OR
Doxycycline:k
>8 years and >45 kg: 100 mg every 12 hours
All other children: 2.2 mg/kg every 12 hours
AND One or two additional antimicrobialsg
IV treatment initiallyh. Switch to oral antimicrobial therapy when clinically appropriate (see previous table for oral therapy). Continue for 60 days (IV and po combined)i
Pregnant womenm
Same as for non-pregnant adults (the high death rate from the infection outweighs the risk posed by the antimicrobial agent) Current recommendations favor ciprofloxacin over doxycycline in pregnant women when susceptibilities are unknown.
IV treatment initiallyh. Switch to oral antimicrobial therapy when clinically appropriate (see previous table for oral therapy). Continue for 60 days (IV and po combined)i
Immuno - compromised persons
Same as for immunocompetent persons and children
Same as for non-immunocompromised persons and children
f
Steroids may be considered as an adjunct therapy for patients with severe edema and for meningitis based on experience with bacterial meningitis of other etiologies.
g
Other agents with in vitro activity include rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, and clarithromycin. Because of concerns of constitutive and inducible beta-lactamases in Bacillus anthracis, penicillin and ampicillin should not be used alone. Consultation with an infectious disease specialist is advised.
h
Initial therapy may be altered based on clinical course of the patient; one or two antimicrobial agents (e.g., ciprofloxacin or doxycycline) may be adequate as the patient improves
i
Because of the potential persistence of spores after an aerosol exposure, antimicrobial therapy should be continued for 60 days.
jIf intravenous ciprofloxacin is not available, oral ciprofloxacin may be acceptable because it is rapidly and well absorbed from the gastrointestinal tract with no substantial loss by first-pass metabolism. Maximum serum concentrations are attained 1-2 hours after oral dosing but may not be achieved if vomiting or ileus are present.
k
The American Academy of Pediatrics recommends treatment of young children with tetracyclines for serious infections (e.g., Rocky Mountain spotted fever)
m
Although tetracyclines or ciprofloxacin are not recommended during pregnancy, their use may be indicated for life-threatening illness. Adverse effects on developing teeth and bones are dose related; therefore, doxycycline might be used for a short time (7-14 days) before 6 months of gestation.
We wish to thank D.S. Stephens, MD, S.X. Zaki, MD, PhD, T.L. Fisk, MD, D.A. Ashford, DVM, MPH, DSC, P.E. Kozarsky, MD and the clinical team, emergency operations center, anthrax investigation, Centers for Disease Control and Prevention for their valuable suggestions and modifications of this algorithm.
References:
1. Dixon TC, Meselson M, Guillemin J, Hanna PC. Anthrax. N Engl J Med;341:815-826. 1999.
http://content.nejm.org/cgi/content/fall/341/11/815
2. Inglesby TV, Henderson DA, Bartlett JT, et al. Anthrax as a Biological Weapon. J Am Med Assoc;281:1735-1745. 1999.
http://jama.ama-assn.org/issues/v281n18/ffull/jst80027.html
3. McGovern TW, Christopher GW. Cutaneous manifestations of biological warfare agents. Electronic Textbook of Dermatology. 1999.
( http://telemedicine.org/stamford.htm )
4. Update: Investigation of anthrax associated with intentional exposure and interim public health guidelines, October 2001. Morb Mortal Wkly Rep 50(41):889-893. 2001.
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5041a1.htm
5. Update: Investigation of Bioterrorism-Related Anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. Morb Mortal Wkly Rep 50;42:909-919. 2001.
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm
6. Update: Investigation of Bioterrorism-related anthrax and interim guidelines for clinical evaluation of person with possible anthrax. Morb Mortal Wkly Rep 50(43):941-948. 2001.
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5043a1.htm
7. Update: Investigation of Bioterrorism-related anthrax and adverse events from antimicrobial prophylaxis. Morb Mortal Wkly Rep 50(44):973.976. 2001.
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5044a1.htm
8. Notice to readers: Update: Recommendations for post-exposure prophylaxis and treatment of children and lactating women with Bacillus anthracis infections. Morb Mortal Wkly Rep 50(45) in press.
These recommendations are subject to regular revision as updated information becomes available.
*AAD Ad Hoc Task Force on Bioterrorism
This algorithm for cutaneous anthrax is intended to offer physicians the current recommendations treating this disease. It is not intended to establish a legal standard of care. Adherence to these guidelines will not ensure successful treatment in every situation. Furthermore, these guidelines should not be deemed inclusive of all proper methods of care or exclusive of other methods of care reasonably directed to obtaining the same results.
The ultimate judgment regarding the propriety of any specific therapy must be made by the physician and the patient in light of all the circumstances presented by
the individual patient.
**One article (Ross J. J of Pathology and Bacteriology; April; 73(2):485-494. 1957) suggests using the hot carbol fuchsin method (similar to Ziehl-Neelsen method) to help demonstrate viable spores in tissue. You may want to mention this additional stain to your dermatopathology laboratory.
