John G. Bartlett, MD, Infectious Diseases;
John Ticehurst, MD, Microbiology;
John Zenilman, MD, Infectious Diseases;
Luciana Borio, MD, Johns Hopkins Center for Civilian Biodefense Studies;
Patricia Charache, MD, Infectious Diseases and Microbiology;
Ciro Martins, MD, Dermatology
Tom Inglesby, MD, Infectious Diseases and Johns Hopkins Center for Civilian
Biodefense Studies
EPIDEMIOLOGY
Occupation: Postal workers, mail room workers, media personnel,
politicians and their associates, and microbiology lab personnel.
Geography: Exposure to a place with confirmed clinical cases or
locations where B. anthracis contamination is identified.
Exposure to spore-containing powder from an envelope or aerosolized from an envelope. (This applies to 16 of the initial 17 cases.)
CUTANEOUS ANTHRAX
Pathogenesis: Cutaneous contamination from direct contact.
Incubation period: Usually 1 - 7 days, up to 14 days. In the
Sverdlovsk, Russia incident, cutaneous anthrax occurred up to 12 days after
B. anthracis release.
Cutaneous lesion: Painless reddish papule develops on exposed
area. Pruritus and burning may be present, mimicking a mosquito bite. The
initial papule enlarges, becomes edematous and in 1-2 days it progresses to
developing a central pustule or blister (known as "malignant pustule"). The
surrounding tissue becomes more erythematous and a brawny, gelatinous,
non-pitting edema develops. Over the next 3-7 days, the central pustule
becomes hemorrhagic and after rupture, the mixture of blood and necrotic
skin produces a dark, leathery eschar. Satellite vesicles may develop. The
surrounding erythema becomes more pronounced, but the lesion remains
painless. Regional lymphadenopathy may be present but lymphangitis is
usually not seen. When the face is involved, the edema tends to be very
pronounced and the central pustule may be very small or even absent.
Systemic symptoms such as fever, headache and tachycardia may accompany
extensive cutaneous lesions. In most cases, however, general symptoms are
mild and healing occurs in 2-3 weeks.
Differential Diagnosis: Brown recluse spider bite, carbuncle,
bullous erysipelas or cellulitis, cowpox, cat-scratch disease.
Mortality: 20% without treatment, <1% with antibiotics.
INHALATION ANTHRAX
Pathogenesis: Inhalation; estimated criteria are particle size of
<3 microns with an ID 50 inoculum size of 8000 - 40,000 spores based on
extrapolation from monkey and mouse models. Particle size is critical for
aerosolization and also for reaching the alveoli where absorption takes
place. The ID50 has caused confusion because it refers to the inoculum
necessary to infect 50%; it is not the minimum infecting dose, which would
be much lower. The inhaled spores are transported to the mediastinal lymph
nodes when they germinate, disseminate, and produce toxins that cause edema
and cell death with arteritis and hemorrhage.
Incubation period: Usually 1 - 7 days; the cases in Sverdlovsk
occurred at 2 - 43 days post release with a mean of 19.5 days (Mendelson M,
et al. Science 1994;266:1202).
Clinical features: The disease is described as biphasic, but the 2
stages may be a continuum. The prodrome is described as flu-like with
malaise, fever, headache, nonproductive cough, substernal pain, myalgias,
nausea, and abdominal pain. In contrast to flu and other common respiratory
infections there has been on coryza with inhalation anthrax. The second
phase of inhalation anthrax is fulminant consisting of severe dyspnea and
shock; about 50% with advanced disease have meningitis with meningismus and
compromised consciousness. In the 1979 Sverdlovsk epidemic of inhalation
anthrax, the average duration of symptoms prior to admission was 4 days, and
the average survival after hospitalization was 1 day.
Laboratory tests
CBC: WBC may be normal or elevated with a left-shift. In late
disease there is hemoconcentration with hematocrits often >50%.
Chest x-ray/CT scan: A highly characteristic feature is
enlargement of hilar and mediastinal nodes giving the wide mediastinum.
Pleural effusions are often prominent; in the autopsy review of 41 cases
from Sverdlovsk, the average patient had 1700 cc of pleural fluid (Grinberg
LM, et al. Mod Path 2001;14:482). The pleural fluid is often hemorrhagic and
may yield a positive Gram stain, culture, or PCR (PCR reagents are not
commercially available). Parenchymal infiltrates are said to be rare, but
were noted in at least 2 of 10 anthrax cases in the current epidemic and
were frequently seen in the Sverdlovsk autopsy series.
CSF: This is an acute hemorrhagic meningitis with RBCs, PMNs, and
characteristic gram-positive bacilli. The diagnosis of the initial case in
the 2001 epidemic was strongly suspected by Dr. Larry Bush in Florida on the
basis of a CSF Gram stain that was teaming with typical GPB
Pathology: The most severe pathology is in the mediastinal lymph
nodes and mediastinum (Grinberg LM, et al. Mod Path 2001;14:482). Here and
elsewhere there is arterial necrosis with hemorrhage and edema fluid that
displaces tissue. Similar changes with vasculitis, hemorrhagic, and edema
were found in the CNS and intestine.
Mortality: The quoted mortality is 80 - 90%, but these data are
possibly antiquated since they do not reflect the experience of care now
available in intensive care units and current antibiotics. The mortality in
the current epidemic is 4/10 (40%).
CULTURE RECOMMENDATIONS
Specimens: B. anthracis is usually easily cultured with routine
media if specimens are obtained before antibiotic treatment or within 21
hours after antibiotics. Appropriate specimens are blood, swabs of cutaneous
ulcers, vesicular fluid, pleural fluid, and CSF. Sputum may be cultured, but
most patients do not have sputum production nor pneumonia.
Skin lesion: 1) Swab of necrotic ulcer or vesicular fluid for Gram
stain and culture. Yield is notably decreased when antibiotics have been
given >24 hours. 2) Skin punch biopsies should be submitted to the lab in
sterile saline for culture and GS; a second biopsy specimen should be
submitted in formalin for histology and immunohistochemistry.
Blood, CSF, pleural fluid: Routine media
Serology: Frozen acute serum and convalescent serum (14 - 21 days
after acute serum).
Lab: Vegetative B. anthracis can be handled in a BSL-2 lab
(standard clinical lab that practices standard "universal" precautions and
has facilities for minimizing aerosols). B. anthracis spores should be
handled in a BSL-3 facility, which a standard clinical lab may have for
organisms like Mycobacterium tuberculosis.
Gram stain: Gram-positive rod measuring 1 - 1.5 x 3 - 5 u singly
or in chains, often with a bamboo appearance. There are oval, central, or
subterminal spores measuring 1 - 1.5 u without swelling of the bacterium;
these are not usually seen with direct stains of specimens and are best seen
with cultures when nutrients have been depleted (e.g. old culture). Buffy
coat exams are often positive of blood.
Colonies: Growth is detected on blood agar within 6 - 24 hours and
shows colonies that are 2 - 5 mm in diameter, gray-white, flat or slightly
convex with irregular edges. Blood cultures usually are positive in 6 - 24
hours.
Identification: A presumptive diagnosis of B. anthracis is made if
there is a gram-positive, sporulating rod that is non-motile, non-hemolytic,
and encapsulated. Encapsulation is demonstrated with India ink. The
identification is confirmed with DFA, PCR, immunohistochemistry, gamma phage
lysis, and/or gas liquid chromatography. Reagents for PCR, DFA, and
immunohistochemistry are available only through selected labs (level B or
higher per Laboratory Response Network; most clinical labs are level A);
contact state or local health department for referrals.
Risk to microbiologist: Two of the recent cutaneous cases in the
current epidemic involve microbiologists who apparently acquired the disease
by handling contaminated envelopes. There is also a theoretical risk of
inhalation of spores with contaminated material such as envelopes or powder.
Processing specimens likely to have spores should be done in a BSL3
facility.
WHEN TO SUSPECT ANTHRAX
1. Skin lesion or flu-like illness associated with exposure or in a
person with a high-risk occupation (mail handlers ) or geographic risk
(building associations).
2. Skin lesion with the characteristic black eschar, especially if there
is prominent surrounding cellulitis and edema.
3. Any patient with unexplained sepsis, respiration failure, or acute
illness associated with large pleural effusions and/or wide mediastinum.
(Other considerations with these findings include pneumonia due to group A
streptococci and other agents of bioterrorism such as tularemia.)
4. Sepsis with characteristic gram-positive bacilli in blood (buffy
coat), pleural fluid, or CSF.
5. Unexplained death following acute febrile illness.
TREATMENT
In vitro sensitivity tests: Results of testing 11 strains indicate
the same strain has been involved in all cases according to DNA
fingerprinting and in vitro sensitivity test results. The organism is
sensitive in vitro to penicillin (see below), clindamycin, rifampin,
chloramphenicol, imipenem, ciprofloxacin, and doxycycline. It is resistant
to extended spectrum cephalosporins. Nuances of drug selection:
· Betalactamase: The organism produces an inducible betalactamase
that is not susceptible to betalactamase inhibitors. Implication: Penicillin
should not be used as a single agent where there is a high microbial load.
· Doxycycline: Doxycycline is active in vitro, in the animal model
(Franz DR. JAMA 1997;278:399) and has a favorable clinical experience with
cutaneous disease. This drug is considered equivalent to ciprofloxacin with
advantages of low price, large stocks, and few side effects.
· Ciprofloxacin: Ciprofloxacin is active in vitro, effective in
the animal model of inhalation anthrax and FDA approved for this indication.
Other fluoroquinolones (levofloxacin, trovafloxacin, gatifloxacin, and
moxifloxacin) are also active in vitro and would probably be as effective as
ciprofloxacin, but have not been FDA approved for anthrax and have not been
tested in primate model of inhalation anthrax.
· Clindamycin: Clindamycin is active in vitro and has a possible
advantage of stopping protein toxin synthesis according to studies with
Strep pyogenes.
· CNS involvement: A concern is CNS penetration of ciprofloxacin
and to some extent, doxycycline. Some authorities have suggested that
combination therapy with CNS involvement should include penicillin or
chloramphenicol. Other considerations are vancomycin and rifampin. Of the
fluoroquinolones, gatifloxacin and trovafloxacin probably have the best CNS
penetration.
Antibiotics
Cutaneous anthrax (CDC recommendations: MMWR October 26,
2001;50:909)
Regimen
| Adults* | Ciprofloxacin 500 mg po bid or doxycycline 100 mg po bid x 60 days** |
| Children | Ciprofloxacin 10-15 mg/kg q12h (<1 gm/d) or doxycycline in the following dose regimens: 8 yrs & >45 kg: 100 mg po q12h >8 yrs & <45 kg or <8 yrs: 2.2 mg/kg q12hr x 60 days** *** |
* Includes pregnant women and immunosuppressed patients.
** Patients with systemic involvement, extensive edema, or lesions on head
or neck
require IV therapy and combination therapy (see inhalation anthrax).
*** Amoxicillin 500 mg po tid (adults) or 80 mg/kg/d tid (children).
Note: Some authorities have expressed concern about a 60-day
course of ciprofloxacin or doxycycline for pregnant women and children since
both are contraindicated in pediatric patients and pregnancy. The
recommendation is made based on perceived risk/benefit. However, it appears
that an acceptable alternative would be to use amoxicillin (500 mg tid for
adults) for the majority of the 60-day course once the patient has shown
clinical improvement.
Inhalation anthrax (MMWR October 26, 2001;50:909)
| Patient Category | IV Therapy*** | Long-Term Therapy**** |
| Adult* | Doxy 100 mg IV q12h plus 1 or 2 other antibiotics** Cipro 400 mg IV q12h plus 1 or 2 other antibiotics** | Switch to po therapy when clinically appropriate Cipro 500 mg bid or doxy 100 mg bid to complete 60 days |
| Children | Cipro 10-15 mg IV q12hDoxy >8 yrs >45 kg: 100 mg IV q12h 8 yrs <45 kg or <8 yrs: 2.2 mg/kg q12hPlus 1 or 2 other antibiotics** | Switch to oral antibiotic when clinically appropriate Cipro 10-15 mg/kg q12h or doxy (same dose regimen) to complete 60 days |
* Pregnant women and immunocompromised patients should receive the same
therapy.
** Other antibiotics that are active in vitro against the current strain:
ampicillin,
penicillin, clindamycin, clarithromycin, imipenem, vancomycin, rifampin,
chloramphenicol.
*** Consider steroids with severe edema or meningitis.
**** One drug may be used when patient has stabilized.
Note: Once patients have stabilized clinically, the IV treatment
may be switched to oral and monotherapy may be used to complete the 60-day
course.
60-day course: The recommendation for a 60-day course is based
largely on the experience in the primate model of inhalation anthrax:
challenge followed by antibiotics for 30 days was followed by late relapse,
but treatment for 60 days was protective (Friedlander A, et al. JID
1993;167:1239; Inglesby T, et al. JAMA 1999;281:1735). The presumption is
that spores persist in vivo and then convert to the vegetative form with
replication and toxin production once suppressive antibiotic therapy is
discontinued.
Costs of oral therapy: Adults, 60-day course, AWP*
· Ciprofloxacin 500 mg po bid - $540
· Doxycycline 100 mg po bid - $24
* Prices are approximate and will vary by purchasing deals, pharmacy charges,
and
other nuances that none of us understand.
Vaccine: ACIP is currently in the process of revising anthrax vaccine guidelines.
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