INFECTIOUS DISEASES UPDATE
ANTHRAX: DIAGNOSIS,
TREATMENT, PREVENTION
Whitney E. Jamie, MD
Anthrax is a zoonotic disease
caused by Bacillus anthracis. Her-
bivores are the natural host. Hu-
mans acquire the disease inciden-
tally by contact with infected
animals or animal products. The
incidence of disease has de-
creased dramatically in devel-
oped countries as a result of ani-
mal vaccination programs and
improved industrial hygiene. Clin-
ical disease in humans presents in
three distinct forms: cutaneous,
gastrointestinal, and inhalational.
More than 90% of naturally occur-
ring cases of anthrax in the United
States are of the cutaneous form.
Eschar formation and edema at
the site of inoculation characterize
cutaneous anthrax. Gastrointesti-
nal anthrax has never been re-
ported in this country. Inhala-
tional anthrax results from
inhalation of B. anthracis endos-
pores. The spores germinate in
mediastinal lymph nodes before
hematogenous dissemination. Dis-
ease progresses rapidly from non-
specific symptoms to death in the
majority of cases. Diagnosis can
be made by Gram stain or by cul-
ture of body fluids or lesions. Se-
rologic tests including enzyme-
linked immunosorbent assay and
polymerase chain reaction are
available in specialized laborato-
ries. Marked widening of the me-
diastinum on chest radiograph is
the most characteristic clinical
finding. Penicillin is the drug of
choice for the treatment of anthrax
infections. Other acceptable alter-
natives include ciprofloxacin and
doxycycline. Supportive care in an
From the Department of Obstetrics and Gynecol-
ogy, University of Florida, Gainesville, Florida.
Volume 9, Number 4, 2002 © 2002 Elsevier Science Inc., all rights reserved. 1068-607X/02/$22.00
intensive care unit is a critical part
of treatment for all but uncompli-
cated cutaneous infections. A vac-
cine is available for anthrax. Per-
sons with high-risk occupations,
such as laboratory workers and
military forces, should receive the
vaccine. In the case of suspected
bioterrorism, ciprofloxacin or
doxycycline should be given as
chemoprophylaxis. The vaccine
should be given concurrently, if
available. (Prim Care Update Ob/
Gyns 2002:9:117–121. © 2002
Elsevier Science Inc. All rights re-
served.)
Anthrax has been an important dis-
ease throughout history. The earli-
est recorded description of anthrax
is in the book of Genesis, in which
the “fifth plague” is reported to have
killed the Egyptians’ cattle.1 Writ-
ings of the ancient Hindus, Greeks,
and Romans, especially Virgil, con-
tain many colorful descriptions of
anthrax. In the 1600s, a pandemic of
anthrax occurred in Europe. The
disease was called the “black bane,”
and the lesions were referred to as
“malignant pustules.” With the in-
dustrialization of Europe in the
1800s, outbreaks of anthrax began to
occur in factories where imported
animal hides and hair were pro-
cessed. Thus, John Bell coined the
name “wool-sorter’s disease.”2
Anthrax also holds a prestigious
place in the history of microbiolog-
ical research. The anthrax bacillus
was used as a model in the 1800s,
when microbiologists were begin-
ning to understand the pathologic
basis of disease. Robert Koch stud-
ied anthrax extensively, which led
● PII S1068-607X(02)00100-2
to his germ theory of disease, as well
as to Koch’s postulates.3 Pasteur
developed the first anthrax vaccine
for sheep from attenuated spores in
1881. Pasteur’s vaccine was used
until 1939, when Sterne developed
the currently recommended animal
vaccine. In the past century, anthrax
has been used in research to delin-
eate the activity of macrophages and
to help understand early events in
the infectious process and the mo-
lecular basis of inflammation.
Anthrax is a zoonotic disease
with a worldwide distribution. Soil
is the reservoir for the anthrax
spores, which can remain dormant
for decades. Herbivores, the natural
hosts, become infected by consum-
ing the soil. Humans are inciden-
tally infected by contact with con-
taminated animals or animal
products. Anthrax can be transmit-
ted from animal to animal or from
animal to human; however, no hu-
man to human transmission has
been documented. Currently, very
few cases of anthrax occur naturally
in developed countries. The inci-
dence of infection has been reduced
dramatically by the vaccination of
high-risk people and animals, along
with improvements in industrial
hygiene. The last naturally occur-
ring case of inhalational anthrax in
the United States was in 1978.4 In
contrast, anthrax spores remain en-
demic in rural regions of the world,
such as Africa and Asia, where vac-
cination programs are difficult to
implement. Important recent epi-
demics occurred in Zimbabwe in
the early 1980s and in Chad in 1988.
Potential for use of anthrax as an
agent of biological warfare has ex-
isted since World War II, when the
117
JAMIE
U.S. and British governments inves-
tigated anthrax along with several
other infectious agents for use as
biologic weapons. This research
was terminated by international
agreement at the end of the Cold
War. In 1979, the accidental release
of anthrax spores from a Soviet of-
fensive biologic weapon facility in
Sverdlovsk led to the largest epi-
demic of inhalational anthrax in
history. Countries that have devel-
oped anthrax as a biological warfare
agent include the United States, Ja-
pan, the United Kingdom, the So-
viet Union, and Iraq. Characteristics
of anthrax that make it a good bio-
logic weapon are low visibility,
high potency, relatively easy deliv-
ery, accessibility, and its ability to
form spores that are resistant to
drying.
Description of
the Microorganism
Bacillus anthracis is the causative
pathogen of anthrax. This large, aer-
obic, Gram-positive rod
(1.0 –1.5 ␮m by 3.0 –10.0 ␮m) is a
member of the B. cereus group of
bacilli. Mucoid colonies are formed
when cultured on standard blood or
nutrient agar. Endospores are seen
in 2- to 3-day-old cultures. Unlike
other bacillus species, B. anthracis
is nonmotile and nonhemolytic on
blood agar, catalase-positive, exhib-
its lysis by gamma-bacteriophage,
and is susceptible to penicillin.3
Other species produce ␤-lactamases
and are penicillin resistant. The or-
ganisms form long chains in vivo
but exist as single organisms or
short chains in vitro. B. anthracis
strains can be separated into five
categories based on variable num-
bers of tandem repeats in the vari-
able region of the vrr A gene. The
category provides a clue as to the
geographic site of origin of a partic-
ular strain.
B. anthracis has two major viru-
lence factors, which are encoded on
118
separate plasmids. Expression of
the virulence factors is regulated by
host-specific factors, including a
temperature of approximately 37°C,
carbon dioxide concentration of
greater than 5%, and the presence of
other serum components. Plasmid
X01 codes for the three proteins,
protective antigen (PA), edema fac-
tor (EF), and lethal factor (LF), that
make up the two exotoxins. PA is
the central component of both tox-
ins. PA binds to target cell recep-
tors, the N-terminal fragment is
cleaved, and a membrane channel is
formed that provides a means for EF
and LF to enter the cell.4
PA and EF together make up
edema toxin, and PA and LF com-
bine to form lethal toxin. EF is a
calmodulin-dependent adenylate
cyclase. Edema toxin functions by
increasing cyclic adenosine mono-
phosphate within the cell, resulting
in a loss of chloride ions and water
from the cell and the subsequent
formation of massive edema in sur-
rounding tissue. Edema toxin has a
secondary role in inhibiting the
phagocytic and oxidative burst ac-
tivity of neutrophils.
LF is a zinc metalloprotease that
inactivates mitogen-activated pro-
tein kinase. This activity interferes
with intracellular signal transduc-
tion. In the low concentrations
present early in the course of dis-
ease, lethal toxin causes increased
expression of tumor necrosis factor
(TNF) and interleukin-1 (IL-1) in-
side macrophages. Later, when high
concentrations are present, lethal
toxin is responsible for the lysis of
macrophages and release of pre-
formed inflammatory mediators.
The lethal toxin– dependent release
of TNF and IL-1 is the major cause
of death in infected animals and
humans. Evidence for this mecha-
nism of death has been demon-
strated in animal studies, which
have shown that mice given anti-
bodies to TNF and IL-1 were pro-
tected against a lethal dose of an-
thrax toxin. Mice depleted of
macrophages were also protected,
further supporting the important
role that macrophages play in the
pathogenesis of anthrax.
Clinical Manifestations
Anthrax occurs in three major clin-
ical forms: cutaneous, gastrointesti-
nal, and inhalational. Cutaneous
anthrax is by far the most common
form, accounting for 95% of natu-
rally occurring cases of anthrax in
the United States.5 Disease usually
results from the occupational expo-
sure of humans to infected animals
or animal products. Any exposed
area of skin may be affected; most
commonly, the arms, hands, head or
neck are affected. The organisms are
inoculated through a break in the
skin. A characteristic clinical pre-
sentation follows. The primary skin
lesion appears as a painless, pruritic
papule 3 to 5 days after exposure.
The papule then enlarges over 1 or
2 days to form an ulcer. The ulcer is
usually 1–3 cm in diameter, with
round, regular borders. Vesicles
may surround the ulcer. Over the
next several days, necrosis and dry-
ing of the ulcer lead to the charac-
teristic black eschar. The lesion is
not purulent unless a super-
infection is present. The eschar sep-
arates in 1–2 weeks and falls off,
leaving a scar in most cases.
The eschar is surrounded by
edema, which may be severe. If the
lesion is on the head or neck, respi-
ratory compromise may occur as a
result of massive edema. Systemic
systems are often present, along
with regional lymphangitis and
lymphadenopathy. Cases of tempo-
ral arteritis and corneal scarring
have been reported. Histologic ex-
amination of skin lesions will reveal
massive edema, necrosis, lympho-
cytic infiltration, focal hemorrhage,
and thrombosis. Liquefaction and
abscess formation will not be
present. The differential diagnosis
of cutaneous anthrax is extensive;
Prim Care Update Ob/Gyns

however, physicians in an endemic
area who are familiar with the dis-
ease usually make the diagnosis
based on clinical presentation.
Death occurs in about 20% of un-
treated cases.
Gastrointestinal (GI) anthrax has
never been reported in the United
States. Most cases occur in devel-
oping countries, where disease re-
sults from the consumption of meat
from sick or dead animals. The two
forms of GI anthrax are abdominal
and oropharyngeal. In abdominal
disease, lesions usually occur in the
cecum. Initial symptoms are non-
specific, often leading to delayed
diagnosis. Patients progressively
develop severe abdominal pain, he-
matemesis, bloody diarrhea, and as-
cites. Death occurs in 2–5 days as a
result of bowel perforation, shock,
and toxemia. The mortality rate of
GI anthrax approaches 100%. Oro-
pharyngeal anthrax is an uncom-
mon variant of GI disease.
Pseudomembranous ulcerations
form in the oral cavity, resulting in
dysphagia, cervical edema, and
lymphadenopathy. This form often
has a more favorable prognosis;
however, some patients die from
respiratory distress or sepsis.
Inhalational anthrax is a deadly
form of anthrax caused by the inha-
lation of pathogenic endospores.
The minimal infectious dose has
not been established, but the U.S.
Department of Defense estimates
that the lethal dose for humans is
approximately 8,000 –10,000
spores.6 Once inside the lungs,
spores are engulfed by alveolar mac-
rophages and transported to medi-
astinal and peribronchial lymph
nodes. Spores germinate into vege-
tative bacilli within the lymph
nodes. The rapid multiplication of
bacilli results in hemorrhagic medi-
astinitis, followed by hematoge-
nous spread throughout the body.
The incubation period varies from 2
days to 6 weeks, with the time
depending on the size of the inoc-
Volume 9, Number 4, 2002
ANTHRAX: DIAGNOSIS, TREATMENT, PREVENTION
ulum and the immune status of the
host.
Clinical disease follows a charac-
teristic biphasic pattern. Initial
symptoms resemble a simple upper
respiratory infection. Over the first
1–3 days, the patient develops mal-
aise, fatigue, myalgias, nonproduc-
tive cough, precordial pressure, and
fever. There then may be a transient
improvement in symptomatology
before the second phase of illness,
because of release of TNF and IL-1
from macrophages, causes a rapidly
deteriorating clinical picture. The
second phase of disease is compli-
cated by acute dyspnea, stridor, and
hypoxemia as a direct result of tra-
cheal compression by enlarged
lymph nodes. Patients often exhibit
cyanosis, diaphoresis, and fever or
hypothermia because of sepsis. In
the late stages, mediastinal hemor-
rhage, septic shock, and coma de-
velop. Other common symptoms in-
clude acute abdominal pain,
delirium, meningismus, hemateme-
sis, and melena.
Physical examination of a patient
with inhalational anthrax is most
remarkable for moist, crepitant
crackles in the lungs. Chest x-ray is
characteristic, with pleural effu-
sions and marked widening of the
mediastinum. The lung paren-
chyma is usually normal in appear-
ance, but pneumonia may be
present. If pneumonia is present, a
focal, hemorrhagic, necrotizing le-
sion resembling the Ghon’s com-
plex of primary tuberculosis will be
seen. Thoracentesis typically re-
veals grossly bloody fluid. Once a
patient reaches the second phase of
disease, death usually occurs from
septic shock in 1–2 days, even with
antibiotic therapy. However, slower
courses may occasionally be ob-
served. Individual variation in sus-
ceptibility to disease has been ob-
served, both in primate studies and
in investigations of the Sverdlovsk
epidemic, in which the 66 deaths all
occurred in individuals older than
24 years of age.7
Table 1. Differential Diagnosis of
Inhalational Anthrax
Bacterial meningitis
Mycoplasmal pneumonia
Legionnaire’s disease
Psittacosis
Tularemia
Q fever
Viral pneumonia
Histoplasmosis
Coccidiomycosis
Ruptured aortic aneurysm
Superior vena cava syndrome
Silicosis
Sarcoidosis
Anthrax meningitis is a rare com-
plication of any of the other three
forms of disease. Meningeal infec-
tion results from hematogenous or
lymphatic spread of bacilli to the
central nervous system. Symptoms
include nuchal rigidity, fever, head-
aches, seizures, agitation, and de-
lirium. Pathologic findings are
hemorrhagic meningitis, bloody ce-
rebrospinal fluid (CSF) containing
inflammatory infiltrates and large
numbers of bacilli, and dark red
meninges at autopsy that have been
called the “cardinal’s cap.” Infec-
tion is almost always fatal within
1– 6 days, even with antibiotic ther-
apy. There were a few survivors
during the Sverdlovsk epidemic;
these patients were treated with an-
tibiotics, steroids, and antitoxin.
Diagnosis
Accurate, timely diagnosis of an-
thrax is essential, and the differen-
tial diagnosis is extensive (Table 1).
A high index of suspicion is neces-
sary in cases in which patients
present with nonspecific symp-
toms. A direct Gram stain of any
tissue or fluid will reveal large num-
bers of the characteristic bacilli.
Any suspicious Gram stain result
should be reported immediately to
the Centers for Disease Control and
Prevention for further investigation.
B. anthracis can be cultured on
sheep’s blood agar from blood, as-
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JAMIE
citic fluid, cerebrospinal fluid, pleu-
ral effusions, or skin lesions. Blood
cultures are almost always positive,
in contrast to culture of skin lesions,
which will be positive in only 60 –
65% of cases. Nasal swab cultures
are investigational. Results can be
used to document exposure to an-
thrax spores but cannot accurately
predict the risk of subsequent ill-
ness. Antibiotic susceptibility test-
ing should be done on all isolates,
especially if biologic warfare or ter-
rorism is a possibility, because
strains can be mutated to be resis-
tant to some antibiotics.
Serologic diagnosis is possible,
but most useful retrospectively, be-
cause acute and convalescent sam-
ples are needed. An enzyme-linked
immunosorbent assay (ELISA) is
available. Quadrupling of antibody
titers directed towards capsular an-
tigens indicates past infection or
vaccination. Sensitivity is highest
for antibodies to protective antigen.
Use of enzyme-linked immunoelec-
trotransfer blotting increases the
specificity of ELISA. An indirect
microhemagglutination test specific
for protective antigen also is avail-
able through state health depart-
ment laboratories.
The anthraxin skin test, per-
formed by subdermal injection of an
attenuated strain, can diagnose
acute as well as prior infections.
The skin test will be positive in 82%
of cases 1–3 days after the onset of
symptoms and in 99% of cases at
the end of 4 weeks. The newest
diagnostic modality, which is be-
coming the preferred method, is a
polymerase chain reaction (PCR).
PCR can amplify specific markers of
B. anthracis or of the B. cereus
group and specific virulence plas-
mid markers carried by different
strains.
Treatment
Antibiotics are the most important
aspect of therapy against anthrax
120
infection. B. anthracis is suscepti-
ble to penicillin, ampicillin, eryth-
romycin, doxycycline, chloram-
phenicol, streptomycin, first-
generation cephalosporins,
vancomycin, fluoroquinolones, and
clindamycin. The organism is resis-
tant to third-generation cephalospo-
rins and trimethoprim–sulfame-
thoxazole.
Patients who have uncompli-
cated cutaneous anthrax can be
treated as outpatients with oral an-
tibiotics. The recommended regi-
men is Penicillin V (200 –500 mg
orally, four times a day) for 7 days.
For cutaneous anthrax with sys-
temic symptoms, and all other
forms of disease, antibiotics should
be administered intravenously (IV)
in an intensive care setting. The
drug of choice is still penicillin,
given as Penicillin G (4 million
units IV every 4 – 6 hours). Strepto-
mycin may have a synergistic effect
with penicillin and may be given
concurrently. Other acceptable reg-
imens, in the case of hypersensitiv-
ity or antibiotic resistance, are:
doxycycline (200 mg IV followed by
100 mg IV every 12 hours) or cipro-
floxacin (400 mg IV every 12 hours).
Treatment should be continued for
14 days after symptoms have re-
solved.
In cases of cutaneous anthrax,
excision of the eschar is contraindi-
cated because of the increase in risk
of hematogenous dissemination.
Topical therapy is not effective. Cor-
ticosteroids have been used, but
indications are not well established.
Antitoxin is not currently available.
Supportive therapy is important to
prevent septic shock, maintain fluid
and electrolyte balance, and ensure
patency of the airway.
Prevention
Antibiotic chemoprophylaxis is
recommended in cases of suspected
exposure to B. anthracis due to
biologic warfare or terrorism. Cip-
rofloxacin was the first antibiotic to
be labeled by the U.S. Food and
Drug Administration for use after
anthrax exposure due to bioterror-
ism. The recommended dosage of
ciprofloxacin is 500 mg orally, twice
a day. An acceptable alternative is
doxycycline, 100 mg orally twice a
day. Treatment should be contin-
ued for 60 days or until 2 weeks after
the third dose of vaccine, if the
vaccine is available. The CDC rec-
ommends ciprofloxacin for postex-
posure prophylaxis in children and
pregnant women until antibiotic
susceptibility is determined. The
benefits far outweigh the potential
risks in this scenario.
An anthrax vaccine is available.
The currently used vaccine is pro-
duced from protective antigen from
an attenuated, nonencapsulated
strain of B. anthracis that is alum
precipitated to form the vaccine.
Individuals at high risk of occupa-
tional exposure, such as laboratory
workers and veterinarians in areas
with a high incidence of anthrax,
should receive the vaccine.8 In
1998, the Pentagon decided to vac-
cinate all military forces in response
to the threat of biologic warfare.
Additional groups that may be con-
sidered for vaccination in the future
are emergency first responders, fed-
eral responders, medical providers,
and possibly civilians. Vaccination
is given at 0, 2, and 4 weeks; then at
6, 12, and 18 months, followed by
yearly boosters. Few studies have
been done to evaluate the efficacy of
the vaccine. One study by Brach-
man et al.9 in 1962 tested the vac-
cine in workers in tanneries in the
northeastern United States. The re-
sults are difficult to interpret be-
cause instances of cutaneous and
inhalational anthrax were not re-
ported separately, and the study did
not have enough power to assess
protection against inhalational an-
thrax. Adverse reactions to the vac-
cine are relatively rare and usually
mild. Current labeling for the vac-
Prim Care Update Ob/Gyns

cine describes the incidence of mild
and moderate local reactions to be
30% and 4%, respectively.
No studies have been published
regarding use of anthrax vaccine in
pregnant women. The vaccine
should be administered only if the
potential benefits outweigh the po-
tential risks. There also are no data
suggesting adverse effects of vacci-
nation while breastfeeding. Admin-
istration of vaccines not containing
the live virus, such as the anthrax
vaccine, is not medically contrain-
dicated during breastfeeding.
The ability of vaccination to pro-
tect humans in the event of biologic
warfare is unknown. Postexposure
vaccination is recommended at 0, 2,
and 4 weeks.10 Antibiotics should
be given concurrently. Most of the
studies supporting this recommen-
dation have been done in animals.
One study evaluating vaccination
with two doses versus placebo in
rhesus monkeys found 100% pro-
tection in the vaccinated group
compared with 100% mortality in
the placebo group. The Cochrane
database review found that in hu-
mans, compared with placebo, vac-
cination was associated with a re-
Volume 9, Number 4, 2002
ANTHRAX: DIAGNOSIS, TREATMENT, PREVENTION
duced risk of contracting anthrax
(relative risk, 0.16).
New vaccines are currently being
studied. Live vaccines based on an-
thrax strains with auxotrophic mu-
tations may become available. An-
other promising preparation
contains protective antigen from re-
combinant sources, combined with
adjuvants from the cell wall of the
BCG strain of the tubercle bacillus,
to increase the cellular response. In
addition to new vaccines, specific
inhibitory drugs directed toward
the zinc metalloprotease of lethal
factor are under development and
may be available in the near future.
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3. Brock T, Madigan M. Biology of
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9. Brachman PS, Gold H, Plotkin SA,
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Address correspondence and reprint re-
quests to Whitney E. Jamie, MD, Uni-
versity of Florida, Department of Obstet-
rics and Gynecology, Box 100294,
Gainesville, FL 32610.
121