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Anthrax as a Biological Weapon, 2002Updated Recommendations for Management


Abstract and Figures

To review and update consensus-based recommendations for medical and public health professionals following a Bacillus anthracis attack against a civilian population. The working group included 23 experts from academic medical centers, research organizations, and governmental, military, public health, and emergency management institutions and agencies. MEDLINE databases were searched from January 1966 to January 2002, using the Medical Subject Headings anthrax, Bacillus anthracis, biological weapon, biological terrorism, biological warfare, and biowarfare. Reference review identified work published before 1966. Participants identified unpublished sources. The first draft synthesized the gathered information. Written comments were incorporated into subsequent drafts. The final statement incorporated all relevant evidence from the search along with consensus recommendations. Specific recommendations include diagnosis of anthrax infection, indications for vaccination, therapy, postexposure prophylaxis, decontamination of the environment, and suggested research. This revised consensus statement presents new information based on the analysis of the anthrax attacks of 2001, including developments in the investigation of the anthrax attacks of 2001; important symptoms, signs, and laboratory studies; new diagnostic clues that may help future recognition of this disease; current anthrax vaccine information; updated antibiotic therapeutic considerations; and judgments about environmental surveillance and decontamination.
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Anthrax as a Biological Weapon, 2002
Updated Recommendations for Management
Thomas V. Inglesby, MD
Tara O’Toole, MD, MPH
Donald A. Henderson, MD, MPH
John G. Bartlett, MD
Michael S. Ascher, MD
Edward Eitzen, MD, MPH
Arthur M. Friedlander, MD
Julie Gerberding, MD, MPH
Jerome Hauer, MPH
James Hughes, MD
Joseph McDade, PhD
Michael T. Osterholm, PhD, MPH
Gerald Parker, PhD, DVM
Trish M. Perl, MD, MSc
Philip K. Russell, MD
Kevin Tonat, DrPH, MPH
for the Working Group on Civilian
that may be used as weap-
ons, the Working Group
on Civilian Biodefense
identified a limited number of organ-
isms that, in worst case scenarios, could
cause disease and deaths in sufficient
numbers to gravely impact a city or re-
gion. Bacillus anthracis, the bacterium
that causes anthrax, is one of the most
serious of these.
Several countries are believed to have
offensive biological weapons pro-
grams, and some independent terrorist
groups have suggested their intent to use
biological weapons. Because the possi-
bility of a terrorist attack using bioweap-
ons is especially difficult to predict, de-
tect, or prevent, it is among the most
feared terrorism scenarios.1In Septem-
ber 2001, B anthracis spores were sent
to several locations via the US Postal Ser-
vice. Twenty-two confirmed or suspect
cases of anthrax infection resulted.
Eleven of these were inhalational cases,
of whom 5 died; 11 were cutaneous cases
(7 confirmed, 4 suspected).2In this ar-
ticle, these attacks are termed the an-
thrax attacks of 2001. The conse-
quences of these attacks substantiated
many findings and recommendations in
the Working Group on Civilian Biode-
fense’s previous consensus statement
published in 19993; however, the new
information from these attacks war-
rant updating the previous statement.
Before the anthrax attacks in 2001,
modern experience with inhalational
anthrax was limited to an epidemic in
Sverdlovsk, Russia, in 1979 following
an unintentional release of B anthracis
spores from a Soviet bioweapons fac-
tory and to 18 occupational exposure
cases in the United States during the
20th century. Information about the po-
tential impact of a large, covert attack
using B anthracis or the possible effi-
Author Affiliations: The Center for Civilian Biode-
fense Strategies (Drs Inglesby, O’Toole, Henderson,
Bartlett, and Perl) and the Schools of Medicine (Drs
Inglesby, Bartlett, and Perl) and Public Health (Drs
O’Toole and Henderson), Johns Hopkins University,
Department of Health and Human Services (Drs Ascher,
and Russell and Mr Hauer), Baltimore, and US Army
Medical Research Institute of Infectious Diseases, (Drs
Eitzen, Friedlander, and Parker), Frederick, Md; Cen-
ters for Disease Control and Prevention, Atlanta, Ga
(Drs Hughes, McDade, and Gerberding); Center for
Infectious Disease Research and Policy, University of
Minnesota School of Public Health, Minneapolis (Dr
Osterholm); and the Office of Emergency Prepared-
ness, Department of Health and Human Services, Rock-
ville, Md (Dr Tonat).
Corresponding Author and Reprints: Thomas V.
Inglesby, MD, Johns Hopkins Center for Civilian Bio-
defense Strategies, Johns Hopkins University, Can-
dler Bldg, Suite 830, 111 Market Pl, Baltimore, MD
21202 (e-mail:
Objective To review and update consensus-based recommendations for medical
and public health professionals following a Bacillus anthracis attack against a civilian
Participants The working group included 23 experts from academic medical cen-
ters, research organizations, and governmental, military, public health, and emer-
gency management institutions and agencies.
Evidence MEDLINE databases were searched from January 1966 to January 2002,
using the Medical Subject Headings anthrax,Bacillus anthracis, biological weapon,
biological terrorism,biological warfare, and biowarfare. Reference review identified
work published before 1966. Participants identified unpublished sources.
Consensus Process The first draft synthesized the gathered information. Written
comments were incorporated into subsequent drafts. The final statement incorpo-
rated all relevant evidence from the search along with consensus recommendations.
Conclusions Specific recommendations include diagnosis of anthrax infection, in-
dications for vaccination, therapy, postexposure prophylaxis, decontamination of the
environment, and suggested research. This revised consensus statement presents new
information based on the analysis of the anthrax attacks of 2001, including develop-
ments in the investigation of the anthrax attacks of 2001; important symptoms, signs,
and laboratory studies; new diagnostic clues that may help future recognition of this
disease; current anthrax vaccine information; updated antibiotic therapeutic consid-
erations; and judgments about environmental surveillance and decontamination.
JAMA. 2002;287:2236-2252
2236 JAMA, May 1, 2002—Vol 287, No. 17 (Reprinted) ©2002 American Medical Association. All rights reserved.
cacy of postattack vaccination or thera-
peutic measures remains limited. Poli-
cies and strategies continue to rely
partially on interpretation and extrapo-
lation from an incomplete and evolv-
ing knowledge base.
The working group comprised 23 rep-
resentatives from academic medical cen-
ters; research organizations; and gov-
ernment, military, public health, and
emergency management institutions and
agencies. For the original consensus
statement,3we searched MEDLINE da-
tabases from January 1966 to April 1998
using Medical Subject Headings of an-
thrax,Bacillus anthracis, biological
weapon,biological terrorism,biological
warfare, and biowarfare. Reference re-
view identified work published before
1966. Working group members identi-
fied unpublished sources.
The first consensus statement, pub-
lished in 1999,3followed a synthesis of
the information and revision of 3 drafts.
We reviewed anthrax literature again
in January 2002, with special atten-
tion to articles following the anthrax at-
tacks of 2001. Members commented on
a revised document; proposed revi-
sions were incorporated with the work-
ing groups support for the final con-
sensus document.
The assessment and recommenda-
tions provided herein represent our best
professional judgment based on cur-
rent data and expertise. The conclu-
sions and recommendations need to be
regularly reassessed as new informa-
tion develops.
For centuries, B anthracis has caused
disease in animals and serious illness
in humans.4Research on anthrax as a
biological weapon began more than 80
years ago.5Most national offensive
bioweapons programs were termi-
nated following widespread ratifica-
tion or signing of the Biological Weap-
ons Convention (BWC) in the early
1970s6; the US offensive bioweapons
program was terminated after Presi-
dent Nixons 1969 and 1970 executive
orders. However, some nations contin-
ued offensive bioweapons develop-
ment programs despite ratification of
the BWC. In 1995, Iraq acknowledged
producing and weaponizing B anthra-
cis to the United Nations Special Com-
mission.7The former Soviet Union is
also known to have had a large B
anthracis production program as part
of its offensive bioweapons program.8
A recent analysis reports that there is
clear evidence of or widespread asser-
tions from nongovernmental sources
alleging the existence of offensive bio-
logical weapons programs in at least
13 countries.6
The anthrax attacks of 2001 have
heightened concern about the feasibil-
ity of large-scale aerosol bioweapons at-
tacks by terrorist groups. It has been
feared that independent, well-funded
groups could obtain a manufactured
weapons product or acquire the exper-
tise and resources to produce the mate-
rials for an attack. However, some ana-
lysts have questioned whether weapons
gradematerial such as that used in the
2001 attacks (ie, powders of B anthracis
with characteristics such as high spore
concentration, uniform particle size, low
electrostatic charge, treated to reduce
clumping) could be produced by those
not supported by the resources of a na-
tion-state. The US Department of De-
fense recently reported that 3 defense em-
ployees with some technical skills but
without expert knowledge of bioweap-
ons manufactured a simulant of B an-
thracis in less than a month for $1 mil-
lion.9It is reported that Aum Shinrikyo,
the cult responsible for the 1995 re-
lease of sarin nerve gas in a Tokyo sub-
way station,10 dispersed aerosols of an-
thrax and botulism throughout Tokyo at
least 8 times.11 Forensic analysis of the
B anthracis strain used in these attacks
revealed that this isolate most closely
matched the Sterne 34F2 strain, which
is used for animal vaccination pro-
grams and is not a significant risk to hu-
mans.12 It is probable that the cult at-
tacks produced no illnesses for this and
other technical reasons. Al Quaeda also
has sought to acquire bioweapons in its
terrorist planning efforts although the ex-
tent to which they have been successful
is not reported.13
In the anthrax attacks of 2001, B an-
thracis spores were sent in at least 5 let-
ters to Florida, New York City, and
Washington, DC. Twenty-two con-
firmed or suspected cases resulted. All
of the identified letters were mailed
from Trenton, NJ. The B anthracis
spores in all the letters were identified
as the Ames strain. The specific source
(provenance) of B anthracis cultures
used to create the spore-containing
powder remains unknown at time of
this publication.
It is now recognized that the origi-
nal Ames strain of B anthracis did not
come from a laboratory in Ames, Iowa,
rather from a laboratory in College Sta-
tion, Tex. Several distinct Ames strains
have been recognized by investigating
scientists, which are being compared
with the Ames strain used in the at-
tack. At least 1 of these comparison
Ames strains was recovered from a goat
that died in Texas in 1997.14
Sen Daschles letter reportedly had 2
gofB anthracis containing powder; the
quantity in the other envelopes has not
been disclosed. The powder has been
reported to contain between 100 bil-
lion to 1 trillion spores per gram15 al-
though no official analysis of the con-
centration of spores or the chemical
composition of the powder has been
The anthrax attacks of 2001 used 1
of many possible methods of attack. The
use of aerosol-delivery technologies in-
side buildings or over large outdoor ar-
eas is another method of attack that has
been studied. In 1970, the World Health
Organization16 and in 1993 the Office of
Technology Assessment17 analyzed the
potential scope of larger attacks. The
1979 Sverdlovsk accident provides data
on the only known aerosol release of B
anthracis spores resulting in an epi-
An aerosol release of B anthracis
would be odorless and invisible and
would have the potential to travel many
kilometers before dissipating.16,19 Aero-
sol technologies for large-scale dissemi-
nation have been developed and tested
©2002 American Medical Association. All rights reserved. (Reprinted) JAMA, May 1, 2002Vol 287, No. 17 2237
by Iraq7and the former Soviet Union8
Few details of those tests are avail-
able. The US military also conducted
such trials over the Pacific Ocean in the
1960s. A US study near Johnston Atoll
in the South Pacific reported a plane
sprayed a 32-mile long line of agent
that traveled for more then 60 miles be-
fore it lost its infectiousness.20
In 1970, the World Health Organi-
zation estimated that 50 kg of B anthra-
cis released over an urban population
of 5 million would sicken 250000 and
kill 100000.16 A US Congressional Of-
fice of Technology assessment analy-
sis from 1993 estimated that between
130000 and 3 million deaths would fol-
low the release of 100 kg of B anthra-
cis, a lethality matching that of a hy-
drogen bomb.17
Naturally occurring anthrax in hu-
mans is a disease acquired from con-
tact with anthrax-infected animals or
anthrax-contaminated animal prod-
ucts. The disease most commonly oc-
curs in herbivores, which are infected
after ingesting spores from the soil.
Large anthrax epizootics in herbi-
vores have been reported.21 A pub-
lished report states that anthrax killed
1 million sheep in Iran in 194522; this
number is supported by an unpub-
lished Iranian governmental docu-
ment.23 Animal vaccination programs
have reduced drastically the animal
mortality from the disease.24 How-
ever, B anthracis spores remain preva-
lent in soil samples throughout the
world and cause anthrax cases among
herbivores annually.22,25,26
Anthrax infection occurs in hu-
mans by 3 major routes: inhalational,
cutaneous, and gastrointestinal. Natu-
rally occurring inhalational anthrax is
now rare. Eighteen cases of inhala-
tional anthrax were reported in the
United States from 1900 to 1976; none
were identified or reported thereafter.
Most of these cases occurred in special-
risk groups, including goat hair mill or
wool or tannery workers; 2 of them
were laboratory associated.27
Cutaneous anthrax is the most com-
mon naturally occurring form, with an
estimated 2000 cases reported annually
worldwide.26 The disease typically fol-
lows exposure to anthrax-infected ani-
mals. In the United States, 224 cases of
cutaneous anthrax were reported be-
tween 1944 and 1994.28 One case was re-
ported in 2000.29 The largest reported
epidemic occurred in Zimbabwe be-
tween 1979 and 1985, when more than
10000 human cases of anthrax were re-
ported, nearly all of them cutaneous.30
Although gastrointestinal anthrax is
uncommon, outbreaks are continu-
ally reported in Africa and Asia26,31,32 fol-
lowing ingestion of insufficiently
cooked contaminated meat. Two dis-
tinct syndromes are oral-pharyngeal
and abdominal.31,33,34Little informa-
tion is available about the risks of di-
rect contamination of food or water
with B anthracis spores. Experimental
efforts to infect primates by direct gas-
trointestinal instillation of B anthracis
spores have not been successful.35 Gas-
trointestinal infection could occur only
after consumption of large numbers of
vegetative cells, such as what might be
found in raw or undercooked meat from
an infected herbivore, but experimen-
tal data is lacking.
Inhalational anthrax is expected to
account for most serious morbidity and
most mortality following the use of B
anthracis as an aerosolized biological
weapon. Given the absence of natu-
rally occurring cases of inhalational an-
thrax in the United States since 1976,
the occurrence of a single case is now
cause for alarm.
B anthracis derives from the Greek word
for coal, anthrakis, because of the black
skin lesions it causes. B anthracisisan
aerobic, gram-positive, spore-forming,
nonmotile Bacillus species. The non-
flagellated vegetative cell is large (1-8 µm
long, 1-1.5 µm wide). Spore size is ap-
proximately 1 µm. Spores grow readily
on all ordinary laboratory media at 37°C,
with a jointed bamboo-rodcellular ap-
pearance (FIGURE 1) and a unique
curled-haircolonial appearance. Ex-
perienced microbiologists should be able
to identify this cellular and colonial mor-
phology; however, few practicing mi-
crobiologists outside the veterinary com-
munity have seen B anthracis colonies
beyond what they may have seen in pub-
lished material.37 B anthracis spores ger-
minate when they enter an environ-
ment rich in amino acids, nucleosides,
and glucose, such as that found in the
blood or tissues of an animal or human
host. The rapidly multiplying vegeta-
tive B anthracis bacilli, on the contrary,
will only form spores after local nutri-
ents are exhausted, such as when an-
thrax-infected body fluids are exposed
to ambient air.22 Vegetative bacteria have
poor survival outside of an animal or hu-
man host; colony counts decline to being
undetectable within 24 hours following
inoculation into water.22 This contrasts
with the environmentally hardy proper-
ties of the B anthracis spore, which can
survive for decades in ambient condi-
Inhalational Anthrax
Inhalational anthrax follows deposi-
tion into alveolar spaces of spore-
bearing particles in the 1- to 5-µm
range.38,39 Macrophages then ingest the
spores, some of which are lysed and de-
stroyed. Surviving spores are trans-
ported via lymphatics to mediastinal
lymph nodes, where germination oc-
Figure 1. Gram Stain of Blood in Culture
Gram-positive bacilli in long chains (original
magnification20). Enlargement shows typical
jointed bamboo-rodappearance of Bacillus an-
thracis (original magnification100). Reprinted from
Borio et al.36
2238 JAMA, May 1, 2002Vol 287, No. 17 (Reprinted) ©2002 American Medical Association. All rights reserved.
curs after a period of spore dormancy of
variable and possibly extended dura-
tion.35,40,41 The trigger(s) responsible for
the transformation of B anthracis spores
to vegetative cells is not fully under-
stood.42 In Sverdlovsk, cases occurred
from 2 to 43 days after exposure.18 In ex-
perimental infection of monkeys, fatal
disease occurred up to 58 days40 and 98
days43 after exposure. Viable spores were
demonstrated in the mediastinal lymph
nodes of 1 monkey 100 days after ex-
Once germination occurs, clinical
symptoms follow rapidly. Replicating
B anthracis bacilli release toxins that
lead to hemorrhage, edema, and necro-
sis.32,45 In experimental animals, once
toxin production has reached a criti-
cal threshold, death occurs even if ste-
rility of the bloodstream is achieved
with antibiotics.27 Extrapolations from
animal data suggest that the human
LD50 (ie, dose sufficient to kill 50% of
persons exposed to it) is 2500 to 55000
inhaled B anthracis spores.46 The LD10
was as low as 100 spores in 1 series of
monkeys.43 Recently published extrapo-
lations from primate data suggest that
as few as 1 to 3 spores may be suffi-
cient to cause infection.47 The dose of
spores that caused infection in any of
the 11 patients with inhalational an-
thrax in 2001 could not be estimated
although the 2 cases of fatal inhala-
tional anthrax in New York City and
Connecticut provoked speculation that
the fatal dose, at least in some indi-
viduals, may be quite low.
A number of factors contribute to the
pathogenesis of B anthracis, which
makes 3 toxinsprotective antigen,le-
thal factor, and edema factorthat com-
bine to form 2 toxins: lethal toxin and
edema toxin (FIGURE 2). The protec-
tive antigen allows the binding of le-
thal and edema factors to the affected
cell membrane and facilitates their sub-
sequent transport across the cell mem-
brane. Edema toxin impairs neutro-
phil function in vivo and affects water
homeostasis leading to edema, and le-
thal toxin causes release of tumor ne-
crosis factor and interleukin 1 , fac-
tors that are believed to be linked to the
sudden death in severe anthrax infec-
tion.48 The molecular target of lethal and
edema factors within the affected cell
is not yet elucidated.49 In addition to
these virulence factors, B anthracis has
a capsule that prevents phagocytosis.
Full virulence requires the presence of
both an antiphagocytic capsule and the
Figure 2. Pathogenesis of Bacillus anthracis
Entry of Toxin Components Into Cell
Spore Germinates
Bacillus Proliferates
Protective Antigen Attaches to ATR
Protease Cleaves PA
PA-ATR Complexes
Form Heptamer
LF and/or EF
Bind to Heptamer
Anthrax Toxin
Receptor (ATR)
Cleavage of MAPKKs and
Possibly Other Target Proteins
Possible Pathogenic Mechanisms of B anthracis
Dysregulation of Signal Transduction Pathways
Inhibition of Immune Function
Inhibition of Phagocytosis (LF, EF, Capsule)
Cytolysis (LF)
Increase in cAMP and Alterations
in Local Water Homeostasis (EF)
Possible Inhibition of Induced Release of
Proinflammatory Mediators (LF, EF)
Inhibition of MAPK and Possibly Other Pathways (LF)
Activation of Oxidative Burst Pathway (LF)
Possible Inhibition (EF) and/or
Possible Activation (LF) of Transcription Factors
Release of Cellular Contents,
Including Proinflammatory Mediators
(eg, Tumor Necrosis Factor α,
Interleukin 1β, Reactive Oxygen
Intermediates) and Lysosomal Enzymes
Toxin Components
B anthracis
Virulence Factors
Protective Antigen (PA)
Edema Factor (EF)
Lethal Factor (LF)
The major known virulence factors of B anthracis include the exotoxins edema toxin (PA and EF) and lethal
toxin (PA and LF) and the antiphagocytic capsule. Although many exact molecular mechanisms involved in
the pathogenicity of the anthrax toxins are uncertain, they appear to inhibit immune function, interrupt in-
tracellular signaling pathways, and lyse cell targets causing massive release of proinflammatory mediators. ATP
indicates adenosine triphosphate; cAMP, cyclic adenosine monophosphate; MAPKK, mitogen-activated pro-
tein kinase kinase; and MAPK, mitogen-activated protein kinase.
©2002 American Medical Association. All rights reserved. (Reprinted) JAMA, May 1, 2002Vol 287, No. 17 2239
3 toxin components.37 An additional
factor contributing to B anthracis patho-
genesis is the high concentration of bac-
teria occurring in affected hosts.49
Inhalational anthrax reflects the na-
ture of acquisition of the disease. The
term anthrax pneumonia is misleading
because typical bronchopneumonia does
not occur. Postmortem pathological
studies of patients from Sverdlovsk
showed that all patients had hemor-
rhagic thoracic lymphadenitis, hemor-
rhagic mediastinitis, and pleural effu-
sions. About half had hemorrhagic
meningitis. None of these autopsies
showed evidence of a bronchoalveolar
pneumonic process although 11 of 42
patient autopsies had evidence of a fo-
cal, hemorrhagic, necrotizing pneu-
monic lesion analogous to the Ghon
complex associated with tuberculo-
sis.50 These findings are consistent with
other human case series and experimen-
tally induced inhalational anthrax in
animals.40,51,52 A recent reanalysis of pa-
thology specimens from 41 of the Sverd-
lovsk patients was notable primarily for
the presence of necrotizing hemor-
rhagic mediastinitis; pleural effusions av-
eraging 1700 mL in quantity; meningi-
tis in 50%; arteritis and arterial rupture
in many; and the lack of prominent
pneumonitis. B anthracis was recov-
ered in concentrations of up to 100 mil-
lion colony-forming units per milliliter
in blood and spinal fluid.53
In animal models, physiological se-
quelae of severe anthrax infection have
included hypocalcemia, profound hy-
poglycemia, hyperkalemia, depres-
sion and paralysis of respiratory cen-
ter, hypotension, anoxia, respiratory
alkalosis, and terminal acidosis,54,55 sug-
gesting that besides the rapid admin-
istration of antibiotics, survival might
improve with vigilant correction of elec-
trolyte disturbances and acid-based im-
balance, glucose infusion, and early me-
chanical ventilation and vasopressor
Historical Data. Early diagnosis of in-
halational anthrax is difficult and re-
quires a high index of suspicion. Prior
to the 2001 attacks, clinical informa-
tion was limited to a series of 18 cases
reported in the 20th century and the
limited data from Sverdlovsk. The clini-
cal presentation of inhalational an-
thrax had been described as a 2-stage
illness. Patients reportedly first devel-
oped a spectrum of nonspecific symp-
toms, including fever, dyspnea, cough,
headache, vomiting, chills, weakness,
abdominal pain, and chest pain.18,27
Signs of illness and laboratory studies
were nonspecific. This stage of illness
lasted from hours to a few days. In some
patients, a brief period of apparent re-
covery followed. Other patients pro-
gressed directly to the second, fulmi-
nant stage of illness.4,27,56
This second stage was reported to have
developed abruptly, with sudden fever,
dyspnea, diaphoresis, and shock. Mas-
sive lymphadenopathy and expansion of
the mediastinum led to stridor in some
cases.57,58 A chest radiograph most of-
ten showed a widened mediastinum con-
sistent with lymphadenopathy.57 Up to
half of patients developed hemorrhagic
meningitis with concomitant meningis-
mus, delirium, and obtundation. In this
second stage, cyanosis and hypoten-
sion progressed rapidly; death some-
times occurred within hours.4,27,56
In the 20th-century series of US cases,
the mortality rate of occupationally ac-
quired inhalational anthrax was 89%, but
the majority of these cases occurred be-
fore the development of critical care
units and, in most cases, before the ad-
vent of antibiotics.27 At Sverdlovsk, it had
been reported that 68 of the 79 pa-
tients with inhalational anthrax died.18
However a separate report from a hos-
pital physician recorded 358 ill with 45
dead; another recorded 48 deaths among
110 patients.59 A recent analysis of avail-
able Sverdlovsk data suggests there may
have been as many as 250 cases with 100
deaths.60 Sverdlovsk patients who had
onset of disease 30 or more days after
release of organisms had a higher re-
ported survival rate than those with
earlier disease onset. Antibiotics, an-
tianthrax globulin, corticosteroids, me-
chanical ventilation, and vaccine were
used to treat some residents in the af-
fected area after the accident, but how
many were given vaccine and antibiot-
ics is unknown, nor is it known which
patients received these interventions or
when. It is also uncertain if the B an-
thracis strain (or strains) to which pa-
tients was exposed were susceptible to
the antibiotics used during the out-
break. However, a community-wide in-
tervention about the 15th day after ex-
posure did appear to diminish the
projected attack rate.60 In fatal cases, the
Table 1. Initial Symptoms, Physical Findings,
and Test Results in Patients With Inhalational
Anthrax Following US Anthrax Attacks in
October and November 2001*
Symptoms (N = 10)
Fever and chills 10
Sweats, often drenching 7
Fatigue, malaise, lethargy 10
Cough, minimal
or nonproductive
Nausea or vomiting 9
Dyspnea 8
Chest discomfort or
pleuritic pain
Myalgias 6
Headache 5
Confusion 4
Abdominal pain 3
Sore throat 2
Rhinorrhea 1
Physical Findings
Fever 37.8°C 7
Tachycardia, heart rate
Hypotension, 110 mm Hg 1
Laboratory Results
White blood cell count, median 9800 ×103/µL
Differential neutrophilia, 70% 7
Neutrophil band forms, 5% 4†
Elevated transaminases,
SGOT or SPGT 40 U/L‡
Hypoxemia, alveolar-arterial
oxygen gradient 30 mm Hg
on room air oxygen
saturation 94%
Metabolic acidosis 2
Elevated creatinine,
1.5 mg/dL (132.6 µmol/L)
Chest X-ray Film Findings
Any abnormality 10
Mediastinal widening 7
Infiltrates or consolidation 7
Pleural effusion 8
Chest Computed Tomographic Findings§
Any abnormality 8
Mediastinal lymphadenopathy,
Pleural effusion 8
Infiltrates or consolidation 6
*This table was adapted with permission from Jernigan,
et al.61
†Five persons had laboratory results measuring neutro-
phil band forms.
‡SGOT indicates serum glutamic oxalacetic transami-
nase; SGPT, serum glutamic pyruvic transaminase.
§Eight persons had computed tomographic scan results.
2240 JAMA, May 1, 2002Vol 287, No. 17 (Reprinted) ©2002 American Medical Association. All rights reserved.
interval between onset of symptoms and
death averaged 3 days. This is similar to
the disease course and case fatality rate
in untreated experimental monkeys,
which have developed rapidly fatal dis-
ease even after a latency as long as 58
2001 Attacks Data. The anthrax at-
tacks of 2001 resulted in 11 cases of in-
halational anthrax, 5 of whom died.
Symptoms, signs, and important labo-
ratory data from these patients are listed
in TABLE 1. Several clinical findings from
the first 10 patients with inhalational an-
thrax deserve emphasis.36,61-66 Malaise
and fever were presenting symptoms in
all 10 cases. Cough, nausea, and vom-
iting were also prominent. Drenching
sweats, dyspnea, chest pain, and head-
ache were also seen in a majority of pa-
tients. Fever and tachycardia were seen
in the majority of patients at presenta-
tion, as were hypoxemia and eleva-
tions in transaminases.
Importantly, all 10 patients had ab-
normal chest x-ray film results: 7 had
mediastinal widening; 7 had infil-
trates; and 8 had pleural effusions.
Chest computed tomographic (CT)
scans showed abnormal results in all 8
patients who had this test: 7 had me-
diastinal widening; 6, infiltrates; 8, pleu-
ral effusions.
Data are insufficient to identify fac-
tors associated with survival although
early recognition and initiation of treat-
ment and use of more than 1 antibi-
otic have been suggested as possible fac-
tors.61 For the 6 patients for whom such
information is known, the median pe-
riod from presumed time of exposure
to the onset of symptoms was 4 days
(range, 4-6 days). Patients sought care
a median of 3.5 days after symptom on-
set. All 4 patients exhibiting signs of ful-
minant illness prior to antibiotic ad-
ministration died.61 Of note, the
incubation period of the 2 fatal cases
from New York City and Connecticut
is not known.
Cutaneous Anthrax
Historically, cutaneous anthrax has
been known to occur following the
deposition of the organism into skin;
previous cuts or abrasions made one es-
pecially susceptible to infection.30,67 Ar-
eas of exposed skin, such as arms,
hands, face, and neck, were the most
frequently affected. In Sverdlovsk, cu-
taneous cases occurred only as late as
12 days after the original aerosol re-
lease; no reports of cutaneous cases ap-
peared after prolonged latency.18
After the spore germinates in skin tis-
sues, toxin production results in local
edema. An initially pruritic macule or
papule enlarges into a round ulcer by the
second day. Subsequently, 1- to 3-mm
vesicles may appear that discharge clear
or serosanguinous fluid containing
numerous organisms on Gram stain. As
shown in FIGURE 3, development of a
painless, depressed, black eschar fol-
lows, often associated with extensive
local edema. The anthrax eschar dries,
loosens, and falls off in the next 1 to 2
weeks. Lymphangitis and painful lymph-
adenopathy can occur with associated
systemic symptoms. Differential diag-
nosis of eschars includes tularemia, scrub
typhus, rickettsial spotted fevers, rat bite
fever, and ecthyma gangrenosum.68 Non-
infectious causes of eschars include
arachnid bites63 and vasculitides.
Although antibiotic therapy does not
appear to change the course of eschar
formation and healing, it does decrease
the likelihood of systemic disease. With-
out antibiotic therapy, the mortality rate
has been reported to be as high as 20%;
with appropriate antibiotic treatment,
death due to cutaneous anthrax has been
reported to be rare.4
Following the anthrax attacks of
2001, there have been 11 confirmed or
probable cases of cutaneous anthrax.
One case report of cutaneous anthrax
resulting from these attacks has been
published (Figure 3).63 This child had
no reported evidence of prior visible
cuts, abrasions, or lesions at the site of
the cutaneous lesion that developed.
The mean incubation period for cuta-
neous anthrax cases diagnosed in 2001
was 5 days, with a range of 1 to 10 days,
based on estimated dates of exposure
to B anthraciscontaminated letters. Cu-
taneous lesions occurred on the fore-
arm, neck, chest, and fingers.69
The only published case report of
cutaneous anthrax from the attacks of
2001 is notable for the difficulty in rec-
ognition of the disease in a previously
healthy 7-month-old, the rapid pro-
gression to severe systemic illness
despite hospitalization, and clinical
manifestations that included microan-
giopathic hemolytic anemia with renal
involvement, coagulopathy, and hypo-
natremia.63 Fortunately, this child
recovered, and none of the cutaneous
cases of anthrax diagnosed after the
2001 attacks were fatal.
Gastrointestinal Anthrax
Some think gastrointestinal anthrax oc-
curs after deposition and germination of
spores in the upper or lower gastroin-
testinal tract. However, considering the
rapid transit time in the gastrointesti-
nal tract, it seems more likely that many
such cases must result from the inges-
tion of large numbers of vegetative ba-
cilli from poorly cooked infected meat
rather than from spores. In any event,
the oral-pharyngeal form of disease re-
sults in an oral or esophageal ulcer and
leads to the development of regional
lymphadenopathy, edema, and sep-
sis.31,33 Disease in the lower gastrointes-
tinal tract manifests as primary intesti-
nal lesions occurring predominantly in
the terminal ileum or cecum,50 present-
ing initially with nausea, vomiting, and
malaise and progressing rapidly to
bloody diarrhea, acute abdomen, or sep-
Figure 3. Lesion of Cutaneous Anthrax
Associated With Microangiopathic Hemolytic
Anemia and Coagulopathy in a
7-Month-Old Infant
1 cm
By hospital day 12, a 2-cm black eschar was present
in the center of the cutaneous lesion. Reprinted from
Freedman et al.63
©2002 American Medical Association. All rights reserved. (Reprinted) JAMA, May 1, 2002Vol 287, No. 17 2241
sis. Massive ascites has occurred in some
cases of gastrointestinal anthrax.34 Ad-
vanced infection may appear similar to
the sepsis syndrome occurring in ei-
ther inhalational or cutaneous an-
thrax.4Some authors suggest that ag-
gressive medical intervention as would
be recommended for inhalational an-
thrax may reduce mortality. Given the
difficulty of early diagnosis of gastroin-
testinal anthrax, however, mortality may
be high.4Postmortem examinations in
Sverdlovsk showed gastrointestinal sub-
mucosal lesions in 39 of 42 patients,50
but all of these patients were also found
to have definitive pathologic evidence of
an inhalational source of infection. There
were no gastrointestinal cases of an-
thrax diagnosed in either the Sverd-
lovsk series or following the anthrax at-
tacks of 2001.
TABLE 2lists the epidemiology, diag-
nostic tests, microbiology, and pathol-
ogy for a diagnosis of inhalational
anthrax infection. Given the rarity of
anthrax infection, the first clinical or
laboratory suspicion of an anthrax ill-
ness must lead to early initiation of
antibiotic treatment pending con-
firmed diagnosis and should provoke
immediate notification of the local or
state public health department, local
hospital epidemiologist, and local or
state public health laboratory. In the
United States, a Laboratory Response
Network (LRN) has been established
through a collaboration of the Associa-
tion of Public Health Laboratories
and the CDC (details are available at:
.asp). Currently 81 clinical laborato-
ries in the LRN can diagnose bioweap-
ons pathogens. Several preliminary
diagnostic tests for B anthracis can be
performed in hospital laboratories us-
ing routine procedures. B anthracis is
a gram-positive, nonhemolytic, encap-
sulated, penicillin-sensitive, spore-
forming bacillus. Confirmatory tests
such as immuno-histochemical stain-
ing, gamma phage, and polymerase
chain reaction assays must still be per-
formed by special reference laborato-
ries in the LRN.
The determination of individual pa-
tient exposure to B anthracis on the ba-
sis of environmental testing is complex
due to the uncertain specificity and sen-
sitivity of rapid field tests and the diffi-
culty of assessing individual risks of ex-
posure. A patient (or patients) seeking
medical treatment for symptoms of in-
halational anthrax will likely be the first
evidence of a clandestine release of B an-
thracis as a biological weapon. The ap-
pearance of even a single previously
healthy patient who becomes acutely ill
with nonspecific febrile illness and symp-
toms and signs consistent with those
listed in Table 1 and whose condition
rapidly deteriorates should receive
prompt consideration for a diagnosis of
anthrax infection. The recognition of cu-
taneous cases of anthrax may also be the
first evidence of an anthrax attack.70
The likely presence of abnormal find-
ings on either chest x-ray film or chest
CT scan is diagnostically important. Al-
though anthrax does not cause a clas-
sic bronchopneumonia pathologically,
it can cause widened mediastinum, mas-
sive pleural effusions, air broncho-
grams, necrotizing pneumonic lesions,
and/or consolidation, as has been noted
above.36,55,56,61,64-66 The result can be hy-
poxemia and chest imaging abnormali-
ties that may or may not be clinically dis-
tinguishable from pneumonia. In the
anthrax attacks of 2001, each of the first
10 patients had abnormal chest x-ray
film results and each of 8 patients for
whom CT scans were obtained had ab-
normal results. These included wid-
ened mediastinum on chest radio-
graph and effusions on chest CT scan
(FIGURE 4). Such findings in a previ-
Figure 4. Chest Radiograph and Computed Tomography (CT) Image
A, Portable chest radiograph of 56-year-old man with inhalational anthrax depicts a widened mediastinum
(white arrowheads), bilateral hilar fullness, a right pleural effusion, and bilateral perihilar air-space disease.
B, Noncontrast spiral CT scan depicts an enlarged and hyperdense right hilar lymph node (white arrowhead),
bilateral pleural effusions (black arrowheads), and edema of the mediastinal fat. Reprinted from Mayer et al.66
Table 2. Diagnosis of Inhalational Anthrax Infection*
Category Findings
Epidemiology Sudden appearance of several cases of severe acute febrile illness
with fulminant course and death
Acute febrile illness in persons identified as being at risk following a
specific attack (eg, those in the 2001attacks: postal workers,
members of the news media, and politicians and their staff)
Diagnostic tests Chest radiograph: widened mediastinum, infiltrates, pleural effusion
Chest computed tomographic scan: hyperdense hilar and
mediastinal nodes, mediastinal edema, infiltrates, pleural effusion
Thoracentesis: hemorrhagic pleural effusions
Microbiology Peripheral blood smear: gram-positive bacilli on blood smear
Blood culture growth of large gram-positive bacilli with preliminary
identification of Bacillus species
Pathology Hemorrhagic mediastinitis, hemorrhagic thoracic lymphadenitis,
hemorrhagic meningitis; DFA stain of infected tissues
*See Table 1 for list of febrile illness symptoms and signs.
Most rapid assays are available only at laboratories participating in the Laboratory Response Network.
2242 JAMA, May 1, 2002Vol 287, No. 17 (Reprinted) ©2002 American Medical Association. All rights reserved.
ously healthy patient with evidence of
overwhelming febrile illness or sepsis
would be highly suggestive of ad-
vanced inhalational anthrax.
The bacterial burden may be so great
in advanced inhalational anthrax in-
fection that bacilli are visible on Gram
stain of peripheral blood, as was seen
following the 2001 attacks. The most
useful microbiologic test is the stan-
dard blood culture, which should show
growth in 6 to 24 hours. Each of the 8
patients who had blood cultures ob-
tained prior to initiation of antibiotics
had positive blood cultures.61 How-
ever, blood cultures appear to be ster-
ilized after even 1 or 2 doses of antibi-
otics, underscoring the importance of
obtaining cultures prior to initiation of
antibiotic therapy (J. Gerberding, oral
communication, March 7, 2002). If the
laboratory has been alerted to the pos-
sibility of anthrax, biochemical test-
ing and review of colonial morphol-
ogy could provide a preliminary
diagnosis 12 to 24 hours after inocu-
lation of the cultures. Definitive diag-
nosis could be promptly confirmed by
an LRN laboratory. However, if the
clinical laboratory has not been alerted
to the possibility of anthrax, B anthra-
cis may not be correctly identified. Rou-
tine procedures customarily identify a
Bacillus species in a blood culture ap-
proximately 24 hours after growth, but
some laboratories do not further iden-
tify Bacillus species unless specifically
requested. This is because the isola-
tion of Bacillus species most often rep-
resents growth of the common con-
taminant Bacillus cereus.71 Given the
possibility of future anthrax attacks, it
is recommended that routine clinical
laboratory procedures be modified, so
B anthracis is specifically excluded af-
ter identification of a Bacillus species
bacteremia unless there are compel-
ling reasons not to do so. If it cannot
be excluded then the isolate should be
transferred to an LRN laboratory.
Sputum culture and Gram stain are
unlikely to be diagnostic of inhalational
anthrax, given the frequent lack of a
pneumonic process.37 Gram stain of spu-
tum was reported positive in only 1 case
of inhalational anthrax in the 2001 se-
ries. If cutaneous anthrax is suspected,
a Gram stain and culture of vesicular
fluid should be obtained. If the Gram
stain is negative or the patient is taking
antibiotics already, punch biopsy should
be performed, and specimens sent to a
laboratory with the ability to perform im-
munohistochemical staining or poly-
merase chain reaction assays.69,70 Blood
cultures should be obtained and antibi-
otics should be initiated pending con-
firmation of the diagnosis of inhala-
tional or cutaneous anthrax.
Nasal swabs were obtained in some
persons believed to be at risk of inha-
lational anthrax following the anthrax
attacks of 2001. Although a study has
shown the presence of B anthracis
spores in nares of some monkeys fol-
lowing experimental exposure to B an-
thracis spores for some time after ex-
posure,72 the predictive value of the
nasal swab test for diagnosing inhala-
tional anthrax in humans is unknown
and untested. It is not known how
quickly antibiotics make spore recov-
ery on nasal swab tests impossible. One
patient who died from inhalational an-
thrax had a negative nasal swab.36 Thus,
the CDC advised in the fall of 2001 that
the nasal swab should not be used as a
clinical diagnostic test. If obtained for
an epidemiological purpose, nasal swab
results should not be used to rule out
infection in a patient. Persons who have
positive nasal swab results for B an-
thracis should receive a course of post-
exposure antibiotic prophylaxis since
a positive swab would indicate that the
individual had been exposed to aero-
solized B anthracis.
Antibodies to the protective antigen
(PA) of B anthracis, termed anti-PA IgG,
have been shown to confer immunity in
animal models following anthrax vacci-
nation.73,74 Anti-PA IgG serologies have
been obtained from several of those in-
volved in the 2001 anthrax attacks, but
the results of these assays are not yet pub-
lished. Given the lack of data in hu-
mans and the expected period required
to develop an anti-PA IgG response, this
test should not be used as a diagnostic
test for anthrax infection in the acutely
ill patient but may be useful for epide-
miologic purposes.
Postmortem findings are especially
important following an unexplained
death. Thoracic hemorrhagic necrotiz-
ing lymphadenitis and hemorrhagic nec-
rotizing mediastinitis in a previously
healthy adult are essentially pathogno-
monic of inhalational anthrax.50,58 Hem-
orrhagic meningitis should also raise
strong suspicion of anthrax infec-
tion.32,50,58,75 However, given the rarity of
anthrax, a pathologist might not iden-
tify these findings as caused by anthrax
unless previously alerted to this possi-
If only a few patients present con-
temporaneously, the clinical similar-
ity of early inhalational anthrax infec-
tion to other acute febrile respiratory
infections may delay initial diagnosis
although probably not for long. The se-
verity of the illness and its rapid pro-
gression, coupled with unusual radio-
logical findings, possible identification
of B anthracis in blood or cerebrospi-
nal fluid, and the unique pathologic
findings should serve as an early alarm.
The index case of inhalational anthrax
in the 2001 attacks was identified be-
cause of an alert clinician who sus-
pected the disease on the basis of large
gram-positive bacilli in cerebrospinal
fluid in a patient with a compatible
clinical illness, and as a result of the sub-
sequent analysis by laboratory staff who
had recently undergone bioterrorism
preparedness training.65
The US anthrax vaccine, named an-
thrax vaccine adsorbed (AVA), is an in-
activated cell-free product, licensed in
1970, and produced by Bioport Corp,
Lansing, Mich. The vaccine is li-
censed to be given in a 6-dose series.
In 1997, it was mandated that all US
military active- and reserve-duty per-
sonnel receive it.76 The vaccine is made
from the cell-free filtrate of a nonen-
capsulated attenuated strain of B an-
thracis.77 The principal antigen respon-
sible for inducing immunity is the
PA.26,32 In the rabbit model, the quan-
tity of antibody to PA has been corre-
©2002 American Medical Association. All rights reserved. (Reprinted) JAMA, May 1, 2002Vol 287, No. 17 2243
lated with the level of protection against
experimental anthrax infection.78
Preexposure vaccination with AVA
has been shown to be efficacious against
experimental challenge in a number of
animal studies.78-80 A similar vaccine was
shown in a placebo-controlled human
trial to be efficacious against cutane-
ous anthrax.81The efficacy of postex-
posure vaccination with AVA has been
studied in monkeys.40 Among 60 mon-
keys exposed to 8 LD50 of B anthracis
spores at baseline, 9 of 10 control ani-
mals died, and 8 of 10 animals treated
with vaccine alone died. None of 29 ani-
mals died while receiving doxycy-
cline, ciprofloxacin, or penicillin for 30
days; 5 developed anthrax once treat-
ment ceased. The remaining 24 all died
when rechallenged. The 9 receiving
doxycycline for 30 days plus vaccine at
baseline and day 14 after exposure did
not die from anthrax infection even af-
ter being rechallenged.40
The safety of the anthrax vaccine has
been the subject of much study. A re-
cent report reviewed the results of sur-
veillance for adverse events in the De-
partment of Defense program of 1998-
2000.82 At the time of that report,
425976 service members had received
1620793 doses of AVA. There were
higher rates of local reactions to the vac-
cine in women than men, but no pat-
terns of unexpected local or systemic ad-
verse eventswere identified.82 A recent
review of safety of AVA anthrax vacci-
nation in employees of the United States
Army Medical Research Institute of In-
fectious Diseases (USAMRIID) over the
past 25 years reported that 1583 per-
sons had received 10 722 doses of AVA.83
One percent of these inoculations (101/
10722) were associated with 1 or more
systemic events (defined as headache,
malaise, myalgia, fever, nausea, vomit-
ing, dizziness, chills, diarrhea, hives, an-
orexia, arthralgias, diaphoresis, blurred
vision, generalized itching, or sore
throat). The most frequently reported
systemic adverse event was headache
(0.4% of doses). Local or injection site
reactions were reported in 3.6%. No
long-term sequelae were reported in this
The Institute of Medicine (IOM) re-
cently published a report on the safety
and efficacy of AVA,84 which con-
cluded that AVA is effective against in-
halational anthrax and concluded that
if given with appropriate antibiotic
therapy, it may help prevent the devel-
opment of disease after exposure. The
IOM committee also concluded that
AVA was acceptably safe. Committee
recommendations for new research in-
clude studies to describe the relation-
ship between immunity and quantita-
tive antibody levels; further studies to
test the efficacy of AVA in combina-
tion with antibiotics in preventing in-
halational anthrax infection; studies of
alternative routes and schedules of ad-
ministration of AVA; and continued
monitoring of reported adverse events
following vaccination. The committee
did not evaluate the production pro-
cess used by the manufacturer.
A recently published report85 ana-
lyzed a cohort of 4092 women at 2 mili-
tary bases from January 1999 to March
2000. The study compared pregnancy
rates and adverse birth outcomes be-
tween groups of women who had been
vaccinated with women who had not
been vaccinated and the study found
that anthrax vaccination with AVA had
no effect on pregnancy or adverse birth
A human live attenuated vaccine has
been produced and used in countries
of the former Soviet Union.86 In the
Western world, live attenuated vac-
cines have been considered unsuit-
able for use in humans because of safety
Current vaccine supplies are lim-
ited, and the US production capacity
remains modest. Bioport is the single
US manufacturing facility for the
licensed anthrax vaccine. Production
has only recently resumed after a halt
required the company to alter produc-
tion methods so that it conformed to
the US Food and Drug Administration
(FDA) Good Manufacturing Practice
standard. Bioport has a contract to
produce 4.6 million doses of vaccine
for the US Department of Defense that
cannot be met until at least 2003 (D.
A. Henderson, oral communication,
February 2002).
The use of AVA was not initiated
immediately in persons believed to have
been exposed to B anthracis during the
2001 anthrax attacks for a variety of rea-
sons, including the unavailability of vac-
cine supplies. Subsequently, near the end
of the 60-day period of antibiotic pro-
phylaxis, persons deemed by investigat-
ing public health authorities to have been
at high risk for exposure were offered
postexposure AVA series (3 inocula-
tions at 2-week intervals, given on days
1, 14, and 28) as an adjunct to pro-
longed postexposure antibiotic prophy-
laxis. This group of affected persons was
also offered the alternatives of continu-
ing a prolonged course of antibiotics or
of receiving close medical follow-up with-
out vaccination or additional antibiot-
ics.87 This vaccine is licensed for use in
the preexposure setting, but because it
had not been licensed for use in the post-
exposure context, it was given under
investigational new drug procedures.
The working group continues to con-
clude that vaccination of exposed per-
sons following a biological attack in con-
junction with antibiotic administration
for 60 days following exposure provide
optimal protection to those exposed.
However, until ample reserve stock-
piles of vaccine are available, reliance
must be placed on antibiotic adminis-
tration. To date, there have been no
reported cases of anthrax infection among
those exposed in the 2001 anthrax attacks
who took prophylactic antibiotics, even
in those persons not complying with the
complete 60-day course of therapy.
Preexposure vaccination of some per-
sons deemed to be in high-risk groups
should be considered when substan-
tial supplies of vaccine become avail-
able. A fast-track program to develop
recombinant anthrax vaccine is now
under way. This may lead to more plen-
tiful vaccine stocks as well as a prod-
uct that requires fewer inoculations.88
Studies to evaluate intramuscular vs
subcutaneous routes of administra-
tion and less frequent dosing of AVA
are also under way. (J. Hughes, oral
communication, February 2002.)
2244 JAMA, May 1, 2002Vol 287, No. 17 (Reprinted) ©2002 American Medical Association. All rights reserved.
Recommendations for antibiotic and
vaccine use in the setting of an aerosol-
ized B anthracis attack are conditioned
by a very small series of cases in hu-
mans, a limited number of studies in ex-
perimental animals, and the possible ne-
cessity of treating large numbers of
casualties. A number of possible thera-
peutic strategies have yet to be ex-
plored experimentally or to be submit-
ted for approval to the FDA. For these
reasons, the working group offers con-
sensus recommendations based on the
best available evidence. The recommen-
dations do not necessarily represent uses
currently approved by the FDA or an of-
ficial position on the part of any of the
federal agencies whose scientists par-
ticipated in these discussions and will
need to be revised as further relevant in-
formation becomes available.
Given the rapid course of symptom-
atic inhalational anthrax, early antibi-
otic administration is essential. A delay
of antibiotic treatment for patients with
anthrax infection may substantially
lessen chances for survival.89,90 Given the
difficulty in achieving rapid microbio-
logic diagnosis of anthrax, all persons in
high-risk groups who develop fever or
evidence of systemic disease should start
receiving therapy for possible anthrax in-
fection as soon as possible while await-
ing the results of laboratory studies.
There are no controlled clinical stud-
ies for the treatment of inhalational
anthrax in humans. Thus, antibiotic regi-
mens commonly recommended for em-
pirical treatment of sepsis have not been
studied. In fact, natural strains of B an-
thracis are resistant to many of the an-
tibiotics used in empirical regimens for
sepsis treatment, such as those regi-
mens based on the extended-spectrum
cephalosporins.91,92 Most naturally oc-
curring B anthracis strains are sensitive
to penicillin, which historically has been
the preferred anthrax therapy. Doxycy-
cline is the preferred option among the
tetracycline class because of its proven
efficacy in monkey studies56 and its ease
of administration. Other members of this
class of antibiotics are suitable alterna-
tives. Although treatment of anthrax in-
fection with ciprofloxacin has not been
studied in humans, animal models sug-
gest excellent efficacy.40,56,93 In vitro data
suggest that other fluoroquinolone an-
tibiotics would have equivalent effi-
cacy although no animal data using a
primate model of inhalational anthrax
are available.92 Penicillin, doxycycline,
and ciprofloxacin are approved by the
FDA for the treatment of inhalational
anthrax infection,56,89,90,94 and other
antibiotics are under study. Other drugs
that are usually active in vitro include
clindamycin, rifampin, imipenem,
aminoglycosides, chloramphenicol, van-
comycin, cefazolin, tetracycline, lin-
ezolid, and the macrolides.
Reports have been published of a
B anthracis strain that was engineered
to resist the tetracycline and penicillin
classes of antibiotics.95 Balancing con-
siderations of treatment efficacy with
concerns regarding resistance, the
working group in 1999 recommended
that ciprofloxacin or other fluoroqui-
nolone therapy be initiated in adults
with presumed inhalational anthrax in-
fection.3It was advised that antibiotic
resistance to penicillin- and tetracy-
cline-class antibiotics should be as-
sumed following a terrorist attack un-
til laboratory testing demonstrated
otherwise. Once the antibiotic suscep-
tibility of the B anthracis strain of the
index case had been determined, the
most widely available, efficacious, and
least toxic antibiotic was recom-
mended for patients requiring treat-
ment and persons requiring postexpo-
sure prophylaxis. Since the 1999
consensus statement publication, a
study96 demonstrated the develop-
ment of in vitro resistance of an iso-
late of the Sterne strain of B anthracis
to ofloxacin (a fluoroquinolone closely
related to ciprofloxacin) following sub-
culturing and multiple cell passage.
Following the anthrax attacks of 2001,
the CDC97 offered guidelines advocat-
ing use of 2 or 3 antibiotics in combina-
tion in persons with inhalational an-
thrax based on susceptibility testing with
epidemic strains. Limited early informa-
tion following the attacks suggested that
persons with inhalational anthrax treated
intravenously with 2 or more antibiot-
ics active against B anthracis had a greater
chance of survival.61 Given the limited
number of persons who developed in-
halational anthrax, the paucity of com-
parative data, and other uncertainties, it
remains unclear whether the use of 2 or
more antibiotics confers a survival ad-
vantage, but combination therapy is a
reasonable therapeutic approach in the
face of life-threatening illness. Another
factor supporting the initiation of com-
bination antibiotic therapy for treat-
ment of inhalational anthrax is the
possibility that an engineered strain of
B anthracis resistant to 1 or more anti-
biotics might be used in a future attack.
Some infectious disease experts have also
advocated the use of clindamycin, cit-
ing the theoretical benefit of diminish-
ing bacterial toxin production, a strat-
egy used in some toxin-mediated
streptococcal infections.98 There are no
data as yet that bear specifically on this
question. Central nervous system pen-
etration is another consideration; doxy-
cycline or fluoroquinolone may not reach
therapeutic levels in the cerebrospinal
fluid. Thus, in the aftermath of the an-
thrax attacks, some infectious disease au-
thorities recommended preferential use
of ciprofloxacin over doxycycline, plus
augmentation with chloramphenicol, rif-
ampin, or penicillin when meningitis is
established or suspected.
The B anthracis isolate recovered
from patients with inhalational an-
thrax was susceptible to all of the an-
tibiotics expected in a naturally occur-
ring strain.97 This isolate showed an
inducible -lactamase in addition to a
constitutive cephalosporinase. The im-
portance of the inducible -lactamase
is unknown; these strains are highly
susceptible to penicillin in vitro, with
minimum inhibiting concentrations less
than .06 µg/mL. A theoretical concern
is that this sensitivity could be over-
come with a large bacterial burden. For
this reason, the CDC advised that pa-
tients with inhalational anthrax should
not be treated with penicillin or amoxi-
cillin as monotherapy and that cipro-
floxacin or doxycycline be considered
the standards based on in vitro activ-
©2002 American Medical Association. All rights reserved. (Reprinted) JAMA, May 1, 2002Vol 287, No. 17 2245
ity, efficacy in the monkey model, and
FDA approval.
In the contained casualty setting (a
situation in which a modest number of
patients require therapy), the work-
ing group supports these new CDC an-
tibiotic recommendations97 (TABLE 3)
and advises the use of intravenous an-
tibiotic administration. These recom-
mendations will need to be revised as
new data become available.
If the number of persons requiring
therapy following a bioterrorist attack
with anthrax is sufficiently high (ie, a
mass casualty setting), the working
group recognizes that combination drug
therapy and intravenous therapy may
no longer be possible for reasons of lo-
gistics and/or exhaustion of equip-
ment and antibiotic supplies. In such
circumstances, oral therapy may be the
only feasible option (TABLE 4). The
threshold number of cases at which
combination and parenteral therapy be-
come impossible depends on a variety
of factors, including local and re-
gional health care resources.
In experimental animals, antibiotic
therapy during anthrax infection has
prevented development of an immune
response.40,95 This suggests that even if
the antibiotic-treated patient survives an-
thrax infection, the risk of recurring
disease may persist for a prolonged pe-
riod because of the possibility of de-
layed germination of spores. There-
fore, we recommend that antibiotic
therapy be continued for at least 60 days
postexposure, with oral therapy replac-
ing intravenous therapy when the pa-
tient is clinically stable enough to take
oral medication.
Cutaneous anthrax historically has
been treated with oral penicillin. For rea-
sons articulated above, the working
group recommends that oral fluoroqui-
nolone or doxycycline in the adult dos-
age schedules described in TABLE 5be
used to treat cutaneous anthrax until an-
tibiotic susceptibility is proven. Amoxi-
cillin is a suitable alternative if there are
contraindications to fluoroquinolones or
doxycycline such as pregnancy, lactat-
ing mother, age younger than 18 years,
or antibiotic intolerance. For cutane-
ous lesions associated with extensive
edema or for cutaneous lesions of the
head and neck, clinical management
should be conservative as per inhala-
tional anthrax treatment guidelines in
Table 3. Although previous guidelines
have suggested treating cutaneous an-
thrax for 7 to 10 days,32,71 the working
group recommends treatment for 60 days
postexposure in the setting of bioterror-
ism, given the presumed concomitant in-
halational exposure to the primary aero-
sol. Treatment of cutaneous anthrax
generally prevents progression to sys-
temic disease although it does not pre-
vent the formation and evolution of the
eschar. Topical therapy is not useful.4
In addition to penicillin, the fluoro-
quinolones and the tetracycline class of
antibiotics, other antibiotics effective in
vitro include chloramphenicol, clinda-
mycin, extended-spectrum penicillins,
macrolides, aminoglycosides, vancomy-
cin, cefazolin, and other first-genera-
tion cephalosporins.91,99 The efficacy of
these antibiotics has not yet been tested
Table 3. Recommended Therapy for Inhalational Anthrax Infection in the Contained Casualty Settinga,b
Category Initial IV Therapy c,d Duration
Adults Ciprofloxacin, 400 mg every 12 h
Doxycycline, 100 mg every 12 hf
1 or 2 Additional antimicrobialsd
IV treatment initiallyebefore switching to oral antimicrobial therapy
when clinically appropriate:
Ciprofloxacin 500 mg twice daily
Doxycycline 100 mg twice daily
Continue oral and IV treatment for 60 dj
Children Ciprofloxacin, 10-15 mg/kg every 12 hg,h
Doxycyclinef,I for those aged
8 y and weight 45 kg: 100 mg every 12 h;
8 y and weight 45 kg: 2.2 mg/kg every 12 h;
8 y: 2.2 mg/kg every 12 h
1 or 2 Additional antimicrobialsd
IV treatment initiallyebefore switching to oral antimicrobial therapy
when clinically appropriate:
Ciprofloxacin 10-15 mg/kg every 12 hh
Doxycyclineifor those aged
8 y and weight 45 kg: 100 mg twice daily
8 y and weight 45 kg: 2.2 mg/kg twice daily
8 y: 2.2 mg/kg 2 daily
Continue oral and IV treatment for 60 d j
Pregnant womenkSame for nonpregnant adults IV treatment initially before switching to oral antimicrobial therapy
when clinically appropriateb; oral therapy regimens are the
same for nonpregnant adults
Immunocompromised persons Same for nonimmunocompromised adults and children
aThis table is adapted with permission from Morbidity and Mortality Weekly Report.97 For gastrointestinal and oropharyngeal anthrax, use regimens recommended for inhalational
bCiprofloxacin or doxycycline should be considered an essential part of first-line therapy for inhalational anthrax.
cSteroids may be considered as an adjunct therapy for patients with severe edema and for meningitis based on experience with bacterial meningitis of other etiologies.
dOther agents with in vitro activity include rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, and clarithromycin. Because of concerns of consti-
tutive and inducible -lactamases in Bacillus anthracis, penicillin and ampicillin should not be used alone. Consultation with an infectious disease specialist is advised.
eInitial therapy may be altered based on clinical course of the patient; 1 or 2 antimicrobial agents may be adequate as the patient improves.
fIf meningitis is suspected, doxycycline may be less optimal because of poor central nervous system penetration.
gIf intravenous (IV) 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 to 2 hours after oral dosing but may not be achieved if vomiting or ileus is present.
hIn children, ciprofloxacin dosage should not exceed 1 g/d.
iThe American Academy of Pediatrics recommends treatment of young children with tetracyclines for serious infections (ie, Rocky Mountain spotted fever).
jBecause of the potential persistence of spores after an aerosol exposure, antimicrobial therapy should be continued for 60 days.
kAlthough tetracyclines are not recommended during pregnancy, their use may be indicated for life-threatening illness. Adverse effects on developing teeth and bones of fetus are
dose related; therefore, doxycycline might be used for a short time (7-14 days) before 6 months of gestation. The high death rate from the infection outweighs the risk posed by
the antimicrobial agent.
2246 JAMA, May 1, 2002Vol 287, No. 17 (Reprinted) ©2002 American Medical Association. All rights reserved.
in humans or animal studies. The work-
ing group recommends the use of these
antibiotics only to augment fluoroqui-
nolones or tetracyclines or if the pre-
ferred drugs are contraindicated, not
available, or inactive in vitro in suscep-
tibility testing. B anthracis strains ex-
hibit natural resistance to sulfamethoxa-
zole, trimethoprim, cefuroxime,
cefotaxime sodium, aztreonam, and
ceftazidime.91,92,99 Therefore, these anti-
biotics should not be used.
Pleural effusions were present in all
of the first 10 patients with inhala-
tional anthrax in 2001. Seven needed
drainage of their pleural effusions, 3 re-
quired chest tubes.69 Future patients
with inhalational anthrax should be ex-
pected to have pleural effusions that will
likely require drainage.
Postexposure Prophylaxis
Guidelines for which populations
would require postexposure prophy-
laxis to prevent inhalational anthrax fol-
lowing the release of a B anthracis aero-
sol as a biological weapon will need to
be developed by public health officials
depending on epidemiological circum-
stances. These decisions would re-
quire estimates of the timing, loca-
tion, and conditions of the exposure.100
Ongoing case monitoring would be
needed to define the high-risk groups,
to direct follow-up, and to guide the ad-
dition or deletion of groups requiring
postexposure prophylaxis.
There are no FDA-approved postex-
posure antibiotic regimens following ex-
posure to a B anthracis aerosol. There-
fore, for postexposure prophylaxis, we
recommend the same antibiotic regi-
men as that recommended for treat-
ment of mass casualties; prophylaxis
should be continued for at least 60 days
postexposure (Table 4). Preliminary
analysis of US postal workers who were
advised to take 60 days of antibiotic pro-
phylaxis for exposure to B anthracis
spores following the anthrax attacks of
2001 showed that 2% sought medical at-
tention because of concern of possible
severe allergic reactions related to the
medications, but no persons required
hospitalization because of an adverse
drug reaction.101 Many persons did not
begin or complete their recommended
antibiotic course for a variety of rea-
sons, including gastrointestinal tract in-
tolerance, underscoring the need for
careful medical follow-up during the pe-
riod of prophylaxis.101 In addition, given
the uncertainties regarding how many
weeks or months spores may remain la-
tent in the period following discontinu-
Table 5. Recommended Therapy for Cutaneous Anthrax Infection Associated With
a Bioterrorism Attack*
Category Initial Oral TherapyDuration, d
Adults Ciprofloxacin, 500 mg twice daily
Doxycycline, 100 mg twice daily
Children§Ciprofloxacin, 10-15 mg/kg every 12 h
(not to exceed 1 g/d)
Doxycycline for those aged§
8 y and weight 45 kg: 100 mg every 12 h
8 y and weight 45 kg: 2.2 mg/kg every 12 h
8 y: 2.2 mg/kg every 12 h
Pregnant womenCiprofloxacin, 500 mg twice daily
Doxycycline, 100 mg twice daily
Same for nonimmunocompromised adults and children
*This table is adapted with permission from the Morbidity and Mortality Weekly Report.98 Cutaneous anthrax with signs
of systemic involvement, extensive edema, or lesions on the head or neck require intravenous therapy, and a mul-
tidrug approach is recommended (Table 3).
Ciprofloxacin or doxycycline should be considered first-line therapy. Amoxicillin can be substituted if a patient cannot
take a fluoroquinolone or tetracycline class drug. Adults are recommended to take 500 mg of amoxicillin orally 3
times a day. For children, 80 mg/kg of amoxicillin to be divided into 3 doses in 8-hour increments 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.
Previous guidelines have suggested treating cutaneous anthrax for 7 to 10 days, but 60 days is recommended for
bioterrorism attacks, given the likelihood of exposure to aerosolized Bacillus anthracis.
§The American Academy of Pediatrics recommends treatment of young children with tetracyclines for serious infec-
tions (eg, Rocky Mountain spotted fever).
Although tetracyclines or ciprofloxacin is not recommended during pregnancy, their use may be indicated for life-
threatening illness. Adverse effects on developing teeth and bones of a fetus are dose related; therefore, doxycycline
might be used for a short time (7-14 days) before 6 months of gestation.
Table 4. Recommended Therapy for Inhalational Anthrax Infection in the Mass Casualty Setting or for Postexposure Prophylaxis*
Category Initial Oral Therapy
Alternative Therapy if Strain
Is Proved Susceptible
Duration After
Exposure, d
Adults Ciprofloxacin, 500 mg orally every 12 h Doxycycline, 100 mg orally every 12 h
Amoxicillin, 500 mg orally every 8 h§
Children Ciprofloxacin, 20-30 mg/kg per d orally taken
in 2 daily doses, not to exceed 1 g/d
Weight 20 kg: amoxicillin, 500 mg orally every 8 h§
Weight 20 kg: amoxicillin, 40 mg/kg taken orally
in 3 doses every 8 h§
Pregnant womenCiprofloxacin, 500 mg orally every 12 h Amoxicillin, 500 mg orally every 8 h§60
Immunosuppressed persons Same as for nonimmunosuppressed adults and children
*Some of these recommendations are based on animal studies or in vitro studies and are not approved by the US Food and Drug Administration.
In vitro studies suggest ofloxacin (400 mg orally every 12 hours, or levofloxacin, 500 mg orally every 24 hours) could be substituted for ciprofloxacin.
In vitro studies suggest that 500 mg of tetracycline orally every 6 hours could be substituted for doxycycline. In addition, 400 mg of gatifloxicin or monifloxacin, both fluoroquino-
lones with mechanisms of action consistent with ciprofloxacin, taken orally daily could be substituted.
§According to the Centers for Disease Control and Prevention recommendations, amoxicillin is suitable for postexposure prophylaxis only after 10 to 14 days of fluoroquinolones or
doxycycline treatment and then only if there are contraindications to these 2 classes of medications (eg, pregnancy, lactating mother, age 18 years, or intolerance of other
Doxycycline could also be used if antibiotic susceptibility testing, exhaustion of drug supplies, adverse reactions preclude use of ciprofloxacin. For children heavier than 45 kg, adult
dosage should be used. For children lighter than 45 kg, 2.5 mg/kg of doxycycline orally every 12 hours should be used.
See Management of Pregnant Populationfor details.
©2002 American Medical Association. All rights reserved. (Reprinted) JAMA, May 1, 2002Vol 287, No. 17 2247
ation of postexposure prophylaxis, per-
sons should be instructed to report
immediately flulike symptoms or fe-
brile illness to their physicians who
should then evaluate the need to ini-
tiate treatment for possible inhala-
tional anthrax. As noted above, postex-
posure vaccination is recommended as
an adjunct to postexposure antibiotic
prophylaxis if vaccine is available.
Management of Special Groups
Consensus recommendations for spe-
cial groups as set forth herein reflect the
clinical and evidence-based judgments
of the working group and at this time
do not necessarily correspond with FDA-
approved use, indications, or labeling.
Children. It has been recommended
that ciprofloxacin and other fluoroqui-
nolones should not be used in children
younger than 16 to 18 years because of
a link to permanent arthropathy in ado-
lescent animals and transient arthropa-
thy in a small number of children.94 How-
ever, balancing these risks against the
risks of anthrax infections caused by an
engineered antibiotic-resistant strain, the
working group recommends that cipro-
floxacin be used as a component of com-
bination therapy for children with inha-
lational anthrax. For postexposure
prophylaxis or following a mass casu-
alty attack, monotherapy with fluoro-
quinolones is recommended by the
working group97 (Table 4).
The American Academy of Pediat-
rics has recommended that doxycy-
cline not be used in children younger
than 9 years because the drug has re-
sulted in retarded skeletal growth in in-
fants and discolored teeth in infants and
children.94 However, the serious risk of
infection following an anthrax attack
supports the consensus recommenda-
tion that doxycycline, instead of cipro-
floxacin, be used in children if antibi-
otic susceptibility testing, exhaustion
of drug supplies, or adverse reactions
preclude use of ciprofloxacin.
According to CDC recommenda-
tions, amoxicillin was suitable for treat-
ment or postexposure prophylaxis of
possible anthrax infection following the
anthrax attacks of 2001 only after 14
to 21 days of fluoroquinolone or doxy-
cycline administration because of the
concern about the presence of a -lac-
tamase.102 In a contained casualty set-
ting, the working group recommends
that children with inhalational an-
thrax receive intravenous antibiotics
(Table 3). In a mass casualty setting and
as postexposure prophylaxis, the work-
ing group recommends that children re-
ceive oral antibiotics (Table 4).
The US anthrax vaccine is licensed
for use only in persons aged 18 to 65
years because studies to date have been
conducted exclusively in this group.77
No data exist for children, but based on
experience with other inactivated vac-
cines, it is likely that the vaccine would
be safe and effective.
Pregnant Women. Fluoroquino-
lones are not generally recommended
during pregnancy because of their known
association with arthropathy in adoles-
cent animals and small numbers of chil-
dren. Animal studies have discovered no
evidence of teratogenicity related to cipro-
floxacin, but no controlled studies of
ciprofloxacin in pregnant women have
been conducted. Balancing these pos-
sible risks against the concerns of anthrax
due to engineered antibiotic-resistant
strains, the working group recom-
mends that pregnant women receive
ciprofloxacin as part of combination
therapy for treatment of inhalational
anthrax (Table 3). We also recommend
that pregnant women receive fluoroqui-
nolones in the usual adult dosages for
postexposure prophylaxis or mono-
therapy treatment in the mass casualty
setting (Table 4). The tetracycline class
of antibiotics has been associated with
both toxic effects in the liver in preg-
nant women and fetal toxic effects,
including retarded skeletal growth.94
Balancing the risks of anthrax infec-
tion with those associated with doxy-
cycline use in pregnancy, the working
group recommends that doxycycline
can be used as an alternative to cipro-
floxacin as part of combination therapy
in pregnant women for treatment of in-
halational anthrax. For postexposure
prophylaxis or in mass casualty set-
tings, doxycycline can also be used as
an alternate to ciprofloxacin in preg-
nant women. If doxycycline is used in
pregnant women, periodic liver func-
tion testing should be performed. No
adequate controlled trials of penicillin
or amoxicillin administration during
pregnancy exist. However, the CDC rec-
ommends penicillin for the treatment
of syphilis during pregnancy and
amoxicillin as a treatment alternative
for chlamydial infections during preg-
nancy.94 According to CDC recommen-
dations, amoxicillin is suitable postex-
posure prophylaxis or treatment of
inhalational anthrax in pregnancy only
after 14 to 21 days of fluoroquinolone
or doxycycline administration.102
Ciprofloxacin (and other fluoroqui-
nolones), penicillin, and doxycycline
(and other tetracyclines) are each ex-
creted in breast milk. Therefore, a
breastfeeding woman should be treated
or given prophylaxis with the same an-
tibiotic as her infant based on what is
most safe and effective for the infant.
Immunosuppressed Persons. The
antibiotic treatment or postexposure
prophylaxis for anthrax among those
who are immunosuppressed has not
been studied in human or animal mod-
els of anthrax infection. Therefore, the
working group consensus recom-
mends administering antibiotics in the
same regimens recommended for im-
munocompetent adults and children.
There are no data to suggest that pa-
tient-to-patient transmission of an-
thrax occurs and no person-to-person
transmission occurred following the an-
thrax attacks of 2001.18,67 Standard bar-
rier isolation precautions are recom-
mended for hospitalized patients with
all forms of anthrax infection, but the
use of high-efficiency particulate air fil-
ter masks or other measures for air-
borne protection are not indicated.103
There is no need to immunize or pro-
vide prophylaxis to patient contacts (eg,
household contacts, friends, cowork-
ers) unless a determination is made that
they, like the patient, were exposed to
the aerosol or surface contamination at
the time of the attack.
2248 JAMA, May 1, 2002Vol 287, No. 17 (Reprinted) ©2002 American Medical Association. All rights reserved.
In addition to immediate notifica-
tion of the hospital epidemiologist and
state health department, the local hos-
pital microbiology laboratories should
be notified at the first indication of an-
thrax so that safe specimen processing
under biosafety level 2 conditions can
be undertaken as is customary in most
hospital laboratories.56 A number of dis-
infectants used for standard hospital
infection control, such as hypochlo-
rite, are effective in cleaning environ-
mental surfaces contaminated with
infected bodily fluids.22,103
Proper burial or cremation of hu-
mans and animals who have died be-
cause of anthrax infection is important
in preventing further transmission of the
disease. Serious consideration should be
given to cremation. Embalming of bod-
ies could be associated with special
risks.103 If autopsies are performed, all re-
lated instruments and materials should
be autoclaved or incinerated.103 The CDC
can provide advice on postmortem pro-
cedures in anthrax cases.
Recommendations for decontamina-
tion in the event of an intentional aero-
solization of B anthracis spores are based
on evidence concerning aerosolization
techniques, predicted spore survival, en-
vironmental exposures at Sverdlovsk and
among goat hair mill workers, and en-
vironmental data collected following the
anthrax attacks of 2001. The greatest risk
to humans exposed to an aerosol of B an-
thracis spores occurs when spores first
are made airborne, the period called pri-
mary aerosolization. The aerobiological
factors that affect how long spores re-
main airborne include the size of the dis-
persed particles and their hydrostatic
properties.100 Technologically sophisti-
cated dispersal methods, such as aero-
sol release from military aircraft of large
quantities of B anthracis spores manipu-
lated for use in a weapon, are poten-
tially capable of exposing high num-
bers of victims over large areas. Recent
research by Canadian investigators has
demonstrated that even low-techde-
livery systems, such as the opening of en-
velopes containing powdered spores in
indoor environments, can rapidly de-
liver high concentrations of spores to
persons in the vicinity.104 In some cir-
cumstances, indoor airflows, activity pat-
terns, and heating, ventilation, and air
conditioning systems may transport
spores to others parts of the building.
Following the period of primary aero-
solization, B anthracis spores may settle
on surfaces, possibly in high concen-
trations. The risk that B anthracis spores
might pose by a process of secondary
aerosolization (resuspension of spores
into the air) is uncertain and is likely
dependent on many variables, includ-
ing the quantity of spores on a sur-
face; the physical characteristics of the
powder used in the attack; the type of
surface; the nature of the human or me-
chanical activity that occurs in the af-
fected area and host factors.
A variety of rapid assay kits are avail-
able to detect B anthracis spores on en-
vironmental surfaces. None of these kits
has been independently evaluated or en-
dorsed by the CDC, FDA, or Environ-
mental Protection Agency, and their
functional characteristics are not
known.105 Many false-positive results
occurred following the anthrax at-
tacks of 2001. Thus, any result using
currently available rapid assay kits does
not necessarily signify the presence of
B anthracis; it is simply an indication
that further testing is required by a cer-
tified microbiology laboratory. Simi-
larly, the sensitivity and false-negative
rate of disease kits are unknown.
At Sverdlovsk, no new cases of in-
halational anthrax developed beyond 43
days after the presumed date of re-
lease. None were documented during
the months and years afterward, de-
spite only limited decontamination and
vaccination of 47000 of the citys 1 mil-
lion inhabitants.59 Some have ques-
tioned whether any of the cases with on-
set of disease beyond 7 days after release
might have represented illness follow-
ing secondary aerosolization from the
ground or other surfaces. It is impos-
sible to state with certainty that sec-
ondary aerosolizations did not occur in
Sverdlovsk, but it appears unlikely. The
epidemic curve reported is typical for
a common-source epidemic,3,60 and it
is possible to account for virtually all
confirmed cases having occurred within
the area of the plume on the day of the
accident. Moreover, if secondary aero-
solization had been important, new
cases would have likely continued well
beyond the observed 43 days.
Although persons working with ani-
mal hair or hides are known to be at in-
creased risk of developing inhalational
or cutaneous anthrax, surprisingly few
occupational exposures in the United
States have resulted in disease. During
the first half of the 20th century, a sig-
nificant number of goat hair mill work-
ers were heavily exposed to aerosolized
spores. Mandatory vaccination became
a requirement for working in goat hair
mills only in the 1960s. Prior to that,
many unvaccinated person-years of high-
risk exposure had occurred, but only 13
cases of inhalational anthrax were re-
ported.27,54 One study of environmental
exposure, conducted at a Pennsylvania
goat hair mill, showed that workers in-
haled up to 510 B anthracis particles of
at least 5 µm in diameter per person per
8-hour shift.54 These concentrations of
spores were constantly present in the en-
vironment during the time of this study,
but no cases of inhalational anthrax
Field studies using B anthracislike
surrogates have been carried out by US
Army scientists seeking to determine
the risk of secondary aerosolization.
One study concluded that there was no
significant threat to personnel in areas
contaminated by 1 million spores per
square meter either from traffic on as-
phalt-paved roads or from a runway
used by helicopters or jet aircraft.106 A
separate study showed that in areas of
ground contaminated with 20 million
Bacillus subtilis spores per square me-
ter, a soldier exercising actively for a
3-hour period would inhale between
1000 and 15000 spores.107
Much has been written about the
technical difficulty of decontaminat-
ing an environment contaminated with
B anthracis spores. A classic case is the
experience at Gruinard Island, Scot-
land. During World War II, British mili-
©2002 American Medical Association. All rights reserved. (Reprinted) JAMA, May 1, 2002Vol 287, No. 17 2249
tary undertook explosives testing with
B anthracis spores. Spores persisted and
remained viable for 36 years following
the conclusion of testing. Decontami-
nation of the island occurred in stages,
beginning in 1979 and ending in 1987
when the island was finally declared
fully decontaminated. The total cost is
unpublished, but materials required in-
cluded 280 tons of formaldehyde and
2000 tons of seawater.108
Following the anthrax attacks of
2001, substantial efforts were under-
taken to decontaminate environmen-
tal surfaces exposed to B anthracis
spores. Sections of the Hart Senate of-
fice building in Washington, DC, con-
taminated from opening a letter laden
with B anthracis, were reopened only
after months of decontamination pro-
cedures at an estimated cost of $23 mil-
lion.109 Decontamination efforts at many
other buildings affected by the an-
thrax attacks of 2001 have not yet been
Prior to the anthrax attacks of 2001,
there had been no recognition or sci-
entific study showing that B anthracis
spores of weapons gradequality
would be capable of leaking out the
edges of envelopes or through the pores
of envelopes, with resulting risk to the
health of those handling or processing
those letters. When it became clear that
the Florida case of anthrax was likely
caused by a letter contaminated with
B anthracis, assessment of postal work-
ers who might have handled or pro-
cessed that letter showed no illness.69
When the anthrax cases were discov-
ered, each was linked to a letter that had
been opened. At first, there was no evi-
dence of illness among persons han-
dling or processing unopened mail. This
fact influenced the judgment that
persons handling or processing un-
opened B anthracis letters were not at
risk. These judgments changed when
illness was discovered in persons who
had handled or processed unopened let-
ters in Washington, DC. Much re-
mains unknown about the risks to per-
sons handling or processing unopened
letters containing B anthracis spores. It
is not well understood how the me-
chanical systems of mail processing in
a specific building would affect the risk
of disease acquisition in a worker han-
dling a contaminated letter in that fa-
cility. It is still uncertain what the mini-
mum dose of spores would be to cause
infection in humans although it may
theoretically be as few as 1 to 3 spores.47
The mechanisms of disease acquisi-
tion in the 2 fatal inhalational anthrax
cases in New York City and in Con-
necticut remain unknown although it
is speculated that disease in these 2
cases followed the inhalation of small
numbers of spores present in some
manner in cross-contaminatedmail.
The discovery of B anthracis spores
in a contaminated letter in the office of
Sen Daschle in the Hart office build-
ing led the Environmental Protection
Agency to conduct tests in this office
to assess the risk of secondary aerosol-
ization of spores. Prior to the initia-
tion of decontamination efforts in the
Hart building, 17 blood agar gel plates
were placed around the office and nor-
mal activity in the office was simu-
lated. Sixteen of the 17 plates yielded
B anthracis. Although this experiment
did not allow conclusions about the spe-
cific risk of persons developing an-
thrax infection in this context, it did
demonstrate that routine activity in an
environment contaminated with B an-
thracis spores could cause significant
spore resuspension.110
Given the above considerations, if an
environmental surface is proved to be
contaminated with B anthracis spores in
the immediate area of a spill or close
proximity to the point of release of B an-
thracis biological weapons, the work-
ing group believes that decontamina-
tion of that area would likely decrease
the risk of acquiring anthrax by second-
ary aerosolization. However, as has been
demonstrated in environmental decon-
tamination efforts following the an-
thrax attacks of 2001, decontamina-
tion of buildings or parts of buildings
following an anthrax attack is techni-
cally difficult. For these reasons, the
working group would advise that deci-
sions about methods for decontamina-
tion following an anthrax attack follow
full expert analysis of the contami-
nated environment and the anthrax
weapon used in the attack and be made
in consultation with experts on envi-
ronmental remediation. If vaccines were
available, postexposure vaccination
might be a useful intervention for those
working in highly contaminated areas,
because it could further lower the risk
of anthrax infection.
In the setting of an announced al-
leged B anthracis release, such as the se-
ries of anthrax hoaxes occurring in many
areas of the United States in 1998111 and
following the anthrax attacks of 2001,
any person coming in direct physical
contact with a substance alleged to be
containing B anthracis should thor-
oughly wash the exposed skin and ar-
ticles of clothing with soap and wa-
ter.112 In addition, any person in direct
physical contact with the alleged sub-
stance should receive postexposure an-
tibiotic prophylaxis until the sub-
stance is proved not to be B anthracis.
The anthrax attacks of 2001 and new re-
search104 have shown that opening let-
ters containing substantial quantities of
B anthracis spores in certain conditions
can confer risk of disease to persons at
some distance from the location of where
the letter was opened. For this reason,
when a letter is suspected of contain-
ing (or proved to contain) B anthracis,
immediate consultation with local and
state public health authorities and the
CDC for advised medical management
is warranted.
Additional Research
Development of a recombinant an-
thrax vaccine that would be more eas-
ily manufactured and would require
fewer doses should remain a top pri-
ority. Rapid diagnostic assays that could
reliably identify early anthrax infec-
tion and quickly distinguish from other
flulike or febrile illnesses would be-
come critical in the event of a large-
scale attack. Simple animal models for
use in comparing antibiotic prophylac-
tic and treatment strategies are also
needed. Operational research to bet-
ter characterize risks posed by envi-
ronmental contamination of spores,
2250 JAMA, May 1, 2002Vol 287, No. 17 (Reprinted) ©2002 American Medical Association. All rights reserved.
particularly inside buildings, and re-
search on approaches to minimize risk
in indoor environments by means of air
filters or methods for environmental
cleaning following a release are also
needed. A better understanding of the
genetics and pathogenesis of anthrax,
as well as mechanisms of virulence and
immunity, will be of importance in the
prospective evaluation of new thera-
peutic and diagnostic strategies. Novel
therapeutic approaches with promise,
such as the administration of competi-
tors against the protective antigen com-
plex,113 should also be tested in ani-
mals and developed where evidence
supports this. Recent developments
such as the publishing of the B anthra-
cis genome and the discovery of the
crystalline structure of the lethal and
edema factor could hold great clinical
hope for both the prevention and treat-
ment of anthrax infection.114
Ex Officio Participants in the Working Group on Ci-
vilian Biodefense: George Curlin, MD, National In-
stitutes of Health, Bethesda, Md; Margaret Ham-
burg, MD, Nuclear Threat Initiative, Washington, DC;
Stuart Nightingale, MD, Office of Assistant Secretary
for Planning and Evaluation, DHHS, Washington, DC;
William Raub, PhD, Office of Public Health Prepared-
ness, DHHS, Washington, DC; Robert Knouss, MD,
Office of Emergency Preparedness, DHHS, Rockville,
Md; Marcelle Layton, MD, Office of Communicable
Disease, New York City Health Department, New York,
NY; and Brian Malkin, formerly of FDA, Rockville, Md.
Funding/Support: Funding for this study primarily was
provided by each participants institution or agency.
Disclaimers: In many cases, the indication and dos-
ages and other information are not consistent with cur-
rent approved labeling by the US Food and Drug Ad-
ministration (FDA). The recommendations on the use
of drugs and vaccine for uses not approved by the FDA
do not represent the official views of the FDA or of
any of the federal agencies whose scientists partici-
pated in these discussions. Unlabeled uses of the prod-
ucts recommended are noted in the sections of this
article in which these products are discussed. Where
unlabeled uses are indicated, information used as the
basis for the recommendation is discussed. The views,
opinions, assertions, and findings contained herein are
those of the authors and should not be construed as
official US Department of Health and Human Ser-
vices, US Department of Defense, or US Department
of Army positions, policies, or decisions unless so des-
ignated by other documentation.
Acknowledgment: The working group wishes to thank
Jeanne Guillemin, PhD, Matthew Meselson, PhD,
Timothy Townsend, MD, Martin Hugh-Jones, MA,
VetMB, MPH, PhD, and Philip Brachman, MD, for their
review and commentary on the originally published
manuscript, and Molly DEsopo for her efforts in the
preparation of the revised manuscript.
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2252 JAMA, May 1, 2002Vol 287, No. 17 (Reprinted) ©2002 American Medical Association. All rights reserved.
Anthrax is a zoonotic infectious disease caused by Bacillus anthracis (anthrax bacterium) that affects not only domestic and wild animals worldwide but also human health. As the study develops in-depth, a large quantity of related biomedical publications emerge. Acquiring knowledge from the literature is essential for gaining insight into anthrax etiology, diagnosis, treatment and research. In this study, we used a set of text mining tools to identify nearly 14 000 entities of 29 categories, such as genes, diseases, chemicals, species, vaccines and proteins, from nearly 8000 anthrax biomedical literature and extracted 281 categories of association relationships among the entities. We curated Anthrax-related Entities Dictionary and Anthrax Ontology. We formed Anthrax Knowledge Graph (AnthraxKG) containing more than 6000 nodes, 6000 edges and 32 000 properties. An interactive visualized Anthrax Knowledge Portal(AnthraxKP) was also developed based on AnthraxKG by using Web technology. AnthraxKP in this study provides rich and authentic relevant knowledge in many forms, which can help researchers carry out research more efficiently. Database URL: AnthraxKP is permitted users to query and download data at
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New strategies in the development of anthrax vaccines and therapeutics have been presented. Recently, considerable progress has been made in the finding of new drugs and suitable therapy for anthrax. Very promising research considers the use of antimicrobials against selected bacteria species, including antibiotic-resistant strains. However, alternative therapeutic options should also be considered, among them vaccines. Bacillus anthracis spores are still the most dangerous weapon amongst pathogens which can be used in a bioterror attack. In this case, research for new anti-anthrax preparations is of primary importance for the protection of humans and animals. The overview of the most recent data shows the many new and promising possibilities for effective strategies in the development of vaccines and anti-anthrax preparations. The most effective of them should be available in the National Stockpile in the event of a biological crisis.
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HitRS is a two-component system that responds to cell envelope damage in the human pathogen Bacillus anthracis. Here we identify an RNA-binding protein, KrrA, that regulates HitRS function by modulating the stability of the hitRS mRNA. In addition to hitRS, KrrA binds to over 70 RNAs and, directly or indirectly, affects the expression of over 150 genes involved in multiple processes, including genetic competence, sporulation, RNA turnover, DNA repair, transport, and cellular metabolism. KrrA does not exhibit detectable nuclease activity in vitro, and thus the mechanism by which it modulates mRNA stability remains unclear. HitRS is a two-component system that responds to cell envelope damage in the bacterium Bacillus anthracis. Here, the authors identify an RNA-binding protein that regulates HitRS function by modulating the stability of the hitRS mRNA. In addition, the protein binds to over 70 RNAs and affects the expression of genes involved in multiple cellular processes.
Anthrax is a zoonosis that causes disease in herbivores. Human anthrax most often occurs in agricultural areas where anthrax is common in animals. However, the global importance of Bacillus anthracis has increased as a potential bioterrorism agent following the “anthrax letter” events of 2001 in the United States (US) [1]. Human cases acquired through natural routes are usually associated with contact with infected animals or contaminated animal products [1]. Anthrax has three main clinical forms, depending on the type of exposure: cutaneous, gastrointestinal, and inhalation anthrax. Each can lead to a visit to a pediatrician or an ear, nose, and throat (ENT) specialist.
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Sensors in the built environment ensure safety and comfort by tracking contaminants in the occupied space. In the event of contaminant release, it is important to use the limited sensor data to rapidly and accurately identify the release location of the contaminant. Identification of the release location will enable subsequent remediation as well as evacuation decision-making. In previous work, we used an operator theoretic approach—based on the Perron–Frobenius (PF) operator—to estimate the contaminant concentration distribution in the domain given a finite amount of streaming sensor data. In the current work, the approach is extended to identify the most probable contaminant release location. The release location identification is framed as a Bayesian inference problem. The Bayesian inference approach requires considering multiple release location scenarios, which is done efficiently using the discrete PF operator. The discrete PF operator provides a fast, effective and accurate model for contaminant transport modeling. The utility of our PF-based Bayesian inference methodology is illustrated using single-point release scenarios in both two and three-dimensional cases. The method provides a fast, accurate, and efficient framework for real-time identification of contaminant source location.
Late-stage anthrax infections are characterized by dysregulated immune responses and hematogenous spread of Bacillus anthracis, leading to extreme bacteremia, sepsis, multiple organ failure, and, ultimately, death. Despite the bacterium being nonhemolytic, some fulminant anthrax patients develop a secondary atypical hemolytic uremic syndrome (aHUS) through unknown mechanisms. We recapitulated the pathology in baboons challenged with cell wall peptidoglycan (PGN), a polymeric, pathogen-associated molecular pattern responsible for the hemostatic dysregulation in anthrax sepsis. Similar to aHUS anthrax patients, PGN induces an initial hematocrit elevation followed by progressive hemolytic anemia and associated renal failure. Etiologically, PGN induces erythrolysis through direct excessive activation of all three complement pathways. Blunting terminal complement activation with a C5 neutralizing peptide prevented the progressive deposition of membrane attack complexes on red blood cells (RBC) and subsequent intravascular hemolysis, heme cytotoxicity, and acute kidney injury. Importantly, C5 neutralization did not prevent immune recognition of PGN and shifted the systemic inflammatory responses, consistent with improved survival in sepsis. Whereas PGN-induced hemostatic dysregulation was unchanged, C5 inhibition augmented fibrinolysis and improved the thromboischemic resolution. Overall, our study identifies PGN-driven complement activation as the pathologic mechanism underlying hemolytic anemia in anthrax and likely other gram-positive infections in which PGN is abundantly represented. Neutralization of terminal complement reactions reduces the hemolytic uremic pathology induced by PGN and could alleviate heme cytotoxicity and its associated kidney failure in gram-positive infections.
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In conducting research using animals, the investigators adhered to the "Guide for the Care and Use of Laboratory Animals," prepared by the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council (NIH Publication No. 86-23, revised 1985). The views, opinions and/or findings contained in this publication are those of the authors and should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation. Summary The efficacy of a licensed human anthrax vaccine was tested in rhesus monkeys challenged by an aerosol of virulent Bacillus anthracis spores. Adult rhesus monkeys were injected intramuscularly at 0 and 2 weeks with 0.5 ml of vaccine or phosphate-buffered saline. At 8 weeks, 38 weeks or 100 weeks, the animals were challenged by B. anthracis aerosolized spores. All immunized animals survived challenge at either 8 weeks or 38 weeks, and seven of eight animals survived challenge at 100 weeks. All control animals died 3 to 5 days after challenge. Serum from immunized animals possessed demonstrable antibodies to protective antigen by ELISA.
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22 Bacillus anthracis isolates were tested for susceptibility to 27 antimicrobial agents by agar dilution. All isolates were sensitive to penicillins and did not produce beta-lactamase. Although all isolates were sensitive to cefazolin, cephalothin, cephradine and cefoperazone 19 isolates were resistant to cefuroxime, 18 to cefotaxime, 18 to ceftizoxime, 9 to ceftriaxone and 21 to ceftazidime. All isolates were also found to be sensitive to other antimicrobials tested. The new antimicrobial agents, ofloxacin and ciprofloxacin showed very good activity with MICs of 0.03–0.06 mg/l.
We describe the 11th case of bioterrorism-related inhalational anthrax reported in the United States. The presenting clinical features of this 94-year-old woman were subtle and nondistinctive. The diagnosis was recognized because blood cultures were obtained prior to administration of antibiotics, emphasizing the importance of this diagnostic test in evaluating ill patients who have been exposed to Bacillus anthracis. The patient's clinical course was characterized by progression of respiratory insufficiency, pleural effusions and pulmonary edema, and, ultimately, death. Although her B anthracis bacteremia was rapidly sterilized after initiation of antibiotic therapy, viable B anthracis was present in postmortem mediastinal lymph node specimens. The source of exposure to B anthracis in this patient is not known. Exposure to mail that was cross-contaminated as it passed through postal facilities contaminated with B anthracis spores is one hypothesis under investigation.
A 61-year-old woman who was a New York City hospital employee developed fatal inhalational anthrax, but with an unknown source of anthrax exposure. The patient presented with shortness of breath, malaise, and cough that had developed 3 days prior to admission. Within hours of presentation, she developed respiratory failure and septic shock and required mechanical ventilation and vasopressor therapy. Spiral contrast–enhanced computed tomography of the chest demonstrated large bilateral pleural effusions and hemorrhagic mediastinitis. Blood cultures, as well as DNA amplification by polymerase chain reaction of the blood, bronchial washings, and pleural fluid specimens, were positive for Bacillus anthracis. The clinical course was complicated by liver failure, renal failure, severe metabolic acidosis, disseminated intravascular coagulopathy, and cardiac tamponade, and the patient died on the fourth hospital day. The cause of death was inhalational anthrax. Despite epidemiologic investigation, including environmental samples from the patient's residence and workplace, no mechanism for anthrax exposure has been identified.
Concern regarding the use of biological agents—bacteria, viruses, or toxins—as tools of warfare or terrorism has led to measures to deter their use or, failing that, to deal with the consequences. Unlike chemical agents, which typically lead to violent disease syndromes within minutes at the site of exposure, diseases resulting from biological agents have incubation periods of days. Therefore, rather than a paramedic, it will likely be a physician who is first faced with evidence of the results of a biological attack. We provide here a primer on 10 classic biological warfare agents to increase the likelihood of their being considered in a differential diagnosis. Although the resultant diseases are rarely seen in many countries today, accepted diagnostic and epidemiologic principles apply; if the cause is identified quickly, appropriate therapy can be initiated and the impact of a terrorist attack greatly reduced.