Anthrax as a Biological Weapon
Medical and Public Health Management
Thomas V. Inglesby, MD; Donald A. Henderson, MD, MPH; John G. Bartlett,
MD; Michael S. Ascher, MD; Edward Eitzen, MD, MPH; Arthur M. Friedlander, MD;
Jerome Hauer, MPH; Joseph McDade, PhD; Michael T. Osterholm, PhD, MPH; Tara
O'Toole, MD, MPH; Gerald Parker, PhD, DVM; Trish M. Perl, MD, MSc; Philip K.
Russell, MD; Kevin Tonat, PhD; for the Working Group on Civilian Biodefense
Objective To develop consensus-based recommendations for measures to be
taken by medical and public health professionals following the use of anthrax
as a biological weapon against a civilian population.
Participants The working group included 21 representatives from staff of major
academic medical centers and research, government, military, public health, and
emergency management institutions and agencies.
Evidence MEDLINE databases were searched from January 1966 to April 1998,
using the Medical Subject Headings anthrax,
Bacillus anthracis, biological weapon, biological terrorism, biological warfare, and biowarfare. Review of references
identified by this search led to identification of relevant references
published prior to 1966. In addition, participants identified other unpublished
references and sources.
Consensus Process The first draft of the consensus statement was a synthesis of
information obtained in the formal evidence-gathering process. Members of the
working group provided formal written comments which were incorporated into the
second draft of the statement. The working group reviewed the second draft on
June 12, 1998. No significant disagreements existed and comments were
incorporated into a third draft. The fourth and final statement incorporates
all relevant evidence obtained by the literature search in conjunction with
final consensus recommendations supported by all working group members.
Conclusions Specific consensus recommendations are made regarding the
diagnosis of anthrax, indications for vaccination, therapy for those exposed,
postexposure prophylaxis, decontamination of the environment, and additional
research needs.
JAMA. 1999;281:1735-1745
Of the numerous biological agents that may be
used as weapons, the Working Group on Civilian Biodefense has identified a
limited number of organisms that could cause disease and deaths in sufficient
numbers to cripple a city or region. Anthrax is one of the most serious of
these diseases.
High hopes were once vested in the Biological
Weapons and Toxins Convention, which prohibited offensive biological weapons
research or production and was signed by most countries. However, Iraq and the
former Soviet Union, both signatories of the convention, have subsequently
acknowledged having offensive biowarfare programs; a number of other countries
are believed to have such programs, as have some autonomous terrorist groups.
The possibility of a terrorist attack using bioweapons would be especially
difficult to predict, detect, or prevent, and thus, it is among the most feared
terrorist scenarios.1
Biological agents have seldom been dispersed in
aerosol form, the exposure mode most likely to inflict widespread disease.
Therefore, historical experience provides little information about the
potential impact of a biological attack or the possible efficacy of postattack
measures such as vaccination, antibiotic therapy, or quarantine. Policies and
strategies must therefore rely on interpretation and extrapolation from an
incomplete knowledge base. The Working Group on Civilian Biodefense reviewed
the available literature and expertise and developed consensus recommendations
for medical and public health measures to be taken following such an attack.
The working group comprised 21 representatives
from academic medical centers and research, government, military, public
health, and emergency management institutions and agencies.
MEDLINE databases were searched from January
1966 to April 1998 for the Medical Subject Headings anthrax,Bacillus anthracis,
biological weapon, biological terrorism, biological warfare, and biowarfare. Review of references led to
identification of additional relevant references published prior to 1966. In
addition, experts in the working group identified unpublished references and sources.
The first draft of the working group's consensus
statement was the result of synthesis of information obtained in the formal
evidence-gathering process. Members of the working group were asked to make
formal written comments on this first draft of the document in May 1998.
Suggested revisions were incorporated into the second draft of the statement.
The working group was convened to review the second draft of the statement on
June 12, 1998, at the Johns Hopkins Center for Civilian Biodefense Studies,
Baltimore, Md. Consensus recommendations were made; no significant
disagreements existed at the conclusion of this meeting. The third draft
incorporated changes suggested at the conference and working group members had
an additional opportunity to review the draft and suggest final revisions. The
final statement incorporates all relevant evidence obtained by the literature
search in conjunction with final consensus recommendations supported by all
working group members. Funding for the development of the working group
consensus statement was primarily provided by each representative's institution
or agency. The Office of Emergency Preparedness, Department of Health and Human
Services (DHHS), provided travel funds for 4 members of the group.
The assessment and recommendations provided
herein represent the best professional judgment of the working group based on
data and expertise currently available. The conclusions and recommendations
need to be regularly reassessed as new information becomes available.
For centuries, anthrax has caused disease in
animals and, uncommonly, serious illness in humans throughout the world.2 Research on anthrax as
a biological weapon began more than 80 years ago.3 Today, at least 17 nations
are believed to have offensive biological weapons programs4; it is uncertain how
many are working with anthrax. Iraq has acknowledged producing and weaponizing
anthrax.5
Most experts concur that the manufacture of a
lethal anthrax aerosol is beyond the capacity of individuals or groups without
access to advanced biotechnology. However, autonomous groups with substantial
funding and contacts may be able to acquire the required materials for a
successful attack. One terrorist group, Aum Shinrikyo, responsible for the
release of sarin in a Tokyo, Japan, subway station in 1995,6 dispersed aerosols of
anthrax and botulism throughout Tokyo on at least 8 occasions. For unclear
reasons, the attacks failed to produce illness.7
The accidental aerosolized release of anthrax
spores from a military microbiology facility in Sverdlovsk in the former Soviet
Union in 1979 resulted in at least 79 cases of anthrax infection and 68 deaths
and demonstrated the lethal potential of anthrax aerosols.8 An anthrax aerosol
would be odorless and invisible following release and would have the potential
to travel many kilometers before disseminating.9, 10 Evidence suggests
that following an outdoor aerosol release, persons indoors could be exposed to
a similar threat as those outdoors.11
In 1970, a World Health Organization (WHO)
expert committee estimated that casualties following the theoretical aircraft
release of 50 kg of anthrax over a developed urban population of 5 million
would be 250,000, 100,000 of whom would be expected to die without treatment.9 A 1993 report by the
US Congressional Office of Technology Assessment estimated that between 130,000
and 3 million deaths could follow the aerosolized release of 100 kg of anthrax
spores upwind of the Washington, DC, arealethality
matching or exceeding that of a hydrogen bomb.12 An economic model
developed by the Centers for Disease Control and Prevention (CDC) suggested a
cost of $26.2 billion per 100,000 persons exposed.13
Naturally occurring anthrax is a disease
acquired following contact with anthrax-infected animals or
anthrax-contaminated animal products. The disease most commonly occurs in
herbivores, which are infected by ingesting spores from the soil. Large anthrax
epizootics in herbivores have been reported; during a 1945 outbreak in Iran, 1
million sheep died.14 Animal vaccination
programs have reduced drastically the animal mortality from the disease.15 However, anthrax
spores continue to be documented in soil samples from throughout the world.16-18
In humans, 3 types of anthrax infection occur:
inhalational, cutaneous, and gastrointestinal. Naturally occurring inhalational
anthrax is now a rare cause of human disease. Historically, wool sorters at
industrial mills were at highest risk. Only 18 cases were reported in the
United States from 1900 to 1978, with the majority occurring in special-risk
groups, including goat hair mill or goatskin workers and wool or tannery
workers. Two of the 18 cases were laboratory associated.19
Cutaneous anthrax is the most common naturally
occurring form, with an estimated 2000 cases reported annually.18 Disease typically
follows exposure to anthrax-infected animals. In the United States, 224 cases
of cutaneous anthrax were reported between 1944 and 1994.20 The largest reported
epidemic occurred in Zimbabwe between 1979 and 1985, when more than 10,000
human cases of anthrax were reported, nearly all of them cutaneous.21
Gastrointestinal anthrax is uncommonly reported.18, 22, 23 However,
gastrointestinal outbreaks have been reported in Africa and Asia.24 Gastrointestinal
anthrax follows ingestion of insufficiently cooked contaminated meat and
includes 2 distinct syndromes, oral-pharyngeal and abdominal.22, 24-27 In 1982, there
were 24 cases of oral-pharyngeal anthrax in a rural northern Thailand outbreak
following the consumption of contaminated buffalo meat.24 In 1987, there were
14 cases of gastrointestinal anthrax reported in northern Thailand with both
oral-pharyngeal and abdominal disease occurring.25
No case of inhalational anthrax has been
reported in the United States since 1978,19, 20 making even a single
case a cause for alarm today. As was demonstrated at Sverdlovsk in 1979,
inhalational anthrax is expected to account for most morbidity and essentially
all mortality following the use of anthrax as an aerosolized biological weapon.8, 28 In the setting of an
anthrax outbreak resulting from an aerosolized release, cutaneous anthrax would
be less common than inhalational anthrax, easier to recognize, simpler to
treat, and associated with a much lower mortality. In the Sverdlovsk
experience, there were no deaths in patients developing cutaneous anthrax.8 There is little
information available about the risks of direct contamination of food or water
with anthrax spores. Although human infections have been reported, experimental
efforts to infect primates by direct gastrointestinal instillation of anthrax
spores have not been successful.29
Bacillus anthracis derives from the Greek word for coal, anthrakis, because the disease causes black, coal-like skin
lesions. Bacillus anthracis is an
aerobic, gram-positive, spore-forming, nonmotile Bacillus species. The nonflagellated vegetative cell is
large (1-8 µm in length, 1-1.5 µm in breadth). Spore size is approximately 1
µm. Spores grow readily on all ordinary laboratory media at 37°C, with a
"jointed bamboo-rod" cellular appearance and a unique "curled-hair"
colonial appearance, and display no hemolysis on sheep agar (Figure 1).
This cellular and colonial morphology theoretically should make its
identification by an experienced microbiologist straightforward, although few
practicing microbiologists outside the veterinary community have seen anthrax
colonies other than in textbooks.30
Anthrax spores germinate when they enter an
environment 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
vegetative anthrax bacilli, on the contrary, will only form spores after local
nutrients are exhausted, such as when anthrax-infected body fluids are exposed
to ambient air.16, 17 Full virulence
requires the presence of both an antiphagocytic capsule and 3 toxin components
(ie, protective antigen, lethal factor, and edema factor).30 Vegetative bacteria
have poor survival outside of an animal or human host; colony counts decline to
undetectable within 24 hours following inoculation into water.17 This contrasts with
the environmentally hardy properties of the B
anthracis spore, which can survive for decades.30
Inhalational Anthrax
Inhalational anthrax follows deposition of spore-bearing particles of 1 to 5 µm
into alveolar spaces.31, 32 Macrophages ingest
the spores, some of which undergo lysis and destruction. Surviving spores are
transported via lymphatics to mediastinal lymph nodes, where germination may
occur up to 60 days later.28, 29, 33 The process
responsible for the delayed transformation of spores to vegetative cells is
poorly understood but well documented. In Sverdlovsk, cases occurred from 2 to
43 days after exposure.8 In experimental
monkeys, fatal disease occurred up to 58 days28 and 98 days34 after exposure.
Viable spores have been demonstrated in the mediastinal lymph nodes of monkeys
100 days after exposure.35
Once germination occurs, disease follows
rapidly. Replicating bacteria release toxins leading to hemorrhage, edema, and
necrosis.23, 36 In experimental
animals, once toxin production has reached critical threshold, death occurs
even if sterility of the bloodstream is achieved with antibiotics.19 Based on primate
data, it has been estimated that for humans the LD 50 (lethal dose sufficient
to kill 50% of persons exposed to it) is 2500 to 55,000 inhaled anthrax spores.37
The term inhalational
anthrax reflects the nature of acquisition of the disease. The term anthrax pneumonia is misleading. Typical
bronchopneumonia does not occur. Postmortem pathological study of patients who
died because of inhalational anthrax in Sverdlovsk showed hemorrhagic thoracic
lymphadenitis and hemorrhagic mediastinitis in all patients. In up to half of
the patients, hemorrhagic meningitis also was seen. No patients who underwent
autopsy had evidence of a bronchoalveolar pneumonic process, although 11 of 42
patients undergoing autopsy had evidence of a focal, hemorrhagic, necrotizing
pneumonic lesion analogous to the Ghon complex associated with tuberculosis.38 These findings are
consistent with other human case series and experimentally induced inhalational
anthrax in animals.33, 39, 40
Early diagnosis of inhalational anthrax would be
difficult and would require a high index of suspicion. Clinical information is
available from only some of the 18 cases reported in the United States in this
century and from the limited available information from Sverdlovsk. The
clinical presentation has been described as a 2-stage illness. Patients first
developed a spectrum of nonspecific symptoms, including fever, dyspnea, cough,
headache, vomiting, chills, weakness, abdominal pain, and chest pain.8, 19 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 recovery followed.
Other patients progressed directly to the second, fulminant stage of illness.2, 19, 41
This second stage developed abruptly, with
sudden fever, dyspnea, diaphoresis, and shock. Massive lymphadenopathy and
expansion of the mediastinum led to stridor in some cases.42, 43 A chest radiograph
most often showed a widened mediastinum consistent with lymphadenopathy (Figure 2).42 Up to half of
patients developed hemorrhagic meningitis with concomitant meningismus,
delirium, and obtundation. In this second stage of illness, cyanosis and
hypotension progress rapidly; death sometimes occurs within hours.2, 19, 41
The mortality rate of occupationally acquired
cases in the United States is 89%, but the majority of cases occurred before
the development of critical care units and, in some cases, before the advent of
antibiotics.19 At Sverdlovsk,
it is reported that 68 of the 79 patients with inhalational anthrax died,
although the reliability of the diagnosis in the survivors is questionable.8 Patients who had onset
of disease 30 or more days after release of organisms had a higher reported
survival rate compared with those with earlier disease onset. Antibiotics,
antianthrax globulin, and vaccine were used to treat some residents in the
affected area some time after exposure, but which patients received these
interventions and when is not known. In fatal cases, the 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 disease even after a latency as long as 58 days.28
Modern mortality rates in the setting of
contemporary medical and supportive therapy might be lower than those reported
historically. However, the 1979 Sverdlovsk experience is not instructive.
Although antibiotics, antianthrax globulin, corticosteroids, and mechanical
ventilation were used, individual clinical records have not been made public.8 It is also uncertain
if the B anthracis strain to
which patients were exposed was susceptible to the predominant antibiotics that
were used during the outbreak.
Physiological sequelae of severe anthrax
infection in animal models have been described as hypocalcemia, profound
hypoglycemia, hyperkalemia, depression and paralysis of respiratory center,
hypotension, anoxia, respiratory alkalosis, and terminal acidosis.44, 45 Those animal studies
suggest that in addition to the rapid administration of antibiotics, survival
might improve with vigilant correction of electrolyte disturbances and
acid-base imbalance, glucose infusion, and early mechanical ventilation and
vasopressor administration.
Cutaneous Anthrax
Cutaneous anthrax occurs following the deposition of the organism into skin
with previous cuts or abrasions especially susceptible to infection.21, 46 Areas of exposed
skin, such as arms, hands, face, and neck, are the most frequently affected.
There are no data to suggest the possibility of a prolonged latency period in
cutaneous anthrax. In Sverdlovsk, cutaneous cases occurred only as late as 12
days after the original aerosol release.8 After the spore
germinates in skin tissues, toxin production results in local edema (Figure 3).
An initially pruritic macule or papule enlarges into a round ulcer by the
second day. Subsequently, 1- to 3-mm vesicles may appear, which discharge clear
or serosanguinous fluid containing numerous organisms on Gram stain. As shown
in Figure 3,
development of a painless, depressed, black eschar follows, often associated
with extensive local edema. The eschar dries, loosens, and falls off in the
next 1 to 2 weeks, most often leaving no permanent scar. Lymphangitis and
painful lymphadenopathy can occur with associated systemic symptoms. Although
antibiotic therapy does not appear to change the course of eschar formation and
healing, it does decrease the likelihood of systemic disease. Without
antibiotic therapy, the mortality rate has been reported to be as high as 20%;
with antibiotics, death due to cutaneous anthrax is rare.2
Gastrointestinal Anthrax
Gastrointestinal anthrax occurs following deposition and subsequent germination
of spores in the upper or lower gastrointestinal tract. The former results in
the oral-pharyngeal form of disease.24-26 An oral or
esophageal ulcer leads to development of regional lymphadenopathy, edema, and
sepsis.24-26 The latter
results in primary intestinal lesions occurring predominantly in the terminal
ileum or cecum,38 presenting
initially with nausea, vomiting, and malaise and progressing rapidly to bloody
diarrhea, acute abdomen, or sepsis.22 Massive ascites has
occurred in some cases of gastrointestinal anthrax.27 Advanced infection
may appear similar to the sepsis syndrome occurring in either inhalational or
cutaneous anthrax.2 Some authors suggest
that aggressive medical intervention such as would be recommended for inhalational
anthrax may reduce mortality, although, given the difficulty of early
diagnosis, mortality almost inevitably would be high.2, 22
Given the rarity of anthrax infection and the
possibility that early cases are a harbinger of a larger epidemic, the first
suspicion of an anthrax illness must lead to immediate notification of the
local or state health department, local hospital epidemiologist, and local or
state health laboratory. By this mechanism, definitive tests can be arranged
rapidly through a reference laboratory and, as necessary, the US Army Medical
Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Md.
The first evidence of a clandestine release of
anthrax as a biological weapon most likely will be patients seeking medical treatment
for symptoms of inhalational anthrax. The sudden appearance of a large number
of patients in a city or region with an acute-onset flulike illness and case
fatality rates of 80% or more, with nearly half of all deaths occurring within
24 to 48 hours, is highly likely to be anthrax or pneumonic plague (Table 1).
Currently, there are no effective atmospheric warning systems to detect an
aerosol cloud of anthrax spores.47
Rapid diagnostic tests for diagnosing anthrax,
such as enzyme-linked immunosorbent assay for protective antigen and polymerase
chain reaction, are available only at national reference laboratories. Given
the limited availability of these tests and the time required to dispatch
specimens and perform assays, rapid diagnostic testing would be primarily for
confirmation of diagnosis and determining in vitro susceptibility to antibiotics.
In addition, these tests will be used in the investigation and management of
anthrax hoaxes, such as the series occurring in late 1998.48 They would also be of
value should suspicious materials in the possession of a terrorist be
identified as possibly containing anthrax.
If only small numbers of cases present
contemporaneously, the clinical similarity of early inhalational anthrax to
other acute respiratory tract infections may delay initial diagnosis for some
days. However, diagnosis of anthrax could soon become apparent through the
astute recognition of an unusual radiological finding, identification in the
microbiology laboratory, or recognition of specific pathologic findings. A
widened mediastinum on chest radiograph (Figure 2)
in a previously healthy patient with evidence of overwhelming flulike illness
is essentially pathognomonic of advanced inhalational anthrax and should prompt
immediate action.23, 42 Although treatment at
this stage would be unlikely to alter the outcome of illness in the patient
concerned, it might lead to earlier diagnosis in others.
Microbiologic studies can also demonstrate B anthracis and may be the means for
initial detection of an outbreak. The bacterial burden may be so great in
advanced infection that bacilli are visible on Gram stain of unspun peripheral
blood, as has been demonstrated in primate studies (Figure 1).
While this is a remarkable finding that would permit an astute clinician or
microbiologist to make the diagnosis, the widespread use of automated
cell-counter technology in diagnostic laboratories makes this unlikely.41
The most useful microbiologic test is the
standard blood culture, which should show growth in 6 to 24 hours. If the
laboratory has been alerted to the possibility of anthrax, biochemical testing
and review of colonial morphology should provide a preliminary diagnosis 12 to
24 hours later. Definitive diagnosis would require an additional 1 to 2 days of
testing in all but a few national reference laboratories. It should be noted,
however, that if the laboratory has not been alerted to the possibility of
anthrax, B anthracis may not be
correctly identified. Routine laboratory procedures customarily identify a Bacillus species from a blood culture
approximately 24 hours after growth, but most laboratories do not further
identify Bacillus species unless
specifically requested to do so. In the United States, the isolation of Bacillus species most often represents
growth of Bacillus cereus. The
laboratory and clinician must determine whether its isolation represents
specimen contamination.49 There have been no B anthracis bloodstream infections
reported for more than 20 years. However, given the possibility of anthrax
being used as a weapon and the importance of early diagnosis, it would be
prudent for laboratory procedures to be modified so that B anthracis is excluded after
identification of a Bacillus
species bacteremia.
Sputum culture and Gram stain are unlikely to be
diagnostic, given the lack of a pneumonic process.30 If cutaneous anthrax
is suspected, a Gram stain and culture of vesicular fluid will confirm the
diagnosis.
A diagnosis of inhalational anthrax also might
occur at postmortem examination following a rapid, unexplained terminal
illness. Thoracic hemorrhagic necrotizing lymphadenitis and hemorrhagic
necrotizing mediastinitis in a previously healthy adult are essentially
pathognomonic of inhalational anthrax.38, 43 Hemorrhagic
meningitis should also raise strong suspicion of anthrax infection.23, 38, 43, 50 Despite pathognomonic
features of anthrax on gross postmortem examination, the rarity of anthrax
makes it unlikely that a pathologist would immediately recognize these
findings. If the case were not diagnosed at gross examination, additional days
would likely pass before microscopic slides would be available to suggest the
disease etiology.
The US anthrax vaccine, an inactivated cell-free
product, was licensed in 1970 and is produced by Bioport Corp, Lansing, Mich
(formerly called the Michigan Biologic Products Institute). The vaccine is
licensed to be given in a 6-dose series and has recently been mandated for all
US military active- and reserve-duty personnel.51 The vaccine is made
from the cell-free filtrate of a nonencapsulated attenuated strain of B anthracis.52 The principal antigen
responsible for inducing immunity is the protective antigen.18, 23 A similar vaccine has
been shown in 1 small placebo-controlled human trial to be efficacious against
cutaneous anthrax.53 As of March 1, 1999,
approximately 590,000 doses of anthrax vaccine have been administered to US
Armed Forces (Gary Strawder, Department of Defense, Falls Church, Va, oral
communication, April 1999); no serious adverse events have been causally
related (Miles Braun, Food and Drug Administration, Rockville, Md, written
communication, April 1999). In a study of experimental monkeys, inoculation
with this vaccine at 0 and 2 weeks was completely protective against an aerosol
challenge at 8 and 38 weeks and 88% effective at 100 weeks.54
A human live attenuated vaccine is produced and
used in countries of the former Soviet Union.55 In the Western world,
live attenuated vaccines have been considered unsuitable for use in humans.55
Current vaccine supplies are limited and the US
production capacity is modest. It will be years before increased production
efforts can make available sufficient quantities of vaccine for civilian use.
However, even if vaccine were available, populationwide vaccination would not
be recommended at this time, given the costs and logistics of a large-scale
vaccination program and the unlikely occurrence of a bioterrorist attack in any
given community. Vaccination of some essential service personnel should be
considered if vaccine becomes available. Postexposure vaccination following a
biological attack with anthrax would be recommended with antibiotic
administration to protect against residual retained spores, if vaccine were
available.
Recommendations regarding antibiotic and vaccine
use in the setting of a biological anthrax attack are conditioned by a limited
number of studies in experimental animals, current understanding of antibiotic
resistance patterns, and the possible requirement to treat large numbers of
casualties. A number of possible therapeutic strategies have yet to be fully
explored experimentally or submitted for approval to the FDA. For these
reasons, the working group offers consensus recommendations based on the best
available evidence. The recommendations do not represent uses currently
approved by the FDA or an official position on the part of any of the federal
agencies whose scientists participated in these discussions and will need to be
revised as further relevant information becomes available.
Given the rapid course of symptomatic
inhalational anthrax, early antibiotic administration is essential. A delay of
antibiotic treatment for patients with anthrax infection even by hours may
substantially lessen chances for survival.56, 57 Given the difficulty
in achieving rapid microbiologic diagnosis of anthrax, all persons with fever
or evidence of systemic disease in an area where anthrax cases are occurring
should be treated for anthrax until the disease is excluded.
There are no clinical studies of the treatment
of inhalational anthrax in humans. Thus, antibiotic regimens commonly
recommended for empirical treatment of sepsis have not been studied in this
setting. In fact, natural strains of B
anthracis are resistant to many of the antibiotics used in these
empirical regimens, such as those of the extended-spectrum cephalosporins.58, 59 Most naturally
occurring anthrax strains are sensitive to penicillin, and penicillin
historically has been the preferred therapy for the treatment of anthrax.
Penicillin is approved by the FDA for this indication,41, 56, 57 as is doxycycline.60 In studies of small
numbers of monkeys infected with susceptible strains of B anthracis, oral doxycycline has proved
efficacious.41
Doxycycline is the preferred option from the
tetracycline class of antibiotics because of its proven efficacy in monkey
studies and its ease of administration. Other members of this class of
antibiotics are suitable alternatives. Although treatment of anthrax infection
with ciprofloxacin has not been studied in humans, animal models suggest
excellent efficacy.28, 41, 61 In vitro data suggest
that other fluoroquinolone antibiotics would have equivalent efficacy in
treating anthrax infection, although no animal data exist for fluoroquinolones
other than ciprofloxacin.59
Reports have been published of a B anthracis vaccine strain that has been
engineered by Russian scientists to resist the tetracycline and penicillin
classes of antibiotics.62 Although the
engineering of quinolone-resistant B
anthracis may also be possible, to date there have been no published
accounts of this.
Balancing considerations of efficacy with
concerns regarding resistance, the working group recommends that ciprofloxacin
or other fluoroquinolone therapy be initiated in adults with presumed
inhalational anthrax infection. Antibiotic resistance to penicillin- and
tetracycline-class antibiotics should be assumed following a terrorist attack
until laboratory testing demonstrates otherwise. Once the antibiotic
susceptibility of the B anthracis
strain of the index case has been determined, the most widely available,
efficacious, and least toxic antibiotic should be administered to patients and
persons requiring postexposure prophylaxis.
In a contained casualty setting (a situation in which
a modest number of patients require therapy), the working group recommends
intravenous antibiotic therapy, as shown in Table 2.
If the number of persons requiring therapy is sufficiently high (ie, a mass
casualty setting), the working group recognizes that intravenous therapy will
no longer be possible for reasons of logistics and/or exhaustion of equipment
and antibiotic supplies, and oral therapy will need to be used (Table 3).
The threshold number of cases at which parenteral therapy becomes impossible
depends on a variety of factors, including local and regional health care
resources.
In experimental animals, antibiotic therapy
during anthrax infection has prevented development of an immune response.28, 62 This suggests that
even if the antibiotic-treated patient survives anthrax infection, risk for
recurrence remains for at least 60 days because of the possibility of delayed
germination of spores. Therefore, the working group recommends that antibiotic
therapy be continued for 60 days, with oral therapy replacing intravenous
therapy as soon as a patient's clinical condition improves. If vaccine were to
become widely available, postexposure vaccination in patients being treated for
anthrax infection might permit the duration of antibiotic administration to be
shortened to 30 to 45 days, with concomitant administration of 3 doses of
anthrax vaccine at 0, 2, and 4 weeks.
The treatment of cutaneous anthrax historically
has been with oral penicillin. The working group recommends that oral
fluoroquinolone or tetracycline antibiotics as well as amoxicillin in the adult
dosage schedules described in Table 2
and Table 3
would be suitable alternatives if antibiotic susceptibility is proved. Although
previous guidelines have suggested treating cutaneous anthrax for 7 to 10 days,23, 49 the working group
recommends treatment for 60 days in the setting of bioterrorism, given the
presumed exposure to the primary aerosol. Treatment of cutaneous anthrax
generally prevents progression to systemic disease, although it does not
prevent the formation and evolution of the eschar. Topical therapy is not
useful.2
Other antibiotics effective against B anthracis in vitro include
chloramphenicol, erythromycin, clindamycin, extended-spectrum penicillins,
macrolides, aminoglycosides, vancomycin hydrochloride, cefazolin, and other
first-generation cephalosporins.58, 59, 64 The efficacy of these
antibiotics has not been tested in humans or animal studies. The working group
recommends the use of these antibiotics only if the previously cited
antibiotics are unavailable or if the strain is otherwise antibiotic resistant.
Natural resistance of B anthracis
strains exists against sulfamethoxazole, trimethoprim, cefuroxime, cefotaxime
sodium, aztreonam, and ceftazidime.58, 59, 64 Therefore, these
antibiotics should not be used in the treatment or prophylaxis of anthrax
infection.
Postexposure Prophylaxis
Guidelines regarding which populations would require postexposure prophylaxis
following the release of anthrax as a biological weapon would need to be
developed quickly by state and local health departments in consultation with
national experts. These decisions require estimates of the timing and location
of the exposure and the relevant weather conditions in an outdoor release.65 Ongoing monitoring of
cases would be needed to define the high-risk areas, direct follow-up, and
guide the addition or deletion of groups to receive postexposure prophylaxis.
There are no FDA-approved postexposure
antibiotic regimens following exposure to an anthrax aerosol. For postexposure
prophylaxis, the working group recommends the same antibiotic regimen as that
recommended for treatment of mass casualties; prophylaxis should be continued
for 60 days (Table 3).
Management of Special Groups
Consensus recommendations for special 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 fluoroquinolones should
not be used in children younger than 16 to 18 years because of a link to
permanent arthropathy in adolescent animals and transient arthropathy in a
small number of children.60 However, balancing
these risks against the risks of anthrax caused by an engineered
antibiotic-resistant strain, the working group recommends that ciprofloxacin be
used in the pediatric population for initial therapy or postexposure
prophylaxis following an anthrax attack (Table 2).
If antibiotic susceptibility testing allows, penicillin should be substituted
for the fluoroquinolone.
As a third alternative, doxycycline could be
used. The American Academy of Pediatrics has recommended that doxycycline not
be used in children younger than 9 years because the drug has resulted in
retarded skeletal growth in infants and discolored teeth in infants and
children.60 However, the
serious risk of infection following an anthrax attack supports the consensus
recommendation that doxycycline be used in children if antibiotic
susceptibility testing, exhaustion of drug supplies, or allergic reaction
preclude use of penicillin and ciprofloxacin.
In a contained casualty setting, the working
group recommends that children receive intravenous antibiotics (Table 2).
In a mass casualty setting and as postexposure prophylaxis, the working group
recommends that children receive oral antibiotics (Table 3).
The US vaccine is licensed for use only in
persons aged 18 to 65 years because studies to date have been conducted exclusively
in this group.52 No data exist
for children, but based on experience with other inactivated vaccines, it is
likely that the vaccine would be safe and effective.
Pregnant Women.
Fluoroquinolones are not generally recommended during pregnancy because of
their known association with arthropathy in adolescent animals and small
numbers of children. Animal studies have discovered no evidence of
teratogenicity related to ciprofloxacin, but no controlled studies of
ciprofloxacin in pregnant women have been conducted. Balancing these possible
risks against the concerns of anthrax due to engineered antibiotic-resistant
strains, the working group recommends that ciprofloxacin be used in pregnant
women for therapy and postexposure prophylaxis following an anthrax attack (Table 2
and Table 3).
No adequate controlled trials of penicillin or amoxicillin administration
during pregnancy exist. However, the CDC recommends penicillin for the
treatment of syphilis during pregnancy and amoxicillin as a treatment
alternative for chlamydial infections during pregnancy.60
The working group recommends that pregnant women
receive fluoroquinolones in the usual adult dosages. If susceptibility testing
allows, intravenous penicillin in the usual adult dosages should be substituted
for fluoroquinolones. As a third alternative, intravenous doxycycline could be
used. The tetracycline class of antibiotics has been associated with both toxic
effects in the liver in pregnant women and fetal toxic effects, including
retarded skeletal growth.60 Balancing the risks
of anthrax infection with those associated with doxycycline use in pregnancy,
the working group recommends that doxycycline be used in pregnant women for
therapy and postexposure prophylaxis if antibiotic susceptibility testing,
exhaustion of drug supplies, or allergic sensitivity preclude the use of
penicillin and ciprofloxacin. If doxycycline is used in pregnant women,
periodic liver function testing should be performed if possible.
Ciprofloxacin (and other fluoroquinolones),
penicillin, and doxycycline (and other tetracyclines) are each excreted in
breast milk. Therefore, a breast-feeding woman should be treated or given
prophylaxis with the same antibiotic as her infant based on what is most safe
and effective for the infant (see pediatric guidelines herein) to minimize risk
to 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 models of
anthrax infection. Therefore, the working group consensus recommendation is to
administer antibiotics as for immunocompetent adults and children (Table 2
and Table 3).
There are no data to suggest patient-to-patient
transmission of anthrax occurs.8, 46 Thus, standard
barrier isolation precautions are recommended for hospitalized patients with
all forms of anthrax infection, but the use of high-efficiency particulate air
filter masks or other measures for airborne protection are not indicated.66 There is no need to
immunize or provide prophylaxis to patient contacts (eg, household contacts,
friends, coworkers) unless a determination is made that they, like the patient,
were exposed to the aerosol at the time of the attack.
In addition to immediate notification of the
hospital epidemiologist and state health department, the local hospital
microbiology laboratories should be notified at the first indication of anthrax
so that safe specimen processing under biosafety level 2 conditions can be
undertaken.41, 67 A number of
disinfectants used for standard hospital infection control, such as
hypochlorite, are effective in cleaning environmental surfaces contaminated
with infected bodily fluids.17, 66
Proper burial or cremation of humans and animals
who have died because of anthrax infection is important in preventing further
transmission of the disease. Serious consideration should be given to
cremation. Embalming of bodies could be associated with special risks.66 If autopsies are
performed, all related instruments and materials should be autoclaved or
incinerated.66 Animal
transmission might occur if infected animal remains are not cremated or buried.16, 21
Recommendations regarding decontamination in the
event of an intentional aerosolization of anthrax spores are based on evidence
concerning aerosolization, anthrax spore survival, and environmental exposures
at Sverdlovsk and among goat hair mill workers. The greatest risk to human
health following an intentional aerosolization of anthrax spores occurs during
the period in which anthrax spores remain airborne, called primary aerosolization. The duration for
which spores remain airborne and the distance spores travel before they become
noninfectious or fall to the ground is dependent on meteorological conditions
and aerobiological properties of the dispersed aerosol.8, 65 Under circumstances
of maximum survival and persistence, the aerosol would be fully dispersed
within hours to 1 day at most, well before the first symptomatic cases would be
seen. Following the discovery that a bioweapon has been used, anthrax spores
may be detected on environmental surfaces using rapid assay kits or culture,
but they provide no indication as to the risk of reaerosolization.
The risk that anthrax spores might pose to
public health after the period of primary aerosolization can be inferred from
the Sverdlovsk experience, investigations in animal hair processing plants, and
modeling analyses by the US Army. At Sverdlovsk, new cases of inhalational
anthrax developed as late as 43 days after the presumed date of release, but
none occurred during the months and years afterward.68 Some have questioned
whether any of those cases with onset of disease beyond 7 days might have
represented illness following resuspension of spores from the ground or other
surfaces, a process that has been called secondary
aerosolization. While it is impossible to state with certainty that
secondary aerosolizations did not occur, it appears unlikely. It should be
noted that few efforts were made to decontaminate the environment after the
accident and only 47,000 of the city's 1 million inhabitants were vaccinated.8 The epidemic curve (Figure 4)
is typical for a common-source epidemic, and it is possible to account for
virtually all patients having been within the area of the plume on the day of
the accident. Moreover, if secondary aerosolization had been important, new
cases almost certainly would have continued for a period well beyond the
observed 43 days.
Although persons working with animal hair or
hides are known to be at increased risk of developing inhalational or cutaneous
anthrax, surprisingly few of those exposed in the United States have developed
disease. During the first half of this century, a significant number of goat
hair mill workers were likely exposed to aerosolized spores. Mandatory
vaccination became a requirement for working in goat hair mills only in the
1960s. Meanwhile, many unvaccinated person-years of high-risk exposure had
occurred, but only 13 cases of inhalational anthrax were reported.19, 44 One study of environmental
exposure was conducted at a Pennsylvania goat hair mill at which workers were
shown to inhale up to 510 B anthracis
particles of at least 5 µm in diameter per person per 8-hour shift. These
concentrations of spores were constantly present in the environment during the
time of this study,44 but no cases of
inhalational anthrax occurred.
Modeling analyses 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
asphalt-paved roads or from a runway used by helicopters or jet aircraft.69 A separate study
showed that in areas of ground contaminated with 20 million Bacillus subtilis spores per square meter,
a soldier exercising actively for a 3-hour period would inhale between 1000 and
15,000 spores.70
Much has been written about the technical
difficulty of decontaminating an environment contaminated with anthrax spores.
A classic case is the experience at Gruinard Island in the United Kingdom.
During World War II, British military undertook explosives testing with anthrax
spores on this island off the Scottish coast. Spores persisted and remained
viable for 36 years following the conclusion of testing. Decontamination 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 included 280 tons of formaldehyde and 2000
tons of seawater.17, 71
If an environmental surface is proved to be
heavily contaminated with anthrax spores in the immediate area of a spill or
close proximity to the point of release of an anthrax aerosol, decontamination
of that area may decrease the slight risk of acquiring anthrax by secondary
aerosolization. However, decontamination of large urban areas or even a
building following an exposure to an anthrax aerosol would be extremely
difficult and is not indicated. Although the risk of disease caused by
secondary aerosolization would be extremely low, it would be difficult to offer
absolute assurance that there was not risk whatsoever. Postexposure
vaccination, if vaccine were available, might be a possible intervention that
could further lower the risk of anthrax infection in this setting.
In the setting of an announced alleged anthrax
release, such as the series of anthrax hoaxes occurring in many areas of the
United States in 1998,48 any person coming in
direct physical contact with a substance alleged to be anthrax should perform
thorough washing of the exposed skin and articles of clothing with soap and
water.72 Further
decontamination of directly exposed individuals or of others is not indicated.
In addition, any person in direct physical contact with the alleged substance
should receive postexposure antibiotic prophylaxis until the substance is
proved not to be anthrax. If the alleged substance is proved to be anthrax,
immediate consultation with experts at the CDC and USAMRIID should be obtained.
To develop a maximally effective response to a
bioterrorist incident involving anthrax, the medical community will require new
knowledge of the organism, its genetics and pathogenesis, improved rapid
diagnostic techniques, improved prophylactic and therapeutic regimens, and an
improved second-generation vaccine.47 A recently published
Russian study indicates that genes transferred from the related B cereus can act to enable B anthracis to evade the protective effect
of the live attenuated Russian vaccine in a rodent model.73 Research is needed to
determine the role of these genes with respect to virulence and ability to
evade vaccine-induced immunity. Furthermore, the relevance of this finding for
the US vaccine needs to be established. An accelerated vaccine development
effort is needed to allow the manufacture of an improved second-generation
product that requires fewer doses. Finally, an expanded knowledge base is
needed regarding possible maximum incubation times after inhalation of
spore-containing aerosols and optimal postexposure antibiotic regimens.
Author/Article Information
Author Affiliations: The Center
for Civilian Biodefense Studies (Drs Inglesby, Henderson, Bartlett, O'Toole,
Perl, and Russell), and the Schools of Medicine (Drs Inglesby, Bartlett, and
Perl) and Public Health (Drs Henderson, O'Toole, and Russell), Johns Hopkins
University, Baltimore, Md; Viral and Rickettsial Diseases, California
Department of Health, Berkeley (Dr Ascher); US Army Medical Research Institute
of Infectious Diseases, Frederick, Md (Drs Eitzen, Friedlander, and Parker);
Office of Emergency Management, New York, NY (Mr Hauer); Centers for Disease
Control and Prevention, Atlanta, Ga (Dr McDade); Acute Disease Epidemiology,
Minnesota Department of Health, Minneapolis (Dr Osterholm); and the Office of
Emergency Preparedness, Department of Health and Human Services, Rockville, Md
(Dr Tonat).
Corresponding Author and Reprints:
Thomas V. Inglesby, MD, Johns Hopkins Center for Civilian Biodefense Studies,
Johns Hopkins University, Candler Bldg, Suite 850, 111 Market Pl, Baltimore, MD
21202 (e-mail: [log in to unmask]).
Ex Officio Participants in the
Working Group on Civilian Biodefense: George Curlin, MD, National Institutes of Health, Bethesda, Md;
Margaret Hamburg, MD, and William Raub, PhD, Office of Assistant Secretary for
Planning and Evaluation, 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 and Stuart Nightingale, MD, FDA, Rockville.
Funding/Support: Funding for this study primarily was provided by each
participant's institution or agency. The Office of Emergency Preparedness,
DHHS, provided travel funds for 4 members of the group.
Disclaimers: In many cases, the indication and dosages and other information
are not consistent with current approved labeling by the US Food and Drug
Administration (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 participated in these
discussions. Unlabeled uses of the products 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 Defense or US Department of Army positions, policies,
or decisions unless so designated by other documentation.
Additional Articles: This article is 1 in a series entitled Medical and Public Health Management Following the Use of a Biological
Weapon: Consensus Statements of the Working Group on Civilian Biodefense.
Acknowledgment: The working group wishes to thank Jeanne Guillermin, PhD,
professor of sociology, Boston College, Boston, Mass, for her comments on the
manuscript. Starting in 1992, Dr Guillermin directed the interview project to
verify onset, hospital, and death data for the 1979 Sverdlovsk victims, which
will be detailed in Anthrax, A Book of Names,
from California Press. We also thank Matthew Meselson, Timothy Townsend, MD,
Martin Hugh-Jones, MA, VetMB, MPH, PhD, and Philip Brachman, MD, for their
review and commentary of the manuscript.
1.
Carter A, Deutsch J, Zelicow P.
Catastrophic terrorism.
Foreign Aff.
1998;77:80-95.
2.
Lew D.
Bacillus anthracis (anthrax).
In: Mandell GL, Bennett JE, Dolin R, eds. Principles
and Practices of Infectious Disease.New York, NY: Churchill
Livingstone Inc; 1995:1885-1889.
3.
Christopher GW, Cieslak TJ, Pavlin JA, Eitzen EM.
Biological warfare: a historical perspective.
JAMA.
1997;278:412-417.
MEDLINE
4.
Cole LA.
The specter of biological weapons.
Sci Am.
December 1996:60-65.
5.
Zilinskas RA.
Iraq's biological weapons: the past as future?
JAMA.
1997;278:418-424.
MEDLINE
6.
Public Health Service Office of Emergency Preparedness.
Proceedings of the Seminar on Responding to
the Consequences of Chemical and Biological Terrorism.
Washington, DC: US Dept of Health and Human Services; 1995.
7.
WuDunn S, Miller J, Broad W.
How Japan germ terror alerted world.
New York Times.
May 26, 1998:1-6.
8.
Meselson M, Guillemin J, Hugh-Jones M, et al.
The Sverdlovsk anthrax outbreak of 1979.
Science.
1994;266:1202-1208.
MEDLINE
9.
World Health Organization.
Health Aspects of Chemical and Biological
Weapons.
Geneva, Switzerland: World Health Organization; 1970:98-99.
10.
Simon JD.
Biological terrorism: preparing to meet the threat.
JAMA.
1997;278:428-430.
MEDLINE
11.
Cristy GA, Chester CV.
Emergency Protection Against Aerosols.
Oak Ridge, Tenn: Oak Ridge National Laboratory; 1981. Publication ORNL-5519.
12.
Office of Technology Assessment, US Congress.
Proliferation of Weapons of Mass Destruction.
Washington, DC: US Government Printing Office; 1993:53-55. Publication
OTA-ISC-559.
13.
Kaufmann AF, Meltzer MI, Schmid GP.
The economic impact of a bioterrorist attack.
Emerg Infect Dis.
1997;3:83-94.
MEDLINE
14.
Kohout E, Sehat A, Ashraf M.
Anthrax: a continuous problem in south west Iran.
Am J Med Sci.
1964;247:565.
15.
Pienaar UV.
Epidemiology of anthrax in wild animals and the control on anthrax epizootics
in the Kruger National Park, South Africa.
Fed Proc.
1967;26:1496-1591.
MEDLINE
16.
Dragon DC, Rennie RP.
The ecology of anthrax spores.
Can Vet J.
1995;36:295-301.
MEDLINE
17.
Titball RW, Turnbull PC, Hutson RA.
The monitoring and detection of Bacillus
anthracis in the environment.
J Appl Bacteriol.
1991;70(suppl):9S-18S.
18.
Brachman PS, Friedlander A.
Anthrax.
In: Plotkin SA, Orenstein WA, eds. Vaccines3rd
ed. Philadelphia, Pa: WB Saunders Co; 1999:629-637.
19.
Brachman PS.
Inhalation anthrax.
Ann N Y Acad Sci.
1980;353:83-93.
MEDLINE
20.
Centers for Disease Control and Prevention.
Summary of notifiable diseases, 1945-1994.
MMWR Morb Mortal Wkly Rep.
1994;43:70-78.
21.
Myenye KS, Siziya S, Peterson D.
Factors associated with human anthrax outbreak in the Chikupo and Ngandu
villages of Murewa district in Mashonaland East Province, Zimbabwe.
Cent Afr J Med.
1996;42:312-315.
MEDLINE
22.
Tekin A, Bulut N, Unal T.
Acute abdomen due to anthrax.
Br J Surg.
1997;84:813.
MEDLINE
23.
Friedlander A.
Anthrax.
In: Zajtchuk R, Bellamy RF, eds. Textbook of
Military Medicine: Medical Aspects of Chemical and Biological WarfareWashington,
DC: Office of the Surgeon General, US Dept of the Army; 1997:467-478.
24.
Sirisanthana T, Nelson KE, Ezzell JW, Abshire TG.
Serological studies of patients with cutaneous and oral-pharyngeal anthrax from
northern Thailand.
Am J Trop Med Hyg.
1988;39:575-581.
MEDLINE
25.
Kunanusont C, Limpakarnjanarat K, Foy HM.
Outbreak of anthrax in Thailand.
Ann Trop Med Parasitol.
1989;84:507-512.
26.
Sirisanthana T, Navachareon N, Tharavichitkul P, Sirisanthana V, Brown AE.
Outbreak of oral-pharyngeal anthrax.
Am J Trop Med Hyg.
1984;33:144-150.
MEDLINE
27.
Dutz W, Saidi F, Kouhout E.
Gastric anthrax with massive ascites.
Gut.
1970;11:352-354.
MEDLINE
28.
Friedlander A, Welkos SL, Pitt ML, et al.
Postexposure prophylaxis against experimental inhalation anthrax.
J Infect Dis.
1993;167:1239-1242.
MEDLINE
29.
Lincoln RE, Hodges DR, Klein F, et al.
Role of the lymphatics in the pathogenesis of anthrax.
J Infect Dis.
1965;115:481-494.
MEDLINE
30.
Williams RP.
Bacillus anthracis and other
spore forming bacilli.
In: Braude AI, Davis LE, Fierer J, eds. Infectious
Disease and Medical Microbiology.Philadelphia, Pa: WB Saunders Co;
1986:270-278.
31.
Druett HA, Henderson DW, Packman L, Peacock S.
Studies on respiratory infection.
J Hyg.
1953;51:359-371.
32.
Hatch TF.
Distribution and deposition of inhaled particles in respiratory tract.
Bacteriol Rev.
1961;25:237-240.
33.
Ross JM.
The pathogenesis of anthrax following the administration of spores by the
respiratory route.
J Pathol Bacteriol.
1957;73:485-495.
34.
Glassman HN.
Industrial inhalation anthrax.
Bacteriol Rev.
1966;30:657-659.
35.
Henderson DW, Peacock S, Belton FC.
Observations on the prophylaxis of experimental pulmonary anthrax in the
monkey.
J Hyg.
1956;54:28-36.
36.
Smith H, Keppie J.
Observations on experimental anthrax.
Nature.
1954;173:869-870.
37.
Defense Intelligence Agency.
Soviet Biological Warfare Threat.
Washington, DC: US Dept of Defense; 1986. Publication DST-161OF-057-86.
38.
Amramova FA, Grinberg LM, Yampolskaya O, Walker DH.
Pathology of inhalational anthrax in 42 cases from the Sverdlovsk outbreak in
1979.
Proc Natl Acad Sci U S A.
1993;90:2291-2294.
MEDLINE
39.
Dalldorf F, Kaufmann AF, Brachman PS.
Woolsorters' disease.
Arch Pathol.
1971;92:418-426.
MEDLINE
40.
Gleiser CA, Berdjis CC, Harman HA, Gochenour WS.
Pathology of experimental respiratory anthrax in Macaca Mulatta.
Br J Exp Pathol.
1963;44:416-426.
41.
Franz DR, Jahrling PB, Friedlander A, et al.
Clinical recognition and management of patients exposed to biological warfare
agents.
JAMA.
1997;278:399-411.
MEDLINE
42.
Vessal K, Yeganehdoust J, Dutz W, Kohout E.
Radiologic changes in inhalation anthrax.
Clin Radiol.
1975;26:471-474.
MEDLINE
43.
Albrink WS, Brooks SM, Biron RE, Kopel M.
Human inhalation anthrax.
Am J Pathol.
1960;36:457-471.
44.
Dahlgren CM, Buchanan LM, Decker HM, et al.
Bacillus anthracis aerosols in
goat hair processing mills.
Am J Hyg.
1960;72:24-31.
45.
Walker JS, Lincoln RE, Klein F.
Pathophysiological and biochemical changes in anthrax.
Fed Proc.
1967;26:1539-1544.
MEDLINE
46.
Pile JC, Malone JD, Eitzen EM, Friedlander A.
Anthrax as a potential biological warfare agent.
Arch Intern Med.
1998;158:429-434.
MEDLINE
47.
Institute of Medicine National Research Council.
Improving Civilian Medical Response to
Chemical and Biological Terrorist Incidents.
Washington, DC: National Academy Press; 1998:1-70.
48.
Centers for Disease Control and Prevention.
Bioterrorism alleging use of anthrax and interim guidelines for managementUnited States, 1998.
MMWR Morb Mortal Wkly Rep.
1999;48:69-74.
MEDLINE
49.
Penn C, Klotz SA.
Anthrax.
In: Gorbach SL, Bartlett JG, Blacklow NR, eds.Infectious
DiseasesPhiladelphia, Pa: WB Saunders Co; 1998:1575-1578.
50.
Brachman PS.
Anthrax.
In: Hoeprich PD, Jordan MC, Ronald AR, eds. Infectious
DiseasesPhiladelphia, Pa: JB Lippincott; 1994:1003-1008.
51.
Anthrax vaccine, military use in Persian Gulf region [press release].
Washington, DC: US Dept of Defense; September 8, 1998.
52.
Michigan Department of Public Health.
Anthrax Vaccine Absorbed.
Lansing: Michigan Dept of Public Health; 1978.
53.
Brachman PS, Gold H, Plotkin SA, Fekety FR, Werrin M, Ingraham NR.
Field evaluation of human anthrax vaccine.
Am J Public Health.
1962;52:632-645.
54.
Ivins BE, Fellows P, Pitt ML, et al.
Efficacy of standard human anthrax vaccine against Bacillus anthracis aerosol spore challenge in rhesus
monkeys.
Salisbury Med Bull.
1996;87:125-126.
55.
Turnbull PC.
Anthrax vaccines: past, present and future.
Vaccine.
1991;9:533-539.
MEDLINE
56.
Barnes JM.
Penicillin and B anthracis.
J Pathol Bacteriol. 1947;194:113-125.
57.
Lincoln RE, Klein F, Walker JS, et al.
Successful treatment of monkeys for septicemic anthrax.
In: Antimicrobial Agents and Chemotherapy1964Washington,
DC: American Society for Microbiology; 1965:759-763.
58.
Odendaal MW, Peterson PM, de Vos V, Botha AD.
The antibiotic sensitivity patterns of Bacillus
anthracis isolated from the Kruger National Park.
Onderstepoort J Vet Res.
1991;58:17-19.
MEDLINE
59.
Doganay M, Aydin N.
Antimicrobial susceptibility of Bacillus
anthracis.
Scand J Infect Dis. 1991;23:333-335.
60.
American Hospital Formulary Service.
AHFS Drug Information.
Bethesda, Md: American Society of Health System Pharmacists; 1996.
61.
Kelly D, Chulay JD, Mikesell P, Friedlander A.
Serum concentrations of penicillin, doxycycline, and ciprofloxacin during
prolonged therapy in rhesus monkeys.
J Infect Dis.
1992;166:1184-1187.
MEDLINE
62.
Stepanov AV, Marinin LI, Pomerantsev AP, Staritsin NA.
Development of novel vaccines against anthrax in man.
J Biotechnol.
1996;44:155-160.
MEDLINE
63.
Schaad UB, Abdus Salam M, Aujard Y, et al.
Use of fluoroquinolones in pediatrics.
Pediatr Infect Dis J.
1995;14:1-9.
MEDLINE
64.
Lightfoot NF, Scott RJ, Turnbull PC.
Antimicrobial susceptibility ofBacillus
anthracis: proceedings of the international workshop on anthrax.
Salisbury Med Bull.
1990;68:95-98.
65.
Perkins WA.
Public health implications of airborne infection.
Bacteriol Rev.
1961;25:347-355.
66.
American Public Health Association.
Anthrax.
In: Benenson AS, ed. Control of Communicable
Diseases ManualWashington, DC: American Public Health Association;
1995:18-22.
67.
Morse S, McDade J.
Recommendations for working with pathogenic bacteria.
Methods Enzymol.
1994;235:1-26.
MEDLINE
68.
Guillermin J.
Anthrax: The Investigation of a Lethal
Outbreak.
Berkeley: University of California Press. In press.
69.
Chinn KS.
Reaerosolization Hazard Assessment for
Biological Agent-Contaminated Hardstand Areas.
Life Sciences Division, Dugway Proving Ground, Utah: US Dept of the Army;
1996:1-40. Publication DPG/JCP-96/012.
70.
Resnick IG, Martin DD, Larsen LD.
Evaluation of Need for Detection of Surface
Biological Agent Contamination.
Dugway Proving Ground, Life Sciences Division, US Dept of the Army; 1990:1-35.
Publication DPG-FR-90-711.
71.
Manchee RJ, Stewart WD.
The decontamination of Gruinard Island.
Chem Br.
July 1988;690-691.
72.
US Army Medical Research Institute of Infectious Diseases, Centers for Disease
Control and Prevention, and US Food and Drug Administration.
Medical Response to Biological Warfare and
Terrorism.
Gaithersburg, Md: US Army Medical Research Institute of Infectious Diseases,
Centers for Disease Control and Prevention, and US Food and Drug
Administration; 1998.
73.
Pomerantsev AP, Staritsin NA, Mockov YV, Marinin LI.
Expression of cereolysine AB genes in Bacillus
anthracis vaccine strain ensures protection against experimental
hemolytic anthrax infection.
Vaccine.
1997;15:1846-1850.
MEDLINE
Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.