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2
Antibiotics for Anthrax
Postexposure Prophylaxis
The symptoms, treatment, and prognosis for a person with anthrax—
the disease caused by Bacillus anthracis—depend on how the disease was
contracted: gastrointestinal anthrax is acquired through ingestion of con-
taminated (undercooked) meat from animals that have ingested naturally
occurring spores from the ground; cutaneous anthrax requires physical
contact with the spores or vegetative bacteria; and inhalational anthrax is
the result of breathing in bacterial spores (Inglesby et al., 2002). Inhala-
tional anthrax is considered the most severe bioterrorism threat of the three
because the spores can travel significant distances through the air while
remaining infectious, and it has the highest mortality rate (approaching
100 percent if untreated) (Inglesby et al., 2002).
This chapter reviews the use of antibiotics for postexposure prophy-
laxis (PEP) for inhalational anthrax, focusing specifically on factors that
impact the design of distribution and dispensing plans, including preposi-
tioning. The chapter begins by briefly examining two issues related to what
is dispensed: first, the antibiotics that have been approved by the Food and
Drug Administration (FDA) for prevention of anthrax and second, the
threat of an attack using a strain of B. anthracis that is resistant to one
or more classes of antibiotics. The remainder of the chapter examines two
issues related to when antibiotics should be dispensed: first, the incubation
period of inhalational anthrax (time from exposure to appearance of symp-
toms) and second, the delay from the time of an attack until the attack is
detected and the decision to begin dispensing antibiotics is made.
41
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42 PREPOSITIONING ANTIBIOTICS FOR ANTHRAX
ANTIBIOTICS APPROVED FOR POSTEXPOSURE
PROPHYLAXIS OF INHALATIONAL ANTHRAX
Four antibiotics are FDA-approved for use for PEP following exposure
to aerosolized spores of B. anthracis: doxycycline, ciprofloxacin, levofloxa-
cin, and parenteral procaine penicillin G.1 Levofloxacin was approved for
PEP for anthrax in 2004 for adults and in 2008 for children (FDA, 2004,
2008a). Controlled human efficacy studies involving anthrax are not pos-
sible, so FDA approval of the inhalational anthrax PEP indications was
based on animal efficacy studies and the large safety database for these
antibiotics in humans (FDA, 2000b, 2002, 2008b, 2009).2
For adults ages 18 to 65 who have potentially been exposed to aerosol-
ized spores of B. anthracis, the Centers for Disease Control and Preven-
tion (CDC) recommends 60 days of treatment with either ciprofloxacin or
doxycycline plus a three-dose series of anthrax vaccine adsorbed (AVA)
starting as soon as possible after exposure (CDC, 2010; Stern et al., 2008).3
CDC recommends that levofloxacin be reserved as a second-line agent,
as safety data on its use in treatment for longer than 28 days are limited
(Stern et al., 2008). Levofloxacin should be used only when treatment with
first-line therapies is hampered by patient drug tolerance issues or antimi-
crobial resistance patterns (Stern et al., 2008). For children, ciprofloxacin
or doxycycline also is used for first-line antimicrobial PEP. Because of the
potential for serious adverse events, however, CDC recommends off-label
use of amoxicillin as the preferred PEP agent if the anthrax strain is proven
to be susceptible to that drug (CDC, 2005, 2010). Additional challenges of
administering anthrax PEP to children include limited data on appropriate
dosing and palatability of drug formulations. There is currently no recom-
mendation for use of AVA in children; however, its use for those under age
18 is currently being considered (CDC, 2010).4
1 Note that no oral penicillin-class of antibiotic is currently FDA-approved for postexposure
prophylaxis (PEP) for anthrax. Current drug information, including PEP dosing for adults and
children, is available on the FDA website at http://www.fda.gov/Drugs/EmergencyPrepared-
ness/BioterrorismandDrugPreparedness/ucm063485.htm. For certain patient groups, includ-
ing children and pregnant women, the Centers for Disease Control and Prevention (CDC)
recommends off-label use of amoxicillin if susceptibility testing proves that the anthrax strain
is susceptible (CDC, 2005).
2See Meyerhoff and Murphy (2002) for a detailed presentation of the antibiotics that were ap-
proved by the Food and Drug Administration for anthrax postexposure prophylaxis as of 2001.
3 See CDC (2010), Table 1, for a summary of the current CDC recommendations for PEP
with antimicrobial agents and AVA, available online at http://www.cdc.gov/mmwr/preview/
mmwrhtml/rr5906a1.htm.
4 On July 7, 2011, the National Biodefense Science Board (NBSB), at the written request
of the Department of Health and Human Services’ Assistant Secretary for Preparedness
and Response (ASPR), convened an initial meeting to discuss vaccine to protect children
from anthrax. The NBSB reported to the ASPR in October 2011. See http://www.phe.gov/
Preparedness/Legal/boards/nbsb/recommendations/Documents/avwgrpt1103.pdf.
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43
ANTIBIOTICS FOR ANTHRAX POSTEXPOSURE PROPHYLAXIS
For security reasons, CDC does not disclose the quantities of the dif-
ferent types of antibiotics that are available from the Strategic National
Stockpile (SNS), either through the initial Push Packages or through vendor-
managed inventory.
THE THREAT OF ANTIBIOTIC-RESISTANT ANTHRAX5
A material threat determination (MTD) was issued by the Secretary
of the Department of Homeland Security on September 22, 2006, specifi-
cally for multi-drug-resistant (MDR) anthrax (DHS, 2008; GAO, 2009).
Multiple papers on the development of B. anthracis strains resistant to
one or more antibiotics have been published in the open literature (e.g.,
Athamna et al., 2004; Brouillard et al., 2006; Price et al., 2003; Stepanov
et al., 1996). Laboratory generation of antibiotic-resistant anthrax involves
relatively straightforward methodology that does not require a high level of
microbiologic knowledge. (Key points and additional concerns regarding
antibiotic-resistant anthrax are summarized in Box 2-1.)
Polymerase chain reaction (PCR) analysis of tissue samples (meninges,
spleen, lymph node) from 11 autopsy-proven inhalational anthrax cases
from the 1979 accidental release of anthrax in Sverdlovsk, Russia,6 revealed
at least four strains of B. anthracis (Jackson et al., 1998). The existence
of multiple strains has been hypothesized to suggest efforts to develop an
antibiotic-resistant form of anthrax (Hugh-Jones, 2011).
Given the current focus on doxycycline (a tetracycline-class antibiotic)
as a first-line PEP treatment, an explicit analysis of the potential impact of
doxycycline-resistant B. anthracis is warranted. Postal workers voluntarily
p articipating in a pilot program for the postal model7 o f distribution
of medical countermeasures (MCM), for example, were provided with
MedKits that contained only doxycycline for storage in their homes. A
large-scale attack with doxycycline-resistant anthrax could result in many
5 Because of cross-resistance of antibiotics within the same class, it is prudent to define
drug resistance by antibiotic class and not by a single antibiotic within a given class (e.g.,
B. anthracis resistant to ciprofloxacin will likely also be resistant to levofloxacin, another
quinolone-class antibiotic) (Athamna et al., 2004). Drugs from three classes of antibiotics
are currently approved by the FDA for anthrax PEP: penicillins; fluoroquinolones (e.g.,
ciprofloxacin, levofloxacin); and tetracyclines (e.g., doxycycline) (FDA, 2011). For the pur-
poses of this report, the committee applied the following definitions of antibiotic-resistant
anthrax: single-drug (class)-resistant B. anthracis (SDR-anthrax) is resistant to a drug in any
one of these three class of antibiotics; multi-drug (class)-resistant B. anthracis (MDR-anthrax)
is resistant to drugs in any two of these three class of antibiotics; and extremely drug (class)-
resistant B. anthracis (XDR-anthrax) is resistant to drugs in all three classes of antibiotics.
(Note that SDR-, MDR-, and XDR-anthrax may or may not be resistant to other classes of
antibiotics that are not currently FDA-approved for anthrax PEP.)
6 Discussed in more detail below.
7 The postal model and other MCM dispensing strategies are discussed further in Chapter 3.
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44 PREPOSITIONING ANTIBIOTICS FOR ANTHRAX
BOX 2-1
Antibiotic-Resistant Anthrax
Key Points
• A
Material Threat Determination (MTD) was issued by the Secretary
of the Department of Homeland Security on September 22, 2006,
specifically for multi-drug-resistant (MDR) anthrax.
• T
he level of microbiologic knowledge needed to create MDR an-
thrax is not high, and descriptive methodology is available in the
open scientific literature.
• W
hile visibility of a response mechanism often functions as a de-
terrent (e.g., visible military strength), in the case of preposition-
ing, increased public certainty about the plan could conceivably
increase the probability of efforts to circumvent the response
(i.e., adversarial development of strains resistant to prepositioned
antibiotics).
Additional Concerns
• T
here may be a loss of public trust if the antibiotic dispensed
(whether prepositioned or dispensed via points of dispensing, the
U.S. Postal Service, or some other mechanism) is ineffective in pre-
venting anthrax as the result of an attack with a strain resistant to
that antibiotic.
• A
s laboratory testing of antibiotic susceptibility is likely to take
more than 2 days, antibiotic distribution and dispensing efforts in
response to an anthrax attack would be initiated before the suscep-
tibility profile of the attack strain was known.
• A
nthrax vaccine and antitoxin will likely be in even greater demand
following an attack with an antibiotic-resistant anthrax strain as
compared with a susceptible strain.
• P
rioritization of potential response plans for resistant anthrax
strains is needed. This includes analysis of all oral antibiotics that
were effective against the B. anthracis isolate from the 2001 an-
thrax attack and other antibiotics studied since that time.
more deaths if doxycycline were the primary (or only) antibiotic dispensed
pre-event via prepositioning strategies.
Prepositioning is a less flexible approach than more centralized dispens-
ing strategies. Inventory flexibility includes the potential for use of multiple
drugs, the potential for redeployment of inventories based on need, and
the ease with which stockpiles can be rotated. With regard to the threat
of antibiotic-resistant anthrax, a distribution and dispensing strategy that
enables the dispensing of multiple drugs may be advantageous because it
could allow selection of the antibiotic dispensed based on the susceptibility
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45
ANTIBIOTICS FOR ANTHRAX POSTEXPOSURE PROPHYLAXIS
of the strain.8 Although it will likely never be possible to have complete
coverage against all potential strains using PEP antibiotics—given that
specific antibiotics must be manufactured and stockpiled in advance and
given the threat of MDR or extremely drug-resistant anthrax—increased
flexibility to provide alternative antibiotics or other MCM would provide
coverage against a broader range of attacks.
Currently the SNS provides more flexibility than prepositioning strat-
egies would be likely to provide because it contains several antibiotics
(some of which are known to be stockpiled in larger quantities and others
available through vendor-managed inventory), whereas only one antibiotic
would likely be included in most prepositioning strategies. It would be
possible, moreover, to purchase and store a greater variety of antibiotics in
the centralized SNS stockpiles than is currently the case. Gaining this level
of coverage using prepositioning strategies would involve purchasing much
larger quantities of these different kinds of antibiotics, and any new anti-
biotics are likely to be more expensive than doxycycline. In addition, while
strategies based on points of dispensing (PODs) would allow the dispensing
of additional MCM if the initially dispensed antibiotic were determined not
to be effective against the anthrax strain used in an attack, a predispensing
strategy would not provide a postattack mechanism for dispensing an alter-
native MCM. The issue of flexibility is raised here because of its relevance
to the threat of antibiotic-resistant anthrax, but it is examined in greater
detail in Chapter 5.
Some information about the current U.S. MCM distribution and dis-
pensing system is already readily available online (e.g., that doxycycline is
a major component of the SNS and that the FDA has issued an Emergency
Use Authorization [EUA] for the use of doxycycline for PEP9). However,
neither the specific quantities of the various antibiotics nor the types of anti-
biotics available through vendor-managed inventory are disclosed. Further-
more, it would theoretically be possible to avoid disclosure of the future
contents of the SNS and state and local stockpiles (e.g., by increasing the
number of public health officials with security clearances and/or by further
using secured websites rather than public pages for formulary information).
In contrast, prepositioning strategies—and predispensing in the home in
particular—involve a higher level of public messaging and storage by a large
number of people without security clearances. The result could be a much
8 As laboratory testing of antibiotic susceptibility is likely to take more than 2 days, anti-
biotic distribution and dispensing efforts in response to an anthrax attack would be initiated
before the susceptibility profile of the attack strain was known. If the strain were ultimately
determined not to be susceptible to the antibiotic dispensed, an alternative MCM would have
to be dispensed, provided one was available in the quantities needed.
9 Discussed in Chapter 3.
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46 PREPOSITIONING ANTIBIOTICS FOR ANTHRAX
greater degree of certainty about the planned response, potentially signal-
ing an adversary to engineer a specific type of antibiotic-resistant anthrax.
Finding 2-1: Prepositioning of a single type of antibiotic (or class of anti-
biotics) would reduce flexibility to respond to the release of an antibiotic-
resistant strain of anthrax, a biothreat recognized by the U.S. Department
of Homeland Security. Furthermore, although some information about
planned responses is already available in the public domain, prepositioning
antibiotics in the home would provide a greater degree of certainty about
the planned response and, therefore, could conceivably increase the prob-
ability of release of a resistant strain of anthrax.
INCUBATION PERIOD OF INHALATIONAL ANTHRAX:
EXISTING DATA AND AREAS OF UNCERTAINTY
Data on human exposure to aerosolized B. anthracis are limited, and
there is a great deal of uncertainty regarding the incubation period (time
from exposure to appearance of symptoms). A clear understanding of the
incubation period is critical for decision making about MCM distribution
and dispensing strategies, including prepositioning.
An exposed population will exhibit a range of times from exposure
to the appearance of symptoms for the exact same exposure/dose, and the
shape of the distribution curve is important for decision making about pro-
phylaxis strategies. If, for example, there is a wide range of incubation times,
then even after the development of a small number of clinically recognized
anthrax cases, sufficient time may exist to distribute and dispense antibiotics
to a large fraction of still-asymptomatic persons, thereby protecting this
fraction of the exposed population. On the other hand, if the distribution
of incubation times is relatively narrow, much less time may be available in
which to distribute and dispense antibiotics to the exposed population after
initial identification of clinical cases. Beyond the shape of the distribution
curve, the shortest incubation time that would be expected in an exposed
population (i.e., the time at which the first person[s] would begin exhibit-
ing symptoms) also is important for public health decision making about
prepositioning. For ease of reference, this time is referred to as the minimum
incubation period throughout the report. The minimum incubation period
for inhalational anthrax is often stated to be 1 to 2 days; however, a review
of the available data suggests that it is likely to be longer. A longer minimum
incubation period, such as 4 days, would permit more time for the delivery
of MCM before the onset of symptoms, and thus would have a direct impact
on decisions regarding the need for prepositioning.
The committee examined the current knowledge base on the incuba-
tion period for inhalational anthrax, including data from several historical
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ANTIBIOTICS FOR ANTHRAX POSTEXPOSURE PROPHYLAXIS
human exposure incidents, from animal studies, and from incubation and
dose-response theoretical modeling.10 This review was informed by a search
of the literature and by discussions with invited experts at open sessions
during committee meetings.11 As noted in Chapter 1, the committee did not
review any classified information.
United States 1900-2000: Occupational and Environmental Exposures
Eighteen cases of inhalational anthrax were reported in the United
States in the 20th century, the most recent (prior to 2001) occurring in 1976
(Brachman, 1980; Jernigan et al., 2001). In most cases, an unequivocal
single-point-in-time exposure was not reported. Many of these cases were
associated with chronic exposures (e.g., the five-person outbreak at a goat-
hair processing mill in Manchester, New Hampshire, in 1957 [Plotkin et al.,
1960]). One case reviewed by Brachman was that of a 46-year-old man who
presented with symptoms 6 days after his last possible exposure to spores
(the man had recently been employed at a metal shop adjacent to a goat-
hair processing mill before the shop closed for a 2-week summer break).
Brachman notes that “the projected incubation period of six days resembled
those of previous cases” (Brachman, 1980, p. 90).
United States 2001: Intentional Attacks by U.S. Mail
In the fall of 2001, 11 people on the East Coast contracted inhalational
anthrax, the source of which was determined to be anthrax-laced letters
and packages sent through the U.S. mail (additional individuals contracted
cutaneous anthrax). Nine of the 11 patients experienced an incubation
period of 4 to 8 days, or possibly longer (Cole, 2003; Jernigan et al., 2001;
see Table 2-1).12 For 2 of the 11 patients (in New York and Connecticut),
the exposure is presumed to have occurred via cross-contaminated letters,
and the date of exposure is unknown.
10 The often-cited systematic review of 82 inhalational anthrax cases from 1900 to 2005 by
Holty and colleagues (2006) does not mention the incubation period for any of those cases.
Moreover, this review “excluded 74 cases from the Sverdlovsk outbreak because symptoms,
treatment, and disease progression variables were not reported” (p. 272).
11 A list of invited speakers/presentations is provided in Appendix B.
12 An account of the 2001 attacks was published by Jeanne Guillemin at the same time as
the release of the prepublication copy of this IOM report (Guillemin, 2011). She relies on a
September 25 scenario for the opening of an anthrax letter in Florida and therefore for the
exposure of the two Florida victims (referenced in Table 2-1). She also identifies September
30 and September 28 as the dates of onset of symptoms of the two Florida victims. Traeger
et al. (2002) identifies September 19 and 25 as the potential dates of exposure for the Florida
victims and September 30 and 28 as the dates of onset of symptoms.
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48 PREPOSITIONING ANTIBIOTICS FOR ANTHRAX
TABLE 2-1
Known and Estimated Inhalational Anthrax Incubation Periods
Following the 2001 Anthrax Attacks
Individuals Incubation Date of Onset of
Patient Location Infected Period (days) Exposure Symptoms
4a
Washington, DC 4 Oct. 12 Oct. 16
5a
New Jersey 1 Oct. 9 Oct. 14
6a
New Jersey 1 Oct. 9 Oct. 15
8–10b
Florida 1 Sept. 19 Sept. 27 or 29
9c
Florida 1 Sept. 19 Sept. 28
5–10d
Virginia 1 Oct. 12–17 Oct. 22
a Brentwood (DC) and Hamilton (New Jersey) postal facility workers with known exposure dates.
b Individual presented on October 2 with anthrax meningitis. Investigators assume exposure
occurred via a letter containing a white powder he was witnessed examining at his desk on
September 19.
c Estimated. The letter handler was admitted to a hospital on October 1, and likely infected by the
same letter as the other Florida patient on September 19.
d Estimated. A State Department postal worker was exposed to an unopened letter to Senator
Leahy that passed through the Brentwood and State Department postal facilities.
SOURCES: Cole, 2003; Jernigan et al., 2001.
United States 2006, Scotland 2006, England 2008, and United States 2011:
Exposure to Animal Hides and Unknown Source of Exposure
Three recent cases were identified in which the likely source of exposure
to aerosolized anthrax spores was determined to be imported African ani-
mal hide drums (Anaraki et al., 2008; CDC, 2006b; Norris, 2009; Walsh et
al., 2007). None of the three individuals infected had a clear-cut incubation
period that could be calculated definitively.
One additional case of inhalational anthrax was identified in Minnesota
shortly before the release of this report (Minnesota Department of Health,
2011a). This case is considered to be naturally occurring inhalational
anthrax, and exposure is believed to have occurred during travel in areas
where anthrax is found in the soil and has been known to cause infections
in animals (Minnesota Department of Health, 2011b). The exact time,
location, and source of this patient’s exposure remain unknown, and thus
an incubation period has not been determined.
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ANTIBIOTICS FOR ANTHRAX POSTEXPOSURE PROPHYLAXIS
Sverdlovsk, Russia 1979: Accidental Release
Much of what is assumed about the incubation period of inhalational
anthrax is based on data from what is believed to have been an accidental
aerosolized release of anthrax spores from a military research facility in
Sverdlovsk, Russia, in 1979. Considerable controversy persists around the
exact nature and date of the release. The issue of the date of the exposure
is worth examining as it pertains directly to the question of the duration of
the incubation period for affected patients.
Initially, the official Soviet explanation of the incident, supported by
a published epidemiological analysis, was that it had been an outbreak
of gastrointestinal anthrax due to meat contaminated with B. anthracis
(Bezdenezhnykh and Nikiforov, 1980; Meselson, 1988). Subsequent state-
ments (in the 1990s) by Russian officials and others support an accidental
aerosolized release of spores from the military research facility as the
probable cause (Meselson et al., 1994; Walker et al., 1994). Analysis by
international investigators was hampered significantly by the confiscation of
clinical, laboratory, and epidemiological data by the KGB (Russian national
security agency) following the incident. To this day, it remains impossible
to verify precise and comprehensive specific clinical and epidemiological
data, including incubation periods, for many of the individuals suspected
to have contracted inhalational anthrax. Most of the analyses that have
been published have pieced together data from a variety of sources (e.g., the
Abramova, Meselson, and Brookmeyer publications discussed below). To
make the present study as comprehensive as possible, a committee member
spoke with members of the U.S. team that traveled to Sverdlovsk in June
1992 to investigate the 1979 incident.13
Patient Exposure
Compelling evidence supports Monday, April 2, as a date of an aero-
solized spore release in Sverdlovsk, including plume modeling consistent
with the wind direction recorded at nearby locations on that date, and the
infection of five military reservists who were only present in the area on
but not before that date (Guillemin, 1999; Meselson et al., 1994). Various
times have been proposed for spore release on Monday, April 2, including
afternoon (1:30-4:00 PM [Guillemin, 1999; Meselson et al., 1994]) and
13A member of the IOM committee contacted each of the members of the U.S. team that
went to Sverdlovsk in 1992—by phone, in person, and/or by email communication—to discuss
the 1979 Sverdlovsk incident. Note that the committee’s conclusions throughout this report are
drawn from the totality of the evidence. The conclusions of the committee do not necessarily
reflect the views of any of the five members of the U.S. team.
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50 PREPOSITIONING ANTIBIOTICS FOR ANTHRAX
early morning (6:15-7:45 AM14 [FDA, 2000a]; 6:00-8:00 AM [Mangold
and Goldberg, 1999]). However, Friday evening on March 30 has also been
proposed as a date of spore release, based on information provided to Ken
Alibek, a former Soviet biological warfare expert, by one of his colleagues
(Alibek and Handelman, 1999). In addition, there is no known evidence to
exclude the possibility of multiple releases or a prolonged multiday release
that encompassed April 2. As noted above, there are great uncertainties
surrounding this incident.
The committee reviewed three key analyses of inhalational anthrax
patients in Sverdlovsk. Microbiology and histopathology are viewed as the
diagnostic gold standard for inhalational anthrax in this outbreak. The
two pathologists who performed the autopsies in 1979—Faina Abramova
and Lev Grinberg—published a report with the U.S. pathologist David
Walker on 41 confirmed cases, 30 of which have known dates of onset
of symptoms (Abramova et al., 1993). The data show a range of onset
of symptoms from 5 to 40 days after the putative release date of April 2,
1979, with a mean incubation period of 16 days (Walker, 2000). Thus, if
the anthrax spore release was a single event that occurred on April 2, then
the shortest incubation period for any of the 41 autopsy-proven cases was
5 days; if the release date was March 30, then the incubation period may
have been as long as 8 days for this patient. Importantly, in its analysis of
previous anthrax incidents, the committee required either microbiologic
or histopathologic confirmation of infection with B. anthracis when de-
termining the minimum incubation period of patients with inhalational
anthrax.
Using a variety of sources, Meselson and colleagues (1994) assembled
data on a set of 77 patients with presumed or confirmed inhalational
anthrax, including 66 fatalities. These fatalities include 41 of the 42 au-
topsied patients described by Abramova and colleagues (Abramova and
Grinberg, 1993; Abramova et al., 1993),15 which are, to the committee’s
knowledge, the only cases confirmed by microbiology or histopathology
in the paper by Meselson and colleagues (1994). Of the 60 patients with
known date of symptom onset, 58 had a reported incubation period of 4
to 43 days, using April 2 as the incident date. For one patient, onset of
symptoms is given as 3 days, and for the other remaining patient, onset
14 FDA (2000a), augmented by personal communication by Martin Hugh-Jones in April
and June 2011.
15 Later analysis of autopsy material showed that one case was not inhalational anthrax; that
case was omitted in Meselson et al. (1994) and Guillemin (1999).
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ANTIBIOTICS FOR ANTHRAX POSTEXPOSURE PROPHYLAXIS
of symptoms is given as 2 days.16 Of note, no autopsy histopathology or
microbiologic evidence of anthrax infection was reported for either of
these patients, and both had an atypically long time interval from reported
onset of symptoms until death (6 and 7 days, respectively, compared with
the 3 days noted by Meselson et al., [1994] as the typical time interval
between onset and death).
Brookmeyer and colleagues (2001) present a statistical analysis of the
outbreak, using April 2 as the exposure date and taking into account “trun-
cated data” in which the disease course of at least some exposed persons
was potentially impacted by public health interventions, such as a short
course (about 5 days or possibly longer) of PEP with tetracycline and a live-
spore anthrax vaccine. The analysis included 70 cases, all fatal (including
the 41 autopsy-confirmed patients described by Abramova and colleagues
[1993]). The 29 patients who were not autopsied were presumed to have
inhalational anthrax, although microbiologic or other confirmation was
lacking (data for these analyses were provided by coauthor Hugh-Jones).
Brookmeyer and colleagues (2001) reported median and mean incubation
periods of 11.0 and 14.2 days, respectively. Sixty-seven of the 70 fatalities
were reported to have an incubation period of 4-40 days. Three of the 70
were reported to have an incubation period of 2-3 days, but again, there
was no autopsy or microbiologic confirmation of the diagnosis of anthrax
for these patients.
Despite the uncertainties and the challenges of obtaining data, there
are valuable lessons to be learned from the Sverdlovsk incident. Examples
are the apparent rapid progression to death after symptom onset without
effective treatment, the existence of a wide range of incubation periods, and
the consistent finding of large volumes of pleural fluid that contributed to
respiratory failure and death (Walker, 2000).
Potential Impact of Anthrax Dose on the Incubation Period in Humans
In addition to host factors, the incubation period for inhalational
anthrax is impacted by the quantity of spores to which individuals are
exposed (Brookmeyer et al., 2001; Inglesby et al., 2002). Estimates of
the anthrax dose released in the 1979 Sverdlovsk aerosolization vary
widely:
16 One patient is listed in Meselson et al. (1994) as having symptom onset on April 5;
however, this date was changed to April 4 in a book by Guillemin (1999) based on interviews
of surviving family members in 1992.
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58 PREPOSITIONING ANTIBIOTICS FOR ANTHRAX
Mechanisms of Detection of an Aerosolized Anthrax Attack
An aerosolized bioterrorism agent, such as anthrax, may initially be
detected by environmental monitoring (e.g., BioWatch sensors, discussed
below) or by the identification of one or more symptomatic or fatal human
infections (e.g., by syndromic surveillance, by clinical or laboratory diagno-
sis, or upon autopsy) (IOM, 2011). The relative timeline of these activities
is shown in Figure 2-1; however, the actual timing is variable—from days
to weeks depending on the nature of the event and the functionality of the
systems. CDC’s Cities Readiness Initiative (see Chapter 3) has set a goal
for state and local health departments to have systems in place to complete
dispensing of the initial course of PEP antibiotic(s) within 48 hours of the
decision to dispense. The potential mechanisms for detection are briefly
described here; a more complete review is presented in IOM (2011).
BioWatch Environmental Sensor Detection
Detection of a biological threat agent via the Department of Homeland
Security’s BioWatch air sampling and monitoring system is estimated to
take 10 to 34 hours from exposure to discovery (Figure 2-2) (IOM, 2011).
Filter units are collected daily; thus, a filter could be collected from 0 to 24
Recovery
Aerosol
Incubation
Exposure Prodrome Illness
Release
Death
BioWatch
Syndromic surveillance
Case reports from clinicians, laboratories
Reports from medical examiners
FIGURE 2-1
Schematic illustration of the temporal relation among potential
mechanisms for detecting an aerosolized biological threat. The
brackets span the interval over which a particular mechanism
Figure 2-1.eps
would have the potential to detect the presence of a pathogen
(e.g., via BioWatch) or illness or death caused by the pathogen.
This illustration represents the initial detection of a bioterrorism
event. The timeline for detection of subsequent events that are
part of the same attack may be compressed because an initial
detection is likely to increase attention to the potential threat.
SOURCE: IOM, 2011, p. 34. Originally adapted from Sosin, 2008.
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ANTIBIOTICS FOR ANTHRAX POSTEXPOSURE PROPHYLAXIS
2
24 hrs Up to 6 hrs
4 hrs hrs
Aerosol collection cycle Filter Primary Full agent-
recovery screening specific
test panel
10–34 hrs from exposure to discovery
Reactive
BAR
FIGURE 2-2
Event-to-detection timeline for BioWatch Generations 1 and 2.
Filter recovery and transport can take up to 4 hours, and
Figure 2-2 new
primary laboratory screening takes about 6 hours. If the primary
screening indicates a positive result, confirmatory testing
requires an additional 2 hours.
SOURCE: IOM , 2011, p. 54. Originally adapted from Runge, 2008.
hours after release of a biological agent. Following collection, it may take
up to 10 hours for initial testing to be completed (up to 4 hours for filter
recovery from the unit, 6 hours for primary screening, and 2 hours for full
agent-specific testing). A BioWatch Actionable Result (BAR) is declared if
the filter tests positive for genetic material from a targeted biological agent.
BioWatch covers only certain metropolitan statistical areas (MSAs); for
security reasons, these locations are not disclosed.
A BAR signifies simply that genetic material has been detected on a
Biowatch filter, not necessarily that a bioterrorism attack has occurred or
that people have been exposed to viable organisms. Factors that might im-
mediately be considered include, for example, the number and locations
of the BioWatch filters testing positive, intelligence and law enforcement
information, evidence of human or animal illnesses consistent with the
biological agent detected, and additional environmental testing apart from
the BioWatch filters. Thus, it is difficult to predict in advance of a specific
event the time period that would be required before the decision to dispense
PEP antibiotics could be made by government officials. In the future, detec-
tion time could be considerably reduced (to a total of 4 to 6 hours from
the current 10 to 34 hours) if “Generation 3” BioWatch sensors, equipped
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60 PREPOSITIONING ANTIBIOTICS FOR ANTHRAX
to conduct automated assays for pathogens, should prove accurate (Garza,
2011).
Note that because anthrax is spread environmentally as spores, the
rather singular potential exists to determine viability by laboratory culture
of spores retrieved from BioWatch filters. If spores are viable and if a pure
culture of the organism can be established, antibiotic susceptibility profiles
can be determined. (As noted above, however, the decision to respond to
the BioWatch signal will likely have been made long before the antibiotic
susceptibility profile is available.)
Detection by Case Reports from Clinicians or Laboratories
As described above, symptoms of inhalational anthrax emerge 4 to
8 days or more after exposure. Therefore, detection of an anthrax attack
by clinical diagnosis or laboratory report of inhalational anthrax would
come many days following an attack. However, the incubation period of
cutaneous anthrax (exposure via skin) is significantly shorter, approxi-
mately 1-3 days (CDC, 2002, 2006a; Freedman et al., 2002; Jernigan et al.,
2002). The 1979 Sverdlovsk release and the 2001 anthrax attack caused
both inhalational and cutaneous forms of the disease (Jernigan et al., 2002,
Meselson et al., 1994). This probably would be replicated in any attack
using aerosolized anthrax spores. Therefore, detection of an attack based
on cases of cutaneous anthrax could occur days before detection based on
cases of inhalational anthrax. The typical skin lesions caused by cutaneous
anthrax in the initial 1 to 2 days could be caused by a number of different
diseases; therefore, in small numbers, they might not be diagnosed immedi-
ately as anthrax. In the case of a large-scale attack, however, patients with
these lesions might appear in large numbers in emergency departments,
raising suspicions and making appropriate diagnosis and detection more
likely. Detection of an attack by diagnosis of cutaneous anthrax could
enable public health authorities to begin efforts to dispense antibiotics to
prevent the more deadly form of the disease and to begin testing the strain
for susceptibility to antibiotics.
The committee did not review in great detail the processes and timing
related to making the decision to begin dispensing antibiotics, which fell
outside the scope of its charge. Nevertheless, this is an important issue
for MCM planning because delays in decision making due to uncertainty
related to the detection mechanisms, political considerations, issues associ-
ated with the interaction among multiple levels of government or multiple
agencies, or other factors could delay the initiation of dispensing and
therefore result in fewer exposed people receiving prophylaxis prior to the
onset of symptoms. Improvements in detection capability (either through
technological enhancements or through additional clinical familiarity and
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61
ANTIBIOTICS FOR ANTHRAX POSTEXPOSURE PROPHYLAXIS
training) and in decision-making processes would allow more time for dis-
tribution and dispensing and, ultimately, shorten the time from exposure
to prophylaxis.
Finding 2-2: Review of the limited available data on human inhalational
anthrax shows that people exposed to aerosolized anthrax have incuba-
tion periods of 4 to 8 days or longer. Much of the modeling used to derive
shorter estimates is based on data from the Sverdlovsk incident, and the
assumptions made potentially lead to an underestimate of the minimum
incubation period.
With the most probable minimum incubation period being approxi-
mately 4 days (or 96 hours), there is no compelling evidence to suggest that
jurisdictions must plan to complete dispensing of initial prophylaxis more
rapidly than 96 hours following the time of the attack, although incremen-
tal improvements appear to be achievable and could provide additional
protection against unforeseen delays.
Therefore, the current operational goal of the Centers for Disease Con-
trol and Prevention’s Cities Readiness Initiative of completing dispensing
of initial prophylaxis within 48 hours of the decision to dispense appears
to be appropriate, as long as the total time from exposure to prophylaxis
does not exceed 96 hours. Achieving this goal depends on robust detection
and surveillance systems that can rapidly detect an anthrax attack, rapid
decision making, and effective distribution and dispensing systems. If detec-
tion or decision making is delayed, faster distribution and dispensing may
be needed to minimize symptomatic disease in the exposed population.
SUMMARY
To be maximally effective in preventing morbidity and mortality, PEP
for inhalational anthrax should be administered during the incubation
period (before the onset of symptoms). There is, however, great uncertainty
around the minimum incubation period for inhalational anthrax. Precise,
confirmed data from human infection from the Sverdlovsk incident are
incomplete, and data from animal models are of limited relevance as ani-
mals exhibit symptoms and succumb to the disease more rapidly than do
humans. Many assumptions regarding minimum incubation time in humans
are based on modeling. Most anthrax modeling has used data from the
Sverdlovsk aerosolized anthrax release and presumes a low-dose exposure.
Yet little is known about the details of that release (including the true size
of the dose), and the actual date(s) of exposure remain unconfirmed. Most
of the available data and modeling suggest that the minimum incubation
period for inhalational anthrax in humans is longer than the often-cited
1 to 2 days. Individuals exposed during the 2001 anthrax attack in the
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62 PREPOSITIONING ANTIBIOTICS FOR ANTHRAX
United States had actual or estimated incubation periods of 4 to 10 days,
and the PEP experience following this incident suggests that asymptomatic
employees who were exposed to an uncertain number of spores and who
began prophylaxis with antibiotics 9, 11, and 19 days after exposure (in
Washington, DC; New Jersey; and Florida, respectively) were protected.
Finally, in considering potential prepositioning strategies, it is critical to
take into account the significant material threat posed by antibiotic-resistant
strains of anthrax. Timely administration of PEP also hinges on prompt
detection and confirmation of the threat through environmental monitoring
systems and astute clinical diagnosis and surveillance.
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