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 contaminated (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). Inhalational 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 prophylaxis (PEP) for inhalational anthrax, focusing specifically on factors that impact the design of distribution and dispensing plans, including prepositioning. 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 symptoms) and second, the delay from the time of an attack until the attack is detected and the decision to begin dispensing antibiotics is made.
Four antibiotics are FDA-approved for use for PEP following exposure to aerosolized spores of B. anthracis: doxycycline, ciprofloxacin, levofloxacin, 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 possible, 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 aerosolized spores of B. anthracis, the Centers for Disease Control and Prevention (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 antimicrobial 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 recommendation for use of AVA in children; however, its use for those under age 18 is currently being considered (CDC, 2010).4
1Note 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/EmergencyPreparedness/BioterrorismandDrugPreparedness/ucm063485.htm. For certain patient groups, including 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 approved by the Food and Drug Administration for anthrax postexposure prophylaxis as of 2001.
3See 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.
4On 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.
For security reasons, CDC does not disclose the quantities of the different types of antibiotics that are available from the Strategic National Stockpile (SNS), either through the initial Push Packages or through vendor-managed inventory.
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 (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 participating in a pilot program for the postal model7 of 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
5Because 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 purposes 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.)
6Discussed in more detail below.
• 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.
• The level of microbiologic knowledge needed to create MDR anthrax is not high, and descriptive methodology is available in the open scientific literature.
• While visibility of a response mechanism often functions as a deterrent (e.g., visible military strength), in the case of prepositioning, 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).
• There 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 preventing anthrax as the result of an attack with a strain resistant to that antibiotic.
• As 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 susceptibility profile of the attack strain was known.
• Anthrax 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.
• Prioritization 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 anthrax 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 dispensing 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
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 strategies 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 antibiotics 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 alternative 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 dispensing 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 antibiotics available through vendor-managed inventory are disclosed. Furthermore, 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
8As 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 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.
greater degree of certainty about the planned response, potentially signaling an adversary to engineer a specific type of antibiotic-resistant anthrax.
Finding 2-1: Prepositioning of a single type of antibiotic (or class of antibiotics) 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 probability of release of a resistant strain of anthrax.
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 prophylaxis 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 exhibiting 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 incubation period for inhalational anthrax, including data from several historical
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.
10The 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).
12An 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.
Known and Estimated Inhalational Anthrax Incubation Periods Following the 2001 Anthrax Attacks
|Patient Location||Individuals Infected||Incubation Period (days)||Date of Exposure||Onset of Symptoms|
|Washington, DC||4||4a||Oct. 12||Oct. 16|
|New Jersey||1||5a||Oct. 9||Oct. 14|
|New Jersey||1||6a||Oct. 9||Oct. 15|
|Florida||1||8-10b||Sept. 19||Sept. 27 or 29|
|Florida||1||9c||Sept. 19||Sept. 28|
|Virginia||1||5-10d||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 animal 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.
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 statements (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
Compelling evidence supports Monday, April 2, as a date of an aerosolized 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.
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 determining 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 autopsied 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
14FDA (2000a), augmented by personal communication by Martin Hugh-Jones in April and June 2011.
15Later analysis of autopsy material showed that one case was not inhalational anthrax; that case was omitted in Meselson et al. (1994) and Guillemin (1999).
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.,  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 “truncated 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 ). 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:
16One 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.
• a few milligrams to less than a gram (Meselson, 2001; Meselson et al., 1994),
• 500 grams (Martin Hugh-Jones cited in FDA, 2000a),
• “pounds” of anthrax (William Patrick III cited in Miller et al., 2001), and
• “as much as 22 pounds (10 kg)” (DIA, 1986, p. 4).
Assumptions about the incubation period have been made presuming a low-dose exposure at Sverdlovsk—in accordance with the estimates of Meselson and colleagues (1994)—including the assumption that the incubation period would be shorter if the dose were higher.
In theory, the incubation period and/or lethality of aerosolized spores could also be impacted by qualitative aspects of the spores released. For example, small particle aerosols of spores (1-5 microns) are more likely than larger particle aerosols to reach the lower respiratory tract (Thomas et al., 2010). Chemical substances added to the spores may increase their ability to remain aloft and travel farther (animals as far as 50 km downwind from the Sverdlovsk release site reportedly developed anthrax) (Meselson et al., 1994). Alibek and Handelman (1999) state that the highly virulent anthrax strain 836 was used in the former Soviet Union, including at Sverdlovsk in 1979, and that the anthrax released contained chemical additives.
Theoretical Modeling of the Incubation Period for Human Inhalational Anthrax
As discussed above, some of the data on the incubation period for inhalational anthrax considered by the committee were based on statistical analyses. The committee heard multiple presentations from both committee members and invited experts regarding theoretical modeling of the incubation period of anthrax in humans.17 Key points are summarized in Box 2-2.
The review by Hupert and colleagues (2009), summarized in Box 2-2, highlights that the estimate of a 2-day incubation period, commonly used in planning documents and the shortest among the various anthrax models, derives in part from data for military planners by Rickmeier and colleagues (2001) that were used later in the model by Baccam and Boechler (2007). The Rickmeier et al. model derives in part from dose-response studies involving Seventh Day Adventist volunteers and using infectious diseases other than anthrax, such as Q-fever and tularemia. Such dose-response studies in humans using anthrax were never performed because of the unacceptable risk of severe disease or death.
Notes on Theoretical Modeling of the Incubation
Period for Human Inhalational Anthrax
• Modeling of the incubation period for human inhalational anthrax has been based primarily on data from the Sverdlovsk release (Hupert et al., 2009).
• Some of the models presume that a low dose of anthrax spores (a few milligrams to almost a gram) was released in Sverdlovsk (Meselson et al., 1994). This assumption has significant implications for when antibiotics should be started and how long prophylaxis should last if a “high-dose” release were to occur (e.g., modeling by Brookmeyer et al.  predicts the need for PEP for at least 4 months following a high-dose exposure).
• Hupert and colleagues (2009) state that the 2001 Brookmeyer analysis “fit the timing of hospitalization of 70 cases of inhalational anthrax to a lognormal distribution . . . [and this] Brookmeyer curve forms the basis for other AMWG [Anthrax Modeling Working Group] models” (Hupert et al., 2009, p. 426).
• In the statistical analysis of Brookmeyer and colleagues (2001), 16 of 70 fatal cases included did not have a known incubation period; instead, the end of the incubation period for these 16 patients was estimated by subtracting 3 days from the date of death. This paper was published prior to the 2001 U.S. anthrax attack and was not designed to address antibiotic prepositioning issues.
• Using a “discrete-time state transition model” (p. 425), Hupert and colleagues (2009) conclude that: “A CRI [Cities Readiness Initiative]-compliant prophylaxis campaign starting 2 days after exposure would protect from 86% to 87% of exposed individuals from illness. . . . Each additional day needed to complete the campaign would result in, on average, 2.4% to 2.9% more hospitalizations in the exposed population; each additional day’s delay to initiating prophylaxis beyond 2 days would result in 5.2% to 6.5% additional hospitalizations” (Hupert et al., 2009, p. 424).
• Hupert and colleagues (2009) summarize anthrax modeling approaches and assumptions of eight key modeling papers published from 2005 through 2008, including those of Baccam and Boechler, 2007; Braithwaite et al., 2006; Brookmeyer and Blades, 2002; Brookmeyer et al., 2003, 2004, 2005; Fowler et al., 2005; Hupert et al., 2009, p. 427, Table 1; Wein and Craft, 2005; Wein et al., 2003; Wilkening, 2008; and Zaric et al., 2008. The shortest incubation period is that used by Baccam and Boechler (2007) at “2.3 to 12.7 days (dose dependent)” (Hupert et al., 2009, p. 427). Baccam and Boechler cite Rickmeier et al. (2001) as the source of the data used for the model (Baccam and Boechler, 2007, p. 27). In the absence
of human studies of anthrax, Rickmeier et al. reason by analogy using data from human studies of tularemia and Q-fever. This methodology may have contributed to the shorter incubation period reported as compared with the other seven studies summarized.
• Wilkening (2006, 2008) assesses the accuracy of four models of inhalational anthrax dose-response and incubation period distribution using the Sverdlovsk data. He concludes that:
— “Dose-response functions that exhibit a threshold for infectivity are contraindicated by the Sverdlovsk data” (Wilkening, 2006, p. 7589).
— Two models are consistent with the Sverdlovsk data. One model “predicts that 50% of the victims received less than approximately two spores”; the other model “predicts that 50% of the victims received </≈ 360 spores” (Wilkening, 2006, p. 7591).
— “The victims at Sverdlovsk either received on the order of 1-10 spores . . . or between 100-2,000 spores . . . , which is in good agreement with Meselson’s estimates” (Wilkening, 2006, p. 7591).
• In sharp contrast to the above conclusions by Wilkening, Coleman and colleagues (2008) reexamine the idea that a dose-response threshold does not exist, arguing that: “The present lack of clarity regarding what is scientific fact and what is more speculative opinion about B. anthracis dose-response relationships has promoted the misunderstanding that a single B. anthracis spore is fatal” (Coleman et al., 2008, p. 148).
Animal Models of Inhalational Anthrax
While animal models have provided much of the data on anthrax disease pathology, no one such model exactly simulates the human experience (Goossens, 2009). The two animal species currently considered most acceptable for anthrax studies from a regulatory point of view under the FDA’s “animal rule”18 are nonhuman primates and rabbits (FDA, 2010).
While useful for studying various aspects of anthrax (e.g., characteristics of the organism, pathogenesis of disease, impact of interventions),
18The “animal rule” (21 Code of Federal Regulations [CFR] 314.600 for drugs; 21 CFR 601.90 for biological products) provides for FDA approval of certain new drugs and biologics based on animal data when efficacy studies in humans cannot ethically be conducted and field trials are not feasible. See Guidance for Industry, Animal Models—Essential Elements to Address Efficacy under the Animal Rule (Draft Guidance), http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078923.pdf.
animal models of inhalational anthrax have not been designed to determine the minimum incubation period, the distribution of incubation times in humans, or the relationship between dose and incubation period in a precise, well-controlled manner. In addition, the majority of experiments in animals are designed to maximize the efficacy of the study through ensured infection, not to determine the incubation period (e.g., Vasconcelos et al., 2003). Most importantly, the time frame from exposure to illness and death is shorter in animal models of anthrax than in humans.
In a presentation to an FDA Advisory Committee regarding animal models and anthrax, Arthur Friedlander stated that mean survival for rabbits is 2.4 days postexposure and for rhesus monkeys is 4.8 days postexposure (Friedlander, 2000). In contrast, he stated that mean survival for humans is 4.7 days post-onset of symptoms (not postexposure). In other words, the time from exposure to death in rhesus monkeys is similar to the time from onset of symptoms to death in humans, consistent with the view that the incubation period is longer in humans than in these commonly employed animal models.
In the landmark study by Friedlander and colleagues (1993) on PEP antibiotics to prevent inhalational anthrax, 9 of the 10 control rhesus monkeys (nonhuman primates) exposed to inhaled anthrax spores died within 3 to 8 days postexposure. (This study, urgently undertaken because of military events in the Persian Gulf in 1990-1991, provided the foundation for PEP with antibiotics in humans following the anthrax attack in 2001.) In a dose-response study of survival in rabbits, Friedlander and colleagues report that the mean survival time of the rabbits was 2.4 days postexposure and that “although there was a trend for a decreased survival time with increasing dose, the effect was minimal” (Zaucha et al., 1998, p. 984).
In summary, studies in animals (such as those by Weiss and colleagues  in guinea pigs and rabbits) confirm the importance of PEP in preventing fatal disease and may inform the development of PEP strategies in humans. Given the differences in incubation period between animals and humans, however, it is not appropriate to extrapolate an exact hour-to-hour correspondence from animal models to humans (e.g., for when to initiate PEP with antibiotics in humans). Studies using nonhuman primates could be designed to explore the distribution of incubation periods across a range of plausible exposures and to determine to what degree exposure influences the incubation period. These studies might better inform strategies for PEP than the existing modeling data.
Impact of the Anthrax Incubation Period on PEP Strategies
Antibiotics are not active against the spore form of B. anthracis; however, when the spore germinates into the vegetative form of the bacteria, the antibi-
otic kills the bacteria and prevents the onset of symptoms (Friedlander et al., 1993; Inglesby et al., 2002). Treatment with a single antibiotic begun while an individual exposed to aerosolized anthrax is still in the incubation period can prevent symptoms from occurring (Friedlander et al., 1993). If a person is no longer in the incubation period and thus is symptomatic from anthrax, two or more antibiotics are recommended as therapy (given intravenously at the beginning of treatment) (Inglesby et al., 2002; Meyerhoff and Murphy, 2002).
No human or animal data exist to support the notion that starting antibiotic treatment earlier in the incubation period is necessary to prevent symptomatic anthrax disease from occurring. In contrast, therapy for a person who is symptomatic from inhalational anthrax is more likely to be successful if given in the early-prodromal or intermediate-progressive stage of disease rather than in the late-fulminant stage (Holty et al., 2006; Lucey, 2005, 2007).
The effectiveness of antibiotics begun later in the incubation period is supported by some data from the 2001 anthrax attack, although notably not from a prospective, controlled experiment:
• Brentwood postal facility in Washington, DC19—More than 2,000 postal workers were potentially exposed to spores reportedly aerosolized from the letter-sorting machine after two letters passed through the facility on Friday morning, October 12, until the facility was closed on Sunday morning, October 21 (Dewan et al., 2002). Although four Brentwood workers had already developed inhalational anthrax with symptom onset on October 16, no PEP antibiotics were given to the other 2,000+ postal workers during the 9 days from October 12 to 21 because the risk was not recognized (Dewan et al., 2002). Despite the delayed initiation of PEP, however, no additional cases of inhalational anthrax were known to have occurred.
• Hamilton, New Jersey, postal facility—The same two anthrax letters addressed to U.S. senators passed through Hamilton after being postmarked October 9. Two postal workers experienced onset of symptomatic inhalational anthrax on October 14 and 15, and the facility was closed on October 18. More than 1,000 postal workers were offered PEP antibiotics beginning on October 20, 11 days after the spores had been released in the facility, and none developed inhalational anthrax (Greene et al., 2002).
19When it reopened in 2003, the Brentwood mail processing facility was renamed the Joseph Curseen, Jr., and Thomas Morris, Jr., Processing and Distribution Center, in honor of the two postal employees who worked there and died of inhalational anthrax in October 2001.
• American Media Inc. (AMI) Building, Boca Raton, Florida—Suspicious letters were opened on September 19 and 25. Two cases of inhalational anthrax occurred with onset in late September. PEP antibiotics were not offered to the 1,114 “workplace-exposed” persons until October 8 (13-19 days after the potential exposure); however, no further cases of inhalational anthrax occurred (Traeger et al., 2002).
Environmental sampling showed that anthrax spores had been widely dispersed in each of these large buildings. Brookmeyer and Blades (2002) estimated that in these three locations, “sensitivity analyses to a range of incubation distributions all indicated that fewer than 50 cases were prevented by AP [antibiotic prophylaxis]” (Brookmeyer and Blades, 2002, p. 1861). Importantly, however, the analysis did not include potential cases prevented by antibiotic prophylaxis on Capitol Hill.
Using a highly sensitive anthrax antibody test, CDC found that “a mild form of inhalational anthrax did not occur, and that surveillance for moderate or severe illness was adequate to identify all inhalational anthrax cases resulting from the Washington, DC, bioterrorism-related anthrax exposures” (Baggett et al., 2005, p. 991). In other words, it is unlikely that there were exposed individuals with unrecognized infection. Those who presented with mild, anthrax-like symptoms, who subsequently did not progress clinically and for whom blood cultures and immunohistochemistry were negative for anthrax, were in fact not infected, at least according to this CDC study.
The time from exposure to prophylaxis encompasses three stages: time to detect the anthrax attack, time to decide to dispense antibiotics, and time to distribute and dispense initial doses to the potentially exposed population. To ensure that potentially exposed people receive antibiotics during the time window in which the antibiotics effectively prevent the appearance of anthrax symptoms, the total time for these three stages should be less than the minimum incubation period (approximately 4 days, as discussed above). As the time for detection and decision increases, the time available for distribution and dispensing decreases, and vice versa. Thus, estimates of the time to detection and time to decision impact public health decisions about the need to adopt prepositioning strategies and, more generally, decisions about an operational goal for dispensing the initial doses of antibiotics.
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 diagnosis, 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
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 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.
Event-to-detection timeline for BioWatch Generations 1 and 2. Filter recovery and transport can take up to 4 hours, and 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 immediately 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, detection 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
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, approximately 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 immediately 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 associated 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
training) and in decision-making processes would allow more time for distribution 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 incubation 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 approximately 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 incremental improvements appear to be achievable and could provide additional protection against unforeseen delays.
Therefore, the current operational goal of the Centers for Disease Control 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 detection or decision making is delayed, faster distribution and dispensing may be needed to minimize symptomatic disease in the exposed population.
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 animals 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
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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