Chemical words. As also before, the appended materials are very useful, especi- ally the ring index. - Some definitions that were not found included: Acridan. The present work is presumed a revision of Bennett's “The Cosmetic. To start off, the present formulary first gives general informa- tion on making up. In 1990 we lost our oldest and most prestigious author and friend, Harry. Bennett at age 95. He is sorely missed. It was his wish that the “COSMETIC FORMULARY' continue with or without him. Our editorial staff has put together this volume, and shall continue to do so without making any changes in style or presentation.

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 (). 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) (). 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. 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, levofloxacin, and parenteral procaine penicillin G. Levofloxacin was approved for PEP for anthrax in 2004 for adults and in 2008 for children (, ). 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 (,,, ). 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 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 (). Levofloxacin should be used only when treatment with first-line therapies is hampered by patient drug tolerance issues or antimicrobial resistance patterns (). 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 (, ).

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 (). 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. THE THREAT OF ANTIBIOTIC-RESISTANT ANTHRAX 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 (; ). Multiple papers on the development of B.

Anthracis strains resistant to one or more antibiotics have been published in the open literature (e.g.,;;; ). 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.). Antibiotic-Resistant Anthrax.

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 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, revealed at least four strains of B. Anthracis (). The existence of multiple strains has been hypothesized to suggest efforts to develop an antibiotic-resistant form of anthrax (). 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 model 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 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. 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. 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 PEP ). 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 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. 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 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. Ping Eye 2 Serial Number Lookup here. 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. This review was informed by a search of the literature and by discussions with invited experts at open sessions during committee meetings. As noted in, 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 (; ).

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 []). 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” (, p. 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 (;; see ). 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. 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 (;;; ).

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 (). 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 (). 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 (; ). 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 (; ).

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. Patient Exposure 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 (; ). Various times have been proposed for spore release on Monday, April 2, including afternoon (1:30-4:00 PM [; ]) and early morning (6:15-7:45 AM []; 6:00-8:00 AM []). 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 (). 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 (). 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 ().

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, 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 (; ), which are, to the committee's knowledge, the only cases confirmed by microbiology or histopathology in the paper. 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 of symptoms is given as 2 days.

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 as the typical time interval between onset and death). 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 ). 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). 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 (). “as much as 22 pounds (10 kg)” (, p. Assumptions about the incubation period have been made presuming a low-dose exposure at Sverdlovsk—in accordance with the estimates of —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 (). 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) (). 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.

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 The review by, summarized in, 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 that were used later in the model. 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. 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 ().

The two animal species currently considered most acceptable for anthrax studies from a regulatory point of view under the FDA's “animal rule” are nonhuman primates and rabbits (). While useful for studying various aspects of anthrax (e.g., characteristics of the organism, pathogenesis of disease, impact of interventions), 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., ).

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 ().

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 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” (, p. In summary, studies in animals (such as those by 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 (; ).

Treatment with a single antibiotic begun while an individual exposed to aerosolized anthrax is still in the incubation period can prevent symptoms from occurring (). 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) (; ). 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 (;, ). 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, DC —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 (). 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 ().

Prince Of Persia Full Movie In Hindi Free Download Kickass. Despite the delayed initiation of PEP, however, no additional cases of inhalational anthrax were known to have occurred. 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 (). Environmental sampling showed that anthrax spores had been widely dispersed in each of these large buildings. 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]” (, p.

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” (, p. 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. IMPACT OF TIME TO DETECTION ON DISPENSING OF PEP ANTIBIOTICS 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) (). The relative timeline of these activities is shown in; 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 ) 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. 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 () (). Filter units are collected daily; thus, a filter could be collected from 0 to 24 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. 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 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 (). 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 (,;; ).

The 1979 Sverdlovsk release and the 2001 anthrax attack caused both inhalational and cutaneous forms of the disease (, ). 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. 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 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. Jernigan DB, Raghunathan PL, Bell BP, Brechner R, Bresnitz EA, Butler JC, Cetron M, Cohen M, Doyle T, Fischer M, Greene C, Griffith KS, Guarner J, Hadler JL, Hayslett JA, Meyer R, Petersen LR, Phillips M, Pinner R, Popovic T, Quinn CP, Reefhuis J, Reissman D, Rosenstein N, Schuchat A, Shieh WJ, Siegal L, Swerdlow DL, Tenover FC, Traeger M, Ward JW, Weisfuse I, Wiersma S, Yeskey K, Zaki S, Ashford DA, Perkins BA, Ostroff S, Hughes J, Fleming D, Koplan JP, Gerberding JL. National Anthrax Epidemiologic Investigation Team.

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Evaluation of public health interventions for anthrax: A report to the Secretary's Council on Public Health Preparedness. Clinical Infectious Diseases.

Biosecurity and Bioterrorism: Biodefense Strategy, Practice, and Science. 2007;2005; 44 3(7)(4):968–971.

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) (). 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) (). 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.) 6. 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 (). 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 ).

She also identifies September 30 and September 28 as the dates of onset of symptoms of the two Florida victims. 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.