Anthrax is a disease caused by Bacillus anthracis. Anthrax infection in humans occurs by 3 major routes: cutaneous, gastrointestinal, and inhalation. Anthrax spores delivered by aerosol spray may result in inhalation anthrax, which develops when the bacterial organism is inhaled into the lungs and/or cutaneous anthrax, which develops following the deposition of the organism into skin. A progressive infection typically follows. Inhalation anthrax is expected to account for the highest morbidity and mortality rates following the use of Bacillus anthracis, most likely as an aerosolized biological weapon. This scenario describes a single aerosol anthrax attack in one city, but does not exclude the possibility of multiple attacks in other cities or time-phased attacks (i.e., “reload”). For Federal planning purposes and as described in National Planning Scenario #2 – Biological Attack Aerosolized Anthrax, it will be assumed that the Universal Adversary (UA) attacks five separate metropolitan areas in a sequential manner. Three cities will be attacked initially, followed by two additional cities 2 weeks later. This scenario describes the UA attack in the first city targeted.
This scenario is similar to one being used by the Anthrax Modeling Working Group, convened by HHS, and the Anthrax National Planning Scenario. It is based on findings from the N-Process Project conducted under an interagency agreement between the HHS Centers for Disease Control and Prevention (CDC), Division of the Strategic National Stockpile (SNS) and Sandia National Laboratories (SNL), Albuquerque, New Mexico.
One of the key factors which will determine the method and the effectiveness of the United States (U.S.) Government response will be the ability to detect the UA’s use of weaponized Bacillus anthracis. In the development of this playbook four different trigger points have been identified, each of which will help determine the HHS response process. The four trigger points identified are: 1) Credible Intelligence of a Plan to Conduct a Biological Attack Using Aerosolized Anthrax, 2) Notification of a BioWatch Actionable Result (BAR), 3) Confirmed Cases of Inhalation Anthrax Identified in a U.S. City, and 4) Demobilization (Upon Release from Region, Tribe, Territory, State, and local Authorities). To build the scenarios, a brief, general overview is provided, followed by more specific information for each of the four trigger points identified in the scenario development process.
Although the scenario described in this playbook focuses on the attack in one major U.S. city, the simultaneous and subsequent attacks assumed for Federal planning purposes in the National Planning Scenarios will place significant additional demands on the public health and medical response systems. Multiple, large-scale attacks using an aerosolized anthrax agent, soon followed by additional attacks, will place a tremendous strain on Federal, Region, Tribe, Territory, State, and local health response agencies and organizations. Shortages of critical healthcare resources, including personnel, equipment, and supplies and material will exist, and careful thought must be given to the allocation of these scarce resources. This is particularly true at the Federal level, where decisions will need to be made quickly on how to allocate scarce Federal healthcare resources to the various Region, Tribe, Territory, and State officials requesting Federal aid.
Bacillus anthracis, the causative agent of anthrax, is a gram-positive sporulating rod. Anthrax is a zoonotic disease and the organism is transferred to man through contact with infected animals (domestic and wild herbivores, such as sheep, goats, and cattle), the carcasses of infected animals or animal products contaminated with viable spores (e.g. animal hides). Virtually no person-to-person transmission has been reported. The spores are very resilient to extremes of environment and may persist for decades (Inglesby, O'Toole et al. 2002; Shepard, Soriano-Gabarro et al. 2002).
There is some concern about the reliability of worldwide estimates of the incidence of human anthrax. The CDC cites progressive declines in annual incidence of human anthrax from 130 cases per year in the early 1900s to none prior to the 2001 intentional release outbreaks (MMWR Dec. 15, 2000) Human cases that occur from contact with infected animals (e.g. during butchering or skinning) or from bites from contaminated flies are considered agricultural while industrial cases are those which result from exposure to contaminated animal hides, hair, wool, or bones (Harrison’s Principles of Internal Medicine 14th ed.).
There are three main clinical forms of anthrax infection based on the route of exposure: cutaneous, gastrointestinal, and inhalation. Cutaneous anthrax is the most common form in humans and most frequently presents with an edematous localized ulcerated lesion with a centralized eschar. During the 2001 attacks, the mean incubation period was 5 days (range 1-10 days)(Inglesby, O'Toole et al. 2002). The mortality rate is 10-20% in the absence of antibiotic therapy and is lower when treatment with appropriate antibiotic therapy is available (Harrison’s Principles of Internal Medicine 14th). Gastrointestinal anthrax is rare but is reported in Africa and Asia (Inglesby, O'Toole et al. 2002). It is associated with the consumption of improperly prepared meat from infected animals. Although the exact mortality rate of gastrointestinal anthrax is not known, it is estimated at 50% even with appropriate antibiotic therapy.
Inhalation anthrax is the form most likely to cause mortality in the event of a bioterrorist attack. The incubation period for anthrax, defined as the time between spore exposure and the onset of clinical disease is generally less than 2 weeks. However because of spore dormancy and slow clearance from the lungs, the incubation period for inhalation anthrax may be prolonged for up to several months (Friedlander, Welkos et al. 1993; Ross 1957). Thus, acute and delayed germination must be considered for prophylactic and therapeutic regimens. For the 2001 anthrax cases, the incubation period was approximately 4 days (range 4-6 days). Inhalation anthrax is associated with hemorrhagic mediastinitis, mediastinal widening, and accumulation of pleural effusion.
The mortality of inhalation anthrax is high, but survival is possible with the prompt initiation of antimicrobial therapy and when the patients are not in late stage disease. During the 2001 anthrax attacks, the overall mortality rate was 45% for inhalation anthrax (5/11 inhalation cases); all cases of cutaneous anthrax (11 suspected, 7 confirmed) survived (Jernigan, Stephens et al. 2001; CDC, 2001). In 2001 death occurred in all 4 persons who manifested signs of fulminant disease before antibiotics were administered.
The LD50 for B. anthracis in humans is not definitively known, but based on primate data is estimated to be in the range of 4,100-10,000 inhaled spores (Glassman HN. Bacteriol Rev 1965; Peters CJ. Lancet 2002; Franz JAMA 1997). Following the 2001 anthrax mail attacks, there was a renewed interest in determining the minimum infective dose for humans. Extrapolation from the LD50 animal data to the lower end of the curve, suggests that lethal infection could be caused by as little as 1-3 spores, however the authors of these estimates acknowledge many unknown host and pathogen factors that would need to be addressed in the interpretation of these data to the occurrence of inhalation anthrax in humans an LD1 could be 1-3 spores (Peters, Hartley, 2002).
Toxemia, due to toxins released by B. anthracis, is the major cause of morbidity and mortality for this disease. Three proteins, protective antigen (PA), edema factor (EF), and lethal factor (LF) are collectively referred to as anthrax toxin.
Bacillus anthracis is considered among the most-likely biological threat agents confronting the national security of the United States. B. anthracis is particularly effective as a terror weapon when its spores are released as an aerosol. This form of attack would be odorless and invisible and could result in widespread dissemination. The former Soviet Union and Iraq developed and tested large-scale aerosolization techniques (Inglesby, O'Toole et al. 2002).
B. anthracis spores persist in the environment and contaminate buildings and equipment requiring decontamination. Remediation requires extensive and expensive decontaminating procedures that may have a significant and long-term impact on the ability to return to a contaminated site to pre-exposure operating levels as well as significant economic implications.
In addition to the threat of unmodified B. anthracis, the emergence of antibiotic resistant bacteria has added complexity to the ability to respond effectively should an emergency occur. Reports exist in the literature concerning the development of B. anthracis strains in the laboratory resistant to a variety of antimicrobial agents. Strains resistant to fluoroquinolones and rifampin have been developed by repeated passage on antibiotic-containing medium. Strains resistant to doxycycline were engineered by introduction of genes encoding resistance factors. Doxycycline, fluoroquinolones, and rifampin are the primary therapeutic and prophylactic agents. Rifampin was used frequently with other antimicrobials to treat patients with inhalation anthrax during the recent US outbreak for potential bacterial meningitis. Furthermore, Stepanov et al (1996) developed a multi-drug resistant strain of B. anthracis, ST-1, by recombinant engineering (1996). This strain was resistant to penicillin, rifampin, tetracycline, chloramphenicol, erythromycin and clindamycin. Thus, the feasibility of creating antibiotic resistance in B. anthracis by a variety of readily available technologies has been demonstrated.
There is relatively little known about the mechanisms of drug resistance in B. anthracis and the correlation of in vitro susceptibility to in vivo efficacy. Susceptibility studies done at the CDC on 15 B. anthracis isolates recovered from the 2001 US anthrax outbreak, showed that although the B. anthracis isolates tested were susceptible to the recommended antimicrobials (ciprofloxacin, tetracycline doxycycline, chloramphenicol, rifampin and vancomycin) the bacteria tended to have reduced susceptibility to erythromycin, clindamycin and ceftriaxone. Of 50 historical isolates also analyzed in that study, one was highly resistant to penicillin (Mohammed, Marston et al. 2002; Lightfoot, Scott et al. 1990). This finding is in keeping with the reports of cutaneous infections caused by penicillin-resistant B. anthracis isolates. This is an important observation, since penicillin is still frequently cited in textbooks and antibiotic pocket-guides as a treatment of choice for naturally occurring cutaneous anthrax infections (Red Book 2006) and is used by many other countries as the primary antimicrobial therapy.
Cavallo and coworkers in 2002 determined the antimicrobial susceptibility of a fairly large number (n = 95) of B. anthracis isolates from environmental and animal origins in France were found to besimilar to those of the human isolates tested by the CDC (Cavallo, Ramisse et al. 2002; CLIS, 2006). Penicillin and amoxicillin resistance was observed in 11.5% of isolates. All isolates had reduced susceptibility to ceftriaxone and produced β-lactamase, as measured by nitrocefin hydrolysis. It has been reported that this β-lactamase is a constitutive cephalosporinase. These data indicate that cephalsoporins should not be used therapeutically for anthrax. This is an important observation because ceftriaxone and cefotaxime are used frequently as empiric therapy in immunocompetent hosts who present with a clinical syndrome consistent with septic shock, a clinical presentation also consistent with fulminant anthrax. An additional question that must be resolved is whether the presence of β-lactamase production, as measured by nitrocefin hydrolysis, predicts the likelihood of therapeutic failure by penicillin (Gilligan 2002).
The clinical significance of resistance mechanisms of B. anthracis isolates is not straightforward. β-lactamase-producing strains have been used to infect animal models, but administration of penicillin appears to prevent disease. Similarly, the B. anthracis Ames strain used during the 2001 attacks in the US was susceptible to all the standard antibiotics for B. anthracis in spite of its inducible β-lactamase and constitutive expression of a cephalosporinase (Inglesby, O'Toole et al. 2002). It will be important to conduct microbiologic assessments of isolates for products used in the prevention and treatment of inhalation anthrax.