A bitter pill to swallow: nonadherence with prophylactic antibiotics during the anthrax attacks and the role of private physicians

To generate recommendations for improving adherence to public health advice during public health crises, we conducted semi-structured interviews with employees at the Brentwood Road Postal Facility and on Capitol Hill to identify key themes associated with decisions to adhere to recommended antibiotic prophylaxis during the 2001 anthrax attacks. Factors used in deciding to adhere to recommended prophylactic antibiotics and concerns about the official response were similar in Brentwood and Capitol Hill employees, and in adherent and nonadherent participants. All participants used multiple sources of information and support as they weighed the risk from anthrax against the advantages and disadvantages of antibiotics. We found that nonadherent participants were commonly following the advice of private physicians, whereas adherent participants commonly described ongoing support from multiple sources when discussing their decisions. Our findings highlight the need for better integration between the public and private health care systems during public health crises and the importance of equipping private physicians for their key role in aiding decision-making during a public health crisis. Special attention also should be given to enhancing support and information from multiple sources throughout the entire period of risk.     

Reducing mortality from anthrax bioterrorism: strategies for stockpiling and dispensing medical and pharmaceutical supplies

A critical question in planning a response to bioterrorism is how antibiotics and medical supplies should be stockpiled and dispensed. The objective of this work was to evaluate the costs and benefits of alternative strategies for maintaining and dispensing local and regional inventories of antibiotics and medical supplies for responses to anthrax bioterrorism. We modeled the regional and local supply chain for antibiotics and medical supplies as well as local dispensing capacity. We found that mortality was highly dependent on the local dispensing capacity, the number of individuals requiring prophylaxis, adherence to prophylactic antibiotics, and delays in attack detection. For an attack exposing 250,000 people and requiring the prophylaxis of 5 million people, expected mortality fell from 243,000 to 145,000 as the dispensing capacity increased from 14,000 to 420,000 individuals per day. At low dispensing capacities (<14,000 individuals per day), nearly all exposed individuals died, regardless of the rate of adherence to prophylaxis, delays in attack detection, or availability of local inventories. No benefit was achieved by doubling local inventories at low dispensing capacities; however, at higher dispensing capacities, the cost-effectiveness of doubling local inventories fell from 100,000 US dollars to 20,000 US dollars/life year gained as the annual probability of an attack increased from 0.0002 to 0.001. We conclude that because of the reportedly rapid availability of regional inventories, the critical determinant of mortality following anthrax bioterrorism is local dispensing capacity. Bioterrorism preparedness efforts directed at improving local dispensing capacity are required before benefits can be reaped from enhancing local inventories.     

The statistical analysis of truncated data: application to the Sverdlovsk anthrax outbreak

An outbreak of anthrax occurred in the city of Sverdlovsk in Russia in the spring of 1979. The outbreak was due to the inhalation of spores that were accidentally released from a military microbiology facility. In response to the outbreak a public health intervention was mounted that included distribution of antibiotics and vaccine. The objective of this paper is to develop and apply statistical methodology to analyse the Sverdlovsk outbreak, and in particular to estimate the incubation period of inhalational anthrax and the number of deaths that may have been prevented by the public health intervention. The data available for analysis from this common source epidemic are the incubation periods of reported deaths. The statistical problem is that incubation periods are truncated because some individuals may have had their deaths prevented by the public health interventions and thus are not included in the data. However, it is not known how many persons received the intervention or how efficacious was the intervention. A likelihood function is formulated that accounts for the effects of truncation. The likelihood is decomposed into a binomial likelihood with unknown sample size and a conditional likelihood for the incubation periods. The methods are extended to allow for a phase-in of the intervention over time. Assuming a lognormal model for the incubation period distribution, the median and mean incubation periods were estimated to be 11.0 and 14.2 days respectively. These estimates are longer than have been previously reported in the literature. The death toll from the Sverdlovsk anthrax outbreak could have been about 14% larger had there not been a public health intervention; however, the confidence intervals are wide (95% CI 0-61%). The sensitivity of the results to model assumptions and the parametric model for the incubation period distribution are investigated. The results are useful for determining how long antibiotic therapy should be continued in suspected anthrax cases and also for estimating the ultimate number of deaths in a new outbreak in the absence of any public health interventions.     

Cost-Effectiveness Comparison of Response Strategies to a Large-Scale Anthrax Attack on the Chicago Metropolitan Area: Impact of Timing and Surge Capacity

Rapid public health response to a large-scale anthrax attack would reduce overall morbidity and mortality. However, there is uncertainty about the optimal cost-effective response strategy based on timing of intervention, public health resources, and critical care facilities. We conducted a decision analytic study to compare response strategies to a theoretical large-scale anthrax attack on the Chicago metropolitan area beginning either Day 2 or Day 5 after the attack. These strategies correspond to the policy options set forth by the Anthrax Modeling Working Group for population-wide responses to a large-scale anthrax attack: (1) postattack antibiotic prophylaxis, (2) postattack antibiotic prophylaxis and vaccination, (3) preattack vaccination with postattack antibiotic prophylaxis, and (4) preattack vaccination with postattack antibiotic prophylaxis and vaccination. Outcomes were measured in costs, lives saved, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). We estimated that postattack antibiotic prophylaxis of all 1,390,000 anthrax-exposed people beginning on Day 2 after attack would result in 205,835 infected victims, 35,049 fulminant victims, and 28,612 deaths. Only 6,437 (18.5%) of the fulminant victims could be saved with the existing critical care facilities in the Chicago metropolitan area. Mortality would increase to 69,136 if the response strategy began on Day 5. Including postattack vaccination with antibiotic prophylaxis of all exposed people reduces mortality and is cost-effective for both Day 2 (ICER=$182/QALY) and Day 5 (ICER=$1,088/QALY) response strategies. Increasing ICU bed availability significantly reduces mortality for all response strategies. We conclude that postattack antibiotic prophylaxis and vaccination of all exposed people is the optimal cost-effective response strategy for a large-scale anthrax attack. Our findings support the US government's plan to provide antibiotic prophylaxis and vaccination for all exposed people within 48 hours of the recognition of a large-scale anthrax attack. Future policies should consider expanding critical care capacity to allow for the rescue of more victims.     

Public health response to an anthrax attack: an evaluation of vaccination policy options

A discrete-time, deterministic, compartmental model was developed and analyzed to provide insight into how the use of anthrax vaccine before or after a large-scale attack can reduce casualties. The model accounts for important response and protection factors such as antibiotic and vaccine efficacy, the protective effects of buildings, the timing of emergency response, and antibiotic adherence and vaccine coverage in the population prior to the attack. The relative benefit of pre- versus post-exposure vaccination is influenced by the timing of the post-exposure antibiotic distribution campaign as well as assumptions of antibiotic adherence. The results indicate that, regardless of which vaccination policy is adopted, a rapid and effective post-attack medical response has a large impact on the number of lives that can be saved by a post-exposure prophylaxis (PEP) campaign. A sensitivity analysis of the model indicates that uncertainty in medical efficacy and the time to initiate a PEP campaign are the model parameters that have the greatest impact on the number of predicted deaths. It is shown that for each day that a mass prophylaxis campaign is delayed, more casualties and deaths result than for each day that the completion of the campaign is delayed.     

False alarms, real challenges--one university's communication response to the 2001 anthrax crisis

Considerable research exists on how government agencies at the federal, state, and local levels communicated during the fall 2001 anthrax attacks. However, there is little research on how other institutions handled this crisis, in terms of their response to potential anthrax contamination (aka "white powder scares") and their approach to disseminating important health and safety information. In this article, we investigate a major university's communication response to the anthrax crisis. First, we describe its communication experiences relating to a large white powder scare that occurred in October 2001. Second, we describe the university's broader communication efforts in terms of several important elements of risk communication research, including influence of source attributes, key messages, preferred channels, responses to information requests, and organizational influences. This study underlines that an institution does not have to be directly affected by a crisis to find itself on the communication "front lines." Moreover, other institutions may find it useful to learn from the experiences of this university, so that they may communicate more effectively during future crises.     

The sepsis model: an emerging hypothesis for the lethality of inhalation anthrax

Inhalation anthrax is often described as a toxin‐mediated disease. However, the toxaemia model does not account for the high mortality of inhalation anthrax relative to other forms of the disease or for the pathology present in inhalation anthrax. Patients with inhalation anthrax consistently show extreme bacteraemia and, in contrast to animals challenged with toxin, signs of sepsis. Rather than toxaemia, we propose that death in inhalation anthrax results from an overwhelming bacteraemia that leads to severe sepsis. According to our model, the central role of anthrax toxin is to permit the vegetative bacteria to escape immune detection. Other forms of B. anthracis infection have lower mortality because their overt symptoms early in the course of disease cause patients to seek medical care at a time when the infection and its sequelae can still be reversed by antibiotics. Thus, the sepsis model explains key features of inhalation anthrax and may offer a more complete understanding of disease pathology for researchers as well as those involved in the care of patients.     

Finding Risk-Based Switchover Points for Response Decisions for Environmental Exposure to Bacillus anthracis

In the wake of the 2001 terrorist attacks, the use of Bacillus anthracis (anthrax) in bioterrorism attacks has emerged as a realistic concern. Thus, a contingency plan is needed to inform decision-makers about which response actions are appropriate and justified under which circumstances. This study considers the decisions: (1) to undertake prophylactic antibiotic treatment; (2) to vaccinate individuals; or (3) to decontaminate the building. While these response actions are clearly justified for highly exposed individuals, a very large number of individuals exposed to very small risks in areas outside of the immediate vicinity of the release are also likely. Our results indicate that there are non-negligible risk thresholds below which response actions produce more costs than benefits. For the base case, the thresholds range from a risk of 1 in 33 for decontamination by fumigation to 1 in 6,547 for antibiotic prophylaxis and 1 in 7,108 for vaccination. A one-way sensitivity analysis on uncertain variables indicates less than an order of magnitude change in these thresholds. Benefit–cost analysis is a useful tool for assessing tradeoffs among alternative decisions, but cannot be the sole criterion in responding to incidents because of inherent limitations.     

2001: a year of major advances in anthrax toxin research

Anthrax is caused when spores of Bacillus anthracis enter a host and germinate. The bacteria multiply and secrete a tripartite toxin causing local edema and, in systemic infection, death. In nature, anthrax is primarily observed in cattle and other herbivores; humans are susceptible but rarely affected. In 2001, anthrax spores were used effectively for the first time in bioterrorist attacks, resulting in 11 confirmed cases of human disease and five deaths. These events have underscored the need for improved prophylaxis, therapeutics and a molecular understanding of the toxin. The good news about anthrax is that several decisive discoveries regarding the toxin have been reported recently. Most notably, the toxin receptor was identified, the 3-D structures of two of the toxin subunits were solved and potent in vivo inhibitors were designed. These findings have improved our understanding of the intoxication mechanism and are stimulating the design of strategies to fight disease in the future.     

Interactions between anthrax toxin receptors and protective antigen

Since the anthrax mail attacks of 2001, much has been learned about the interactions between anthrax toxin and its receptors. Two distinct cellular receptors for anthrax toxin have been identified and are designated capillary morphogenesis protein 2 (CMG2) and anthrax toxin receptor/tumor endothelial marker 8 (ATR/TEM8). The molecular details of the toxin-receptor interactions have been revealed through crystallographic, biochemical and genetic studies. In addition, a novel pathway by which anthrax toxin enters cells is starting to be uncovered.     

Treatment of anthrax infection with combination of ciprofloxacin and antibodies to protective antigen of Bacillus anthracis

Currently there is no effective treatment for inhalational anthrax beyond administration of antibiotics shortly after exposure. There is need for new, safe and effective treatments to supplement traditional antibiotic therapy. Our study was based on the premise that simultaneous inhibition of lethal toxin action with antibodies and blocking of bacterial growth by antibiotics will be beneficial for the treatment of anthrax. In this study, we tested the effects of a combination treatment using purified rabbit or sheep anti-protective antigen (PA) antibodies and the antibiotic ciprofloxacin in a rodent anthrax model. In mice infected with a dose of Bacillus anthracis Sterne strain corresponding to 10 LD(50), antibiotic treatment with ciprofloxacin alone only cured 50% of infected animals. Administration of anti-PA IgG in combination with ciprofloxacin produced 90-100% survival. These data indicate that a combination of antibiotic/immunoglobulin therapy is more effective than antibiotic treatment alone in a rodent anthrax model.     

Preparedness for an anthrax attack

Bacillus anthracis is a long-known bacterial organism with a uniquely stable spore stage. Its stability and the lethal disease which results when the spore is inhaled made it a favorite of state-sponsored biological weapons programs throughout the Cold War era. It is also believed to be high on the list of candidate microbial agents which could be used by terrorist groups or lone actors. Its unique characteristics make protection of humans, especially civilians, from an intentional biological attack very difficult. The author argues that an all-hazards/public health approach – which would also be needed for any natural or deliberate outbreak, no matter the agent – should serve as a foundation of preparation for the specific anthrax countermeasures. Because B. anthracis is a unique organism, specific countermeasures for anthrax detection, diagnostics, prophylaxis and therapy, should be developed in nations or regions where the threat of biological attack is believed to warrant such preparation. Other considerations for a nation interested in anthrax preparedness are discussed.     

Total decontamination cost of the anthrax letter attacks

All of the costs associated with decontamination following the 2001 anthrax letter attacks were summarized, estimated, and aggregated based on existing literature and news media reports. A comprehensive list of all affected structures was compiled. Costs were analyzed by building class and decontamination type. Sampling costs and costs of worker relocation were also included. Our analysis indicates that the total cost associated with decontamination was about $320 million.     

Inhalation anthrax: dose response and risk analysis

The notion that inhalation of a single Bacillus anthracis spore is fatal has become entrenched nearly to the point of urban legend, in part because of incomplete articulation of the scientific basis for microbial risk assessment, particularly dose-response assessment. Risk analysis (ie, risk assessment, risk communication, risk management) necessitates transparency: distinguishing scientific facts, hypotheses, judgments, biases in interpretations, and potential misinformation. The difficulty in achieving transparency for biothreat risk is magnified by misinformation and poor characterization of both dose-response relationships and the driving mechanisms that cause susceptibility or resistance to disease progression. Regrettably, this entrenchment unnecessarily restricts preparedness planning to a single response scenario: decontaminate until no spores are detectable in air, water, or on surfaces-essentially forcing a zero-tolerance policy inconsistent with the biology of anthrax. We present evidence about inhalation anthrax dose-response relationships, including reports from multiple studies documenting exposures insufficient to cause inhalation anthrax in laboratory animals and humans. The emphasis of the article is clarification about what is known from objective scientific evidence for doses of anthrax spores associated with survival and mortality. From this knowledge base, we discuss the need for future applications of more formal risk analysis processes to guide development of alternative non-zero criteria or standards based on science to inform preparedness planning and other risk management activities.     

Evaluation of public health interventions for Anthrax: a report to the secretary's council on Public Health Preparedness

To aid in understanding how best to respond to a bioterror anthrax attack, we analyze a system of differential equations that includes a disease progression model, a set of spatially distributed queues for distributing antibiotics, and vaccination (pre-event and/or post-event). We derive approximate expressions for the number of casualties as a function of key parameters and management levers, including the time at which the attack is detected, the number of days to distribute antibiotics, the adherence to prophylactic antibiotics, and the fraction of the population that is preimmunized. We compare a variety of public health intervention policies in the event of a hypothetical anthrax attack in a large metropolitan area. Modeling assumptions were decided by the Anthrax Modeling Working Group of the Secretary's Council on Public Health Preparedness. Our results highlight the primary importance of rapid antibiotic distribution and lead us to argue for ensuring post-attack surge capacity to rapidly produce enough anthrax vaccine for an additional 100 million people.     

Modeling the host response to inhalation anthrax

Inhalation anthrax, an often fatal infection, is initiated by endospores of the bacterium Bacillus anthracis, which are introduced into the lung. To better understand the pathogenesis of an inhalation anthrax infection, we propose a two-compartment mathematical model that takes into account the documented early events of such an infection. Anthrax spores, once inhaled, are readily taken up by alveolar phagocytes, which then migrate rather quickly out of the lung and into the thoracic/mediastinal lymph nodes. En route, these spores germinate to become vegetative bacteria. In the lymph nodes, the bacteria kill the host cells and are released into the extracellular environment where they can be disseminated into the blood stream and grow to a very high level, often resulting in the death of the infected person. Using this framework as the basis of our model, we explore the probability of survival of an infected individual. This is dependent on several factors, such as the rate of migration and germination events and treatment with antibiotics.     

Raxibacumab

Raxibacumab (ABthrax) is a human IgG1 monoclonal antibody against Bacillus anthracis protective antigen. HGS is currently providing stockpiles of the agent to the US government for use in the prevention and treatment of inhalation anthrax. As of May 2009, the candidate was undergoing review by the US Food and Drug Administration. The availability of bioterrorism countermeasures has become more important since the September 2001 anthrax attacks, and development of raxibacumab is a significant advance in this area.     

Rabbit and nonhuman primate models of toxin-targeting human anthrax vaccines.

The intentional use of Bacillus anthracis, the etiological agent of anthrax, as a bioterrorist weapon in late 2001 made our society acutely aware of the importance of developing, testing, and stockpiling adequate countermeasures against biological attacks. Biodefense vaccines are an important component of our arsenal to be used during a biological attack. However, most of the agents considered significant threats either have been eradicated or rarely infect humans alive today. As such, vaccine efficacy cannot be determined in human clinical trials but must be extrapolated from experimental animal models. This article reviews the efficacy and immunogenicity of human anthrax vaccines in well-defined animal models and the progress toward developing a rugged immunologic correlate of protection. The ongoing evaluation of human anthrax vaccines will be dependent on animal efficacy data in the absence of human efficacy data for licensure by the U.S. Food and Drug Administration.     

Responding to the threat of bioterrorism: a microbial ecology perspective – the case of anthrax

Anthrax is a disease of herbivores caused by the gram-positive bacterium Bacillus anthracis. It can affect cattle, sheep, swine, horses and various species of wildlife. The routes for the spread among wildlife are reviewed. There are three kinds of human anthrax – inhalation, cutaneous, and intestinal anthrax – which differ in their routes of infection and outcomes. In the United States, confirmation of cases is made by the isolation of B. anthracis and by biochemical tests. Vaccination is not recommended for the general public; civilians who should be vaccinated include those who, in their work places, come in contact with products potentially contaminated with B. anthracis spores, and people engaged in research or diagnostic activities. After September 11, 2001, there were bioterrorism anthrax attacks in the United States: anthrax-laced letters sent to multiple locations were the source of infectious B. anthracis. The US Postal Service issued recommendations to prevent the danger of hazardous exposure to the bacterium. B. anthracis spores can spread easily and persist for very long times, which makes decontamination of buildings very difficult. Early detection, rapid diagnosis, and well-coordinated public health response are the key to minimizing casualties. The US Government is seeking new ways to deter bioterrorism, including a tighter control of research on infectious agents, even though pathogens such as B. anthracis are widely spread in nature and easy to grow. It is necessary to define the boundary between defensive and offensive biological weapons research. Deterring bioterrorism should not restrict critical scientific research. Electronic Publication