On March 13–14, 2006, a meeting on anthrax, sponsored by the Centers for Disease Control and Prevention (CDC) in collaboration with the Southeastern Center for Emerging Biologic Threats, was held at Emory University in Atlanta, Georgia, USA. The meeting’s agenda included discussion of postexposure prophylaxis (PEP), screening and evaluation, and treatment of the various manifestations of human anthrax. The goal was to convene subject matter experts for a review of research developments and clinical experience with anthrax prophylaxis and treatment and to make consensus recommendations for updating guidelines for PEP, treatment, and clinical evaluation of patients with anthrax. A 2001 conference on guidelines for anthrax has previously been summarized in this journal (1). This article summarizes the meeting’s presentations and discussion. Consensus recommendations are summarized in the Table. Updated CDC guidelines for treatment and prophylaxis of anthrax will be published in detail in other CDC publications and are available on CDC’s website at http://www.bt.cdc.gov/agent/anthrax/index.asp.

Participants included representatives and members of academic research and clinical institutions, the Health Protection Agency of the United Kingdom, the Health Protection Agency and Armed Forces of Canada, the US Department of Defense, the US Department of Homeland Security, the US Department of Health and Human Services Office of Research and Development Coordination, the Food and Drug Administration, the National Institutes of Health, the Council of State and Territorial Epidemiologists, the American Board of Obstetricians and Gynecologists, the Infectious Diseases Society of America, and CDC (Figure). Among these participants were researchers, health department personnel, and clinicians, including the Pennsylvania pulmonologist who treated the 2006 case of inhalation anthrax (IA), the first naturally occurring case of IA in the United States since 1976 (2).

Participants discussed whether a shortened course of antimicrobial therapy plus a 3-dose AVA series would be effective, based on recent nonhuman primate research of a successful 14-day PEP course of ciprofloxacin combined with 3 AVA doses, and demonstrated immune response to AVA ( 26 ), and on evidence of seroconversion among clinical trial participants following 3 doses of AVA ( 27 ). However, there are no well-defined serologic correlates of protection to demonstrate that AVA vaccination has conferred adequate protective immunity in a person receiving PEP. Additionally, there are no human clinical trial data supporting any reduction in the duration of antimicrobial PEP, and there are isolated AVA study participants who have failed to seroconvert following vaccination (CDC, unpub. data). Therefore, it was deemed prudent to maintain the recommended 60-day course of antimicrobial therapy combined with the 3-dose AVA series to ensure adequate protection for all persons requiring PEP after aerosolized B. anthracis exposure.

The PEP antimicrobial regimen should remain for 60 days, combined with 3 doses of AVA. This duration is supported by data from the 1979 Sverdlovsk anthrax outbreak ( 25 ): illness up to 58 days following inhalation exposure to anthrax in nonhuman primates receiving antibiotics alone for 30 days ( 17 ), and demonstrated efficacy of the PEP combination of antimicrobial therapy and vaccination with AVA ( 17 ).

Penicillins should not be initially used for PEP of anthrax, due to concern for penicillin resistance, which has been found in naturally occurring isolates, and because of the low concentrations achieved with oral penicillins in pulmonary secretions, tissue, and within alveolar macrophages ( 23 , 24 ). Amoxicillin can be used for PEP once the B. anthracis strain has been proven penicillin susceptible, when other antimicrobial agents are not considered safe to use, such as for pediatric patients and for nursing or pregnant women. However, amoxicillin is not FDA-approved for this indication, and this use is considered “off-label.” Therefore, amoxicillin use for PEP in a mass-exposure event might be provided under an IND or under an Emergency Use Authorization in a declared emergency. Amoxicillin use for PEP is discussed further in the section below on special populations. Other antimicrobial agents, including clindamycin, chloramphenicol, rifampin, vancomycin, and other fluoroquinolones, may be considered for off-label use in patients unable to tolerate FDA-approved antimicrobial agents for PEP.

Levofloxacin is FDA-approved for “inhalational anthrax (postexposure)” in adults 18 years of age and older ( 22 ). There are safety data for up to 28 days of use, but safety data on extended use up to 60 days are limited ( 22 ). Therefore, levofloxacin is recommended as a second-line PEP antimicrobial agent, to be reserved for instances where medical issues may call for its use.

Ciprofloxacin, doxycycline, and penicillin G procaine have demonstrated efficacy for PEP in a nonhuman primate model ( 17 ) and are FDA-approved for “inhalational anthrax (postexposure)” in all age groups ( 18 ). Meeting participants reiterated existing CDC recommendations for ciprofloxacin and doxycycline as equivalent first-line antimicrobial agents for PEP, as they are equally efficacious for PEP and have similar susceptibility profiles among naturally occurring isolates ( 9 , 17 ). Both have similar safety profiles, with a low rate of anaphylactic reactions ( 19 , 20 ). Following the bioterrorism event of 2001, there were no differences in self-reported symptoms with use of either drug for PEP, and no serious adverse events could be definitely related to their use ( 21 ).

Selection of the antimicrobial agent for PEP should involve consideration of antimicrobial resistance. Variable β-lactam resistance, particularly to the cephalosporins, has been reported among naturally occurring B. anthracis isolates ( 7 – 9 ). β-lactamase genes have been identified in the B. anthracis chromosome ( 10 , 11 ), and evaluation of isolates from the 2001 event indicated the presence of both cephalosporinase and penicillinase enzymes ( 12 ). Additionally, resistance can be readily induced in vitro in B. anthracis to a variety of antimicrobial classes including fluoroquinolones, tetracyclines, macrolides, penicillins, and other β-lactams ( 8 , 13 – 16 ).

During the 2001 US outbreak of bioterrorism-related anthrax, 22 confirmed or suspected anthrax cases occurred after envelopes containing Bacillus anthracis spores in powder were sent through the mail ( 3 ). Approximately 10,000 persons were offered at least 60 days of antimicrobial PEP ( 4 ). Current CDC recommendations for PEP following potential inhalation exposure to aerosolized B. anthracis spores are 60 days of oral antimicrobial therapy in combination with a 3-dose series of anthrax vaccine adsorbed (AVA), BioThrax (BioPort Corporation, Lansing, MI, USA) administered at time zero, 2 weeks, and 4 weeks ( 5 , 6 ). AVA is not FDA-approved for PEP and therefore would be available under an Investigational New Drug (IND) protocol.

Clinical Screening and Evaluation of Inhalation Anthrax

Since 2001, when CDC guidelines for the clinical evaluation of patients with possible IA in the event of possible mass exposure were published in the MMWR (28), several alternative screening algorithms have been suggested including the Inova Fairfax protocol proposed by Mayer et al (29), and the 3-tier screening protocol from Hupert et al (30).

The goal of all IA screening algorithms should be to evaluate large numbers of patients seeking treatment in emergency departments and identify potential IA cases: 1) during a potential or confirmed mass event; 2) when there is a known threat or epidemiologic data suggesting an increased risk for anthrax; or 3) when there is clinical suspicion of anthrax based on symptoms consistent with IA, including fever and persistent tachycardia, among others (28,29). The low sensitivity and specificity of such screening algorithms may not detect an isolated IA case; therefore, these algorithms are not meant to serve as general guidance for identifying IA without appropriate epidemiologic or clinical data. For example, neither the original CDC guidelines nor the proposed Inova Fairfax guidelines would have detected the solitary 2006 IA case (2). Nor should IA screening algorithms replace existing emergency department (ED) screening guidelines for patients with symptoms of community-acquired pneumonia (CAP); routine CAP cases are likely to be selected as potential IA cases when using these algorithms; additional diagnostics will be required to rule out IA.

Mayer et al retrospectively evaluated CDC’s screening guidelines, using the 11 IA cases from 2001 included among an ED patient population from the same period. On the basis of their analysis, they proposed revised screening guidelines. CDC guidelines successfully identified only 1 of the 11 cases, whereas the Inova Fairfax algorithm modified from CDC guidelines successfully identified 9 of the 11 cases (29). Participants debated whether the recommendation to reduce the number of clinical symptoms required by the Inova Fairfax guidelines warranted further evaluation (Table) because IA case-patients who seek treatment early in the course of the disease could be missed as they may not yet have all of the required symptoms. Including fever and tachycardia as necessary symptoms to begin the algorithm, timing public health notification, and reducing the stringency of the requirement for an epidemiologic link were discussed. Participants agreed that elements of the Inova Fairfax protocol should be incorporated into future CDC-recommended screening algorithms. They further recommended that validation studies be conducted and feedback collected to determine the accuracy and effectiveness of the algorithm in identifying cases of IA in an outbreak setting.

Hupert et al proposed a 3-tier screening protocol to identify potential early IA case-patients in the setting of a large-scale anthrax exposure, to aid ED physicians in decisions regarding PEP, and to support the clinical treatment decision process (30). Participants agreed that such a large-scale screening algorithm for persons with potential aerosol exposure to anthrax in a mass exposure setting should be addressed in CDC’s guidelines; however, such an algorithm was not adequately validated for adoption as a CDC recommendation.

Clinicians considering IA as a differential diagnosis should alert hospital microbiology staff of their suspicions and obtain blood cultures as early as possible before antimicrobial treatment. Gram-stain analyses of blood samples have previously detected bacteremia in systemic anthrax cases and in animal models (31,32) and may be informative.

Thoracic imaging remains a critical tool for the diagnosis of IA. Thoracic imaging studies were abnormal in all 11 of the IA cases from 2001 (8/11 with widened mediastinum, 9/11 with pleural effusions, and 7/11 with pulmonary infiltrates). However, initial ED thoracic radiographs may not reveal the classic widened mediastinum described for IA in all cases (33,34). In severe IA cases, thoracic computerized tomography without contrast was suggested as having utility for viewing hemorrhagic mediastinal lymph nodes.

Sensitivity and specificity analyses were recommended for evaluating any proposed IA screening algorithms, using historical IA cases incorporated into ED populations from annual influenza seasons or other periods with increased numbers of respiratory illness cases. Neither current CDC nor proposed alternative guidelines are applicable for pediatric patients because of lack of data on pediatric IA cases. Participants called for development of screening guidelines for children in collaboration with the American Association of Pediatrics and other pediatric care partners.