This report updates previous CDC guidelines and recommendations on preferred prevention and treatment regimens regarding naturally occurring anthrax. Also provided are a wide range of alternative regimens to first-line antimicrobial drugs for use if patients have contraindications or intolerances or after a wide-area aerosol release of Bacillus anthracis spores if resources become limited or a multidrug-resistant B. anthracis strain is used (Hendricks KA, Wright ME, Shadomy SV, et al.; Workgroup on Anthrax Clinical Guidelines. Centers for Disease Control and Prevention expert panel meetings on prevention and treatment of anthrax in adults. Emerg Infect Dis 2014;20:e130687; Meaney-Delman D, Rasmussen SA, Beigi RH, et al. Prophylaxis and treatment of anthrax in pregnant women. Obstet Gynecol 2013;122:885−900; Bradley JS, Peacock G, Krug SE, et al. Pediatric anthrax clinical management. Pediatrics 2014;133:e1411-36). Specifically, this report updates antimicrobial drug and antitoxin use for both postexposure prophylaxis (PEP) and treatment from these previous guidelines best practices and is based on systematic reviews of the literature regarding 1) in vitro antimicrobial drug activity against B. anthracis; 2) in vivo antimicrobial drug efficacy for PEP and treatment; 3) in vivo and human antitoxin efficacy for PEP, treatment, or both; and 4) human survival after antimicrobial drug PEP and treatment of localized anthrax, systemic anthrax, and anthrax meningitis.
Changes from previous CDC guidelines and recommendations include an expanded list of alternative antimicrobial drugs to use when first-line antimicrobial drugs are contraindicated or not tolerated or after a bioterrorism event when first-line antimicrobial drugs are depleted or ineffective against a genetically engineered resistant B. anthracis strain. In addition, these updated guidelines include new recommendations regarding special considerations for the diagnosis and treatment of anthrax meningitis, including comorbid, social, and clinical predictors of anthrax meningitis.
The previously published CDC guidelines and recommendations described potentially beneficial critical care measures and clinical assessment tools and procedures for persons with anthrax, which have not changed and are not addressed in this update. In addition, no changes were made to the Advisory Committee on Immunization Practices recommendations for use of anthrax vaccine (Bower WA, Schiffer J, Atmar RL, et al. Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices, 2019. MMWR Recomm Rep 2019;68[No. RR-4]:1–14). The updated guidelines in this report can be used by health care providers to prevent and treat anthrax and guide emergency preparedness officials and planners as they develop and update plans for a wide-area aerosol release of B. anthracis.
IntroductionAnthrax is a zoonotic disease caused by infection with Bacillus anthracis and still occurs in agricultural regions of the Americas, sub-Saharan Africa, central and southwestern Asia, and southern and eastern Europe.[1] Sheep, goats, cattle, and other herbivores are primarily affected. Humans are secondarily infected through contact with infected animals, contaminated animal products (e.g., meat or hides), or, rarely, from injection drug use [2]. Anthrax in humans usually is characterized by the route of B. anthracis inoculation [3]. Cutaneous anthrax, which results from direct inoculation of spores through the skin, is the most common form and accounts for >95% of human cases. Ingestion anthrax usually results from consumption of infected meat. Inhalation anthrax results from the inhalation of aerosolized spores. Injection anthrax, which is a relatively new form, results from injection of heroin contaminated with B. anthracis spores. Anthrax meningitis can complicate any form of anthrax or occur alone.
In the United States, anthrax has almost been eliminated through livestock vaccination. Wildlife and livestock anthrax still occurs sporadically in an area from southwest Texas through Colorado, North and South Dakota, and Montana [4,5]. Since 2006, nine confirmed or probable U.S. cases of anthrax have been reported to CDC: two inhalation [6,7], one ingestion [8], four cutaneous [9,10], and two with no documented route of infection. In addition, since 1997, seven cases of severe pneumonia have been identified that were caused by Bacillus cereus group species that harbor a plasmid that encodes anthrax toxins similar to those found in B. anthracis[11].
B. anthracis is a Tier 1 select agent and considered one of the most likely bioterrorism agents to be used because it is relatively easy to acquire from the natural environment, mass produce, and disseminate as spores via aerosolization [12]. Although approximately 180 countries have signed on to the 1975 Biological Weapons Convention prohibiting the development, production, acquisition, transfer, stockpiling, and use of bioweapons, a wide-area aerosol release of B. anthracis spores remains a concern. In 2001, B. anthracis spores were sent in letters through the U.S. Postal Service. Exposure to aerosolized spores in these letters resulted in 11 inhalation and 11 cutaneous cases; five inhalation cases were fatal [13,14]. A wide-area aerosol release of B. anthracis spores would likely result in a mass-casualty incident [15,16] that could possibly be complicated by use of genetically engineered B. anthracis strains resistant to first-line antimicrobial drugs for postexposure prophylaxis (PEP) and treatment. In 2015, CDC published recommendations for hospital-based acute care that addressed antitoxin and intravenous (IV) antimicrobial drug use and the diagnosis and management of common anthrax-specific complications during a mass-casualty incident that would require a shift from conventional to contingency or crisis standards of care [17].
B. anthracis possesses three primary virulence factors: an extracellular capsule and two bipartite exotoxins (lethal toxin [composed of lethal factor and protective antigen] and edema toxin [composed of edema factor and protective antigen]) 18– 20. The capsule prevents phagocytosis of the vegetative form of B. anthracis by macrophages, allowing it to evade the immune system. The two toxins also facilitate immune system evasion by disrupting various immune cell functions (e.g., cellular signaling and cell migration) [21,22]. In addition, they impair macrophages, neutrophils, and dendritic cell functions [23,24] and inhibit host B- and T-cell immune responses [25]. Lethal toxin causes apoptosis of endothelial cells within the vascular system and is thought to contribute to hemorrhage [26]. These combined effects allow bacterial proliferation and lead to the high morbidity and mortality associated with anthrax. Historically, antiserum appeared to be an effective treatment. In aggregate data from the preantibiotic era, patients with cutaneous anthrax who were treated with antiserum had a substantially lower mortality rate than those who remained untreated (7.6% for patients who received antiserum during 1903−1941 compared with 23.7% for patients who did not receive antiserum during 1888−1920) [27].
Before the bioterrorism-related inhalation anthrax cases in 2001 [13], the anthrax mortality rate for the cases before the 1960s approached 90% for inhalation anthrax [28] and neared 100% for anthrax meningitis [29]. Mortality rates have improved with advancements in critical care; however, even with treatment, mortality ranges from <2% for cutaneous anthrax [30], to 45% for inhalation anthrax [28], and to 92% for anthrax meningitis [30]. In a mass-casualty event after a wide-area aerosol release of B. anthracis spores, mortality rates potentially could resemble those observed before the advent of modern critical care.
In 2013 and 2014, CDC published guidelines and recommendations for PEP and treatment of anthrax in pregnant and lactating persons [31], nonpregnant adults [27], and children [32]. Those guidelines incorporated published and unpublished data from in vitro studies and U.S. inhalation anthrax cases since 2001 and also relied on expert opinion. In addition to addressing PEP and treatment of anthrax across all populations, those previously published guidelines described potentially beneficial critical care measures and clinical procedures for persons with anthrax, which are not addressed in this report. The ACIP recommendations for the use of anthrax vaccine remain unchanged [33]. Vaccination of persons at risk for anthrax infection (e.g., travelers and laboratorians) can prevent disease. For unvaccinated or incompletely vaccinated persons exposed to B. anthracis, PEP includes both antimicrobial drugs with activity against B. anthracis (PEPAbx) and anthrax vaccine (PEPVx). This report updates best practices from previous guidelines for antimicrobial drug and antitoxin use for both PEP and treatment. The updated guidelines in this report are based on systematic reviews of the literature and associated data analyses regarding in vitro antimicrobial drug activity against B. anthracis; in vivo antimicrobial drug efficacy for PEPAbx and treatment; in vivo and human antitoxin efficacy for PEP, treatment, or both; and human survival after PEPAbx and treatment of localized anthrax, systemic anthrax, and anthrax meningitis. A review of safety information for the Food and Drug Administration (FDA)-approved antimicrobial drugs under consideration also served as a basis for the updated guidelines. Furthermore, these updated guidelines include new recommendations regarding special considerations for the diagnosis and treatment of anthrax meningitis, including comorbid, social, and clinical predictors of meningitis. This report recommends use of the following antimicrobial drugs that are not approved by FDA for anthrax PEPAbx or treatment: amoxicillin, amoxicillin/clavulanate, ampicillin/sulbactam, chloramphenicol, clarithromycin, clindamycin, dalbavancin, eravacycline, imipenem/cilastatin, linezolid, meropenem, moxifloxacin, ofloxacin, omadacycline, penicillin VK, piperacillin/tazobactam, rifampin, and vancomycin. Ciprofloxacin, doxycycline, levofloxacin, minocycline, penicillin G, and tetracycline are approved by FDA for anthrax PEPAbx, treatment, or both, but the specific uses (e.g., doses and dosing schedules) recommended in this report might differ from the FDA-approved labeling.
The intended audiences for the guidelines in this report are primary care providers and public health professionals. The antimicrobial drug, antitoxin, and other recommendations for PEP and treatment are best practices for the clinical management of single patient cases or limited outbreaks of naturally acquired anthrax. In addition, these guidelines address the issue of B. anthracis strains resistant to previously recommended antimicrobial drugs. Extensive antimicrobial drug options are provided for situations when first-line antimicrobial drugs are not tolerated or are contraindicated or after a bioterrorism event involving a wide-area aerosol release of B. anthracis spores over a heavily populated area. The latter might require a shift to crisis standards of care when supplies of first-line antimicrobial drugs have been depleted.
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