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Clinical manifestations and diagnosis of anthrax
Sean V Shadomy, DVM, MPH
Alex R Hoffmaster, PhD
Nancy E Rosenstein, MD
UpToDate performs a continuous review of over 375 journals and other resources. Updates are added as important new information is published. The literature review for version 15.1 is current through December 2006; this topic was last changed on November 14, 2006. The next version of UpToDate (15.2) will be released in June 2007.
INTRODUCTION ” Anthrax, caused by Bacillus anthracis, is an uncommon illness in the United States. From 1980 through 2000, only seven cases of anthrax were reported to the Centers for Disease Control and Prevention (CDC) [1]. In 2001, an outbreak of bioterrorism-related anthrax occurred in the United States, when 22 confirmed or suspected anthrax cases occurred after B. anthracis spores in powder-containing envelopes were sent through the mail [2-4]. In February 2006, a case of inhalation anthrax occurred in an African drum maker in New York City, the first naturally-occurring case of inhalation anthrax in the United States since 1976. The exposure was the result of his making drums using animal hides, which were contaminated with B. anthracis spores [5].
The clinical manifestations and diagnosis of anthrax will be reviewed here. The pathogenesis, epidemiology, treatment, and prevention of anthrax are discussed separately. (See "Pathogenesis and epidemiology of anthrax" and see "Treatment and prevention of anthrax").
CLINICAL MANIFESTATIONS ” There are three major anthrax syndromes: cutaneous, inhalation, and gastrointestinal anthrax [5-7].
Cutaneous anthrax ” Cutaneous anthrax is the most common form of the disease. Naturally occurring cases of cutaneous anthrax develop after spores of B. anthracis are introduced subcutaneously, often as a result of contact with infected animals or animal products. Cuts or abrasions increase susceptibility to cutaneous infection [8-10]. Spores vegetate and multiply, and the antiphagocytic capsule facilitates local spread. (See "Pathogenesis and epidemiology of anthrax").
The incubation period is usually five to seven days with a range of one to 12 days [11,12]. However, during an anthrax outbreak in Sverdlovsk, Union of Soviet Socialist Republics, cutaneous cases developed up to 13 days following the aerosol release of spores [13]; an outbreak in Algeria was reported with a median incubation period of 19 days [14].
Over 90 percent of cutaneous anthrax lesions occur in exposed areas such as the face, neck, arms, and hands. The disease begins as a small, painless, but often pruritic papule and quickly enlarges and develops a central vesicle or bulla, followed by erosion leaving a painless necrotic ulcer with a black, depressed eschar [8]. Extensive edema of the surrounding tissues, due to toxin release, is often present along with regional lymphadenopathy and lymphangitis.
Systemic symptoms, including fever, malaise, and headache can accompany the cutaneous lesion [11]. In one case during the bioterrorism (BT) event of 2001, a microangiopathic hemolytic anemia, thrombocytopenia, coagulopathy, and renal dysfunction developed in a seven-month old child; these manifestations resolved following treatment with antibiotics [15].
Historically, the case fatality rate is <1 percent with antibiotic therapy, however, without appropriate therapy, mortality can be as high as 20 percent [16].
Inhalation anthrax ” Inhalation anthrax results from the inhalation into the alveolar spaces of B. anthracis spore-containing particles aerosolized through industrial processing, when working with animal products such as wool, hair, or hides that are contaminated with anthrax spores, or from intentional release.
Inhaled airborne particles >5 microns in size are either physically trapped in the nasopharynx or cleared by the mucociliary escalator system. In comparison, inhaled particles <5 microns in size can be deposited on alveolar ducts or alveoli [11,17]. Spores are phagocytosed by alveolar macrophages and transported to mediastinal lymph nodes. There they germinate, multiply and release toxins, causing hemorrhagic necrosis of the thoracic lymph nodes draining the lungs, a hemorrhagic mediastinitis, and, in occasional cases, a necrotizing pneumonia at the portal of entry [18]. The organisms then become blood-borne, causing bacteremia and potentially meningitis.
The incubation period for inhalation anthrax is estimated to be one to seven days, but was reported to be as long as 43 days for fatal cases in the 1979 outbreak in Sverdlovsk [13]. Information from a single case report suggests that the incubation period can be as little as one day [19]. This case report describes an office worker at a textile mill with a history of anthrax cases, who developed inhalation anthrax one day in 1961 following exposure in a grossly contaminated, dusty carding room in the mill; she previously rarely entered the mill.
During the BT event in 2001, the time between known exposure and symptom onset ranged from four to six days with a mean of 4.5 days [20,21]. In primate studies, spores have been found in the lungs up to 100 days following exposure [22], and inhalation anthrax has developed up to 58 days following experimental aerosol exposure in primates receiving 30 days of postexposure antibiotics [23].
Early clinical symptoms of inhalation anthrax are nonspecific, complicating assessment and diagnosis [5,24,25]. The course of the disease may be biphasic, with initial symptoms, such as myalgia, fever, and malaise mimicking those of influenza. Two to three days later, infected patients become dramatically sicker with the development of respiratory symptoms, including severe dyspnea and hypoxemia.
Progressive disease leads to the development of hypotension, with diaphoresis, cyanosis, shock, and stridor [9,19]. As with any form of anthrax, hematogenous spread can result in lesions in other organ systems, including hemorrhagic meningitis and submucosal gastrointestinal lesions [9,18]. Untreated, inhalation anthrax is usually fatal; among the 18 cases reported in the United States in the 20th century, the case fatality ratio was 89 percent [19]. However, antibiotic therapy can be successful especially if initiated early in the course of disease [13,19,21]; 6 of the 11 cases (55 percent) associated with the 2001 BT event in the United States responded successfully to treatment [20]. (See "Treatment and prevention of anthrax").
Gastrointestinal anthrax ” Gastrointestinal anthrax presents in two clinical forms, oropharyngeal and intestinal. The disease develops following the consumption of undercooked infected meat from animals with anthrax, and tends to occur in family clusters or point source outbreaks. The incubation period is estimated to be one to six days [26]; the case fatality rate is estimated to range from 25 to 60 percent [11].
Following ingestion, the spores infect the gastrointestinal tract epithelium. Extensive edema of the infected intestinal segment and mesentery can develop, and lesions may become necrotic and ulcerated [16,27]. The mesenteric lymph nodes may be enlarged and infected [27]. Symptoms may include fever, nausea and vomiting, anorexia, abdominal pain and tenderness, and progress to hematemesis and bloody diarrhea [27,28]. Abdominal distension with voluminous, hemorrhagic ascites may be present [27]. The disease may progress to toxemia, cyanosis, shock, and death [11].
The oropharyngeal form develops following infection of the oropharyngeal epithelium with consumption of undercooked, contaminated meat. Edematous lesions develop, which progress to necrotic ulcers covered with a pseudomembrane. Edema and swelling develop in the oropharynx and neck, accompanied with cervical lymphadenopathy, pharyngitis, and fever [26,29,30].
Meningitis ” Meningitis has been reported in association with cutaneous, inhalation, and gastrointestinal anthrax cases [31]. About one-half of patients with inhalation anthrax will develop hemorrhagic meningitis [18]. Cerebrospinal fluid analysis reveals an elevated protein (70 percent), low glucose (37 percent), and a positive Gram's stain (77 percent) and culture (81 percent) [31]. Parenchymal hemorrhage may be so severe that a grossly bloody lumbar puncture may be confused with a traumatic tap.
Delirium or coma follows quickly and refractory seizures, cranial nerve palsies, and myoclonus have been reported [6,31]. A review of 44 well-documented cases found that 75 percent of patients died within 24 hours of presentation with an overall survival of only 6 percent [31].
DIFFERENTIAL DIAGNOSIS
Cutaneous anthrax lesions ” The following diseases should be considered in the differential diagnosis of a blackened eschar lesion: Brown recluse spider bite Rickettsial pox Cutaneous leishmaniasis Varicella zoster Herpes simplex Staphylococcal or streptococcal cellulitis Ecthyma gangrenosum Ulceroglandular tularemia Plague Eczema Typhus Glanders Rat-bite fever Aspergillosis Mucormycosis Leprosy Vaccinia
Inhalation anthrax ” The following diseases should be considered in the differential diagnosis of a respiratory syndrome: Community-acquired (viral or mycoplasma) pneumonia Influenza Influenza-like illnesses (eg, rhinovirus, adenovirus, and parainfluenza virus infection) Pneumonic tularemia Q fever Legionnaires' disease Psittacosis Histoplasmosis (fibrous mediastinitis) Coccidioidomycosis Malignancy
Gastrointestinal anthrax ” The following diseases should be considered in the differential diagnosis of a hemorrhagic gastroenteritis or oropharyngeal lesions suspect for gastrointestinal anthrax [32]: Food poisoning Acute appendicitis Ruptured viscus Diverticulitis Dysentery Diseases causing acute cervical lymphadenitis or acute gastritis or abdomen Hemorrhagic gastroenteritis due to other microorganisms Necrotizing enteritis due to Clostridium perfringens Streptococcal pharyngitis Vincent's angina Ludwig's angina Parapharyngeal abscess Malignancy
DIAGNOSIS ” Because of the rarity of anthrax in the United States and the rapid course of disease progression, clinical or laboratory suspicion of anthrax should be followed by rapid testing of clinical samples and early initiation of antibiotic therapy. Immediate notification of the local or state health department and laboratory with isolates suspected to be B. anthracis sent to a Laboratory Response Network (LRN) reference laboratory for identification and characterization (see "Laboratory diagnosis" below).
Criteria for diagnosis ” In 2001, the CDC developed interim case definitions for anthrax.
A confirmed case of anthrax was defined as a clinically compatible case that was laboratory confirmed by the isolation of B. anthracis from the patient, or by laboratory evidence based on at least two other supportive tests using nonculture methods for detection of B. anthracis. Supportive laboratory tests include the LRN PCR assay, immunohistochemical staining (IHC) of tissues, and an anti-PA IgG detected by an enzyme-linked immunosorbent assay (ELISA) [33].
A suspect case was a clinically compatible illness without isolation of B. anthracis and with only a single supportive test, or a clinically compatible case epidemiologically linked to a confirmed exposure to B. anthracis but without corroborative laboratory evidence [33].
Laboratory Diagnosis ” The Laboratory Response Network (LRN) was established in 1999 by the CDC, the Association of Public Health Laboratories (APHL), the Federal Bureau of Investigation (FBI) and the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) for the rapid identification of select agents including B. anthracis [34]. The LRN is part of a linked hierarchy of sentinel, reference and national level laboratories. There are LRN reference laboratories (generally state public health laboratories) in all 50 states.
  Specimen transport ” The following specimens should be sent to the CDC: Stool, sputum, pleural fluid, and blood at 2 to 8º C Swabs at room temperature Fresh tissue samples frozen Formalin fixed specimens at room temperature.
Blood specimens for PCR should optimally be collected in tubes containing EDTA or citrate as anticoagulant and not heparin. Isolates of Bacillus can be transported on most nonselective laboratory media at room temperature. Specific information on specimen types, volumes, and transport conditions is summarized in the table (show table 1).
  Culture of B. anthracis ” Isolation of B. anthracis from the patient remains the best way to diagnose anthrax. B. anthracis can be recovered from numerous clinical samples including: blood, skin lesion exudates, cerebrospinal fluid (CSF), pleural fluid, sputum, and feces. In systemic infections, common in gastrointestinal and inhalation anthrax, organisms can easily be cultured from the blood (if collected prior to antimicrobial therapy). Concentrations of B. anthracis can reach 10(8) CFU/mL blood. Anthrax should immediately be considered if Gram's stain of blood or CSF reveals high concentrations of gram-positive bacilli growing in chains.
Most clinical laboratories do not have experience identifying B. anthracis and generally lack the specific tests necessary for identification. Thus, isolates suspected of being B. anthracis should be forwarded to an LRN reference laboratory for identification and further characterization. LRN laboratories have phenotypic, molecular and antigenic tests available for the specific and rapid identification of B. anthracis. These tests include susceptibility to gamma phage lysis [35], a LRN real-time PCR assay [36], a direct fluorescent assay (DFA) [37] and time-resolved fluorescent assay (TRF) for specific detection of B. anthracis antigens.
A commercially available immunochromatographic test, the Redline Alert (Tetracore, Inc.), can be used for the presumptive identification of B. anthracis isolates. This test has been approved by the Food and Drug Administration (FDA) for testing of nonhemolytic Bacillus isolates cultured on sheep blood agar plates [38]. A summary of these tests, their use and availability is presented in the table (show table 2).
  Non-culture detection of B. anthracis ” Although isolation of B. anthracis is optimal for diagnosis, it is unlikely once antimicrobial therapy has been initiated. Under these circumstances, tests that detect B. anthracis DNA, antigens, or antibody responses against B. anthracis must be used. LRN PCR ” The LRN PCR targets three distinct loci on the B. anthracis chromosome and each of the two virulence plasmids, pXO1 and pXO2. It has a limit of detection of 1 pg of DNA, which corresponds to approximately 167 cells [36]. The assay was 100 percent sensitive and specific when tested on 81 B. anthracis isolates and 56 closely related Bacillus isolates in a validation study [36]. IHC assays ” IHC assays allow for the specific detection of B. anthracis cells in formalin-fixed tissues using antibodies specific for a B. anthracis cell wall antigen or capsule antigen [39,40] (show table 2). These assays were particularly useful in diagnosing cutaneous anthrax cases in 2001 [40]. Skin biopsies from 8 of 10 cutaneous cases were positive by the IHC assay for the B. anthracis cell wall and capsule antigen [40]. Serology ” Several serologic assays have been developed for the detection of an antibody response against the anthrax toxin protein, protective antigen (PA). These include the quantitative human anti-PA IgG Enzyme-Linked Immunosorbent Assay (ELISA) and a commercially available qualitative kit (QuickELISATM Anthrax-PA Kit; Immunetics, Boston, MA) (show table 2).
The human anti-PA IgG ELISA when used on specimens from confirmed anthrax cases in 2001 and anthrax vaccine adsorbed vaccines had a 97.6 percent diagnostic sensitivity and 94.2 percent diagnostic specificity [41]. In addition, a competitive inhibition version of this assay was used to enhance the diagnostic specificity to 100 percent.
The QuickELISATM Anthrax-PA Kit was tested on sera from individuals with anthrax, individuals vaccinated with anthrax vaccine adsorbed (AVA, BioThrax, BioPort, Lansing, MI), healthy individuals, individuals with other infections, and influenza vaccine recipients[42]. The kit had a >99 percent specificity and 100 percent sensitivity.
DIAGNOSTIC APPROACH BY CLINICAL SYNDROME
Inhalation anthrax
  Distinction from common respiratory infections ” During a potential BT episode, an important issue is distinguishing potential inhalation anthrax cases from more common disorders such as community-acquired pneumonia (CAP), influenza, and influenza-like illnesses (ILI), such as, rhinovirus, adenovirus, and parainfluenza virus infection. Confirmatory testing should be performed on specimens from patients being evaluated for inhalation anthrax, including patients with a known exposure or high risk of exposure, patients with a clear epidemiologic link to exposure presenting with symptoms of inhalation anthrax, and patients with symptoms compatible with anthrax but no diagnosis.
The BT event of 2001 illustrated the importance of screening for inhalation anthrax, because the window of opportunity for successful treatment is narrow once symptoms appear. An analysis of clinical characteristics predictive of inhalation anthrax used data from 47 historical cases of inhalation anthrax (including 11 cases from the 2001 BT event) compared with 376 controls with CAP, influenza, or ILI [43]. The following findings were noted: The most accurate predictors of inhalation anthrax were mediastinal widening or pleural effusion on chest x-ray, and one or both of these findings were 100 percent sensitive for inhalation anthrax, and 72 and 96 percent specific when compared to CAP or ILI controls, respectively. Clinical signs more frequently associated with inhalation anthrax compared to CAP or ILI included shortness of breath, nausea, vomiting, altered mental status, pallor or cyanosis, and hematocrit >45 percent [43,44]. In contrast, symptoms more suggestive of an ILI included rhinorrhea and sore throat [44].
The CDC developed recommendations for the clinical evaluation of persons with possible inhalation anthrax during the 2001 bioterrorism event [45]. (Available online at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm).
  Imaging studies ” Widening of the mediastinum, secondary to mediastinitis, is considered a "classic" finding in inhalation anthrax (show radiograph 1). Seven of the first 10 cases associated with the 2001 BT event had this finding [21,43]. (See "Distinction from common respiratory infections" below).
Other chest x-ray abnormalities seen with inhalation anthrax include hilar abnormalities, pulmonary infiltrates or consolidation, and pleural effusion. Either these abnormalities or mediastinal widening were documented in all 11 cases associated with the 2001 event. The abnormalities, however, were often subtle, and presenting chest radiographs were initially interpreted as normal in three of 11 cases [21,45,46].
We recommend the following diagnostic testing of patients with suspected inhalation anthrax: Blood cultures obtained prior to antimicrobial therapy. Pleural fluid, if present, for Gram's stain, culture, and PCR. CSF, in patients with meningeal signs, for Gram's stain, culture, and PCR. Acute and convalescent serum samples for serologic testing. Pleural and/or bronchial biopsies for IHC, if other tests are negative.
Cutaneous anthrax ” The CDC developed recommendations for the clinical evaluation of persons with possible cutaneous anthrax [45]. (Available online at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm). In an appropriate epidemiologic setting, the presence of an eschar with extensive edema out of proportion to the size of the lesion (show picture 1), and the presence of gram-positive rods and few polymorphonuclear leukocytes on Gram's stain, is strongly suggestive of cutaneous anthrax.
We recommend the following diagnostic testing of patients with suspected cutaneous anthrax: For vesicular lesions, two swabs of vesicular fluid from an unopened vesicle, one for Gram's stain and culture, the second for PCR. For eschars, the edge should be lifted and two swab samples rotated underneath and submitted, one for Gram's stain and culture, the second for PCR. For ulcers, the base of the lesion should be sampled with two saline moistened swabs and submitted, one for Gram's stain and culture, the second for PCR.
In addition, from all patients, a full thickness punch biopsy of a papule or vesicle including adjacent skin should be submitted in 10 percent formalin for histopathology and IHC. In patients not on antibiotic therapy or on therapy for <24 hours, a second biopsy specimen should be submitted for Gram's stain, culture, and PCR [12,39,40].
Gastrointestinal anthrax
We recommend the following diagnostic testing of patients with suspected gastrointestinal anthrax: Blood cultures obtained prior to antimicrobial therapy. Ascites fluid for Gram's stain, culture, and PCR. Stool or rectal swab for Gram's stain, culture, and PCR. Oropharyngeal lesion, if present, for Gram's stain, culture, and PCR. Acute and convalescent serum samples for serologic testing.
There are few well studied cases of gastrointestinal anthrax, as a result, information regarding reliability of diagnostic testing is limited. Culture from stool frequently does not yield B. anthracis [26], but Gram's stain or culture of oropharyngeal lesions or ascitic fluid may be positive [27]. Blood cultures may also be positive when collected prior to initiating antimicrobial therapy [27]. Serologic testing for anti-PA antibodies were positive in seven of 10 oropharyngeal anthrax cases tested [47].
SUMMARY
Clinical manifestations There are three major anthrax syndromes: cutaneous, inhalation, and gastrointestinal anthrax. (See "Clinical manifestations" aboveSee "Clinical manifestations" above). Cutaneous anthrax is the most common form of the disease (show picture 1). Naturally occurring cases of cutaneous anthrax develop after spores of B. anthracis are introduced subcutaneously, often as a result of contact with infected animals or animal products. (See "Cutaneous anthrax" aboveSee "Cutaneous anthrax" above). The disease begins as a small, painless, but often pruritic papule and quickly enlarges and develops a central vesicle or bulla, followed by erosion leaving a necrotic ulcer with a black, depressed eschar. Extensive edema of the surrounding tissues is often present along with regional lymphadenopathy and lymphangitis. (See "Cutaneous anthrax" aboveSee "Cutaneous anthrax" above). Inhalation anthrax results from the inhalation of B. anthracis spores into the alveolar spaces aerosolized through either industrial processing, working with animal products such as wool, hair, or hides that are contaminated with anthrax spores, or intentional release. (See "Inhalation anthrax" aboveSee "Inhalation anthrax" aboveSee "Inhalation anthrax" above). Early clinical symptoms of inhalation anthrax are nonspecific complicating assessment and diagnosis. Initial symptoms, such as myalgia, fever, and malaise mimic those of influenza. However, anthrax-infected patients become dramatically sicker a few days later with the development of respiratory symptoms, including severe dyspnea and hypoxemia. About one-half of patients with inhalation anthrax will develop hemorrhagic meningitis. (See "Inhalation anthrax" aboveSee "Inhalation anthrax" aboveSee "Inhalation anthrax" above). Gastrointestinal anthrax presents in two clinical forms, oropharyngeal and intestinal. The disease develops following the consumption of undercooked infected meat from animals with anthrax. (See "Gastrointestinal anthrax" aboveSee "Gastrointestinal anthrax" aboveSee "Gastrointestinal anthrax" above).
Diagnosis Because of the rarity of anthrax in the United States and the rapid course of disease progression, clinical or laboratory suspicion of anthrax should be followed by rapid testing of clinical samples and early initiation of antibiotic therapy. Immediate notification of the local or state health department and laboratory is essential. (See "Diagnosis" aboveSee "Diagnosis" above). During a potential BT episode, an important issue is distinguishing inhalation anthrax from more common disorders such as CAP, influenza, and ILI. (See "Distinction from common respiratory infections" above). The most accurate predictors of inhalation anthrax are mediastinal widening (show radiograph 1) or pleural effusion on chest x-ray. (See "Distinction from common respiratory infections" above). Criteria and case definitions established for diagnosis include:
      - Confirmed case ” A clinically compatible case that is laboratory confirmed by the isolation of B. anthracis from the patient, or by laboratory evidence based on at least two other supportive tests using nonculture methods for detection of B. anthracis (LRN PCR assay, IHC of tissues, and an anti-PA IgG ELISA).
      - Suspect case ” A clinically compatible illness without isolation of B. anthracis and with only a single supportive test, or a clinically compatible case epidemiologically linked to a confirmed exposure to B. anthracis but without laboratory confirmation.
(See "Criteria for diagnosis" above). The diagnostic approach is dependent on the clinical syndrome. (See "Diagnostic approach by clinical syndrome" above).
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INTRODUCTION ” Anthrax, caused by Bacillus anthracis, is an uncommon illness in the United States. From 1980 through 2000, only seven cases of anthrax were reported to the Centers for Disease Control and Prevention (CDC) [1].
In 2001, an outbreak of bioterrorism-related anthrax occurred in the United States, when 22 confirmed or suspected anthrax cases occurred after B. anthracis spores in powder-containing envelopes were sent through the mail [2-4]. In February 2006, a case of inhalation anthrax occurred in an African drum maker in New York City, the first naturally-occurring case of inhalation anthrax in the United States since 1976. The exposure was the result of his making drums using animal hides, which were contaminated with B. anthracis spores [5].
Animals become infected with B. anthracis by ingesting spores while grazing on contaminated grass or feed. Naturally-occurring transmission to humans is accomplished through direct exposure to infected animals or animal products through skin exposure, ingestion, or inhalation.
Spores can persist in the soil for long periods of time. Surface decontamination is not practical except in very unusual circumstances; thus, epizootic anthrax continues to occur in highly endemic areas, such as Iran, Iraq, Turkey, Pakistan, and sub-Saharan Africa, where the use of animal anthrax vaccine is not comprehensive.
The treatment and prevention of anthrax will be reviewed here. The pathogenesis, epidemiology, clinical manifestations, and diagnosis of anthrax are discussed separately. (See "Pathogenesis and epidemiology of anthrax" and see "Clinical manifestations and diagnosis of anthrax").
TREATMENT ” Anthrax is a reportable disease and immediate notification should be made to the local or state health department and public health laboratory following clinical or laboratory suspicion of anthrax or exposure to B. anthracis.
B. anthracis is highly susceptible to a variety of antibiotics including penicillin, chloramphenicol, tetracycline, erythromycin, streptomycin, and the fluoroquinolones [6,7]. B. anthracis is not susceptible to cephalosporins or trimethoprim-sulfamethoxazole; these antibiotics should not be used for the treatment of anthrax [6-9].
Testing of isolates from the bioterrorism-related cases in the United States showed that the organisms were susceptible in vitro to ciprofloxacin, doxycycline, tetracycline, rifampin, vancomycin, chloramphenicol, imipenem, clindamycin, and clarithromycin [10]. Although sensitive to penicillin and ampicillin, the presence of inducible beta-lactamase led the CDC to advise against the use of either of these drugs alone for therapy of anthrax cases related to the 2001 bioterrorism event. The CDC issued interim treatment recommendations for cases and exposure related to the bioterrorism event, but the CDC cautions that these recommendations are based upon expert opinion because of the paucity of clinical data [10]. The treatment recommendations presented in this topic are in agreement with the recommendations of the CDC.
Cutaneous anthrax ” Penicillin has been used most extensively for the treatment of naturally-occurring cases of cutaneous anthrax. Organisms are rapidly cleared from skin lesions following antibiotic therapy. In one study, for example, 25 patients with cutaneous anthrax and positive initial cultures of blister fluid were given two million units of crystalline penicillin intravenously every six hours for up to 10 days, with hourly subsequent blister fluid or lesion cultures and Gram's stain [11]. All cultures were negative within five hours of the first penicillin dose, and all smears were negative within six hours of initiating therapy. Antibiotic therapy, however, does not prevent progression to the eschar phase.
For localized or uncomplicated naturally-occurring cutaneous anthrax cases, we recommend treatment with penicillin V (500 mg orally every 6 hours for five to seven days) or doxycycline (100 mg orally twice a day). For more severe cases of cutaneous anthrax, we recommend treatment with penicillin G (4 to 6 million units intravenously every 6 hours for 7 to 10 days) or doxycycline (100 mg intravenously every 12 hours) [6,12,13]. Case fatality rates as high as 20 percent have been reported for untreated cutaneous anthrax but fatalities are now unusual with appropriate antibiotic treatment [14]. Surgical excision of the cutaneous lesions is not recommended.
  Bioterrorism-related cutaneous anthrax ” During the bioterrorism event of 2001, the CDC recommended oral ciprofloxacin (500 mg twice daily) or doxycycline (100 mg twice daily) for treatment of cutaneous anthrax (show table 1). The recommended duration of treatment was 60 days based upon the possibility of inhalation aerosol exposure in the patients with cutaneous anthrax. Penicillin class antibiotics were not recommended based upon the presence of an inducible beta-lactamase in the B. anthracis isolates from the 2001 bioterrorism event.
We recommend empiric treatment of bioterrorism-related cutaneous anthrax with ciprofloxacin (500 mg twice daily in adults or 10 to 15 mg/kg twice daily, maximum dose 1 g in children) even for children and pregnant women, despite usual contraindications against their use, because of the seriousness of the disease. In the case of ciprofloxacin-allergic patients, we recommend treatment with doxycycline (100 mg twice daily in adults and children >8 years and >45 kg or 2.2 mg/kg twice daily in children 8 years or 45 kg).
In patients with cutaneous disease and signs of systemic involvement or in patients with extensive edema involving lesions on the head and neck, we recommend treatment with a regimen as for inhalation anthrax (see below) [10].
Inhalation anthrax ” Patients with inhalation anthrax (IA) frequently present late in the course of their illness, and in these patients virtually all cases are fatal even if the patient receives antibiotic therapy since such therapy does not act on the toxins produced by B. anthracis. However, in the 1979 outbreak in Sverdlovsk, 11 survivors (with more than 60 deaths) were reported, indicating that IA is not a universally fatal disease [1]. Furthermore, six of 11 IA cases (55 percent) associated with the 2001 bioterrorism attack in the United States were successfully treated with antibiotics [15]. Thus, antibiotic therapy should be initiated in any patient with suspected IA. Three antibiotics have received Food and Drug Administration (FDA) approval for the treatment of anthrax, including IA: ciprofloxacin, doxycycline, and penicillin G procaine [16].
Empiric treatment recommendations for IA are the same multidrug regimens regardless of whether the case is associated with bioterrorism or is a naturally occurring case. Once culture and susceptibility results are available, treatment should be modified based upon the susceptibility results of the isolate.
A systematic review of 82 IA cases that were reported in the medical literature between 1900 and 2005 found that the mortality rate observed during the 2001 United States anthrax attack was significantly lower than that historically reported for IA (45 versus 92 percent) [17]. The review identified the following statistically significant differences in treatment of IA survivors (12 patients) compared to those who died (70 patients): Therapy initiated during the prodromal phase (75 versus 10 percent) Multidrug antibiotic regimen (67 versus 21 percent) Pleural fluid drainage (83 versus 9 percent) Anthrax antiserum therapy (among cases prior to 2001; 25 versus 3 percent)
  Bioterrorism-related inhalation anthrax ” There are no clinical trials of multidrug therapy for IA, however, the failure of single-drug antibiotic therapy for IA has previously been noted [17,18]. The CDC recommended multidrug therapy for IA cases during the bioterrorism event in 2001 because of the seriousness of the illness and early clinical data on treatment of the IA cases suggested that intravenous treatment with two or more antibiotics improved survival. The multidrug regimens used in the 2001 case patients who survived included: Ciprofloxacin, rifampin, and vancomycin OR Ciprofloxacin, rifampin, and clindamycin
Penicillin was not recommended based upon the presence of inducible beta-lactamase in the B. anthracis isolates [10,19].
Based on these clinical data (show table 2), we recommend initial empiric intravenous antibiotic treatment of IA with either ciprofloxacin (400 mg every 12 hours) or doxycycline (100 mg every 12 hours) plus
      - One or two of the following intravenous antimicrobials with demonstrated in vitro activity against B. anthracis: rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, meropenem, or clindamycin
Once culture and susceptibility results of the B. anthracis isolate is available, the antibiotic regimen can be modified based upon these results.
For patients with serious systemic illness, intravenous ciprofloxacin is favored as the primary antimicrobial over intravenous doxycycline, unless there is a contraindication to the use of ciprofloxacin. Clindamycin is recommended as one of the additional antibiotics due to its potential inhibition of toxin production [20]. In addition, at least one of the additional antibiotics should have good central nervous system (CNS) penetration and efficacy against B. anthracis (eg, meropenem, imipenem, rifampin, vancomycin, penicillin, or ampicillin), due to the potential for clinical or subclinical meningeal involvement.
Although initial therapy should be intravenous, patients may be switched to oral therapy once they have shown a significant clinical response to treatment and are stable, usually after 14 to 21 days of intravenous antibiotics. We recommend a total duration of treatment of 60 days (combination of intravenous and oral therapy).
  Pleural effusion drainage ” We recommend the use of chest tubes or thoracentesis to drain pleural effusions as adjunctive treatment of all IA cases, due to the role that aggressive drainage of pleural effusions played in the successful clinical therapy of the five surviving IA patients in 2001 [17,19]. In addition, mortality was statistically significantly lower for IA patients prior to 2001 treated with pleural fluid drainage.
  Corticosteroids ” Corticosteroids may be considered as adjunctive therapy for patients with serious systemic illness due to IA, including patients with meningoencephalitis and patients with cutaneous anthrax with extensive edema involving the head and neck [10]. Supporting data are limited, however, a retrospective review of 70 cases of anthrax meningoencephalitis from 1966 to 2002 reported a mortality rate of 94 percent, but among 10 patients treated with corticosteroids as an adjunct to antimicrobial therapy, mortality was 80 percent [21].
Gastrointestinal anthrax ” There are few well studied cases of gastrointestinal anthrax. In the absence of case or study data on treatment of gastrointestinal anthrax, we recommend following the same treatment protocol for patients with gastrointestinal anthrax as is recommended for IA.
Meningoencephalitis ” The optimal management of anthrax meningitis is unknown [22]. There is a high likelihood of clinical or subclinical meningitis in cases of severe systemic anthrax, such as IA [23]. Early and aggressive therapy is crucial in anthrax meningitis due to the rapid progression and high mortality of the disease [21]. We recommend treatment include agents with activity against B. anthracis and good central nervous system penetration for treatment of anthrax cases with meningeal involvement. We recommend treatment with intravenous antimicrobial therapy including ciprofloxacin (based on CNS penetration of ciprofloxacin when meningeal inflammation is present [22]) plus one or two additional antibiotics with good CNS penetration and efficacy against B. anthracis (eg, meropenem, imipenem, rifampin, vancomycin, penicillin, or ampicillin).
Immunotherapeutics ” Animal origin antiserum was used with some success in the treatment of anthrax prior to the advent of widespread antibiotic use [24-26]. In addition, in a systematic review of IA cases from 1900 to 2005, mortality was significantly lower for patients receiving antiserum [17].
In animal models, passive immunization with immune serum containing antibodies against the B. anthracis protective antigen (PA) administered up to 24 hours after exposure proved effective in preventing infection [27], and a human monoclonal antibody to PA was demonstrated to be protective against inhalation anthrax in animal studies [28]. In the rat, high-affinity antibodies from persons immunized against anthrax were shown to protect rats injected with anthrax toxin [29].
Immunoglobulin derived from plasma harvested from persons immunized with the Anthrax Vaccine Adsorbed is available from the CDC (phone: 770-488-7100; http://cdc.gov) under an Investigational New Drug (IND) protocol for the treatment of persons with life-threatening anthrax. This product was used as a part of the successful clinical treatment of the February 2006 IA patient [30]. State and local health departments should be immediately notified following clinical or laboratory suspicion of anthrax and for any request for anthrax immunoglobulin.
PREVENTION ” Prevention of naturally-occurring anthrax in humans is primarily dependent on the control of the disease in animals, especially livestock. Animal vaccination is the major means of preventing naturally occurring epizootics of anthrax, since widespread decontamination of infected soil is impractical. Annual vaccination of livestock in areas with enzootic anthrax is recommended.
An anthrax vaccine for human use is licensed in the United States but is not available to the general public. The Advisory Committee on Immunization Practices (ACIP) recommends immunization in the following populations at high risk of repeated exposure to B. anthracis aerosols [31,32]: Persons with repeated risk of exposure or working with large quantities or concentrations of B. anthracis cultures Veterinarians and others at high risk for handling potentially infected animals in areas with a high disease incidence Persons working in high risk industries, such as those processing imported animal hides, hair, and wool
The vaccine is also recommended by the ACIP and CDC as part of the PEP protocol for inhalation anthrax as a three-dose series in conjunction with antibiotic therapy [32]. (See "Anthrax vaccine" below).
In 1997, a decision was made to immunize all United States military personnel against anthrax because of the threat of anthrax as a biological warfare agent, with initial vaccination given to service members assigned to regions designated to be at greater risk (eg, Persian Gulf and Korea) [33]. (See "Identifying and managing casualties of biological terrorism").
Anthrax vaccine ” The Sterne vaccine is a live, toxigenic, unencapsulated, avirulent vaccine strain that is widely used as a veterinary vaccine. This vaccine has not been used widely in humans because of development of necrosis at the inoculation site; due to such safety concerns, spore vaccines have generally not been used as human vaccines. However, a live spore vaccine has been developed in Russia for human use and is considered to be highly effective [34].
Anthrax vaccine adsorbed (BioThrax, BioPort, Lansing, MI) (AVA) is the only licensed human anthrax vaccine in the United States [31]. A similar, protective antigen-based vaccine was tested in a field trial and shown to be highly effective in preventing inhalation and cutaneous anthrax in wool mill workers at risk for infection [35]. The recommended vaccination schedule is complex; vaccination consists of subcutaneous injections at zero, two, and four weeks and at six, 12, and 18 months. In addition, to maintain immunity, an annual booster injection is recommended. Studies are currently underway to evaluate the immunogenicity of a reduced number of doses and administration via the intramuscular route [36,37].
Despite concerns that vaccination with AVA might adversely affect pregnancies or future reproductive health, a cohort study of 4092 women (3136 of whom had received at least one dose of vaccine) stationed at two army bases in Georgia from 1999 to 2000 found no difference in pregnancy rate or odds of having a live birth in women receiving at least one dose of vaccine compared to those who had not [38]. The study, however, was not powered sufficiently to determine whether there was an effect on birth outcomes.
A recombinant protective antigen vaccine (rPA) has demonstrated efficacy in animal models, and human clinical trials are under way [39,40].
POSTEXPOSURE PROPHYLAXIS ” Early studies of experimental IA in monkeys showed that treatment with penicillin beginning one day after aerosol exposure to B. anthracis spores was protective during the 5 to 10 days of drug therapy; however, the animals died when penicillin was discontinued [41].
In a subsequent study of experimental IA, monkeys were challenged with aerosolized B. anthracis spores; 24 hours later three groups of animals were treated with either penicillin, or ciprofloxacin, or doxycycline for 30 days, and a fourth group received the combination of doxycycline and immunization with anthrax vaccine [42]. The 30-day antibiotic regimens completely protected animals while they were on therapy; post treatment survival in animals given only antibiotics ranged from 70 to 90 percent compared to 100 percent survival in animals given antibiotics plus vaccine. However, when the monkeys were rechallenged with airborne B. anthracis spores, all animals died except for those that had been immunized.
An additional study in monkeys compared a 14-day course of ciprofloxacin therapy with the combination of a 14-day regimen of ciprofloxacin plus three doses of anthrax vaccine [43]. Only 44 percent of animals receiving 14 days of antibiotic alone survived, compared to 100 percent survival among animals given both antibiotics and vaccine. These data offer compelling evidence that the use of antibiotic postexposure prophylaxis (PEP) combined with active immunization provides effective protection against the development of IA.
Antibiotics ” Three oral antibiotics have been approved by the FDA and are recommended for PEP (show table 3). Ciprofloxacin (500 mg orally twice daily) and doxycycline (100 mg orally twice daily) are approved for use in adults and children, and levofloxacin (500 mg orally once daily) is approved for use in adults (eg, 18 years of age) [16,44]. The recommended duration of PEP antibiotic therapy is 60 days.
We recommend ciprofloxacin as the first-line drug for PEP in pregnant women and nursing mothers [45-47]. If susceptibility of the infecting B. anthracis strain to penicillin class antibiotics has been demonstrated, then we recommend amoxicillin (500 mg orally every 8 hours in adults, 80 mg/kg per day in divided doses every 8 hours for children) for PEP in this population and in children when other antibiotics are not as safe to use; however, amoxicillin has not been approved for this use by the FDA [45,46]. CDC notes that the organism burden is likely to be low in an individual who is exposed but not ill, and thus, the concerns about the presence of an inducible beta-lactamase are reduced when the drug is being used for prophylaxis rather than for therapy.
Use of the anthrax vaccine ” Anthrax vaccine (BioThrax) is recommended by the ACIP and CDC as part of the PEP regimen for IA exposure and is available through CDC (phone: 770-488-7100; http://cdc.gov) as part of an IND protocol. The anthrax vaccine should be administered in three doses (at zero, two and four weeks) in conjunction with antibiotic therapy [32,48]. State and local health departments should be immediately notified in the event of suspicion of exposure to anthrax and for any request for anthrax vaccine.
Adverse reactions ” In 2001, approximately 10,000 individuals were offered 60 days of antibiotic PEP therapy for the prevention of IA. Anaphylactoid reactions were reported in four persons provided PEP antibiotics within 30 days [49]. Overall, 3032 of 5,343 individuals (57 percent) who took at least one dose of antibiotics reported clinical symptoms; most of these were mild. The most common adverse events were gastrointestinal (44 percent) and neurologic (33 percent); 16 percent of patients sought medical care for adverse events [49].
The Anthrax Vaccine and Antibiotic Availability Program (AVAAP) offered extended antibiotic PEP (>60 days) for persons at risk for IA, and 1727 individuals received anthrax vaccine in addition to extended antibiotic PEP. Three serious adverse events with a probable or possible relationship to the AVAAP protocol were identified; one case of allergic interstitial nephritis was classified as likely causally related to ciprofloxacin PEP, and two serious adverse events were determined to be possibly related to doxycycline PEP. No serious adverse events were associated with anthrax vaccine use [50].
SUMMARY AND RECOMMENDATIONS Sporadic cases and outbreaks of naturally-occurring anthrax continue to occur worldwide, although they are relatively rare in developed nations. However, the threat of IA resulting from bioterrorism activity is now a reality. (See "Introduction" above).
Treatment We recommend treatment with either penicillin V (500 mg orally every 6 hours for 5 to 7 days) or doxycycline (100 mg orally twice a day for 5 to 7 days) for localized, naturally-occurring cutaneous anthrax (Grade 1C). For more severe cases of cutaneous anthrax, we recommend treatment with penicillin G (4 to 6 million units intravenously every 6 hours for 7 to 10 days) or doxycycline (100 mg intravenously twice a day) (Grade 1C). (See "Cutaneous anthrax" above). We recommend oral ciprofloxacin (500 mg twice daily) or doxycycline (100 mg twice daily) for treatment of cutaneous anthrax (show table 1) associated with bioterrorism events (Grade 1C). We recommend a duration of treatment of 60 days (Grade 1C). (See "Bioterrorism-related cutaneous anthrax" above). We recommend that patients with possible IA be started promptly on multidrug antibiotic therapy (Grade 1B). Empiric treatment regimens include:
      - Ciprofloxacin, preferred (400 mg IV every 12 hours) or in ciprofloxacin intolerant patients, doxycycline (100 mg IV every 12 hours) plus
      - One or two of the following intravenous antimicrobials with demonstrated in vitro activity against B. anthracis:
      - Rifampin
      - Vancomycin
      - Penicillin
      - Ampicillin
      - Chloramphenicol
      - Imipenem or meropenem
      - Clindamycin
(See "Bioterrorism-related inhalation anthrax" above). We typically switch to oral therapy (ciprofloxacin 500 mg twice daily or doxycycline 100 mg twice daily) when clinically appropriate, (eg, when patients show a sufficient clinical response to treatment and are stable), usually after 14 to 21 days of intravenous antibiotics. We recommend a duration of antimicrobial therapy for 60 days (total combination of IV and oral therapy) (Grade 1C). (See "Bioterrorism-related inhalation anthrax" above). We recommend the use of chest tubes or thoracentesis to drain pleural effusions, if present, as adjunctive treatment of all IA cases (Grade 1C). (See "Pleural effusion drainage" above). For patients with meningoencephalitis, we recommend intravenous antimicrobial therapy with ciprofloxacin (400 mg IV every 12 hours) plus one or two additional antibiotics with good CNS penetration and efficacy against B. anthracis (Grade 1C). The additional antibiotics include the following:
      - Rifampin
      - Vancomycin
      - Penicillin
      - Ampicillin
      - Imipenem or meropenem
(See "Meningoencephalitis" above). We suggest corticosteroids as adjunctive therapy for patients with serious systemic illness due to IA, including patients with meningoencephalitis and patients with cutaneous anthrax with extensive edema involving the head and neck (Grade 2C). (See "Corticosteroids" above).
Prevention Animal vaccination against anthrax is the major means of preventing naturally occurring anthrax in humans. Vaccination of the military in combat areas at high-risk for biological warfare is the best method for prevention of bioterrorism-related anthrax disease in this population. (See "Prevention" aboveSee "Prevention" above). We recommend postexposure prophylaxis treatment for patients at risk of inhalation anthrax (Grade 1B). Regimens include one of the following in nonpregnant adults:
      - Ciprofloxacin (500 mg twice daily) or
      - Doxycycline (100 mg twice daily) or
      - Levofloxacin (500 mg orally once daily)
The preferred regimen in children and nursing and pregnant women is ciprofloxacin (500 mg twice daily)??????
I think we shouldn't give Cipro to nursing pregnant and Children!!!
. If susceptibility of the anthrax strain to penicillin antibiotics is demonstrated, then the treatment of children and nursing and pregnant women can be changed to amoxicillin (500 mg orally every eight hours in adults, 80 mg/kg per day in divided doses every eight hours for children). (See "Antibiotics" above). We recommend a duration of postexposure prophylaxis antibiotic therapy of 60 days (Grade 1C). (See "Antibiotics" above). In conjunction with antibiotic treatment, we recommend vaccination with the anthrax vaccine adsorbed for postexposure prophylaxis for inhalation anthrax exposure (Grade 1C). The anthrax vaccine absorbed is available from the CDC (phone: 770-488-7100; http://cdc.gov) as part of an IND protocol. (See "Use of the anthrax vaccine" abov
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INTRODUCTION ” Anthrax, caused by Bacillus anthracis, is an uncommon illness in the United States. From 1980 through 2000, only seven cases of anthrax were reported to the Centers for Disease Control and Prevention (CDC) [1].
In 2001, an outbreak of bioterrorism-related anthrax occurred in the United States, when 22 confirmed or suspected anthrax cases occurred after B. anthracis spores in powder-containing envelopes were sent through the mail [2-4]. In February 2006, a case of inhalation anthrax occurred in an African drum maker in New York City, the first naturally-occurring case of inhalation anthrax in the United States since 1976. The exposure was the result of his making drums using animal hides, which were contaminated with B. anthracis spores [5].
Animals become infected with B. anthracis by ingesting spores while grazing on contaminated grass or feed. Naturally-occurring transmission to humans is accomplished through direct exposure to infected animals or animal products through skin exposure, ingestion, or inhalation.
Spores can persist in the soil for long periods of time. Surface decontamination is not practical except in very unusual circumstances; thus, epizootic anthrax continues to occur in highly endemic areas, such as Iran, Iraq, Turkey, Pakistan, and sub-Saharan Africa, where the use of animal anthrax vaccine is not comprehensive.
The treatment and prevention of anthrax will be reviewed here. The pathogenesis, epidemiology, clinical manifestations, and diagnosis of anthrax are discussed separately. (See "Pathogenesis and epidemiology of anthrax" and see "Clinical manifestations and diagnosis of anthrax").
TREATMENT ” Anthrax is a reportable disease and immediate notification should be made to the local or state health department and public health laboratory following clinical or laboratory suspicion of anthrax or exposure to B. anthracis.
B. anthracis is highly susceptible to a variety of antibiotics including penicillin, chloramphenicol, tetracycline, erythromycin, streptomycin, and the fluoroquinolones [6,7]. B. anthracis is not susceptible to cephalosporins or trimethoprim-sulfamethoxazole; these antibiotics should not be used for the treatment of anthrax [6-9].
Testing of isolates from the bioterrorism-related cases in the United States showed that the organisms were susceptible in vitro to ciprofloxacin, doxycycline, tetracycline, rifampin, vancomycin, chloramphenicol, imipenem, clindamycin, and clarithromycin [10]. Although sensitive to penicillin and ampicillin, the presence of inducible beta-lactamase led the CDC to advise against the use of either of these drugs alone for therapy of anthrax cases related to the 2001 bioterrorism event. The CDC issued interim treatment recommendations for cases and exposure related to the bioterrorism event, but the CDC cautions that these recommendations are based upon expert opinion because of the paucity of clinical data [10]. The treatment recommendations presented in this topic are in agreement with the recommendations of the CDC.
Cutaneous anthrax ” Penicillin has been used most extensively for the treatment of naturally-occurring cases of cutaneous anthrax. Organisms are rapidly cleared from skin lesions following antibiotic therapy. In one study, for example, 25 patients with cutaneous anthrax and positive initial cultures of blister fluid were given two million units of crystalline penicillin intravenously every six hours for up to 10 days, with hourly subsequent blister fluid or lesion cultures and Gram's stain [11]. All cultures were negative within five hours of the first penicillin dose, and all smears were negative within six hours of initiating therapy. Antibiotic therapy, however, does not prevent progression to the eschar phase.
For localized or uncomplicated naturally-occurring cutaneous anthrax cases, we recommend treatment with penicillin V (500 mg orally every 6 hours for five to seven days) or doxycycline (100 mg orally twice a day). For more severe cases of cutaneous anthrax, we recommend treatment with penicillin G (4 to 6 million units intravenously every 6 hours for 7 to 10 days) or doxycycline (100 mg intravenously every 12 hours) [6,12,13]. Case fatality rates as high as 20 percent have been reported for untreated cutaneous anthrax but fatalities are now unusual with appropriate antibiotic treatment [14]. Surgical excision of the cutaneous lesions is not recommended.
  Bioterrorism-related cutaneous anthrax ” During the bioterrorism event of 2001, the CDC recommended oral ciprofloxacin (500 mg twice daily) or doxycycline (100 mg twice daily) for treatment of cutaneous anthrax (show table 1). The recommended duration of treatment was 60 days based upon the possibility of inhalation aerosol exposure in the patients with cutaneous anthrax. Penicillin class antibiotics were not recommended based upon the presence of an inducible beta-lactamase in the B. anthracis isolates from the 2001 bioterrorism event.
We recommend empiric treatment of bioterrorism-related cutaneous anthrax with ciprofloxacin (500 mg twice daily in adults or 10 to 15 mg/kg twice daily, maximum dose 1 g in children) even for children and pregnant women, despite usual contraindications against their use, because of the seriousness of the disease. In the case of ciprofloxacin-allergic patients, we recommend treatment with doxycycline (100 mg twice daily in adults and children >8 years and >45 kg or 2.2 mg/kg twice daily in children 8 years or 45 kg).
In patients with cutaneous disease and signs of systemic involvement or in patients with extensive edema involving lesions on the head and neck, we recommend treatment with a regimen as for inhalation anthrax (see below) [10].
Inhalation anthrax ” Patients with inhalation anthrax (IA) frequently present late in the course of their illness, and in these patients virtually all cases are fatal even if the patient receives antibiotic therapy since such therapy does not act on the toxins produced by B. anthracis. However, in the 1979 outbreak in Sverdlovsk, 11 survivors (with more than 60 deaths) were reported, indicating that IA is not a universally fatal disease [1]. Furthermore, six of 11 IA cases (55 percent) associated with the 2001 bioterrorism attack in the United States were successfully treated with antibiotics [15]. Thus, antibiotic therapy should be initiated in any patient with suspected IA. Three antibiotics have received Food and Drug Administration (FDA) approval for the treatment of anthrax, including IA: ciprofloxacin, doxycycline, and penicillin G procaine [16].
Empiric treatment recommendations for IA are the same multidrug regimens regardless of whether the case is associated with bioterrorism or is a naturally occurring case. Once culture and susceptibility results are available, treatment should be modified based upon the susceptibility results of the isolate.
A systematic review of 82 IA cases that were reported in the medical literature between 1900 and 2005 found that the mortality rate observed during the 2001 United States anthrax attack was significantly lower than that historically reported for IA (45 versus 92 percent) [17]. The review identified the following statistically significant differences in treatment of IA survivors (12 patients) compared to those who died (70 patients): Therapy initiated during the prodromal phase (75 versus 10 percent) Multidrug antibiotic regimen (67 versus 21 percent) Pleural fluid drainage (83 versus 9 percent) Anthrax antiserum therapy (among cases prior to 2001; 25 versus 3 percent)
  Bioterrorism-related inhalation anthrax ” There are no clinical trials of multidrug therapy for IA, however, the failure of single-drug antibiotic therapy for IA has previously been noted [17,18]. The CDC recommended multidrug therapy for IA cases during the bioterrorism event in 2001 because of the seriousness of the illness and early clinical data on treatment of the IA cases suggested that intravenous treatment with two or more antibiotics improved survival. The multidrug regimens used in the 2001 case patients who survived included: Ciprofloxacin, rifampin, and vancomycin OR Ciprofloxacin, rifampin, and clindamycin
Penicillin was not recommended based upon the presence of inducible beta-lactamase in the B. anthracis isolates [10,19].
Based on these clinical data (show table 2), we recommend initial empiric intravenous antibiotic treatment of IA with either ciprofloxacin (400 mg every 12 hours) or doxycycline (100 mg every 12 hours) plus
      - One or two of the following intravenous antimicrobials with demonstrated in vitro activity against B. anthracis: rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, meropenem, or clindamycin
Once culture and susceptibility results of the B. anthracis isolate is available, the antibiotic regimen can be modified based upon these results.
For patients with serious systemic illness, intravenous ciprofloxacin is favored as the primary antimicrobial over intravenous doxycycline, unless there is a contraindication to the use of ciprofloxacin. Clindamycin is recommended as one of the additional antibiotics due to its potential inhibition of toxin production [20]. In addition, at least one of the additional antibiotics should have good central nervous system (CNS) penetration and efficacy against B. anthracis (eg, meropenem, imipenem, rifampin, vancomycin, penicillin, or ampicillin), due to the potential for clinical or subclinical meningeal involvement.
Although initial therapy should be intravenous, patients may be switched to oral therapy once they have shown a significant clinical response to treatment and are stable, usually after 14 to 21 days of intravenous antibiotics. We recommend a total duration of treatment of 60 days (combination of intravenous and oral therapy).
  Pleural effusion drainage ” We recommend the use of chest tubes or thoracentesis to drain pleural effusions as adjunctive treatment of all IA cases, due to the role that aggressive drainage of pleural effusions played in the successful clinical therapy of the five surviving IA patients in 2001 [17,19]. In addition, mortality was statistically significantly lower for IA patients prior to 2001 treated with pleural fluid drainage.
  Corticosteroids ” Corticosteroids may be considered as adjunctive therapy for patients with serious systemic illness due to IA, including patients with meningoencephalitis and patients with cutaneous anthrax with extensive edema involving the head and neck [10]. Supporting data are limited, however, a retrospective review of 70 cases of anthrax meningoencephalitis from 1966 to 2002 reported a mortality rate of 94 percent, but among 10 patients treated with corticosteroids as an adjunct to antimicrobial therapy, mortality was 80 percent [21].
Gastrointestinal anthrax ” There are few well studied cases of gastrointestinal anthrax. In the absence of case or study data on treatment of gastrointestinal anthrax, we recommend following the same treatment protocol for patients with gastrointestinal anthrax as is recommended for IA.
Meningoencephalitis ” The optimal management of anthrax meningitis is unknown [22]. There is a high likelihood of clinical or subclinical meningitis in cases of severe systemic anthrax, such as IA [23]. Early and aggressive therapy is crucial in anthrax meningitis due to the rapid progression and high mortality of the disease [21]. We recommend treatment include agents with activity against B. anthracis and good central nervous system penetration for treatment of anthrax cases with meningeal involvement. We recommend treatment with intravenous antimicrobial therapy including ciprofloxacin (based on CNS penetration of ciprofloxacin when meningeal inflammation is present [22]) plus one or two additional antibiotics with good CNS penetration and efficacy against B. anthracis (eg, meropenem, imipenem, rifampin, vancomycin, penicillin, or ampicillin).
Immunotherapeutics ” Animal origin antiserum was used with some success in the treatment of anthrax prior to the advent of widespread antibiotic use [24-26]. In addition, in a systematic review of IA cases from 1900 to 2005, mortality was significantly lower for patients receiving antiserum [17].
In animal models, passive immunization with immune serum containing antibodies against the B. anthracis protective antigen (PA) administered up to 24 hours after exposure proved effective in preventing infection [27], and a human monoclonal antibody to PA was demonstrated to be protective against inhalation anthrax in animal studies [28]. In the rat, high-affinity antibodies from persons immunized against anthrax were shown to protect rats injected with anthrax toxin [29].
Immunoglobulin derived from plasma harvested from persons immunized with the Anthrax Vaccine Adsorbed is available from the CDC (phone: 770-488-7100; http://cdc.gov) under an Investigational New Drug (IND) protocol for the treatment of persons with life-threatening anthrax. This product was used as a part of the successful clinical treatment of the February 2006 IA patient [30]. State and local health departments should be immediately notified following clinical or laboratory suspicion of anthrax and for any request for anthrax immunoglobulin.
PREVENTION ” Prevention of naturally-occurring anthrax in humans is primarily dependent on the control of the disease in animals, especially livestock. Animal vaccination is the major means of preventing naturally occurring epizootics of anthrax, since widespread decontamination of infected soil is impractical. Annual vaccination of livestock in areas with enzootic anthrax is recommended.
An anthrax vaccine for human use is licensed in the United States but is not available to the general public. The Advisory Committee on Immunization Practices (ACIP) recommends immunization in the following populations at high risk of repeated exposure to B. anthracis aerosols [31,32]: Persons with repeated risk of exposure or working with large quantities or concentrations of B. anthracis cultures Veterinarians and others at high risk for handling potentially infected animals in areas with a high disease incidence Persons working in high risk industries, such as those processing imported animal hides, hair, and wool
The vaccine is also recommended by the ACIP and CDC as part of the PEP protocol for inhalation anthrax as a three-dose series in conjunction with antibiotic therapy [32]. (See "Anthrax vaccine" below).
In 1997, a decision was made to immunize all United States military personnel against anthrax because of the threat of anthrax as a biological warfare agent, with initial vaccination given to service members assigned to regions designated to be at greater risk (eg, Persian Gulf and Korea) [33]. (See "Identifying and managing casualties of biological terrorism").
Anthrax vaccine ” The Sterne vaccine is a live, toxigenic, unencapsulated, avirulent vaccine strain that is widely used as a veterinary vaccine. This vaccine has not been used widely in humans because of development of necrosis at the inoculation site; due to such safety concerns, spore vaccines have generally not been used as human vaccines. However, a live spore vaccine has been developed in Russia for human use and is considered to be highly effective [34].
Anthrax vaccine adsorbed (BioThrax, BioPort, Lansing, MI) (AVA) is the only licensed human anthrax vaccine in the United States [31]. A similar, protective antigen-based vaccine was tested in a field trial and shown to be highly effective in preventing inhalation and cutaneous anthrax in wool mill workers at risk for infection [35]. The recommended vaccination schedule is complex; vaccination consists of subcutaneous injections at zero, two, and four weeks and at six, 12, and 18 months. In addition, to maintain immunity, an annual booster injection is recommended. Studies are currently underway to evaluate the immunogenicity of a reduced number of doses and administration via the intramuscular route [36,37].
Despite concerns that vaccination with AVA might adversely affect pregnancies or future reproductive health, a cohort study of 4092 women (3136 of whom had received at least one dose of vaccine) stationed at two army bases in Georgia from 1999 to 2000 found no difference in pregnancy rate or odds of having a live birth in women receiving at least one dose of vaccine compared to those who had not [38]. The study, however, was not powered sufficiently to determine whether there was an effect on birth outcomes.
A recombinant protective antigen vaccine (rPA) has demonstrated efficacy in animal models, and human clinical trials are under way [39,40].
POSTEXPOSURE PROPHYLAXIS ” Early studies of experimental IA in monkeys showed that treatment with penicillin beginning one day after aerosol exposure to B. anthracis spores was protective during the 5 to 10 days of drug therapy; however, the animals died when penicillin was discontinued [41].
In a subsequent study of experimental IA, monkeys were challenged with aerosolized B. anthracis spores; 24 hours later three groups of animals were treated with either penicillin, or ciprofloxacin, or doxycycline for 30 days, and a fourth group received the combination of doxycycline and immunization with anthrax vaccine [42]. The 30-day antibiotic regimens completely protected animals while they were on therapy; post treatment survival in animals given only antibiotics ranged from 70 to 90 percent compared to 100 percent survival in animals given antibiotics plus vaccine. However, when the monkeys were rechallenged with airborne B. anthracis spores, all animals died except for those that had been immunized.
An additional study in monkeys compared a 14-day course of ciprofloxacin therapy with the combination of a 14-day regimen of ciprofloxacin plus three doses of anthrax vaccine [43]. Only 44 percent of animals receiving 14 days of antibiotic alone survived, compared to 100 percent survival among animals given both antibiotics and vaccine. These data offer compelling evidence that the use of antibiotic postexposure prophylaxis (PEP) combined with active immunization provides effective protection against the development of IA.
Antibiotics ” Three oral antibiotics have been approved by the FDA and are recommended for PEP (show table 3). Ciprofloxacin (500 mg orally twice daily) and doxycycline (100 mg orally twice daily) are approved for use in adults and children, and levofloxacin (500 mg orally once daily) is approved for use in adults (eg, 18 years of age) [16,44]. The recommended duration of PEP antibiotic therapy is 60 days.
We recommend ciprofloxacin as the first-line drug for PEP in pregnant women and nursing mothers [45-47]. If susceptibility of the infecting B. anthracis strain to penicillin class antibiotics has been demonstrated, then we recommend amoxicillin (500 mg orally every 8 hours in adults, 80 mg/kg per day in divided doses every 8 hours for children) for PEP in this population and in children when other antibiotics are not as safe to use; however, amoxicillin has not been approved for this use by the FDA [45,46]. CDC notes that the organism burden is likely to be low in an individual who is exposed but not ill, and thus, the concerns about the presence of an inducible beta-lactamase are reduced when the drug is being used for prophylaxis rather than for therapy.
Use of the anthrax vaccine ” Anthrax vaccine (BioThrax) is recommended by the ACIP and CDC as part of the PEP regimen for IA exposure and is available through CDC (phone: 770-488-7100; http://cdc.gov) as part of an IND protocol. The anthrax vaccine should be administered in three doses (at zero, two and four weeks) in conjunction with antibiotic therapy [32,48]. State and local health departments should be immediately notified in the event of suspicion of exposure to anthrax and for any request for anthrax vaccine.
Adverse reactions ” In 2001, approximately 10,000 individuals were offered 60 days of antibiotic PEP therapy for the prevention of IA. Anaphylactoid reactions were reported in four persons provided PEP antibiotics within 30 days [49]. Overall, 3032 of 5,343 individuals (57 percent) who took at least one dose of antibiotics reported clinical symptoms; most of these were mild. The most common adverse events were gastrointestinal (44 percent) and neurologic (33 percent); 16 percent of patients sought medical care for adverse events [49].
The Anthrax Vaccine and Antibiotic Availability Program (AVAAP) offered extended antibiotic PEP (>60 days) for persons at risk for IA, and 1727 individuals received anthrax vaccine in addition to extended antibiotic PEP. Three serious adverse events with a probable or possible relationship to the AVAAP protocol were identified; one case of allergic interstitial nephritis was classified as likely causally related to ciprofloxacin PEP, and two serious adverse events were determined to be possibly related to doxycycline PEP. No serious adverse events were associated with anthrax vaccine use [50].
SUMMARY AND RECOMMENDATIONS Sporadic cases and outbreaks of naturally-occurring anthrax continue to occur worldwide, although they are relatively rare in developed nations. However, the threat of IA resulting from bioterrorism activity is now a reality. (See "Introduction" above).
Treatment We recommend treatment with either penicillin V (500 mg orally every 6 hours for 5 to 7 days) or doxycycline (100 mg orally twice a day for 5 to 7 days) for localized, naturally-occurring cutaneous anthrax (Grade 1C). For more severe cases of cutaneous anthrax, we recommend treatment with penicillin G (4 to 6 million units intravenously every 6 hours for 7 to 10 days) or doxycycline (100 mg intravenously twice a day) (Grade 1C). (See "Cutaneous anthrax" above). We recommend oral ciprofloxacin (500 mg twice daily) or doxycycline (100 mg twice daily) for treatment of cutaneous anthrax (show table 1) associated with bioterrorism events (Grade 1C). We recommend a duration of treatment of 60 days (Grade 1C). (See "Bioterrorism-related cutaneous anthrax" above). We recommend that patients with possible IA be started promptly on multidrug antibiotic therapy (Grade 1B). Empiric treatment regimens include:
      - Ciprofloxacin, preferred (400 mg IV every 12 hours) or in ciprofloxacin intolerant patients, doxycycline (100 mg IV every 12 hours) plus
      - One or two of the following intravenous antimicrobials with demonstrated in vitro activity against B. anthracis:
      - Rifampin
      - Vancomycin
      - Penicillin
      - Ampicillin
      - Chloramphenicol
      - Imipenem or meropenem
      - Clindamycin
(See "Bioterrorism-related inhalation anthrax" above). We typically switch to oral therapy (ciprofloxacin 500 mg twice daily or doxycycline 100 mg twice daily) when clinically appropriate, (eg, when patients show a sufficient clinical response to treatment and are stable), usually after 14 to 21 days of intravenous antibiotics. We recommend a duration of antimicrobial therapy for 60 days (total combination of IV and oral therapy) (Grade 1C). (See "Bioterrorism-related inhalation anthrax" above). We recommend the use of chest tubes or thoracentesis to drain pleural effusions, if present, as adjunctive treatment of all IA cases (Grade 1C). (See "Pleural effusion drainage" above). For patients with meningoencephalitis, we recommend intravenous antimicrobial therapy with ciprofloxacin (400 mg IV every 12 hours) plus one or two additional antibiotics with good CNS penetration and efficacy against B. anthracis (Grade 1C). The additional antibiotics include the following:
      - Rifampin
      - Vancomycin
      - Penicillin
      - Ampicillin
      - Imipenem or meropenem
(See "Meningoencephalitis" above). We suggest corticosteroids as adjunctive therapy for patients with serious systemic illness due to IA, including patients with meningoencephalitis and patients with cutaneous anthrax with extensive edema involving the head and neck (Grade 2C). (See "Corticosteroids" above).
Prevention Animal vaccination against anthrax is the major means of preventing naturally occurring anthrax in humans. Vaccination of the military in combat areas at high-risk for biological warfare is the best method for prevention of bioterrorism-related anthrax disease in this population. (See "Prevention" aboveSee "Prevention" above). We recommend postexposure prophylaxis treatment for patients at risk of inhalation anthrax (Grade 1B). Regimens include one of the following in nonpregnant adults:
      - Ciprofloxacin (500 mg twice daily) or
      - Doxycycline (100 mg twice daily) or
      - Levofloxacin (500 mg orally once daily)
The preferred regimen in children and nursing and pregnant women is ciprofloxacin (500 mg twice daily)??????
I think we shouldn't give Cipro to nursing pregnant and Children!!!
. If susceptibility of the anthrax strain to penicillin antibiotics is demonstrated, then the treatment of children and nursing and pregnant women can be changed to amoxicillin (500 mg orally every eight hours in adults, 80 mg/kg per day in divided doses every eight hours for children). (See "Antibiotics" above). We recommend a duration of postexposure prophylaxis antibiotic therapy of 60 days (Grade 1C). (See "Antibiotics" above). In conjunction with antibiotic treatment, we recommend vaccination with the anthrax vaccine adsorbed for postexposure prophylaxis for inhalation anthrax exposure (Grade 1C). The anthrax vaccine absorbed is available from the CDC (phone: 770-488-7100; http://cdc.gov) as part of an IND protocol. (See "Use of the anthrax vaccine" abov
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INTRODUCTION ” Anthrax, caused by Bacillus anthracis, is an uncommon illness in the United States. From 1980 through 2000, only seven cases of anthrax were reported to the Centers for Disease Control and Prevention (CDC) [1].
In 2001, an outbreak of bioterrorism-related anthrax occurred in the United States, when 22 confirmed or suspected anthrax cases occurred after B. anthracis spores in powder-containing envelopes were sent through the mail [2-4]. In February 2006, a case of inhalation anthrax occurred in an African drum maker in New York City, the first naturally-occurring case of inhalation anthrax in the United States since 1976. The exposure was the result of his making drums using animal hides, which were contaminated with B. anthracis spores [5].
Animals become infected with B. anthracis by ingesting spores while grazing on contaminated grass or feed. Naturally-occurring transmission to humans is accomplished through direct exposure to infected animals or animal products through skin exposure, ingestion, or inhalation.
Spores can persist in the soil for long periods of time. Surface decontamination is not practical except in very unusual circumstances; thus, epizootic anthrax continues to occur in highly endemic areas, such as Iran, Iraq, Turkey, Pakistan, and sub-Saharan Africa, where the use of animal anthrax vaccine is not comprehensive.
The treatment and prevention of anthrax will be reviewed here. The pathogenesis, epidemiology, clinical manifestations, and diagnosis of anthrax are discussed separately. (See "Pathogenesis and epidemiology of anthrax" and see "Clinical manifestations and diagnosis of anthrax").
TREATMENT ” Anthrax is a reportable disease and immediate notification should be made to the local or state health department and public health laboratory following clinical or laboratory suspicion of anthrax or exposure to B. anthracis.
B. anthracis is highly susceptible to a variety of antibiotics including penicillin, chloramphenicol, tetracycline, erythromycin, streptomycin, and the fluoroquinolones [6,7]. B. anthracis is not susceptible to cephalosporins or trimethoprim-sulfamethoxazole; these antibiotics should not be used for the treatment of anthrax [6-9].
Testing of isolates from the bioterrorism-related cases in the United States showed that the organisms were susceptible in vitro to ciprofloxacin, doxycycline, tetracycline, rifampin, vancomycin, chloramphenicol, imipenem, clindamycin, and clarithromycin [10]. Although sensitive to penicillin and ampicillin, the presence of inducible beta-lactamase led the CDC to advise against the use of either of these drugs alone for therapy of anthrax cases related to the 2001 bioterrorism event. The CDC issued interim treatment recommendations for cases and exposure related to the bioterrorism event, but the CDC cautions that these recommendations are based upon expert opinion because of the paucity of clinical data [10]. The treatment recommendations presented in this topic are in agreement with the recommendations of the CDC.
Cutaneous anthrax ” Penicillin has been used most extensively for the treatment of naturally-occurring cases of cutaneous anthrax. Organisms are rapidly cleared from skin lesions following antibiotic therapy. In one study, for example, 25 patients with cutaneous anthrax and positive initial cultures of blister fluid were given two million units of crystalline penicillin intravenously every six hours for up to 10 days, with hourly subsequent blister fluid or lesion cultures and Gram's stain [11]. All cultures were negative within five hours of the first penicillin dose, and all smears were negative within six hours of initiating therapy. Antibiotic therapy, however, does not prevent progression to the eschar phase.
For localized or uncomplicated naturally-occurring cutaneous anthrax cases, we recommend treatment with penicillin V (500 mg orally every 6 hours for five to seven days) or doxycycline (100 mg orally twice a day). For more severe cases of cutaneous anthrax, we recommend treatment with penicillin G (4 to 6 million units intravenously every 6 hours for 7 to 10 days) or doxycycline (100 mg intravenously every 12 hours) [6,12,13]. Case fatality rates as high as 20 percent have been reported for untreated cutaneous anthrax but fatalities are now unusual with appropriate antibiotic treatment [14]. Surgical excision of the cutaneous lesions is not recommended.
  Bioterrorism-related cutaneous anthrax ” During the bioterrorism event of 2001, the CDC recommended oral ciprofloxacin (500 mg twice daily) or doxycycline (100 mg twice daily) for treatment of cutaneous anthrax (show table 1). The recommended duration of treatment was 60 days based upon the possibility of inhalation aerosol exposure in the patients with cutaneous anthrax. Penicillin class antibiotics were not recommended based upon the presence of an inducible beta-lactamase in the B. anthracis isolates from the 2001 bioterrorism event.
We recommend empiric treatment of bioterrorism-related cutaneous anthrax with ciprofloxacin (500 mg twice daily in adults or 10 to 15 mg/kg twice daily, maximum dose 1 g in children) even for children and pregnant women, despite usual contraindications against their use, because of the seriousness of the disease. In the case of ciprofloxacin-allergic patients, we recommend treatment with doxycycline (100 mg twice daily in adults and children >8 years and >45 kg or 2.2 mg/kg twice daily in children 8 years or 45 kg).
In patients with cutaneous disease and signs of systemic involvement or in patients with extensive edema involving lesions on the head and neck, we recommend treatment with a regimen as for inhalation anthrax (see below) [10].
Inhalation anthrax ” Patients with inhalation anthrax (IA) frequently present late in the course of their illness, and in these patients virtually all cases are fatal even if the patient receives antibiotic therapy since such therapy does not act on the toxins produced by B. anthracis. However, in the 1979 outbreak in Sverdlovsk, 11 survivors (with more than 60 deaths) were reported, indicating that IA is not a universally fatal disease [1]. Furthermore, six of 11 IA cases (55 percent) associated with the 2001 bioterrorism attack in the United States were successfully treated with antibiotics [15]. Thus, antibiotic therapy should be initiated in any patient with suspected IA. Three antibiotics have received Food and Drug Administration (FDA) approval for the treatment of anthrax, including IA: ciprofloxacin, doxycycline, and penicillin G procaine [16].
Empiric treatment recommendations for IA are the same multidrug regimens regardless of whether the case is associated with bioterrorism or is a naturally occurring case. Once culture and susceptibility results are available, treatment should be modified based upon the susceptibility results of the isolate.
A systematic review of 82 IA cases that were reported in the medical literature between 1900 and 2005 found that the mortality rate observed during the 2001 United States anthrax attack was significantly lower than that historically reported for IA (45 versus 92 percent) [17]. The review identified the following statistically significant differences in treatment of IA survivors (12 patients) compared to those who died (70 patients): Therapy initiated during the prodromal phase (75 versus 10 percent) Multidrug antibiotic regimen (67 versus 21 percent) Pleural fluid drainage (83 versus 9 percent) Anthrax antiserum therapy (among cases prior to 2001; 25 versus 3 percent)
  Bioterrorism-related inhalation anthrax ” There are no clinical trials of multidrug therapy for IA, however, the failure of single-drug antibiotic therapy for IA has previously been noted [17,18]. The CDC recommended multidrug therapy for IA cases during the bioterrorism event in 2001 because of the seriousness of the illness and early clinical data on treatment of the IA cases suggested that intravenous treatment with two or more antibiotics improved survival. The multidrug regimens used in the 2001 case patients who survived included: Ciprofloxacin, rifampin, and vancomycin OR Ciprofloxacin, rifampin, and clindamycin
Penicillin was not recommended based upon the presence of inducible beta-lactamase in the B. anthracis isolates [10,19].
Based on these clinical data (show table 2), we recommend initial empiric intravenous antibiotic treatment of IA with either ciprofloxacin (400 mg every 12 hours) or doxycycline (100 mg every 12 hours) plus
      - One or two of the following intravenous antimicrobials with demonstrated in vitro activity against B. anthracis: rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, meropenem, or clindamycin
Once culture and susceptibility results of the B. anthracis isolate is available, the antibiotic regimen can be modified based upon these results.
For patients with serious systemic illness, intravenous ciprofloxacin is favored as the primary antimicrobial over intravenous doxycycline, unless there is a contraindication to the use of ciprofloxacin. Clindamycin is recommended as one of the additional antibiotics due to its potential inhibition of toxin production [20]. In addition, at least one of the additional antibiotics should have good central nervous system (CNS) penetration and efficacy against B. anthracis (eg, meropenem, imipenem, rifampin, vancomycin, penicillin, or ampicillin), due to the potential for clinical or subclinical meningeal involvement.
Although initial therapy should be intravenous, patients may be switched to oral therapy once they have shown a significant clinical response to treatment and are stable, usually after 14 to 21 days of intravenous antibiotics. We recommend a total duration of treatment of 60 days (combination of intravenous and oral therapy).
  Pleural effusion drainage ” We recommend the use of chest tubes or thoracentesis to drain pleural effusions as adjunctive treatment of all IA cases, due to the role that aggressive drainage of pleural effusions played in the successful clinical therapy of the five surviving IA patients in 2001 [17,19]. In addition, mortality was statistically significantly lower for IA patients prior to 2001 treated with pleural fluid drainage.
  Corticosteroids ” Corticosteroids may be considered as adjunctive therapy for patients with serious systemic illness due to IA, including patients with meningoencephalitis and patients with cutaneous anthrax with extensive edema involving the head and neck [10]. Supporting data are limited, however, a retrospective review of 70 cases of anthrax meningoencephalitis from 1966 to 2002 reported a mortality rate of 94 percent, but among 10 patients treated with corticosteroids as an adjunct to antimicrobial therapy, mortality was 80 percent [21].
Gastrointestinal anthrax ” There are few well studied cases of gastrointestinal anthrax. In the absence of case or study data on treatment of gastrointestinal anthrax, we recommend following the same treatment protocol for patients with gastrointestinal anthrax as is recommended for IA.
Meningoencephalitis ” The optimal management of anthrax meningitis is unknown [22]. There is a high likelihood of clinical or subclinical meningitis in cases of severe systemic anthrax, such as IA [23]. Early and aggressive therapy is crucial in anthrax meningitis due to the rapid progression and high mortality of the disease [21]. We recommend treatment include agents with activity against B. anthracis and good central nervous system penetration for treatment of anthrax cases with meningeal involvement. We recommend treatment with intravenous antimicrobial therapy including ciprofloxacin (based on CNS penetration of ciprofloxacin when meningeal inflammation is present [22]) plus one or two additional antibiotics with good CNS penetration and efficacy against B. anthracis (eg, meropenem, imipenem, rifampin, vancomycin, penicillin, or ampicillin).
Immunotherapeutics ” Animal origin antiserum was used with some success in the treatment of anthrax prior to the advent of widespread antibiotic use [24-26]. In addition, in a systematic review of IA cases from 1900 to 2005, mortality was significantly lower for patients receiving antiserum [17].
In animal models, passive immunization with immune serum containing antibodies against the B. anthracis protective antigen (PA) administered up to 24 hours after exposure proved effective in preventing infection [27], and a human monoclonal antibody to PA was demonstrated to be protective against inhalation anthrax in animal studies [28]. In the rat, high-affinity antibodies from persons immunized against anthrax were shown to protect rats injected with anthrax toxin [29].
Immunoglobulin derived from plasma harvested from persons immunized with the Anthrax Vaccine Adsorbed is available from the CDC (phone: 770-488-7100; http://cdc.gov) under an Investigational New Drug (IND) protocol for the treatment of persons with life-threatening anthrax. This product was used as a part of the successful clinical treatment of the February 2006 IA patient [30]. State and local health departments should be immediately notified following clinical or laboratory suspicion of anthrax and for any request for anthrax immunoglobulin.
PREVENTION ” Prevention of naturally-occurring anthrax in humans is primarily dependent on the control of the disease in animals, especially livestock. Animal vaccination is the major means of preventing naturally occurring epizootics of anthrax, since widespread decontamination of infected soil is impractical. Annual vaccination of livestock in areas with enzootic anthrax is recommended.
An anthrax vaccine for human use is licensed in the United States but is not available to the general public. The Advisory Committee on Immunization Practices (ACIP) recommends immunization in the following populations at high risk of repeated exposure to B. anthracis aerosols [31,32]: Persons with repeated risk of exposure or working with large quantities or concentrations of B. anthracis cultures Veterinarians and others at high risk for handling potentially infected animals in areas with a high disease incidence Persons working in high risk industries, such as those processing imported animal hides, hair, and wool
The vaccine is also recommended by the ACIP and CDC as part of the PEP protocol for inhalation anthrax as a three-dose series in conjunction with antibiotic therapy [32]. (See "Anthrax vaccine" below).
In 1997, a decision was made to immunize all United States military personnel against anthrax because of the threat of anthrax as a biological warfare agent, with initial vaccination given to service members assigned to regions designated to be at greater risk (eg, Persian Gulf and Korea) [33]. (See "Identifying and managing casualties of biological terrorism").
Anthrax vaccine ” The Sterne vaccine is a live, toxigenic, unencapsulated, avirulent vaccine strain that is widely used as a veterinary vaccine. This vaccine has not been used widely in humans because of development of necrosis at the inoculation site; due to such safety concerns, spore vaccines have generally not been used as human vaccines. However, a live spore vaccine has been developed in Russia for human use and is considered to be highly effective [34].
Anthrax vaccine adsorbed (BioThrax, BioPort, Lansing, MI) (AVA) is the only licensed human anthrax vaccine in the United States [31]. A similar, protective antigen-based vaccine was tested in a field trial and shown to be highly effective in preventing inhalation and cutaneous anthrax in wool mill workers at risk for infection [35]. The recommended vaccination schedule is complex; vaccination consists of subcutaneous injections at zero, two, and four weeks and at six, 12, and 18 months. In addition, to maintain immunity, an annual booster injection is recommended. Studies are currently underway to evaluate the immunogenicity of a reduced number of doses and administration via the intramuscular route [36,37].
Despite concerns that vaccination with AVA might adversely affect pregnancies or future reproductive health, a cohort study of 4092 women (3136 of whom had received at least one dose of vaccine) stationed at two army bases in Georgia from 1999 to 2000 found no difference in pregnancy rate or odds of having a live birth in women receiving at least one dose of vaccine compared to those who had not [38]. The study, however, was not powered sufficiently to determine whether there was an effect on birth outcomes.
A recombinant protective antigen vaccine (rPA) has demonstrated efficacy in animal models, and human clinical trials are under way [39,40].
POSTEXPOSURE PROPHYLAXIS ” Early studies of experimental IA in monkeys showed that treatment with penicillin beginning one day after aerosol exposure to B. anthracis spores was protective during the 5 to 10 days of drug therapy; however, the animals died when penicillin was discontinued [41].
In a subsequent study of experimental IA, monkeys were challenged with aerosolized B. anthracis spores; 24 hours later three groups of animals were treated with either penicillin, or ciprofloxacin, or doxycycline for 30 days, and a fourth group received the combination of doxycycline and immunization with anthrax vaccine [42]. The 30-day antibiotic regimens completely protected animals while they were on therapy; post treatment survival in animals given only antibiotics ranged from 70 to 90 percent compared to 100 percent survival in animals given antibiotics plus vaccine. However, when the monkeys were rechallenged with airborne B. anthracis spores, all animals died except for those that had been immunized.
An additional study in monkeys compared a 14-day course of ciprofloxacin therapy with the combination of a 14-day regimen of ciprofloxacin plus three doses of anthrax vaccine [43]. Only 44 percent of animals receiving 14 days of antibiotic alone survived, compared to 100 percent survival among animals given both antibiotics and vaccine. These data offer compelling evidence that the use of antibiotic postexposure prophylaxis (PEP) combined with active immunization provides effective protection against the development of IA.
Antibiotics ” Three oral antibiotics have been approved by the FDA and are recommended for PEP (show table 3). Ciprofloxacin (500 mg orally twice daily) and doxycycline (100 mg orally twice daily) are approved for use in adults and children, and levofloxacin (500 mg orally once daily) is approved for use in adults (eg, 18 years of age) [16,44]. The recommended duration of PEP antibiotic therapy is 60 days.
We recommend ciprofloxacin as the first-line drug for PEP in pregnant women and nursing mothers [45-47]. If susceptibility of the infecting B. anthracis strain to penicillin class antibiotics has been demonstrated, then we recommend amoxicillin (500 mg orally every 8 hours in adults, 80 mg/kg per day in divided doses every 8 hours for children) for PEP in this population and in children when other antibiotics are not as safe to use; however, amoxicillin has not been approved for this use by the FDA [45,46]. CDC notes that the organism burden is likely to be low in an individual who is exposed but not ill, and thus, the concerns about the presence of an inducible beta-lactamase are reduced when the drug is being used for prophylaxis rather than for therapy.
Use of the anthrax vaccine ” Anthrax vaccine (BioThrax) is recommended by the ACIP and CDC as part of the PEP regimen for IA exposure and is available through CDC (phone: 770-488-7100; http://cdc.gov) as part of an IND protocol. The anthrax vaccine should be administered in three doses (at zero, two and four weeks) in conjunction with antibiotic therapy [32,48]. State and local health departments should be immediately notified in the event of suspicion of exposure to anthrax and for any request for anthrax vaccine.
Adverse reactions ” In 2001, approximately 10,000 individuals were offered 60 days of antibiotic PEP therapy for the prevention of IA. Anaphylactoid reactions were reported in four persons provided PEP antibiotics within 30 days [49]. Overall, 3032 of 5,343 individuals (57 percent) who took at least one dose of antibiotics reported clinical symptoms; most of these were mild. The most common adverse events were gastrointestinal (44 percent) and neurologic (33 percent); 16 percent of patients sought medical care for adverse events [49].
The Anthrax Vaccine and Antibiotic Availability Program (AVAAP) offered extended antibiotic PEP (>60 days) for persons at risk for IA, and 1727 individuals received anthrax vaccine in addition to extended antibiotic PEP. Three serious adverse events with a probable or possible relationship to the AVAAP protocol were identified; one case of allergic interstitial nephritis was classified as likely causally related to ciprofloxacin PEP, and two serious adverse events were determined to be possibly related to doxycycline PEP. No serious adverse events were associated with anthrax vaccine use [50].
SUMMARY AND RECOMMENDATIONS Sporadic cases and outbreaks of naturally-occurring anthrax continue to occur worldwide, although they are relatively rare in developed nations. However, the threat of IA resulting from bioterrorism activity is now a reality. (See "Introduction" above).
Treatment We recommend treatment with either penicillin V (500 mg orally every 6 hours for 5 to 7 days) or doxycycline (100 mg orally twice a day for 5 to 7 days) for localized, naturally-occurring cutaneous anthrax (Grade 1C). For more severe cases of cutaneous anthrax, we recommend treatment with penicillin G (4 to 6 million units intravenously every 6 hours for 7 to 10 days) or doxycycline (100 mg intravenously twice a day) (Grade 1C). (See "Cutaneous anthrax" above). We recommend oral ciprofloxacin (500 mg twice daily) or doxycycline (100 mg twice daily) for treatment of cutaneous anthrax (show table 1) associated with bioterrorism events (Grade 1C). We recommend a duration of treatment of 60 days (Grade 1C). (See "Bioterrorism-related cutaneous anthrax" above). We recommend that patients with possible IA be started promptly on multidrug antibiotic therapy (Grade 1B). Empiric treatment regimens include:
      - Ciprofloxacin, preferred (400 mg IV every 12 hours) or in ciprofloxacin intolerant patients, doxycycline (100 mg IV every 12 hours) plus
      - One or two of the following intravenous antimicrobials with demonstrated in vitro activity against B. anthracis:
      - Rifampin
      - Vancomycin
      - Penicillin
      - Ampicillin
      - Chloramphenicol
      - Imipenem or meropenem
      - Clindamycin
(See "Bioterrorism-related inhalation anthrax" above). We typically switch to oral therapy (ciprofloxacin 500 mg twice daily or doxycycline 100 mg twice daily) when clinically appropriate, (eg, when patients show a sufficient clinical response to treatment and are stable), usually after 14 to 21 days of intravenous antibiotics. We recommend a duration of antimicrobial therapy for 60 days (total combination of IV and oral therapy) (Grade 1C). (See "Bioterrorism-related inhalation anthrax" above). We recommend the use of chest tubes or thoracentesis to drain pleural effusions, if present, as adjunctive treatment of all IA cases (Grade 1C). (See "Pleural effusion drainage" above). For patients with meningoencephalitis, we recommend intravenous antimicrobial therapy with ciprofloxacin (400 mg IV every 12 hours) plus one or two additional antibiotics with good CNS penetration and efficacy against B. anthracis (Grade 1C). The additional antibiotics include the following:
      - Rifampin
      - Vancomycin
      - Penicillin
      - Ampicillin
      - Imipenem or meropenem
(See "Meningoencephalitis" above). We suggest corticosteroids as adjunctive therapy for patients with serious systemic illness due to IA, including patients with meningoencephalitis and patients with cutaneous anthrax with extensive edema involving the head and neck (Grade 2C). (See "Corticosteroids" above).
Prevention Animal vaccination against anthrax is the major means of preventing naturally occurring anthrax in humans. Vaccination of the military in combat areas at high-risk for biological warfare is the best method for prevention of bioterrorism-related anthrax disease in this population. (See "Prevention" aboveSee "Prevention" above). We recommend postexposure prophylaxis treatment for patients at risk of inhalation anthrax (Grade 1B). Regimens include one of the following in nonpregnant adults:
      - Ciprofloxacin (500 mg twice daily) or
      - Doxycycline (100 mg twice daily) or
      - Levofloxacin (500 mg orally once daily)
The preferred regimen in children and nursing and pregnant women is ciprofloxacin (500 mg twice daily)??????
I think we shouldn't give Cipro to nursing pregnant and Children!!!
. If susceptibility of the anthrax strain to penicillin antibiotics is demonstrated, then the treatment of children and nursing and pregnant women can be changed to amoxicillin (500 mg orally every eight hours in adults, 80 mg/kg per day in divided doses every eight hours for children). (See "Antibiotics" above). We recommend a duration of postexposure prophylaxis antibiotic therapy of 60 days (Grade 1C). (See "Antibiotics" above). In conjunction with antibiotic treatment, we recommend vaccination with the anthrax vaccine adsorbed for postexposure prophylaxis for inhalation anthrax exposure (Grade 1C). The anthrax vaccine absorbed is available from the CDC (phone: 770-488-7100; http://cdc.gov) as part of an IND protocol. (See "Use of the anthrax vaccine" abov
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