Prevention of anthrax

INTRODUCTION — The incidence of anthrax in humans has decreased during the past century, and it is now very rare in developed countries, including the United States. However, anthrax remains a concern in the developed world because of its potential as an agent of bioterrorism.

The prevention of anthrax will be reviewed here. The microbiology, pathogenesis, epidemiology, clinical manifestations, diagnosis, and treatment of anthrax are discussed separately. (See "Microbiology, pathogenesis, and epidemiology of anthrax" and "Clinical manifestations and diagnosis of anthrax" and "Treatment of anthrax".)

VACCINE FORMULATIONS IN THE UNITED STATES — Different anthrax vaccines are used globally. (See 'International considerations' below.)

In the United States, two have been licensed for prevention of anthrax:

●Anthrax vaccine adsorbed (AVA) – This is a protein-based vaccine that cell-free filtered supernatant from culture of an avirulent, nonencapsulated strain of Bacillus anthracis [1]. It contains no live or dead organisms. The filtrate is adsorbed onto an aluminum base.

AVA is approved for both pre-exposure and post-exposure prophylaxis. Dosing varies by use. (See 'Pre-exposure vaccination in select individuals' below and 'PEP regimen' below.)

●Anthrax vaccine adsorbed, adjuvanted (AVA-adjuvanted) – This has the same components as AVA, with the addition of an adjuvant immunostimulatory oligodeoxynucleotide (CpG 7909) [2]. It was previously known as AV7909.

AVA-adjuvanted is approved for post-exposure prophylaxis only. It is given as two intramuscular doses, two weeks apart as part of a post-exposure regimen.

Human efficacy studies are not available for these vaccines. In an unpublished trial comparing the immunogenicity of these vaccines in healthy adults, the likelihood of reaching antibody thresholds that were associated in nonhuman primate studies with 70 percent survival was higher with two intramuscular doses of AVA-adjuvanted than with three subcutaneous doses of AVA (86 versus 61 percent) [2]. The rates of local injection site reactions were similar, but AVA-adjuvanted was associated with a higher rate of high-grade systemic side effects (eg, myalgias, fatigue, headache, fever; 6.6 versus 3.8 percent)

PRE-EXPOSURE VACCINATION IN SELECT INDIVIDUALS

Indications — In the United States, the Advisory Committee on Immunization Practices (ACIP) recommends pre-exposure use of anthrax vaccine among persons considered to be at risk for exposure to aerosolized Bacillus anthracis spores (table 1) [3,4]:

●Selected persons who handle animals or animal products:

•Veterinarians and other high-risk persons, only if handling potentially infected animals or in areas with a high incidence of anthrax cases in animals.

•Persons working in high-risk industries (such as those processing imported animal hides, hair, or wool) for whom improved industrial hygiene standards and restrictions are insufficient to prevent exposure to anthrax spores.

●Laboratory workers:

•Those at risk for repeated exposures to B. anthracis spores, including those who work with preparations of B. anthracis spores, handle environmental samples associated with anthrax investigations, routinely work with pure cultures of B. anthracis, or frequently work in spore-contaminated areas or other settings where repeated exposure to aerosols may occur.

●Environmental investigators/remediation workers:

•Persons who, as part of their occupation, may enter areas contaminated with B. anthracis spores.

●Certain military personnel:

•Military personnel determined by the United States Department of Defense to have a calculable risk of exposure to aerosolized B. anthracis spores are recommended to receive pre-event vaccination.

●Certain emergency and other responders:

•Emergency and other responders are not recommended for routine pre-event anthrax vaccination, but units engaged in response activities that may lead to exposure to aerosolized B. anthracis spores may choose to offer their workers pre-event vaccination on a voluntary basis under the direction of a comprehensive occupational health and safety program.

Additional details regarding the target groups are included in the table (table 1).

Vaccine administration — Anthrax vaccine adsorbed (AVA) is the only anthrax vaccine approved for anthrax pre-exposure prophylaxis in the United States, and it is available from the manufacturer [3]. (See 'Vaccine formulations in the United States' above.)

For pre-exposure vaccination, AVA is administered intramuscularly as a three-dose priming series followed by two booster doses, then ongoing maintenance vaccination (table 2) [3,5]. Each dose is 0.5 mL:

●Priming series – Give at 0, 1, and 6 months

●Initial booster doses – Give at 12 and 18 months

If the vaccination schedule is interrupted or delayed, it can be restarted without repeating any doses.

For ongoing maintenance vaccination in people at high risk, an annual booster injection is recommended. For individuals who have received the priming series and two initial booster doses and are not at high risk for B. anthracis exposure but want to maintain protection (eg, emergency workers who had voluntarily undergone anthrax vaccination), subsequent booster injections can be given every three years (instead of annually).

Individuals may work in high-risk areas of exposure once they have completed the priming series. If an individual has completed the priming and initial booster doses but has not received a booster dose in the past year, prior to entering a high-risk area of inhalation exposure, that individuals should receive an additional booster dose and delay entry into the high-risk area until two weeks later; if immediate entry is required, antimicrobials should be given for two weeks following vaccination (see 'Antimicrobial regimen selection' below). The approach to individuals who have not completed the priming and initial booster doses but who have a potential inhalation exposure or plan to enter a high-risk area is discussed elsewhere (see 'PEP for previously vaccinated individuals' below). Appropriate personal protective equipment is also essential for individuals in high-risk areas. (See 'Infection control' below.)

AVA has not been tested clinically in the pre-exposure setting. However, a similar antigen-based vaccine was tested in a field trial and shown to be highly effective in preventing subsequent inhalation and cutaneous anthrax in wool mill workers at risk for infection [6].

Similarly, there are only indirect data to support the recommended schedule. A randomized noninferiority trial was performed to assess the immunogenicity of a reduced number of doses and administration via the intramuscular route [7]. In the trial, 1563 volunteers were randomly assigned to one of six groups: AVA subcutaneously on a six-dose schedule; AVA intramuscularly on a six-dose schedule; AVA intramuscularly on one of three reduced-dose schedules; or saline placebo. A midpoint analysis of the first 1005 participants who received the first four doses of vaccine through month 7 showed that immunogenicity at month 7 was noninferior for groups receiving either three (zero, four weeks, and six months) or four (zero, two, four weeks, and six months) intramuscular injections. At month 43, immunogenicity was greater with the intramuscularly administered schedules compared with the subcutaneously administered schedule [8]. Furthermore, there was a significantly lower incidence and severity of injection site adverse effects for the intramuscular route compared with the subcutaneous route [7].

Adverse events — Severe adverse events (SAEs) appear to be overall uncommon with AVA. In a trial of different AVA dosing schedules that involved 1563 volunteers, there were 229 SAEs among 186 participants [7]. Nine SAEs (involving seven participants) were rated as possibly related to AVA (eg, generalized allergic reaction, new-onset seizure). All other events were considered unrelated or unlikely to be related to AVA.

Pre-exposure vaccination is generally not used for pregnant individuals because of uncertain risk to the fetus. Data informing this risk are discussed elsewhere. (See 'Pregnancy' below.)

PROPHYLAXIS FOLLOWING AEROSOLIZED EXPOSURE — Individuals exposed to aerosolized B. anthracis are considered to be at risk for inhalation anthrax. Post-exposure prophylaxis (PEP) for inhalation anthrax involves antimicrobial agents and vaccination. The recommendations presented here are in agreement with the recommendations of the United States Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics [3,9-12].

Timing and indications — PEP against anthrax should be offered to all individuals who have documented or suspected exposure to aerosolized B. anthracis. Clinicians should seek advice from public health officials to determine which individuals should receive PEP [10].

PEP should start as soon as possible following exposure and ideally within 48 hours, because its effectiveness decreases with delay in administration [9,10].

PEP regimen — Individuals with an indication for post-exposure prophylaxis (PEP) for inhalation anthrax should receive both [9]:

●Antimicrobial drug prophylaxis (table 3) (see 'Antimicrobials' below)

and

●Anthrax vaccination (table 4) (see 'Anthrax vaccination' below)

Raxibacumab or obiltoxaximab, monoclonal antibodies against protective antigen (PA), should be used when these preventive therapies are not available or are not appropriate. (See 'Monoclonal antibodies' below.)

Evidence that post-exposure antimicrobial prophylaxis combined with active immunization provides effective protection against the development of inhalation anthrax is mainly from primate studies. Early studies of experimental inhalation anthrax 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 [13].

Subsequent studies demonstrated that adding vaccination to the antimicrobial regimen improved survival after the antimicrobials were discontinued. In an experimental inhalation anthrax trial, monkeys were challenged with aerosolized B. anthracis spores [14]. Thirty-day antimicrobial treatment regimens using penicillin, ciprofloxacin, or doxycycline completely protected animals while they were on therapy. However, post-treatment survival in animals given only antimicrobial therapy ranged from 70 to 90 percent compared with 100 percent survival in animals given antimicrobial therapy plus vaccine.

A third study in monkeys showed that PEP with a 14-day course of ciprofloxacin plus three doses of anthrax vaccine resulted in a 100 percent survival rate compared with 44 percent in animals who received ciprofloxacin alone [15].

Antimicrobials — B. anthracis is typically highly susceptible to a variety of antimicrobial agents, including penicillin, tetracycline, erythromycin, streptomycin, linezolid, vancomycin, meropenem, clarithromycin, and fluoroquinolones [16-19]. B. anthracis is not susceptible to cephalosporins or trimethoprim-sulfamethoxazole [16-20]. Three oral antimicrobial agents (ciprofloxacin, doxycycline, and levofloxacin) have been approved by the US Food and Drug Administration (FDA) for post-exposure prophylaxis.

Antimicrobial regimen selection — Antimicrobial agents are given in conjunction with anthrax vaccination for prophylaxis following an aerosolized exposure. (See 'Anthrax vaccination' below.)

When selecting a PEP regimen, the potential for antimicrobial drug resistance and any available susceptibility testing must be taken into account. First-line antimicrobial agents for PEP include (table 3):

●For nonpregnant adults [9]:

•Doxycycline – 100 mg every 12 hours in adults.

or

•Ciprofloxacin – 500 mg every 12 hours in adults.

●For pregnant women and nursing mothers:

•Ciprofloxacin – 500 mg orally every 12 hours is the first-line option.

If ciprofloxacin is unavailable, clindamycin 600 mg every 8 hours or doxycycline 100 mg every 12 hours may be given [11].

●For children [10]:

•Doxycycline

-<45 kg: 4.4 mg/kg per day divided every 12 hours (not to exceed 100 mg/dose).

-≥45 kg: 100 mg every 12 hours daily.

or

•Ciprofloxacin – 30 mg/kg per day divided every 12 hours (not to exceed 500 mg/dose).

or

•If the exposure strain is known to be amoxicillin susceptible (minimum inhibitory concentration [MIC] ≤0.12 mcg/mL [21]), amoxicillin 75 mg/kg per day divided every eight hours (not to exceed 1 g/dose) is another first-line option for children.

Duration of therapy depends on several factors and is discussed elsewhere. (See 'Duration' below.)

Ciprofloxacin and doxycycline are first-line options because these have been directly evaluated in primate efficacy studies (see 'PEP regimen' above). In the United States, they are FDA approved for PEP of anthrax and are stockpiled for this purpose. Use of doxycycline or ciprofloxacin has been described in individuals potentially exposed to aerosolized anthrax during a 2001 bioterrorist attack and a laboratory incident; rates of discontinuation were high and associated with low perceived risk of anthrax and side effects [22,23]. (See 'Adverse reactions' below.)

If first-line agents are not tolerated or are unavailable, alternative agents include levofloxacin, moxifloxacin, clindamycin, and amoxicillin if the isolate is susceptible (MIC ≤0.12 mcg/mL) or penicillin VK if the isolate is susceptible (MIC ≤0.5 mcg/mL) (table 3) [9,21]. The risk of developing resistance must be considered in those receiving amoxicillin or penicillin VK. Data supporting the use of these alternative agents (other than penicillin) are lacking.

Duration — The duration of antibiotic prophylaxis is based on the concept that individuals exposed to aerosolized B. anthracis are presumed to be at risk for inhalation anthrax from ungerminated spores retained in their lungs; the risk lasts from the initial exposure until the immune response from vaccination is thought to be protective. The recommended duration of antibiotic prophylaxis depends on the age, immune status, and vaccination status [3]:

●For individuals who had not received pre-exposure vaccination, the recommended antimicrobial duration ranges from 42 to 60 days:

•For nonpregnant, immunocompetent adults aged 18 to 65 years who completed the post-exposure vaccination regimen on schedule, antimicrobial prophylaxis is continued for 42 days after initiation of the vaccine series or for 14 days after the last dose, whichever is later (but duration should not exceed 60 days).

This same duration applies whether a standard or dose-sparing post-exposure vaccination approach was taken. (See 'Anthrax vaccination' below and 'PEP for large-scale emergency response' below.)

•All other individuals should receive 60 days of antimicrobial prophylaxis. These include:

-Individuals younger than 18 or older than 65 years

-Pregnant women and nursing mothers

-Individuals with immunocompromising conditions (eg, malignancy, HIV, immunosuppressive use such as high-dose corticosteroids >2 weeks, radiation therapy)

-Individuals who were unable to complete the post-exposure vaccination regimen

●For individuals who have received pre-exposure vaccination, use and duration of antimicrobial prophylaxis are discussed elsewhere. (See 'PEP for previously vaccinated individuals' below.)

As these are prolonged courses of antimicrobials, clinicians should remain alert to the possibility of nonadherence to prescribed regimens, which can be very high in this setting [22,23].

Although expert organizations do not recommend antimicrobial prophylaxis for more than 60 days because of the lack of data, the optimal duration is uncertain, and we suggest extending the duration to three to four months in patients who are immunocompromised or remain unvaccinated, as long as they are tolerating the antibiotic well. The recommended durations listed above were based on experimental studies using small numbers of animals and successful uncontrolled clinical experience involving unknown numbers of exposed people. However, in animal studies, some monkeys can harbor viable spores up to 100 days after exposure [14]. Thus, it is possible that a small proportion of individuals, particularly the immunocompromised or unvaccinated, may still be at risk beyond 60 days.

Adverse reactions — Adverse events (eg, gastrointestinal distress) associated with long-term use of antimicrobial agents are to be expected and should be evaluated. Clinicians and public health personnel should be aware when prescribing fluoroquinolones for long-term use that they have been associated with tendinitis, tendon rupture, and central nervous system effects. (See "Fluoroquinolones", section on 'Tendinopathy'.)

Although tetracyclines may cause permanent tooth discoloration in children younger than eight years of age, doxycycline is thought to be less likely to cause visible tooth staining than tetracycline [10], though it could be a risk with long-term use of doxycycline. In addition, the potential benefit of preventing life-threatening anthrax infection outweighs the risk of tooth staining. Similarly, the potential benefit of ciprofloxacin use for anthrax PEP outweighs the potential cartilage toxicity in children. (See "Tetracyclines", section on 'Teeth and bone' and "Fluoroquinolones", section on 'Adverse effects'.)

In 2001, approximately 10,000 individuals were offered 60 days of antimicrobial PEP therapy for the prevention of inhalation anthrax [23]. Anaphylactoid reactions were reported within 30 days in four persons who received antimicrobial PEP. Overall, 3032 of 5343 individuals (57 percent) who took at least one antimicrobial prophylactic dose 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.

The Anthrax Vaccine and Antibiotic Availability Program (AVAAP) offered extended antimicrobial PEP (>60 days) for persons at risk of inhalation anthrax [24]. 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.

Anthrax vaccination — Anthrax vaccine adsorbed (AVA) is approved by the FDA and recommended by the Centers for Disease Control and Prevention (CDC) as part of the PEP regimen for inhalation anthrax exposure, and it is given in addition to antimicrobial prophylaxis [3,9,10,25] (see 'Antimicrobials' above). Clinicians should immediately notify state and local health departments if they suspect anthrax exposure; those institutions and/or the CDC can advise on vaccine use and facilitate vaccine acquisition.

●AVA dosing – The dose of AVA for PEP depends on prior receipt of anthrax vaccination:

•For PEP in patients who had not previously received anthrax vaccination, AVA is administered in three subcutaneous 0.5 mL doses at zero, two, and four weeks (table 4).

•Use of AVA for PEP in patients who have previously received anthrax vaccination (eg, those who received pre-exposure vaccination) is discussed elsewhere. (See 'PEP for previously vaccinated individuals' below.)

The recommendations for use of AVA as a component of prophylaxis following exposure to aerosolized B. anthracis spores apply to both pregnant and lactating women as well as children [3,11]. Exposed infants <6 weeks of age should be given antimicrobial prophylaxis immediately but should receive the first dose of the AVA series when they reach six weeks of age [10]. For exposed children, AVA should be given priority over routine childhood immunizations; administration of routine immunizations should be delayed until four weeks after the last AVA dose. In the United States, AVA is not FDA approved for children, so administration would presumably require institutional review board approval under an investigational protocol.

●Alternatives – If AVA supplies are insufficient to meet demand in an emergency situation, alternative AVA dosing regimens may be options. Additionally, another vaccine, AVA-adjuvanted has also been approved by the FDA for post-exposure prophylaxis and is a potential option if AVA is unavailable, although the CDC has not formally made recommendations on its use. (See 'PEP for large-scale emergency response' below and 'Vaccine formulations in the United States' above.)

The benefit of vaccination as a component of PEP has been demonstrated in animal studies, which are discussed elsewhere. (See 'PEP regimen' above.)

Evidence supporting the recommended schedule for PEP is primarily from immunogenicity studies. In a trial evaluating different dosing schedules of AVA, individuals who received vaccine only at week 0 had lower antibody levels after four weeks than those who received vaccine at weeks 0 and 2 [7]. Although long-term antibody levels were higher with intramuscular than subcutaneous administration, the ACIP recommends subcutaneous administration for post-exposure prophylaxis, because of higher antibody levels and seroconversion rates at week 4 [8]. This time period is particularly important for people who have been exposed and are taking prophylactic antibiotics. (See 'Antimicrobials' above.)

Efficacy, immunogenicity, and safety data related to use in the pre-exposure setting are discussed elsewhere. (See 'Vaccine administration' above.)

Considerations for special situations

PEP for large-scale emergency response — In the setting of a large-scale inhalational exposure (eg, widespread release of aerosolized B. anthracis), adjustments in the post-exposure prophylaxis (PEP) recommendations may be warranted for implementation reasons or to manage drug or vaccine shortages.

The Advisory Committee on Immunization Practices (ACIP) suggests the following possible modifications to the standard vaccine recommendations in such an event [3]. All of these modified vaccine approaches are administered in addition to an antimicrobial regimen for PEP (see 'Antimicrobials' above):

●Intramuscular administration – AVA may be administered intramuscularly rather than subcutaneously (which is the preferred route for PEP) if subcutaneous administration would result in delays or other implementation challenges (table 4). Although the subcutaneous route resulted in higher antibody concentrations in the first few weeks compared with the intramuscular route in immunogenicity studies, the differences were not statistically significant after week 9 [8].

●Dose-sparing regimen – A dose-sparing regimen of AVA can be used if the AVA supply is not sufficient to allow standard vaccination (three full doses of vaccine) of all exposed individuals (table 4). Options include:

•Two doses of full-dose vaccine – 0.5 mL administered at zero and two to four weeks

•Three doses of half-dose vaccine – 0.25 mL administered at zero, two, and four weeks

Based on immunogenicity, animal efficacy, and cross-species prediction models, these dose-sparing regimens were estimated to result in high levels of protection by two weeks after the second dose [26].

●Use of alternative formulation (AVA-adjuvanted) – If the AVA supply is not sufficient to allow vaccination of all exposed individuals, AVA-adjuvanted is an option [3]. Fifty million doses had previously been purchased for the Strategic National Stockpile for this purpose [27]. If this were to become necessary, the ACIP would convene an emergency meeting to determine specific recommendations for use of AVA-adjuvanted. It is not known whether AVA and AVA-adjuvanted are interchangeable; use of the same formulation for the entire series has been suggested. If this is not feasible, then three total doses of vaccine are suggested. (See 'Vaccine formulations in the United States' above.)

PEP for previously vaccinated individuals — For patients who have previously received AVA for pre-exposure prophylaxis, the prophylaxis regimen following a known or suspected exposure (including entry into a high-risk area for aerosolized B. anthracis exposure) depends on the extent and timing of the prior vaccination [3].

●For individuals who had received at least all three priming doses:

•If their most recent vaccine was <6 months ago, no further post-exposure prophylaxis (PEP; ie, no immediate vaccination nor antimicrobials) is indicated.

•If their most recent vaccine was ≥6 months ago, an immediate AVA dose and antimicrobial prophylaxis until 14 days after the vaccine dose are indicated.

●For individuals who had received only two of the priming doses, an immediate AVA dose and antimicrobial prophylaxis until 14 days after the vaccine dose are indicated.

●For individuals who had received only one of the priming doses, an immediate AVA dose and a subsequent AVA dose two weeks later are indicated. Antimicrobial prophylaxis should also be given and continued until 28 days after the first post-exposure vaccine dose was given or 14 days after the last vaccine dose, whichever occurs later.

Antimicrobial regimen selection is discussed elsewhere. (See 'Antimicrobial regimen selection' above.)

Individuals who continue to be at risk for future B. anthracis exposure warrant ongoing vaccination for pre-exposure prophylaxis. The schedule is discussed elsewhere. (See 'Vaccine administration' above.)

Pregnancy — Consistent with the general practice of avoiding unnecessary exposure to vaccinations during pregnancy, pre-event vaccination is avoided in women who are known to be pregnant. However, in a post-exposure situation, the risk of developing inhalation anthrax outweighs any potential risk vaccination may carry, and exposed women should receive vaccination as a component of PEP in addition to antimicrobial prophylaxis [3,11]. (See 'Antimicrobials' above.)

A cohort study of 4092 women found no difference in pregnancy rate or odds of having a live birth in women who received at least one dose of anthrax vaccine compared with those who had not [28]. The study, however, was not powered sufficiently to determine whether there was an effect on birth outcomes.

An additional study of 115,169 infants born to military women inadvertently vaccinated with AVA during pregnancy indicated that infants born to women receiving anthrax vaccine in their first trimester could have a slightly higher risk of congenital anomalies compared with infants born to women receiving anthrax vaccine outside of pregnancy [29]. The statistically significant finding was small and was not present when the comparison was made using women vaccinated during the second or third trimester. In addition, no overall pattern or type of congenital anomaly was found in association with receipt of maternal anthrax vaccination.

Alternative prophylactic agents

Monoclonal antibodies — Two monoclonal antibodies, raxibacumab and obiltoxaximab, have been approved in the United States for the prevention of inhalation anthrax when alternative preventive therapies are not available or not appropriate [30,31]. Supplies of raxibacumab and obiltoxaximab are held in the United States Strategic National Stockpile for use by the CDC in the event of an anthrax emergency [32]. Clinicians should contact the CDC if one of these agents is indicated.

●Raxibacumab – Raxibacumab is a human immunoglobulin (Ig)G1-gamma monoclonal antibody that inhibits binding of protective antigen to anthrax toxin receptors and translocation of the two primary toxins (lethal toxin and edema toxin) into cells [9]. In 2012, raxibacumab was approved by the FDA for the prevention of inhalation anthrax when alternative preventive therapies are not available or not appropriate [30,32].

Raxibacumab is given as a single dose following premedication with diphenhydramine; dosing recommendations for raxibacumab are as follows [33]:

•Adults and children >50 kg: 40 mg/kg intravenously (IV)

•Children 15 kg to 50 kg: 60 mg/kg IV

•Children ≤15 kg: 80 mg/kg

The efficacy of raxibacumab has been evaluated only in animals since it is not possible to perform efficacy trials in humans, given that inhalation anthrax is both rare and lethal. However, in phase II safety studies in humans, the therapeutic levels of the antibody achieved in humans were equal to or greater than those that provide protection in animal models [34]. Common adverse effects in 326 healthy humans included rash, extremity pain, pruritus, and drowsiness [30].

Both rabbits and monkeys had significantly improved survival when raxibacumab was administered immediately following an aerosolized challenge with B. anthracis spores (80 to 100 percent survival rate at 14 to 28 days compared with 0 percent with placebo) [35]. In the same report, raxibacumab was also highly effective for the treatment of anthrax (see "Treatment of anthrax", section on 'Raxibacumab'). In a study of raxibacumab in mice, guinea pigs, and rabbits, efficacy decreased as time from exposure to B. anthracis spores to raxibacumab administration increased beyond 24 hours [36]. Administration of raxibacumab does not appear to interfere with vaccine efficacy [37].

●Obiltoxaximab – Obiltoxaximab, a monoclonal antibody directed against the protective antigen of B. anthracis, was approved in 2016 by the US Food and Drug Administration for the prevention of inhalational anthrax when alternative therapies are not available or not appropriate [31,38].

Obiltoxaximab is given as a single dose following premedication with diphenhydramine; dosing recommendations are as follows [38]:

•Weight >40 kg: 16 mg/kg IV

•Weight 15 to 40 kg: 24 mg/kg IV

•Weight ≤15 kg: 32 mg/kg IV

The most common adverse effects in trials of 320 humans included headache, pruritus, upper respiratory tract infection, cough, vessel puncture site bruise, infusion site swelling, urticaria, nasal congestion, infusion site pain, and pain in an extremity [38]. Obiltoxaximab was discontinued in 8 of 320 individuals (2.5 percent) due to hypersensitivity reactions or anaphylaxis.

The evidence supporting its efficacy for the prevention of inhalation anthrax also comes from studies in animal models for the reasons mentioned above for raxibacumab. Obiltoxaximab has been evaluated in studies of macaque monkeys for the prevention of inhalation anthrax and resulted in improved survival compared with placebo [38]. There are no data evaluating the effect of obiltoxaximab on vaccine efficacy.

Immune serum — Immune serum containing B. anthracis antibodies has also been evaluated for PEP. However, in a rabbit model, anthrax immune serum interfered with vaccine efficacy, so it is not approved for PEP after anthrax exposure [37].

In other animal studies, passive immunization within 24 hours post-exposure with immune serum containing antibodies against the B. anthracis protective antigen has conferred some degree of protection against an intranasal live-spore challenge [39]. The efficacy of passive immunization used for prophylaxis has not been studied throughout the entire duration of PEP (60 days following exposure), and protection conferred by antiserum prophylaxis begins to decrease at approximately three weeks following the first dose [40].

OTHER PREVENTIVE ISSUES

Infection control — Patients with suspected or confirmed anthrax infection should be placed on standard precautions, which include the routine use of gloves for contact with nonintact skin [41]. In the case of cutaneous anthrax in patients in whom there is uncontained drainage, contact isolation is recommended [42]. Appropriate personal protective equipment should be used when generation of aerosols or splatter of body fluids is anticipated, including during postmortem care.

Transmission can occur through direct contact with skin lesions. Private room placement is not necessary since airborne transmission does not occur. (See "Infection prevention: Precautions for preventing transmission of infection".)

Decontamination — In the setting of B. anthracis infection caused by bioterrorism, the United States Centers for Disease Control and Prevention has recommended the following measures for decontamination of patients and the surrounding environment [41] (see "Identifying and managing casualties of biological terrorism", section on 'Decontamination (overt exposure)'):

●Instructing patients to remove contaminated clothing and to store in labeled plastic bags

●Handling clothing minimally to avoid agitation

●Instructing and/or assisting patients to shower thoroughly with soap and water

●Instructing health care and other emergency response personnel regarding standard precautions and using appropriate personal protective equipment (eg, gloves, gown, and respiratory protection) when handling contaminated clothing or other potentially contaminated fomites

●Decontaminating environmental surfaces using 0.5% hypochlorite solution (one part bleach added to nine parts water) or another approved sporicidal/germicidal agent

Control of animal infection — Prevention of naturally occurring anthrax in humans is primarily dependent on the control of the disease in animals, especially livestock. Annual vaccination of livestock in areas with enzootic anthrax is recommended.

Animal vaccination is the major means of preventing naturally occurring epizootics of anthrax, since widespread decontamination of infected soil is impractical.

Management of cutaneous or gastrointestinal exposure — In the event of a naturally occurring cutaneous exposure, such as from handling an anthrax-affected animal or its carcass, appropriate medical and public health personnel should be notified, and exposed persons should be monitored for development of a spot, pimple, or boil, especially in the exposed areas. For naturally occurring gastrointestinal exposure, such as the consumption of meat from a poorly cooked carcass of an anthrax-infected animal, antimicrobial prophylaxis may be considered for a 7- to 14-day period [3]. Antimicrobial choices are the same as those recommended for post-exposure prophylaxis to prevent inhalation anthrax (see 'Prophylaxis following aerosolized exposure' above). Vaccination is not recommended following either naturally occurring cutaneous or gastrointestinal exposure in which there is no risk of inhalation exposure.

INTERNATIONAL CONSIDERATIONS — This topic mostly covers anthrax prevention recommendations from the United States. World Health Organization (WHO) guidelines are largely in agreement with those of the United States Centers for Disease Control and Prevention (CDC) [43].

Anthrax vaccine availability varies throughout the world. There are four anthrax vaccines produced globally.

●One of the vaccines licensed in the United States (anthrax vaccine absorbed [AVA]) is produced by Emergent BioSolutions and is available through state health departments. Internationally, it is marketed in Canada, France, the Netherlands, Poland, the United Kingdom, Germany, and Italy, and it is available to the United States military and at United States government installations. Further information about access throughout the world can be found by calling the Emergent Biosystems customer service number at 888-773-3266 or by email at [email protected].

●The British vaccine is produced by Porton Biopharma on behalf of the United Kingdom government. It is available to physicians in the United Kingdom through the usual medical supply process. The manufacturer is open to supplying other governments or public health agencies around the world, but, because the vaccine requires an export license and cold chain, it is not available for individual practitioners from other countries to order. The company can be contacted at [email protected] or at the main switchboard number of +44 (0)1980 612100.

●In Russia and China, attenuated vaccines are made and are probably available through the respective governments. The Russian product is longstanding, and available information suggests that it is safe but possibly less effective than AVA.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anthrax".)

SUMMARY AND RECOMMENDATIONS

●Pre-exposure prophylaxis for selected individuals – For individuals likely to have occupational exposure to aerosolized Bacillus anthracis spores, we recommend pre-exposure vaccination with anthrax vaccine adsorbed (AVA) (table 1 and table 2) (Grade 1C). (See 'Pre-exposure vaccination in select individuals' above.)

●Post-exposure prophylaxis – Post-exposure prophylaxis (PEP) against anthrax should be offered to all asymptomatic individuals who have documented or suspected exposure to aerosolized B. anthracis; clinicians should seek advice from public health officials to make this determination. PEP includes both antimicrobial prophylaxis and vaccination:

•Antimicrobial prophylaxis – For the antimicrobial component of post-exposure prophylaxis in nonpregnant individuals, we suggest doxycycline or ciprofloxacin (table 3) (Grade 2C). For children, amoxicillin is another option if the B. anthracis isolate is susceptible (minimum inhibitory concentration ≤0.12 mcg/mL). For pregnant or breastfeeding individuals, the preferred option is ciprofloxacin. These agents protected against infection for the duration of therapy in animal studies; data supporting the use of other antibiotics are lacking. The duration of therapy is prolonged and depends on patient factors. (See 'Antimicrobial regimen selection' above.)

•Plus vaccination – We also recommend vaccination against anthrax for post-exposure prophylaxis (Grade 1C). In animal studies, adding vaccination to prophylactic antimicrobials improved survival following exposure.

For PEP in patients who have not previously received anthrax vaccination, AVA is given in three subcutaneous doses (at zero, two, and four weeks) (table 4). In the United States, AVA is available from the CDC or through state and local health departments. If AVA is not available, a different vaccine anthrax vaccine adsorbed, adjuvanted (AVA-adjuvanted) may be another option. (See 'Anthrax vaccination' above.)

Clinicians should be aware that nonadherence to PEP regimens can be high.

When these preventive interventions are not available or individually appropriate, the monoclonal antibodies raxibacumab or obiltoxaximab are appropriate alternatives for the prevention of inhalation anthrax. Clinicians should contact the CDC or their state or local health department if one of these is indicated. (See 'Monoclonal antibodies' above.)

●Treatment – The treatment of anthrax is discussed separately. (See "Treatment of anthrax".)