Treatment and Postexposure Prophylaxis

Last update May 25, 2011

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Treatment
Postexposure Prophylaxis
New Therapeutic Approaches
Bibliography

Treatment

Anthrax countermeasures include antibiotics (for treatment and postexposure prophylaxis [PEP]), antibodies, antitoxin agents, and vaccines. The current status of these countermeasures is summarized elsewhere (Bouzianas 2009).

The tables below review current treatment recommendations for clinical disease caused by B anthracis.

Protocol for Treatment of Cutaneous Anthraxa-c
Patient Category	Initial Therapy (Oral)d	Duratione
Adults	Ciprofloxacin: 500 mg PO twice daily or Doxycycline: 100 mg PO twice daily	60 days
Children	Ciprofloxacin: 10-15 mg/kg PO twice daily (maximum daily dose, 1 g) or Doxycyclinef: >8 yr and >45 kg: same as adult >8 yr and <45 kg: 2.2 mg/kg PO twice daily <8 yr: 2.2 mg/kg PO twice daily	60 days
Pregnant womeng	Same as for nonpregnant adults (high death rate from the infection outweighs risk posed by antimicrobial agent)	60 days
Immunocompromised persons	Same as for nonimmunocompromised persons and children	60 days
Abbreviation: PO, orally. aThese treatment recommendations were made during the US 2001 anthrax outbreak. In other settings, antimicrobial susceptibility testing should be used to guide therapy decisions. bCutaneous anthrax cases with signs of systemic involvement, extensive edema, or lesions on the head or neck require intravenous therapy, and a multidrug approach is recommended (see table just below). cTreatment of cutaneous anthrax does not prevent the evolution of the skin lesions; however, it usually will prevent progression to systemic disease (Inglesby 2002). dCiprofloxacin or doxycycline should be considered first-line therapy. Amoxicillin (500 mg orally 3 times daily for adults or 80 mg/kg/day divided every 8 hr for children) is an option for completion of therapy after clinical improvement. Oral amoxicillin dose is based on need to achieve appropriate minimum inhibitory concentration. eIn cases of naturally occurring cutaneous anthrax, previous recommendations have indicated that treatment for 7 to 10 days is adequate; however, in the setting where inhalational exposure also is likely, treatment should be continued for 60 days. fThe American Academy of Pediatrics recommends treatment of young children with tetracyclines for serious infections (eg, Rocky Mountain spotted fever). gAlthough tetracyclines and ciprofloxacin are not recommended for pregnant women, their use may be indicated for life-threatening illness. Adverse effects on developing teeth and bones are dose-related; therefore, doxycycline might be used for a short time (7-14 days) before 6 months of gestation. Adapted from CDC 2001: Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001

Protocol for Treatment of Inhalational and Gastrointestinal Anthraxa
Patient Category	Initial IV Therapyb,c	Oral Regimens (continue therapy for 60 days [IV and PO combined])
Adults	Ciprofloxacin: 400 mg twice daily or Doxycycline: 100 mg twice dailye    and One or two additional antimicrobials (agents with in vitro activity include rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, and clarithromycin)f	Patients should be treated with IV therapy initially.d Treatment can be switched to oral therapy when clinically appropriate: Ciprofloxacin: 500 mg PO twice daily or Doxycycline: 100 mg PO twice daily
Children	Ciprofloxacin: 10-15 mg/kg twice daily (maximum daily dose, 1 g)g or Doxycyclinee,h: >8 yr and >45 kg: same as adult >8 yr and <45 kg: 2.2 mg/kg twice daily <8 yr: 2.2 mg/kg twice daily    and One or two additional antimicrobials (see agents listed under therapy for adults)f	Patients should be treated with IV therapy initially.d Treatment can be switched to oral therapy when clinically appropriate: Ciprofloxacin: 10-15 mg/kg PO twice daily (maximum daily dose, 1 g) or Doxycyclineh: >8 yr and >45 kg: same as adult >8 yr and <45 kg: 2.2 mg/kg PO twice daily <8 yr: 2.2 mg/kg PO twice daily
Pregnant womeni	Same as for nonpregnant adults (high death rate from the infection outweighs risk posed by antimicrobial agent)	Patients should be treated with IV therapy initially. d Treatment can be switched to oral therapy when clinically appropriate. Oral therapy regimens are the same as for nonpregnant adults.
Immunocompromised persons	Same as for nonimmunocompromised persons and children.	Same as for nonimmunocompromised persons and children.
Abbreviations: IV, intravenously; PO, orally. aMeningitis involvement must be assumed in all systemic infections. Antibiotic selection must consider penetration across blood-brain barrier (Stern 2008). These treatment recommendations were made during US 2001 anthrax outbreak. In other situations, antimicrobial susceptibility testing should be used to guide therapy decisions. bCiprofloxacin or doxycycline should be considered an essential part of first-line therapy for inhalational anthrax. cSteroids may be considered an adjunct therapy for patients with severe edema (Doust 1968) and for meningitis based on experience with bacterial meningitis of other causes. dInitial therapy may be altered based on clinical course of patient; one or two antimicrobial agents (eg, ciprofloxacin or doxycycline) may be adequate as patient improves. eIf meningitis is suspected, doxycycline may be less optimal because of poor central nervous system penetration. fBecause of concerns of constitutive and inducible beta-lactamases in B anthracis isolates, penicillin and ampicillin should not be used alone. Consultation with an infectious disease specialist is advised. Other agents with in vitro activity include tetracycline, linezolid, macrolides, aminoglycosides, and cefazolin (Inglesby 2002). B anthracis strains are naturally resistant to sulfamethoxazole, trimethoprim, cefuroxime, cefotaxime sodium, aztreonam, and ceftazidime (Inglesby 2002). gIf IV ciprofloxacin is not available, oral ciprofloxacin may be acceptable because it is rapidly and well absorbed from gastrointestinal tract with no substantial loss by first-pass metabolism. Maximum serum concentrations are attained 1-2 hr after oral dosing but may not be achieved if vomiting or ileus is present. hThe American Academy of Pediatrics recommends treatment of young children with tetracyclines for serious infections (eg, Rocky Mountain spotted fever). iAlthough tetracyclines are not recommended for pregnant women, their use may be indicated for life-threatening illness. Adverse effects on developing teeth and bones are dose-related; therefore, doxycycline might be used for a short time (7-14 days) before 6 months of gestation. Adapted from CDC 2001: Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001, Stern 2008.

A systematic review of inhalational anthrax cases identified between 1900 and 2005 reported the following observations with regard to treatment (Holty 2006: Systematic review: a century of inhalational anthrax cases from 1900 to 2005).

• Initiation of therapy with antibiotics or anthrax antiserum during the prodromal phase was associated with improved survival.
• Patients who progressed to the fulminant phase, regardless of therapy, had a very high case-fatality rate (97%).
• Multidrug antibiotic therapy and pleural fluid drainage were associated with decreased mortality; however, since these modalities were predominantly used during the 2001 US anthrax outbreak, other confounding factors (eg, differences in patient characteristics, anthrax exposure, supportive care, antibiotic efficacy) may have contributed to enhanced overall survival.

Because mortality for inhalational anthrax remains high despite use of antibiotics, potential adjuvant therapies are being studied. Examples include gamma and alpha/beta interferon and adefovir (Gold 2004, Shen 2004). As noted above, drainage of pleural fluid (through repeated thoracentesis or chest tube drainage) may enhance survival in cases of inhalational anthrax (Holty 2006: Systematic review: a century of inhalational anthrax cases from 1900 to 2005).

Raxibacumab is a human monoclonal antibody directed against PA. The efficacy of raxibacumab for the treatment of inhalational anthrax has been evaluated in rabbits and monkeys. Following inhalational challenge, the survival rate was significantly higher among rabbits that received a 40 mg/kg dose of raxibacumab (44%; 8 of 18) than among rabbits that received placebo (0%; 0 of 18). Treated monkeys also had significantly increased survival (64%; 9 of 14) compared with untreated monkeys (0%, 0 of 12) (Migone 2009).

Treatment of Anthrax Meningitis

Anthrax meningitis is treated in similar fashion to inhalational anthrax, although initial treatment should include an intravenous (IV) fluoroquinolone and not doxycycline, because doxycycline has poor central nervous system (CNS) penetration. In addition to an IV fluoroquinolone, one or two other agents that have good CNS penetration and activity against B anthracis should be added (eg, penicillin, ampicillin, meropenem, vancomycin, rifampin) (Sejvar 2005). Case reports suggest that adding corticosteroids may be of benefit in the management of cerebral edema/inflammation (Sejvar 2005).

The optimal duration of therapy is not known, but treatment should be continued for 10 to 14 days or as long as is clinically indicated.

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Postexposure Prophylaxis

The CDC currently recommends 60 days of oral antimicrobial therapy in combination with a three-dose series of anthrax vaccine adsorbed (AVA) for PEP following potential inhalational exposure to aerosolized B anthracis spores (Stern 2008).

Antimicrobial therapy should be continued for at least 60 days for the following persons:

• Those exposed to an air space known to be contaminated with aerosolized B anthracis
• Those exposed to an air space known to be the source of an inhalational anthrax case
• Those along the transit path of an envelope or other vehicle containing B anthracis that may have been aerosolized (eg, a postal sorting facility in which an envelope containing B anthracis was processed)
• Unvaccinated laboratory workers exposed to confirmed B anthracis cultures in situations where aerosolization is suspected

Antimicrobial prophylaxis is not indicated for the following:

• Prevention of cutaneous anthrax
• Autopsy personnel examining bodies infected with anthrax when appropriate isolation precautions and procedures are followed
• Hospital personnel caring for patients with anthrax
• Persons who routinely open or handle mail (in the absence of a suspicious letter or credible threat)

The decision to prescribe PEP to asymptomatic persons in the setting of an outbreak of inhalational anthrax should be based on the likelihood of exposure and not on nasal swab testing (see Tests for Exposure in the Clinical Laboratory Testing section).

In the event of a mass exposure, local and state public health agencies would rapidly make antibiotics available to the exposed population (see the discussion of mass exposure in the Management of Exposure Events section).

Since experience with gastrointestinal anthrax is limited, currently there are no recommendations for using PEP in the setting of gastrointestinal exposure, such as in a foodborne outbreak or intentional contaminaton of a food source. However, if public health officials determine that the risk of B anthracis infection is high, it may be reasonable to consider using PEP in the setting of gastrointestinal exposure (CDC 2000: Human ingestion of Bacillus anthracis-contaminated meat—Minnesota, August 2000).

The FDA has approved several antimicrobial agents for use as anthrax PEP (FDA 2001, FDA: Levaquin [levofloxacin] information for inhalational anthrax; Meyerhoff 2004).

• Ciprofloxacin
• Doxycycline
• Penicillin G procaine
• Levofloxacin

Analysis of published reports suggests that development of antibiotic resistance may be less likely to occur with doxycycline than with fluoroquinolones. In addition, doxycycline is several times less expensive than most fluoroquinolones and appears in clinical studies to have similar efficacy in most scenarios (Brouillard 2006).

Other antimicrobial agents, including clindamycin, chloramphenical, rifampin, vancomycin, and other fluoroquinolones, may be considered for off-label use in patients unable to tolerate FDA-approved antimicrobial agents for PEP (Stern 2008). Athamna and colleagues found that the combination of rifampin and clindamycin demonstrated a synergistic effect in vitro against two strains of B anthracis (Athamna 2005). A number of other combinations were either indifferent or antagonistic.

The CDC recommendations for PEP to prevent inhalational anthrax (those issued during the 2001 bioterrorism anthrax attack as well as later modifications) are outlined in the table below.

Initial CDC Recommendations for PEP for Prevention of Inhalational Anthrax Following Exposure to Bacillus anthracis
Patient Category	Initial Therapy	Durationa
Adults (including immunocompromised patients)	Ciprofloxacin: 500 mg PO twice daily or Doxycycline: 100 mg PO twice daily or Levofloxacin: 500 mg PO once daily [Note: Levofloxacin is FDA-approved for PEP for inhalational anthrax in adults >18 years; however, data on the safety of using levofloxacin beyond 28 days are limited. Therefore, levofloxacin is recommended as a second-line PEP agent, to be reserved for instances in which medical issues call for its use (FDA: Levaquin [levofloxacin] information for inhalational anthrax, Stern 2008).]	60 days
Pregnant women and breastfeeding mothers	Ciprofloxacin: 500 mg PO twice daily (first-line oral agent for PEP in pregnant women.) or Doxycycline: 100 mg PO twice daily (In pregnant women, doxycycline should be used only during the third trimester.) [Note: Amoxicillin, 500 mg orally three times daily, may be used if isolate involved in exposure is determined to be susceptible to penicillin.b-d]	60 days
Children (including immunocompromised patients)	Ciprofloxacin: 10-15 mg/kg PO twice daily (maximum daily dose, 1 g) or Doxycycline: >8 yr and >45 kg: same as adult >8 yr and <45 kg: 2.2 mg/kg PO twice daily <8 yr: 2.2 mg/kg PO twice daily [Note: Amoxicillin, 80 mg/kg/day divided every 8 hr not to exceed 500 mg/dose, may be used if the isolate involved in exposure is determined to be susceptible to penicillinc] or Levofloxacin: 500 mg PO once daily for children >50 kg, or 8 mg/kg twice daily (not to exceed 250 mg per dose) for children <50 kg. [Note: In May 2008, the FDA approved the use of levofloxacin for PEP for inhalational anthrax in children. As noted above for adults, data on the safety of using levofloxacin beyond 28 days are limited. In addition, levofloxacin may cause an increase in musculoskeletal adverse events in children (FDA: Levaquin [levofloxacin] information for inhalational anthrax).]	60 days
Abbreviation: FDA, Food and Drug Administration; PEP, postexposure prophylaxis; PO, orally. aRecommended in combination with a 3-dose series of anthrax vaccine adsorbed (AVA) (BioThrax [BioPort Corp, Lansing, MI]) administered at time zero, 2 weeks, and 4 weeks. AVA is not FDA-approved for PEP and therefore would be available under an Investigational New Drug (IND) protocol (Stern 2008). After the 2001 attack, exposed persons were subsequently given the option to take an additional 40 days of antibiotics with or without anthrax vaccine; see comments below. Other antimicrobial agents, including clindamycin, chloramphenical, rifampin, vancomycin, and other fluoroquinolones, may be considered for off-label use in patients unable to tolerate FDA-approved antimicrobial agents for PEP (Stern 2008). bSee comments below from American College of Obstetricians and Gynecologists regarding use of amoxicillin. cAmoxicillin is not approved by the FDA for PEP or treatment of anthrax; however, the CDC has indicated that it could be used for pregnant women or children for PEP if the isolate is determined to be susceptible. In such situations, amoxicillin could be provided under an IND or under an Emergency Use Authorization in a declared emergency (CDC 2001: Interim recommendations for antimicrobial prophylaxis for children and breastfeeding mothers and treatment of children with anthrax, CDC 2001: Updated recommendations for antimicrobial prophylaxis among asymptomatic pregnant women after exposure to Bacillus anthracis, Stern 2008). A study to evaluate the pharmacokinetics of amoxicillin during pregnancy and postpartum found that drug concentrations adequate to prevent anthrax may be difficult to achieve during pregnancy and in the postpartum period (Andrew 2007). Amoxicillin given to pediatric patients <40 kg should yield adequate time above the minimum inhibitory concentration for susceptible B anthracis (0.5 mcg/mL) over most of the dosing interval (Alexander 2008) dThe American Academy of Pediatrics considers ciprofloxacin and tetracyclines to usually be compatible with breastfeeding because the amount of either drug absorbed by infants is small, but little is known about the safety of long-term use. Therefore, amoxicillin may be considered an alternative for breastfeeding mothers if the isolate causing exposure is known to be susceptible to penicillin. Alternatively, mothers could consider expressing and discarding breast milk during therapy with ciprofloxacin or doxycycline and resuming breastfeeding after therapy is complete. Adapted from CDC 2001: Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001, Stern 2008.

More than 10,000 people were placed on PEP during the 2001 anthrax outbreak; no cases of anthrax occurred among this group (CDC 2001: CDC responds: an update on treatment options for postal and other workers exposed to anthrax).

• A follow-up study of those persons who were offered antimicrobial prophylaxis demonstrated that 5,343 took at least one dose of antimicrobial therapy (Shepard 2002). Of this group, 3,032 (57%) reported adverse events during the first 60 days of therapy. Gastrointestinal complaints (nausea, vomiting, diarrhea, stomach pain) were reported by 44% of those with adverse events and neurologic symptoms (headache, dizziness, light-headedness, fainting, and seizures) were reported by 33%. Fewer than half of respondents (2,712 [44%]) reported taking antimicrobial prophylaxis for at least 60 days. Of the 2,631 persons who stopped therapy before 60 days, 43% stopped because of adverse events, 25% stopped because of a low perceived risk of anthrax, and 7% stopped because of concern about long-term side effects of prolonged antimicrobial therapy.
• A statistical model was used to estimate the number of anthrax cases prevented among about 5,000 persons placed on prophylaxis who were potentially exposed to airborne anthrax spores at one of three locations (the media center in Florida, the two postal facilities in New Jersey, and the postal facility in Washington, DC). The model suggested that about nine cases were prevented through the use of postexposure antibiotics (Brookmeyer 2002).
• Another model-based study explored the impact of initial response time, anthrax incubation period, and antibiotic effectiveness on hospital surge after a large-scale release of anthrax spores over a major urban area. If an antibiotic prophylaxis campaign was begun within 2 days after the exposure event and completed within 48 hours, approximately 87% of exposed persons would be protected from illness (assuming a 95% attack rate and 90% antibiotic effectiveness). On average, each additional day of delay in initiating the campaign (beyond 2 days) would result in 5.2% to 6.5% additional hospitalizations in the exposed population, whereas every additional day needed to complete the campaign would result in 2.4% to 2.9% additional hospitalizations. The authors concluded that commencement of the prophylaxis campaign (no more than 3 days) and antibiotic effectiveness (greater than 90%) are the parameters with the greatest preventive impact (Hupert 2009).

The American College of Obstetricians and Gynecologists (ACOG) has recommended the following for anthrax prophylaxis in pregnant women (ACOG):

• Prophylactic treatment should be limited to women who have been exposed to confirmed environmental contamination or a high-risk source as determined by public health authorities.
• Pregnant women who have been exposed to anthrax should be started on a 60-day course of ciprofloxacin.
• Therapy should be switched to amoxicillin if the strain is found to be penicillin-sensitive.

According to ACOG, doxycycline use in pregnant women generally should be avoided because it can cause problems in fetuses, including staining of teeth and impeded bone growth; however, doxycycline should be used for exposed pregnant women who are allergic to amoxicillin and ciprofloxacin, since the risk of anthrax outweighs any potential risks to the fetus from doxycycline.

A national poll conducted by the Harvard School of Public Health in December 2009 revealed that 89% of adults probably would follow public health recommendations to obtain prophylactic antibiotics at a dispensing site. However, of those, only 57% said they would start taking the antibiotics immediately, while 39% said they would wait before taking them (in most cases to see if they had been exposed). In response to a fictional scenario of an anthrax attack, more than 80% of adults said they would be worried about becoming seriously ill or dying (see Feb 19, 2010, CIDRAP News story).

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New Therapeutic Approaches

In addition to available treatment protocols, a variety of promising new therapeutic approaches for treatment of anthrax are being researched; many involve use of monoclonal antibodies (Borio 2005, Bouzianas 2009, Migone 2009). An alternative to monoclonal antibodies is antisera from previously vaccinated persons undergoing serial plasmapheresis. Hyperimmune plasma and immune globulin isolated in this way could potentially serve as the basis for new therapeutic treatments (Pittman 2006).

• The Department of Health and Human Services (HHS) awarded a contract to Human Genome Sciences, Inc (HGS) of Rockville, Maryland, to provide the US government with 10 grams of ABthrax (raxibacumab), a human monoclonal antibody for treating anthrax (see Dec 19, 2005, CIDRAP News story). In June 2006, HHS announced that it would purchase 20,000 treatment courses of ABthrax (HHS 2006: HHS to acquire new anthrax therapeutic treatment for stockpile). In February 2009, HGS began delivery of the first 20,000 doses of ABThrax (HGS 2009).
• Similarly, HHS has contracted with Cangene (a company based in Winnipeg, Manitoba) to supply anthrax immune globulin (AIG) for preliminary efficacy testing. The company describes AIG as a hyperimmune product for treating or preventing inhalational anthrax. In July 2006, HHS announced that it will purchase 10,000 treatment courses of AIG from Cangene (HHS 2006: HHS to acquire anthrax immune globulin for stockpile).

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