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AnthraxTreatment OverviewInhalational. Early initiation of appropriate antibiotics is paramount for patient survival of IA. Initial therapy for adults with IA due to a strain with unknown antibiotic susceptibilities should include ciprofloxacin (400 mg intravenous q 12 hr for adults, and 10-15 mg/kg IV q12 hr (up to 1 g/day) for children) OR doxycycline (200 mg intravenous load, followed by 100 mg intravenous q12 hr for adults and children > 8 yr and >45 kg, and 2.2mg/kg q12 hr for children < 8 yr (up to 200 mg/day))* PLUS one or two additional antibiotics effective against anthrax. Some additional antibiotics to which naturally occurring strains of B. anthracis are susceptible include imipenem, meropenem, daptomycin, quinupristin-dalfopristin, linezolid, vancomycin, rifampin, macrolides (e.g., erythromycin, azithromycin, and clarithromycin), clindamycin, chloramphenocol, and aminoglycosides (e.g., gentamicin). While optimal combination antibiotic therapy for IA is not known, many infectious disease physicians have suggested a combination of a quinolone, clindamycin, and rifampin for susceptible B. anthracis strains. Penicillin (or other beta-lactam antibiotics) should NEVER be used as monotherapy for severe anthrax disease as B. anthracis genome encodes for both constitutive and inducible beta-lactamases and resistance may occur in vivo despite apparent in vitro susceptibility. Antibiotic choices must be adjusted for strain susceptibility patterns, and consultation with an infectious disease physician is imperative. If meningitis is suspected, at least one antibiotic with good CSF penetration (e.g., rifampin or chloramphenicol) should be used, as quinolones and tetracyclines do not enter the CSF well. Generally, ciprofloxacin or doxycycline use is avoided during pregnancy and in children due to safety concerns; however, a consensus group and the American Academy of Pediatrics have suggested that ciprofloxacin or doxycycline should still be used as first line therapy in life-threatening anthrax disease until strain susceptibilities are known. In fact, ciprofloxacin has been approved by the FDA for prophylaxis and treatment of anthrax in children. Recommended treatment duration is at least 60 days, and should be changed to oral therapy as clinical condition improves. *other quinolone antibiotics (levofloxacin, trovofloxacin) or tetracyclines (minocycline, tetracycline) would likely be affective as well, although they have not been specifically approved by the FDA for this purpose. In the event of a mass-casualty situation intravenous antibiotics may not be available. In this case oral ciprofloxacin OR doxycycline may have to suffice as initial therapy. The doses for ciprofloxacin are 500 mg po bid for adults, and 10-15 mg/kg po bid (up to 1 g/day) for children. The doses for doxycycline are 200 mg po initially then 100 mg po bid thereafter for adults (or children > 8 yr and > 45 kg), and 2.2 mg/kg po bid (up to 200 mg/day) for children < 8 yr. Supportive therapy for shock, fluid volume deficit, and adequacy of airway may be needed. In the IA cases from the 2001 attacks, aggressive drainage of pleural effusions seemed to improve clinical outcome. Corticosteroids may be considered as adjunct therapy in patients with severe edema or meningitis, based upon experience in treating other bacterial diseases. Human anthrax immune globulin may be available soon as a therapy for IA under an IND from the CDC (see Appendix L for instructions on Investigational New Drug (INDs). The role of postexposure anthrax vaccine for patients with IA has not yet been determined. Cutaneous anthrax Uncomplicated cutaneous anthrax disease should be treated initially with either ciprofloxacin (500 mg po bid for adults or 10-15 mg/kg/day divided bid (up to 1000 mg/day) for children) or doxycycline (100 mg po bid for adults, 5 mg/kg/day divided bid for children less than 8 yr (up to 200 mg/day)). If the strain proves to be penicillin susceptible, then the treatment may be switched to amoxicillin (500 mg po tid for adults or 80 mg/kg po divided tid (up to 1500 mg/day) for children). While B. anthracis' genome encodes for beta-lactamases, the organism may still respond to penicillins (such as amoxicillin) if slowly growing as in localized cutaneous disease. In the event that the exposure route is unknown or suspected to be related to a BW event, then antibiotics should be continued for at least 60 days. If the exposure is known to have been due to contact with infected livestock or their products, then 7-10 days of antibiotics may suffice. For patients with significant edema, non-steroidal anti-inflammatory agents (NSAIDS) or corticosteroids may be of benefit. Debridement of lesions is not indicated. If systemic illness accompanies cutaneous anthrax, then intravenous antibiotics should be administered as per the inhalational anthrax recommendations discussed above. Gastrointestinal anthrax. Documentation of clinical experience in treating oropharyngeal and intestinal anthrax is limited. Supportive care to include fluid, shock, and airway management should be anticipated. Both forms of GI disease should receive the intravenous antibiotic regimen described for inhalational anthrax above. For oropharyngeal anthrax, airway compromise is a significant risk, and consideration should be given for the early administration of corticosteroids to reduce the development of airway edema. If despite medical therapy, airway compromise develops, early airway control with intubation should be considered. Incision and drainage of affected lymph nodes is not generally indicated. No specific guidance exists for drainage of ascites in patients with intestinal anthrax. However, large fluid collections could at a minimum compromise respiration and consideration should be given to therapeutic (and potentially diagnostic) paracentesis. Infection Control. Standard precautions are recommended for patient care in all forms of anthrax disease. There are no data to suggest direct person-to-person spread from any form of anthrax disease. However, for patients with systemic anthrax disease, especially before antibiotic initiation, invasive procedures, autopsy, or embalming of remains could potentially lead to the generation of infectious droplets; thus, such procedures should be avoided when possible. After an invasive procedure or autopsy, the instruments and materials used should be autoclaved or incinerated, and the immediate environment where the procedure took place should be thoroughly disinfected with a sporicidal agent. Iodine can be used, but must be used at disinfectant strengths, as antiseptic-strength iodophors are not usually sporicidal. Chlorine, in the form of sodium or calcium hypochlorite, can also be used, but with the caution that the activity of hypochlorites is greatly reduced in the presence of organic material. The clinical laboratory should be warned before the delivery of anthrax specimens as growth of B. anthracis in culture requires BSL-2 precautions. Animal anthrax experience indicates that incineration of carcasses and contaminated ground is the environmental control method of choice. A prior recommendation was deep burial (at least 6 feet deep) in pits copiously lined with lye (sodium hydroxide); however, this practice may still leave a significant proportion of viable spores. This has led a consensus group to recommend "serious consideration" of cremation of human anthrax victim remains. Treatment and Postexposure ProphylaxisAnthrax countermeasures include antibiotics (for treatment and postexposure prophylaxis [PEP]), antibodies, antitoxin agents, and vaccines. The current status of these countermeasures is summarized elsewhere (see References: Bouzianas 2009). The tables below review current treatment recommendations for clinical disease caused by B anthracis.
A systematic review of inhalational anthrax cases identified between 1900 and 2005 reported the following observations with regard to treatment (see References: Holty 2006: Systematic review: a century of inhalational anthrax cases from 1900 to 2005).
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 (see References: 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 (see References: 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) (see References: Migone 2009). Treatment of Anthrax MeningitisAnthrax 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) (see References: Sejvar 2005). Case reports suggest that adding corticosteroids may be of benefit in the management of cerebral edema/inflammation (see References: 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. Postexposure ProphylaxisThe 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 (see References: Stern 2008). Antimicrobial therapy should be continued for at least 60 days for the following persons:
Antimicrobial prophylaxis is not indicated for the following:
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 the Clinical Laboratory Testing: Tests for Exposure section above). In the event of a mass exposure, local and state public health agencies would rapidly make antibiotics available to the exposed population (see the section below on Mass Exposure Events). 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 (see References: CDC 2000: Human ingestion of Bacillus anthracis-contaminated meatMinnesota, August 2000). The FDA has approved several antimicrobial agents for use as anthrax PEP (see References: FDA 2001, FDA: Levaquin [levofloxacin] information for inhalational anthrax, Meyerhoff 2004).
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 (see References: 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 (see References: 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 (see References: 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.
More than 10,000 people were placed on PEP during the 2001 anthrax outbreak; no cases of anthrax occurred among this group (see References: CDC 2001: CDC responds: an update on treatment options for postal and other workers exposed to anthrax).
The American College of Obstetricians and Gynecologists (ACOG) has recommended the following for anthrax prophylaxis in pregnant women (see References: ACOG):
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). New Therapeutic ApproachesIn 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 (see References: 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 (see References: Pittman 2006).
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