Anthrax medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

Medical therapy of anthrax infection includes antibiotic and antitoxin drugs. Uncomplicated cutaneous anthrax is treated with a single oral antimicrobial drug for a duration of 7-10 days for naturally acquired anthrax and 60 days for bioterrorism-related exposure. In case of systemic anthrax with excludes meningitis, the initial treatment should include ≥2 antimicrobial drugs for ≥2 weeks or until the patient is clinically stable, whichever is longer. In case of systemic anthrax with suspected or confirmed meningitis, the initial treatment should include ≥3 antimicrobial drugs for ≥2 weeks or until the patient is clinically stable, whichever is longer. Once patients with systemic illness who were exposed to aerosolized spores have completed initial combination treatment, they should be transitioned to single-agent oral treatment to prevent relapse from surviving B. anthracis spores. These patients should be monitored at all times to evaluate the need for supportive care measures, such as hemodynamic support, mechanical ventilation, corticosteroids, procedures, and surgical interventions in certain occasions. An antitoxin should be added to combination antibiotic treatment. Currently there are 2 antitoxins in the CDC Strategic National Stockpile: raxibacumab and Anthrax Immune Globulin Intravenous (AIGIV).

Medical Therapy

The treatment of anthrax infection includes antibiotic and antitoxin agents. This treatment and postexposure prophylaxis differs from other bacterial infections because anthrax is associated with:

• Production of toxin
• Potential antibiotic resistance
• Frequent occurrence of meningitis
• Presence of latent spores that must be taken into account when selecting post-exposure prophylaxis or a combination of antibiotics for treatment of anthrax

Antibiotic Treatment

Cutaneous Anthrax without Systemic Involvement

Choice of Antibiotics

• Uncomplicated cutaneous anthrax has been successfully treated with a single oral antimicrobial drug.
• Oral fluoroquinolones (ciprofloxacin, levofloxacin, and moxifloxacin) and doxycycline are equivalent first-line agents.
• Clindamycin is an alternative option if fluoroquinolones and doxycycline are contraindicated or unavailable.
• Given the long history of successful treatment of localized uncomplicated cutaneous anthrax with penicillin, amoxicillin and penicillin VK are also alternative therapeutic options if the isolate is known to be susceptible to penicillin. However, adequate dosages must be used because of the potential for development of drug resistance during treatment with subtherapeutic dosing.

Duration of Treatment

• Duration of treatment for localized or uncomplicated cutaneous disease depends on the B. anthracis exposure source:
  • Naturally acquired (e.g., animals with anthrax, products such as hides from animals with anthrax): 7–10-day course
  • Bioterrorism-related exposure or an aerosol exposure is suspected: 60 days (because the patient is likely to have also inhaled spores.)

Systemic Anthrax When Meningitis Has Been Excluded

Choice of Antibiotics

• The initial treatment should include ≥2 antimicrobial drugs with activity against B. anthracis:
  • ≥1 should have bactericidal activity, and
  • ≥1 should be a protein synthesis inhibitor

• Intravenous ciprofloxacin is preferred as the primary bactericidal component in the treatment of systemic disease. Linezolid or clindamycin are the preferred as the first-line protein synthesis inhibitor.

• If the B. anthracis strain is susceptible to penicillin, then penicillin G is considered equivalent to the fluoroquinolone options for primary bactericidal treatment.

• Treatment with antimicrobial drugs that have good CNS penetration is not a crucial factor. Thus, meropenem is recommended as an acceptable alternative option than as a first-line antimicrobial drug, and vancomycin is also an acceptable alternative. Clindamycin and linezolid are considered equivalent first-line choices for protein synthesis inhibitors. Doxycycline is added as an alternative protein synthesis inhibitor option if linezolid or clindamycin are contraindicated or unavailable.

Duration of Treatment

• Initial intravenous combination treatment should be given for ≥2 weeks or until the patient is clinically stable, whichever is longer.

Follow–up Oral Treatment for Systemic Disease

Once patients with systemic illness who were exposed to aerosolized spores have completed initial combination treatment, they should be transitioned to single-agent oral treatment to prevent relapse from surviving B. anthracis spores.

Systemic Anthrax with Possible/Confirmed Meningitis

Choice of Antibiotics

• Empiric treatment for anthrax in which anthrax meningitis is suspected or cannot be ruled out should include ≥3 antimicrobial drugs with activity against B. anthracis:
  • ≥1 drug should have bactericidal activity
  • ≥1 should be a protein synthesis inhibitor
  • All should have good CNS penetration

• Hospitalized patients for systemic anthrax should be immediately treated with a combination of broad-spectrum intravenous antibiotic drug treatment pending confirmatory test results because any delay may prove fatal. Because meningitis and hemorrhagic brain parenchymal infection was observed in ≤50% of cases, meningitis must be considered in all cases of systemic anthrax. Therefore antibiotics to treat possible meningitis must have good penetration of the central nervous system (CNS).

• Intravenous ciprofloxacin is preferred as the primary bactericidal component in the treatment of systemic disease on the basis of efficacy in non-human primates (NHP) infection models and recent use for anthrax cases. Levofloxacin and moxifloxacin are considered equivalent alternatives to ciprofloxacin. The fluoroquinolones have adequate CNS penetration and there are no reports of natural resistance.

• The carbapenem class of antimicrobial drugs is highly resistant to β-lactamases and provides good CNS penetration. Meropenem is preferred as the second antimicrobial drug in the combination antimicrobial drug regimen for anthrax meningitis. If meropenem is unavailable, doripenem and imipenem/cilastatin are considered equivalent alternatives. Imipenem/cilastatin is associated with increased seizure risk and should be used with caution in patients with suspected meningitis. If the B. anthracis strain is susceptible to penicillin (MIC <0.125 µg/mL), penicillin G or ampicillin are acceptable alternatives to carbapenems.

• At least 1 antimicrobial drug that inhibits protein synthesis should be used to reduce exotoxin production. Linezolid is preferred as the first-line protein synthesis inhibitor. It is preferred over clindamycin because it is likely to provide better CNS penetration, although randomized controlled trials on treatment for CNS infections with either agent are lacking. However, linezolid toxicity issues must be taken into consideration. Myelosuppression, peripheral and optic neuropathies, and serotonin syndrome have been reported in patients receiving linezolid. Linezolid should be used cautiously in patients with pre-existing myelosuppression. In patients receiving monoamine oxidase inhibitors or serotonin reuptake inhibitors, the benefit of linezolid treatment should be weighed against the risk for serotonin toxicity and an alternative should be considered. If patients experience visual impairment, prompt ophthalmic evaluation is recommended. If patients have contraindications to linezolid use or it is unavailable, clindamycin is an acceptable alternative. Rifampin, although not a protein synthesis inhibitor, has been widely used for its synergistic effect with a primary drug and could also be used in this capacity if linezolid or clindamycin are unavailable. The protein synthesis inhibitor chloramphenicol has good CNS penetration and has historically been used to successfully treat anthrax. Where available, it could be an acceptable alternative if linezolid, clindamycin, and rifampin are unavailable. Doxycycline should not be used if meningitis is suspected because it does not adequately penetrate the CNS.

Duration of Treatment

• Intravenous combination treatment for systemic anthrax with possible meningitis should be provided for ≥2 weeks or until the patient is clinically stable, whichever is longer.
• Given the high mortality rate associated with meningitis, some expert panelists favored 3 weeks of treatment for patients in whom meningitis could not be ruled out.

Follow–up Oral Treatment for Systemic Disease

Once patients with systemic illness who were exposed to aerosolized spores have completed initial combination treatment, they should be transitioned to single-agent oral treatment to prevent relapse from surviving B. anthracis spores.

Dosage of Antibiotics

▸ Click on the following categories to expand treatment regimens.

Cutaneous Anthrax Without Systemic Involvement   ▸  Adult Patients   ▸  Pediatric Patients   ▸  Pregnant Patients Systemic Anthrax with Possible/Confirmed Meningitis   ▸  Adult Patients   ▸  Pediatric Patients   ▸  Pregnant Patients Systemic Anthrax Without Meningitis   ▸  Adult Patients   ▸  Pediatric Patients   ▸  Pregnant Patients

Cutaneous Anthrax, Adult Patients Preferred Regimen ▸ Ciprofloxacin 500 mg PO q12h OR ▸ Levofloxacin 750 mg PO q24h OR ▸ Moxifloxacin 400 mg PO q24h OR ▸ Doxycycline 100 mg PO q12h Alternative Regimen ▸ Clindamycin 600 mg PO q8h OR ▸ Penicillin VK 500 mg PO q6h OR ▸ Amoxicillin 1 g PO q8h Cutaneous Anthrax, Pediatric Patients Preferred Regimen ▸ Ciprofloxacin 30 mg/kg/day PO q12h, max: 500 mg/dose OR ▸ Levofloxacin 16 mg/kg/day PO q12h, max: 250 mg/dose (<50 kg) OR ▸ Levofloxacin 500 mg PO q24h (≥50 kg) OR ▸ Doxycycline 4.4 mg/kg/day PO q12h, max: 100 mg/dose (<45 kg) OR ▸ Doxycycline 100 mg/dose PO q12h (≥45 kg) Alternative Regimen ▸ Clindamycin 30 mg/kg/day PO q8h, max: 600 mg/dose OR ▸ Penicillin VK 50–75 mg/kg/day PO q6–8h OR ▸ Amoxicillin 75 mg/kg/day PO q8h, max: 1 g/dose Cutaneous Anthrax, Pregnant Patients Preferred Regimen ▸ Ciprofloxacin 500 mg PO q12h Systemic Anthrax with Meningitis, Adult Patients Preferred Regimen ▸ Ciprofloxacin 400 mg IV q8h OR ▸ Levofloxacin 750 mg IV q24h OR ▸ Moxifloxacin 400 mg IV q24h PLUS ▸ Meropenem 2 g IV q8h OR ▸ Imipenem 1 g IV q6h OR ▸ Doripenem 500 mg IV q8h PLUS ▸ Linezolid 600 mg IV q12h OR ▸ Clindamycin 900 mg IV q8h OR ▸ Rifampin 600 mg IV q12h OR ▸ Chloramphenicol 1 g IV q6–8h Alternative Regimen ▸ Ciprofloxacin 400 mg IV q8h OR ▸ Levofloxacin 750 mg IV q24h OR ▸ Moxifloxacin 400 mg IV q24h PLUS ▸ Penicillin G 4 MU IV q4h OR ▸ Ampicillin 3 g IV q6h PLUS ▸ Linezolid 600 mg IV q12h OR ▸ Clindamycin 900 mg IV q8h OR ▸ Rifampin 600 mg IV q12h OR ▸ Chloramphenicol 1 g IV q6–8h Systemic Anthrax with Meningitis, Pediatric Patients Preferred Regimen ▸ Ciprofloxacin 30 mg/kg/day IV q8h, max: 400 mg/dose OR ▸ Levofloxacin 20 mg/kg/day IV q12h, max: 250 mg/dose (<50 kg) OR ▸ Levofloxacin 500 mg IV q24h (≥50 kg) OR ▸ Meropenem 60 mg/kg/day IV q12h, max: 2 g/dose OR ▸ Imipenem/Cilastatin 100 mg/kg/day IV q6h, max: 1 g/dose OR ▸ Vancomycin 60 mg/kg/day IV q8h PLUS ▸ Clindamycin 30 mg/kg/day PO q8h, max: 600 mg/dose OR ▸ Linezolid 30 mg/kg/day IV q8h, max: 1 g/dose (<12 yr) OR ▸ Linezolid 30 mg/kg/day IV q12h, max: 600 mg/dose (≥12 yr) OR ▸ Doxycycline 4.4 mg/kg/day IV q12h, max: 100 mg/dose (<45 kg) OR ▸ Doxycycline 200 mg IV x1 then 100 mg IV q12h, max: 200 mg/dose (≥45 kg) OR ▸ Rifampin 20 mg/kg/day IV q12h, max: 300 mg/dose Alternative Regimen ▸ Penicillin G 0.4 MU/kg/day IV q4h, max: 4 MU/dose OR ▸ Ampicillin 200 mg/kg/day IV q6h, max: 900 mg/dose PLUS ▸ Clindamycin 30 mg/kg/day PO q8h, max: 600 mg/dose OR ▸ Linezolid 30 mg/kg/day IV q8h, max: 1 g/dose (<12 yr) OR ▸ Linezolid 30 mg/kg/day IV q12h, max: 600 mg/dose (≥12 yr) OR ▸ Doxycycline 4.4 mg/kg/day IV q12h, max: 100 mg/dose (<45 kg) OR ▸ Doxycycline 200 mg IV x1 then 100 mg IV q12h, max: 200 mg/dose (≥45 kg) OR ▸ Rifampin 20 mg/kg/day IV q12h, max: 300 mg/dose Systemic Anthrax with Meningitis, Pregnant Patients Preferred Regimen ▸ Ciprofloxacin 400 mg IV q8h PLUS ▸ Clindamycin 900 mg IV q8h OR ▸ Rifampin 600 mg IV q12h Alternative Regimen ▸ Levofloxacin 750 mg IV q24h OR ▸ Meropenem 2 g IV q8h OR ▸ Penicillin G 4 MU IV q4h OR ▸ Ampicillin 3 g IV q6h PLUS ▸ Clindamycin 900 mg IV q8h OR ▸ Rifampin 600 mg IV q12h Systemic Anthrax Without Meningitis, Adult Patients Preferred Regimen ▸ Ciprofloxacin 400 mg q8h OR ▸ Levofloxacin 750 mg q24h OR ▸ Moxifloxacin 400 mg PO q24h OR ▸ Meropenem 2 g q8h OR ▸ Imipenem 1 g IV q6h OR ▸ Doripenem 500 mg q8h OR ▸ Vancomycin 60 mg/kg/day IV q8h, trough: 15–20 μg/mL PLUS ▸ Clindamycin 900 mg q8h OR ▸ Linezolid 600 mg q12h OR ▸ Doxycycline 200 mg x1 then 100 mg IV q12h OR ▸ Rifampin 600 mg q12h Alternative Regimen ▸ Penicillin G 4 MU IV q4h OR ▸ Ampicillin 3 g IV q6h PLUS ▸ Clindamycin 900 mg q8h OR ▸ Linezolid 600 mg q12h OR ▸ Doxycycline 200 mg x1 then 100 mg IV q12h OR ▸ Rifampin 600 mg q12h Systemic Anthrax Without Meningitis, Pediatric Patients Preferred Regimen ▸ Ciprofloxacin 30 mg/kg/day IV q8h, max: 400 mg/dose OR ▸ Levofloxacin 16 mg/kg/day IV q12h, max: 250 mg/dose (<50 kg) OR ▸ Levofloxacin 500 mg IV q24h (≥50 kg) OR ▸ Moxifloxacin 12 mg/kg/day IV q12h, max: 200 mg/dose (3 mo–2 yr) OR ▸ Moxifloxacin 10 mg/kg/day IV q12h, max: 200 mg/dose (2 yr–5 yr) OR ▸ Moxifloxacin 8 mg/kg/day IV q12h, max: 200 mg/dose (6 yr–11 yr) OR ▸ Moxifloxacin 8 mg/kg/day IV q12h, max: 200 mg/dose (12 yr–17 yr, <45 kg) OR ▸ Moxifloxacin 400 mg IV q24h (12 yr–17 yr, ≥45 kg) PLUS ▸ Meropenem 120 mg/kg/day IV q8h, max: 2 g/dose OR ▸ Imipenem/Cilastatin 100 mg/kg/day IV q6h, max: 1 g/dose OR ▸ Doripenem 120 mg/kg/day IV q8h, max: 1 g/dose OR ▸ Vancomycin 60 mg/kg/day IV q8h PLUS ▸ Linezolid 30 mg/kg/day IV q8h, max: 600 mg/dose (<12 yr) OR ▸ Linezolid 30 mg/kg/day IV q12h, max: 600 mg/dose (≥12 yr) OR ▸ Clindamycin 40 mg/kg/day IV q8h, max: 900 mg/dose OR ▸ Rifampin 20 mg/kg/day IV q12h, max: 300 mg/dose OR ▸ Chloramphenicol 100 mg/kg/day IV q6h Alternative Regimen ▸ Ciprofloxacin 30 mg/kg/day IV q8h, max: 400 mg/dose OR ▸ Levofloxacin 16 mg/kg/day IV q12h, max: 250 mg/dose (<50 kg) OR ▸ Levofloxacin 500 mg IV q24h (≥50 kg) OR ▸ Moxifloxacin 12 mg/kg/day IV q12h, max: 200 mg/dose (3 mo–2 yr) OR ▸ Moxifloxacin 10 mg/kg/day IV q12h, max: 200 mg/dose (2 yr–5 yr) OR ▸ Moxifloxacin 8 mg/kg/day IV q12h, max: 200 mg/dose (6 yr–11 yr) OR ▸ Moxifloxacin 8 mg/kg/day IV q12h, max: 200 mg/dose (12 yr–17 yr, <45 kg) OR ▸ Moxifloxacin 400 mg IV q24h (12 yr–17 yr, ≥45 kg) PLUS ▸ Penicillin G 0.4 MU/kg/day IV q4h, max: 4 MU/dose OR ▸ Ampicillin 400 mg/kg/day IV q6h, max: 3 g/dose PLUS ▸ Linezolid 30 mg/kg/day IV q8h, max: 600 mg/dose (<12 yr) OR ▸ Linezolid 30 mg/kg/day IV q12h, max: 600 mg/dose (≥12 yr) OR ▸ Clindamycin 40 mg/kg/day IV q8h, max: 900 mg/dose OR ▸ Rifampin 20 mg/kg/day IV q12h, max: 300 mg/dose OR ▸ Chloramphenicol 100 mg/kg/day IV q6h Systemic Anthrax Without Meningitis, Pregnant Patients Preferred Regimen ▸ Ciprofloxacin 400 mg IV q8h PLUS ▸ Clindamycin 900 mg IV q8h OR ▸ Rifampin 600 mg IV q12h Alternative Regimen ▸ Levofloxacin 750 mg IV q24h OR ▸ Meropenem 2 g IV q8h OR ▸ Penicillin G 4 MU IV q4h OR ▸ Ampicillin 3 g IV q6h PLUS ▸ Clindamycin 900 mg IV q8h OR ▸ Rifampin 600 mg IV q12h

Antitoxins

An antitoxin should be added to combination antibiotic treatment for any patient for whom there is a high level of clinical suspicion for systemic anthrax. Given that systemic anthrax has a high case-fatality rate and the risk for antitoxin treatment appears to be low, the potential benefit achieved by adding antitoxin to combination antibiotic treatment outweighs the potential risk.

Currently there are 2 antitoxins in the CDC Strategic National Stockpile: raxibacumab and Anthrax Immune Globulin Intravenous (AIGIV). Both antitoxins inhibit binding of Protective Antigen (PA) to anthrax toxin receptors and translocation of the 2 primary toxins (Lethal Toxin (LT) and Edema Toxin (ET)) into cells.

Raxibacumab

Raxibacumab is a recombinant, fully humanized, IgG1λ monoclonal antibody. It appeared safe and well tolerated in 333 healthy adults who received the recommended dose of 40 mg/kg.

Most adverse events were transient and mild to moderate in severity. Pruritis was noted in 2.1% of persons treated with raxibacumab and in none treated with placebo. Although raxibacumab has not been given to patients with systemic anthrax, it is FDA-approved for postexposure prophylaxis PEP.

Anthrax Immune Globulin

AIGIV is a human polyclonal antiserum made from plasma of persons immunized with Anthrax Vaccine Absorbed (AVA), which might have some direct effect on Lethal Factor (LF) and Edema Factor (EF). It was evaluated in 74 healthy adult volunteers and appears safe and well tolerated at all doses tested.

The most frequently reported adverse events were headache pharyngolaryngeal pain, and nausea.

AIGIV is not FDA approved and could be made available under an Investigational New Drug protocol or an Emergency Use Authorization during a declared emergency.

Hospitalization

Many patients with cutaneous anthrax can be treated as outpatients.

Patients with symptoms or signs of systemic involvement (e.g., tachycardia, tachypnea, hypotension, hyperthermia, hypothermia, leukocytosis) or with lesions that involve the head, neck, or upper torso or that are large, bullous, multiple, or surrounded by edema, have higher mortality rates. Hospitalization is warranted for all patients with systemic cutaneous anthrax; gastrointestinal, injection, or inhalation anthrax; or anthrax meningitis or bacteremia.

Supportive Treatment

Failure to fulfill systemic inflammatory response syndrome criteria should not decrease concern for sepsis because patients with systemic anthrax might not initially appear critically ill. Inhalation anthrax can have a prodromal phase followed by a fulminant phase. Patients with systemic anthrax have had debilitating symptoms, followed first by transitory improvement and then by precipitous hemodynamic deterioration. Because of this potential for sudden decompensation, hospitalized patients should have careful hemodynamic monitoring, including continuous pulse oximetry and telemetry.

Hemodynamic Support

Standard sepsis and septic shock guidelines should be followed for anthrax patients. Common complications of anthrax infections including microangiopathic hemolytic anemia, coagulopathy, thrombocytopenia, and hemorrhage must be aggressively managed, since they might pose contraindications to invasive central catheter placement.

Fresh frozen plasma and plasmapheresis should be considered, and fibrinogen levels should be kept >100 mg/dL.

An echocardiogram might be needed to identify pericardial effusions.

Mechanical Ventilation

In addition to the need for mechanical ventilation for respiratory distress or airway protection for persons with altered mental status, some patients with anthrax might require respiratory support for airway edema. Substantial edema with fatal outcome can occur with cutaneous lesions involving the head, neck, or thorax, and with oropharyngeal lesions.

In inhalation anthrax, although respiratory failure is more consistent with reaccumulating pleural effusions than with adult respiratory distress syndrome, standard mechanical ventilator principles apply. The need for ventilation in some patients and the duration of ventilation in others may be reduced by pleural space drainage.

Adjunctive Corticosteroids

There are limited data on steroid use for documented anthrax meningitis, however, adjunctive intravenous dexamethasone is the standard of care for patients with suspected bacterial meningitis and should be started at the time of initial antibiotic therapy to prevent neurologic sequelae.

Adjunctive corticosteroids should be considered in patients who had a history of use of:

• Endocrine
• Corticosteroid therapy
• Edema, especially of the head or neck
• Evidence of anthrax meningitis
• Vasopressor-resistant shock

Interventions

Procedures

Drainage of pleural fluid and ascites is believed to improve survival by reducing the toxin level and by decreasing mechanical lung compression. These data support the need for early and aggressive drainage of any clinically or radiographically apparent pleural effusions; chest tube drainage is recommended over thoracentesis because many effusions will require prolonged drainage.

Thoracotomy or video-assisted thoracic surgery might be required to remove gelatinous or loculated collections. Ascites should also be drained and monitored for reaccumulation.

Surgery

Surgery for cutaneous anthrax can lead to dissemination and poor outcome. Surgery is contraindicated for acute disease, with the exception of tracheotomy for airway obstruction and surgical intervention for large or circumferential extremity lesions causing compartment syndrome.

Surgery may be indicated for gastrointestinal anthrax to identify and address potentially fatal complications, such as bowel ischemia, necrosis, and perforation.

For injection anthrax, surgery is used to obtain diagnostic specimens to differentiate the infection from necrotizing fasciitis and to remove the necrotic nidus of infection, which may be a toxin and spore reservoir. Surgery for injection anthrax should be more limited than that for necrotizing fasciitis, and resection should be performed only to healthy tissue. Compression of soft tissues can be released by incision, excision, or fasciotomy and might be required for treatment of compartment syndrome.

References

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