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

The mainstay of therapy for anthrax infection is antimicrobial therapy. Antitoxin drugs should be added to combination antimicrobial therapy for any patient with suspected systemic anthrax. Uncomplicated cutaneous anthrax is treated with a single oral antimicrobial agent for a duration of 7-10 days for naturally acquired anthrax and 60 days for bioterrorism-related exposure. In cases of systemic anthrax without meningitis, the initial treatment should include ≥2 antimicrobial drugs for ≥2 weeks or until the patient is clinically stable, whichever is longer. Patients with systemic anthrax with suspected or confirmed meningitis are treated with ≥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 therapy, they should be transitioned to single-agent oral treatment to prevent relapse from surviving B. anthracis spores. Supportive therapy includes hemodynamic support, mechanical ventilation, corticosteroids, procedures, and surgical intervention in certain occasions. [1]

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:[1]

Antimicrobial Regimen

  • 1. Treatment for cutaneous anthrax, without systemic involvement[2]
  • Preferred regimen (1): Ciprofloxacin 500 mg PO bid for 7-10 days (regardless of penicillin susceptibility or if susceptibility is unknown)
  • Preferred regimen (2): Doxycycline 100 mg PO bid for 7-10 days (regardless of penicillin susceptibility or if susceptibility is unknown)
  • Preferred regimen (3): Levofloxacin 750 mg PO qd for 7-10 days (regardless of penicillin susceptibility or if susceptibility is unknown)
  • Preferred regimen (4): Moxifloxacin 400 mg PO qd for 7-10 days (regardless of penicillin susceptibility or if susceptibility is unknown)
  • Alternative regimen (1): Clindamycin 600 mg PO tid for 7-10 days
  • Alternative regimen (2): Amoxicillin 1 g PO tid (for penicillin-susceptible strains) for 7-10 days
  • Alternative regimen (3): Penicillin VK 500 mg PO qid (for penicillin-susceptible strains) for 7-10 days
  • Note: Duration of treatment is 60 days for bioterrorism-related cases and 7-10 days for naturally acquired cases.
  • 2. Treatment for systemic anthrax including anthrax meningitis, inhalational anthrax, injectional anthrax, and gastrointestinal anthrax; and cutaneous anthrax with systemic involvement, extensive edema, or lesions of the head or neck[2]
  • 2.1 Systemic anthrax with possible/confirmed meningitis
  • Treatment is with a combination of Bactericidal agent (fluoroquinolone) AND Bactericidal agent (ß-lactam) AND Protein synthesis inhibitor
  • 2.1.1 Bactericidal agent (fluoroquinolone)
  • Preferred regimen (1): Ciprofloxacin 400 mg IV q8h for 2-3 weeks
  • Alternative regimen (1): Levofloxacin 750 mg IV q24h for 2-3 weeks
  • Alternative regimen (2): Moxifloxacin 400 mg IV q24h for 2-3 weeks
  • 2.1.2 Bactericidal agent (ß-lactam) for all strains, regardless of penicillin susceptibility or if susceptibility is unknown
  • Preferred regimen (1): Meropenem 2 g IV q8h for 2-3 weeks
  • Alternative regimen (1): Imipenem 1 g IV q6h for 2-3 weeks
  • Alternative regimen (2): Doripenem 500 mg IV q8h for 2-3 weeks
  • Alternative regimen (3): Penicillin G 4 MU IV q4h (for penicillin-susceptible strains) for 2-3 weeks
  • Alternative regimen (4): Ampicillin 3 g IV q6h (for penicillin-susceptible strains) for 2-3 weeks
  • 2.1.3 Protein synthesis inhibitor
  • Preferred regimen (1): Linezolid 600 mg IV q12h for 2-3 weeks
  • Alternative regimen (1): Clindamycin 900 mg IV q8h for 2-3 weeks
  • Alternative regimen (2): Rifampin 600 mg IV q12h for 2-3 weeks
  • Alternative regimen (3): Chloramphenicol 1 g IV q6-8h for 2-3 weeks
  • Note (1): Patients exposed to aerosolized spores will require prophylaxis to complete an antimicrobial drug course of 60 days from onset of illness.
  • Note (2): Increased risk for seizures associated with Imipenem/Cilastatin treatment.
  • Note (3): Linezolid should be used with caution in patients with thrombocytopenia because it might exacerbate it. Linezolid use for > 14 days has additional hematopoietic toxicity.
  • Note (4): Rifampin is not a protein synthesis inhibitor. However, it may be used in combination with other antimicrobial drugs on the basis of its in vitro synergy.
  • 2.2 Systemic anthrax when meningitis has been excluded
  • 2.2.1 Bactericidal agent
  • Preferred regimen (1): Ciprofloxacin 400 mg IV q8h for 2 weeks
  • Preferred regimen (2): Levofloxacin 750 mg IV q24h for 2 weeks
  • Preferred regimen (3): Moxifloxacin 400 mg q24h for 2 weeks
  • Preferred regimen (4): Meropenem 2 g IV q8h for 2 weeks
  • Preferred regimen (5): Imipenem 1 g IV q6h for 2 weeks
  • Preferred regimen (6): Doripenem 500 mg IV q8h for 2 weeks
  • Preferred regimen (7): Vancomycin 20 mg/kg IV q8h (maintain serum trough concentrations of 15-20 µg/mL) for 2 weeks
  • Preferred regimen (8): Penicillin G 4 MU IV q4h (penicillin-susceptible strains) for 2 weeks
  • Preferred regimen (9): Ampicillin 3 g IV q6h (penicillin-susceptible strains) for 2 weeks
  • 2.2.2 Protein synthesis inhibitor
  • Preferred regimen (1): Clindamycin 900 mg IV q8h for 2 weeks
  • Preferred regimen (2): Linezolid 600 mg IV q12h for 2 weeks
  • Preferred regimen (3): Doxycycline 200 mg IV initially, then 100 mg IV q12h for 2 weeks
  • Preferred regimen (4): Rifampin 600 mg IV q12h for 2 weeks
  • Note: Patients exposed to aerosolized spores will require prophylaxis to complete an antimicrobial drug course of 60 days from onset of illness.
  • 3. Specific considerations
  • 3.1 Treatment of anthrax for pregnant Women
  • 3.1.1 Intravenous antimicrobial treatment for systemic anthrax with possible/confirmed meningitis [3]
  • 3.1.1.1 A Bactericidal Agent (Fluoroquinolone)
  • Preferred regimen (1): Ciprofloxacin 400 mg IV q8h for 2–3 weeks
  • Preferred regimen (2): Levofloxacin 750 mg IV q24h for 2–3 weeks
  • 3.1.1.2 A Bactericidal Agent (ß-lactam)
  • 3.1.1.2.1 For all strains, regardless of penicillin susceptibility or if susceptibility is unknown
  • Preferred regimen: Meropenem 2 g q8h for 2–3 weeks
  • 3.1.1.2.2 Alternatives for penicillin-susceptible strains
  • Alternative regimen (1): Ampicillin 3 g IV q6h for 2–3 weeks
  • Alternative regimen (2): Penicillin G 4 MU IV q4h for 2–3 weeks
  • 3.1.1.3 A Protein Synthesis Inhibitor
  • Preferred regimen (1): Clindamycin 900 IV mg q8h for 2–3 weeks
  • Preferred regimen (2): Rifampin 600 IV mg q12h for 2–3 weeks
  • Note: At least one antibiotic with transplacental passage is recommended.
  • 3.1.2 Intravenous antimicrobial treatment for systemic anthrax when meningitis has been excluded
  • 3.1.2.1 A Bactericidal Antimicrobial
  • Preferred regimen (1): Ciprofloxacin 400 mg IV q8h for 2 weeks
  • Preferred regimen (2): Levofloxacin 750 mg IV q24h for 2 weeks
  • 3.1.2.2 A Bactericidal Agent (ß-lactam)
  • 3.1.2.2.1 For all strains, regardless of penicillin susceptibility or if susceptibility is unknown
  • Preferred regimen: Meropenem 2 g q8h for 2 weeks
  • 3.1.2.2.2 Alternatives for penicillin-susceptible strains
  • Alternative regimen (1): Ampicillin 3 g IV q6h for 2 weeks
  • Alternative regimen (2): Penicillin G 4 MU IV q4h for 2 weeks
  • 3.1.2.3 A Protein Synthesis Inhibitor
  • Preferred regimen (1): Clindamycin 900 IV mg q8h for 2 weeks
  • Preferred regimen (2): Rifampin 600 IV mg q12h for 2 weeks
  • 3.1.3 Oral antimicrobial treatment for cutaneous anthrax without systemic involvement
  • 3.1.3.1 For all strains, regardless of penicillin susceptibility or if susceptibility is unknown
  • Preferred regimen: Ciprofloxacin 400 mg IV q8h
  • Note: Duration of treatment is 60 days
  • 3.2 Treatment for anthrax in childern [4]
  • 3.2.1 Treatment of cutaneous anthrax without systemic involvement (for children 1 month of age and older)
  • 3.2.1.1 For all strains, regardless of penicillin susceptibility or if susceptibility is unknown
  • Preferred regimen (1): Ciprofloxacin 30 mg/kg/day PO bid (not to exceed 500 mg/dose) for 7-10 days
  • Preferred regimen (2):
  • If patients body weight is < 45 kg: Doxycycline 4.4 mg/kg/day PO bid (not to exceed 100 mg/dose) for 7-10 days
  • If patients body weight is = 45 kg: Doxycycline 100 mg/dose PO bid for 7-10 days
  • Preferred regimen (3): Clindamycin 30 mg/kg/day PO tid (not to exceed 600 mg/dose) for 7-10 days
  • Preferred regimen (4):
  • If patients body weight is < 50 kg: Levofloxacin 16 mg/kg/day PO bid (not to exceed 250 mg/dose) for 7-10 days
  • If patients body weight is > 50 kg: Levofloxacin 500 mg PO qd for 7-10 days
  • 3.2.1.2 Alternatives for penicillin-susceptible strains
  • Alternative regimen (1):Amoxicillin 75 mg/kg/day PO tid (not to exceed 1 g/dose) for 7-10 days
  • Alternative regimen (2): Penicillin VK 50-75 mg/kg/day PO tid or qid for 7-10 days
  • 3.2.2 Combination therapy for systemic anthrax when meningitis can be ruled out (for children 1 month of age and older)
  • 3.2.2.1 A bactericidal antimicrobial
  • 3.2.2.1.1 For all strains, regardless of penicillin susceptibility or if susceptibility is unknown
  • Preferred regimen (1): Ciprofloxacin 30 mg/kg/day IV divided q8h (not to exceed 400 mg/dose) for 14 days
  • Preferred regimen (2): Meropenem 60 mg/kg/day IV divided q8h (not to exceed 2 g/dose) for 14 days
  • Preferred regimen (3):
  • If patients body weight is < 50 kg: Levofloxacin 20 mg/kg/day IV divided q12h (not to exceed 250 mg/dose) for 14 days
  • If patients body weight is > 50 kg: Levofloxacin 500 mg IV q24h for 14 days
  • Preferred regimen (4): Imipenem/Cilastatin 100 mg/kg/day IV divided q6h (not to exceed 1 g/dose) for 14 days
  • Preferred regimen (5): Vancomycin 60 mg/kg/day IV divided q8h (follow serum concentrations) for 14 days
  • 3.2.2.1.2 Alternatives for penicillin-susceptible strains
  • Alternative regimen (1): Penicillin G 400 000 U/kg/day IV divided q4h (not to exceed 4 MU/dose) for 14 days
  • Alternative regimen (2): Ampicillin 200 mg/kg/day IV divided q6h (not to exceed 3 g/dose) for 14 days
  • 3.2.2.2 A Protein Synthesis Inhibitor
  • Preferred regimen (1): Clindamycin, 40 mg/kg/day IV divided q8h (not to exceed 900 mg/dose) for 14 days
  • Preferred regimen (2): (non-CNS infection dose)
  • If patient is < 12 y old: Linezolid 30 mg/kg/day IV divided q8h for 14 days
  • If patient is = 12 y old: Linezolid 30 mg/kg/day IV divided q12h (not to exceed 600 mg/dose) for 14 days
  • Preferred regimen (3):
  • If patients body weight is < 45 kg: Doxycycline 4.4 mg/kg/day IV loading dose (not to exceed 200 mg) THEN Doxycycline 4.4 mg/kg/day IV divided q12h (not to exceed 100 mg/dose) for 14 days
  • If patients body weight is =45 kg: Doxycycline 200 mg IV loading dose THEN Doxycycline 100 mg IV given q12h for 14 days
  • Preferred regimen (4): Rifampin 20 mg/kg/day IV divided q12h (not to exceed 300 mg/dose) for 14 days
  • Note: Duration of therapy for 14 days or longer until clinical criteria for stability are met. Will require prophylaxis to complete an antimicrobial course of up to 60 days from onset of illness.
  • 3.2.3 Triple therapy for systemic anthrax (anthrax meningitis or disseminated infection and meningitis cannot be ruled out) for Children 1 Month of Age and Older
  • 3.2.3.1 A bactericidal antimicrobial (fluoroquinolone)
  • Preferred regimen (1): Ciprofloxacin 30 mg/kg/day IV divided q8h (not to exceed 400 mg/dose) for 2–3 weeks
  • Preferred regimen (2):
  • If patients body weight is < 50 kg: Levofloxacin 16 mg/kg/day IV divided q12h (not to exceed 250 mg/dose) for 2–3 weeks
  • If patients body weight is > 50 kg: Levofloxacin 500 mg IV q24h for 2–3 weeks
  • Preferred regimen (3):
  • If patients age is 3 months to < 2 years: Moxifloxacin 12 mg/kg/day IV, divided q12h (not to exceed 200 mg/dose) for 2–3 weeks
  • If patients age is 2-5 years: Moxifloxacin 10 mg/kg/day IV divided q1h (not to exceed 200 mg/dose) for 2–3 weeks
  • If patients age is 6–11 years: Moxifloxacin 8 mg/kg/day IV divided q12h (not to exceed 200 mg/dose) for 2–3 weeks
  • If patients age is 12–17 years, = 45 kg body weight: Moxifloxacin 400 mg IV q24h for 2–3 weeks
  • If patients age is 12–17 years, < 45 kg body weight: Moxifloxacin 8 mg/kg/day IV divided q12h (not to exceed 200 mg/dose) for 2–3 weeks
  • 3.2.3.2 A bactericidal antimicrobial (ß-lactam or glycopeptide)
  • 3.2.3.2.1 For all strains, regardless of penicillin susceptibility testing or if susceptibility is unknown:
  • Preferred regimen (1): Meropenem 120 mg/kg/day IV divided q8h (not to exceed 2 g/dose) for 2–3 weeks
  • Preferred regimen (2): Imipenem/Cilastatin 100 mg/kg/day IV divided q6h (not to exceed 1 g/dose) for 2–3 weeks
  • Preferred regimen (3): Doripenem 120 mg/kg/day IV divided q8h (not to exceed 1 g/dose) for 2–3 weeks
  • Preferred regimen (4): Vancomycin 60 mg/kg/day IV divided q8h for 2–3 weeks
  • 3.2.3.2.2 Alternatives for penicillin-susceptible strains
  • Alternative regimen (1): Penicillin G 400 000 U/kg/day IV divided q4h (not to exceed 4 MU/dose) for 2–3 weeks
  • Alternative regimen (2): Ampicillin 400 mg/kg/day IV divided q6h (not to exceed 3 g/dose) for 2–3 weeks
  • 3.2.3.3 A Protein Synthesis Inhibitor
  • Preferred regimen (1):
  • If patients age is < 12 y old: Linezolid 30 mg/kg/day IV divided q8h for 2–3 weeks
  • If patients age is = 12 y old: Linezolid 30 mg/kg/day,IV divided q12h (not to exceed 600 mg/dose) for 2–3 weeks
  • Preferred regimen (2): Clindamycin 40 mg/kg/day IV divided q8h (not to exceed 900 mg/dose) for 2–3 weeks
  • Preferred regimen (3): Rifampin 20 mg/kg/day IV divided q12h (not to exceed 300 mg/dose) for 2–3 weeks
  • Preferred regimen (4): Chloramphenicol 100 mg/kg/day IV divided q6h for 2–3 weeks
Note (1): Duration of therapy for 2–3 weeks or greater, until clinical criteria for stability are met.Will require prophylaxis to complete an antimicrobial course of up to 60 days from onset of illness.
Note (2): A 400-mg dose of Ciprofloxacin IV, provides an equivalent exposure to that of a 500-mg ciprofloxacin oral tablet.
  • 3.2.4 Oral follow-up combination therapy for severe anthrax (for Children 1 Month of Age and Older)
  • 3.2.4.1 A bactericidal antimicrobial
  • 3.2.4.1.1 For all strains, regardless of penicillin susceptibility or if susceptibility is unknown
  • Preferred regimen (1): Ciprofloxacin 30 mg/kg/day PO bid (not to exceed 500 mg/dose)
  • Preferred regimen (2):
  • If patients body weight is < 50 kg: Levofloxacin 16 mg/kg/day PO bid (not to exceed 250 mg/dose)
  • If patients body weight is = 50 kg: Levofloxacin 500 mg PO qd
  • 3.2.4.1.2 Alternatives for penicillin-susceptible strains
  • Alternative regimen (1): Amoxicillin 75 mg/kg/day PO tid (not to exceed 1 g/dose)
  • Alternative regimen (2): Penicillin VK 50–75 mg/kg/day PO tid or qds
  • 3.2.4.2 A protein synthesis inhibitor:
  • Preferred regimen (1):Clindamycin 30 mg/kg/day PO tid (not to exceed 600 mg/dose)
  • Preferred regimen (2):
  • If the patients body weight is < 45 kg: Doxycycline 4.4 mg/kg/day PO bid (not exceed 100 mg/dose)
  • If the patients body weight is = 45 kg: Doxycycline 100 mg PO bid
  • Preferred regimen (3): (non-CNS infection dose):
  • If the patients age is < 12 yrs old: Linezolid 30 mg/kg/day PO tid
  • If the patients age is = 12 yrs old: Linezolid 30 mg/kg/day PO bid (not to exceed 600 mg/dose)
  • Note: Duration of therapy to complete a treatment course of 14 days or greater. May require prophylaxis to complete an antimicrobial course of up to 60 days from onset of illness.
  • 3.2.5 Dosing in preterm and term neonates 32 to 44 Weeks postmenstrual Age (Gestational Age Plus Chronologic Age)
  • 3.2.5.1 Triple therapy for severe anthrax(anthrax meningitis or disseminated infection and meningitis cannot be ruled out)
  • 3.2.5.1.1 Bactericidal antimicrobial (fluoroquinolone) therapy
  • 3.2.5.1.1.1 For 32–34 weeks gestational age
  • For 0–1 week of age
  • Preferred regimen (1): Ciprofloxacin 20 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (2): Moxifloxacin 5 mg/kg/day IV q24h for 2–3 weeks
  • For 1–4 weeks of age
  • Preferred regimen (1): Ciprofloxacin 20 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (2): Moxifloxacin 5 mg/kg/day IV q24h for 2–3 weeks
  • 3.2.5.1.1.2 For 34–37 week gestational age
  • For 0–1 week of age
  • Preferred regimen (1): Ciprofloxacin 20 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (2):Moxifloxacin 5 mg/kg/day IV q24h for 2–3 weeks
  • For 1–4 week of age
  • Preferred regimen (1): Ciprofloxacin 20 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (2): Moxifloxacin 5 mg/kg/day IV q24h for 2–3 weeks
  • 3.2.5.1.1.3 Term newborn infant
  • For 0–1 week of age
  • Preferred regimen (1): Ciprofloxacin 30 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (2): Moxifloxacin 10 mg/kg/day IV q24h for 2–3 weeks
  • For 1–4 weeks of age
  • Preferred regimen (1): Ciprofloxacin 30 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (2): Moxifloxacin 10 mg/kg/day IV q24h for 2–3 weeks
  • 3.2.5.1.2 A bactericidal antimicrobial (ß-lactam)
  • 3.2.5.1.2.1 For all strains, regardless of penicillin susceptibility or if susceptibility is unknown:
  • 3.2.5.1.2.1.1 For 32–34 weeks gestational age
  • For 0–1 week of Age :
  • Preferred regimen (1): Meropenem 60 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (2): Imipenem 50 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (3): Doripenem 20 mg/kg/day IV divided q12h for 2–3 weeks
  • For 1–4 week of Age :
  • Preferred regimen (1): Meropenem 90 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (2): Imipenem 75 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (3): Doripenem 30 mg/kg/day IV divided q8h for 2–3 weeks
  • 3.2.5.1.2.1.2 For 34–37 week gestational age
  • For 0–1 week of Age :
  • Preferred regimen (1): Meropenem 60 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (2): Imipenem 50 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (3): Doripenem 20 mg/kg/day IV divided q12h for 2–3 weeks
  • For 1–4 week of Age :
  • Preferred regimen (1): Meropenem 90 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (2): Imipenem 75 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (3): Doripenem 30 mg/kg/day IV divided q8h for 2–3 weeks
  • 3.2.5.1.2.1.3 Term newborn infant
  • For < 1 week of age
  • Preferred regimen (1): Meropenem 60 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (2): Imipenem 50 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (3): Doripenem 20 mg/kg/day IV divided q12h for 2–3 weeks
  • For 1–4 week of age
  • Preferred regimen (1): Meropenem 90 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (2): Imipenem 75 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (3): Doripenem 30 mg/kg/day IV divided q8h for 2–3 weeks
  • 3.2.5.1.2.2 Alternatives for penicillin-susceptible strains
  • 3.2.5.1.2.2.1 For 32–34 weeks gestational age
  • For 0–1 week of age
  • Alternative regimen (1): Penicillin G 200000 Units/kg/day IV divided q12h for 2–3 weeks
  • Alternative regimen (2): Ampicillin 100 mg/kg/day IV divided q12h for 2–3 weeks
  • For 1–4 week of age :
  • Alternative regimen (1): Penicillin G 300000 Units/kg/day IV divided q12h for 2–3 weeks
  • Alternative regimen (2): Ampicillin 150 mg/kg/day divided IV q12h for 2–3 weeks
  • 3.2.5.1.2.2.2 For 34–37 week gestational age
  • For < 1 week of age
  • Alternative regimen (1): Penicillin G 300000 Units/kg/day IV divided q12h for 2–3 weeks
  • Alternative regimen (2): Ampicillin 150 mg/kg/day IV divided q12h for 2–3 weeks
  • For 1–4 week of age
  • Alternative regimen (1): Penicillin G 400000 Units/kg/day IV divided q12h for 2–3 weeks
  • Alternative regimen (2): Ampicillin 200 mg/kg/day IV divided q12h for 2–3 weeks
  • 3.2.5.1.2.2.3 Term newborn infant
  • For 0–1 week of age
  • Alternative regimen (1): Penicillin G 300000 Units/kg/day IV divided q12h for 2–3 weeks
  • Alternative regimen (2): Ampicillin 150 mg/kg/day IV divided q12h for 2–3 weeks
  • For 1–4 week of age
  • Alternative regimen (1): Penicillin G 400000 Units/kg/day IV divided q12h for 2–3 weeks
  • Alternative regimen (2): Ampicillin 200 mg/kg/day IV divided q12h for 2–3 weeks
  • 3.2.5.1.3 A protein synthesis inhibitor
  • 3.2.5.1.3.1 For 32–34 weeks gestational age
  • For < 1 week of age
  • Preferred regimen (1): Linezolid 20 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (2): Clindamycin 10 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (3): Rifampin 10 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (4): Chloramphenicol 25 mg/kg/day IV q24h for 2–3 weeks
  • For 1–4 week of age
  • Preferred regimen (1): Linezolid 30 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (2): Clindamycin 15 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (3): Rifampin 10 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (4): Chloramphenicol 50 mg/kg/day IV q12h for 2–3 weeks
  • 3.2.5.1.3.2 For 34–37 week gestational age
  • For < 1 week of age
  • Preferred regimen (1): Linezolid 30 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (2): Clindamycin 15 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (3): Rifampin 10 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (4): Chloramphenicol 25 mg/kg/day IV q24h for 2–3 weeks
  • For 1–4 week of age
  • Preferred regimen (1): Linezolid 30 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (2): Clindamycin 20 mg/kg/day IV divided q6h for 2–3 weeks
  • Preferred regimen (3): Rifampin 10 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (4): Chloramphenicol 50 mg/kg/day IV q12h for 2–3 weeks
  • 3.2.5.1.3.3 Term newborn infant
  • For < 1 week of age
  • Preferred regimen (1): Linezolid 30 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (2): Clindamycin 15 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (3): Rifampin 10 mg/kg/day IV divided q12h for 2–3 week
  • Preferred regimen (4): Chloramphenicol 25 mg/kg/day IV q24h for 2–3 weeks
  • For 1–4 week of age
  • Preferred regimen (1): Linezolid 30 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (2): Clindamycin 20 mg/kg/day IV divided q6h for 2–3 weeks
  • Preferred regimen (3): Rifampin 20 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (4): Chloramphenicol 50 mg/kg/day IV q12h for 2–3 weeks
  • Note :Duration of therapy for 2–3 weeks, until clinical criteria for stability are met. Will require prophylaxis to complete an antibiotic course of upto 60 days from onset of illness.
  • 3.2.5.2 Therapy for severe anthrax when meningitis can be ruled out
  • 3.2.5.2.1 A bactericidal antimicrobial
  • 3.2.5.2.1.1 For all strains, regardless of penicillin susceptibility or if susceptibility is unknown
  • 3.2.5.2.1.1.1 For 32–34 weeks gestational age
  • For < 1 week of age
  • Preferred regimen (1): Ciprofloxacin 20 mg/kg/day IV divided q12h for 2-3 weeks
  • Preferred regimen (2): Meropenem 40 mg/kg/day IV divided q8h for 2-3 weeks
  • Preferred regimen (3): Imipenem 40 mg/kg/day IV divided q12h for 2-3 weeks
  • For 1–4 week of age
  • Preferred regimen (1): Ciprofloxacin 20 mg/kg/day IV divided q12h for 2-3 weeks
  • Preferred regimen (2): Meropenem 60 mg/kg/day IV divided q8h for 2-3 weeks
  • Preferred regimen (3): Imipenem 50 mg/kg/day IV divided q12h for 2-3 weeks
  • 3.2.5.2.1.1.2 For 34–37 week gestational age
  • For < 1 week of age
  • Preferred regimen (1): Ciprofloxacin 20 mg/kg/day IV divided q12h for 2-3 weeks
  • Preferred regimen (2): Meropenem 60 mg/kg/day IV divided q8h for 2-3 weeks
  • Preferred regimen (3): Imipenem 50 mg/kg/day IV divided q12h for 2-3 weeks
  • For 1–4 week of age
  • Preferred regimen (1): Ciprofloxacin 20 mg/kg/day IV divided q12h for 2-3 weeks
  • Preferred regimen (2): Meropenem 60 mg/kg/day IV divided q8h for 2-3 weeks
  • Preferred regimen (3): Imipenem 75 mg/kg/day IV divided q8h for 2-3 weeks
  • 3.2.5.2.1.1.3 Term Newborn Infant
  • For < 1 week of age
  • Preferred regimen (1): Ciprofloxacin 30 mg/kg/day IV divided q12h for 2-3 weeks
  • Preferred regimen (2): Meropenem 60 mg/kg/day IV divided q8h for 2-3 weeks
  • Preferred regimen (3): Imipenem 50 mg/kg/day IV divided q12h for 2-3 weeks
  • For 1–4 week of age
  • Preferred regimen (1): Ciprofloxacin 30 mg/kg/day IV divided q12h for 2-3 weeks
  • Preferred regimen (2): Meropenem 60 mg/kg/day IV divided q8h for 2-3 weeks
  • Preferred regimen (3): Imipenem 75 mg/kg/day IV divided q8h for 2-3 weeks
  • Vancomycin IV (dosing based on serum creatinine for infants of 32 weeks gestational age). Follow vancomycin serum concentrations to modify dose.
  • If Serum creatinine < 0.7 then Vancomycin 15 mg/kg/dose IV q12h for 2-3 weeks
  • If Serum creatinine 0.7 -0.9 then Vancomycin 20 mg/kg/dose IV q24h for 2-3 weeks
  • If Serum creatinine 1–1.2 then Vancomycin 15 mg/kg/dose IV q24h for 2-3 weeks
  • If Serum creatinine 1.3–1.6 then Vancomycin 10 mg/kg/dose IV q24h for 2-3 weeks
  • If Serum creatinine > 1.6 then Vancomycin mg/kg/dose IV q48h for 2-3 weeks
  • Note: Begin treatment with a 20 mg/kg loading dose OR
  • 3.2.5.2.1.2 Alternatives for penicillin-susceptible strains
  • 3.2.5.2.1.2.1 For 32–34 weeks gestational age
  • For < 1 week of age
  • Alternative regimen (1): Penicillin G 200000 U/kg/day IV divided q12h for 2-3 weeks
  • Alternative regimen (2): Ampicillin 100 mg/kg/day IV divided q12h for 2-3 weeks
  • For 1–4 week of age
  • Alternative regimen (1): Penicillin G 300000 U/kg/day IV divided q8h for 2-3 weeks
  • Alternative regimen (2): Ampicillin 150 mg/kg/day IV divided q8h for 2-3 weeks
  • 3.2.5.2.1.2.2 For 34–37 week gestational age
  • For < 1 week of age
  • Alternative regimen (1): Penicillin G 300000 U/kg/day IV divided q8h for 2-3 weeks
  • Alternative regimen (2): Ampicillin 150 mg/kg/day IV divided q8h for 2-3 weeks
  • For 1–4 week of age
  • Alternative regimen (1): Penicillin G 400000 U/kg/day IV divided q6h for 2-3 weeks
  • Alternative regimen (2): Ampicillin 200 mg/kg/day IV divided q6h for 2-3 weeks
  • 3.2.5.2.1.2.3 Term newborn infant
  • For < 1 week of age
  • Alternative regimen (1): Penicillin G 300000 U/kg/day IV divided q8h for 2-3 weeks
  • Alternative regimen (2): Ampicillin 150 mg/kg/day IV divided q8h for 2-3 weeks
  • For 1–4 week of age
  • Alternative regimen (1): Penicillin G 400000 U/kg/day IV divided q6h for 2-3 weeks
  • Alternative regimen (2):Ampicillin 200 mg/kg/day IV divided q6h for 2-3 weeks
  • 3.2.5.2.2 A protein synthesis inhibitor
  • 3.2.5.2.2.1 For 32–34 weeks gestational age
  • For < 1 week of age
  • Preferred regimen (1): Clindamycin 10 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (2): Linezolid 20 mg/kg/day IV divided q12h for 2–3 weeks
  • Preferred regimen (3): Rifampin 10 mg/kg/day IV q24h for 2–3 weeks
  • For 1–4 week of age
  • Preferred regimen (1): Clindamycin 15 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (2): Linezolid 30 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (3): Rifampin 10 mg/kg/day IV q24h for 2–3 weeks
  • 3.2.5.2.2.2 For 34–37 week gestational age
  • For < 1 week of age
  • Preferred regimen (1): Clindamycin 15 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (2): Linezolid 30 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (3): Rifampin 10 mg/kg/day IV q24h for 2–3 weeks
  • For 1–4 week of age
  • Preferred regimen (1): Clindamycin 20 mg/kg/day IV divided q6h for 2–3 weeks
  • Preferred regimen (2): Linezolid 30 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (3): Rifampin 10 mg/kg/day IV q24h for 2–3 weeks
  • 3.2.5.2.2.3 Term newborn infant
  • For 0–1 week of age :
  • Preferred regimen (1): Clindamycin 15 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (2): Linezolid 30 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (3): Doxycycline 4.4 mg/kg/day IV divided q12h, (loading dose 4.4 mg/kg) for 2–3 weeks
  • Preferred regimen (4): Rifampin 10 mg/kg/day IV q24h for 2–3 weeks
  • For 1–4 week of age :
  • Preferred regimen (1): Clindamycin 20 mg/kg/day IV divided q6h for 2–3 weeks
  • Preferred regimen (2): Linezolid 30 mg/kg/day IV divided q8h for 2–3 weeks
  • Preferred regimen (3): Doxycycline 4.4 mg/kg/day IV divided q12h, (loading dose 4.4 mg/kg) for 2–3 weeks
  • Preferred regimen (4): Rifampin 10 mg/kg/day IV q24h for 2–3 weeks
  • Note: Duration of therapy for 2–3 weeks, until clinical criteria for stability are met (see text). Will require prophylaxis to complete an antimicrobial course of upto 60 days from onset of illness
  • 3.2.5.3 Oral follow-up combination therapy for severe anthrax
  • 3.2.5.3.1 A bactericidal antimicrobial
  • 3.2.5.3.1.1 For all strains, regardless of penicillin susceptibility or if susceptibility is unknown
  • 3.2.5.3.1.1.1 For 32–34 weeks gestational age
  • For < 1 week of age
  • 3.2.5.3.1.1.2 For 34–37 week gestational age
  • For < 1 week of age
  • For 1–4 week of age
  • 3.2.5.3.1.1.3 Term newborn infant
  • For < 1 week of age
  • For 1–4 week of age
  • 3.2.5.3.1.2 Alternatives for penicillin-susceptible strains
  • 3.2.5.3.1.2.1 For 32–34 weeks gestational age
  • For < 1 week of age
  • Alternative regimen (1): Amoxicillin 50 mg/kg/day PO bid
  • Alternative regimen (2): Penicillin VK 50 mg/kg/day PO bid
  • For 1–4 week of age
  • Alternative regimen (1): Amoxicillin 75 mg/kg/day PO bid
  • Alternative regimen (2): Penicillin VK 75 mg/kg/day PO bid
  • 3.2.5.3.1.2.2 For 34–37 week gestational age
  • For < 1 week of age
  • Alternative regimen (1): Amoxicillin 50 mg/kg/day PO bid
  • Alternative regimen (2): Penicillin VK 50 mg/kg/day PO bid
  • For 1–4 week of age
  • Alternative regimen (1): Amoxicillin 75 mg/kg/day PO bid
  • Alternative regimen (2): Penicillin VK 75 mg/kg/day PO tid
  • 3.2.5.3.1.2.3 Term newborn infant
  • For < 1 week of age
  • Alternative regimen (1): Amoxicillin 75 mg/kg/day PO tid
  • Alternative regimen (2): Penicillin VK 75 mg/kg/day PO tid
  • For 1–4 week of age
  • Alternative regimen (1): Amoxicillin 75 mg/kg/day PO tid
  • Alternative regimen (2): Penicillin VK 75 mg/kg/day PO tid or qid
  • 3.2.5.3.2 A protein synthesis inhibitor
  • 3.2.5.3.2.1 For 32–34 weeks gestational age
  • For < 1 week of age
  • Preferred regimen (1): Clindamycin 10 mg/kg/day PO bid
  • Preferred regimen (2): Linezolid 20 mg/kg/day PO bid
  • For 1–4 week of age
  • Preferred regimen (1): Clindamycin 15 mg/kg/day PO bid
  • Preferred regimen (2): Linezolid 30 mg/kg/day PO bid
  • 3.2.5.3.2.2 For 34–37 week gestational age
  • For < 1 week of age
  • Preferred regimen (1): Clindamycin 15 mg/kg/day PO tid
  • Preferred regimen (2): Linezolid 30 mg/kg/day PO tid
  • For 1–4 week of age
  • Preferred regimen (1): Clindamycin 20 mg/kg/day PO qid
  • Preferred regimen (2): Linezolid 30 mg/kg/day PO tid
  • 3.2.5.3.2.3 Term newborn infant
  • For < 1 week of age
  • Preferred regimen (1): Clindamycin 15 mg/kg/day PO tid
  • Preferred regimen (2): Doxycycline 4.4 mg/kg/day PO bid (loading dose 4.4 mg/kg)
  • Preferred regimen (3): Linezolid 30 mg/kg/day PO tid
  • For 1–4 week of age
  • Preferred regimen (1): Clindamycin 20 mg/kg/day PO qid
  • Preferred regimen (2): Doxycycline 4.4 mg/kg/day PO bid (loading dose 4.4 mg/kg)
  • Preferred regimen (3): Linezolid 30 mg/kg/day PO tid
  • Note: Duration of therapy to complete a treatment course of 10–14 days or greater. May require prophylaxis to complete an antimicrobial course of upto 60 days from onset of illness.
  • 3.2.5.4 Treatment of cutaneous anthrax without systemic involvement
  • 3.2.5.4.1 For all strains, regardless of penicillin susceptibility or if susceptibility is unknown
  • 3.2.5.4.1.1 For 32–34 weeks gestational age
  • For < 1 week of age
  • For 1–4 week of age
  • 3.2.5.4.1.2 For 34–37 week gestational age
  • For < 1 week of age
  • For 1–4 week of age
  • 3.2.5.4.1.3 'Term newborn infant
  • For < 1 week of age
  • Preferred regimen (1): Ciprofloxacin 30 mg/kg/day PO bid
  • Preferred regimen (2): Doxycycline 4.4 mg/kg/day PO bid (Loading dose 4.4 mg/kg)
  • Preferred regimen (3): Clindamycin 15 mg/kg/day PO tid
  • For 1–4 week of age
  • Preferred regimen (1): Ciprofloxacin 30 mg/kg/day PO bid
  • Preferred regimen (2): Doxycycline 4.4 mg/kg/day PO bid (Loading dose 4.4 mg/kg)
  • Preferred regimen (3): Clindamycin 20 mg/kg/day PO qid
  • 3.2.5.4.2 Alternatives for penicillin-susceptible strains
  • 3.2.5.4.2.1 For 32–34 weeks gestational age
  • For < 1 week of age
  • Alternative regimen (1): Amoxicillin 50 mg/kg/day PO bid
  • Alternative regimen (2): Penicillin Vk 50 mg/kg/day PO bid
  • For 1–4 week of age
  • Alternative regimen (1): Amoxicillin 75 mg/kg/day PO tid
  • Alternative regimen (2): Penicillin Vk 75 mg/kg/day PO tid
  • 3.2.5.4.2.2 For 34–37 week gestational age
  • For < 1 week of age
  • Alternative regimen (1): Amoxicillin 50 mg/kg/day PO bid
  • Alternative regimen (2): Penicillin Vk 50 mg/kg/day PO bid
  • For 1–4 week of age
  • Alternative regimen (1): Amoxicillin 75 mg/kg/day PO bid
  • Alternative regimen (2): Penicillin Vk 75 mg/kg/day PO bid
  • 3.2.5.4.2.3 Term newborn infant
  • For < 1 week of age
  • Alternative regimen (1): Amoxicillin 75 mg/kg/day PO tid
  • Alternative regimen (2): Penicillin Vk 75 mg/kg/day PO tid
  • For 1–4 week of age
  • Alternative regimen (1): Amoxicillin 75 mg/kg/day PO tid
  • Alternative regimen (2): Penicillin Vk 75 mg/kg/day PO tid or qid
  • Note : Duration of therapy for naturally acquired infection is 7–10 days and for a biological weapon–related event,may require additional prophylaxis for inhaled spores to complete an antimicrobial course of up to 60 days from onset of illness.

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.[1]

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.[1]

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.[1]

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.[5]

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.[6]

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.[7]

In inhalation anthrax, although respiratory failure is more consistent with reaccumulating pleural effusions than with adult respiratory distress syndrome, standard mechanical ventilator principles apply.[8] 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.[9]

Adjunctive corticosteroids should be considered in patients who had a history of use of:[10][11]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "Centers for Disease Control and Prevention Expert Panel Meetings on Prevention and Treatment of Anthrax in Adults".
  2. ↑ 2.0 2.1 Hendricks KA, Wright ME, Shadomy SV, Bradley JS, Morrow MG, Pavia AT; et al. (2014). "Centers for disease control and prevention expert panel meetings on prevention and treatment of anthrax in adults". Emerg Infect Dis. 20 (2). doi:10.3201/eid2002.130687. PMC 3901462. PMID 24447897.
  3. ↑ Meaney-Delman D, Zotti ME, Creanga AA, Misegades LK, Wako E, Treadwell TA; et al. (2014). "Special considerations for prophylaxis for and treatment of anthrax in pregnant and postpartum women". Emerg Infect Dis. 20 (2). doi:10.3201/eid2002.130611. PMC 3901460. PMID 24457117.
  4. ↑ Bradley JS, Peacock G, Krug SE, Bower WA, Cohn AC, Meaney-Delman D; et al. (2014). "Pediatric anthrax clinical management". Pediatrics. 133 (5): e1411–36. doi:10.1542/peds.2014-0563. PMID 24777226.
  5. ↑ Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM; et al. (2013). "Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012". Intensive Care Med. 39 (2): 165–228. doi:10.1007/s00134-012-2769-8. PMID 23361625.
  6. ↑ Jernigan JA, Stephens DS, Ashford DA, Omenaca C, Topiel MS, Galbraith M; et al. (2001). "Bioterrorism-related inhalational anthrax: the first 10 cases reported in the United States". Emerg Infect Dis. 7 (6): 933–44. doi:10.3201/eid0706.010604. PMC 2631903. PMID 11747719.
  7. ↑ Peck RN, Fitzgerald DW (2007). "Cutaneous anthrax in the Artibonite Valley of Haiti: 1992-2002". Am J Trop Med Hyg. 77 (5): 806–11. PMID 17984330.
  8. ↑ Artigas A, Bernard GR, Carlet J, Dreyfuss D, Gattinoni L, Hudson L; et al. (1998). "The American-European Consensus Conference on ARDS, part 2: Ventilatory, pharmacologic, supportive therapy, study design strategies, and issues related to recovery and remodeling. Acute respiratory distress syndrome". Am J Respir Crit Care Med. 157 (4 Pt 1): 1332–47. doi:10.1164/ajrccm.157.4.ats2-98. PMID 9563759.
  9. ↑ de Gans J, van de Beek D, European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators (2002). "Dexamethasone in adults with bacterial meningitis". N Engl J Med. 347 (20): 1549–56. doi:10.1056/NEJMoa021334. PMID 12432041. Review in: ACP J Club. 2003 May-Jun;138(3):60
  10. ↑ Sejvar JJ, Tenover FC, Stephens DS (2005). "Management of anthrax meningitis". Lancet Infect Dis. 5 (5): 287–95. doi:10.1016/S1473-3099(05)70113-4. PMID 15854884.
  11. ↑ Annane D, Bellissant E, Bollaert PE, Briegel J, Confalonieri M, De Gaudio R; et al. (2009). "Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review". JAMA. 301 (22): 2362–75. doi:10.1001/jama.2009.815. PMID 19509383.


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