Yersinia pestis infection medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editors-In-Chief: Esther Lee, M.A.; João André Alves Silva, M.D. [2]

Overview

According to treatment experts, a patient diagnosed with suspected plague should be hospitalized and medically isolated. Laboratory tests should be done, including blood cultures for plague bacteria and microscopic examination of lymph gland, blood, and sputum samples. Antibiotic treatment should begin as soon as possible after laboratory specimens are taken. Effective antibiotics are streptomycin, gentamicin (used when streptomycin is not available), tetracyclines and chloramphenicol. (used for critically ill patients, or rarely for suspected neuro-involvement)

Medical Therapy

When a diagnosis of human plague is suspected on clinical and epidemiological grounds, appropriate specimens for diagnosis should be obtained immediately and the patient should be started on specific antimicrobial therapy without waiting for a definitive answer from the laboratory.

Suspect plague patients with evidence of pneumonia should be placed in isolation, and managed under respiratory droplet precautions.

Specific Therapy

Aminoglycosides

Streptomycin is the most effective antibiotic against Yersinia pestis and the drug of choice for treatment of plague, particularly the pneumonic form. Therapeutic effect may be expected with 30 mg/kg/day (up to a total of 2 g/day) in divided doses given intramuscularly, to be continued for a full course of 10 days of therapy or until 3 days after the temperature has returned to normal.

Gentamicin has been found to be effective in animal studies, and is used to treat human plague patients.

Chloramphenicol

Chloramphenicol is a suitable alternative to aminoglycosides in the treatment of bubonic or septicaemic plague and is the drug of choice for treatment of patients with Yersinia pestis invasion of tissue spaces into which other drugs pass poorly or not at all (such as plague meningitis, pleuritis, or endophthalmitis. Dosage should be 50 mg/kg/day administered in divided doses either parenterally or, if tolerated, orally for 10 days. Chloramphenicol may be used adjunctively with aminoglycosides.

Tetracyclines

This group of antibiotics is bacteriostatic but effective in the primary treatment of patients with uncomplicated plague. An oral loading dose of 15 mg/kg tetracycline (not to exceed 1 g total) should be followed by 25-50 mg/kg/day (up to a total of 2 g/day) for 10 days. Tetracyclines may also be used adjunctively with other antibiotics.

Sulfonamides

Sulfonamides have been used extensively in plague treatment and prevention: however, some studies have shown higher mortality, increased complications, and longer duration of fever as compared with the use of streptomycin, chloramphenicol or tetracycline antibiotics. Sulfadiazine is given as a loading dose of 2-4 g followed by a dose of 1 g every 4-6 hours for a period of 10 days. In children, the oral loading dose is 75 mg/kg, followed by 150 mg/kg/day orally in six divided doses. The combination drug trimethoprim-sulfamethoxazole has been used both in treatment and prevention of plague.

Fluoroquinolones

Fluoroquinolones, such as ciprofloxacin, have been shown to have good effect against Y. pestis in both in vitro and animal studies. Ciprofloxacin is bacteriocidal and has broad spectrum activity against most Gram-negative aerobic bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa, as well as against many Gram-positive bacteria. Although it has been used successfully to treat humans with Francisella tularensis infection, no studies have been published on its use in treating human plague.

Other classes of antibiotics

Other cases of antibiotics, such as penicillins, cephalosporins, and macrolides have been shown to be ineffective or of variable effect in treatment of plague and they should not be used for this purpose.

Treatment Regimen

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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

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Supportive therapy

The clinician must prepare for intense supportive management of plague complications, utilizing the latest developments for dealing with Gram-negative sepsis. Aggressive monitoring and management of possible septic shock, multiple organ failure, adult respiratory distress syndrome (ARDS) and disseminated intravascular coagulopathy should be instituted.

Treatment of plague during pregnancy and in children

With correct and early therapy, complications of plague in pregnancy can be prevented.

The choice of antibiotics during pregnancy is confounded by the potential adverse effects of three of the most effective drugs.

• Streptomycin may be ototoxic and nephrotoxic to the fetus .
• Tetracycline has an adverse effect on developing teeth and bones of the fetus.
• Chloramphenicol carries a low risk of "gray baby" syndrome or bone marrow suppression.
• An aminoglycoside judiciously administered is effective and safe for both mother and fetus, and in children. Because of its safety, intravenous or intramuscular administration, and ability to have blood concentrations monitored, gentamicin is the preferred antibiotic for treating plague in pregnancy.