Guidelines Summary
The Centers for Disease Control and Prevention (CDC) published clinical practice guidelines on the treatment of plague in July 2021 in the Morbidity and Mortality Weekly Report. [35, 36] These are some of the highlights of the guidelines.
Plague is treatable with antimicrobials and supportive care. Early recognition and administration of effective antimicrobials are key to saving lives. Persons exposed to Yersinia pestis can avoid illness if given effective antimicrobial prophylaxis.
Aminoglycosides and fluoroquinolones are the mainstays of treatment for plague. Tetracyclines, chloramphenicol, and trimethoprim-sulfamethoxazole might also be suitable treatment, depending on the type of disease and the age and pregnancy status of the patient. Dual therapy with distinct classes of antimicrobials is recommended in the case of a bioterrorist attack with Y. pestis engineered for resistance to treatment.
FDA-approved antimicrobials for plague include streptomycin, ciprofloxacin, levofloxacin, moxifloxacin, and doxycycline. Although not approved for plague, gentamicin, chloramphenicol, and trimethoprim-sulfamethoxazole are considered effective.
Patients initially treated with parenteral antimicrobials can be transitioned to oral administration when they are improving clinically.
All of the recommended oral antimicrobials except for ciprofloxacin recommended by the CDC can be given by enteral routes such as nasogastric tube and gastric tube. All clinical forms of plague require 10-14 days of treatment in total. The duration of treatment can be extended for those with continuing fever or other worrisome signs or symptoms.
Treatment recommendations for those who are elderly or immunocompromised ar the same as those for adults; however, these patients may experience decreased glomerular filtration rate or polypharmacy, and clinicians should adjust treatment as necessary.
Pneumonic plague or septicemic plague in adults aged ≥ 18 years
For naturally occurring pneumonic plague, the CDC recommends levofloxacin or moxifloxacin. Because plague is life threatening, doxycycline is not considered contraindicated in children and has not been shown to cause tooth staining, unlike other tetracyclines, which should be avoided if possible.
Pneumonic and septicemic plague are the most severe and quickly progressive forms of plague. Subclinical pneumonic infection has been seen in patients with septicemic plague.
Ciprofloxacin is now a first-line agent instead of an alternative agent. Levofloxacin and moxifloxacin (recommended for naturally-occurring plague) have been added as first-line or alternative agents for treatment and prophylaxis.
Institute dual therapy with 2 distinct antimicrobial classes for patients with severe septicemic or pneumonic disease, and narrow therapy to a single antimicrobial after the patient improves clinically.
Please see the Pediatric Plague article for clinical guidelines for infants, breastfeeding infants and mothers, and children aged 17 years and younger.
First-line
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Ciprofloxacin (Fluoroquinolone) - 400 mg every 8 hrs IV or 750 mg every 12 hrs PO
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Levofloxacin (Fluoroquinolone) - 750 mg every 24 hrs IV or PO
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Moxifloxacin (Fluoroquinolone) - 400 mg every 24 hrs IV or PO
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Gentamicin (Aminoglycoside) - 5 mg/kg every 24 hrs IV or IM
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Streptomycin (Aminoglycoside) - 1 g every 12 hrs IV or IM
Alternatives
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Doxycycline (Tetracycline) - 200 mg loading dose , then 100 mg every 12 hrs IV or PO
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Chloramphenicol (Amphenicol) - 12.5–25 mg/kg every 6 hrs IV (maximum 1 g/dose)
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Ofloxacin (Fluoroquinolone) - 400 mg every 12 hrs PO
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Gemifloxacin (Fluoroquinolone) - 320 mg every 24 hrs PO
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Amikacin (Aminoglycoside) - 15–20 mg/kg every 24 hrs IV or IM
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Tobramycin (Aminoglycoside) - 5–7 mg/kg every 24 hrs IV or IM
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Plazomicin (Aminoglycoside) - 15 mg/kg every 24 hrs IV
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Trimethoprim-sulfamethoxazole (Sulfonamide) - 5 mg/kg (trimethoprim component) every 8 hrs IV or PO
Gentamicin, chloramphenicol, and trimethoprim-sulfamethoxazole are not approved by the FDA but are considered to be effective.
Because of the potential for adverse effects including nephrotoxicity and ototoxicity, when treating with aminoglycosides, check drug concentrations as indicated based on dosing strategy (eg, extended interval or traditional dosing) and adjust dose and dosing interval as appropriate. Aminoglycosides lack oral formulations; therefore other medications may be preferable.
Please see the Pediatric Plague article for pediatric guidelines.
Pharyngeal plague or bubonic plague
Pharyngeal and bubonic plague are milder forms of illness and often occur along with focal lymphadenopathy.
Gentamicin or streptomycin are first-line agents for bubonic plague; they must be given parenterally and are associated with nephrotoxicity and ototoxicity. Alternative first-line agents include high-dose ciprofloxacin, levofloxacin, moxifloxacin, and doxycycline, administered intravenously or orally. Consider dual therapy and drainage for patients with large buboes. Treatment is for 10-14 days.
It may be necessary to perform surgical incision and drainage if the bubo becomes suppurative.
Please see Pediatric Plague article for pediatric guidelines.
First-line
Ciprofloxacin (Fluoroquinolone) - 400 mg every 8 hrs IV or 750 mg every 12 hrs PO
Levofloxacin (Fluoroquinolone) 750 mg every 24 hrs IV or PO
Moxifloxacin (Fluoroquinolone) - 400 mg every 24 hrs IV or PO
Doxycycline (Tetracycline) - 200 mg loading dose , then 100 mg every 12 hrs IV or PO
Gentamicin (Aminoglycoside) - 5 mg/kg every 24 hrs IV or IM
Streptomycin (Aminoglycoside) - 1 gm every 12 hrs IV or IM
Alternatives
Chloramphenicol (Amphenicol) 12.5-25 mg/kg every 6 hrs IV (maximum 1 g/dose)
Ofloxacin (Fluoroquinolone) - 400 mg every 12 hrs PO
Gemifloxacin (Fluoroquinolone) - 320 mg every 24 hrs PO
Amikacin (Aminoglycoside) - 15-20 mg/kg every 24 hrs IV or IM
Tobramycin (Aminoglycoside) - 5-7 mg/kg every 24 hrs IV or IM
Plazomicin (Aminoglycoside) - 15 mg/kg every 24 hrs IV
Tetracycline (Tetracycline) - 500 mg every 6 hrs PO
Omadacycline (Tetracycline) - 200 mg loading dose on day 1, then 100 mg every 24 hrs IV or 450 mg loading dose every 24 hrs on days 1 and 2, then 300 mg every 24 hrs PO
Minocycline (Tetracycline) - 200 mg loading dose , then 100 mg every 12 hrs IV or PO
Eravacycline (Tetracycline) - 1 mg/kg every 12 hrs IV
Trimethoprim-sulfamethoxazole - 5 mg/kg (trimethoprim component) every 8 hrs IV or PO
Plague meningitis
Moxifloxacin and levofloxacin have robust activity against Yersinia pestis and excellent CNS penetration; therefore, they should be effective for plague meningitis. Quinolones, however, can cause seizures. When possible, dual therapy with chloramphenicol and moxifloxacin or levofloxacin should be used as initial treatment in patients with plague and signs of meningitis, such as nuchal rigidity. If chloramphenicol is not available, a non-fluoroquinolone first-line antimicrobial or an alternative antimicrobial for septicemic plague can be used.
Because plague has a high case-fatality rate, the CDC recommends antimicrobial treatment and prophylaxis for affected pregnant women even if antimicrobial treatment carries risk to the fetus. Fetal safety concerns should not prevent access to rapid treatment or prophylaxis for pregnant women during a plague outbreak. Antimicrobial safety profiles can help the clinician select the antimicrobial treatment that maximizes benefit to the pregnant woman while minimizing potential risk. In pregnant women with secondary plague meningitis, chloramphenicol should be added to the antimicrobial treatment regimen for all trimesters.
Gentamicin is preferred over streptomycin because streptomycin has been shown to have the greater risk of irreversible fetal ototoxicity. Both ciprofloxacin and levofloxacin are preferred over moxifloxacin because of the lack of safety and efficacy data for moxifloxacin in pregnant women.
Please see the Pediatric Plague article for pediatric guidelines.
First-line
Chloramphenicol (Amphenicol) - 25 mg/kg every 6 hrs IV (maximum 1 g/dose)
Levofloxacin (Fluoroquinolone) - 750 mg every 24 hrs IV or PO
Moxifloxacin (Fluoroquinolone) - 400 mg every 24 hrs IV or PO
Treatment of pregnant women with pneumonic, septicemic, bubonic, or pharyngeal plague
Because plague has a high case-fatality rate, the CDC recommends antimicrobial treatment and prophylaxis for affected pregnant women even if antimicrobial treatment carries risk to the fetus. Fetal safety concerns should not prevent access to rapid treatment or prophylaxis for pregnant women during a plague outbreak.
Antimicrobial safety profiles can help the clinician select the antimicrobial treatment that maximizes benefit to the pregnant woman while minimizing potential risk. In pregnant women with secondary plague meningitis, chloramphenicol should be added to the antimicrobial treatment regimen for all trimesters.
First-line: Gentamicin plus either ciprofloxacin or levofloxacin
Ciprofloxacin (Fluoroquinolone) - 400 mg every 8 hrs IV or 500 mg every 8 hrs PO
Levofloxacin (Fluoroquinolone) - 750 mg every 24 hrs IV or PO
Gentamicin (Aminoglycoside) - 5 mg/kg every 24 hrs IV or IM
Alternatives
Moxifloxacin (Fluoroquinolone) - 400 mg every 24 hrs IV or PO
Ofloxacin (Fluoroquinolone) - 400 mg every 12 hrs PO
Streptomycin (Aminoglycoside) - 1 g every 12 hrs IV or IM
Amikacin (Aminoglycoside) - 15-20 mg/kg every 24 hrs IV or IM
Tobramycin (Aminoglycoside) - 5-7 mg/kg every 24 hrs IV or IM
Plazomicin (Aminoglycoside) - 15 mg/kg every 24 hrs IV
Doxycycline (Tetracycline) - 200 mg loading dose IV, then 100 mg every 12 hrs IV or PO or 200 mg every 24 hrs IV
Chloramphenicol (Amphenicol) - 12.5- 25 mg/kg every 6 hrs IV (maximum 1 g/dose)
Trimethoprim-sulfamethoxazole (Sulfonamide) - 5 mg/kg (trimethoprim component) every 8 hrs IV or PO
Personal protective equipment
Caretakers should wear a mask in addition to taking standard precautions, as well as wear eye protection and a face shield if splashing is likely.
Pre-and post-exposure prophylaxis
The CDC’s clinical guidelines include information on pre- and post-exposure prophylaxis for adults (including pregnant patients) and children.
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1998 world distribution of plague. Image courtesy of the Centers for Disease Control and Prevention (CDC), Atlanta, GA.
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The prairie dog is a burrowing rodent of the genus Cynomys. It can harbor fleas infected with Yersinia pestis, the plague bacillus. Image courtesy of the Centers for Disease Control and Prevention (CDC), Atlanta, Ga.
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Oriental rat flea (Xenopsylla cheopis), the primary vector of plague, engorged with blood. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.
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Ulcerated flea bite caused by Yersinia pestis bacteria. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.
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Swollen lymph glands, termed buboes, are a hallmark finding in bubonic plague. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.
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Wayson stain showing the characteristic "safety pin" appearance of Yersinia pestis, the plague bacillus. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.
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Fluorescence antibody positivity is observed as bright, intense green staining around the cell wall of Yersinia pestis, the plague bacillus. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.
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Histopathology of lung in fatal human plague–fibrinopurulent pneumonia. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.
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Histopathology of lung showing pneumonia with many Yersinia pestis organisms (the plague bacillus) on a Giemsa stain. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.
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Histopathology of spleen in fatal human plague. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.
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Histopathology of lymph node showing medullary necrosis and Yersinia pestis, the plague bacillus. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.
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Histopathology of liver in fatal human plague. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.
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Focal hemorrhages in islet of Langerhans in fatal human plague. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.
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Pictured is a flea with a blocked proventriculus, which is equivalent to the gastroesophageal region in a human. In nature, this flea would develop a ravenous hunger because of its inability to digest the fibrinoid mass of blood and bacteria. If this flea were to bite a mammal, the proventriculus would be cleared, and thousands of bacteria would be regurgitated into the bite wound. Courtesy of the United States Army Environmental Hygiene Agency.
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After the femoral lymph nodes, the next most commonly involved regions in plague are the inguinal, axillary, and cervical areas. This child has an erythematous, eroded, crusting, necrotic ulcer at the presumed primary inoculation site in the left upper quadrant. This type of lesion is uncommon in patients with plague. The location of the bubo is primarily a function of the region of the body in which an infected flea inoculates plague bacilli. Courtesy of Jack Poland, PhD, Centers for Disease Control and Prevention (CDC), Fort Collins, Colo.
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Ecchymoses at the base of the neck in a girl with plague. The bandage is over the site of a prior bubo aspirate. These lesions are probably the source of the line from the children's nursery rhyme, "ring around the rosy." Courtesy of Jack Poland, PhD, Centers for Disease Control and Prevention (CDC), Fort Collins, Colo.
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Acral necrosis of the nose, the lips, and the fingers and residual ecchymoses over both forearms in a patient recovering from bubonic plague that disseminated to the blood and the lungs. At one time, the patient's entire body was ecchymotic. Reprinted from Textbook of Military Medicine. Washington, DC, US Department of the Army, Office of the Surgeon General, and Borden Institute. 1997:493. Government publication, no copyright on photos.
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Acral necrosis of the toes and residual ecchymoses over both forearms in a patient recovering from bubonic plague that disseminated to the blood and the lungs. At one time, the patient's entire body was ecchymotic. Reprinted from Textbook of Military Medicine. Washington, DC: US Department of the Army, Office of the Surgeon General, and Borden Institute. 1997:493. Government publication, no copyright on photos.
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Rock squirrel in extremis coughing blood-streaked sputum related to pneumonic plague. Courtesy of Ken Gage, PhD, Centers for Disease Control and Prevention (CDC), Fort Collins, Colo.
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CDC, Reported Cases of Human Plague - United States, 1970-2018. Image courtesy of the Centers for Disease Control and Prevention (CDC), Atlanta, GA.
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CDC, Reported Plague Cases by Country, 2013-2018. Image courtesy of the Centers for Disease Control and Prevention (CDC), Atlanta, GA.
