Resources for Clinicians

Diagnosis

Plague should be considered in any patient with clinical signs of plague and a recent history of residence in or travel to the western United States or other plague endemic areas. Bubonic plague is the most common primary manifestation, with a bubo usually occurring in the groin, axilla, or cervical nodes. Buboes are often so painful that patients are generally guarded and have restricted movement in the affected region. The incubation period for bubonic plague is usually 2 to 6 days. If bubonic plague is untreated, Yersinia pestis can invade the bloodstream and spread rapidly, causing sepsis; if the lungs are seeded, pneumonia can develop.

Sepsis and pneumonia can also be primary manifestations of plague. A person with pneumonic plague may experience high fever, chills, cough, and dyspnea and may expel bloody sputum. If patients with pneumonic or septicemic plague are not given specific antibiotic therapy, the disease can progress rapidly to death.

Although the majority of patients with plague present with a bubo, some may have nonspecific symptoms. For example, septicemic plague can present with prominent gastrointestinal symptoms such as nausea, vomiting, diarrhea, and abdominal pain (MMWR, 2006). Additional rare forms of plague include pharyngeal, meningeal, and cutaneous.

Appropriate diagnostic samples include blood cultures, lymph node aspirates if possible, and/or sputum, if indicated. If plague is suspected, local and state health departments should be notified immediately. If the patient has signs of pneumonic plague, they should also be isolated and placed on droplet precautions to reduce the risk of person-to-person transmission pdf icon[PDF – 2 pages] of plague.

Laboratory Testing

If plague is suspected, pre-treatment specimens should be taken if possible, but treatment should not be delayed. Specimens should be obtained from appropriate sites for isolating the bacteria, based on the clinical presentation, and may include:

  • Lymph node aspirate: An affected bubo typically contains numerous organisms that can be evaluated microscopically and by culture.
  • Blood cultures: Routine blood cultures are a sensitive means of detecting plague. In later stages of disease, levels of bacteremia are high enough that organisms may occasionally be seen on blood smears.
  • Sputum: Culture is possible from sputum of very ill patients with pneumonic plague; however, blood is usually culture positive at this time as well.
  • Bronchial/tracheal wash samples may be taken from patients with suspected pneumonic plague. Throat specimens are not ideal for isolation of Y. pestis since they often contain many other bacteria that can mask the presence of Y. pestis.
  • In cases where live organisms are unculturable, lymphoid, spleen, lung, and liver tissue or bone marrow samples may yield evidence of Y. pestis by direct detection methods such as direct fluorescent antibody (DFA) or PCR.

Y. pestis may be identified microscopically by examination of Gram, Wright, Giemsa, or Wayson’s stained smears of peripheral blood, lymph node specimen, or sputum. Visualization of small Gram negative rods with Gram stain and bipolar-staining with Wright, Giemsa or Wayson stains, (organisms with a “safety pin” appearance) should trigger the suspicion of plague. Automated biochemical identification systems and matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) identification systems may misidentify the cultured organism.

If cultures yield negative results and plague is still suspected, serologic testing is possible to confirm the diagnosis. One serum specimen should be taken as early in the illness as possible, followed by a convalescent sample 4-6 weeks or more after disease onset.

More information about specimen submission.

Recommended antimicrobial treatment for plague

Begin appropriate therapy as soon as plague is suspected. Gentamicin and fluoroquinolones are first-line treatments in the United States. Duration of treatment is 10 to 14 days, but treatment can be extended for patients with ongoing fever or other concerning signs. Patients can be treated with intravenous or oral antimicrobials, depending on severity of illness and other clinical factors.

The regimens listed below may need to be adjusted depending on a patient’s age, medical history, underlying health conditions, or allergies. Please use clinical judgment and, if needed, consult an infectious disease specialist regarding individual patient treatment decisions.

Additional information:

Recommended antimicrobial treatment of adults and children with pneumonic or septicemic plague

Pediatric regimens are for children aged ≥1 month to ≤17 years. Only first-line treatment options are listed here. For additional treatment options, see: Antimicrobial Treatment and Prophylaxis of Plague: Recommendations for Naturally Acquired Infections and Bioterrorism Response

Recommended antibiotic treatment for plague pdf icon[PDF – 3 pages] – Print only

Recommended antibiotic treatment of Adults for plague
Antibiotic Dose Route of administration Notes
Ciprofloxacin Adults: 400 mg every 8 hrs IV FDA approved based on animal studies and clinical data. 1
Children: 10 mg/kg every 8 or 12 hrs (maximum 400 mg/dose)
Adults: 750 mg every 12 hrs PO
Children: 15 mg/kg every 8 or 12 hrs (maximum 500 mg/dose every 8 hrs or 750 mg/dose every 12 hrs)
Levofloxacin Adults: 750 mg every 24 hrs IV or PO FDA approved based on animal studies; clinical data for human plague is limited.
Children:
Weight <50 kg: 8 mg/kg every 12 hrs
Weight ≥50 kg: 500-750 mg every 24 hrs
Moxifloxacin Adults: 400 mg every 24 hrs IV or PO FDA approved based on animal studies; clinical data for human plague is limited. Moxifloxacin is a first-line treatment for adults but an alternative for children, since it is not FDA approved for use in children aged ≤17 years.
Children: see notes
Gentamicin Adults: 5 mg/kg every 24 hrs IV or IM Not FDA approved but considered an effective alternative to streptomycin.2,3
Children: 4.5-7.5 mg/kg every 24 hrs
Streptomycin Adults: 1 g every 12 hrs IV or IM FDA approved based on clinical experience. Not widely available in the US. The IV formulation is not approved by FDA; however, the IM formulation has been given IV as an off-label use.4
Children: 15 mg/kg every 12 hrs (maximum 1 g/dose)

1Apangu T, Griffith K, Abaru J, et al. Successful treatment of human plague with oral ciprofloxacinexternal icon. Emerg Infect Dis. 2017;23:553-5.

2Boulanger LL, Ettestad P, Fogarty JD, Dennis DT, Romig D, Mertz G. Gentamicin and tetracyclines for the treatment of human plague: Review of 75 cases in New Mexico, 1985–1999.external icon Clin Infect Dis. 2004 38(5):663-669.

3Mwengee W, Butler T, Mgema S, Mhina G, Almasi Y, Bradley C, Formanik JB, Rochester CG. Treatment of plague with gentamicin or doxycycline in a randomized clinical trial in Tanzania.external icon Clin Infect Dis. 2006 42(5):614-21.

4Morris JT, Cooper RH. Intravenous streptomycin: a useful route of administrationexternal icon. Clin Infect Dis. 1994;19:1150–1.

Recommended antimicrobial treatment of adults and children with bubonic or pharyngeal plague

Pediatric regimens are for children aged ≥1 month to ≤17 years. Only first-line treatment options are listed here. For additional treatment options, see: Antimicrobial Treatment and Prophylaxis of Plague: Recommendations for Naturally Acquired Infections and Bioterrorism Response

Recommended antibiotic treatment of children for plague
Antimicrobial Dose Route of administration Notes
Ciprofloxacin Adults: 400 mg every 8 hrs IV FDA approved based on animal studies and clinical data. 1
Children: 10 mg/kg every 8 or 12 hrs (maximum 400 mg/dose)
Adults: 750 mg every 12 hrs PO
Children: 15 mg/kg every 8 or 12 hrs (maximum 500 mg/dose every 8 hrs or 750 mg/dose every 12 hrs)
Levofloxacin Adults: 750 mg every 24 hrs IV or PO FDA approved based on animal studies; clinical data for human plague is limited.
Children:
Weight <50 kg: 8 mg/kg every 12 hrs (maximum 250 mg/dose)
Weight ≥50 kg: 500-750 mg every 24 hrs
Moxifloxacin Adults: 400 mg every 24 hrs IV or PO FDA approved based on animal studies; clinical data for human plague is limited. Moxifloxacin is a first-line treatment for adults but an alternative for children, since it is not FDA approved for use in children aged ≤17 years.
Children:  see notes
Doxycycline Adults: 200 mg loading dose, then 100 mg every 12 hrs IV or PO Bacteriostatic, but FDA approved and effective in a randomized trial when compared to gentamicin.2 No evidence of tooth staining after multiple short courses.3
Children: Weight <45 kg: 4.4 mg/kg loading dose, then 2.2 mg/kg evert 12 hrs (maximum 100 mg/dose)

Weight ≥45 kg: same as adult dose

Gentamicin Adults: 5 mg/kg every 24 hrs IM or IV Not FDA approved but considered an effective alternative to streptomycin.2,4,5
Children: 4.5-7.5 mg/kg every 24 hrs
Streptomycin Adults: 1 g every 12 hrs IM or IV FDA approved based on clinical experience. Not widely available in the US. The IV formulation is not approved by FDA; however, the IM formulation has been given IV as an off-label use.5, 6
Children: 15 mg/kg every 12 hrs (maximum 1 g/dose)

1Apangu T, Griffith K, Abaru J, et al. Successful treatment of human plague with oral ciprofloxacinexternal icon. Emerg Infect Dis. 2017;23:553-5.

2 Mwengee W, Butler T, Mgema S, Mhina G, Almasi Y, Bradley C, Formanik JB, Rochester CG. Treatment of plague with gentamicin or doxycycline in a randomized clinical trial in Tanzania.external icon Clin Infect Dis. 2006 42(5):614-21.

3Todd SR, Dahlgren FS, Traeger MS, Beltrán-Aguilar ED, Marianos DW, Hamilton C, McQuiston JH, Regan JJ. No visible dental staining in children treated with doxycycline for suspected Rocky Mountain spotted fever.external icon J Pediatr. 2015 May;166(5):1246-51.

4Boulanger LL, Ettestad P, Fogarty JD, Dennis DT, Romig D, Mertz G. Gentamicin and tetracyclines for the treatment of human plague: Review of 75 cases in New Mexico, 1985–1999.external icon Clin Infect Dis. 2004 38(5):663-669.

5 Since abscesses such as buboes have lower pH than most human tissues, transport of aminoglycosides into the bacterial cell may be reduced. Clinicians may consider alternative or dual therapy for patients with large buboes.

6Morris JT, Cooper RH. Intravenous streptomycin: a useful route of administrationexternal icon. Clin Infect Dis. 1994;19:1150–1.

Recommended antimicrobial treatment of pregnant women with pneumonic, bubonic, septicemic, or pharyngeal plague

Only first-line treatment options are listed here. For additional treatment options, see: Antimicrobial Treatment and Prophylaxis of Plague: Recommendations for Naturally Acquired Infections and Bioterrorism Response

Recommended antibiotic treatment of Pregnant women for plague
Antimicrobial Dose Route of administration Notes
Gentamicin

PLUS

Same as adult dose IM or IV Not FDA approved but considered an effective alternative to streptomycin.1,2,3
Ciprofloxacin

OR

400 mg every 8 hrs IV FDA approved based on animal studies and clinical data.4
500 mg every 8 hrs PO
Levofloxacin Same as adult dose IV or PO FDA approved based on animal studies; clinical data for human plague is limited.

1Mwengee W, Butler T, Mgema S, Mhina G, Almasi Y, Bradley C, Formanik JB, Rochester CG. Treatment of plague with gentamicin or doxycycline in a randomized clinical trial in Tanzaniaexternal iconClin Infect Dis. 2006 42(5):614-21.

2Boulanger LL, Ettestad P, Fogarty JD, Dennis DT, Romig D, Mertz G. Gentamicin and tetracyclines for the treatment of human plague: Review of 75 cases in New Mexico, 1985–1999external iconClin Infect Dis. 2004 38(5):663-669.

3Since abscesses such as buboes have lower pH than most human tissues, transport of aminoglycosides into the bacterial cell may be reduced. Clinicians may consider alternative or dual therapy for patients with large buboes.

4Apangu T, Griffith K, Abaru J, et al. Successful treatment of human plague with oral ciprofloxacinexternal icon. Emerg Infect Dis. 2017;23:553-5.

Pre-exposure prophylaxis

Pre-exposure prophylaxis for first responders and health care providers who will care for patients with pneumonic plague is not considered necessary as long as standard and droplet precautions can be maintained. In cases of surgical mask shortages, patient overcrowding, poor ventilation in hospital wards, or other situations, pre-exposure prophylaxis might be warranted if sufficient supplies of antimicrobials are available. Prophylaxis can be discontinued 48 hours after the last perceived exposure. For more information, see Antimicrobial Treatment and Prophylaxis of Plague: Recommendations for Naturally Acquired Infections and Bioterrorism Response.

Post-exposure prophylaxis

Post-exposure prophylaxis is indicated for persons with known exposure to plague, such as close (< 6 ft), sustained contact with a patient or animal with pneumonic plague or direct contact with infected body fluids or tissues. Post-exposure prophylaxis should be given for 7 days. Prophylaxis with a single antimicrobial agent is recommended for potentially exposed persons following a case of naturally acquired infection or intentional release of Y. pestis. If engineered resistance is detected in the aftermath of a bioterrorism attack, antimicrobial choice can be targeted based on available information. For more information, see Antimicrobial Treatment and Prophylaxis of Plague: Recommendations for Naturally Acquired Infections and Bioterrorism Response.

Pre- and post-exposure prophylaxis for adults and children potentially exposed to Yersinia pestis

Pediatric regimens are for children aged ≥1 month to ≤17 years. Only first-line prophylaxis options are listed here. For additional prophylaxis options, see: Antimicrobial Treatment and Prophylaxis of Plague: Recommendations for Naturally Acquired Infections and Bioterrorism Response

Recommended antimicrobial pre-and post-exposure prophylaxis for plague pdf icon[PDF – 1 page] – Print only

Post-exposure prophylaxis (PEP)
1No evidence of tooth staining after multiple short courses. Source: Todd SR, Dahlgren FS, Traeger MS, Beltrán-Aguilar ED, Marianos DW, Hamilton C, McQuiston JH, Regan JJ. No visible dental staining in children treated with doxycycline for suspected Rocky Mountain spotted fever.external icon J Pediatr. 2015 May;166(5):1246-51.
Antimicrobial Dose Route of administration
Adults Ciprofloxacin 500-750 mg every 12 hrs PO
Levofloxacin 500-750 mg every 24 hrs PO
Moxifloxacin 400 mg every 24 hrs PO
Doxycycline 100 mg every 12 hrs PO
Children Ciprofloxacin 15 mg/kg every 12 hrs (maximum 750 mg/dose) PO
Levofloxacin Weight <50 kg: 8 mg/kg every 12 hrs (maximum 250 mg/dose)

Weight ≥50 kg: 500-750 mg every 24 hrs

PO
Doxycycline1 Weight <45 kg: 2.2 mg/kg every 12 hrs

Weight ≥45 kg: 100 mg every 12 hrs

PO
Pregnant women Ciprofloxacin 500 mg every 8 hrs or 750 mg every 12 hrs PO
Levofloxacin 750 mg every 24 hrs PO

Case Definition and Report Forms