Bubonic plague is a high-consequence zoonotic infection caused by the gram-negative coccobacillus Yersinia pestis, transmitted primarily via infected flea bites. It is the most common clinical form of plague, characterized by painful regional lymphadenopathy (buboes) with fever, and carries a case fatality rate of 10–26% even with treatment, and >66% untreated. [1-3] Plague is a medical emergency — early antibiotic therapy is lifesaving. [2-3]
1. History
- Exposure: Flea bites, contact with rodents or wild animals (prairie dogs, ground squirrels), handling infected animal carcasses, domestic cat scratches/bites [2][4]
- Travel/residence: Endemic areas — western US (Four Corners region), Madagascar, Democratic Republic of Congo, sub-Saharan Africa, Central Asia [1-2]
- Onset: Sudden, 2–8 days after flea bite or exposure [2][5]
- Symptom characterization: Acutely painful, swollen lymph node(s) in the drainage region of the flea bite; high fever, rigors, headache, malaise, prostration [1][5]
- Bubo location: Most commonly inguinal (reflecting lower extremity flea bites), also axillary, cervical, or submaxillary; children more likely to present with cervical/axillary buboes [5]
- Important negatives: Ask about cough, hemoptysis, dyspnea (to rule out secondary pneumonic plague), GI symptoms (nausea, vomiting, diarrhea — may suggest septicemic plague), neck stiffness (meningeal plague) [2][6]
2. Alarm Features
- Cough, hemoptysis, or dyspnea → secondary pneumonic plague (develops in ~12% of US cases); nearly 100% fatal if untreated [2][6-7]
- Sepsis signs: Hypotension, tachycardia, altered mental status, DIC, purpura/petechiae → secondary septicemic plague [2][6]
- Acral gangrene (digits, nose) — late finding of septicemic plague ("Black Death") [6]
- Nuchal rigidity, confusion → plague meningitis (typically 9–14 days after onset, more common in ages 10–15) [2]
- Rapidly enlarging bubo or multiple buboes with systemic toxicity
- Any suspected plague case warrants immediate public health notification (nationally notifiable disease, potential bioterrorism agent) [3][6]
3. Medications
First-line treatment (CDC 2021 guidelines): [2][4]
- Streptomycin 15 mg/kg IM q12h (adjusted for renal function)
- Gentamicin 5 mg/kg IV/IM q24h (reasonable substitute)
- Doxycycline 100 mg PO BID (first-line for uncomplicated bubonic plague per CDC) [2]
- Ciprofloxacin 500 mg PO BID × 10 days — shown noninferior to aminoglycoside–ciprofloxacin combination in the landmark IMASOY trial (2025 NEJM) [1]
Treatment duration: 10–14 days [2]
Alternatives: Levofloxacin 750 mg IV/PO q24h, moxifloxacin 400 mg IV/PO q24h, chloramphenicol, TMP-SMX [2]
Contraindicated/ineffective: Penicillins — associated with 75% case fatality rate; not effective for plague [8]
Pregnancy: Dual therapy recommended (gentamicin + fluoroquinolone); doxycycline is an alternative [2]
Key pearl: If progression to pneumonic or septicemic plague, escalate to parenteral aminoglycoside ± fluoroquinolone dual therapy [2]
4. Diet
- No specific dietary triggers or restrictions
- Maintain adequate hydration, especially in febrile/septic patients
- NPO if surgical I&D of suppurative bubo is planned
5. Review of Systems
- Respiratory: Cough, hemoptysis, dyspnea, chest pain (pneumonic plague) [5-6]
- GI: Nausea, vomiting, abdominal pain, diarrhea (septicemic plague) [2]
- Neuro: Headache, altered mental status, neck stiffness (meningeal plague) [2]
- Skin: Flea bite papule/pustule at portal of entry, petechiae, purpura, ecchymoses [6]
- Constitutional: Fever, chills, rigors, malaise, prostration [1][5]
6. Collateral History and Family History
- Household contacts: Other symptomatic individuals (especially cough → pneumonic plague cluster) [5]
- Occupational exposure: Hunters, trappers, veterinarians, wildlife biologists, farmers in endemic areas [3]
- Animal exposure: Dead rodents in vicinity, sick/dead cats, flea-infested environments [2][4]
- Recent travel to endemic regions within 14 days [1]
- Family history is not a significant contributor (non-hereditary disease)
7. Risk Factors
- Residence in or travel to plague-endemic areas (western US, Madagascar, DRC, parts of Asia) [1-2]
- Contact with rodents, rabbits, or domestic cats (cats can develop pneumonic plague and transmit to humans) [4][6]
- Poverty — increased rodent exposure, poor housing conditions [3]
- Outdoor activities in endemic areas (camping, hiking, hunting) [2]
- Flea exposure — lack of flea control measures [2]
8. Differential Diagnosis
- Tularemia (Francisella tularensis) — ulceroglandular form with painful lymphadenopathy; similar exposure history; distinguished by ulcer at inoculation site [3][9]
- Cat-scratch disease (Bartonella henselae) — regional lymphadenopathy, fluctuant/tender; cat/kitten exposure [3]
- Pyogenic lymphadenitis (staph/strep) — localized skin infection with reactive nodes
- Lymphogranuloma venereum — inguinal lymphadenopathy; sexual exposure history [3]
- Tuberculous lymphadenitis — chronic, firm, fixed, nontender nodes; bilateral [3]
- Lymphoma — painless, progressive lymphadenopathy; B symptoms [10]
- Strangulated inguinal hernia — if inguinal bubo mimics a mass
Cannot-miss: Tularemia (similar treatment urgency), septicemic plague masquerading as undifferentiated sepsis, and secondary pneumonic plague [2-3]
9. Past Medical History
- Prior plague infection (rare recurrence; prior treatment within 3 months was an exclusion in clinical trials) [1]
- Immunosuppression — may alter presentation and increase mortality
- Renal impairment — requires aminoglycoside dose adjustment [4]
- Myasthenia gravis or tendinitis — relative contraindications to fluoroquinolones [1]
- Pregnancy — alters antibiotic selection (aminoglycosides category D, ciprofloxacin category C) [1]
10. Physical Exam
- Vital signs: High fever (often >38.5°C), tachycardia; hypotension suggests septicemic progression [5][11]
- Bubo: Tense, exquisitely tender, erythematous lymph node swelling (1–10 cm) with surrounding periganglionic edema; most commonly inguinal [5]
- Generally a single bubo, though multiple may occur
- May become fluctuant/suppurative
- Skin: Look for flea bite papule/vesicle at portal of entry; petechiae, purpura, ecchymoses in septicemic disease [6]
- Lungs: Auscultate for crackles, consolidation (secondary pneumonic plague) [6]
- Neuro: Mental status, meningismus [2]
- Acral exam: Gangrene of digits/nose in advanced septicemic disease [6]
11. Lab Studies
- Blood cultures (usually positive in septicemic plague; obtain before antibiotics) [4-5]
- Bubo aspirate: Gram stain (gram-negative coccobacilli with bipolar "safety pin" staining on Wright-Giemsa or Wayson stain), culture [4-6]
- CBC: Leukocytosis with left shift expected
- CMP: Assess renal function (aminoglycoside dosing), hepatic function
- Coagulation studies: DIC screen (PT, PTT, fibrinogen, D-dimer) if septicemic features [7]
- Lactate: If sepsis suspected
- PCR (pla and caf1 genes): Available at reference labs (CDC); remains positive even after antibiotics [3][5]
- F1 antigen rapid diagnostic test (RDT): Point-of-care dipstick; sensitive and specific for bubo aspirate, sputum, blood [3][5]
- Serology: Anti-F1 IgG; useful for retrospective confirmation (seroconversion in paired samples) [3][5]
Lab safety: Notify the laboratory that plague is suspected — Y. pestis is a BSL-3 pathogen and poses risk to lab workers [5]
12. Imaging
- Chest X-ray: Obtain in all suspected plague cases to evaluate for secondary pneumonic plague (bilateral infiltrates, consolidation) [12]
- CT chest: If CXR equivocal and pneumonic plague suspected
- Ultrasound: May help characterize bubo (lymph node vs. abscess vs. hernia) and guide aspiration
- Imaging of the bubo itself is generally unnecessary if clinical diagnosis is clear
13. Special Tests
- F1 antigen rapid dipstick test: Point-of-care; results in 15 minutes; validated in field conditions in Madagascar [3][5]
- Specific bacteriophage lysis test: Lyses only Y. pestis (not Y. pseudotuberculosis); performed at reference labs [5]
- Direct fluorescent antibody (DFA) testing on clinical specimens [6]
- qPCR targeting pla and caf1 genes — most sensitive molecular method [1][5]
14. ECG
- Not routinely indicated for uncomplicated bubonic plague
- Obtain if sepsis/septic shock develops (evaluate for arrhythmias, myocardial dysfunction)
- Monitor QTc if using fluoroquinolones, especially with concurrent QT-prolonging medications
15. Assessment
Bubonic plague is a rapidly progressive infection that presents with acute febrile illness and painful regional lymphadenopathy (bubo) 2–8 days after flea bite or animal contact in an endemic area. [1-2][5] The classic bubo is a tense, tender, erythematous lymph node swelling, most commonly inguinal.
Severity stratification
- Uncomplicated bubonic: Fever + bubo, hemodynamically stable, no respiratory symptoms → can be treated with oral monotherapy [1-2]
- Complicated: Progression to secondary septicemic plague (DIC, shock), pneumonic plague (cough, hemoptysis), or meningitis → requires parenteral therapy and ICU-level care [2]
Atypical presentations: Primary septicemic plague (no bubo, GI symptoms predominate), pharyngeal plague (cervical lymphadenopathy + pharyngitis), meningeal plague [2]
Complications: DIC, ARDS, multiorgan failure, gangrene, death [6-7]
16. Treatment Plan
Initial stabilization
- Standard sepsis resuscitation if indicated (IV fluids, vasopressors)
- Droplet precautions until pneumonic plague excluded; standard precautions for bubonic plague without cough [6]
- Obtain cultures/aspirate before antibiotics when possible [3]
Antibiotic therapy (start empirically — do not wait for confirmatory testing): [2-3]
Procedural: Surgical incision and drainage if bubo becomes suppurative [2]
Post-exposure prophylaxis (close contacts, especially of pneumonic cases): Doxycycline 100 mg PO BID or ciprofloxacin 500 mg PO BID × 7 days [2]
17. Disposition
- Admit all suspected plague cases — plague is a medical emergency [3]
- ICU admission: Septic shock, respiratory failure, DIC, altered mental status, secondary pneumonic plague
- Isolation: Droplet precautions until pneumonic plague is excluded or treated for ≥48 hours [6]
- Mandatory public health reporting: Notify local/state health department and CDC immediately [6]
- Discharge criteria: Afebrile, clinically improving, tolerating oral antibiotics, no signs of pneumonic or septicemic progression; can complete oral antibiotic course as outpatient with close follow-up
Specialist consultation: Infectious disease consultation for all cases; critical care if septic; surgery if bubo requires I&D [2]
18. Follow Up / Return Precautions
- Follow-up: Daily clinical assessment during treatment (in-person or community health worker visit); reassess at day 10–11 for treatment response [1]
- Return immediately for: New cough, hemoptysis, dyspnea, worsening fever, increasing bubo size, signs of bleeding/bruising, confusion, or hemodynamic instability
- Expected course: Fever typically resolves within 3–5 days of appropriate antibiotics; bubo may take weeks to fully resolve and may require drainage [2]
- Contact tracing: All close contacts (especially household) should receive post-exposure prophylaxis and be monitored for 7 days [6]
- Counsel on prevention: Flea control, avoid handling wild rodents/rabbits, keep pets treated for fleas in endemic areas [2]
References
1. Ciprofloxacin versus Aminoglycoside–Ciprofloxacin for Bubonic Plague. — Randremanana RV, Raberahona M, Bourner J, et al. The New England Journal of Medicine. 2025.
2. Antimicrobial Treatment and Prophylaxis of Plague: Recommendations for Naturally Acquired Infections and Bioterrorism Response. — Nelson CA, Meaney-Delman D, Fleck-Derderian S, et al. MMWR. Recommendations and Reports : Morbidity and Mortality Weekly Report. Recommendations and Reports. 2021.
3. Rapid Diagnostic Tests for Plague. — Jullien S, Dissanayake HA, Chaplin M. The Cochrane Database of Systematic Reviews. 2020.
4. Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America. — Stevens DL, Bisno AL, Chambers HF, et al. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 2014.
5. Plague. — Prentice MB, Rahalison L. Lancet. 2007.
6. Plague as a Biological Weapon: Medical and Public Health Management. — Inglesby TV, Dennis DT, Henderson DA, et al. The Journal of the American Medical Association. 2000.
7. Immune defense against pneumonic plague. — Smiley ST. Immunological Reviews. 2008.
8. Treatment of Human Plague: A Systematic Review of Published Aggregate Data on Antimicrobial Efficacy, 1939-2019. — Godfred-Cato S, Cooley KM, Fleck-Derderian S, et al. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 2020.
9. A Clinical Pitfall in Caseating Necrotizing Granulomatous Lymphadenitis: Tularemia. — Özan Köse S, Erdem H, Köse ÖC, Yılmaz Ertürk F. Diagnostic Microbiology and Infectious Disease. 2025.
10. Lymphadenopathy: Evaluation and Differential Diagnosis. — Falk N, Joseph R, Dieujuste M. American Family Physician. 2025.
11. Epidemiological Characteristics of an Urban Plague Epidemic in Madagascar, August-November, 2017: An Outbreak Report. — Randremanana R, Andrianaivoarimanana V, Nikolay B, et al. The Lancet. Infectious Diseases. 2019.
12. Clinical Management of Potential Bioterrorism-Related Conditions. — Adalja AA, Toner E, Inglesby TV. The New England Journal of Medicine. 2015.