Tularemia (Ulceroglandular)

Ulceroglandular tularemia is the most common clinical form of tularemia, caused by the gram-negative intracellular coccobacillus Francisella tularensis. It is characterized by a cutaneous ulcer at the inoculation site with painful regional lymphadenopathy, typically following a tick bite or direct contact with infected animals.[1-3] It is a CDC Category A bioterrorism agent due to its extremely low infectious dose (~10 organisms) and ease of aerosolization.[4-5]

The following figure illustrates the various modes of acquisition and their corresponding clinical syndromes:

View full figure Figure 1. Tularemia — Modes of Acquisition and Manifestations. Going Down the Rabbit Hole. N Engl J Med. July 31, 2024.

1. History

• Exposure history is paramount: Ask about tick bites (most common US vector, ~69% of cases), handling rabbits/hares/rodents, skinning or butchering wild game, cat bites/scratches, deer fly bites, mowing over animal carcasses, and contaminated water exposure[2][5][7]
• Incubation period: Typically 3–5 days (range 1–21 days)[1][8-9]
• Symptom characterization: Abrupt onset of fever (38–40°C), chills, headache, malaise, myalgia, and anorexia, followed by development of a skin lesion at the inoculation site and painful swollen lymph nodes[1-2][5]
• Timing: Patients seek care after a median of 3 days of illness[7]
• Important negatives: No person-to-person transmission; no respiratory symptoms (distinguishes from pneumonic form); no pharyngitis (distinguishes from oropharyngeal form)[2][5]

2. Alarm Features

• High fever with systemic toxicity (rigors, prostration, confusion) — suggests progression to typhoidal or septic tularemia[5]
• Respiratory symptoms (cough, dyspnea, pleuritic pain) — any form can develop secondary pneumonia via hematogenous spread[5][9]
• Pulse-temperature dissociation — noted in up to 42% of patients; should raise suspicion[5][10]
• Suppurative lymphadenopathy with fluctuance — occurs in ~30% and may require surgical drainage[9][11]
• Immunocompromised patients — at risk for severe, atypical, and disseminated disease[2][12]
• Delayed treatment >2–3 weeks from onset — associated with higher treatment failure and relapse rates[11]

3. Medications

Effective treatments

Mild-moderate disease (outpatient)

• Ciprofloxacin 500–750 mg PO BID × 10–14 days[1][13-14]
• Levofloxacin 500 mg PO daily × 10–14 days[1]
• Doxycycline 100 mg PO BID × 14–21 days (higher relapse rate with shorter courses)[1][13]

Severe disease (inpatient)

• Gentamicin 5 mg/kg/day IV (or 1.5 mg/kg q8h) — first-line for severe tularemia[1][4]
• Streptomycin 15 mg/kg IM q12h (max 2 g/day) — historical gold standard[1][15]
• Step-down: Parenteral aminoglycoside until clinical improvement, then oral fluoroquinolone or doxycycline to complete 10–14 days[1]

Contraindicated/ineffective

• Beta-lactams — F. tularensis is intrinsically resistant; empiric use is a common cause of treatment failure[1][11]
• Most macrolides — generally ineffective[11]
• Anti-tuberculosis agents — ineffective[11]

Cautions

• Doxycycline and tetracyclines are bacteriostatic → higher relapse rates, especially with courses <7–10 days[1]
• Aminoglycosides require renal dose adjustment and monitoring[1]
• The 2025 CDC guidelines now designate fluoroquinolones and doxycycline as first-line for outbreaks of any size[13]

4. Diet

• No specific dietary triggers or restrictions
• Ensure adequate hydration, especially in febrile patients with systemic symptoms
• Avoid consumption of untreated water from natural sources in endemic areas (potential transmission route)[2][5]
• Ensure thorough cooking of wild game meat

5. Review of Systems

• Constitutional: Fever, chills, rigors, night sweats, weight loss, fatigue, anorexia[2][5]
• Skin: Ulcer or eschar at bite/contact site; erythema nodosum or erythema multiforme (rare)[8-9]
• Lymphatic: Painful regional lymphadenopathy (inguinal/femoral for lower extremity bites; axillary for upper extremity; cervical for head/neck)[3][10]
• Respiratory: Cough, dyspnea, pleuritic chest pain (screen for secondary pneumonia)[5]
• GI: Nausea, vomiting, diarrhea, abdominal pain[2][5]
• Musculoskeletal: Myalgia, arthralgia, low back pain[5][9]
• Neurologic: Headache; confusion/stupor in severe typhoidal forms[9]
• Ophthalmologic: Photophobia, conjunctivitis (if oculoglandular form suspected)[2]

6. Collateral History and Family History

• Occupational exposure: Hunting, trapping, butchering, farming, landscaping/mowing, veterinary work, laboratory work[5][16]
• Recreational exposure: Hiking, camping, outdoor activities in endemic areas during summer months[7][16]
• Animal contact: Recent contact with rabbits, hares, rodents, or domestic cats; dead animal sightings near home[2][5]
• Geographic context: Residence or travel to endemic areas (Arkansas, Missouri, Oklahoma, South Dakota, Montana; Scandinavia, former Soviet Union)[5][17]
• Household contacts: No person-to-person transmission, but shared environmental exposures may indicate cluster/outbreak[5]
• Family history is generally not relevant (no hereditary predisposition)

7. Risk Factors

• Tick exposure — most common US vector (~69% of cases); peak incidence in summer months[7][16]
• Direct animal contact — handling infected rabbits, hares, rodents, or their carcasses[2][5]
• Male sex — 65% of cases; reflects occupational/recreational exposure patterns[7][17]
• Age bimodal distribution — highest incidence in children aged 5–9 years and men >55 years[17]
• Rural residence in endemic states[5]
• Occupational risk: Hunters, trappers, farmers, landscapers, laboratory workers[5]
• Immunocompromised status — anti-TNF-α therapy, other immunosuppression → risk of severe/disseminated disease[12]
• Cat bites/scratches — increasingly recognized transmission route[1][18]

8. Differential Diagnosis

Cannot-miss diagnoses

• Plague (bubonic) — similar ulcer + lymphadenopathy; more rapid progression, higher mortality; exposure to rodent fleas
• Anthrax (cutaneous) — painless black eschar with surrounding edema; no significant lymphadenopathy initially
• Necrotizing soft tissue infection — rapidly progressive; systemic toxicity disproportionate to local findings

Most important alternatives

• Cat scratch disease (Bartonella henselae) — lymphadenopathy with cat exposure; typically less systemic toxicity; no ulcer at inoculation site[19]
• Sporotrichosis — nodular lymphangitis pattern; gardening/soil exposure; chronic course
• Staphylococcal/streptococcal lymphadenitis — responds to beta-lactams (tularemia does not)
• Tuberculosis — chronic lymphadenopathy with caseating granulomas; tularemia can mimic TB histologically[20]
• Lymphoma — painless lymphadenopathy; B symptoms; tularemia lymphadenopathy can mimic malignancy on PET/CT[20-21]
• Other tick-borne diseases — RMSF, ehrlichiosis, Lyme disease (different rash patterns, different lymph node involvement)[3]
• Mycobacterium marinum — if water exposure; chronic granulomatous skin lesion
• Key distinguishing feature: Failure to respond to beta-lactam antibiotics in a patient with ulcer + lymphadenopathy should raise strong suspicion for tularemia[11][22]

9. Past Medical History

• Immunosuppression — HIV, organ transplant, anti-TNF-α therapy, chemotherapy → increased risk of severe/disseminated disease[2][12]
• Prior tularemia — cellular immunity is long-lasting; reinfection tends to be localized[10]
• Chronic kidney disease — impacts aminoglycoside dosing[1]
• Prior tick-borne illness — suggests ongoing arthropod exposure risk
• Splenectomy — increased susceptibility to encapsulated and intracellular organisms

10. Physical Exam

Vital signs

• Fever 38–40°C (often high-grade)[5]
• Pulse-temperature dissociation (relative bradycardia) in up to 42%[5][10]
• Tachycardia if septic; hypotension in severe cases

Focused exam

• Skin: Tender papule → pustule → punched-out ulcer with raised borders and necrotic base (eschar) at inoculation site; typically on lower extremities (tick bite), upper extremities (animal handling), or trunk[1][3]
• Lymph nodes: Tender, enlarged regional lymphadenopathy — inguinal/femoral (lower extremity inoculation), axillary (upper extremity), cervical (head/neck); may be fluctuant if suppurated[1][3][9]
• Lungs: Usually clear in ulceroglandular form; crackles or decreased breath sounds if secondary pneumonia develops[5]
• Abdomen: Hepatosplenomegaly possible in systemic disease[10]
• Skin rashes: Erythema nodosum, erythema multiforme (uncommon complications)[8-9]

11. Lab Studies

Recommended

• Tularemia serology (microagglutination test) — preferred diagnostic method; seroconversion or 4-fold rise in paired sera is confirmatory; single titer ≥1:128 is presumptive[1][9]
• Antibodies typically detectable 1–2 weeks after symptom onset; peak at 3–4 weeks[9]
• PCR for F. tularensis — from ulcer swab, lymph node aspirate, or biopsy; rapid and highly sensitive/specific[9][12]
• Blood cultures — low yield (<10%), but should be obtained; must notify lab of tularemia suspicion (biosafety risk)[1][9][15]
• CBC — may show leukocytosis or normal WBC; nonspecific
• CMP — mild hepatitis (elevated transaminases) is common[10]
• CRP/ESR — typically elevated; nonspecific
• Key lab pearl: Routine cultures are often negative unless cysteine-supplemented media are used. Unsuspected growth of F. tularensis poses a serious laboratory-acquired infection risk — always alert the microbiology lab[1][15][19]

12. Imaging

• Ulceroglandular form: Imaging is generally not necessary for straightforward presentations
• Ultrasound of lymph nodes — useful to assess for suppuration/abscess formation requiring drainage[9]
• Chest X-ray — obtain if respiratory symptoms present; findings are nonspecific (infiltrates, hilar lymphadenopathy, pleural effusion)[15][23]
• CT chest — if pneumonic involvement suspected; may show mediastinal lymphadenopathy, pulmonary nodules, pleural effusion[21]
• PET/CT — can show intensely hypermetabolic lymph nodes mimicking lymphoma; avoid unnecessary biopsy if tularemia is in the differential[21]

13. Special Tests

• Tularemia microagglutination test — gold standard serologic method; paired sera 2–4 weeks apart[9]
• PCR (F. tularensis-specific) — from wound swab, lymph node aspirate; faster than serology[9][12]
• Immunofluorescence staining — can be performed on tissue specimens[15]
• Culture on cysteine heart agar with 9% chocolate blood or chocolate agar — growth in 24–48 hours at 37°C; requires BSL-3 precautions[9]
• Lymph node FNA or biopsy — may show necrotizing granulomatous inflammation; can mimic TB (caseating granulomas)[20]
• Point-of-care: No rapid bedside test currently available

14. ECG

• Not routinely indicated for ulceroglandular tularemia
• Cardiovascular complications are very rare but reported: myocarditis, pericarditis (usually with concomitant pneumonia), and extremely rare endocarditis[18][24-25]
• Obtain ECG if: chest pain, dyspnea out of proportion to exam, new arrhythmia, or signs of myocarditis (elevated troponin, new heart failure)
• If myocarditis suspected: look for diffuse ST changes, low voltage, new conduction abnormalities[18]

15. Assessment

• Clinical summary: Ulceroglandular tularemia presents as an acute febrile illness with a skin ulcer at the inoculation site and painful regional lymphadenopathy, typically 3–5 days after tick bite or animal contact. It is the most common form, accounting for ~37–47% of all tularemia cases in the US.[7][22]

Severity stratification

• Mild-moderate: Localized ulcer + lymphadenopathy, low-grade fever, non-toxic appearance → outpatient oral therapy
• Severe: High fever, systemic toxicity, suppurative nodes, immunocompromised host, concern for secondary pneumonia or sepsis → inpatient IV therapy

Typical vs. atypical

• Typical: Ulcer + regional adenopathy + fever after tick/animal exposure
• Atypical: Ulcer may be healed/inconspicuous at presentation ("glandular" form); granulomatous lymphadenitis mimicking TB or lymphoma[1][20]

Complications

• Lymph node suppuration (~30%)[9][11]
• Secondary pneumonia via hematogenous spread[5]
• Sepsis (rare in ulceroglandular form)
• Meningitis, brain abscess (very rare)[9]
• Myocarditis, pericarditis (very rare)[18][25]
• Erythema nodosum, erythema multiforme[8-9]

16. Treatment Plan

Initial stabilization

• IV access, fluid resuscitation, and antipyretics for febrile/toxic patients
• Obtain cultures and serology before starting antibiotics, but do not delay treatment while awaiting results

Mild-moderate ulceroglandular (outpatient)

• Ciprofloxacin 500 mg PO BID × 10–14 days, OR
• Doxycycline 100 mg PO BID × 14–21 days (longer course to reduce relapse)[1][13]

Severe disease (inpatient)

• Gentamicin 5 mg/kg/day IV divided q8h (adjust for renal function), OR
• Streptomycin 1 g IM q12h[1]
• Step down to oral fluoroquinolone or doxycycline once clinically improved; total course 10–14 days[1]

Suppurative lymph nodes

• Incision and drainage or surgical excision may be necessary, especially in patients with delayed treatment[9][11]

Special populations

• Children: Gentamicin 6 mg/kg/day IV divided q8h for severe disease; ciprofloxacin or doxycycline for mild disease[1]
• Pregnancy: Gentamicin preferred for severe disease; ciprofloxacin may be considered for mild disease (risk-benefit discussion)[13]
• Immunocompromised: Lower threshold for aminoglycoside therapy and longer treatment courses[13]

17. Disposition

Admission criteria

• Systemic toxicity, hemodynamic instability, or sepsis
• Pneumonic or typhoidal features
• Inability to tolerate oral medications
• Immunocompromised host with moderate-severe disease
• Need for IV aminoglycoside therapy
• Suppurative lymphadenopathy requiring surgical intervention
• Diagnostic uncertainty with concern for dangerous mimics (plague, anthrax)

Discharge criteria (outpatient management appropriate if)

• Non-toxic appearance, stable vitals
• Localized ulceroglandular disease without systemic complications
• Able to tolerate oral antibiotics
• Reliable follow-up available
• Immunocompetent

Observation

• Consider for borderline cases — moderate fever with early systemic symptoms, pending serology/culture results

Specialist consultation triggers

• Infectious disease — all confirmed/suspected cases (uncommon disease, complex treatment decisions)
• Surgery — suppurative lymph nodes requiring drainage
• Pulmonology — if pneumonic involvement suspected
• Public health notification — tularemia is a nationally notifiable disease; report to local/state health department[16-17]

18. Follow Up / Return Precautions

Follow-up timing

• Recheck in 48–72 hours after initiating antibiotics to assess clinical response
• Repeat serology at 2–4 weeks for paired sera confirmation[9]
• Follow-up at 2 weeks to assess ulcer healing and lymph node regression

Symptoms requiring immediate reassessment

• Worsening fever or new rigors despite 48–72 hours of appropriate antibiotics
• New respiratory symptoms (cough, dyspnea, chest pain) — concern for secondary pneumonia
• Increasing lymph node size, fluctuance, or new drainage — may need I&D
• Altered mental status, neck stiffness — concern for meningitis
• Rash progression (erythema nodosum, erythema multiforme)

Patient counseling

• No person-to-person transmission — standard precautions are sufficient[5][15]
• Ulcer healing may take weeks to months; lymphadenopathy can persist for months[9]
• Relapse is possible, especially with bacteriostatic agents (doxycycline) or short courses — complete the full antibiotic course[1][11]
• Tick prevention: DEET-based repellents, permethrin-treated clothing, daily tick checks, prompt tick removal[2]
• Avoid handling sick/dead wild animals without gloves[5]

Expected recovery

• With appropriate antibiotics, clinical improvement typically occurs within 48–72 hours[7]
• Overall mortality for ulceroglandular form is low (<2% with treatment)[8][14]
• Untreated fatality rate for all forms can reach up to 60%, though ulceroglandular carries the best prognosis among tularemia subtypes[4][10]

References

1. 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.

2. Tickborne Diseases of the United States: A Reference Manual for Healthcare Providers Sixth Edition. — Nancy Shadick MD MPH, Nancy Maher MPH, Dennis Hoak MD United States Centers for Disease Control and Prevention (2022). 2022.

3. Tick-Borne Diseases in the United States. — Spach DH, Liles WC, Campbell GL, et al. The New England Journal of Medicine. 1993.

4. Tularemia for Clinicians: An Up-to-Date Review on Epidemiology, Diagnosis, Prevention and Treatment. — Antonello RM, Giacomelli A, Riccardi N. European Journal of Internal Medicine. 2025.

5. Tularemia as a Biological Weapon: Medical and Public Health Management. — Dennis DT, Inglesby TV, Henderson DA, et al. The Journal of the American Medical Association. 2001.

6. Going Down the Rabbit Hole. — Burdick KJ, Ealick W, Vargas Acevedo H, Sectish TC, Sandora TJ. The New England Journal of Medicine. 2024.

7. Clinical Recognition and Management of Tularemia in Missouri: A Retrospective Records Review of 121 Cases. — Weber IB, Turabelidze G, Patrick S, et al. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 2012.

8. Tularemia‐induced erythema multiforme minor in an 11‐year‐old girl. — Coates SJ, Briggs B, Cordoro KM. Pediatric Dermatology. 2018.

9. Tularaemia: Clinical Aspects in Europe. — Maurin M, Gyuranecz M. The Lancet. Infectious Diseases. 2016.

10. Tularemia: A 30-Year Experience With 88 Cases. — Evans ME, Gregory DW, Schaffner W, McGee ZA. Medicine. 1985.

11. Tularemia Treatment: Experimental and Clinical Data. — Maurin M, Pondérand L, Hennebique A, et al. Frontiers in Microbiology. 2023.

12. Pulmonary tularaemia in a female adolescent with inflammatory bowel disease receiving infliximab: Do not miss the diagnosis. — Schwarzová V, Schwarz J, Mitrová K, et al. Pediatric Pulmonology. 2023.

13. Tularemia Antimicrobial Treatment and Prophylaxis: CDC Recommendations for Naturally Acquired Infections and Bioterrorism Response - United States, 2025. — Nelson CA, Meaney-Delman D, Fleck-Derderian S, Winberg J, Mead PS. MMWR. Recommendations and Reports : Morbidity and Mortality Weekly Report. Recommendations and Reports. 2025.

14. Tularemia Clinical Manifestations, Antimicrobial Treatment, and Outcomes: An Analysis of US Surveillance Data, 2006-2021. — Wu HJ, Bostic TD, Horiuchi K, et al. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 2024.

15. Clinical Management of Potential Bioterrorism-Related Conditions. — Adalja AA, Toner E, Inglesby TV. The New England Journal of Medicine. 2015.

16. Tularemia - Missouri, 2000-2007. — MMWR. Morbidity and Mortality Weekly Report. 2009.

17. Tularemia - United States, 2001-2010. — MMWR. Morbidity and Mortality Weekly Report. 2013.

18. Tularemia: An Experience of 13 Cases Including a Rare Myocarditis in a Referral Center in Eastern Switzerland (Central Europe) and a Review of the Literature. — Frischknecht M, Meier A, Mani B, et al. Infection. 2019.

19. Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2024 Update by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM). — Miller JM, Binnicker MJ, Campbell S, et al. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 2024.

20. 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.

21. Pulmonary Tularemia: A Diagnosis Not to Overlook. — Zaghdoudi A, Robin F, Moulinie J, et al. International Journal of Infectious Diseases : IJID : Official Publication of the International Society for Infectious Diseases. 2026.

22. Tularemia in Pediatric Patients: A Case Series and Review of the Literature. — Kossadoum RF, Baron A, Parizot M, et al. The Pediatric Infectious Disease Journal. 2025.

23. Tularaemia. — Tärnvik A, Berglund L. The European Respiratory Journal. 2003.

24. ACCF/­AHA/­CDC Conference Report on Emerging Infectious Diseases and Biological Terrorism Threats. Task Force III: Prevention and Control of Cardiovascular Complications of Emerging Infectious Diseases and Potential Biological Terrorism Agents and Diseases. — Cooper LT, Mensah GA, Baddour LM, et al. Journal of the American College of Cardiology. 2007.

25. ACCF/­AHA/­CDC Conference Report on Emerging Infectious Diseases and Biological Terrorism Threats. Task Force I: Direct Cardiovascular Implications of Emerging Infectious Diseases and Biological Terrorism Threats. — Baddour LM, Zheng ZJ, Labarthe DR, O'Connor S. Journal of the American College of Cardiology. 2007.