Buruli ulcer is a slowly progressive necrotizing disease of the skin and subcutaneous tissue caused by Mycobacterium ulcerans, the third most common mycobacterial disease after tuberculosis and leprosy. [1-2] The organism produces mycolactone, a lipid-like exotoxin that inhibits the Sec61 translocon, driving tissue destruction and local immune suppression. [1] Approximately 2,000 cases are reported annually worldwide, though this significantly underestimates the true burden. [1]
1. History
- Painless subcutaneous nodule, papule, plaque, or area of edema — often on an exposed extremity [2-3]
- Slow progression over days to weeks; nodule eventually breaks down into an ulcer with characteristic undermined edges [4]
- Timing: Incubation period is poorly defined but estimated at weeks to months
- Triggers: History of minor skin trauma, abrasion, or insect bite in an endemic area [5]
- Ask about travel to or residence in endemic regions: West/Central Africa (especially Ghana, Benin, Cameroon, Nigeria), southeast Australia (Victoria), French Guiana, Japan [6-7]
- Ask about contact with slow-flowing or stagnant water, swampy environments, or outdoor soil exposure [5][8]
- Notably absent: fever, systemic symptoms, lymphadenopathy — the patient typically feels well [5][9]
- Pain is usually absent unless secondary bacterial infection develops [3]
2. Alarm Features
- Oedematous form: Rapidly expanding, aggressive variant with extensive tissue destruction [4]
- Lesions involving critical sites: eye, breast, genitalia, head/neck, or overlying joints [10]
- Signs of osteomyelitis: bone pain, deep extension (up to 14.9% in some series) [4]
- Secondary sepsis or tetanus — rare but the primary causes of mortality [3][5]
- Disseminated disease, especially in HIV-positive patients [4]
- Category III lesions (>15 cm, multifocal, or critical-site involvement) [10]
- Rapid enlargement during treatment may represent a paradoxical reaction (not treatment failure) — occurs in ~2–26% of patients [3][11]
3. Medications
First-line treatment (WHO-recommended)
- Rifampicin 10 mg/kg PO daily + Clarithromycin 15 mg/kg PO daily × 8 weeks — now the preferred fully oral regimen, non-inferior to rifampicin + streptomycin with fewer adverse effects [6]
- Alternative: Rifampicin + a fluoroquinolone (ciprofloxacin or moxifloxacin) [12]
- Emerging evidence supports 6 weeks for small, low-risk lesions and 4 weeks post-surgical excision [12]
Important cautions
- Never use rifampicin as monotherapy — risk of resistance [3]
- Rule out active tuberculosis before starting rifampicin-based therapy to avoid generating MDR-TB [3]
- Monitor for rifampicin drug interactions (CYP3A4 inducer): oral contraceptives, antiretrovirals, warfarin, etc.
- Clarithromycin + rifampicin interaction: rifampicin reduces clarithromycin levels; extended-release clarithromycin is preferred [6]
- Streptomycin (legacy regimen): ototoxicity, nephrotoxicity, painful IM injections — largely replaced [6]
Paradoxical reactions (severe)
4. Diet
- No specific dietary triggers or restrictions
- Adequate protein and caloric intake is important for wound healing, particularly in malnourished populations in endemic areas
- Hydration support during prolonged antibiotic therapy
5. Review of Systems
- Skin: Other nodules, plaques, or ulcers (multifocal disease?)
- MSK: Joint stiffness, limited range of motion near lesion (contracture risk)
- Constitutional: Absence of fever/weight loss helps distinguish from TB or other systemic infections
- Neurologic/ENT: If on streptomycin — hearing changes, tinnitus, vestibular symptoms
- GI: Nausea, abdominal pain (antibiotic side effects)
- Psych: Social stigma, depression, school/work absenteeism [1][5]
6. Collateral History and Family History
- Household contacts with similar lesions (shared environmental exposure, not person-to-person transmission)
- Community awareness of Buruli ulcer in the area
- BCG vaccination history — prior BCG vaccination may confer mild but significant protection [8]
- HIV status — co-infection may lead to disseminated disease and complicates management [4][13]
- Social context: access to wound care, ability to complete 8-week antibiotic course, distance to health facility
7. Risk Factors
- Residence in or travel to endemic areas — the single most important risk factor [8][14]
- Proximity to slow-flowing/stagnant water bodies, swamps, and wetlands [5]
- Contact with soil during outdoor work [8]
- Minor skin trauma or abrasions sustained outdoors [5]
- Diabetes mellitus (>2-fold increased odds in Australian data) [8]
- Lack of protective clothing, failure to use insect repellent [8]
- Not washing wounds immediately after outdoor injury [8]
- Age: median ~20 years in sub-Saharan Africa; ~60 years in Australia [6]
- Absence of BCG vaccination [8]
- Possum contact and bore water use at residences (Australian data) [8]
8. Differential Diagnosis
In endemic areas, the differential for chronic skin ulcers is broad: [7][15-16]
- Cutaneous leishmaniasis — painless ulcer with raised borders; sand fly exposure; biopsy with Leishmania amastigotes [7]
- Tropical ulcer — similar appearance on shins but exceptionally painful (key distinguishing feature) [7]
- Pyoderma / bacterial skin infection — painful, purulent; responds to standard antibiotics [15]
- Cutaneous tuberculosis — rare in travelers; systemic symptoms more common
- Mycobacterium marinum infection — aquarium/fish tank exposure; sporotrichoid pattern
- Vascular ulcers (venous/arterial) — 22% of ulcers in one endemic-area study [15]
- Cutaneous anthrax — painless black eschar; animal exposure history [7]
- Sporotrichosis / chromomycosis — fungal; nodular lymphangitic spread [16]
- Squamous cell carcinoma / other neoplasia — 5% of ulcers in endemic areas [15]
- Fistulated osteomyelitis — especially in children (11.4%) [15]
Pearl: In endemic areas, every suspicious lesion should be treated as M. ulcerans until proven otherwise. [9] A characteristic smell recognized by experienced clinicians is strongly predictive (OR 16.4). [17]
9. Past Medical History
- Prior episodes of Buruli ulcer (recurrence is rare with antibiotic treatment but possible) [12]
- HIV/AIDS — risk of disseminated disease [4]
- Diabetes mellitus — independent risk factor [8]
- BCG vaccination status [8]
- Prior TB or leprosy treatment (drug resistance considerations)
- Surgical history — prior skin grafts, excisions, contracture releases
- Immunosuppressive conditions or medications
10. Physical Exam
Vital signs: Typically normal — absence of fever is characteristic [5][9]
Skin exam (key findings)
- Pre-ulcerative: Painless, firm, non-tender subcutaneous nodule (1–2 cm), tethered to overlying skin; or indurated plaque; or diffuse non-pitting edema [3-4]
- Ulcerative: Necrotic slough at base, undermined (overhanging) edges — the ulcer appears smaller than its true extent [3-4]
- Surrounding skin may appear normal despite extensive subcutaneous necrosis
- Lesions most commonly on extremities (especially lower limbs), but can involve trunk, head, face [4]
- Measure and document lesion diameter — determines WHO category [10]
Focused exam
- Assess for joint involvement, range of motion limitations
- Palpate for satellite nodules or distant lesions (multifocal disease)
- Evaluate for signs of secondary bacterial infection (erythema, warmth, purulence, pain)
- Lymph node exam — typically non-tender; lymphadenopathy is uncommon
11. Lab Studies
Diagnostic confirmation
- IS2404 PCR — gold standard; sensitivity >90%, highly specific [1][9]
- Ulcerated lesion: dry swab under the undermined edge [12]
- Non-ulcerated lesion: punch biopsy or fine-needle aspirate [12]
- Incorrectly performed swabs (e.g., on non-ulcerated skin) can yield false negatives [12]
- Ziehl-Neelsen stain (AFB smear) — sensitivity 40–80%; the only field-deployable test [9]
- Culture on Löwenstein-Jensen medium at 29–33°C — sensitivity 20–60%; results take 6–12 weeks [9]
- Histopathology — sensitivity >90%; shows coagulative necrosis of subcutaneous fat with extracellular AFB clusters [9]
Baseline labs before treatment
- LFTs, renal function (rifampicin/clarithromycin monitoring) [6]
- HIV test [10]
- Pregnancy test in females of reproductive age [6]
- Audiometry if streptomycin is used [6]
Monitoring during treatment
12. Imaging
- Plain radiographs of the affected limb if osteomyelitis is suspected (bone pain, deep lesion, prolonged disease duration) [18]
- Ultrasound may help delineate subcutaneous extent of non-ulcerated lesions
- MRI for complex cases to assess deep tissue/bone involvement
- Imaging is generally unnecessary for typical small, superficial Category I lesions
13. Special Tests
WHO Severity Classification: [10]
- Acetate sheet tracings or serial photography for objective lesion size monitoring [6][20]
- Punch biopsy for non-ulcerated lesions when PCR swab is not feasible [12]
14. ECG
- Not routinely indicated
- Consider if using fluoroquinolones (QTc prolongation risk), especially with concurrent clarithromycin
- Baseline ECG if significant cardiac history or polypharmacy
15. Assessment
Buruli ulcer is a clinical diagnosis confirmed by PCR in the appropriate epidemiologic context. Key clinical pearls:
- The hallmark is a painless, slowly progressive skin lesion with undermined edges in a patient with exposure to an endemic area [2][4]
- Absence of systemic symptoms is characteristic and helps distinguish from other infections [9]
- Late presentation is common due to painlessness, lack of systemic illness, and limited healthcare access [9]
- Severity ranges from small nodules (Category I) to massive tissue-destructive ulcers with osteomyelitis (Category III) [10]
- Paradoxical reactions (transient worsening during/after treatment) occur in ~2–26% of patients, peak around week 8, and should not be mistaken for treatment failure — cultures are negative [11][20]
- Complications: contractures, functional disability, amputation (rare), secondary sepsis, psychosocial stigma [1][5]
16. Treatment Plan
Antibiotics
- Rifampicin 10 mg/kg PO daily + Clarithromycin (extended release) 15 mg/kg PO daily × 8 weeks [1][6]
- Alternative: Rifampicin + moxifloxacin or ciprofloxacin [12]
- Shorter courses (6 weeks for small lesions; 4 weeks post-excision) are emerging but not yet standard WHO recommendation [12]
Wound care
- Critical adjunct — enhances healing and prevents secondary infection [12]
- Absorptive dressings for exudative wounds; vaseline gauze for non-exuding wounds [6]
- Short-stretch bandages for lymphedema prevention [6]
- Daily dressing changes if excessive discharge [6]
Surgery
- Not required for most Category I lesions treated with antibiotics [6]
- Indicated for Category II/III lesions not responding to antibiotics, functional limitation, or severe paradoxical reactions [10][12]
- WHO recommends antibiotics for minimum 4 weeks before surgery [10]
- Excision with small rim of healthy tissue; skin grafting as needed [14]
Paradoxical reactions
- Continue antibiotics — do not extend beyond 8 weeks [13]
- Conservative management for mild reactions
- Prednisolone for severe reactions with marked tissue necrosis [11][13]
- Surgery may be needed for refractory paradoxical reactions [12]
Rehabilitation
- Physiotherapy for contracture prevention, especially for peri-articular lesions [1]
- Psychosocial support [1]
17. Disposition
Outpatient management is appropriate for
- Category I lesions with reliable follow-up and wound care access
- Patients able to complete supervised oral antibiotic therapy
Admission criteria
- Category II/III lesions requiring intensive wound care or surgical planning
- Lesions involving joints or critical sites [6]
- Patients from remote areas unable to access regular follow-up [6]
- Severe paradoxical reactions
- Secondary sepsis or systemic complications
Specialist consultation triggers
- Infectious disease consultation for all confirmed/suspected cases
- Surgical consultation for Category II/III lesions or non-healing wounds
- Pediatric specialist referral for children (higher rates of non-ulcerative and severe lesions, more paradoxical reactions) [12]
- Orthopedic consultation if osteomyelitis suspected
Reporting: Buruli ulcer is a notifiable disease in endemic regions; cases in non-endemic areas should be discussed with public health authorities [12]
18. Follow Up / Return Precautions
Follow-up schedule
- Every 2 weeks during the 8-week antibiotic course [6]
- Monthly thereafter until complete healing (median 4–5 months to full epithelialization) [12]
- Assess for recurrence at 12 months post-treatment [6]
Critical patient counseling
- Ulcers typically enlarge during antibiotic treatment — this is expected and does not indicate failure [12][20]
- Ulcers will not have healed by completion of antibiotics [12]
- 83% of non-ulcerative lesions will ulcerate after starting treatment (paradoxical reaction) [20]
- Relapse is very rare (<5%) with completed antibiotic therapy [6]
Return precautions — seek immediate reassessment for
- Rapid expansion of lesion with new pain, fever, or purulent discharge (secondary infection vs. severe paradoxical reaction)
- New lesions at distant sites
- Signs of systemic illness (fever, rigors)
- Joint stiffness or functional limitation developing near the lesion
Prevention counseling
- Wear protective clothing outdoors in endemic areas [8]
- Use insect repellent [8]
- Promptly clean and cover any skin abrasions sustained outdoors [8][14]
- Avoid direct contact with stagnant water bodies in endemic regions [5]
References
1. Buruli Ulcer. — Yotsu RR, Simmonds RE, de Souza DK, et al. Nature Reviews. Disease Primers. 2025.
2. Buruli Ulcer: Review of a Neglected Skin Mycobacterial Disease. — Guarner J. Journal of Clinical Microbiology. 2018.
3. Drugs for Treating Buruli Ulcer (Mycobacterium Ulcerans Disease). — Yotsu RR, Richardson M, Ishii N. The Cochrane Database of Systematic Reviews. 2018.
4. Buruli Ulcer: Emerging From Obscurity. — Wansbrough-Jones M, Phillips R. Lancet. 2006.
5. Mycobacterium Ulcerans Infection. — van der Werf TS, van der Graaf WT, Tappero JW, Asiedu K. Lancet. 1999.
6. Rifampicin and Clarithromycin (Extended Release) Versus Rifampicin and Streptomycin for Limited Buruli Ulcer Lesions: A Randomised, Open-Label, Non-Inferiority Phase 3 Trial. — Phillips RO, Robert J, Abass KM, et al. Lancet. 2020.
7. Post-Travel Dermatologic Conditions. — Karolyn A. Wanat and Scott A. Norton CDC Yellow Book. 2025.
8. Comprehensive Case-Control Study of Protective and Risk Factors for Buruli Ulcer, Southeastern Australia. — McNamara BJ, Blasdell KR, Yerramilli A, et al. Emerging Infectious Diseases. 2023.
9. Mycobacterium Ulcerans Infection: Control, Diagnosis, and Treatment. — Sizaire V, Nackers F, Comte E, Portaels F. The Lancet. Infectious Diseases. 2006.
10. Delayed Versus Standard Assessment for Excision Surgery in Patients With Buruli Ulcer in Benin: A Randomised Controlled Trial. — Wadagni AC, Barogui YT, Johnson RC, et al. The Lancet. Infectious Diseases. 2018.
11. Incidence, Clinical Spectrum, Diagnostic Features, Treatment and Predictors of Paradoxical Reactions During Antibiotic Treatment of Mycobacterium Ulcerans Infections. — O'Brien DP, Robson M, Friedman ND, et al. BMC Infectious Diseases. 2013.
12. Management of Mycobacterium Ulcerans Infection (Buruli Ulcer) in Australia: Consensus Statement. — Muhi S, Cox VR, O'Brien M, et al. The Medical Journal of Australia. 2025.
13. Clinical Features and Management of a Severe Paradoxical Reaction Associated With Combined Treatment of Buruli Ulcer and HIV Co-Infection. — Wanda F, Nkemenang P, Ehounou G, et al. BMC Infectious Diseases. 2014.
14. Consensus Recommendations for the Diagnosis, Treatment and Control of Mycobacterium Ulcerans Infection (Bairnsdale or Buruli Ulcer) in Victoria, Australia. — Johnson PD, Hayman JA, Quek TY, et al. The Medical Journal of Australia. 2007.
15. Differential Diagnosis of Skin Ulcers in a Mycobacterium Ulcerans Endemic Area: Data From a Prospective Study in Cameroon. — Toutous Trellu L, Nkemenang P, Comte E, et al. PLoS Neglected Tropical Diseases. 2016.
16. Imported Tropical Infectious Ulcers in Travelers. — Zeegelaar JE, Faber WR. American Journal of Clinical Dermatology. 2008.
17. Improving Clinical and Epidemiological Predictors of Buruli Ulcer. — Ayelo GA, Sopoh GE, Houezo JG, et al. PLoS Neglected Tropical Diseases. 2018.
18. Clinical Epidemiology of Buruli Ulcer From Benin (2005-2013): Effect of Time-Delay to Diagnosis on Clinical Forms and Severe Phenotypes. — Capela C, Sopoh GE, Houezo JG, et al. PLoS Neglected Tropical Diseases. 2015.
19. Antimicrobial Treatment for Early, Limited Mycobacterium Ulcerans Infection: A Randomised Controlled Trial. — Nienhuis WA, Stienstra Y, Thompson WA, et al. Lancet. 2010.
20. Paradoxical Responses After Start of Antimicrobial Treatment in Mycobacterium Ulcerans Infection. — Nienhuis WA, Stienstra Y, Abass KM, et al. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 2012.