01Approach to the Critical Patient/attcp39

Immediate priorities

›Life-threatening complications of Buruli ulcer

›Secondary sepsis from superinfected ulcer

›Fever, rigors, tachycardia, hypotension

›Broad-spectrum IV antibiotics within 1 hour if septic shock

›Tetanus risk from contaminated wound

›Tetanus toxoid booster if not up to date

›Tetanus immunoglobulin if unvaccinated and high-risk wound

›Osteomyelitis with deep extension

›Bone pain, periosteal tenderness, sinus tract formation

›Orthopedic consultation for surgical planning

Alarm features requiring escalation

›High-risk lesion features

›Category III lesion (>15 cm diameter, multifocal, or critical-site)

›Critical sites: eye, breast, genitalia, head/neck, joints

›Immediate infectious disease consultation

›Oedematous form

›Rapidly expanding non-pitting edema

›Highest risk for functional impairment and amputation

›Disseminated disease in immunocompromised host

›HIV co-infection with multiple distant lesions

›Requires specialist management

Monitoring and targets

›Clinical monitoring during antibiotic therapy

›Lesion size and undermined edge extent at each visit

›Measure diameter at each biweekly visit

›Photograph for objective documentation

›Paradoxical reaction monitoring

02History/hx40

Presentation pattern

›Core syndrome

›Painless subcutaneous nodule, papule, plaque, or area of edema

›Typically 1–2 cm on exposed extremity

›Tethered to overlying skin

›Slow progression over days to weeks

›Nodule breaks down into ulcer with undermined edges

›Ulcer appears smaller than true subcutaneous extent

›Absence of pain unless secondary bacterial superinfection

›Absence of fever and systemic symptoms in uncomplicated disease

›Patient typically feels well despite significant tissue destruction

Exposure and travel history

›Geographic exposure

›Residence in or travel to endemic regions

›West and Central Africa: Ghana, Benin, Cameroon, Nigeria

›Southeast Australia: Victoria (Bairnsdale or Daintree region)

›French Guiana, Japan, Papua New Guinea

›Environmental exposure

›Proximity to slow-flowing or stagnant water, swamps, wetlands

›Outdoor soil contact during agricultural or recreational activities

›Minor skin trauma or abrasion sustained outdoors in endemic area

Risk factors

›Host risk factors

›Age

›Median ~20 years in sub-Saharan Africa

›Median ~60 years in Australia

›Diabetes mellitus: >2-fold increased odds in Australian data

›HIV/AIDS: risk of disseminated and severe disease

03Physical Exam/exam39

Vital signs

›Vital sign pattern

›Temperature typically normal — absence of fever is characteristic

›Fever suggests secondary bacterial superinfection

›Fever suggests paradoxical reaction with systemic component

›Hemodynamic stability expected in uncomplicated disease

›Shock physiology indicates secondary sepsis

Skin examination

›Pre-ulcerative lesion forms

›Nodule: painless, firm, non-tender subcutaneous nodule 1–2 cm

›Tethered to overlying skin, mobile from deep structures

›Plaque: indurated, painless, raised area of skin induration

›Oedema: diffuse, non-pitting edema without erythema or warmth

›Most aggressive form; may involve entire limb

›Ulcerative lesion features

›Necrotic slough at ulcer base

›Undermined (overhanging) edges — pathognomonic feature

›Ulcer appears smaller than true subcutaneous extent

›Surrounding skin appears normal despite extensive subcutaneous necrosis

›Most common sites: lower limbs (predominant), upper limbs, trunk

›Measure diameter in two perpendicular planes for WHO categorization

Focused regional examination

›Musculoskeletal assessment

›Joint range of motion near lesion

›Limitation indicates peri-articular involvement

›Contracture risk with lesions overlying major joints

›Bone tenderness on palpation (osteomyelitis assessment)

›Lymph node examination

04Differential Diagnosis/ddx41

Life-threatening mimics

›Secondary sepsis from any chronic skin ulcer

›ICD-10: A31.1 (Cutaneous mycobacterial infection)

›Sepsis workup if systemic features present

›Necrotizing fasciitis

›ICD-10: M72.6

›Rapid spread, crepitus, severe systemic toxicity — distinguishes from Buruli

Infectious skin ulcer mimics

›Cutaneous leishmaniasis

›ICD-10: B55.1

›Painless ulcer with raised borders; sand fly exposure history

›Biopsy reveals Leishmania amastigotes

›Tropical ulcer (Fusobacterium / Treponema)

›ICD-10: A69.1

›Exceptionally painful — key distinguishing feature from Buruli

›Lower shins; responds to penicillin

›Mycobacterium marinum infection

›ICD-10: A31.1

›Aquarium or fish tank exposure; sporotrichoid nodular spread

›Treated with clarithromycin-based regimens

›Cutaneous tuberculosis (lupus vulgaris, scrofuloderma)

›ICD-10: A18.4

›Systemic TB features; positive TST/IGRA

›Pyoderma / impetigo / cellulitis

›ICD-10: L08.9

›Painful, purulent; rapid response to standard antibiotics

Non-infectious mimics

›Venous or arterial ulcer

05Laboratory Tests/lt38

Microbiological confirmation

›IS2404 PCR (gold standard)

›Sensitivity >90%, highly specific for M. ulcerans

›Preferred first-line diagnostic test

›Ulcerated lesion: dry swab under undermined edge (not surface swab)

›Non-ulcerated lesion: punch biopsy or fine-needle aspirate preferred

›False negatives occur with incorrect sampling technique

›Surface swab of non-ulcerated skin yields false negatives

›Inadequate depth of sampling under undermined edge

›Ziehl-Neelsen (AFB) smear

›Sensitivity 40–80%; only field-deployable test in resource-limited settings

›Positive smear sufficient to initiate treatment in endemic areas

›Extracellular AFB clusters in necrotic tissue are characteristic

›Mycobacterial culture

›Sensitivity 20–60%; results take 6–12 weeks

›Löwenstein-Jensen medium at 29–33°C (suboptimal growth at 37°C)

›Used for antibiotic sensitivity testing, not acute diagnosis

›Histopathology

›Sensitivity >90%; shows coagulative necrosis of subcutaneous fat

›Extracellular AFB clusters in necrotic zone

›Minimal inflammatory infiltrate due to mycolactone immunosuppression

Baseline and monitoring labs

›Pre-treatment baseline

›LFTs (ALT, AST, ALP, bilirubin) — rifampicin hepatotoxicity monitoring

›Repeat at 4 weeks and 8 weeks during therapy

›Serum creatinine and eGFR — clarithromycin/rifampicin monitoring

›HIV test — all patients with suspected Buruli ulcer (WHO recommendation)

›Co-infection alters prognosis and may require ART co-administration

06Diagnostic Tests/dt42

Scoring Systems

›WHO Buruli Ulcer category classification

›Category I: single small lesion <5 cm

›Outpatient oral antibiotics; lower disability risk

›Category II: single lesion 5–15 cm

›May require wound care admission; moderate disability risk

›Category III: lesion >15 cm, multifocal, or critical-site location

›Highest disability and mortality risk; specialist care required

›Critical sites: periocular, face, breast, genitalia, overlying joints

›Clinical prediction score for endemic settings

›Characteristic smell recognized by experienced clinicians

›OR 16.4 for Buruli ulcer diagnosis (Ayelo et al., 2018)

›Painlessness: key clinical feature

›Undermined edge: pathognomonic on examination

MRI

›MRI indications in Buruli ulcer

›Suspected bone or joint involvement

›Superior soft-tissue contrast for osteomyelitis delineation

›STIR sequences for bone marrow edema

›Pre-surgical planning for Category II/III lesions

›Defines true subcutaneous extent of necrosis beyond visible ulcer margins

›Limitations

›Not routinely available in most endemic settings

›Availability in non-endemic referral centres for returning travellers

CT

›CT indications in Buruli ulcer

›Suspected osteomyelitis or periosteal involvement

›Cortical destruction, periosteal reaction, sequestrum formation

07Disposition/dispo29

Outpatient management criteria

›Eligible for outpatient oral antibiotic therapy

›Category I lesion (single lesion <5 cm)

›Reliable access to biweekly wound care and follow-up

›Ability to complete supervised 8-week antibiotic course

›No secondary bacterial infection requiring IV antibiotics

›Hemodynamically stable, afebrile

›Adequate social support and access to healthcare facility

Admission indications

›Inpatient management required for

›Category II/III lesions requiring intensive wound care

›Lesions overlying joints or critical sites

›Oedematous form with rapid progression

›Patients from remote areas unable to access regular follow-up

›Severe paradoxical reactions with tissue necrosis

›Secondary sepsis or systemic infection

›Surgical planning requirement (pre-operative antibiotic course)

›HIV co-infection with complex management needs

Transfer and referral criteria

›Specialist referral triggers

›All confirmed or suspected cases: infectious disease consultation

›Category II/III lesions: surgical consultation

›Osteomyelitis: orthopedic consultation

›Children with non-ulcerative or severe lesions: pediatric specialist

›Non-endemic country cases: public health notification required

Follow-up schedule

›Monitoring plan after discharge

›Biweekly visits during 8-week antibiotic course

08Treatment/t54

First-line antibiotic therapy

›WHO-recommended oral regimen (preferred)

›Rifampicin 10 mg/kg PO daily for 8 weeks

›Maximum 600 mg/day in adults

›Non-inferior to rifampicin + streptomycin (Lancet 2020 RCT)

›NEVER use rifampicin as monotherapy — resistance risk

›Clarithromycin (extended-release formulation) 15 mg/kg PO daily for 8 weeks

›Extended-release preferred to counteract rifampicin-mediated CYP3A4 induction

›Reduces clarithromycin plasma levels by ~75% compared to without rifampicin

›Maximum 1000 mg/day

Alternative antibiotic regimens

›Alternative oral combinations (evidence level B)

›Rifampicin 10 mg/kg PO daily + Moxifloxacin 400 mg PO daily for 8 weeks

›Used when clarithromycin not tolerated or unavailable

›Rifampicin 10 mg/kg PO daily + Ciprofloxacin 500 mg PO twice daily for 8 weeks

›Lower evidence base than clarithromycin combination

›Legacy regimen (replaced by oral therapy)

›Rifampicin + Streptomycin IM 15 mg/kg/day

›Now largely replaced due to ototoxicity, nephrotoxicity, painful injections

›Streptomycin: avoid in pregnancy (aminoglycoside ototoxicity to fetus)

Treatment duration modifications

›Emerging shorter-course evidence

›6-week course for Category I lesions (small, low-risk) — not yet WHO standard

›Based on Phillips et al. 2020 Lancet data subset

›4 weeks post-surgical excision for Category II lesions

›WHO minimum 4 weeks pre-operatively before surgery

Wound care

›Wound management (critical adjunct)

09Special Populations/sp43

Pregnancy

›Pregnancy-specific considerations

›Rifampicin: generally considered safe in pregnancy

›Category C; benefits outweigh risks given disease morbidity

›Vitamin K supplementation recommended near term (CYP450 induction affects neonatal clotting)

›Clarithromycin: Category C; limited human data

›Animal studies show embryotoxicity at high doses

›Use if benefits outweigh risks; alternative is fluoroquinolone-based regimen

›Fluoroquinolones (moxifloxacin, ciprofloxacin): generally avoided in pregnancy

›Theoretical cartilage toxicity; limited human safety data

›Streptomycin: contraindicated in pregnancy

›Aminoglycoside ototoxicity causes congenital sensorineural hearing loss

›Wound care and surgical options remain unchanged

›Infectious disease consultation mandatory for all pregnant patients with Buruli ulcer

Geriatric

›Geriatric-specific considerations

›Epidemiology in Australia

›Median age ~60 years in Australian endemic regions

›Higher rates of diabetes mellitus (independent risk factor)

›Rifampicin drug interactions increased in older patients

›Polypharmacy: warfarin, statins, antihypertensives affected by CYP3A4 induction

›Anticoagulation monitoring required — INR fluctuation with rifampicin

›Renal function decline

›Adjust clarithromycin if eGFR <30 mL/min/1.73m2

›Creatinine clearance-based dosing

›Wound healing impaired

›Diabetes, peripheral vascular disease prolong healing time

›Nutritional assessment and protein supplementation

10Background/b59

Epidemiology

›Global burden

›Approximately 2,000 cases reported annually worldwide

›Significantly underestimates true burden due to underreporting

›Third most common mycobacterial disease globally after TB and leprosy

›Notifiable disease in endemic regions

›Non-endemic country cases require public health notification

›Geographic distribution

›West and Central Africa: Ghana, Benin, Cameroon, Nigeria (highest burden)

›Southeast Australia: Victoria (Bairnsdale region; rising incidence since 2010s)

›French Guiana, Japan, Papua New Guinea, Democratic Republic of Congo

›Demographics

›Sub-Saharan Africa: median age ~20 years; affects children disproportionately

›Australia: median age ~60 years; associated with diabetes and outdoor activities

›No clear sex predilection

›Lower limb involvement: 50–80% of cases in most series

›Mortality and morbidity

›Case fatality rate low for cutaneous disease

›Mortality primarily from secondary sepsis and tetanus

›Disability rate significant: limb contractures, amputations in severe cases

›Delay to diagnosis major driver of poor functional outcomes

Pathophysiology

›Causative organism

›Mycobacterium ulcerans: slow-growing, non-tuberculous mycobacterium

›Optimal growth temperature 29–33°C (not 37°C — explains skin tropism)

›Environmental reservoir: stagnant and slow-flowing water, soil

›Transmission route: not fully established; insect vector (water bugs) proposed

›Minor skin trauma enabling inoculation is key cofactor

›Mycolactone toxin: central pathogenic mechanism

›Lipid-like polyketide exotoxin — unique to M. ulcerans among mycobacteria

›Inhibits Sec61 translocon, blocking co-translational protein translocation

›Causes local anesthesia (explains painlessness of lesions)

›Drives coagulative necrosis of subcutaneous fat and dermis

›Suppresses local innate and adaptive immune response

›Explains minimal inflammatory infiltrate on histopathology

›Enables organism survival without triggering pain or systemic immune response

›Tissue destruction sequence

›Subcutaneous fat necrosis progresses before skin ulceration

›Explains characteristic undermined edge (skin intact beyond necrotic deep tissue)

›Eventual skin breakdown produces classic Buruli ulcer morphology

›Osteomyelitis occurs by direct extension (up to 14.9% in some series)

Therapeutic Considerations

›Antibiotic mechanism and rationale

›Rifampicin: inhibits RNA polymerase beta subunit; bactericidal against M. ulcerans

›Never use as monotherapy — resistance selects rapidly

›Rule out active TB before initiating — risk of generating MDR-TB

›Clarithromycin: macrolide inhibiting 50S ribosomal subunit; bacteriostatic then bactericidal

›Extended-release formulation preferred to mitigate rifampicin CYP3A4 induction

›Non-inferiority established for rifampicin + clarithromycin vs. rifampicin + streptomycin

›Lancet 2020 RCT (Phillips et al.): primary endpoint met with better tolerability

›Healing trajectory

›Ulcers will not have healed at end of 8-week antibiotic course

›Median 4–5 months to complete epithelialization after antibiotics

›Wound care is essential adjunct throughout healing phase

›BCG vaccination

›Prior BCG confers mild but significant protection against severe Buruli ulcer

›Mechanism: cross-reactive cell-mediated immunity to mycobacterial antigens

›Does not prevent infection but may limit disease severity

›Drug resistance

›Natural resistance to rifampicin reported rarely

›No clinically significant resistance to clarithromycin or fluoroquinolones reported to date

›Surveillance for resistance important as oral regimens scale up

11Patient Discharge Instructions/pdi33

copy discharge instructions

›Discharge instructions for Buruli ulcer (Mycobacterium ulcerans infection)

›You have been diagnosed with Buruli ulcer, a skin infection caused by a bacterium called Mycobacterium ulcerans

›This infection is treatable with antibiotics taken by mouth for 8 weeks

›Complete the full course even if the wound looks worse during treatment

›Your medications

›Rifampicin: take once daily with a small amount of food to reduce nausea

›Clarithromycin extended-release: take once daily with food

›Do not stop either medication without contacting your doctor

›Rifampicin will turn your urine, tears, and sweat orange-red — this is harmless

›Wound care instructions

›Keep the wound clean and covered with the dressings provided

›Change dressings as instructed (typically daily or every 2 days)

›Do not apply any creams or remedies not prescribed by your doctor

›What to expect during recovery

›Your wound will likely get larger during the first weeks of antibiotic treatment — this is normal and expected

›Non-ulcerative lesions may open into a wound after antibiotics begin — this is part of healing

›Full wound healing takes an average of 4–5 months after finishing antibiotics

›Follow-up appointments

›You must be seen every 2 weeks during your 8-week antibiotic course

›Bring your medications to each appointment

›Blood tests will be done to check your liver and kidneys during treatment

›Return to emergency department immediately if you develop

›Fever, chills, or feeling very unwell

›Rapid expansion of your wound with new severe pain or pus

›Yellowing of your skin or eyes (jaundice)

›New ulcers or lesions appearing at other sites on your body

›Inability to move a joint near your wound

12References/r38

Guidelines and key sources

›Yotsu RR, Simmonds RE, de Souza DK, et al.

›Buruli Ulcer. Nature Reviews Disease Primers. 2025

›PMID 41413430

›Phillips RO, Robert J, Abass KM, et al.

›Rifampicin and Clarithromycin vs. Rifampicin and Streptomycin for Buruli Ulcer. Lancet. 2020

›PMID 32171422; landmark non-inferiority RCT establishing oral regimen

›Nienhuis WA, Stienstra Y, Thompson WA, et al.

›Antimicrobial Treatment for Early, Limited M. ulcerans Infection. Lancet. 2010

›PMID 20137805

›Yotsu RR, Richardson M, Ishii N.

›Drugs for Treating Buruli Ulcer. Cochrane Database of Systematic Reviews. 2018

›Cochrane systematic review; treatment evidence synthesis

›Guarner J.

›Buruli Ulcer: Review of a Neglected Skin Mycobacterial Disease. J Clin Microbiology. 2018

›PMID 29343539

›Wansbrough-Jones M, Phillips R.

›Buruli Ulcer: Emerging From Obscurity. Lancet. 2006

›PMID 16753488

›McNamara BJ, Blasdell KR, Yerramilli A, et al.

›Comprehensive Case-Control Study of Risk Factors for Buruli Ulcer, SE Australia. Emerging Infectious Diseases. 2023

›PMID 37735741

›Muhi S, Cox VR, O'Brien M, et al.

›Management of M. ulcerans Infection in Australia: Consensus Statement. Med J Australia. 2025

›PMID 39987502

›O'Brien DP, Robson M, Friedman ND, et al.

›Paradoxical Reactions During Antibiotic Treatment of M. ulcerans Infections. BMC Infectious Diseases. 2013

›PMID 24007371

Evidence & Review

Evidence & Review