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Buruli ulcer (Mycobacterium ulcerans infection)

Buruli ulcer (Mycobacterium ulcerans infection)
Literature review current through: Jan 2024.
This topic last updated: Dec 13, 2023.

INTRODUCTION — Buruli ulcer is a disabling skin infection caused by Mycobacterium ulcerans. It is named for the Buruli district in Uganda, a region where many of the early cases in the literature were described [1-4]. Buruli ulcer begins as localized skin lesions that progress to extensive ulceration, leading to functional disability, loss of economic productivity, and social stigma [5-8]. Since the 1998 World Health Organization (WHO) Buruli ulcer initiative, there has been increased attention to research efforts for treatment and control of Buruli ulcer [9].

EPIDEMIOLOGY — M. ulcerans is the third most common mycobacterial infection worldwide in immunocompetent hosts (after tuberculosis and leprosy) [10,11]. Buruli ulcer due to M. ulcerans mainly affects individuals in humid, rural, tropical regions with limited access to medical care. It has been reported in about 33 (mostly tropical) countries, with the greatest frequency in Africa, particularly in the West African countries of Côte d'Ivoire, Ghana, and Bénin (20 to 158 cases per 100,000) [12-19]. Cases have also been described in other locales including Mexico, South America, Papua New Guinea, and Australia (where the disease is known as Bairnsdale ulcer) [20-24]. In Victoria, Australia, and in Japan [25], transmission has been observed in moderate, nontropical climates. Since 2010, the incidence has decreased in African endemic zones but emerged unprecedentedly in the temperate zone in Victoria, Australia [26].

The peak age group in West African studies is 5 to 15 years, although Buruli ulcer can affect any age group [16,27,28]. In Japan, the median age is 40 to 57 years [29], and, in Australia, the median age is 50 to 66 years [22]. The disease has a low mortality rate, but its disabling sequelae have an enormous physical and socioeconomic impact on affected individuals.

Transmission — The mode of M. ulcerans transmission is not fully understood. Areas affected by Buruli ulcer disease are located near stagnant or slow-moving water, and outbreaks appear to be related to environmental changes (deforestation, agriculture, hydraulic installations) involving surface water [13,30-32]. Buruli ulcers have been observed more frequently during the rainy season in Africa, and exposure may occur in muddy farming fields [21,33,34].

Transmission of the organism may result from direct inoculation of the causative organism into subcutaneous tissue through skin trauma. However, extensive sampling of exposed skin surface among residents in highly endemic locales in Victoria, Australia was negative for genomic M. ulcerans [35].

Insects may play a role in some cases [36,37] though not in all foci where transmission occurs [38]. Water insects (Naucoris and Belostoma spp) have been implicated in laboratory transmission of infection, but their potential role as vectors [39] has been questioned by studies in West Africa [40,41]. In Australia, salt marsh mosquitoes appear to have positive polymerase chain reaction (PCR) signals [31,42,43].

Intermediate hosts including aquatic animals may also play a role [39,42,44-46]; amebae have also been implicated [47], but their role in transmission is limited [48]. Human-to-human transmission is rare [49,50]. Extensive evidence suggests that M. ulcerans is contracted from environmental reservoirs [51,52]; only once has the causative organism been isolated by culture from the environment [36].

MICROBIOLOGY — Buruli ulcer is caused by M. ulcerans, a slow-growing mycobacterium that can be cultured in vitro at 29 to 33°C [53-55]. M. ulcerans is closely related to Mycobacterium marinum (98 percent DNA homology), but M. ulcerans is unique among human pathogens in that it is capable of producing mycolactone, a potent cytotoxin that induces necrosis and ulceration [56-58]. In Japan, a subspecies, M. ulcerans subsp shinshuense, has been identified as a cause of Buruli ulcer [25,59,60]. (See "Microbiology of nontuberculous mycobacteria".)

PATHOGENESIS — Mycolactones, secreted by M. ulcerans, drive the pathogenesis. The molecular structure of the mycolactones is well understood [61-67]. Mycolactones A and B are associated with African strains of M. ulcerans, while mycolactone C is associated with the Australian strains. Mycolactones A and B are more potent toxins than mycolactone C, but whether this reflects the clinical differences in disease severity is uncertain [68,69]. Toxicity of mycolactones appears to depend on specific isomers of these molecules [70]. Further understanding of the mycolactone production mechanisms and other aspects of M. ulcerans pathogenesis could facilitate development of a protective vaccine [71].

Excess mycolactone production may play an important role in the pathophysiology of the less common presentation of initial edema and relatively rapid progression [61]. The effects of mycolactones include cell structural deformation and apoptosis of several cell types including immune cells. Analgesia is mediated predominantly by host angiotensin 2 receptor activation, resulting in hyperpolarization induced by blocking potassium channels [72,73]. (See 'Clinical manifestations' below.)

Disruption of the intracellular Sec61 translocon plays a central role in immunosuppression and cell death, but other mechanisms are also active, including damage to the cytoskeleton of several different host cells through activation of the Wiskott-Aldrich syndrome proteins [74,75] by a mechanism that blocks protein synthesis post-translation in the endoplasmic reticulum in target cells [76]. Mycolactone causes Sec61-dependent loss of endothelial glycocalyx and basement membranes [77]. Host CD4+ helper T lymphocytes, as well as other immune cells are also downregulated by mycolactone, resulting in transient systemic impairment of a Th1 phenotype immune response [78,79] as well as a more general transient downregulation including Th2, Th17, and Treg responses [80]. Upregulation of IL1-beta may contribute to a proinflammatory effect of the mycolactone after an initial stage of cytotoxicity and immunosuppression [81]. IL-18 is an important driver of progression of Buruli ulcer lesions [82]. Mycolactone has been measured in tissues and in the bloodstream [83]. With successful antimicrobial treatment, mycolactone tissue concentrations appear to drop over time; in larger lesions, mycolactone may still be detectable after eight weeks of antimicrobial treatment [84].


Incubation period — In Victoria, Australia, where transmission during the study period was limited to the Bellarine and Mornington peninsular areas south of Melbourne, the incubation period could be computed from the time lapsed for patients living elsewhere who developed disease manifestations after visiting endemic areas. The mean incubation period was 138 days, Interquartile Range: 107 to 162 days; the minimal incubation time was 61 days [85]. In a report from Ghana, two cases of neonatal Buruli ulcer, confirmed by PCR, where infection was likely post-partum, suggested that the incubation period in these very young could be as short as 4 to 14 days [86].

Signs and symptoms — Buruli ulcer usually begins as a painless nodule less than 5 cm in diameter. Less common forms of initial skin lesions include papules (described in Australia), plaques, and edematous lesions (picture 1). The limbs are the most frequently involved areas; other involved areas include the head, neck, trunk, and genital regions [3,4,87-89].

The initial lesion usually breaks down after days to weeks, forming an ulcer with characteristic undermined edges (picture 2A-D). Ulceration tends to progress slowly and painlessly, and systemic symptoms are characteristically absent unless secondary bacterial infections or paradoxical responses occur. Studies have begun to unravel the role of paradoxical immune reactions [90-92] and secondary bacterial infections [93,94], but their relative importance remains to be elucidated.

Less commonly, patients may present with an initial edematous lesion with relatively rapid progression and tissue swelling leading to massive ulceration within a few days. They also tend to have associated pain and low-grade fever.

Superficial M. ulcerans infection can progress to involve deeper tissues including tendons, joints, and bones. Contiguous or hematogenous spread leads to osteomyelitis in up to 15 percent of cases, while involvement of other organs is rare [12,88,95,96]. Up to 25 percent of patients with osteomyelitis have no history of Buruli ulcer skin lesions [89]. Disseminated disease in association with HIV has been described [97-100].

The natural history of Buruli ulcer includes spontaneous healing in up to one-third of cases; the mechanisms by which this occurs are poorly understood [11,101]. Such healing is quite slow; it can take months and lead to deep scarring and retractions. Contractures can develop when the lesion is close to a joint, and more than half of patients have persistent functional disability years following acute infection (picture 3 and picture 4) [5,6,27,102-104]. In addition, extensive tissue destruction may warrant amputation [12,17]. Without treatment, it is estimated that a very small proportion of patients with established disease heal spontaneously without sequelae [105]; however, a similar proportion of patients not receiving treatment develop chronic ulceration, which may result in squamous cell carcinoma [106].

DIFFERENTIAL DIAGNOSIS — Buruli ulcers are readily recognized in endemic regions given their chronicity and characteristic appearance of undermined edges. The differential diagnosis of ulcerative lesions associated with Buruli ulcer includes:

Tropical ulcer – Tropical ulcer occurs as a result of a necrotic reaction induced by anaerobic bacteria. It occurs as a result of exposure to vegetation and/or dampness; malnutrition may also play a role. It typically presents with margins that are not undermined (as is typical of Buruli ulcer) and not raised (as is typical for cutaneous leishmaniasis).

Cutaneous leishmaniasis – Cutaneous leishmaniasis typically begins as a papule that enlarges to a nodule with a central crust that drops off to expose an ulcer that is painless, chronic, and may have a raised border. Diagnosis requires demonstration of the parasite by histology, culture, or polymerase chain reaction. (See "Cutaneous leishmaniasis: Clinical manifestations and diagnosis".)

Eumycetoma – Eumycetoma is a chronic subcutaneous mycotic infection of the skin and soft tissue. Uncovered areas exposed to trauma are most commonly affected; the feet are most frequently involved, followed by the legs and hands. Lesions begin as painless nodules and swell, forming large tumors that evolve into necrotic abscesses and draining sinus tracts. The characteristic clinical triad includes tumor, sinus tracts, and macroscopic grains. (See "Eumycetoma".)

Pyoderma gangrenosum – Ulcerative pyoderma gangrenosum begins as a tender, inflammatory papule that develops on normal-appearing skin or at a site of trauma. The initial lesion expands peripherally and degenerates centrally, leading to ulcer formation. The lower extremities and trunk are the most common sites of involvement, though lesions may occur in other areas. (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis".)

Venous stasis ulcer – Ulcers that arise as a result of chronic venous insufficiency occur between the ankle and the knee; the malleoli are the most common sites. Stasis dermatitis of the surrounding skin is common. Pain is not usually severe; patients with concomitant diabetes lack sensation and have signs of neuropathy on examination. (See "Diagnostic evaluation of lower extremity chronic venous disease".)

Diabetes mellitus and sickle cell disease may be associated with skin ulcers involving the lower leg. Diabetic ulceration occurs over weight-bearing areas as a result of diabetic neuropathy, autonomic dysfunction, and/or vascular insufficiency. Leg ulcers associated with sickle cell disease occur near the medial or lateral malleolus and are frequently bilateral. (See "Evaluation of the diabetic foot" and "Overview of the clinical manifestations of sickle cell disease", section on 'Leg ulcers'.)

Squamous cell carcinoma – Squamous cell carcinoma frequently manifests as erythematous papules, plaques, or nodules; ulceration may occur. In addition, squamous cell carcinoma can develop in sites of chronic wounds, chronic inflammation, or scarring. The diagnosis is confirmed by biopsy. (See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".)

Nodules associated with Buruli ulcer generally do not cause significant symptoms. The differential diagnosis includes:

Onchocerciasis – The clinical manifestations of onchocerciasis are ocular changes, pruritus, subcutaneous nodules, and skin disease. The subcutaneous nodules associated with onchocerciasis are deep (not palpable) and typically appear over bony prominences. The diagnosis is established by biopsy. (See "Onchocerciasis".)

Lipoma – Lipomas are benign adipocyte tumors that are asymptomatic and do not enlarge quickly; superficial lipomas rarely cause symptoms. The diagnosis is established by biopsy. (See "Overview of benign lesions of the skin", section on 'Lipoma'.)

Epidermoid cyst – An epidermoid cyst is a discrete, freely movable nodule; it is a benign lesion and often resolves spontaneously. (See "Overview of benign lesions of the skin", section on 'Epidermoid cyst'.)

The differential diagnosis of plaques associated with Buruli ulcer includes:

Eczema – Eczema is a chronic inflammatory skin condition that commonly occurs on flexor surfaces, whereas Buruli ulcer commonly occurs on extensor surfaces. In addition, eczema is associated with itching; Buruli ulcers are not pruritic. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

Kaposi sarcoma – Kaposi sarcoma is an angioproliferative disorder that occurs in the setting of infection with human herpes virus 8. It is characterized by macules, plaques, and nodules on the skin. The course of Kaposi sarcoma is relatively indolent compared with that of Buruli ulcer. (See "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment".)

The differential diagnosis of edema associated with Buruli ulcer includes:

Cellulitis – Cellulitis manifests as areas of skin erythema, edema, and warmth; it may be associated with fever. The presentation of cellulitis is more acute than that of Buruli ulcer. (See "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

Snake or scorpion bite – Local evidence of envenomation includes redness, swelling, blistering, and ecchymosis; necrosis may occur. (See "Snakebites worldwide: Clinical manifestations and diagnosis" and "Scorpion envenomation causing autonomic dysfunction (North Africa, Middle East, Asia, South America, and the Republic of Trinidad and Tobago)".)

Lymphatic filariasis – Lymphatic filariasis consists of lymphatic dilatation and abnormalities in lymphatic drainage; it is a more chronic condition than Buruli ulcer. (See "Lymphatic filariasis: Epidemiology, clinical manifestations, and diagnosis".)

DIAGNOSIS — The diagnosis of Buruli ulcer is frequently based upon clinical manifestations and is often not confirmed because of limited access to laboratory services. In endemic regions, clinical diagnosis by experienced health staff appears favorable [107]. Laboratory diagnostic tools include staining for acid-fast bacilli, histopathology, mycobacterial culture, and polymerase chain reaction (PCR).

Acid-fast staining – The most readily available laboratory technique is acid-fast staining of a swab taken from the undermined edge of an ulcer [108]. In the setting of an endemic area with a strong clinical suspicion for Buruli ulcer, this test is only about 40 percent sensitive [108,109]. In addition, the presence of acid-fast bacilli does not rule out other related infections such as Mycobacterium tuberculosis or other environmental mycobacteria.

Culture – M. ulcerans grows slowly in the laboratory on Lowenstein-Jensen or liquid media (positive results require at least six weeks); the sensitivity of culture diagnosis is usually low but may approach 60 percent [109]. Specimens can be obtained by punch biopsy or fine needle aspiration of the edge of ulcerated lesions or the center of nonulcerated lesions. Alternatively, specimens can be obtained by cotton swab from undermined ulcer edges. Culture yield is highest from plaque specimens and lowest from edematous lesions. The optimal transport medium is Liquid Middlebrook 7H9 broth supplemented with polymyxin B, amphotericin B, nalidixic acid, trimethoprim, and azlocillin (PANTA); specimens in this medium can be stored and transported at room temperature.

Histology – Histology has good sensitivity (up to 82 percent) but requires significant skills and training [10,110]. Diagnostic features of early lesions (eg, within six months of infection) include coalescent necrosis, vascular occlusion, hemorrhage, and large numbers of extracellular acid-fast bacilli. In later disease, granuloma formulation is more prominent and fewer acid-fast bacilli may be observed.

Polymerase chain reaction – PCR for M. ulcerans utilizes the insertion sequence 2404, one of two multicopy insertion sequences in the M. ulcerans genome. The sensitivity of this technique is high; most series report between 70 and 80 percent sensitivity [111]. This tool has been implemented clinically in endemic areas, and it is an important research tool for studying environmental sources of infection. Quantitative real-time (multiplex) PCR (qPCR) technology may gradually replace older technology [109,112,113].

Most experience with PCR has been in the setting of surgical and punch biopsy specimens, although the test may also be used for swabs taken from the undermined edges of ulcers. In edematous forms of the disease, the diagnostic yield of PCR is usually relatively low [109]. Fine needle aspiration is the preferred specimen for PCR evaluation of nonulcerated lesions [111,114-116].

The tuberculin skin test typically turns positive during the course of disease, although skin testing is not recommended for a number of reasons. Skin testing may be negative early in the course of infection and, when positive, cannot differentiate between mycobacterial infections. Serological tests are also not helpful, nor have interferon-gamma release assays for Buruli ulcer been developed for diagnostic purposes. As M. ulcerans (unlike its ancestral species and the closely related M. marinum) lacks the region of difference 1 genes encoding for early secretory antigenic target (ESAT-) 6 and culture filtrate protein (CFP-) 10 [117,118], interferon-gamma release assays are expected to yield a negative result in individuals infected by M. ulcerans.

An assay to demonstrate the presence of mycolactone using thin-layer chromatography [119] is under investigation to be used as a potential point-of-care test [119,120]. In one study the sensitivity and specificity of this test were 66 and 88 percent, respectively [121]. The use of alternative boronic acids might further improve this diagnostic test [122].

If osteomyelitis is suspected, radiologic imaging is useful for further evaluation. (See "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis".)

TREATMENT — Antimicrobial therapy is the cornerstone of treatment, with a very low recurrence rate and high cure rate [123-125]. Antimicrobial treatment alone is highly efficacious in small, relatively new Buruli ulcer lesions [108]. In an Australian cohort study, cultures turned negative within a period of three weeks [126].

The optimal approach to determining if and when surgery is warranted is uncertain [94]. Debridement has been shown to reduce mycobacterial burden and mycolactone production, resulting in improved cellular protective immune response [99]. Limited debridement remains an important component of wound management, especially for larger lesions; however, extensive debridement is no longer considered standard care.

In one report from Benin, delaying the decision to operate (from 8 weeks to 14 weeks after completion of antimicrobial therapy) was not associated with harm; fewer patients underwent surgery, procedures were less extensive, time to healing was shortened, and residual functional limitations after healing were similar [127].

Treatment practices vary widely, depending upon the available resources, the stage of clinical presentation, and clinical expertise [128]. In resource-rich settings, antimicrobial treatment has been combined with surgery [24,129]. In resource-limited settings, surgery and anesthesiology services are scant.

Approach by WHO category

Definitions — The approach to treatment differs slightly depending upon the size and stage of the lesion, as outlined by the following World Health Organization (WHO) classification categories [130]:

Category I – Single nodules, papules, plaques, and ulcers ≤5 cm in diameter; up to one-third of early nodules may heal spontaneously [101].

Category II – Single plaques and ulcers 5 to 15 cm in diameter; edematous lesions.

Category III – Single plaques and ulcers >15 cm in diameter; multiple lesions; joint involvement or osteomyelitis; any lesion at critical sites such as genital organs or the head and neck.

Antimicrobial therapy is the initial therapy of choice. For lesions that require some form of surgery, delayed surgical intervention is preferred, since deterioration during antimicrobial treatment is uncommon and extensive early debridement leaves more tissue damage than necessary. Progression of lesion size on antimicrobial therapy may reflect a paradoxical reaction. (See 'Category II' below.)

Category I — For pre-ulcerative lesions and clean ulcers that are smaller than 5 cm, four weeks of antibiotic therapy may be combined with simple surgical excision followed by immediate closure [24,130]. Some data suggest that simple excision may be curative for category I lesions; others have described recurrence rates of up to 18 percent with surgery alone [101,131-134]. Therefore, antimicrobial therapy should be administered in conjunction with surgery to optimize the likelihood of recurrence-free cure.

In regions where surgical expertise is not available, we favor eight weeks of antibiotic therapy. (See 'Systemic antibiotics' below.)

Category II — For lesions larger than 5 cm or lesions at critical sites, antibiotic therapy should be initiated with close follow-up to evaluate for recovery of potentially viable tissue. If the lesion appears unchanged or is improving, antibiotics should be continued for eight weeks, with ongoing supportive care.

Accumulating observations suggest that many category II ulcers gradually heal with antimicrobial therapy alone, although ulcer healing may not necessarily be observed during therapy [123,135,136]. Category II lesions appear to heal more slowly than smaller category I lesions and therefore are more likely to require skin grafting.

Paradoxical deterioration during antimicrobial therapy or in the two to four weeks following completion of therapy occurs in around 25 to 30 percent of patients [137,138], reflecting antimicrobial killing accompanied by enhanced immune response [137,139]. Genetic factors [140] may drive this phenomenon that may be predicted by persistently enhanced IL-6 and TNF-alpha levels in the blood stream 4 to 8 weeks after start of treatment [138]. Paradoxical deterioration likely occurs because of decreasing concentrations of cytotoxic mycolactone that causes immune paralysis [90,137,139].

If the lesion appears to be worsening (eg, the swelling has increased or the surface area is larger), surgical intervention with debridement of superimposed bacterial infection or for skin graftcccxing to accelerate healing of large ulcers may be warranted [141]. Generous excision margins including healthy tissue are not necessary; in the past, such intervention was believed necessary for cure [5,10]. In Australia, paradoxical deterioration has been observed to improve with use of corticosteroids (prednisolone 0.5 to 1.0 mg/kg daily, tapered over four to eight weeks) [142,143].

Edematous lesions appear to be highly amenable to antimicrobial therapy, which can reduce the surface area of ulceration. This may be a result of direct antibiotic activity against mycolactone production [61,87,90]. In such cases, it is important to monitor for clinical response to antimicrobial therapy; surgery should be limited to removal of necrotic tissue and skin grafting [124,130].

In regions where surgical expertise is not available, we favor eight weeks of antibiotic therapy. Extending antibiotics beyond eight weeks is of no proven benefit and increases the risk of adverse effects.

Category III — For lesions larger than 15 cm, we favor initial treatment with antibiotic therapy. In some cases, limited surgical debridement of necrotic tissue followed by skin grafting is helpful for acceleration of healing. Patients with large category III lesions with resulting contractures may benefit from plastic reconstructive surgery. Reconstruction should be combined with physiotherapy to reduce the likelihood of disability. (See 'Supportive care' below.)

Surgery should be avoided for lesions at critical sites such as orbital, facial, and genital lesions.

No reports have been published on the optimal management of complications such as joint involvement and osteomyelitis; the approach to these cases must be tailored to individual patient circumstances. A general approach to osteomyelitis is outlined in detail separately. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis".)


Systemic antibiotics — For treatment of early, limited Buruli ulcer disease, antimicrobial therapy has been shown to be highly effective. Healing requires several months, even in the setting of appropriate antimicrobial therapy.

The additional value of debridement for such cases has been overestimated; in one trial involving 310 participants, a healing rate of 95 percent was achieved with no debridement [144]. In earlier studies, debridement surgery was practiced in a small minority of cases [123,135-137,145].

Several antimicrobial agents have been evaluated for treatment of Buruli ulcer. The most effective regimens appear to be those that combine rifampin with an additional agent such as a macrolide, aminoglycoside, fluoroquinolone, or dapsone [146-149]. Since M. ulcerans has a slow replication rate, most favor a once-daily dosing regimen.

The approach to antimicrobial therapy was initially based by a small study including patients with nodules who underwent antimicrobial therapy followed by subsequent excision and culture [145]. In patients who received at least four weeks of antimicrobial therapy, cultures remained negative; thereafter, a regimen of at least eight weeks of antimicrobial treatment was proposed to optimize the likelihood of definitive management. Observational data suggest that for some patients with small lesions, four to six weeks of treatment may suffice [150,151]; however, thus far, shorter treatment regimens have not been evaluated in randomized trials.

Preferred approach — We favor treatment with rifampin (10 to 15 mg/kg/day orally up to a maximum of 1200 mg daily) plus oral clarithromycin (500 mg orally once or twice daily) [143,144,152-154]. For category I disease, we favor eight weeks of antibiotic therapy; four weeks of therapy may be sufficient in some circumstances [150]. For category II and III disease, the preferred duration is eight weeks. (See 'Approach by WHO category' above.)

If clarithromycin is not an option (due to drug intolerance or lack of availability), oral rifampin and injectable streptomycin is an acceptable alternative regimen; however, streptomycin injections are painful, logistically challenging, and associated with ototoxicity [155].

Many ulcers heal with antimicrobial therapy alone; however, improvement may not be observed during therapy, and healing is often incomplete until after completion of antimicrobial treatment [123,136,144].

We advise caution in performing early surgical debridement. In a randomized trial including more than 100 patients, postponing surgical decisions until 14 weeks after the start of antimicrobial therapy was not associated with delayed healing or an increase in residual functional limitations [127]. Slight lesion enlargement may reflect paradoxical inflammation [137]; once lesions are clean and granulating, skin grafting may accelerate healing of large ulcers [156].

The above approach is supported by a randomized trial including 310 patients with Buruli ulcer (category I or II) treated with RS8 (rifampin [10 mg/kg orally once daily] plus streptomycin [15 mg/kg intramuscularly daily] for 8 weeks) or RC8 (rifampin plus clarithromycin extended release [15 mg/kg orally once daily] for 8 weeks) [144]. Lesion healing at 12 months was similar between the groups (95 versus 96 percent; difference in proportion -0.5 percent [-5.2 to 4.2]). The median time to healing for RS8 was 24 weeks (interquartile range [IQR] 8 to 28 weeks); the median time to healing for RC8 was 16 weeks (IQR 8 to 25 weeks). Treatment-related adverse events were recorded in 13 percent of patients receiving RS8 and in 7 percent of patients receiving RC8. Most adverse events were grade 1 to 2; one patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection; 4 patients (2 in each study group) underwent skin grafts.

An earlier randomized trial including 151 patients noted that the efficacy of rifampin-streptomycin for four weeks followed by rifampin-clarithromycin for four weeks was comparable with rifampin-streptomycin for eight weeks (96 versus 91 percent healed after one year, respectively), and surgery was avoided in the majority of patients [123]. Category I lesions healed after median 20 weeks, while category II and III lesions healed after median 30 weeks.

Other regimens — The combination of rifampin with a fluoroquinolone (such as moxifloxacin, ciprofloxacin, levofloxacin, or ofloxacin) has been effective in vitro and in animal models, but clinical trials are needed [147,157-160]. The combination of rifampin with clarithromycin (7.5 mg/kg orally once daily) has also been used [123,161]. In Australia, successful outcomes with combination therapy using oral fluoroquinolones and rifampicin have been observed [153,160].

The combination of rifampin with dapsone demonstrated some reduction in ulcer size in a small study [162]. It has also been suggested that heparin combined with rifampin and amikacin may improve blood circulation and antibiotic penetration [141,163].

Monotherapy with clofazimine, trimethoprim-sulfamethoxazole, rifampin, or other agents should not be used for treatment of Buruli ulcer [101,159,164]. Resistant strains have been demonstrated after rifampin monotherapy in an experimental setting [159,165].

Topical therapies — Topical treatment of ulcerative lesions should include wet dressing materials. Topical therapies including nitrogen oxide, phenytoin powder, and local heat have been suggested for treatment of Buruli ulcer [166-168]. Nitric oxide kills M. ulcerans in vitro, while phenytoin powder appears to promote healing through acceleration of fibrogenesis [166,167]. Local heat application to 40°C takes advantage of the temperature sensitivity of M. ulcerans (whose optimal growth conditions are 29 to 33°C) [53,168-170]. Topical modalities require further study before they should be considered for routine use.

Limited role of debridement — Debridement may or may not be necessary. Any debridement should be limited to removal of necrotic tissue and delayed for at least 14 weeks following initiation of antibiotic therapy. Once the wound surface is clean and granulating, skin grafting might be planned. Surgery should be avoided for lesions at critical sites such as orbital, facial, and genital lesions. In large category III lesions with resulting contractures, specialized centers may provide plastic reconstructive surgery.

Secondary infection — Superficial swabs of the ulcer should not be used to diagnose a secondary infection, and superficial specimen culture results should not prompt initiation of additional antimicrobial therapy [94].

Supportive care — Principles of wound care should be applied universally [123,171]. These consist of cleansing with saline, covering granulating wound surfaces with nonadherent material (eg, petroleum jelly gauze with absorbent dressing materials), and compression bandaging. Lesions near joints are prone to development of contractures [5]; therefore, physiotherapy should be started early to prevent functional limitations. Pain management is also important [172-174].

HIV coinfection — Potential drug-drug interactions warrant careful attention in the management of patients with Buruli ulcer and HIV infection. Some interactions between rifampin and antiretroviral agents are discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy", section on 'Interactions between ART classes and the rifamycins'.)

Patients should start antiretroviral therapy as soon as possible if drug-drug interactions can be managed appropriately [175].


Water exposure — A better understanding of transmission mechanisms is needed for development of effective approaches to Buruli ulcer prevention. Limiting exposure to contaminated water sources may be helpful, although this is difficult to achieve in endemic areas where farming activities require close contact with waterways [22]. Other prevention strategies, such as wearing protective clothing while farming and prompt cleansing of traumatic skin injuries, may be helpful [27,87]. In Victoria, Australia, where salt marsh mosquitoes have been associated with transmission, insect repellants, and wearing outdoor protective clothing were associated with reduced risk for Buruli ulcer [176]. (See 'Transmission' above.)

Vaccination — Bacillus Calmette-Guérin (BCG) vaccination appears to offer limited protection against Buruli ulcer [177-181]. This was illustrated in a randomized trial of over 8000 individuals in which BCG vaccination had a 47 percent short-term protective effect against Buruli ulcer (6 to 12 months); the trial did not determine whether BCG provided long-lasting protection [177]. Two other studies have suggested that BCG may have a protective effect against severe disease (osteomyelitis and multiple lesions) [95,178,180].

Further study of the mycolactone production mechanisms [74] and other aspects of M. ulcerans pathogenesis may facilitate development of a more effective vaccine [71,180-182].


Buruli ulcer is a disabling skin infection due to Mycobacterium ulcerans that affects individuals in humid, rural, tropical regions with limited access to medical care. Transmission is related to contaminated water; inoculation probably occurs via skin trauma. (See 'Epidemiology' above and 'Microbiology' above and 'Transmission' above.)

Buruli ulcer usually begins as a small painless papule that breaks down after days to weeks, forming an ulcer with characteristic undermined edges. Sequelae may include osteomyelitis, scarring, retractions, and contractures. (See 'Clinical manifestations' above.)

Clinical diagnosis is fairly reliable in endemic regions if health staff have sufficient experience. The most widely available laboratory diagnostic technique is acid-fast staining of a swab taken from the undermined edge of an ulcer. However, in endemic areas, the diagnosis of Buruli ulcer is frequently based upon clinical manifestations and rarely confirmed because of limited access to laboratory services. (See 'Diagnosis' above.)

For category I, II, and III disease, we suggest antibiotic therapy with rifampin and clarithromycin (Grade 2C). The preferred duration of antibiotic therapy is eight weeks. (See 'Preferred approach' above and 'Approach by WHO category' above.)

Mild paradoxical deterioration may occur during antimicrobial therapy or in the two to four weeks following completion of therapy, reflecting antimicrobial killing accompanied by enhanced immune response. (See 'Approach by WHO category' above.)

Debridement may or may not be necessary. Any debridement should be limited to removal of necrotic tissue and delayed for at least 14 weeks following initiation of antibiotic therapy. Once the wound surface is clean and granulating, skin grafting might be planned. Surgery should be avoided for lesions at critical sites such as orbital, facial, and genital lesions. In large category III lesions with resulting contractures, specialized centers may provide plastic reconstructive surgery. (See 'Limited role of debridement' above and 'Approach by WHO category' above.)

Complications including joint deformities, and secondary bacterial infection may be diminished with physiotherapy and attention to wound care. (See 'Supportive care' above.)

Prevention measures may include limiting exposure to contaminated water sources, and wearing of protective clothing, but a better understanding of transmission mechanisms is needed. Bacillus Calmette-Guérin vaccination of neonates appears to afford limited protection, although mycolactone may be a good target for a more effective vaccine. (See 'Prevention' above.)

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Topic 5349 Version 27.0


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