Mycobacterium ulcerans causes slowly progressive, destructive skin and soft tissue infections, known as Bairnsdale or Buruli ulcer (BU).
Forty-six delegates with experience in the management of BU attended a 1-day conference in Melbourne on 10 February 2006, with the aim of developing a consensus approach to the diagnosis, treatment and control of BU. An initial draft document was extended and improved during a facilitated round table discussion.
BU is an environmental infection that occurs in specific locations. The main risk factor for infection is contact with an endemic area.
Prompt cleaning of abrasions sustained outdoors, wearing protective clothing, and avoiding mosquito bites may reduce an individual’s risk of infection.
BU can be rapidly and accurately diagnosed by polymerase chain reaction testing of ulcer swabs or biopsies.
Best outcomes are obtained when the diagnosis is made early. To aid early diagnosis, health authorities should keep local populations informed of new outbreaks.
BU is best treated with surgical excision, which, if possible, should include a small rim of healthy tissue. For small lesions this may be all that is required. However, there is a role for antibiotics for more extensive disease, and their use may allow more conservative surgery.
Bairnsdale or Buruli ulcer (BU) had been a rare disease in Victoria, but its incidence has risen markedly since 1990. Clinicians are increasingly called upon to diagnose and treat BU, but there is little information on the best approach. These guidelines reflect contemporary clinical practice in Victoria. They may not be applicable in countries with less developed health infrastructure. Existing guidelines, approved by the World Health Organization, are recommended for such areas.1
Plastic surgeons, general practitioners, laboratory scientists, pathologists, infectious diseases physicians and public health experts known to have experience with BU were invited to participate. Of 85 invitees, 46 attended the conference on 10 February 2006.
Before the conference, participants received a draft document written by the conference conveners. In the morning, 10 speakers reviewed the published literature and presented and discussed recent cases. In the afternoon, the draft document was systematically reviewed, extended and improved through interactive round table discussion, with the help of a professional facilitator. The next draft was circulated to all participants after the conference, and final comments and suggestions were incorporated. The penultimate document underwent peer review and was edited for publication. The level of evidence throughout this document is level 4/5 (observational case series/expert opinion), except where specific references are cited.
Mycobacterium ulcerans was discovered in 1948 by Australian scientists who were investigating a cluster of patients with unusual skin ulcers in the Bairnsdale region of eastern Victoria.2 M. ulcerans is related to the causative agents of tuberculosis and leprosy, but is transmitted from the environment rather than from person to person.3 The major virulence factor is a lipid toxin, mycolactone, which causes necrosis of fat and subcutaneous tissue.4
M. ulcerans infection is not fatal, but can result in significant morbidity and is expensive to treat.5,6 It has been reported in more than 30 countries, and is currently a significant public health problem in sub-Saharan Africa (Buruli ulcer).3 In Australia, there are active foci in coastal Victoria (Bairnsdale ulcer),7 Far North Queensland (Daintree ulcer),8 and near Rockhampton.9 Single cases also occur elsewhere in the Wet Tropics. The reason for this patchy distribution is unknown, but molecular typing has shown differences between strains isolated from patients in different regions.10
BU continues to occur in low numbers in the Bairnsdale/Gippsland Lakes area. In 1980, a new focus was noted near Tooradin and Warneet (Box 1) on Westernport,7 and this was followed by significant outbreaks at East Cowes on Phillip Island (1992–1995),7,11,12 Frankston and Langwarrin (1990–1998),7 St Leonards (1998–2001), Point Lonsdale (since 2002)13 and Barwon Heads and Ocean Grove (since 2005). There are also frequent single cases from other parts of the Mornington and Bellarine Peninsulas.
The incidence of BU in Victoria has increased sharply in recent years (Box 2). It is unlikely that this increase is due to improved diagnosis, as there has been considerable publicity since 1994, and all diagnostic polymerase chain reaction (PCR) assays have been available at a single institution since 1995.14 BU was made formally notifiable in Victoria from January 2004. Although the incidence in Victoria is currently only 1.4 per 100 000 overall, it is estimated that up to 6% of the permanent population of East Cowes (1992–1995)15 and 1% of the permanent population of Point Lonsdale have required treatment. Visitors to endemic areas are also at risk, and brief contact may be sufficient to become infected.
BU typically presents as a slowly progressive skin papule that undergoes necrosis and evolves to a deeply undermined ulcer. Lesions are usually painless or minimally painful. Less commonly, the initial lesion may resemble a plaque or necrotic patch of skin. Systemic symptoms (fever, malaise) are rare.
Fully developed ulcers are characteristically deeply undermined, meaning a probe can be passed easily under the edge into the space left by necrotic liquefied fat tissue. Lesions can occur anywhere and may be multiple, but a single lesion on the leg or arm is most common. Infections on the buttock, abdominal wall, ear and face have all occurred in Victoria in the past 10 years. There is also an unusual oedematous presentation that can cause extensive swelling (eg, involving most of a limb).
Once an ulcer is present, diagnosis is usually straightforward, provided BU is considered. Delays are most likely when patients present outside endemic areas, or when the patient has a non-ulcerative presentation (eg, nodule, papule, plaque or acute oedema).
IS2404 PCR,8,14,17 which can be performed directly from ulcer swabs, approaches 100% sensitivity and specificity (P D R J, J A M F, independent personal observations). Culture is also diagnostic, but generally takes several weeks. A positive M. ulcerans PCR result is sufficient evidence to proceed to treatment.
If an ulcer is present, obtain samples deep to the undermined edge using two standard cotton-tipped swabs. These swabs may be dry or of the standard transport medium type (swabs stored in charcoal transport medium should be avoided). Ensure that some material is visible on each swab. The swabs (one labelled “for PCR only”) should be sent to your usual pathology service for microscopy for AFB, M. ulcerans PCR, and culture. “Possible Bairnsdale ulcer” should be written on the clinical notes. A smear result is usually available within the same working day. Separate swabs or specimens should be obtained for other pathogens or conditions, depending on the clinical situation.
Other specimen types suitable for PCR include fresh tissue biopsies (preferably not stored in large volumes of buffer or saline, nor wrapped in gauze) and paraffin-embedded fixed tissue sections (not suitable for culture).
If an ulcer is not present but there is a suspicious plaque, necrotic patch, nodule or acute oedematous presentation in an at-risk patient, an incisional or excisional biopsy should be performed. Some patients notice an apparent increase in the rate of progression of the disease following biopsy, and this should be carefully discussed.
Small lesions sometimes resolve spontaneously, but this is thought to be uncommon. The rate of progression varies among patients. Even though host immunity progressively develops during infection, ulcers may become very extensive. Relapse after treatment is not uncommon,18 so regular follow-up is recommended.
Cure with medical therapy alone is possible, and there is increasing interest in this approach in western Africa.1,19 However, in Victoria, where there is ready access to surgery, we believe that surgery or combined surgical and medical therapy is the most efficient way of effecting cure. The trend in management is towards conservative surgery with macroscopic removal of necrotic tissue and the use of adjuvant antibiotics. Patients may be best managed by a team, with surgeons working with infectious diseases specialists, GPs and allied health practitioners.
In most situations, we recommend surgery that aims to remove all necrotic tissue, but preserves any involved deep structures (eg, tendons, nerves, joint capsules, major blood vessels). If bone is involved, it should be conservatively debrided.
Where possible, remove a small buffer of normal tissue, if doing this will not unduly increase the morbidity of the procedure. The skin defect should then be closed primarily, or by grafting if necessary.
An orientated resection specimen that includes the skin and subcutaneous tissue should be submitted for histopathology. There is evidence from a recent case series that AFB or granulomatous inflammation or necrosis at the margins predicts relapse and the need for antibiotic treatment.20 If margins are clear, drug therapy is usually not necessary. However, clinicians are advised to discuss the risk of relapse versus antibiotic cost and risk of side effects to assist patients in making an informed choice. PCR testing of resection margins is not recommended.
While preparations are being made for surgery, combination drug therapy should be commenced (see below). If significant oedema makes it difficult or impossible to determine how much tissue is involved in the infection, preoperative antibiotic therapy (eg, for 2–4 weeks) is recommended, as this may significantly reduce the extent of the resection required.
There is anecdotal evidence that continuous warming of the affected skin at 38–39°C using one of a range of available servo-controlled devices improves outcome, particularly when lesions are extensive or relapse has occurred. The theoretical basis for this is the organism’s preference for growth at 32°C and enhanced human effector cell function at 39°C.
Some clinicians favour the use of hyperbaric oxygen to assist healing, and there are supportive data from a mouse model.21 An Italian group is investigating the use of adjuvant hyperbaric oxygen for BU in Benin, but results are not yet available.
In the laboratory, M. ulcerans is susceptible to a range of antibiotics. The WHO recommends the combination of oral rifampicin and parenteral streptomycin for initial treatment.1 The use of streptomycin (replaced by amikacin in Australia) combined with oral rifampicin is supported by animal data,22 a published case series from western Africa,19 and observational data presented at the annual meetings of the WHO Global Buruli Ulcer Initiative.23 In Victoria, where many patients are elderly, clinicians have encountered problems with toxicity from amikacin (renal, balance or hearing difficulties), and may prefer less toxic oral combinations. However, there is less human evidence to support this practice, and in animal models, oral-only combinations are less effective at killing M. ulcerans,24 with the possible exception of rifampicin plus moxifloxacin.25
Antibiotic treatment is relatively expensive, may require monitoring for toxicity, and is generally given for at least 3 months in total, with the intravenous component typically for 4 weeks. However, appropriate use of antibiotics allows more conservative surgery and reduces the risk of relapse. Box 3 presents recommendations for use of oral antibiotics, and Box 4 contains recommendations for use of intravenous amikacin.
The use of antibiotics for the treatment of M. ulcerans is “off label”. The usual precautions should be taken whenever new drugs are prescribed. Always refer to the full product information. Ciprofloxacin is not generally recommended in prepubertal children, as studies in animal models have demonstrated arthropathy.26 However, there is limited evidence from human studies that short courses of ciprofloxacin may be safe in children.27 Patients should be warned about the small risk of drug-related hepatitis associated with combinations that include rifampicin, and liver function tests should be monitored periodically. There is a small risk of tendinitis associated with quinolone use, and an alternative agent should be found if tendon stiffness develops during treatment.
Some clinicians would commence amikacin in combination with two oral antibiotics (eg, rifampicin plus moxifloxacin). The toxicity of intravenous amikacin needs to be balanced against the potential benefit, particularly in the elderly and when renal impairment is present. Patients should be warned about the risk of hearing loss and balance disturbance, and be asked to report tinnitus or hearing or balance disturbance immediately. The use of amikacin beyond 4–8 weeks is not usually recommended, but it may be given for up to 12 weeks if necessary.
It is not understood why M. ulcerans outbreaks occur in new areas or why the disease has spread westwards from the original endemic area near the Gippsland Lakes. There are no public health interventions that can remove M. ulcerans from the environment, although there may be a natural cycle of human infection that lasts several years, after which the incidence of new cases in a given area abates. There is circumstantial evidence that nutrient enrichment of very low-lying coastal environments may be a factor in the appearance of outbreaks.7,12,28
M. ulcerans has been detected by PCR in plant material and mud obtained from swamps in endemic areas,29 a golf course irrigation system that used recycled water,28,29 and from aquatic water insects in Africa.30 At Point Lonsdale, M. ulcerans has been detected by PCR in soil and leaf litter from a stormwater drainage system, mud from a lake, and about 0.5% of more than 10 000 mosquitoes trapped during 2004–2006 (unpublished data). It is yet to be determined whether mosquitoes play a role in human disease.
Studies from African endemic areas have reported that farming activities close to rivers31 and swimming32 may be risk factors, and that wearing trousers31 and a shirt33 when working outdoors appears protective. A recent case–control study performed on the Bellarine Peninsula has shown that direct exposure to the environment and to mosquitoes are risk factors, and wearing protective clothing and insect repellent appears protective (unpublished data).
Morbidity and cost can be reduced by early diagnosis. Therefore, local doctors are central to early detection. When an outbreak occurs in a new area it may take some time for this disease to be recognised, so public health authorities need to provide timely information to both clinicians and the general public about disease activity and the location of new endemic areas.
People living in endemic areas should be encouraged to wear long-sleeved shirts and trousers when outdoors and to use insect repellent to avoid insect bites. Prompt cleaning and covering of cuts and abrasions is also recommended.
BU is notifiable in Victoria and up-to-date figures are displayed on a publicly accessible website.34 However, it is recommended that the exact location of cases be documented (eg, by postcode), and that clinical photographs and notes on diagnosis be made available through the site.
2 Notified cases of Mycobacterium ulcerans infection in Victoria since 1998
Notification was voluntary before 2004. Data for 2006 are only to August. Data are from the Victorian Department of Human Services and reference 7.
3 Recommendations for oral antibiotic use in the treatment of Bairnsdale ulcer
For a total of 3 months when the histology of resection margins shows either necrosis or acid fast bacilli or granulomata
or when the initial lesion was large enough to require grafting
or for complex, recurrent disease or where surgical resection is necessarily incomplete. Consider including intravenous amikacin in this situation (see Box 4)
Rifampicin 10 mg/kg per day up to 600 mg daily for 3 months, plus
clarithromycin 500 mg twice daily for 3 months
or ciprofloxacin 500–750 mg twice daily for 3 months
or moxifloxacin 400 mg once daily for 3 months (not recommended for children)
Rifampicin 10–20 mg/kg per day in one daily dose; not to exceed 600 mg per day
Clarithromycin 15–30 mg/kg per day in two divided doses for children < 12 years; dose as for adults when > 12 years, not to exceed adult doses
Ciprofloxacin 20 mg/kg per day in two divided doses, not to exceed adult doses
4 Recommendations for use of intravenous amikacin in the treatment of Bairnsdale ulcer
Severe or extensive disease
When deep structures (such as tendons, nerves, joint capsules, major blood vessels) that need to be preserved are involved
Large lesions that could not be fully resected
When trying to avoid or minimise surgery (eg, lesions involving the eye or face)
Initial therapy of acute oedematous disease
Amikacin 15 mg/kg (ideal weight) intravenously (maximum 1000 mg) daily on 5–7 days each week for 4–8 weeks
Monitor renal function
Monitor hearing and vestibular function at least monthly
Monitor trough levels once or twice weekly
Aim for trough level < 1 mg/L. Dosing should be spaced to three times weekly if drug accumulation is detected (ie, trough levels begin to rise) or if prolonged continuation therapy is envisaged
Appendix: Conference delegates
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- 3. Johnson PDR, Stinear T, Small PLC, et al. Buruli ulcer (M. ulcerans infection): new insights, new hope for disease control. PLoS Med 2005; 2(4): e108.
- 4. George KM, Chatterjee D, Gunawardana G, et al. Mycolactone: a polyketide toxin from Mycobacterium ulcerans required for virulence. Science 1999; 283: 854-857.
- 5. Asiedu K, Etuaful SA. Socioeconomic implications of Buruli ulcer in Ghana: a three-year review. Am J Trop Med Hyg 1998; 59: 1015-1022.
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- 7. Johnson PDR, Veitch MGK, Leslie DE, et al. The emergence of Mycobacterium ulcerans infection near Melbourne. Med J Aust 1996; 164: 76-78.
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- 11. Flood P, Street A, O’Brien P, Hayman J. Mycobacterium ulcerans infection on Phillip Island, Victoria. Med J Aust 1994; 160: 160.
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- 16. Atkinson RK, Farrell DJ, Leis AP. Evidence against the involvement of Mycobacterium ulcerans in most cases of necrotic arachnidism. Pathology 1995; 27: 53-57.
- 17. Russell FM, Starr M, Hayman J, et al. Mycobacterium ulcerans infection diagnosed by polymerase chain reaction. J Paediatr Child Health 2002; 38: 311-313.
- 18. Debacker M, Aguiar J, Steunou C, et al. Buruli ulcer recurrence, Benin. Emerg Infect Dis 2005; 11: 584-589.
- 19. Etuaful S, Carbonnelle B, Grosset J, et al. Efficacy of the combination rifampin-streptomycin in preventing growth of Mycobacterium ulcerans in early lesions of Buruli ulcer in humans. Antimicrob Agents Chemother 2005; 49: 3182-3186.
- 20. O’Brien DP, Hughes AJ, Cheng AC, et al. Outcomes for Mycobacterium ulcerans infection with combined surgery and antibiotic therapy: findings from a south-eastern Australian case series. Med J Aust 2007; 186: 58-68. <MJA full text>
- 21. Krieg RE, Wolcott JH, Confer A. Treatment of Mycobacterium ulcerans infection by hyperbaric oxygenation. Aviat Space Environ Med 1975; 46: 1241-1245.
- 22. Dega H, Bentoucha A, Robert J, et al. Bactericidal activity of rifampin-amikacin against Mycobacterium ulcerans in mice. Antimicrob Agents Chemother 2002; 46: 3193-3196.
- 23. World Health Organization. Global Buruli ulcer initiative. http://www.who.int/buruli/en/ (accessed Aug 2006).
- 24. Bentoucha A, Robert J, Dega H, et al. Activities of new macrolides and fluoroquinolones against Mycobacterium ulcerans infection in mice. Antimicrob Agents Chemother 2001; 45: 3109-3112.
- 25. Ji B, Lefrancois S, Robert J, et al. In vitro and in vivo activities of rifampin, streptomycin, amikacin, moxifloxacin, R207910, linezolid, and PA-824 against Mycobacterium ulcerans. Antimicrob Agents Chemother 2006; 50: 1921-1926.
- 26. Yoshida K, Yabe K, Nishida S, et al. Pharmacokinetic disposition and arthropathic potential of oral ofloxacin in dogs. J Vet Pharmacol Ther 1998; 21: 128-132.
- 27. Zimbabwe Bangladesh South Africa (Zimbasa) Dysentery Study Group. Multicenter, randomized, double blind clinical trial of short course versus standard course oral ciprofloxacin for Shigella dysenteriae type 1 dysentery in children. Pediatr Infect Dis J 2002; 21: 1136-1141.
- 28. Ross BC, Johnson PDR, Oppedisano F, et al. Detection of Mycobacterium ulcerans in environmental samples during an outbreak of ulcerative disease. Appl Environ Microbiol 1997; 63: 4135-4138.
- 29. Stinear TP, Davies JK, Jenkin GA, et al. Identification of Mycobacterium ulcerans in the environment from regions in southeast Australia in which it is endemic with sequence-capture PCR. Appl Environ Microbiol 2000; 66: 3206-3213.
- 30. Marsollier L, Robert R, Aubry J, et al. Aquatic insects as a vector for Mycobacterium ulcerans. Appl Environ Microbiol 2002; 68: 4623-4628.
- 31. Marston BJ, Diallo MO, Horsburgh CR Jr, et al. Emergence of Buruli ulcer disease in the Daloa region of Cote d’Ivoire. Am J Trop Med Hyg 1995; 52: 219-224.
- 32. Aiga H, Amano T, Cairncross S, et al. Assessing water-related risk factors for Buruli ulcer: a case–control study in Ghana. Am J Trop Med Hyg 2004; 71: 387-392.
- 33. Raghunathan PL, Whitney EA, Asamoa K, et al. Risk factors for Buruli ulcer disease (Mycobacterium ulcerans infection): results from a case–control study in Ghana. Clin Infect Dis 2005; 40: 1445-1453.
- 34. Victorian Department of Human Services. Notifications of infectious diseases: summary reports. http://www.health.vic.gov.au/ideas/downloads/daily_reports/rptVictorianSummary.pdf (accessed Aug 2006).
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