Buruli Ulcer

An updated consensus statement on the management of Buruli ulcer has recently been published. Buruli ulcer is a skin infection caused by the bacteria Mycobacterium ulcerans. This condition is named after the Buruli district in Uganda where many of the earliest documented cases occurred. The condition is sometimes also referred to as Bairnsdale or Daintree ulcer.

The M. ulcerans bacterium produces the mycolactone toxin which can cause significant tissue damage. Infection typically begins with a dermal papule or subcutaneous nodule. Over the following weeks or months, these painless lesions can develop into necrotic ulcers. Less common presentations are plaques without ulceration or atypical cellulitis involving all or part of a limb.

While Buruli ulcer is considered a tropical or subtropical condition around the world, it does occur in cooler regions of Australia. In Australia, outbreaks have previously been limited to coastal regions of Victoria and north Queensland. However, infections have now been reported in many suburbs of Melbourne, coastal regions of New South Wales, and the Northern Territory. The spread into new areas of Australia has been accompanied with an increased incidence of infection.

Treatment includes effective wound care in combination with antibiotics. Surgery may be required in some cases.

Antibiotic therapy

The complex cell wall structure of the Mycobacterium species makes them intrinsically resistant to many antibiotics. Many antibiotics commonly used for skin and soft tissue infections, such as flucloxacillin and cefalexin, are not effective in the treatment of Buruli ulcer.

Dual antibiotic therapy is recommended for the treatment of Buruli ulcer. This increases the effectiveness of therapy and minimises the risk of resistance emerging. Observational data supports the use of rifampicin with either clarithromycin or a quinolone in Australian cases. A Victorian study demonstrated that this therapy was associated with excellent cosmetic outcomes and a cure rate of 99.2%. In this study, cure was defined as healing within 12 months.

The current consensus guidelines recommend the following oral therapies:

• Rifampicin 10 mg/kg per day (up to 600 mg daily)

PLUS one of:

• Clarithromycin 7.5 mg/kg twice daily (up to 500 mg every 12 hours) OR
• Moxifloxacin 400 mg once daily OR
• Ciprofloxacin 500 mg every 12 hours.

Clarithromycin and ciprofloxacin doses should be adjusted according to renal function. If rifampicin is contraindicated or not tolerated, clarithromycin may be prescribed in combination with a quinolone.

Rifampicin

Rifampicin belongs to the rifamycin class of antibiotics. It is broad-spectrum with activity against Mycobacteria, most Gram-positive bacteria, and some Gram-negative bacteria.

Doses are typically given once a day and should be taken on an empty stomach, either half an hour before meals or two hours after a meal. To avoid unnecessary concern, patients should be advised that rifampicin can cause a red-orange discolouration of urine, faeces, sweat, and tears. This can cause permanent staining of soft contact lenses.

Rifampicin is implicated in many clinically important drug interactions. It is a potent inducer of various drug metabolising enzymes and transporters, including cytochrome P450 enzymes and P-glycoprotein. Rifampicin can accelerate the metabolism of some co-administered medicines which may result in reduced efficacy. For example, rifampicin has been shown to decrease lurasidone exposure by 81% and this combination is contraindicated. Conversely, in the case of pro-drugs, it may increase their efficacy and risk of adverse events by accelerating their metabolic activation. For example, rifampicin increases the conversion of clopidogrel to its active metabolite. This combination should be avoided as it may increase the risk of bleeding.

Rifampicin can cause liver dysfunction. Caution is required in patients with liver disease and patients receiving other hepatotoxic agents.

Clarithromycin

Clarithromycin is a macrolide antibiotic. The consensus statement advises that clarithromycin plus rifampicin is preferred for patients who are pregnant.

Clarithromycin has many clinically relevant drug interactions. It is a strong inhibitor of CYP3A4 and inhibits P-glycoprotein and organic anion transporting polypeptide (OATP) 1B1. The manufacturer contraindicates use with many drugs including colchicine, domperidone, oral midazolam, ticagrelor, and simvastatin. As simvastatin is extensively metabolised by CYP3A4, concomitant use of clarithromycin can lead to increased simvastatin levels and a higher risk of myopathy. Caution is also required with other statins. Fluvastatin and pravastatin are safer options as their metabolism is not dependent on CYP3A4.

Azithromycin is another antibiotic in this class that may have activity against M. ulcerans. However, there is less experience with azithromycin in this setting.

Quinolones

Moxifloxacin and ciprofloxacin belong to the quinolone class of antibiotics. It is preferable for ciprofloxacin to be taken on an empty stomach. However, both of these agents may be taken without regards to meals. Co-administration with food does delay absorption but there is not a substantial impact on the extent of absorption.

Important points:

• Photosensitivity – ciprofloxacin may cause photosensitivity reactions. Patients should be advised to avoid direct exposure to sunlight and to wear protective clothing and a broad-spectrum sunscreen when outdoors. Moxifloxacin has not been associated with phototoxicity.
• Driving ability – quinolones can cause dizziness, light-headedness, and visual disturbances. Patients should be advised that these medications may affect their ability to drive or operate machinery.
• Tendinopathies – quinolones can cause tendinopathies. Factors that may increase the risk include older age, strenuous physical activity, renal impairment, and coadministration with corticosteroids. Patients should be advised to consult their doctor if they develop any signs of tendonitis.
• Neuropathy – quinolones are rarely associated with peripheral neuropathy. The antibiotic should be discontinued at the first symptoms of neuropathy to prevent the development of a potentially irreversible reaction.

General information

It is recommended that full blood examination, and hepatic and renal function be checked at baseline and repeated periodically where required. Alcohol should be avoided during therapy to minimise the risk of liver injury.

Prolongation of the QT interval can occur with clarithromycin and the quinolone antibiotics. An electrocardiogram is recommended at baseline and again two weeks later for patients at increased risk, i.e. patients with pre-existing cardiac disease and those taking another medication associated with QT prolongation. Many medications are associated with prolongation of the QT interval, including hydroxychloroquine, domperidone, and methadone. A complete list is maintained at www.qtdrugs.org.

Drug interactions are very common with these antibiotics. Patients should be advised to check with their healthcare professional before starting any new medication, including alternative and over-the-counter medicines.

Buruli ulcer lesions are notoriously slow to heal and may even enlarge upon initiation of antibiotic therapy. Evidence supports a treatment duration of eight weeks in most cases. There is some evidence to support a six-week duration in patients with small lesions at low risk of relapse, and a four-week course for patients who have undergone surgical excision. As the median time to heal is around four to five months, patients should be warned that ulcers may not have healed completely by the time the antibiotic course is finished.

Paradoxical reactions can occur during or after antibiotic therapy. These reactions, also known as immune reconstitution inflammatory reactions, are associated with increased tissue necrosis and delayed healing. These reactions are common, affecting around one in five patients treated with antibiotics. Older adults and those with oedematous lesions may be at greater risk. Early identification of paradoxical reactions is important to prevent significant tissue loss.

Prevention

The exact mode of transmission of M. ulcerans is not currently understood, which makes it difficult to implement effective preventative strategies. However, there is increasing evidence that mosquitos, possums, and environmental factors play a role in transmission in Australia.

Based on this information, the consensus statement makes the following recommendations to reduce the risk of Buruli ulcer:

• Avoid mosquito bites (i.e. mosquito repellents, protective clothing, fly screens, etc.);
• Minimise potential mosquito breeding sites (i.e. remove sources of still water around the home);
• Wear gloves and protective clothing when gardening or working outdoors;
• Keep any cuts and abrasions clean and use effective wound management practices; and
• Minimise contact with possums and their excreta.