In our chapter here, we will give you a brief overview of the current treatment principles

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Antibiotic therapy:

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Today, it is well established that when patients with Buruli ulcers are treated with antibiotic regimes as recommended, most lesions heal without requiring surgery and with low recurrence rates. Oedematous lesions, the most aggressive form of the disease, have also responded to antibiotic treatment.

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In the last 15 years, the first-line antibiotic treatment in many regions has been combined with Rifampicin and streptomycin. The standard dosage recommendations are Rifampicin at 10 mg/kg body weight by mouth daily for eight weeks and streptomycin at 15 mg/kg body weight by intramuscular injection daily for eight weeks. The fact that streptomycin has to be administered as an injection over such a long time has obviously been a challenge. It challenges the logistics of the treatment – not all patients live close to a clinic where the injections can be given daily, which may lead to compliance issues because of socio-economic factors. Another disadvantage is that streptomycin is contraindicated during pregnancy.

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A recent study suggests the combination of rifampicin (10 mg/kg once daily) and clarithromycin (7.5 mg/kg twice daily) - it appears that this is now the recommended treatment. Both antibiotics are administered together over a period of 8 weeks. One significant advantage is that both these antibiotics are given orally, making the treatment logistics a lot easier. Furthermore, clarithromycin can be given to pregnant women.

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A combination of rifampicin (10 mg/kg once daily) and moxifloxacin (400 mg once daily) is routinely used with good results in Australia, but its effectiveness has not been proven.

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Telacebec is a new anti-tuberculous drug developed by a Korean company Qurient. The drug has demonstrated extreme potent activity against Mycobacterium ulcerans in animal studies, reducing treatment duration from 8 to 2 weeks. In January 2021, the US Food and Drug Administration granted orphan drug designation (ODD) to Telacebec as Buruli ulcer treatment. A clinical trial is being planned to evaluate the drug in patients.

 

Surgical treatment

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Until about 2004, wide surgical excision of infected tissue was deemed necessary to achieve microbiological cure in Buruli ulcers. Today, however, surgical debridement is no longer seen as a  first-line treatment for Buruli ulcer disease. Antibiotics have shown to be fully effective in eradicating the mycobacteria without surgery in most cases. Today surgery has a more complimentary role, and we use a much more conservative surgical approach than previously.

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If there is abundant necrosis, debridement of the wound bed will most likely speed up the healing process. When it comes to surgical debridement technique in Buruli ulcers, we generally apply the same principles as wounds of other etiologies. We have written a separate chapter on the debridement of wounds – please also refer to that. In that chapter, we also discuss alternative methods for debriding chronic wounds like using medicinal maggots, for example. While we have extensive experience using medicinal maggots for debridement in other ulcers, we do not have any hands-on experience in using this method in Buruli ulcers, and we have not found any documentation on this either. However, we would expect that medicinal maggots could be a useful method in debriding Buruli ulcers.

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As with all debridement – it is not always feasible to debride the wound entirely in one sitting. While the primary lesions of Buruli ulcers usually are pain-free, the ulcerative stages are typically accompanied by quite a lot of pain, and debridement is often experienced as highly uncomfortable by the patient. Therefore it is usually necessary to do a staged debridement over several sessions. If you have local anesthesia available, you may apply this topically onto the wound bed ( drip it into the wound, not inject) and let it work for about 10-15 minutes before debriding gently.

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When we debride in a hospital setting with the help of general or regional anesthesia, we usually do a more aggressive debridement since it can be done entirely pain-free.

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In extensive ulcers, it is still advisable to consider split-thickness skin grafting to shorten the healing time considerably. This can first be done when the wound bed is clean and sufficiently granulated. As a rule of thumb, many advise that this should be done at the earliest, four weeks after the antibiotic treatment regime has started. This is probably a sensible approach. At four weeks into the antibiotic treatment, the activity of M ulcerans is probably negligible, and further deterioration of the ulcer is unlikely. The other reason for waiting for several weeks is the rare paradoxical reaction, which sometimes occurs a few weeks after starting antibiotic treatment. This refers to the phenomenon that, for unknown reasons, the ulcer suddenly deteriorates even though the antibiotic treatment has been going on for a few weeks. 

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Wound care principles for Buruli ulcers

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There are very few guidelines on best wound care practices for BU, and the current guidance is based on expert advice. Basic principles involve maintaining a moist wound environment.   Again, we have to be realistic regarding what types of dressings are available in areas with minimal resources. Therefore, a lot of our advice is aimed at healthcare workers who only have a minimal choice of dressings available and may have to improvise a lot. 

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In general, we treat these ulcers like many other chronic ulcers. Indeed our recommendations here are the same as in the chapter on tropical phagedenic ulcers. Remember, though, that M ulcerans, although also present on the surface of the wound bed, hides in deeper tissues. Topical antibacterial solutions or even topical antibiotics cannot eradicate the bacteria. The only cure is by prescribing systemic antibiotics. However, topical antibacterial solutions and dressings may prevent and treat some secondary bacterial infections. 

 

If there are only moderate amounts of necrotic tissue, you may choose more conservative methods of debridement- processes that aid the autolytic debridement process. Covering the wound bed in honey and using moistened gauze dressings can be helpful here. We have also used granulated sugar to debride leg ulcerations in both the acute and chronic phases. Fill the entire ulcer cavity with white granulated sugar. This works best if applied daily, as the wound exudate quickly dissolves the sugar. It is essential to have a good absorbent dressing over this, as sugar draws fluid from the wound bed and causes an increase in exudate, at least in the initial phase of the treatment. The patient must be informed that both honey and sugar can attract ants, especially during the night.   Another method of debridement is using papaya directly applied to the wound bed. Again, please refer to our chapter on debridement for more information about this and other methods. 

 

 If there is an abundance of necrotic tissue, this will not only delay the healing of the wound but can encourage secondary infection by other bacterial strains. A careful surgical debridement of the wound may not only reduce the healing time but also reduce the pain in the ulcer and reduce the length of the antibiotic treatment.​

 

In ulcers with extensive necrosis and infection, a thorough debridement under sedation or even general anesthesia may have to be done, if that is available. We have written a separate chapter on debridement and refer to this. We also believe that debridement by medicinal maggots is a suitable method here ( although we do not have any hands-on experience with this in Buruli ulcer treatment yet) - we also refer to the chapter about medicinal maggots.​

 

We generally like to use antibacterial rinse solutions to irrigate the ulcers at dressing changes to prevent secondary infections. It is generally recommended to let these substances soak into the wound for about 15-20 minutes. We usually saturate a cotton gauze pad with this ( dripping wet) and lay this into the ulcer bed. Depending on what you have available, you can use a 2% vinegar solution for this, super-oxidized water, or 3% hydrogen peroxide. Remember that you can make the vinegar rinsing solution yourself.   After this rinse, we like to paint the entire wound bed with gentian violet - this normally penetrates a few millimeters into the wound's surface, and we believe it may lead to quicker eradication of bacteria. We only use the gentian violet during the first two or three dressing changes as it is unknown how beneficial ( or harmful) this substance is to healthy tissues.  

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It appears that filling the wound bed with activated charcoal, especially during the initial phases, may delay further bacterial growth and probably aids in neutralizing bacterial toxins, which cause tissue destruction. You will find more about the charcoal method under " Antibacterial dressings."

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Once the ulcer has " stabilized" and is not growing anymore, we can go over to more regular dressing choices. If you have few resources, cotton gauze dressings can be used. If the wound has little exudate, you can premoisten the gauze with, for example, the 2% vinegar solution ( they should only be slightly moist, not dripping wet!). You can apply a thin layer of zinc paste mixed with petrolatum jelly ( 50:50 ratio) over the entire wound bed to prevent the gauze from sticking to the wound bed, making removal painful during dressing changes. 

 

If you have access to more modern dressings, then most polyurethane foam dressings would be appropriate here, especially those with antibiotic properties like silver coatings or those containing iodine. Another excellent, modern dressing for this purpose is Sorbact gauze. Once the ulcer bed is clean from necrotic tissue and shows promising granulation tissue, negative pressure wound therapy (NPWT) can probably be safely utilized to speed up the formulation of granulation tissue. Although there are case reports about the successful use of NPWT in M ulcerans ulcerations, we have little knowledge about that subject matter. We strongly advise you not to start with NPWT in Buruli ulcers until the antibiotic treatment has been going on for at least four weeks. If available, NPWT with irrigation would be the preferred method, in our opinion, utilizing an antibacterial solution as the irrigation fluid. You should have some experience using NPWT before using this method in patients with Buruli ulcers. 

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Once the wound bed is covered in good granulation tissue, partial thickness skin grafting can be done to shorten the healing time and possibly lead to a better cosmetic result. Again, we recommend you to wait with skin grafting until at least four weeks of antibiotic treatment have been given. Remember that there are also simpler techniques for transferring epidermal cells like the " blister technique" and punch-grafting methods. Please refer to the chapter on skin grafting for more information about these methods. In most rural areas, however, these techniques are not available, and Buruli ulcers are left to heal by the natural process with the aid of antibiotics and good general wound care.

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Remember, as always in wound care: nutrition plays a decisive role. Especially protein supplementation and vitamin supplements ( Vitamin C!) are advised. 

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If you have the resources and facilities, it is wise to get the patient hospitalized for the initial part of the treatment ( about seven days). In this way, we can better control what is going on in the wound, do careful serial debridements  (which are less painful), and frequent dressing changes. Furthermore, we can use those days to supply the patients with extra proteins and vitamins. During that time, the patient should also be taught how to change the dressing by themself or teach a caregiver.   We are, of course, aware that many rural hospitals do not have the resources to take in all patients with ulcerations, or even more commonly, that the nearest hospital is a day's travel away. In most cases in rural areas, patients will therefore need to be treated as out-patients. 

 

In summary, there are a number of treatment modalities you can apply here. It really depends on what you have available and your own personal preferences. At the start of the treatment, it will be wise to do frequent dressing changes and gradually decrease the frequency as the wound improves. In most situations in rural areas, you cannot expect the patient to return for a new visit the next day, and we advise you to use the time to inform the patient/caretakers thoroughly and teach them how to do the dressing changes themselves. To summarize the treatment options, we have listed them here:

 

Wound irrigation: 

 

• 2% vinegar, Super-oxidized water or 3% hydrogen peroxide

 

Antibacterial effect:

 

• Gentiana violet 1-2% solution applied to the entire wound bed at least during the first two dressing changes ( at least during the first treatment at your clinic)

 

Primary Wound dressings if resources are limited:

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• Honey ( applied daily until necrosis has cleared, then longer intervals) 

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• White granulated sugar ( applied daily until necrosis has cleared, then longer intervals) 

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• Activated carbon powder: fill the entire wound cavity with this powder. If the wound is drier, it can also be mixed with honey at a 50:50 ratio. 

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• Cotton gauze dressings. If the wound has much exudate, place the cotton gauze in dry. If the ulcer is drier, pre-moisten the gauze slightly with saline or, for example, 2% vinegar. You can use a 50:50 mixture of zinc paste and petrolatum jelly as a barrier layer over the entire wound surface to prevent the gauze from sticking to the wound bed. We recommend frequent dressing changes when using the gauze method. 

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Secondary wound dressings if resources are limited:

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• cotton pads

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• ladies hygiene pads

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Primary wound dressings, if all resources are available

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• Silver coated polyurethane dressings

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• Iodine containing polyurethane dressings

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• Sorbact

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• Polymem

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Other treatment modalities (advanced):

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• Negative pressure wound therapy (NPWT) once the wound is clean and shows early granulation. Note: we do not recommend the start of NPWT before four weeks of antibiotic treatment have been given. We do not have any documentation about how M ulcerans thrive under the partially anaerobic environment of the NPWT treated wound. NPWT with irrigation is preferred here, in our opinion. 

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• Platelet-rich plasma (PRP) may be useful if there is exposed bone or tendon. 

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• Partial-thickness skin transplant, ultra-thin transfer of epidermal cells ( blister technique) or pinch/punch grafting. Again, wait at least 4 weeks into the antibiotic treatment before attempting a skin graft.