Buruli Ulcer

Buruli ulcer, caused by Mycobacterium ulcerans, is a chronic, debilitating, necrotizing disease of the skin and soft tissue. Buruli ulcer is an emerging infectious disease and is the third most common mycobacterial disease of the immunocompetent host, after tuberculosis and leprosy.[1] Although it has been reported in over 33 countries around the world, the greatest burden of disease is in the tropical regions of West and Central Africa, Australia, and Japan.[2] It primarily affects children aged 5-15 years.[2] Buruli ulcers generally begin as a painless dermal papule or subcutaneous edematous nodule, which, over a period of weeks to months, breaks down to form an extensive necrotic ulcer with undermined edges. Treatment includes a prolonged course of antibiotics and surgical debridement. Early identification and treatment are key, as lesions heal with scarring that can be a significant source of morbidity. Other names for this entity include Bairnsdale ulcer, Daintree ulcer, Mossman ulcer, and Searl ulcer. Note the image below.

Buruli ulcer was first described by Sir Albert Cook in patients from Buruli County in Uganda, and the causative organism was isolated in 1948 by MacCallum in the Bairnsdale region of Victoria, Australia. A reemergence of cases led the 1998 World Health Organization (WHO) to reclassify Buruli ulcer as a "neglected emerging infectious disease," which has stimulated ongoing research into diagnosis, pathogenesis, and effective treatment.[3, 4, 5]

M ulcerans are slow-growing mycobacteria that produce a soluble polyketide exotoxin called mycolactone, which can diffuse extensively in the subcutaneous tissue. Because mycolactone has both immunosuppressive properties and cytotoxic properties, dramatic tissue destruction occurs without inducing inflammation or systemic symptoms, such as fever, malaise, or adenopathy.[6, 7, 8, 9, 10] Mycolactone was first identified in 1999. Research has revealed the mechanisms of action of mycolactone, as described below.

Molecular targets

Mycolactone targets scaffolding proteins, such as the Wiskott-Aldrich syndrome protein (WASP),[11] which controls actin dynamics and leads to a loss of cellular detachments and cell death.[12]

Mycolactone also inhibits the function of the Sec61 translocation, which is responsible for protein translocation into the endoplasmic reticulum. This affects 30-50% of mammalian proteins, including circulating inflammatory mediators and proteins involved in lipid metabolism, coagulation, and tissue remodeling.[13] Therefore, patients with M ulcerans infections have global and chronic defects in protein metabolism. This is evident by reduced levels of total serum proteins and blood urea nitrogen, without the presence of malnutrition, kidney impairment, or liver impairment.[13]

Buruli ulcers are traditionally thought to be painless ulcers. Research has shown that the hypoalgesic effect occurs via activation of the angiotensin II type 2 receptor (AT2R), leading to neurite degeneration and cell death.[14] Another prominent feature of Buruli ulcers is extensive coagulative necrosis caused by mycolactone.

Ogbechi et al showed that mycolactone decreased thrombomodulin expression on the surface of human dermal microvascular endothelial cells, thereby impairing the activation of protein C. This study also showed that fibrin deposition is a prominent feature of these ulcers and the tissue necrosis could be caused by fibrin-driven ischemia.[15]

Genetic susceptibility

Genetic susceptibility may be associated with the SCLC11A1 (NRAMP1) D543 polymorphism.[16]

M ulcerans are slow-growing mycobacteria and are the causative agent of Buruli ulcers. The optimal temperature for growth is 30-32°C. This temperature is slightly below that of core body temperature and may explain some of the predisposition for lesions on the extremities and lack of visceral involvement. M ulcerans is sensitive to temperatures above 37°C, which has led to ongoing clinical trials using local heat application devices for treatment.[17]

M ulcerans is an environmental pathogen that has been isolated from biofilms and small aquatic animals of slow-moving or stagnant bodies of water.[18, 19, 20, 21] Although the exact mode of transmission is unknown, M ulcerans most likely causes infection through contamination of a traumatic wound. The absence of protective equipment during agricultural activities is a well-documented risk factor.[22] Proper wound hygiene has been shown to decrease infection rates.[23, 24, 25]

Because of its fragility and sensitivity to direct sunlight, M ulcerans likely persists within a protective host, although no hosts have been identified to date.[22] Transmission via the bites of Australian salt marsh mosquitoes with possums serving as the reservoir is supported by scientific evidence, but a mammalian reservoir has not been identified in other areas of the world.[23, 26, 27, 28] African biting water insects (Naucoridae, Belostomatidae, and Acanthamoeba species) have been implicated in the transmission of M ulcerans in ongoing research.[29, 28] Human-to-human transmission has rarely been reported. There is not an increased risk of infection associated with living with an infected family member.[23] In 2010, investigation of a familial outbreak of Buruli ulcers in Japan revealed matching insertion sequence 2404 in the infected wounds and crayfish found near the family's house. Given the location of the ulcers, direct inoculation was deemed unlikely. This supports the evidence that aquatic environments act as a reservoir for M ulcerans.[30]

A plasmid-encoded polyketide toxin termed mycolactone is responsible for the extensive destruction and suppressed host response in Buruli ulcers. Four variants have been identified. Mycolactone A and B are the more virulent variants and are found in Africa. Mycolactone C is found in Australia, and mycolactone D is found in Asia.[31] For more information, see Overview/Pathophysiology.

US frequency

According to the World Health Organization (WHO), as of 2015, there have been no cases of confirmed Buruli ulcers originating in the United States.[3]

International frequency

Approximately 6000 cases are reported annually around the world, especially from rural Africa.[3]

Buruli ulcers have been reported in 33 countries. The largest number of endemic cases occur in countries in central and western Africa, such as Côte d'Ivoire, Benin, Ghana, Democratic Republic of the Congo, Cameroon, Nigeria, Togo, and Liberia.[32] Other involved geographic areas include Australia, Papa New Guinea, Japan, and sporadic cases in Central and South America. Subtropical and swampy terrain are major endemic foci for M ulcerans.

Race

No specific racial predilection is known.

Sex

No differences exist in the rates of infection among males and females.

Age

Buruli ulcer may affect any age group, but most cases occur in children ages 5-15 years, except in Australia, where Buruli ulcer is more prevalent in adults older than 50 years.[33]

Most patients have complete healing, with or without significant scarring or impairment. Even with medical and surgical care, patients often require hospitalizations averaging 3 months. The best prognosis occurs when treatment is instituted as early as possible before significant tissue destruction can occur. Without medical care, more than half the affected individuals are left with a functional limitation. The scarring can be disfiguring and can have a significant emotional and socioeconomic impact on patients. Treatment involves long hospital stays (average of 3 months), antibiotic regimens, and surgical procedures, which are resources often limited in endemic areas.[34]

Buruli ulcer has a low mortality rate; however, it is a significant source of morbidity and socioeconomic burden. Skin and soft-tissue necrosis can be extensive, involving as much as 15% of the patient's skin surface and may extend deep, exposing fascia, muscle, and bone.

When Buruli ulcers are identified early and treated appropriately, the prognosis is good. Klis et al found that 85% of patients who presented with small lesions and who received 8 weeks of antibiotics indicated no effect, or only a small effect, of the disease on their current life at long-term follow up visits.[35] The median score on the Dermatology Life Quality Index was 0 (range, 0-4), indicating a good quality of life.[35] These results highlight the importance of early identification and treatment, in stark contrast with the debilitating contracted scars that result if these ulcers are not treated in a timely manner.

The majority of the systemic complications from Buruli ulcers are from the toxicities of long-term antibiotic use. See Treatment/Complications section.

Elderly patients have a tendency towards more severe disease and increased complications from treatment.[33]

 

Owing to the long incubation period of Mycobacterium ulcerans, ranging from 1-9 months, with a mean of 4.5 months, most patients do not recall an inciting event.[36] Lesions usually begin as a single, painless, occasionally pruritic, dermal papule or subcutaneous nodule. Because the initial lesion is painless, many patients do not seek immediate medical attention. Suppuration and necrotic ulceration occurs within 1-2 months. Otherwise, the patients are generally healthy. Systemic symptoms such as fever or lymphadenopathy are rare owing to the immunosuppressive effects of mycolactone.

The peak incidence of cases is in March, typically in swampy areas, suggesting an association with rainy seasons in West Africa.[37]

 

Classically, Buruli ulcers are considered an expanding ulceration on the lower extremity, although they can occur anywhere. Approximately 90% of lesions occur on the limbs, with 60% occurring on the lower extremities. Patients present with nonulcerative lesions in 0-30% of cases and with ulcerative lesions in 70-100% of cases.[38] See the image below.

In the preulcerative stage, Buruli ulcer manifests initially as firm, nontender, subcutaneous nodule 1-2 cm in diameter. Less common presentations include a dermal papule or indurated plaque. A more aggressive edematous variant is frequently seen in Australia. The edematous variant causes a rapid onset of diffuse swelling, which can involve an entire extremity and evolves into an extensive ulcer. This is frequently misdiagnosed as cellulitis.[39]

The ulcerative stage occurs days to weeks later. The skin covering the plaque or nodule slowly sloughs, leaving an extensive necrotic ulcer with undermined edges. Subcutaneous necrosis may extend several centimeters beyond the edge of the ulcer; therefore, the lesion appears smaller than its actual size. Characteristic lesions have a scalloped border and a sloughing, necrotic base. The ulcers may appear yellow or green and have a characteristic smell. Pain and local lymphadenopathy suggest secondary infection.[40]

Buruli ulcers may destroy nerves, appendages, and blood vessels and may invade bone. Metastatic lesions may occur in the skin, soft tissue, or bone via spread through the vasculature or lymphatics. Approximately 33% of patients present with underlying osteitis, osteomyelitis, or joint involvement.[3] Interestingly, one fourth of the patients with M ulcerans osteomyelitis have no apparent history of cutaneous Buruli ulcer.[41] . Half of these patients have crippling sequelae.[41]

Healing is a slow process and may result in cosmetically disfiguring scars and functional disabilities if treatment is delayed.

Rapid diagnosis and treatment are necessary. Unfortunately, the major burden of Buruli ulcers occurs in remote rural areas, where fast and accurate testing is not available. Currently, the only available point-of-care test is microscopic detection of acid-fast bacilli (AFB), which is obtained from biopsy specimens from deep subcutaneous tissue within the ulcers, and is neither sensitive nor specific.[42] The development of point-of-care tests, such as fluorescent thin-layer chromatography, is considered a research priority by the World Health Organization (WHO).[3]

 

Regardless of the test or sampling method, at least two sites per suspicious lesion should be submitted to increase the sensitivity by 25% over a single specimen.[43]

Polymerase chain reaction (PCR) testing for IS2404 (and IS2606) of punch biopsy, swab, and fine-needle aspiration specimens is the criterion standard for laboratory confirmation. Studies have demonstrated swabs are more beneficial than punch biopsy specimens or fine-needle aspirations for ulcerated lesions. For nonulcerated lesions, fine-needle aspiration is preferred over a 3-mm punch biopsy sample and provides sensitivities of more than 90%.[44, 45] PCR provides results within 48 hours and has a sensitivity of 90-98%.[46, 47] PCR remains positive for as long as 40 days into the antibiotic course. Unfortunately, PCR is only available in research laboratory settings and is expensive.

A direct smear from the necrotic base of the lesion may be stained with Ziehl-Neelsen stain, revealing clumps of AFB. This method has a sensitivity of 40-50% in the ulcerative form, 60% in the nodular form, and 80% in the edematous form.[10] Improvement in the yield can be achieved by good sample collection, concentration of the specimen before smearing, good microscopy practices, and analysis of at least three separate swabs.[48]

Mycobacterium ulcerans can be cultured from ulcer exudate or fresh tissue, or by swabbing the entire undermined rim of the ulcer. The inoculums must be incubated at 30-35°C (most sources recommend 32-33°C) on Lowenstein-Jensen medium. Because the organism is a slow grower, it can take 6-8 weeks before it can be isolated by culture.[34] This method has a sensitivity of only 20-60%.[10]

Biopsy for histological evaluation has a sensitivity of 82-90%, and this technique is generally done when surgical treatment is performed or there is a paradoxical reaction.[10]

Point-of-care tests that can be deployed to clinics throughout the world are a current area of research. A new dry reagent–based PCR assay, loop-mediated isothermal amplification (LAMP) technique,[49] and reverse transcriptase RNA PCR are being researched and may be better suited for countries where Buruli ulcer is endemic. These methods have a sensitivity similar to or better than conventional PCR.[50, 51]

For patients with multiple episodes of Buruli ulcers, next-generation sequencing (NGS) techniques may be performed to distinguish relapses from reinfections.[52]

Table 1. Pros and Cons of Sampling Techniques From the WHO ^[38] (Open Table in a new window)

 

 

Ultrasonography can reveal the depth and extension of Buruli ulcers and can be used to follow the response to antibiotics.[53]

If osteomyelitis is suspected, then a radiologic evaluation is recommended.

Histopathologic specimens reveal extensive coagulation necrosis in the dermal collagen and the subcutaneous fat, with destruction of cutaneous nerves, blood vessels, and adnexal structures. The necrosis may extend well beyond the edges of the ulceration. In early lesions, extracellular clumps of AFB may be seen at the base of the ulcer in the deep subcutaneous tissue. In active lesions, the inflammatory infiltrate is usually absent to mild, although a leukocytoclastic vasculitis or thrombosis of small- and medium-sized vessels may be seen. In older lesions, a granulomatous reaction occurs, with fewer organisms present, eventuating into cicatrix formation. Epidermal hyperplasia is more common in ulcerative than preulcerative lesions.[54]

Treatment of Buruli ulcers relies on timely and accurate diagnoses. When treated early, antibiotics alone are adequate. If treatment is delayed, surgical debridement, skin grafts, extensive wound care, and physical therapy may be needed to attenuate debilitating sequelae.

Antibiotics

Since 2004, the medical management of Buruli ulcers has become an active area of research. Through the use of the mouse footpad model developed by Fenner, rifampicin, rifabutin, amikacin, and streptomycin have demonstrated bactericidal activity and azithromycin, clarithromycin, and moxifloxacin to have bacteriostatic activity.[55, 56] Antibiotics not only destroy or inhibit the causative mycobacteria, they reverse the immunosuppression of the mycolactone.[43, 55] Antibiotics have reduced the rate of infection recurrence and reduced the need for surgical intervention. Unfortunately, the antibiotic treatment courses are prolonged and may lead to permanent sequelae.

In 2004, the WHO recommended a treatment protocol that divided lesions into three categories (see Table 2 below). The WHO recommended that all categories receive an eight-week course of rifampicin (10 mg/kg once daily) and streptomycin (15 mg/kg once daily) as the standard of care.[57] Recurrence rates after antibiotic treatment are reported to be 2-3%.[10, 58, 59] This regimen has been reported to heal lesions without requiring surgery in 47-95% of patients.[58, 60] The median healing times for category I, II, and III were 8, 10, and 20 weeks, respectively.[60]

Table 2. Categories of Treatment ^[57] (Open Table in a new window)

Streptomycin use is limited by patient compliance, as it has poor bioavailability and requires daily intramuscular administration. Additionally, it has ototoxic, nephrotoxic, and neurotoxic effects, which may be permanent. It is pregnancy risk factor category D and may cause bilateral congenital deafness by crossing the placenta.[61] Therefore, alternative antibiotics are currently being researched.

Nienhuis et al compared the efficacy of two antibiotic regimens for Mycobacterium ulcerans infection. In Ghana, patients aged 5 years or older were randomly assigned to receive streptomycin (15 mg/kg IM daily) plus rifampicin (10 mg/kg PO daily) for 8 weeks (n = 76) or streptomycin and rifampin for 4 weeks followed by rifampin and clarithromycin (7.5 mg/kg PO daily) for 4 weeks (n = 75). No significant difference was observed for each treatment regimen (healed lesions at 1 y were 96% for 8-wk streptomycin vs 91% for 4-wk streptomycin); however, the number of streptomycin injections was able to be reduced by switching to oral clarithromycin after 4 weeks.[62]

In 2007, the Australian Victorian Department of Human Services recommended the combination of rifampicin and clarithromycin or ciprofloxacin or moxifloxacin for 3 months.[63] It has proven effective in small case series.[51] . Friedman et al demonstrated a successful treatment in 42 of 43 patients using rifampin (10 mg/kg PO daily) combined with either ciprofloxacin (500 mg twice daily) or clarithromycin (500 mg twice daily). The majority of these patients had WHO category I lesions.[64] In severe disease, oral rifampicin with intravenous amikacin is the treatment of choice.

Converse et al, in 2015, demonstrated on the mouse footpad model that rifampin plus clofazimine has potential as a continuation-phase regimen for treatment of M ulcerans infection.[65]

While further research is needed to determine the optimal duration of treatment of an all-oral antibiotic regimen, the existing research has led the WHO to summarize its stance on treatment as follows[57] :

"In summary, there is now overwhelming evidence that 8 weeks of streptomycin–rifampicin or 4 weeks of rifampicin–streptomycin followed by 4 weeks of rifampicin–clarithromycin or 8 weeks of other oral regimens all achieve recurrence-free healing with an acceptable level of side-effects. This is true for ulcers of all sizes, even without additional surgery to remove necrosis or skin grafting to accelerate healing."

While awaiting further confirmation of efficacy, the WHO has stated that an alternative regimen based on vast clinical practice is as follows[57] :

• Rifampicin (10 mg/kg PO daily) for 8 weeks and clarithromycin (7.5 mg/kg PO twice daily) for 8 weeks OR
• Rifampicin (10 mg/kg PO daily) for 8 weeks and moxifloxacin (400 mg PO daily) for 8 weeks (for adults only)

Wound care

While traditionally Buruli ulcers are thought to be painless as a result of the neurotoxic effects of mycolactone, many patients experience pain during wound care, which must be addressed. Currently, the only dressing used for wound care is gauze, which results in pain and bleeding when removed. More research needs to be performed to determine the best dressings to be used for these patients.[66] Additionally, the availability of clean water and good hygiene are important for the management of Buruli ulcers and prevention of secondary infections.

Other supportive treatments

Other treatment modalities are currently being explored.

Given the sensitivity of M ulcerans to temperatures greater than 37°C, hyperthermia with a 40°C water bath, such as a circulating water jacket, and local heat application devices have shown some success.[67, 68, 17]

Hyperbaric oxygen also has been reported as effective in a small number of patients.[69]

Ozone therapy is being explored after initially encouraging results.[70]

Negative-pressure wound therapy (NPWT) has also been shown to be effective.[71]

One report suggested that acid-oxidizing solutions can help kill M ulcerans and possibly can be used in support of antibiotic therapy, as well as to prevent cross-contamination.[72]

 

Prior to 2004, excision was the treatment of choice for Buruli ulcers. Most patients required multiple staged surgeries and extensive skin grafts, which resulted in prolonged hospitalizations, averaging around three months.[57] Recurrence rates after surgery alone were 16-28%.[57] With the use of antibiotics, 40% of patients do not require surgery. In conjunction with antibiotics, surgery is used to remove devitalized tissue, cover open wounds with skin grafts, and correct or minimize deformities.[73] Note the images below.

For those who refuse or cannot tolerate antibiotics, surgeries can have excellent cure rates in certain cases. Small subcutaneous nodules or small ulcerations younger than 6 months and smaller than 10 cm in diameter may be excised en bloc with primary closure. Risk factors for recurrence in surgery-alone patients include immunosuppression, positive histologic margins for inflammation or infection, patients older than 60 years, and clinical symptoms present longer than 75 days.[39] Use of PCR to evaluate surgical margins may reduce recurrences.[74]

Scarring, contractures, and lymphedema may result after healing of Buruli ulcers. Scarring and contractures can have significant social, psychological, physical, and economic impact on patients. Osteomyelitis, metastatic lesions, and secondary infections are additional potential complications. Squamous cell carcinomas have been reported in Buruli ulcers.[75]

Debilitation

The most common complication from Buruli ulcers is physical disability. In a 2015 study from Togo, of 199 patients with confirmed cases of M ulcerans infection, 109 patients (84.5%) healed completely without any complications, 5 patients (3.9%) had secondary lesions, and 15 patients (11.6%) had functional limitations.[76] Risks factors for complications included edema, ulcers larger than 15 cm, healing times longer than 180 days, and a limitation of movement at the time of discharge.[76] A study from Benin in 2014 showed that 55.6% of patients who present with M ulcerans osteomyelitis had long-term crippling sequelae.[77]

Paradoxical reactions

Antibiotic treatment leads to a reversal of the immune suppression, which can lead to a brisk inflammatory response and release mycobacterial antigens from dead organisms. Clinically, this is apparent as clinical deterioration of lesions after initial improvement on antibiotics or the appearance of new lesions. This phenomenon, known as a paradoxical reaction, was first described in Buruli ulcers by O'Brien et al.[78] A similar process has been well documented in Mycobacterium tuberculosis infection, Mycobacterium leprae infection, and HIV infection among patients who are undergoing antiviral treatment.

This immune response can be misinterpreted as treatment failure or secondary infection and lead to unnecessary medical or surgical intervention if a paradoxical reaction is not considered. Paradoxical reactions occur in 9-23% of patients treated with antibiotics.[64, 39, 79, 80] Most occur within 3-10 weeks of initiating antibiotic treatment, but they can occur anywhere from the first week of treatment to 6 months after antibiotic treatment has been completed. Paradoxical reactions may mimic treatment failure, and they do not necessitate restarting antibiotics.

Patients who are at an increased risk of paradoxical reactions include those with an edematous lesion, patients treated with amikacin, patients with polymorphisms in the SLC11A1 gene, larger ulcers, or ulcers located on the trunk.[79, 81]

If a paradoxical reaction is suspected, a specimen should be sent for histopathological examination and culture. It should be cautioned that PCR and AFB stains can be positive because of the detection of nonviable M ulcerans.

Treatment strategies include clinical observation, needle aspiration of fluctuant lesions, minimal debridement if necessary, and adjunctive corticosteroid administration to settle inflammation in severe reactions. Prednisone may be used at a dose of 0.5-1 mg/kg for 2-3 weeks with gradual tapering for a course of 4-8 weeks.[80] Prolonging the antibiotic course to 12 weeks can be considered.

Coinfections

Secondary infections are common with Buruli ulcers, as clean water sources for wound care are frequently limited. A staggering 23% of patients diagnosed with Buruli ulcers in Ghana between August 2010 and December 2012 were coinfected with Mansonella perstans nematodes.[82] Proper wound care hygiene should be emphasized with these patients.

In coendemic countries, M ulcerans infections in HIV-positive patients lead to rapidly spreading osteomyelitis. Additionally, a severe paradoxical reaction may occur after starting antibiotic treatment for Buruli ulcers combined with antiretroviral therapy. Wanda et al reported successful treatment of a severe paradoxical reaction in a patient with HIV and M ulcerans coinfection.[83]

Aminoglycoside toxicity

As discussed in Treatment/Medical Care, prolonged streptomycin use is limited by systemic toxicity. In a long-term follow-up study from the BURULICO Drug Trial, Klis et al found that ototoxicity was present in 29% of adults and 25% of children, especially in the high-frequency range. In contrast, nephrotoxicity that had been detected in 14% of adults and in 13% of children during treatment was present in only 2.4% of patients at long-term follow-up.[84] Further research needs to be done to find safer alternatives for long-term treatments. In the meantime, streptomycin should be given with caution in patients at risk for renal dysfunction or hearing loss.

Buruli ulcers disproportionally affect children and may result in functional limitations. Accurate and timely laboratory diagnosis is difficult in endemic rural areas. Standard treatment requires a minimum of 8 weeks of intramuscular injections, which may leave the patients with permanent adverse effects. Prevention of M ulcerans infections is crucial, but difficult, as the exact mode of transmission has yet to be identified. Further research is needed to better understand this neglected emerging infectious disease.

The regular use of insect repellent, wearing protective clothing, avoiding exposure to stagnant natural water sources, and prompt treatment of minor wounds with alcohol can reduce the incidence of infection.[43, 55] Using bed nets has also demonstrated a slight decrease in the incidence of disease.[23, 25]

Vaccine

A vaccine to prevent M ulcerans infections would be ideal. Unfortunately, studies of the effectiveness of the BCG vaccine against M ulcerans have been disappointing, with most studies demonstrating no lasting benefit. The BCG vaccine may provide some protection against the onset of disease, although this effect does not last more than one year.[85, 86] Individuals who were previously immunized were less likely to have ulcers that cause osteomyelitis. Despite the disappointing results with the BCG vaccine, a new vaccine is an active area of research. See BuruliVac for more information.

Public health efforts

In highly endemic areas, public health officials have trained community-based volunteers to aid in education and early detection of Buruli ulcers. As a result, in Ghana, the percentage of cases being reported in the earliest WHO category I-stage of the disease has increased from 32% to nearly 70%.[87] Public health efforts are necessary for patient education and assistance with early detection to minimize associated morbidity. Although these programs have had encouraging results with improved clinical outcomes and decreased morbidity, studies have shown that continued refinement of these programs is needed.[88, 89, 90]

Patients who receive extended courses of streptomycin should be monitored for kidney function and hearing loss.

The WHO recommends teaching patients basic physical therapy to minimize functional limitations.[91] This self-administered physiotherapy has been show to improve and even resolve existing functional limitations during antibiotic therapy.[60]

The Infectious Diseases Society of America updated their guidelines for the diagnosis and management of skin and soft tissue infections. For the full guidelines, see Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America.[92, 93]

Treatment guidance for health workers can be found in the WHO publication “Treatment of mycobacterium ulcerans disease (Buruli ulcer).”

The goal of therapy is to reduce morbidity and prevent complications.

Rifampin (Rifadin, Rimactane)

Rifampin inhibits DNA-dependent bacterial but not mammalian RNA polymerase. Cross-resistance may occur.

Ciprofloxacin (Cipro)

Ciprofloxacin is a fluoroquinolone that inhibits bacterial DNA synthesis and, consequently, growth, by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. It has no activity against anaerobes. Continue treatment for at least 2 days (7-14 d typical) after signs and symptoms have disappeared.

Moxifloxacin (Avelox, Vigamox)

Moxifloxacin inhibits the A subunits of DNA gyrase, resulting in the inhibition of bacterial DNA replication and transcription.

Streptomycin sulfate (G-Mycin, Garamycin)

Streptomycin sulfate is for the treatment of susceptible mycobacterial infections. Use it in combination with rifampin. Streptomycin sulfate may be used in patients with severe liver dysfunction (transaminase levels >3- to 5-fold normal).

Amikacin (Amikin)

Amikacin irreversibly binds to the 30S subunit of bacterial ribosomes; it blocks the recognition step in protein synthesis and causes growth inhibition. Use the patient's ideal body weight for dosage calculation. The same principles of drug monitoring for gentamicin apply to amikacin.

Clarithromycin (Biaxin)

Clarithromycin is a semisynthetic macrolide antibiotic that reversibly binds to the P site of the 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating dissociation of peptidyl t-RNA from ribosomes, causing bacterial growth inhibition.