Drugs for treating Buruli ulcer (Mycobacterium ulcerans disease).

BACKGROUND: Buruli ulcer is a necrotizing cutaneous infection caused by infection with Mycobacterium ulcerans bacteria that occurs mainly in tropical and subtropical regions. The infection progresses from nodules under the skin to deep ulcers, often on the upper and lower limbs or on the face. If left undiagnosed and untreated, it can lead to lifelong disfigurement and disabilities. It is often treated with drugs and surgery. OBJECTIVES: To summarize the evidence of drug treatments for treating Buruli ulcer. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE (PubMed); Embase (Ovid); and LILACS (Latin American and Caribbean Health Sciences Literature; BIREME). We also searched the US National Institutes of Health Ongoing Trials Register (clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en/). All searches were run up to 19 December 2017. We also checked the reference lists of articles identified by the literature search, and contacted leading researchers in this topic area to identify any unpublished data. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared antibiotic therapy to placebo or alternative therapy such as surgery, or that compared different antibiotic regimens. We also included prospective observational studies that evaluated different antibiotic regimens with or without surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the inclusion criteria, extracted the data, and assessed methodological quality. We calculated the risk ratio (RR) for dichotomous data with 95% confidence intervals (CI). We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included a total of 18 studies: five RCTs involving a total of 319 participants, ranging from 12 participants to 151 participants, and 13 prospective observational studies, with 1665 participants. Studies evaluated various drugs usually in addition to surgery, and were carried out across eight countries in areas with high Buruli ulcer endemicity in West Africa and Australia. Only one RCT reported adequate methods to minimize bias. Regarding monotherapy, one RCT and one observational study evaluated clofazimine, and one RCT evaluated sulfamethoxazole/trimethoprim. All three studies had small sample sizes, and no treatment effect was demonstrated. The remaining studies examined combination therapy.Rifampicin combined with streptomycinWe found one RCT and six observational studies which evaluated rifampicin combined with streptomycin for different lengths of treatment (2, 4, 8, or 12 weeks) (941 participants). The RCT did not demonstrate a difference between the drugs added to surgery compared with surgery alone for recurrence at 12 months, but was underpowered (RR 0.12, 95% CI 0.01 to 2.51; 21 participants; very low-certainty evidence).An additional five single-arm observational studies with 828 participants using this regimen for eight weeks with surgery (given to either all participants or to a select group) reported healing rates ranging from 84.5% to 100%, assessed between six weeks and one year. Four observational studies reported healing rates for participants who received the regimen alone without surgery, reporting healing rates ranging from 48% to 95% assessed between eight weeks and one year.Rifampicin combined with clarithromycinTwo observational studies administered combined rifampicin and clarithromycin. One study evaluated the regimen alone (no surgery) for eight weeks and reported a healing rate of 50% at 12 months (30 participants). Another study evaluated the regimen administered for various durations (as determined by the clinicians, durations unspecified) with surgery and reported a healing rate of 100% at 12 months (21 participants).Rifampicin with streptomycin initially, changing to rifampicin with clarithromycin in consolidation phaseOne RCT evaluated this regimen (four weeks in each phase) against continuing with rifampicin and streptomycin in the consolidation phase (total eight weeks). All included participants had small lesions, and healing rates were above 90% in both groups without surgery (healing rate at 12 months RR 0.94, 95% CI 0.87 to 1.03; 151 participants; low-certainty evidence). One single-arm observational study evaluating the substitution of streptomycin with clarithromycin in the consolidation phase (6 weeks, total 8 weeks) without surgery given to a select group showed a healing rate of 98% at 12 months (41 participants).Novel combination therapyTwo large prospective studies in Australia evaluated some novel regimens. One study evaluating rifampicin combined with either ciprofloxacin, clarithromycin, or moxifloxacin without surgery reported a healing rate of 76.5% at 12 months (132 participants). Another study evaluating combinations of two to three drugs from rifampicin, ciprofloxacin, clarithromycin, ethambutol, moxifloxacin, or amikacin with surgery reported a healing rate of 100% (90 participants).Adverse effects were reported in only three RCTs (158 participants) and eight prospective observational studies (878 participants), and were consistent with what is already known about the adverse effect profile of these drugs. Paradoxical reactions (clinical deterioration after treatment caused by enhanced immune response to M ulcerans) were evaluated in six prospective observational studies (822 participants), and the incidence of paradoxical reactions ranged from 1.9% to 26%. AUTHORS' CONCLUSIONS: While the antibiotic combination treatments evaluated appear to be effective, we found insufficient evidence showing that any particular drug is more effective than another. How different sizes, lesions, and stages of the disease may contribute to healing and which kind of lesions are in need of surgery are unclear based on the included studies. Guideline development needs to consider these factors in designing practical treatment regimens. Forthcoming trials using clarithromycin with rifampicin and other trials of new regimens that also address these factors will help to identify the best regimens.

Surgical Management of Chronic Wounds in a Buruli Ulcer Endemic Area in Central Africa.

BACKGROUND: Chronic wounds, especially Buruli ulcers (BU) are emerging public health threat in West and Central Africa. Akonolinga in Cameroon is one of the four health districts affected by BU. Since 2002, Médécins Sans Frontières has established a specialized wound carecenter to actively diagnose and provide treatment of chronic wounds that is accessible and affordable for all patients. Our objectives were to report the surgical activities in Akonolinga, to provide description of the types of chronic wounds and elements of anticipation of treatment needs in a public health perspective. METHOD: We carried out a retrospective cohort and descriptive study from January 2012 to June 2014 (30 months) on a series of consecutive patients with chronic wounds, managed surgically in Akonolinga, Centre Region, Cameroon. Among BU patients only those with necessity of surgery were included and the others followed only their 8 weeks medical treatment with antibiotics. RESULTS: A total of 148 patients were recorded. 101 cases of BU and related disability and 47 cases of non-Buruli chronic wounds. Patients had a mean age of 34 years. Most of the procedures used were debridement 40 %, skin graft 29 %, stripping 5 %, plastic procedures 7 %, and amputation 4 %. The mean number of procedures was 2 for each patient in this series. CONCLUSION: Chronic wounds occur worldwide and may be caused by specific health conditions. Medical and paramedical education should provide both the theoretical knowledge and practical skills to help health care personnel to face this problem in their communities.

Treatment and prevention of Mycobacterium ulcerans infection (Buruli ulcer) in Australia: guideline update.

• Guidelines reflecting contemporary clinical practice in the management of Buruli ulcer (Mycobacterium ulcerans infection) in Australia were published in 2007. • Management has continued to evolve, as new evidence has become available from randomised trials, case series and increasing clinical experience with oral antibiotic therapy. • Therefore, guidelines on the diagnosis, treatment and prevention of Buruli ulcer in Australia have been updated. They include guidance on the new role of antibiotics as first-line therapy; the shortened duration of antibiotic treatment and the use of all-oral antibiotic regimens; the continued importance, timing and role of surgery; the recognition and management of paradoxical reactions during antibiotic treatment; and updates on the prevention of disease.

[Paradoxical reactions and responses during antibiotic treatment for Mycobacterium ulcerans infection (Buruli ulcer). Four cases from French Guiana]. / Réponses et réactions paradoxales au cours du traitement médicamenteux de l'infection à Mycobacterium ulcerans (ulcère de Buruli). Quatre observations en Guyane française.

BACKGROUND: In recent years, first-line therapy for Mycobacterium ulcerans infection in French Guiana has consisted of antibiotics active against this organism. Two regimens are used comprising rifampicin associated with clarithromycin or amikacin. PATIENTS AND METHODS: We describe four patients presenting apparent worsening of their lesions during treatment: ulceration of a nodular lesion in a 32-year-old woman and worsening of an ulcerated lesion in three patients aged 16, 27 and 79 years. DISCUSSION: In these 4 patients, we concluded that the symptoms were caused by a paradoxical response or a reaction, a phenomenon already described in tuberculosis and leprosy. Such worsening is transient and must not be misinterpreted as failure to respond to treatment. The most plausible pathophysiological hypothesis involves the re-emergence of potentially necrotizing cellular immunity secondary to the loss of mycolactone, a necrotizing and immunosuppressive toxin produced by M. ulcerans, resulting from the action of the antibiotics.

Risk factors for recurrent Mycobacterium ulcerans disease after exclusive surgical treatment in an Australian cohort.

OBJECTIVE: To describe risk factors for recurrence after exclusive surgical treatment of Mycobacterium ulcerans infection. DESIGN, SETTING AND PARTICIPANTS: Prospective observational cohort study of all M. ulcerans cases managed with surgery alone at Barwon Health, a tertiary referral hospital, from 1 January 1998 to 31 December 2011. A random-effects Poisson regression model was used to assess rates and associations of treatment failure. MAIN OUTCOME MEASURES: Rates of treatment failure and rate ratios (RRs) for factors associated with treatment failure. RESULTS: Of 192 patients with M. ulcerans infection, 50 (26%) had exclusive surgical treatment. Median age was 65.0 2013s (interquartile range [IQR], 45.5-77.7 2013s), and median duration of symptoms was 46 days (IQR, 26-90 days). There were 20 recurrences in 16 patients. For first lesions, the recurrence incidence rate was 41.8 (95% CI, 25.6-68.2) per 100 person-2013s, and median time to recurrence was 50 days (IQR, 30-171 days). Recurrence occurred ≤ 3 cm from the original lesion in 13 cases, and > 3 cm in nine. On univariable analysis, age ≥ 60 2013s (RR 13.84; 95% CI, 2.21-86.68; P < 0.01), distal lesions (RR, 20.43; 95% CI, 1.97-212.22; P < 0.01), positive histological margins (RR, 21.02; 95% CI, 5.51-80.26; P < 0.001), immunosuppression (RR, 17.97; 95% CI, 4.17-77.47; P < 0.01) and duration of symptoms > 75 days (RR, 10.13; 95% CI, 1.76-58.23; P = 0.02) were associated with treatment failure. On multivariable analysis, positive margins (RR, 7.72; 95% CI, 2.71-22.01; P < 0.001) and immunosuppression (RR, 6.45; 95% CI, 2.42-17.20; P = 0.01) remained associated with treatment failure. CONCLUSIONS: Recurrence rates after exclusive surgical treatment of M. ulcerans disease in an Australian cohort are high, with increased rates associated with immunosuppression or positive histological margins.

Reconstructive surgery for sequellae of Mycobacterium ulcerans infection (Buruli ulcer) of the upper limb.

INTRODUCTION: Infection by Mycobacterium ulcerans constitutes a neglected tropical disease whose prevalence seems to have overrun those of cutaneous tuberculosis and leprosy. Its aggressivity depends on a mycolactone toxin. Lesions may involve skin, tendon and bone with a large spectrum of manifestations: non-ulcerative (papules, nodules, plaques), ulcerative and oedematous presentations as well as osteomyelitis with muscular contraction and ankylosis. Upper limbs account for more than two thirds of the infection sites. Surgical treatment may involve tendon transpositions, partial and total skin grafts. Amputation is relegated to extreme cases. MATERIAL AND METHODS: Selected iconography from patients during the last 15 years is presented. At least 1500 cases had partial skin grafts (anterior thigh). Total skin grafts (inguinal region) were used in about 200 cases. Complex lesions involved 9 ilioinguinal flaps (5 boys, 4 girls, mean age 11.2 years, range 2-16 years), 5 tendon transfers (4 boys, one girl, mean age 15.4 years, range 12-19 years) and 3 resections of the first carpal row (2 girls, 1 boy, mean age 8 years, range 4-15 years). RESULTS AND DISCUSSION: Out of 9 ilioinguinal flaps mild, marginal necrosis was the only complication in 2 patients without flap loss. Mean hospital stay was 26.44 days (range, 18-41 days), with return to full weight-bearing after a mean of 12 weeks (range 9-25 weeks) after discharge. Functional thumb opposition to allow pencil prehension was achieved in all three cases of resection of first carpal row resection without postoperative complications.

Buruli ulcer. A disabling infection.

Buruli ulcers result from an initial skin infection that often leads to extensive tissue necrosis. The causative agent is Mycobacterium ulcerans, a bacterium prevalent in humid, rural tropical areas. Several thousand people are infected each year, especially in Africa, where Buruli ulcers are a source of major disability. A combination of oral rifampicin and injectable streptomycin is effective. Surgical treatment and functional rehabilitation are often necessary. Diagnostic tests suitable for use in primary care settings are needed, along with well-tolerated, effective oral treatments.

Excision of pre-ulcerative forms of Buruli ulcer disease: a curative treatment?

BACKGROUND: Previous investigations have revealed that Mycobacterium ulcerans is extensively distributed spatially throughout ulcerative lesions, including in the margins of excised tissue. In contrast, bacilli in pre-ulcerative lesions are assumed to be concentrated in the center of the lesion. In order to assess the extent to which the surgical excision of pre-ulcerative lesions is capable of removing all infected tissue, we subjected the excision margins of pre-ulcerative lesions to laboratory analysis. PATIENTS AND METHODS: Eleven patients with laboratory-confirmed pre-ulcerative lesions were included in the study. The diameter of the lesion and excised tissue and the "surgical distance" between the border of the lesion and excision margin were measured. The entire excision margin was cut into segments and subjected to IS2404 PCR. RESULTS: The results from the PCR analysis on the samples of excision margins were highly significantly associated with the surgical distance (p < 0.001). The margin samples of nodules were significantly more often PCR positive than the plaques (p = 0.025). The size of the lesion and the size of the excised tissue did not significantly influence the PCR results. Statistically, a surgical distance of more than 9 mm was found to reduce the risk of remaining infected tissue to less than 10%, that of 13 mm to reduce the risk to less than 5%, and that of 25 mm to reduce the risk to nearly 0%. CONCLUSION: The results of this study show that in preulcerative Buruli ulcer disease, bacilli may extend beyond the actual size of the lesion and that there is a strong correlation between the presence of M. ulcerans in the margin samples and the surgical distance. Excision with a surgical distance of 25 mm avoided the risk of remaining mycobacteria in this study. However, no recurrences occurred in the patients with M. ulcerans-positive excision margins. The need of postoperative antimycobacterial treatment in these patients remains to be determined.

Primitive breast localisation of Buruli ulcer in an endemic zone: a rare case.

A case of Buruli ulcer with primitive breast localisation with evident epidemiological and clinical aspects is reported. This localisation is exceptional; the differential diagnosis with breast cancer is essential. If diagnosed early, it can be cured with surgery, broad-spectrum antibiotherapy and thermotherapy.

[About a case of Mycobacterium ulcerans infection with cold abscess]. / A propos d'un cas d'infection due a Mycobacterium ulcerans se présentant sous la forme d'un abcès froid.

Buruli ulcer is still a public health problem in Côte d'Ivoire. Its physiopathology is poorly described and suggests a new clinical form. We report a clinical case in a 18-year-old patient who had a cold abscess on the right elbow. The histopathology test revealed a Mycobacterium ulcerans infection. The treatment consisted in antimycobacterial therapy and surgical care. The clinical healing was observed during 4 months of hospitalization. This form of Mycobacterium ulcerans with cold abscess, the first case described so far, requires great vigilance in clinical detection of cases and underlines the importance to intensify microbiological research mainly in endemic areas.

[Relapse after surgical treatment of mycobacterium ulcerans infection (buruli ulcer): study of risk factors in 84 patients in the Democratic Republic of the Congo]. / Rechutes après traitement chirurgical exclusif de l'infection à Mycobacterium ulcerans (ulcère de Buruli): étude des facteurs de risque chez 84 patients congolais.

OBJECTIVE: To identify risk factors for relapse after exclusively surgical treatment of Mycobacterium ulcerans infection (Buruli ulcer). METHODS: Study was carried out in 102 patients treated exclusively by surgery for Buruli ulcer at various care facilities in the Congo from January 1, 2000 to January 1, 2005. RESULTS: Outcomes included relapse in 22 patients (21.5%), cure in 62 (60.7%), and unknown in 18 (17.6%). Statistical analysis identified the following variables as independent risk factors for relapse after exclusively surgical treatment: incomplete surgical excision (OR = 91.83; P = 0.0000; IC to 95%), age under 16 years (OR = 14.80; P = 0.0000; IC to 95%) and pre-ulcerative Buruli lesions (edema and plaque) (OR = 3.18; P = 0.0215; IC to 95%). CONCLUSION: Quality of excision, patient age, and clinical form of lesion are the main predictors of relapse after isolated surgical treatment of Buruli ulcer.

Mycobacterium ulcerans disease management in Australian patients: the re-emergence of surgery as an important treatment modality.

With the demonstration of the effectiveness of antibiotic treatment, the management of Mycobacterium ulcerans disease has changed from a predominantly surgically to a predominantly medically treated disease. However, research among Australian patients has revealed that antibiotic treatment alone is associated with prolonged wound healing times, high rates of treatment toxicity, and the potential for significant tissue destruction associated with severe paradoxical reactions. We present the current state of M. ulcerans management in Barwon Health, Australia, where a close working relationship exists between the Plastic Surgical and Infectious Diseases units. Here treatment has evolved based on nearly 20 years of experience gained from managing more around 600 patients from a M. ulcerans epidemic on the nearby Bellarine and Mornington Peninsulas. In our experience, surgery has re-emerged to play an important role in the treatment of M. ulcerans in improving the rate of wound healing, minimizing antibiotic associated toxicity and preventing further tissue loss associated with severe paradoxical reactions. For selected small lesions surgery without antibiotics may also be an effective treatment option, however aggressive surgical resection of lesions with wide margins through uninvolved tissue should no longer be performed. Furthermore, extensive excisional surgery that will require the use of split skin grafts and vascularized tissue flaps to repair skin defects should be avoided if possible.

Buruli ulcer: Evaluation of its medical and surgical management at the Allada (Benin) Screening and Treatment Center, 2010-2014.

The objective of our study was to evaluate the medico-surgical management of Buruli ulcer (BU) in the BU Screening and Treatment Center (CDTUB) of Allada in Benin. This retrospective and descriptive study retrospectively reviewed records of patients seen from 2010 to 2014 at the CDTUB of Allada. It included patients diagnosed with BU according to WHO epidemiological and clinical criteria as well as laboratory results and who were treated according to WHO medical and surgical recommendations. In all, 274 patients were diagnosed and treated, 57.7% of them children younger than 15 years. Ulcerative lesions (189, 69%) and WHO category II lesions (144, 52.5%) predominated. All patients received dual antibiotic therapy and 43.4% (119) underwent surgery as well. Category III lesions and multifocal lesions required more surgery, whereas most category I lesions healed under medical treatment. The overall rate of healing was 92%: 53.3% for patients who received only antibiotic therapy and 38.7% for those who also had surgery. The median healing time was 13 weeks and ranged from 4 to 56 weeks. In the CDTUB of Allada, between 2010 and 2014, most patients were treated with antibiotic therapy alone, but a significant number still received surgery.

Buruli ulcer treatment: Rate of surgical intervention differs highly between treatment centers in West Africa.

BACKGROUND: Antibiotic treatment proved itself as the mainstay of treatment for Buruli ulcer disease. This neglected tropical disease is caused by Mycobacterium ulcerans. Surgery persists as an adjunct therapy intended to reduce the mycobacterial load. In an earlier clinical trial, patients benefited from delaying the decision to operate. Nevertheless, the rate of surgical interventions differs highly per clinic. METHODS: A retrospective study was conducted in six different Buruli ulcer (BU) treatment centers in Benin and Ghana. BU patients clinically diagnosed between January 2012 and December 2016 were included and surgical interventions during the follow-up period, at least one year after diagnosis, were recorded. Logistic regression analysis was carried out to estimate the effect of the treatment center on the decision to perform surgery, while controlling for interaction and confounders. RESULTS: A total of 1193 patients, 612 from Benin and 581 from Ghana, were included. In Benin, lesions were most frequently (42%) categorized as the most severe lesions (WHO criteria, category III), whereas in Ghana lesions were most frequently (44%) categorized as small lesions (WHO criteria, category I). In total 344 (29%) patients received surgical intervention. The percentage of patients receiving surgical intervention varied between hospitals from 1.5% to 72%. Patients treated in one of the centers in Benin were much more likely to have surgery compared to the clinic in Ghana with the lowest rate of surgical intervention (RR = 46.7 CI 95% [17.5-124.8]). Even after adjusting for confounders (severity of disease, age, sex, limitation of movement at joint at time of diagnosis, ulcer and critical sites), rates of surgical interventions varied highly. CONCLUSION: The decision to perform surgery to reduce the mycobacterial load in BU varies highly per clinic. Evidence based guidelines are needed to guide the role of surgery in the treatment of BU.

Mycobacterium ulcerans disease, Peru.

Eight adult patients (ages 18-58, 5 women) with Buruli ulcer (BU) confirmed by at least 2 diagnostic methods were seen in a 10-year period. Attempts to culture Mycobacterium ulcerans failed. Five patients came from jungle areas, and 3 from the swampy northern coast of Peru. The patients had 1-5 lesions, most of which were on the lower extremities. One patient had 5 clustered gluteal lesions; another patient had 2 lesions on a finger. Three patients were lost to follow-up. All 5 remaining patients had moderate disease. Diverse treatments (antituberculous drugs, World Health Organization [WHO] recommended antimicrobial drug treatment for BU, and for 3 patients, excision surgery) were successful. Only 1 patient (patient 7) received the specific drug treatment recommended by WHO. BU is endemic in Peru, although apparently infrequent. Education of populations and training of health workers are first needed to evaluate and understand the full extent of BU in Peru.