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Surgical intervention was once the mainstay of treatment for Buruli ulcer disease, a neglected tropical disease caused by Mycobacterium ulcerans. Since the introduction of streptomycin and rifampicin for 8 weeks as standard care, surgery has persisted as an adjunct therapy, but its role is uncertain. We investigated the effect of delaying the decision to operate to 14 weeks on rates of healing without surgery. In this randomised controlled trial, we enrolled patients aged 3 years or older with confirmed disease at one hospital in Lalo, Benin. Patients were randomly assigned (1:1) to groups assessing the need for excision surgery 8 weeks (standard care) or 14 weeks after initiation of antimicrobial treatment. The primary endpoint was the number of patients healed without the need for surgery (not including skin grafting), assessed in all patients in follow-up at 50 weeks (or last observation for those healed for >10 weeks). A doctor masked to treatment assignment checked the indications for surgery according to predefined criteria. This study is registered with ClinicalTrials.gov, number NCT01432925. Between July 1, 2011, and Jan 15, 2015, 119 patients were enrolled, with two patients per group lost to follow-up. 55 (96%) of 57 participants in the delayed-decision group and 52 (90%) of 58 participants in the standard-care group had healed lesions 1 year after start of antimicrobial treatment (relative risk [RR] 1·08, 95% CI 0·97–1·19). 37 (67%) of 55 patients in the delayed-decision group had their lesions healed without surgical intervention, as did 25 (48%) of 52 in the standard-care group (RR 1·40, 95% CI 1·00–1·96). The time to heal and residual functional limitations did not differ between the two groups (median time to heal 21 weeks [IQR 10–27] in the delayed-decision group and 21 weeks [10–39] in the standard-care group; functional limitations in six [11%] of 57 and three [5%] of 58 patients; p=0·32). Postponing the decision to operate resulted in reduced median duration of hospitalisation (5 days [IQR 0–187] vs 131 days [0–224]; p=0·024) and wound care (153 days [IQR 56–224] vs 182 days [94–307]; p=0·036). In our study, patients treated for Buruli ulcer benefited from delaying the decision to operate. Even large ulcers can heal with antibiotics alone, without delaying healing rate and without an increase in residual functional limitations. NWO-VENI grant 241500, BUG Foundation, and UBS OPTIMUS.

Buruli ulcer (BU) is a rare, neglected tropical disease caused by Mycobacterium ulcerans that can lead to severe skin ulcers. To determine the epidemiology of BU in Victoria, Australia, during 2017-2022 we analyzed surveillance data. A total of 1,751 cases of BU were notified; 968 (55%) patients were male and 781 (45%) female (2 were missing sex data), and 984 (56%) resided in established BU-endemic areas, although an increasing number were in new BU-endemic areas. Most cases (83%, 1,301) were classified as category I. Multivariate modeling demonstrated that factors for severe BU included being male, being older, and living in a new BU-endemic or non-BU-endemic area. A relatively shorter interval between first visit to a clinician and receipt of diagnosis was protective against severe disease. The expansion of BU-endemic areas throughout Victoria remains a public health concern and calls for targeted action, particularly for patients and clinicians in new BU-endemic areas.

Buruli ulcer (BU) is an emerging infectious disease that causes disfiguring skin ulcers. The causative agent, Mycobacterium ulcerans , secretes toxin called mycolactone that triggers inflammation and immunopathology. Existing treatments are lengthy and consist of drugs developed for tuberculosis. Here, we report that a pyrazolo[1,5-a]pyridine-3-carboxamide, TB47, is highly bactericidal against M. ulcerans both in vitro and in vivo. In the validated mouse model of BU, TB47 alone reduces M. ulcerans burden in mouse footpads by more than 2.5 log 10 CFU compared to the standard BU treatment regimen recommended by the WHO. We show that mutations of ubiquinol-cytochrome C reductase cytochrome subunit B confer resistance to TB47 and the dissimilarity of CydABs from different mycobacteria may account for their differences in susceptibility to TB47. TB47 is highly potent against M. ulcerans and possesses desirable pharmacological attributes and low toxicity that warrant further assessment of this agent for treatment of BU. Combination therapy for Buruli ulcer (BU) is suboptimal. Here, Liu et al. show that the candidate drug TB47 has potent bactericidal activity against Mycobacterium ulcerans in vitro and in a mouse model, which underscores its potential for shortening the course of BU and treating other mycobacterial diseases.

We describe emergence of Buruli ulcer in urban Geelong, Victoria, Australia, and examine timing and proximity of human cases to detection of Mycobacterium ulcerans DNA in possum feces. M. ulcerans-positive feces preceded human cases by up to 39 months, constituting an early warning of impending risk for Buruli ulcer.

Alphavirus infections are transmitted by mosquitoes, but the mode of transmission for Mycobacterium ulcerans, which causes Buruli ulcer, is contested. Using notification data for Victoria, Australia, during 2017-2022, adjusted for incubation period, we show close alignment between alphavirus and Buruli ulcer seasons, supporting the hypothesis of mosquito transmission of M. ulcerans.

Infection with Mycobacterium ulcerans causes slowly progressive skin lesions known as Buruli ulcer (BU). An M. ulcerans controlled human infection model (MuCHIM) is likely to accelerate our understanding of this otherwise neglected disease, and may be an efficient platform for testing vaccines and other interventions. The aim of this study was to understand perceptions of this model across a range of key stakeholders in an endemic Australian community setting. We recruited young adults who live near an Australian BU endemic area but without a personal history of BU, clinicians involved in the management of BU, young adults with a personal history of a small, treated BU, and participants of any age with a demonstrated interest in public advocacy related to their personal BU lived experience. Participants reviewed an abridged version of the provisional protocol. A series of three focus groups were then conducted by video, and the transcribed text was analysed using reflexive thematic analysis to generate themes for exploration. Participants universally valued the outcomes that MuCHIM might deliver. The predominant theme was that informed consent required fully transparent communication with potential participants regarding what their participation would involve, how it would impact their lives, and both the expected outcome and 'worst-case scenario'. They also offered actionable recommendations on how best to communicate the tension between the expected outcome and the 'worst-case scenario' of disease associated with delayed diagnosis and comorbidity, as typically portrayed by the media. Participants recommended including images and testimonials from people who have had BU to support the conditions for informed consent. Focus groups also gave a clear sense of who they believed would volunteer for this type of research. This study offers valuable guidance regarding the content and presentation of information to inform potential participants, with focus group participants suggesting a multimodal approach of communication, including lived experience testimonials and clinical images of the expected outcome. This information will inform development of materials for enrolment to adequately communicate risks and expectations to potential study participants.

Background. Antimicrobial killing in mycobacterial infections may be accompanied by (transient) clinical deterioration, known as paradoxical reaction. To search for patterns reflecting such reactions in the treatment of Buruli ulcer (Mycobacterium ulcerans infection), the evolution of lesions of patients treated with antimicrobials was prospectively assessed. Methods. The lesion size of participants of the BURULICO antimicrobial trial (with lesions ≤ 10 cm crosssectional diameter) was assessed by careful palpation and recorded by serial acetate sheet tracings. Patients were treated with antimicrobials for 8 weeks. For the size analysis, participants whose treatment had failed, had skin grafting, or were coinfected with human immunodeficiency virus were excluded. For every time point, surface area was compared with the previous assessment. A generalized additive mixed model was used to study lesion evolution. Nonulcerative lesions were studied using digital images recording possible subsequent ulceration. Results. Of 151 participants, 134 were included in the lesion size analysis. Peak paradoxical response occurred at week 8; > 30% of participants showed an increase in lesion size as compared with the previous (week 6) assessment. Seventy-five of 90 (83%) of nonulcerative lesions ulcerated after start of treatment. Nine participants developed new lesions during or after treatment. All lesions subsequently healed. Conclusions. After start of antimicrobial treatment for Buruli ulcer, new or progressive ulceration is common before healing sets in. This paradoxical response, most prominent at the end of the 8-week antimicrobial treatment, should not be misinterpreted as failure to respond to treatment.

Surgical debridement was the standard treatment for Mycobacterium ulcerans infection (Buruli ulcer disease) until WHO issued provisional guidelines in 2004 recommending treatment with antimicrobial drugs (streptomycin and rifampicin) in addition to surgery. These recommendations were based on observational studies and a small pilot study with microbiological endpoints. We investigated the efficacy of two regimens of antimicrobial treatment in early-stage M ulcerans infection. In this parallel, open-label, randomised trial undertaken in two sites in Ghana, patients were eligible for enrolment if they were aged 5 years or older and had early (duration <6 months), limited (cross-sectional diameter <10 cm), M ulcerans infection confirmed by dry-reagent-based PCR. Eligible patients were randomly assigned to receive intramuscular streptomycin (15 mg/kg once daily) and oral rifampicin (10 mg/kg once daily) for 8 weeks (8-week streptomycin group; n=76) or streptomycin and rifampicin for 4 weeks followed by rifampicin and clarithromycin (7·5 mg/kg once daily), both orally, for 4 weeks (4-week streptomycin plus 4-week clarithromycin group; n=75). Randomisation was done by computer-generated minimisation for study site and type of lesion (ulceration or no ulceration). The randomly assigned allocation was sent from a central site by cell-phone text message to the study coordinator. The primary endpoint was lesion healing at 1 year after the start of treatment without lesion recurrence or extensive surgical debridement. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00321178. Four patients were lost to follow-up (8-week streptomycin, one; 4-week streptomycin plus 4-week clarithromycin, three). Since these four participants had healed lesions at their last assessment, they were included in the analysis for the primary endpoint. 73 (96%) participants in the 8-week streptomycin group and 68 (91%) in the 4-week streptomycin plus 4-week clarithromycin group had healed lesions at 1 year (odds ratio 2·49, 95% CI 0·66 to infinity; p=0·16, one-sided Fisher's exact test). No participants had lesion recurrence at 1 year. Three participants had vestibulotoxic events (8-week streptomycin, one; 4-week streptomycin plus 4-week clarithromycin, two). One participant developed an injection abscess and two participants developed an abscess close to the initial lesion, which was incised and drained (all three participants were in the 4-week streptomycin plus 4-week clarithromycin group). Antimycobacterial treatment for M ulcerans infection is effective in early, limited disease. 4 weeks of streptomycin and rifampicin followed by 4 weeks of rifampicin and clarithromycin has similar efficacy to 8 weeks of streptomycin and rifampicin; however, the number of injections of streptomycin can be reduced by switching to oral clarithromycin after 4 weeks. European Union (EU FP6 2003-INCO-Dev2-015476) and Buruli Ulcer Groningen Foundation.

Mycolactone, a lipid-like toxin, is the major virulence factor of Mycobacterium ulcerans , the etiological agent of Buruli ulcer. Its involvement in lesion development has been widely described in early stages of the disease, through its cytotoxic and immunosuppressive activities, but less is known about later stages. Here, we revisit the role of mycolactone in disease outcome and provide the first demonstration of the pro-inflammatory potential of this toxin. We found that the mycolactone-containing mycobacterial extracellular vesicles produced by M . ulcerans induced the production of IL-1β, a potent pro-inflammatory cytokine, in a TLR2-dependent manner, targeting NLRP3/1 inflammasomes. We show our data to be relevant in a physiological context. The in vivo injection of these mycolactone-containing vesicles induced a strong local inflammatory response and tissue damage, which were prevented by corticosteroids. Finally, several soluble pro-inflammatory factors, including IL-1β, were detected in infected tissues from mice and Buruli ulcer patients. Our results revisit Buruli ulcer pathophysiology by providing new insight, thus paving the way for the development of new therapeutic strategies taking the pro-inflammatory potential of mycolactone into account.

Buruli ulcer, a chronic subcutaneous infection caused by Mycobacterium ulcerans , is increasing in prevalence in southeastern Australia. Possums are a local wildlife reservoir for M. ulcerans and, although mosquitoes have been implicated in transmission, it remains unclear how humans acquire infection. We conducted extensive field survey analyses of M. ulcerans prevalence among mosquitoes in the Mornington Peninsula region of southeastern Australia. PCR screening of trapped mosquitoes revealed a significant association between M. ulcerans and Aedes notoscriptus . Spatial scanning statistics revealed overlap between clusters of M. ulcerans -positive Ae. notoscriptus , M. ulcerans -positive possum excreta and Buruli ulcer cases, and metabarcoding analyses showed individual mosquitoes had fed on humans and possums. Bacterial genomic analysis confirmed shared single-nucleotide-polymorphism profiles for M. ulcerans detected in mosquitoes, possum excreta and humans. These findings indicate Ae. notoscriptus probably transmit M. ulcerans in southeastern Australia and highlight mosquito control as a Buruli ulcer prevention measure. Genomic evidence reveals that Mycobacterium ulcerans recovered from Aedes notoscriptus mosquitoes are genetically identical to bacteria from possums and humans, implicating mosquitoes as a vector for Buruli’s ulcer transmission in southeastern Australia.