Addressing the transmission enigma of the neglected disease Buruli ulcer (BU) is a World Health Organization priority. In Australia, we have observed an association between mosquitoes harboring the causative agent, Mycobacterium ulcerans, and BU. Here we tested a contaminated skin model of BU transmission by dipping the tails from healthy mice in cultures of the causative agent, Mycobacterium ulcerans. Tails were exposed to mosquito (Aedes notoscriptus and Aedes aegypti) blood feeding or punctured with sterile needles. Two of 12 of mice with M. ulcerans contaminated tails exposed to feeding A. notoscriptus mosquitoes developed BU. There were no mice exposed to A. aegypti that developed BU. Eighty-eight percent of mice (21/24) subjected to contaminated tail needle puncture developed BU. Mouse tails coated only in bacteria did not develop disease. A median incubation time of 12 weeks, consistent with data from human infections, was noted. We then specifically tested the M. ulcerans infectious dose-50 (ID50) in this contaminated skin surface infection model with needle puncture and observed an ID50 of 2.6 colony-forming units. We have uncovered a biologically plausible mechanical transmission mode of BU via natural or anthropogenic skin punctures. Buruli ulcer is a neglected tropical disease caused by infection with Mycobacterium ulcerans. Unfortunately, how people contract this disease is not well understood. Here we show for the first time using experimental infections in mice that a very low dose of M. ulcerans delivered beneath the skin by a minor injury caused by a blood-feeding insect (mosquito) or an experimental needle puncture is sufficient to cause Buruli ulcer. This research provides important laboratory evidence to advance our understanding of Buruli ulcer disease transmission.

Buruli Ulcer, 2010–2017, and WHO Targets

Mycobacterium ulcerans causes Buruli ulcer (BU), a debilitating infection of subcutaneous tissue. There is a WHO-recommended antibiotic treatment requiring an 8-week course of streptomycin and rifampicin. This regime has revolutionized the treatment of BU but there are problems that include reliance on daily streptomycin injections and side effects such as ototoxicity. Trials of all-oral treatments for BU show promise but additional drug combinations that make BU treatment safer and shorter would be welcome. Following on from reports that avermectins have activity against Mycobacterium tuberculosis, we tested the in-vitro efficacy of ivermectin and moxidectin on M. ulcerans. We observed minimum inhibitory concentrations of 4–8 μg/ml and time-kill assays using wild type and bioluminescent M. ulcerans showed a significant dose-dependent reduction in M. ulcerans viability over 8-weeks. A synergistic killing-effect with rifampicin was also observed. Avermectins are well tolerated, widely available and inexpensive. Based on our in vitro findings we suggest that avermectins should be further evaluated for the treatment of BU. Neglected tropical diseases such as Buruli ulcer predominantly afflict the poorest populations in the world and reduce quality of life. Buruli ulcer is a necrotising infection that destroys the skin and soft tissue, frequently presenting as nodules or open ulcers. Buruli ulcer is treated with antibiotics and sometimes surgery. Unfortunately the antibiotic treatment can have toxic side effects, such as hearing loss. Also, patients must either be hospitalized or report daily to a treatment centre to get their medicine as the treatment is delivered by injection. In laboratory experiments we tested the susceptibility of Mycobacterium ulcerans, which causes Buruli ulcer, to avermectins. Avermectins are drugs that are used to treat common parasite and worm infections, such as river blindness. These drugs are inexpensive, have few side effects and are widely available. Our findings show that two avermectins called ivermectin and moxidectin inhibit the growth and also kill Mycobacterium ulcerans strains from both Africa and Australia. If their efficacy and safety also can be proven in animal and human studies, these drugs will provide an inexpensive addition to the current treatment of Buruli ulcer.

Buruli ulcer may induce severe disabilities impacting on a person's well-being and quality of life. Information about long-term disabilities and participation restrictions is scanty. The objective of this study was to gain insight into participation restrictions among former Buruli ulcer patients in Ghana and Benin. In this cross-sectional study, former Buruli ulcer patients were interviewed using the Participation Scale, the Buruli Ulcer Functional Limitation Score to measure functional limitations, and the Explanatory Model Interview Catalogue to measure perceived stigma. Healthy community controls were also interviewed using the Participation Scale. Trained native interviewers conducted the interviews. Former Buruli ulcer patients were eligible for inclusion if they had been treated between 2005 and 2011, had ended treatment at least 3 months before the interview, and were at least 15 years of age. In total, 143 former Buruli ulcer patients and 106 community controls from Ghana and Benin were included in the study. Participation restrictions were experienced by 67 former patients (median score, 30, IQR; 23;43) while 76 participated in social life without problems (median score 5, IQR; 2;9). Most restrictions encountered related to employment. Linear regression showed being female, perceived stigma, functional limitations, and larger lesions (category II) as predictors of more participation restrictions. Persisting participation restrictions were experienced by former BU patients in Ghana and Benin. Most important predictors of participation restrictions were being female, perceived stigma, functional limitations and larger lesions. Disabilities among Buruli ulcer patients remain a problem. Previous studies revealed contractures, deformities and functional limitations in daily life after treatment. According to the International Classification of Functioning, Disability and Health, disabilities occur not only at the physical and activity level but at the participation level (participation restrictions) as well. The latter are the social consequences of the disease such as problems in relationships, going to festivals and visiting public places. This study focused on participation restrictions by using the Participation Scale among former Buruli ulcer patients and healthy persons residing in two areas endemic for Buruli ulcer in Ghana and Benin. This study showed that almost half of the former Buruli ulcer patients encountered problems in social life, especially related to employment. In addition, the results suggest that being female, perceived stigma, functional limitations and a larger lesion (category II) predict participation restrictions. These findings indicate that rehabilitation programs should not only focus on physical disabilities but also on participation after completion of medical treatment.

The antileprosy drug clofazimine was recently repurposed as part of a newly endorsed short-course regimen for multidrug-resistant tuberculosis. It also enables significant treatment shortening when added to the first-line regimen for drug-susceptible tuberculosis in a mouse model. However, clofazimine causes dose- and duration-dependent skin discoloration in patients, and the optimal clofazimine dosing strategy in the context of the first-line regimen is unknown. We utilized a well-established mouse model to systematically address the impacts of duration, dose, and companion drugs on the treatment-shortening activity of clofazimine in the first-line regimen. In all studies, the primary outcome was relapse-free cure (culture-negative lungs) 6 months after stopping treatment, and the secondary outcome was bactericidal activity, i.e., the decline in the lung bacterial burden during treatment. Our findings indicate that clofazimine activity is most potent when coadministered with first-line drugs continuously throughout treatment and that equivalent treatment-shortening results are obtained with half the dose commonly used in mice. However, our studies also suggest that clofazimine at low exposures may have negative impacts on treatment outcomes, an effect that was evident only after the first 3 months of treatment. These data provide a sound evidence base to inform clofazimine dosing strategies to optimize the antituberculosis effect while minimizing skin discoloration. The results also underscore the importance of conducting long-term studies to allow the full evaluation of drugs administered in combination over long durations.

Scabies is a skin infestation with the mite Sarcoptes scabiei causing itch and rash and is a major risk factor for bacterial skin infections and severe complications. Here, we evaluated the treatment outcome of 2866 asylum seekers who received (preventive) scabies treatment before and during a scabies intervention programme (SIP) in the main reception centre in the Netherlands between January 2014 and March 2016. A SIP was introduced in the main national reception centre based on frequent observations of scabies and its complications amongst Eritrean and Ethiopian asylum seekers in the Netherlands. On arrival, all asylum seekers from Eritrea or Ethiopia were checked for clinical scabies signs and received ivermectin/permethrin either as prevention or treatment. A retrospective cohort study was conducted to compare the reinfestations and complications of scabies in asylum seekers who entered the Netherlands before and during the intervention and who received ivermectin/permethrin. In total, 2866 asylum seekers received treatment during the study period (January 2014 –March 2016) of which 1359 (47.4%) had clinical signs of scabies. During the programme, most of the asylum seekers with scabies were already diagnosed on arrival as part of the SIP screening (580 (64.7%) of the 897). Asylum seekers with more than one scabies episode reduced from 42.0% (194/462) before the programme to 27.2% (243/897) during the programme (RR = 0.64, 95% CI = 0.55–0.75). Development of scabies complications later in the asylum procedure reduced from 12.3% (57/462) to 4.6% (41/897). A scabies prevention and treatment programme at start of the asylum procedure was feasible and effective in the Netherlands; patients were diagnosed early and risk of reinfestations and complications reduced. To achieve a further decrease of scabies, implementation of the programme in multiple asylum centres may be needed. The high number of asylum seekers arriving in Europe between 2014 and 2016 emphasized the importance to expand knowledge on best practice regarding health care provision and control of infectious diseases that may come with migration. Adequate control of scabies is important to prevent severe forms of scabies and prevent spread of the disease. Studies on interventions preventing or treating scabies in asylum seekers are very limited. To the best of our knowledge, this is the first study that provides data on an intervention targeting scabies in asylum seekers. This study shows that a scabies prevention and treatment programme at start of the asylum procedure is feasible and effective in the Netherlands. Patients were diagnosed early and risk of reinfestations and complications reduced. The programme may be used both to improve clinical practice and could serve as model for future policies on similar programmes.