Abstract
MacCallum and coworkers described Buruli ulcer (BU) as an infectious disease caused by Mycobacterium ulcerans in Victoria, Australia. They first considered the skin lesions in their patients to be caused by tuberculosis or leprosy, when they observed numerous acid-fast bacilli in the biopsy specimens [1]. The typical duration of illness was between 1 and 2 years; treatment was essentially surgical. With the advent of chemotherapy for tuberculosis [2–4], and later for leprosy, doctors made individual attempts to treat the lesions with anti-tuberculosis and anti-leprosy drugs. The anecdotal evidence suggested poor or no response to chemotherapy with rifampicin monotherapy [5], despite the fact that in vitro susceptibility of 33 strains of M. ulcerans was as good as for M. tuberculosis [6]. A randomized clinical trial by the British Medical Research Council in Buruli county (now called Nakasongola; Uganda) failed to show any benefit from clofazimine, a drug then first marketed for leprosy [7]. A small-sized trial with cotrimoxazole (18 participants; 12 evaluable) was inconclusive [8]. A small-sized randomized study in Cote d’Ivoire compared a combination of dapsone and rifampicin with placebo; the follow-up was limited; the ulcer size decreased slightly faster in the intervention group but the baseline characteristics of both groups differed, and the study did not allow to draw any firm conclusions about the effectiveness of these drugs [9]. By the turn of the millennium, the discrepancy between in vitro efficacy of rifampicin [6] or clarithromycin [10] and lack of clinical response prompted to stressing the need for well-designed and well-powered drug trials, but in the meantime, to also improve early detection and surgical treatment [11].
Highlights
MacCallum and coworkers described Buruli ulcer (BU) as an infectious disease caused by Mycobacterium ulcerans in Victoria, Australia
Even long before the chemical structure of the toxin mycolactone was discovered [12], it was realized that a toxin secreted by M. ulcerans was responsible for the extensive tissue necrosis [13, 14] as well as for the immune suppression observed and replicated in experimental animals, using a culture filtrate of M. ulcerans [15]
With increased understanding of the dominant role of the secreted toxin mycolactone in the pathogenesis of Buruli ulcer, and realizing that perhaps the best measure of efficacy of antimicrobial treatment might be complete healing without recurrence, the effectiveness of antimicrobial treatment might have been underestimated in the past
Summary
Patients having non-ulcerated lesions suspected to be M. ulcerans infection were randomly allocated to 0, 4, 8 or 12 weeks of antimicrobial treatment with a combination of streptomycin and rifampicin; later a 5th group receiving 2 weeks of treatment was added; the total number of study participants was 21. Some questions remained unanswered, this study provided the first robust evidence that antimicrobial treatment alone was able to sterilize non-ulcerated lesions of M. ulcerans infection, with no recurrence or positive culture in patients treated for at least 4 weeks with the antimicrobial combination [29]. We systematically discuss the literature on antimicrobial susceptibility of M. ulcerans in vitro and in animal models; and the accumulated evidence for effectiveness as well as safety (i.e., adverse reactions) of antimicrobial treatment regimens emerging from clinical studies. Such studies are extremely challenging, as the majority of potential study participants are patients (many being children) that live in underprivileged circumstances with limited access to health care, and generally low educational background [35–37]
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