ABSTRACT
INTRODUCTION: Pharmacological treatment of Buruli ulcer (Mycobacterium ulcerans infection; BU) is highly effective, as shown in two randomized trials in Africa. AREAS COVERED: We review BU drug treatment - in vitro, in vivo and clinical trials (PubMed: '(Buruli OR (Mycobacterium AND ulcerans)) AND (treatment OR therapy).' We also highlight the pathogenesis of M. ulcerans infection that is dominated by mycolactone, a secreted exotoxin, that causes skin and soft tissue necrosis, and impaired immune response and tissue repair. Healing is slow, due to the delayed wash-out of mycolactone. An array of repurposed tuberculosis and leprosy drugs appears effective in vitro and in animal models. In clinical trials and observational studies, only rifamycins (notably, rifampicin), macrolides (notably, clarithromycin), aminoglycosides (notably, streptomycin) and fluoroquinolones (notably, moxifloxacin, and ciprofloxacin) have been tested. EXPERT OPINION: A combination of rifampicin and clarithromycin is highly effective but lesions still take a long time to heal. Novel drugs like telacebec have the potential to reduce treatment duration but this drug may remain unaffordable in low-resourced settings. Research should address ulcer treatment in general; essays to measure mycolactone over time hold promise to use as a readout for studies to compare drug treatment schedules for larger lesions of Buruli ulcer.
Subject(s)
Anti-Bacterial Agents/pharmacology , Buruli Ulcer/drug therapy , Mycobacterium ulcerans/drug effects , Animals , Anti-Bacterial Agents/administration & dosage , Buruli Ulcer/microbiology , Drug Repositioning , Drug Therapy, Combination , Humans , Macrolides/metabolism , Mycobacterium ulcerans/isolation & purification , Randomized Controlled Trials as Topic , Wound Healing/drug effectsABSTRACT
OBJECTIVE: Mycobacterium ulcerans is the causative agent of Buruli ulcer disease, the third most common mycobacteriosis after tuberculosis and leprosy and an emerging public health threat in sub-Saharan Africa. The bacteria produce a diffusible cytotoxin called mycolactone, which triggers the formation of necrotic lesions in cutaneous and subcutaneous tissues. The principal aim of this study was to characterise the cell surface hydrophobicity of Mycobacterium ulcerans and determine if bacteria bind to dialkyl carbamoyl chloride (DACC)-coated dressings through hydrophobic interactions in vitro. Since mycolactone displays hydrophobic groups, a secondary aim was to compare mycolactone binding to hydrophobic and standard dressings. METHODS: We used hydrophobic interaction chromatography to evaluate the cell surface hydrophobicity of Mycobacterium ulcerans, compared to that of other microorganisms colonising wounds. The binding of Mycobacterium ulcerans bacteria to DACC-coated and control dressings was then assessed quantitatively by measurement of microbial adenosine triphosphate (ATP), while that of mycolactone was evaluated by fluorescence spectroscopy. RESULTS: Compared to Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa, Mycobacterium ulcerans displayed the highest cell surface hydrophobicity, irrespective of the bacterial production of mycolactone. Mycobacterium ulcerans bacteria bound to DACC-coated dressings [corrected] better than untreated controls. Mycolactone did not bind stably to hydrophobic, nor standard dressings, in the conditions tested. CONCLUSION: Retention of Mycobacterium ulcerans and other wound pathogens to DACC-coated dressings may help reduce the bacterial load in Buruli ulcers and thereby improve healing. Dressings efficiently capturing mycolactone may bring an additional clinical benefit, by accelerating the elimination of the toxin during the course of antibiotic treatment.
Subject(s)
Bacterial Adhesion , Bandages/microbiology , Buruli Ulcer/microbiology , Carbamates/administration & dosage , Mycobacterium ulcerans/physiology , Wound Healing/drug effects , Bacterial Load/drug effects , Buruli Ulcer/drug therapy , Cell Movement , Escherichia coli/physiology , Humans , Hydrophobic and Hydrophilic Interactions , Macrolides/metabolism , Pseudomonas aeruginosa/physiology , Staphylococcus aureus/physiologyABSTRACT
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.
Subject(s)
Amikacin/adverse effects , Anti-Bacterial Agents/adverse effects , Buruli Ulcer/drug therapy , Clarithromycin/adverse effects , Rifampin/adverse effects , Adolescent , Adult , Aged , Amikacin/administration & dosage , Amikacin/pharmacology , Amikacin/therapeutic use , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Asia/ethnology , Brazil/ethnology , Buruli Ulcer/pathology , Buruli Ulcer/surgery , Clarithromycin/administration & dosage , Clarithromycin/pharmacology , Clarithromycin/therapeutic use , Combined Modality Therapy , Debridement , Drug Therapy, Combination , Europe/ethnology , Female , Foot Ulcer/drug therapy , Foot Ulcer/etiology , Foot Ulcer/surgery , French Guiana , Humans , Immunity, Cellular/drug effects , Macrolides/metabolism , Male , Mycobacterium ulcerans/drug effects , Mycobacterium ulcerans/metabolism , Rifampin/administration & dosage , Rifampin/pharmacology , Rifampin/therapeutic use , Wound HealingABSTRACT
Buruli ulcer (BU), caused by Mycobacterium ulcerans, is the third most common mycobacterial infection in immunocompetent humans besides tuberculosis and leprosy. We have compared by ex vivo enzyme-linked immunospot analysis interferon-gamma (IFN-gamma) responses in peripheral blood mononuclear cells (PBMC) from BU patients, household contacts, and individuals living in an adjacent M. ulcerans nonendemic region. PBMC were stimulated with purified protein derivative (PPD) and nonmycobacterial antigens such as reconstituted influenza virus particles and isopentenyl-pyrophosphate. With all three antigens, the number of IFN-gamma spot-forming units was reduced significantly in BU patients compared with the controls from a nonendemic area. This demonstrates for the first time that M. ulcerans infection-associated systemic reduction in IFN-gamma responses is not confined to stimulation with live or dead mycobacteria and their products but extends to other antigens. Interleukin (IL)-12 secretion by PPD-stimulated PBMC was not reduced in BU patients, indicating that reduction in IFN-gamma responses was not caused by diminished IL-12 production. Several months after surgical excision of BU lesions, IFN-gamma responses of BU patients against all antigens used for stimulation recovered significantly, indicating that the measured systemic immunosuppression was not the consequence of a genetic defect in T cell function predisposing for BU but is rather related to the presence of M. ulcerans bacteria.