Antimicrobial treatment for early, limited Mycobacterium Ulcerans infection: A randomised controlled trial

Department of Internal Medicine, University Medical Centre Groningen, University of Groningen, Netherlands.
The Lancet (Impact Factor: 45.22). 02/2010; 375(9715):664-72. DOI: 10.1016/S0140-6736(09)61962-0
Source: PubMed


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, 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.

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    • "Combination antibiotic treatment for BU should be commenced before commencing ART for HIV to minimise pill burden and avoid drug interactions and side effects in the early stages of BU treatment, to allow the time needed for patient preparation for ART, and to follow the usual principle of HIV care to treat and stabilize any co-infections prior to commencing ART. Based on experience with excellent BU outcomes in non-HIV-infected populations (Chauty et al. 2007; Nienhuis et al. 2010; Sarfo et al. 2010), the recommended combination is rifampicin 10 mg/kg daily up to a maximum of 600 mg/day plus streptomycin 15 mg/kg daily. If this regimen is not tolerated , acceptable or available, then an alternative regimen is rifampicin 10 mg/kg daily up to a maximum of 600 Table 1 Considerations for drugs used to treat BU and HIV co-infection Potential concerns Potential benefits ARV drugs Efavirenz Contraindicated in children <3 years of age Reduce clarithromycin levels Increased toxicity when combined with clarithromycin Efavirenz levels remain therapeutic when combined with rifampicin Once daily administration Nevirapine Reduction in nevirapine levels when combined with rifampicin Twice daily administration Risk of hypersensitivity particularly at higher CD4 counts Can be used in children <3 years of age PI Significant reduction in levels when combined with rifampicin. "
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    ABSTRACT: Background: Buruli Ulcer (BU)-HIV co-infection is an important emerging management challenge for BU disease. Limited by paucity of scientific studies, guidance for management of this co-infection has been lacking. Methods: Initiated by WHO, a panel of experts in BU and HIV management developed guidance principles for the management of BU-HIV co-infection based on review of available scientific evidence, current treatment experience, and global recommendations established for management of HIV infection and tuberculosis. Results: The expert panel agreed that all BU patients should be offered quality provider-initiated HIV testing and counselling. In areas with high prevalence of malaria and/or bacterial infections, all patients with HIV co-infection should be started on cotrimoxazole preventative therapy. Combination antibiotic treatment for BU should be commenced before starting antiretroviral therapy (ART) and provided for 8 weeks duration. The suggested combination is rifampicin (10 mg/kg daily up to a maximum of 600 mg/day) plus streptomycin (15 mg/kg daily). An alternative regimen is rifampicin plus clarithromycin (7.5 mg/kg twice daily up to a maximum of 1000 mg daily) although due to drug interactions with antiretroviral drugs this regimen should be used with caution. ART should be initiated in all BU-HIV co-infected patients with symptomatic HIV disease (WHO clinical stage 3 or 4) regardless of CD4 cell count and in asymptomatic individuals with CD4 count ≤500 cells/mm(3) . If CD4 count is not available, BU-HIV co-infected individuals with category 2 or 3 BU disease should be offered ART. For eligible individuals, ART should be commenced as soon as possible within 8 weeks after commencing BU treatment, and as a priority in those with advanced HIV disease (CD4 ≤ 350 cells/mm(3) or WHO stage 3 or 4 disease). All co-infected patients should be actively screened for tuberculosis before commencing BU treatment and before starting ART. Programmes should implement a monitoring and reporting system to document the outcomes of BU-HIV interventions. Conclusions: Knowledge of the clinical and epidemiological interactions between BU and HIV disease is limited. While awaiting more urgently needed evidence, current management practice of both diseases has been useful to build simple 'common sense' preliminary guidance on how to manage BU-HIV co-infection.
    Full-text · Article · Jun 2014 · Tropical Medicine & International Health
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    • "The current treatment consists of 8 weeks of oral rifampicin combined with intramuscular streptomycin, with healing rates of over 90%. Although antibiotics are successful in the treatment of BU, the reported median time to healing of ulcers was found to be 18 weeks in early, limited BU lesions2; the median time to healing for larger ulcers and those that require surgical intervention is unknown and likely to be longer. In addition, persistent wounds were found to be a risk factor for functional limitations.3,4 "
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    ABSTRACT: Buruli ulcer (BU) is a disease affecting the skin, subcutaneous fat, and bone tissues. Wound care is important in the prevention of disabilities. Awareness of current wound care practices in BU-endemic regions is necessary for future wound care interventions. Thirty-one health care workers in Ghana and Benin were interviewed with a semi-structured interview, complemented by structural observations. Quantitative data were analyzed through t tests and one-way analysis of variance, and qualitative data through descriptive statistics. There appeared to be a general understanding of wound assessment. A large variety of different topical antiseptics was reported to be used, pressure irrigation was never reported. Gauze was the main dressing type and a moist environment was preferred, but could not be maintained. Bleeding and pain were observed frequently. Standard of wound care differed importantly between health care personnel and between institutions and adherence to World Health Organization guidelines was low.
    Full-text · Article · Jun 2014 · The American journal of tropical medicine and hygiene
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    • "Clinical observations have shown that some small Buruli lesions take a considerable time to heal with antibiotic therapy [14,22] and our study has provided some evidence to explain these observations. The persistence of mycolactone within Buruli lesions during and after antibiotic therapy could retard healing by killing keratinocytes [23] and by inhibiting the secretion of growth factors required for wound healing [24]. "
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    ABSTRACT: Mycobacterium ulcerans (M. ulcerans) causes a devastating necrotising infection of skin tissue leading to progressive ulceration. M. ulcerans is the only human pathogen that secretes mycolactone, a polyketide molecule with potent cytotoxic and immunomodulatory properties. These unique features make mycolactone an attractive biomarker for M. ulcerans disease. We sought to measure the concentration of mycolactone within lesions of patients with Buruli ulcer before, during and after antibiotic treatment to evaluate its association with the clinical and bacteriological response to therapy. Biopsies of M. ulcerans infected skin lesions were obtained from patients before, during and after antibiotic therapy. Lipids were extracted from the biopsies and concentration of mycolactone was assayed by mass spectrometry and a cytotoxicity assay and correlated with clinical and bacteriological response to therapy. Baseline concentration of mycolactone measured by mass spectrometry predicted time to complete healing of small nodules and ulcers. Even though intra-lesional concentrations of mycolactone declined with antibiotic treatment, the toxin was still present after antibiotic treatment for 6 weeks and also 4 weeks after the end of treatment for 8 weeks in a subgroup of patients with slowly healing lesions. Additionally viable bacilli were detected in a proportion of these slowly healing lesions during and after treatment. Our findings indicate that baseline intra-lesional mycolactone concentration and its kinetics with antibiotic therapy are important prognostic determinants of clinical and bacteriological response to antibiotic treatment for Mycobacterium ulcerans disease. Mycolactone may be a useful biomarker with potential utility in optimising antibiotic therapy.
    Full-text · Article · Apr 2014 · BMC Infectious Diseases
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