The effectiveness of treatment of Buruli Ulcer with Streptomycin- Rifampicin: A systematic review

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1 The effectiveness of treatment of Buruli Ulcer with Streptomycin- Rifampicin: A systematic review REVIEWERS Constantine A 1 Julius YF 2 Saidu Y 3 AFFILIATIONS AND CONTACT DETAILS. 1 Behavioral Research Coordinator, Medical Research Centre, IMPM, MINRESI,JBI ESG Cameroon. 2 MD, Physician and Research Officer, Neurology Unit, Central Hospital Yaoundé. JBI ESG Cameroon 3 MD, Head, Sickle Cell Unit, Mother and Child Centre, CHANTAL BIYA Foundation Yaoundé. Clinical Monitor, laboratory for Public Health Biotechnology, the Biotechnology Centre, University of Yaoundé I. JBI ESG Cameroon.

2 TABLE OF CONTENTS Background..3 Research question. 3 Objective..3 Inclusion criteria.4 Search strategy 4 Critical appraisal.4 Data collection.5 Data synthesis..5 Conclusion.5 Potential conflict of interests 6 Acknowledgements..6 Sources of support..6 References 6 Appendices 8

3 Background Buruli ulcer disease is a chronic ulcerative skin disease caused by Mycobacterium ulcerans which may lead to extensive destruction of the skin, soft tissues and occasionally of bones 1. This disease has been reported in more than 30 countries worldwide, mainly in tropical and subtropical regions 2, including Cameroon, where Buruli ulcer disease is endemic in the southern, centre, littoral and south west provinces, notably areas of Ayos and Akonolinga 3. The disease is caused by soluble polyketide toxins named mycolactones that are produced by pathogenic strains of M. ulcerans 4-6 which are responsible for tissue damage and local immunosuppression. Although several antibiotics have demonstrated activity against M. ulcerans in vitro 7, 8, no consensus about their clinical efficacy against M. ulcerans has been reached. Consequently, wide surgical excision of necrotic tissue followed by skin grafting has long been considered to be the only effective treatment A pilot clinical trial conducted in Ghana under the auspices of WHO demonstrated that after daily treatment with Rifampin and Streptomycin for at least 4 weeks, M. ulcerans could no longer be cultured from the lesions 12. In addition, the antibiotic treatment reduced the surface area of most lesions by more than 50%, thus allowing a less extensive surgical excision. Encouraged by these promising results, the 6th WHO Advisory Committee on M. ulcerans diseases recommends the daily administration of Rifampin and an aminoglycoside, usually Streptomycin, for 8 weeks as the first-line treatment for all forms of M. ulcerans disease 2. The two antibiotics should always be given in combination and under supervision so as to prevent the selection of resistant mutant bacteria 13. While it was anticipated that antibiotics alone might be curative in some patients in early stages of the disease (i.e., with nodules, papules, plaques, and ulcers of less than 5 cm in diameter), the primary aims of chemotherapy for more advanced lesions were to reduce the extent of surgical excision and to prevent recurrence. Wide surgical excision has long been the recommended technique, but this often causes significant morbidity, and it is technically difficult, resource intensive, expensive, and often not easily accessible in endemic areas A recent study showed there is some promising efficacy of the rifampicin streptomycin combination in treating early stage disease 17. Although it is becoming common practice to implement the WHO recommendations, there are no systematic reviews to our knowledge to support the use of the rifampicin-streptomycin combination therapy in the treatment of Buruli ulcers at an early stage. Research question What is the effectiveness of Streptomycin-Rifampicin combination compared to surgery in the treatment of early lesions in patients with Buruli ulcers? Objective The objective is to review all randomized controlled trials (RCTs) and quasi-randomised trials of treatment for Buruli ulcer in order to present the best available evidence related to the use of Streptomycin-Rifampicin combination therapy compared to surgery in the treatment of early stage lesions. Early stage lesions are small size or preulcerative nodules.

4 INCLUSION CRITERIA FOR THIS REVIEW Types of participants This review will consider all studies that include patients with early stage (preulcerative or small size nodules and plaques) BU, regardless of their age or gender. Types of interventions Intervention A: Streptomycin-Rifampicin, administered for 8 weeks and 12 weeks (experimental groups). Intervention B: Surgical intervention with antibiotics (control group). Intervention C: Surgical intervention without antibiotics (control group). Intervention D: No treatment intervention. Types of outcomes measures The outcome measures of interest will include the difference in cure rates between the experimental and control interventions. Cure rates will be defined as the ratio of negative: positive in vitro cultures and/or identification by definite histopathology of the lesions after a defined number of days of treatment. Another outcome measure of interest will be the extent of the lesion after antibiotic treatment. Type of studies This review will consider any randomized controlled trial that evaluates the effectiveness of Streptomycin-Rifampicin in combination on Buruli ulcer. In the absence of RCTs, other research designs such non-randomised controlled trials, before and after studies will be considered for inclusion in narrative summary, to enable the identification of current best evidence and possible future strategies regarding the treatment of BU. Only papers published in English and French and published since 1990 will be considered. SEARCH STRATEGY The search will seek to find both published and unpublished studies in English or French from 1990 to the present date. A three step search strategy will be used. An initial limited search of Medline and CINAHL will be undertaken to identify keywords contained in the title or abstract, and index terms used to describe relevant articles. A second extensive search will be undertaken using all identified keywords and index terms. The third step will be a search of the reference list and bibliographies of all relevant articles. Initial search terms will be; Buruli ulcer, Mycobacterium ulcerans Streptomycin Rifampicin Surgical excision Surgical debridement RCTs Data bases for published studies to be searched will include CINAHL Medline Current contents

5 Cochrane library Expanded academic index Embase Databases to be searched for unpublished studies will include; Dissertation abstract international All studies identified during the database search will be assessed for relevance to the review based on the information provided in the title, abstract and descriptor/mesh terms and a full report will be retrieved for studies that meet the inclusion criteria. Studies identified from reference list searches will be assess for relevance based on the study title. Critical appraisal The methodological quality of included papers for this study will be assessed by two independent reviewers using standardised critical appraisal tools developed by the Joanna Briggs Institute (JBI Mastari, Appendix I). Any disagreements that arise between reviewers will be resolved through discussion, or in consultation with a third reviewer. Data collection Data will be extracted using a standardised data extraction tool developed by the Joanna Briggs Institute (JBI Mastari, Appendix II). The data to be extracted from papers included in the review will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. Data Synthesis Where possible, results will be pooled in a statistical meta-analysis with the use of review manager (Revman software, Version 5) from the Cochrane collaboration. All results will be subject to double entry. Odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence interval, will be calculated for analysis. Heterogeneity of included studies will be tested using the standard Chi-square test. Pooling of data will initially be based on comparable intervention. If possible with the available data, subgroup analysis will be undertaken to determine the effectiveness of Streptomycin-Rifampicin compared with surgical intervention in the treatment of early stage Buruli ulcer. Where statistical pooling is not appropriate or possible, the findings will be summarized in narrative form. Conclusion This review hopes to generate useful information that may inform best practice in the management of Buruli ulcers.

6 Potential conflict of interests The authors have no conflicts of interest to declare. Acknowledgements None Sources of support None yet References 1. Portaels, F., J. Aguiar, M. Debacker, A. Guedenon, C. Steunou, C. Zinsou, and W. M. Meyers Mycobacterium bovis BCG vaccination as prophylaxis against Mycobacterium ulcerans osteomyelitis in Buruli ulcer disease. Infect. Immun. 72: [PubMed]. 2. World Health Organization Provisional guidance on the role of specific antibiotics in the management of Mycobacterium ulcerans disease (Buruli ulcer). World Health Organization, Geneva, Switzerland. WHO/CDS/CPE/GBUI/ Ravisse P, Rocques MC, Le Bourthe F, Tchuembou CJ, Menard JJ. Une affection méconnue au Cameroun, l'ulcère à Mycobactérie. Med Trop (Mars). 1975;35: George, K. M., D. Chatterjee, G. Gunawardana, D. Welty, J. Hayman, R. Lee, and P. L. Small Mycolactone: a polyketide toxin from Mycobacterium ulcerans required for virulence. Science 283: [PubMed]. 5. George, K. M., L. Pascopella, D. M. Welty, and P. L. Small A Mycobacterium ulcerans toxin, mycolactone, causes apoptosis in guinea pig ulcers and tissue culture cells. Infect. Immun. 68: [PubMed]. 6. Krieg, R. E., W. T. Hockmeyer, and D. H. Connor Toxin of Mycobacterium ulcerans. Production and effects in guinea pig skin. Arch. Dermatol. 110: [PubMed]. 7. Portaels, F., H. Traore, K. De Ridder, and W. M. Meyers In vitro susceptibility of Mycobacterium ulcerans to clarithromycin. Antimicrob. Agents Chemother. 42: [PubMed]. 8. Thangaraj, H. S., O. Adjei, B. W. Allen, F. Portaels, M. R. W. Evans, D. K. Banerjee, and M. H. Wansbrough-Jones In vitro activity of ciprofloxacin, sparfloxacin, ofloxacin, amikacin, and rifampicin against Ghanaïan isolates of Mycobacterium ulcerans. J. Antimicrob. Chemother. 45: [PubMed]. 9. Muelder, K., and A. Nourou Buruli ulcer in Benin. Lancet 336: [PubMed]. 10. Sizaire, V., F. Nackers, E. Comte, and F. Portaels Mycobacterium ulcerans infection: control, diagnosis, and treatment. Lancet Infect. Dis. 6: [PubMed].

7 11. Van der Werf, T. S., W. T. A. van der Graaf, J. W. Tappero, and K. Asiedu Mycobacterium ulcerans infection. Lancet 354: [PubMed]. 12. Etuaful, S., B. Carbonnelle, J. Grosset, S. Lucas, C. Horsfield, R. Phillips, M. Evans, D. Ofori-Adjei, E. Klustse, J. Owusu-Boateng, G. K. Amedofu, P. Awuah, E. Ampadu, G. Amofah, K. Asiedu, and M. Wansbrough-Jones Efficacy of the combination rifampinstreptomycin in preventing growth of Mycobacterium ulcerans in early lesions of Buruli ulcer in humans. Antimicrob. Agents Chemother. 49: [PubMed]. 13. Marsollier, L., N. Honoré, P. Legras, A. L. Manceau, H. Kouakou, B. Carbonnelle, and S. T. Cole Isolation of three Mycobacterium ulcerans strains resistant to rifampin after experimental chemotherapy of mice. Antimicrob. Agents Chemother. 47: PubMed 14. Asiedu K, Etuaful S. Socioeconomic implications of Buruli ulcer in Ghana: a three-year review. Am J Trop Med Hyg 1998; 59: PubMed 15. World Health Organization. Provisional guidance on the role of specific antibiotics in the management of Mycobacterium ulcerans disease. Geneva: WHO, Van der Werf TS, Stienstra Y, Johnson RC, et al. Mycobacterium ulcerans disease. Bull World Health Organ 2005; 83: PubMed 17. Chauty, A., Ardant, M.-F., Adeye, A., Euverte, H., Guedenon, A., Johnson, C., Aubry, J., Nuermberger, E., Grosset, J. (2007). Promising Clinical Efficacy of Streptomycin-Rifampin Combination for Treatment of Buruli Ulcer (Mycobacterium ulcerans Disease). Antimicrob. Agents Chemother. 51:

8 Appendix I The JBI Critical Appraisal tool of Evidence of Effectiveness to be used in this review Reviewer Date Author year Record Number 1. Was the assignment to treatment groups? 2. Were participants blinded to treatment allocation? 3. Was allocation to treatment groups concealed from allocator? 4. Were the outcome of people who withdrew described and included in the analysis? 5. Were those assessing the outcomes blind to the treatment allocation? 6. Were control and treatment groups comparable at entry? 7. Were groups treated identically? 8. Were outcomes measured in the same way for all groups? 9. Were outcomes measured in a reliable way? 10. Was appropriate statistical analysis used? Overall appraisal: Include Exclude Seek further info Comments (including reasons for exclusion):

9 Appendix II JBI Data Extraction Form for Experimental/Observational Studies Reviewer Date Author Year Journal Record Number Study Method RCT Quasi-RCT Longitudinal Participants Setting Retrospective Observational Other Population Sample size Intervention 1 Intervention 2 Intervention 3 Interventions Intervention 1 Intervention 2 Intervention 3 Clinical outcome measures Outcome Description Scale/measure

10 Study results Dichotomous data Outcome Intervention ( ) number / total number Intervention ( ) number / total number Continuous data Outcome Intervention ( ) number / total number Intervention ( ) number / total number Authors conclusions Comments