Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial

Phillips, Richard Odame; Robert, Jérôme; Abass, Kabiru Mohamed; Thompson, W. A.; Sarfo, Fred Stephen; Wilson, Tracey E.; Sarpong, Godfred; Gateau, Thierry; Chauty, Annick; Omollo, Raymond; Otieno, Michael Ochieng; Egondi, Thaddaeus; Ampadu, Edwin; Agossadou, Didier; Marion, Estelle; Ganlonon, Line; Wansbrough‐Jones, Mark; Grosset, J; MacDonald, John M.; Treadwell, Terry; Saunderson, Paul; Paintsil, Albert; Lehman, Linda; Frimpong, Michael; Sarpong, Nanaa Francisca; Saizonou, Raoul; Tiendrébéogo, Alexandre; Ohene, Sally-Ann; Stienstra, Ymkje; Asiedu, Kingsley; Werf, Tjip S van der; Mireku, Samuel Osei; Abotsi, Justice; Poku, Joseph Ken Adu; Asamoah-Frimpong, Richard; Osei-Wusu, Bright; Sarpong, Edward; Konadu, Beatrice; Opoku, Ernest; Forson, Mark; Ndogyele, Mathias; Ofori, Elizabeth; Aboagye, Felicity; Berko, Thomas; Amofa, George; Nsiah, Anastasia; Mensah-Bonsu, Joyce; Nyarko, Joseph Ofori; Amoako, Yaw Ampem; Tannor, Elliot Koranteng; Boakye-Appiah, Justice K.; Loglo, Aloysius; Sarpong-Duah, Mabel; Agbavor, Bernadette; Ardent, Marie Françoise; Yamadjako, Arnaud; Gersande, Naomi Adanmado; Adeye, Ambroise; Kindjinou, Martial; Akpolan,; Kiki, Gbètogo Maxime; Sodjinou, Espoir; Guegnard, Clémence; Klis, Sandor-Adrian; Velding, Kristien; Omansen, Till F.; Ofori‐Adjei, David; Eyangoh, Sarah; Knell, A.J.; Faber, William R.

doi:10.1016/s0140-6736(20)30047-7

Cited by 78 publications

(62 citation statements)

References 39 publications

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“…Streptomycin used for the treatment of secondary BU infection may be unsuitable due to the high level of resistance of secondary bacteria as observed in a similar study [14]. M. ulcerans is sensitive not just to streptomycin and rifampicin but also to clarithromycin [62][63][64].…”

Section: Discussionmentioning

confidence: 97%

Microbiology of secondary infections in Buruli ulcer lesions; implications for therapeutic interventions

et al. 2021

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Background Buruli ulcer (BU) is a skin disease caused by Mycobacterium ulcerans and is the second most common mycobacterial disease after tuberculosis in Ghana and Côte d’Ivoire. M. ulcerans produces mycolactone, an immunosuppressant macrolide toxin, responsible for the characteristic painless nature of the infection. Secondary infection of ulcers before, during and after treatment has been associated with delayed wound healing and resistance to streptomycin and rifampicin. However, not much is known of the bacteria causing these infections as well as antimicrobial drugs for treating the secondary microorganism. This study sought to identify secondary microbial infections in BU lesions and to determine their levels of antibiotic resistance due to the prolonged antibiotic therapy required for Buruli ulcer. Results Swabs from fifty-one suspected BU cases were sampled in the Amansie Central District from St. Peters Hospital (Jacobu) and through an active case surveillance. Forty of the samples were M. ulcerans (BU) positive. Secondary bacteria were identified in all sampled lesions (N = 51). The predominant bacteria identified in both BU and Non-BU groups were Staphylococci spp and Bacilli spp. The most diverse secondary bacteria were detected among BU patients who were not yet on antibiotic treatment. Fungal species identified were Candida spp, Penicillium spp and Trichodema spp. Selected secondary bacteria isolates were all susceptible to clarithromycin and amikacin among both BU and Non-BU patients. Majority, however, had high resistance to streptomycin. Conclusions Microorganisms other than M. ulcerans colonize and proliferate on BU lesions. Secondary microorganisms of BU wounds were mainly Staphylococcus spp, Bacillus spp and Pseudomonas spp. These secondary microorganisms were less predominant in BU patients under treatment compared to those without treatment. The delay in healing that are experienced by some BU patients could be as a result of these bacteria and fungi colonizing and proliferating in BU lesions. Clarithromycin and amikacin are likely suitable drugs for clearance of secondary infection of Buruli ulcer.

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Section: Discussionmentioning

confidence: 97%

Microbiology of secondary infections in Buruli ulcer lesions; implications for therapeutic interventions

et al. 2021

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“…The disease is regaining importance in West Africa and South East Australia with increasing incidence and severity (1, 2). The current treatment strategy involves an eight-week regimen of rifampicin administered with streptomycin or clarithromycin (3, 4). Disease management is complicated by an underreporting, especially in rural Africa (5), social stigmata, and lack of awareness that impede the deployment of medical treatment.…”

Section: Textmentioning

confidence: 99%

Toward a single dose cure for Buruli ulcer

Thomas

Kalia²,

Ruf

et al. 2020

Preprint

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25A single dose of TELACEBEC (Q203), a phase 2 clinical candidate for tuberculosis, eradicates 26 Mycobacterium ulcerans in a mouse model of Buruli ulcer infection without relapse up to 19 27 weeks post treatment. Clinical use of Q203 could dramatically simplify the clinical management 28 of Buruli ulcer, a neglected mycobacterial disease. 29 Text 30 Buruli ulcer is a chronic ulcerating disease of the skin and underlying tissues caused by 31 Mycobacterium ulcerans. The disease is regaining importance in West Africa and South East 32Australia with increasing incidence and severity (1, 2). The current treatment strategy involves 33 an eight-week regimen of rifampicin administered with streptomycin or clarithromycin (3, 4). 34Disease management is complicated by an underreporting, especially in rural Africa (5), social 35 stigmata, and lack of awareness that impede the deployment of medical treatment. Inadequate 36 therapy may drive a substantial number of permanent disabilities, especially in children. 37Compliance to an eight-week therapy is also a serious limitation. 38Telacebec (Q203) is an imidazopyridine amide drug targeting the mycobacterial cytochrome 39 bcc:aa 3 terminal oxidase. The drug candidate, currently in clinical trial phase 2 for tuberculosis 40 (6), has excellent activity against M. ulcerans in vitro and in vivo (7)(8)(9). In Mycobacterium 41 3 tuberculosis, the bactericidal potency of Q203 is limited by the presence of the cytochrome bd 42 oxidase, an alternate terminal oxidase. The exquisite sensitivity of M. ulcerans to Q203 is 43 explained by the absence of a functional cytochrome bd oxidase in this species (10, 11). 44Considering the distinct potency of Q203 coupled with a long half-life and favourable 45 toxicological profile (7, 10), we evaluated the potency of a single dose of Q203 to eradicate M. 46 ulcerans in an established mouse model of Buruli ulcer infection. BALB/c mice were infected in 47 97

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“…A randomised controlled trial reported similar efficacy between the use of either rifampicin and streptomycin (8 weeks) or rifampicin and streptomycin (4 weeks) followed by rifampicin and clarithromycin (4 weeks) which resulted in high recovery rates of exceeding 90% for patients inflicted with early (<6 months) and small lesion (<10 cm) [64] . Recently, a fully oral rifampicin and an extended release formulation of clarithromycin has shown comparable effectiveness for treatment of early and limited Buruli ulcer [65] .…”

Section: Prevention and Treatment Strategiesmentioning

confidence: 99%

Mycobacterium ulcerans and Mycobacterium marinum: Pathogenesis, Diagnosis and Treatment

Tan¹,

Raghunath²,

Ming³

et al. 2020

Prog Micobes Mol Biol

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Skin and soft tissue infections are common presentations for non-tuberculous mycobacteria (NTM). The cutaneous infections caused by NTM may cause localized or diffuse lesions. M. ulcerans is one of the most identified pathogens that involves in the skin and soft tissue mycobacterial infections. Meanwhile, M. marinum, as an NTM has also become important emerging causal agents of cutaneous disease in various geographical regions. Although having common ancestry and highly similar in genetic makeup, M. ulcerans and M. marinum have differential impacts on the host innate immune system. In term pathogenesis, prolonged cell exposure to exotoxin mycolactone produced by M. ulcerans could lead to Buruli ulcer. Meanwhile, like most pathogenic mycobacteria, M. marinum evades the host immune responses by invading and replicating inside host cells and it is capable of modulating host immune responses. This article aims to provide a general overview and comparisons between the pathogenesis, diagnosis, prevention and therapeutic strategies for M. ulcerans and M. marinum.

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Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial

Cited by 78 publications

References 39 publications

Microbiology of secondary infections in Buruli ulcer lesions; implications for therapeutic interventions

Microbiology of secondary infections in Buruli ulcer lesions; implications for therapeutic interventions

Toward a single dose cure for Buruli ulcer

Mycobacterium ulcerans and Mycobacterium marinum: Pathogenesis, Diagnosis and Treatment

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