All patients (both genders) with a new very likely or likely (WHO scoring criteria) clinical diagnosis of BU (all categories: I, II, III) and normal electrocardiogram (ECG) at baseline giving informed consent will be included in the study, as agreed by study site treatment team led by the lead clinicians.

• Children < 5 years and adults >70 years.
• Children in foster care.
• Patients weighing less than 11 kilograms.
• Pregnancy positive (urine test: beta-HCG positive).
• Previous treatment of Buruli ulcer, tuberculosis or leprosy with at least one of the study drugs.
• Patients with diagnose leprosy or tuberculosis disease.
• Hypersensitivity to at least one of the study drugs or to any of the excipients.
• History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam).
• History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid or rifampicin.
• Patients with history of treatment with macrolide or quinolone antibiotics, anti-tuberculosis medication, or immuno-modulatory drugs including corticosteroids within one month.
• Patients currently receiving treatment with any drugs likely to interact with the study medications, i.e. anticoagulants, cyclosporine, phenytoin or phenobarbitone. Users of oral contraceptives should be notified that such contraceptive is less reliable if taken with rifampicin; additional (mechanical) contraceptive methods will be discussed with the study participant (Appendix 5).
• Patients with HIV co-infection.
• Patients with QTc prolongation >450 ms on ECG or on other medication known to prolong the QTc interval. In this case, if suspected of BU disease, patients will be offered 8-weeks rifampicin plus streptomycin therapy.
• Patients unable to take oral medication or having gastrointestinal disease likely to interfere with drug absorption.
• Patients with history or having current clinical signs of ascites, jaundice, myasthenia gravis, renal dysfunction (known or suspected), diabetes mellitus, and severe immune compromise, or evidence of tuberculosis, or leprosy; terminal illness (e.g., metastasized cancer), haematological malignancy, chronic liver disease, abnormal liver function test and coronary artery disease or any other condition that would preclude enrolment into the study in the study physician's opinion.
• Evidence of a clinically significant (as judged by the Investigator) condition or abnormality (other than the indication being studied) that might compromise safety or the interpretation of trial efficacy or safety endpoints
• Patients with known or suspected bowel strictures who cannot tolerate clarithromycin.
• Patients with a mental health condition that is likely to interfere with compliance with the study protocol in the opinion of the study physician.
• Patients (or parent/legal representative) who are not willing to give informed consent or withdrawal of consent.
• Specific exclusion criteria for the PK sub-study are patients less than 15 years old or less than 40 kg or with renal impairment with a creatinine level higher than the normal one in Benin (7-14 mg/L).