Rifampicin at High Dose for Difficult-to-Treat Tuberculosis

Inclusion criteria: The participant must fulfill either criteria nr. 1-4 AND nr. 5 OR criteria nr. 1-4 AND 6, AND anyone of 7-14: 1. Subjects with confirmed or probable pulmonary or extra pulmonary DS-TB. 2. Informed consent provided. 3. Positive smear, positive Xpert® MTB/RIF test, positive M. tuberculosis culture (confirmed cases) OR histological study compatible with necrotizing granulomas OR a liquid biochemistry (pleural, pericardial, ascites or cerebrospinal fluid) suggestive of TB together with clinical symptoms resembling TB disease in the absence of any other possible cause (probable cases). 4. Female participants of childbearing age must have a negative pregnancy test at baseline. AND 5. Age ≥ 60 years old. OR 6. Age ≥ 18 years AND one of the following 7. Body mass index ≤ 18.5 8. Human Immunodeficiency Virus (HIV) infection. 9. Diabetes Mellitus 10. Hepatitis C virus (HCV) infection (positive HCV serology) 11. Hepatitis B virus (HBV) infection (positive HBV surface antigen or anti-core antibodies) 12. Daily alcohol intake ≥ 2 units of alcohol (1 unit of alcohol: 4% alcohol 250ml (ie beer); 4.5% alcohol 218ml (i.e. cider); 13% alcohol 76ml (i.e. wine); 40% alcohol 25ml (i.e. whisky)) 13. Chronic liver disease of any other cause (metabolic, toxic, autoimmune) 14. Central Nervous System TB involvement Exclusion criteria: Subjects will be excluded from entry if ANY ONE of the criteria listed below is met: 1. Rifampicin resistance confirmation. 2. Barthel index \<40 for subjects older than 60 years old. 3. Signs of significant liver disease: * Liver enzymes (AST or ALT) \> 5x upper limit of normal * Total bilirubin \> 3x upper limit of normal * Subjects with a Child-Pugh grade C cirrhosis or acute decompensation of their chronic liver disease at enrolment. * Any other grade 3-4 hepatobiliary alteration according to the CTCAE v5. 4. Subjects with known allergy or sensitivity to rifampicin, or any of the other components of DS-TB treatment. 5. Treatment with any of the following: rifampicin, isoniazid, pyrazinamide, ethambutol, levofloxacin, or moxifloxacin within the last month for at least 14 days or current TB treatment for more than 7 days. 6. The subject is enrolled in any other investigational trial that includes a drug intervention. 7. Subjects with solid organ transplantation or bone marrow transplantation. 8. Subjects with an active onco-hematological neoplasm requiring chemotherapy or immune therapy. 9. Previous severe pulmonary disease, other than pulmonary DS-TB, according to local investigator. 10. Pre-existing epilepsy or psychiatric disorder according to local investigator. 11. Ischemic heart disease OR severe arrhythmia within 6 months OR Atrial Fibrillation with oral anticoagulant therapy indication when transitioning to low-molecular weight heparin is not feasible. 12. Positive pregnancy test 13. Breastfeeding women. 14. The subject used any drugs or substances known to be strong inhibitors or inducers of cytochrome P450 enzymes which are involved in the degradation pathways of rifampicin within the time windows specified in table 2.