Ethionamide can be replaced by 2 months of linezolid (600 mg daily). Patients with MDR-/ RR-TB are eligible for this regimen if resistance to fluoroquinolones has been excluded (based on operational data from South Africa [46]). 3. Longer individualised regimens: for patients with MDR-/RR-TB who are not eligible for or had no favourable treatment outcome using the above 6-month or 9-month regimens, have TB disease caused by M. tuberculosis strains with extensive drug resistance (e.g. XDR-TB) or have intolerance to key components of the above-mentioned regiments (table 5). These regimens have a duration of at least 18 months and are individually designed based on a hierarchical grouping of second-line TB medicines, the drug-resistance profile and the patient’s medical history (based on the results of an individual patient data analysis [76]). Patients with XDR-TB or those who have failed treatments with MDR-/RR-TB therapies should be managed in referral centres. The management of difficult-to-treat patients should be discussed in interdisciplinary boards (consilia). Anti-TB medicines in clinical evaluation Currently the pipeline of new TB drugs candidate is flourishing like never before. Thus, 19 new or repurposed compounds for treatment of DS-TB and DR-TB are at present in phase 1 or 2 clinical trials (table 6). Of these new drugs, 10 are of new classes or with a new mechanism of action. Particularly these new medicines target QcrB cytochrome complex (an essential components of the respiratory electron transport chain required for ATP synthesis), DprE1 and MmpL3 (enzymes important for cell wall synthesis), LeuRS (enzyme involved in protein synthesis), gyrB (a gyrase taking part in DNA replication), and cholesterol catabolism (nospecific target fully determined yet) [77–81]. Apart of the conceptually novel drugs, the pipeline of TB compounds in clinical development includes four oxazolidinones (delpazolid, sutezolid, tedizolid, TBI-223), three diarylquinoline (TBAJ-587, TBAJ-876, Sudapyridine) and one riminophenazine (pyrifazimine), of interest as potential effective alternatives to the existing TB drugs such as linezolid, bedaquiline and clofazimine respectively [82]. Novel compounds are evaluated in phase 2a clinical trials to demonstrate the potential for these medicines to be components of simpler TB treatment regimens in the future [83]. GSK-656 in particular showed early bactericidal activity with a low, once-daily oral dose after 14 days of treatment in participants with drug-susceptible PTB [84]. Treatment was generally well tolerated with no serious adverse events identified. Similarly, Telacebec and BTZ-043 demonstrated good dose-dependent early bactericidal activity, with increasing doses of the drug associated with greater reductions in viable TB bacteria measured in sputum and reported acceptable adverse-event rates [85, 86]. In addition, a phase 2b study on sutezolid (SUDOCU) has been completed and reporting of its results is expected. The new TB drugs in clinical development are oral formulations: this is particularly relevant for further design of full-oral TB treatment regimens which usually are preferred by doctors and patients and ensure better adherence [7]. Drugs that have new targets and/or mechanisms of action are important for constructing effective regimens and to overcome emerging drug resistance. However, despite the unprecedented recent https://doi.org/10.1183/2312508X.10024622 129 TREATMENT OF DS-TB AND DR-TB |C. LANGE ET AL.