The introduction of new drugs such as bedaquiline, delamanid, and pretomanid has changed the treatment of MDR/XDR TB, improved the treatment success, and reduced the length of therapy [22, 23•, 24]. Recently, in TB WHO guidelines, a new shorter oral regimens were proposed for patients with confirmed MDR/RR TB. A 6-month regimen with bedaquiline, pretomanid, linezolid (600 mg), and moxifloxacin is recommended for MDR/RR TB patients with confirmed pulmonary or extrapulmonary TB (except central nervous system Tb, osteoarticular or miliary TB), and without previous exposure to bedaquiline, linezolid, pretomanid, or delamanid. Two clinical trials showed that the regimen with a linezolid dose of 600 mg was more effective than the conventional longer treatment, without severe adverse events. Moreover, WHO guidelines include an alternative short regimen (9 months) for patients without a history of treatment with second-line TB drugs for more than 1 month and in whom resistance to fluoroquinolones has been ruled out. This regimen is not indicated for disseminated TB and severe extrapulmonary TB. The combined therapy includes bedaquiline for 6 months, levofloxacin/moxifloxacin, ethionamide, ethambutol, isoniazid (high-dose), pyrazinamide, and clofazimine for 4 months (extended to 6 months if the sputum smear is positive at the end of 4 months), followed by 5 months of treatment with levofloxacin/moxifloxacin, clofazimine, ethambutol, and pyrazinamide. This regimen was associated with a high treatment success rate and a low rate of loss to follow up [25••]. The results of the STREAM stage 2 trial, an international, multi-center, parallel-group, open-label, randomized, controlled phase III trial examining a shorter all-oral bedaquiline-containing regimen, confirmed the efficacy and safety of this regimen for treatment of MDR TB (Table 1) [26,27,28,29,30].

Pretomanid (Pa) is a nitroimidazole prodrug that undergoes nitroreduction within the mycobacterial cell. The primary mechanism of activity is inhibition of mycolic acid biosynthesis, like delamanid, but it has lower protein binding and higher tissue penetration than delamanid. The metabolites of pretomanid induce also the killing of latent bacteria. Pa was approved in 2019 by the FDA and in 2020 by the European Medicines Agency (EMA), both as part of a 6-month regimen containing bedaquiline (B) and linezolid (L; BPaL regimen) for treatment of XDR TB, and treatment intolerant or non-responsive MDR TB. In the studies, the regimen showed a favorable outcome 6 months after treatment completion and sustained favorable outcome after 24 months; also, due to the adverse events correlated to linezolid, the trial that compares different doses of linezolid, had showed improving of tolerability with reduced linezolid dosing with high cure rate [31,32,33]. Currently, about 16 compounds for TB treatment are in the early clinical development phase, thanks to genetic approaches that could detect new potential drug target. New oxazolidinone as sutezolid (PNU-100480), delpazolid (LCB01-0371), and TBI-223 showed promising antimycobacterial activity; also, delpazolid (LCB01-0371) and TBI-223 have lower potency against mitochondrial protein synthesis, and a shorter half-life than linezolid, which may improve mitochondrial toxicity [34,35,36,37]. New targets and new compounds have been identified, and new clinical trials will change the treatment of TB (Table 2).