**1. Introduction**

*Mycobacterium tuberculosis* (Mtb) is the etiologic agent of tuberculosis (TB), the leading cause of death from a single infectious disease agent worldwide [1]. In 2018, the World Health Organization (WHO) estimates of the global burden of TB were 10 million cases and 1.45 million deaths. Furthermore, about 1.7 billion people are known to be latently infected with Mtb, with about 10% of them reactivating to active TB in their lifetime. The current antibiotic treatment of active, drug-susceptible TB, requires administration of a combination therapy for 6 months, including the first-line drugs rifampin (RIF), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB) for 2 months, followed by RIF and INH for 4 months. To prevent reactivation of latent TB, a long treatment is also used, consisting of at least 6 months of INH, or 3 to 4 months of RIF plus INH [1,2].

Poor regimen selection, inadequate drug supply and poor adherence of patients to the 6-months therapy may lead to development of drug-resistant Mtb strains, including multidrug-resistant (MDR: resistant at least to INH and RIF) and extensively-drug-resistant (XDR) strains [MDR resistant to a fluoroquinolone (FQ) and a second-line injectable drug [kanamycin (KM), amikacin (AM), capreomycin

(CM)] [3]. Shortening the duration of therapy could increase adherence to treatment and reduce development of MDR and XDR TB.

The goal of this Review is to give a comprehensive overview of the interplay of clinical, biological and microbiological factors involved in the development of drug-resistant TB.
