**4. Drug Resistance Mechanisms in TB**

If the 6-months combination therapy for the treatment of drug-susceptible TB is adequately taken, patients achieve cure rates of > 95%, and the development of resistance by simultaneous mutations to various drugs is very rare [13]. The resistance developed by Mtb to any antimicrobial agent is not due to a single mechanism, but to the interplay of biological, clinical and microbiological reasons, including:


#### *4.1. Human Errors and Advances in MDR-TB Management*

Human errors may contribute to the development of drug-resistance because of the improper use of anti-TB drugs. Two pathways lead to the development of genetic resistance: (i) primary resistance, when a person is infected with a drug-resistant strain, and (ii) acquired resistance, when a person infected with a drug susceptible strain is inadequately treated with drugs, allowing the selection of resistant mutants [13]. The first case mostly occurs in highly crowded communities (e.g., prisons), or in countries with high MDR-TB prevalence, where it is essential to rapidly diagnose and treat patients, so as to reduce transmission [15]. In the second case, it is essential to follow the WHO recommendations on how to adequately treat the TB patients whose disease is caused by a drug-susceptible strain. The clinicians need also to ensure that infection control measures are established, particularly when MDR-patients are hospitalized [26].

To implement the Stop TB Strategy (developed from the DOTS framework), WHO identified a number of factors contributing to poor treatment outcomes, including the acquisition of acquired drug-resistant TB [13]. They were: (i) Inappropriate treatment by health care providers (inappropriate or absent guidelines, poor training of physicians and nurses, sub-optimal education of patients, poor management of adverse drug reactions, no monitoring of treatment, poorly organized or funded TB control programs); (ii) Inadequate drug supply (poor quality medicines, stock-outs, poor storage conditions, wrong dose or combination); (iii) Inadequate drug intake or treatment response by patients (lack of information on treatment adherence, adverse effects, malabsorption).

Common clinical errors in MDR-TB management, particularly in developing countries, include the addition of a single drug to a failing regimen, failure to recognize existing drug resistance, failure to provide directly observed therapy and to manage nonadherence, suboptimal dosages of second-line drugs to decrease side effects, drug treatment based on clinical facts while waiting for DST results [13,14]. In any case, it is important to know that only drug combinations decrease the risk of selection of resistant strains.

Since the treatment of MDR/XDR-TB cases is difficult, WHO recommended that their management be performed by a multidisciplinary team (TB Consilium) at local, regional and/or national levels, including experts (e.g., clinicians, microbiologists, public health officers) with different professional backgrounds [13,15]. In medium and high incidence countries, TB Consilia are important for accessing second-line drugs and/or new drugs BDQ and DLM.

A comparative analysis of the TB Consilia for management of difficult-to-treat MDR/XDR TB cases in Europe and Latin America has been reported [27]. In October 2018, a Global TB Consilium was launched by the Global TB Network, with the goal to provide to a clinician a response on difficult TB cases within 48 h [15,28].
