Abstract
The control of tuberculosis (TB) is hampered by the emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains, defined as resistant to at least isoniazid and rifampin, the two bactericidal drugs essential for the treatment of the disease. Due to the worldwide estimate of almost half a million incident cases of MDR/rifampin-resistant TB, it is important to continuously update the knowledge on the mechanisms involved in the development of this phenomenon. Clinical, biological and microbiological reasons account for the generation of resistance, including: (i) nonadherence of patients to their therapy, and/or errors of physicians in therapy management, (ii) complexity and poor vascularization of granulomatous lesions, which obstruct drug distribution to some sites, resulting in resistance development, (iii) intrinsic drug resistance of tubercle bacilli, (iv) formation of non-replicating, drug-tolerant bacilli inside the granulomas, (v) development of mutations in Mtb genes, which are the most important molecular mechanisms of resistance. This review provides a comprehensive overview of these issues, and releases up-dated information on the therapeutic strategies recently endorsed and recommended by the World Health Organization to facilitate the clinical and microbiological management of drug-resistant TB at the global level, with attention also to the most recent diagnostic methods.
Highlights
Mycobacterium tuberculosis (Mtb) is the etiologic agent of tuberculosis (TB), the leading cause of death from a single infectious disease agent worldwide [1]
A single founder Mtb strain underwent genetic mutations during treatment, leading to the acquisition of additional drug resistance in different sections of the lung of the same patient, preferentially in the cavity wall [42]. In keeping with this observation, drug-specific gradients in the walls of human pulmonary cavities were reported to be associated with the development of acquired resistance in patients with MDR-TB, due to the low level of some drugs in the cavities centers, where there is a high number of replicating bacilli [43]
The Efflux pumps (EPs) of Mtb belongs to the ATP-binding cassette (ABC), major facilitator superfamily (MFS) and resistance nodulation division (RND) superfamilies, and to the Following exposure of Mtb to sub-inhibitory concentration of INH and EMB, EP genes are overexpressed resulting in the development of low-level resistance for a prolonged period of time
Summary
Mycobacterium tuberculosis (Mtb) is the etiologic agent of tuberculosis (TB), the leading cause of death from a single infectious disease agent worldwide [1]. 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. 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. 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
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