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Drug Resistance in Mycobacterium tuberculosisMechanisms of Drug Resistance in TB: Molecular Mechanisms Challenging Fluoroquinolones and Pyrazinamide Effectiveness

Paolo Miotto, PhD; Daniela M. Cirillo, MD, PhD; Giovanni Battista Migliori, MD
Author and Funding Information

From the Emerging Bacterial Pathogens Unit (Drs Miotto and Cirillo), Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan; and WHO Collaborating Centre for TB and Lung Diseases (Dr Migliori), Fondazione S. Maugeri, Care and Research Institute, Tradate, Italy.

CORRESPONDENCE TO: Giovanni Battista Migliori, MD, WHO Collaborating Centre for Tuberculosis and Lung Diseases, Fondazione Salvatore Maugeri, Care and Research Institute, via Roncaccio 16, 21049, Tradate (VA), Italy; e-mail: giovannibattista.migliori@fsm.it


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(4):1135-1143. doi:10.1378/chest.14-1286
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Physicians are more and more often challenged by difficult-to-treat cases of TB. They include patients infected by strains of Mycobacterium tuberculosis that are resistant to at least isoniazid and rifampicin (multidrug-resistant TB) or to at least one fluoroquinolone (FQ) and one injectable, second-line anti-TB drug in addition to isoniazid and rifampicin (extensively drug-resistant TB). The drug treatment of these cases is very long, toxic, and expensive, and, unfortunately, the proportion of unsatisfactory outcomes is still considerably high. Although FQs and pyrazinamide (PZA) are backbone drugs in the available anti-TB regimens, several uncertainties remain about their mechanisms of action and even more remain about the mechanisms leading to drug resistance. From a clinical point of view, a better understanding of the genetic basis of drug resistance will aid (1) clinicians to provide quality clinical management to both drug-susceptible and drug-resistant TB cases (while preventing emergence of further resistance), and (2) developers of new molecular-based diagnostic assays to better direct their research efforts toward a new generation of sensitive, specific, cheap, and easy-to-use point-of-care diagnostics. In this review we provide an update on the molecular mechanisms leading to FQ- and PZA-resistance in M tuberculosis.

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