Tuberculosis (TB) continues being a leading cause of death due to a single infectious disease agent. The HIV/AIDS pandemic and the emergence of drug resistance are compounding factors that hinder the control of the disease. Associated with this problem is the emergence of multidrug-resistant (MDR) strains of Mycobacterium tuberculosis, defined as strains resistant to at least isoniazid and rifampicin, the most valuable drugs in the treatment of the disease. More recently, the appearance of extensively drug resistant (XDR) strains has been reported. These strains, in addition to being MDR, are also resistant to key second-line drugs. Patients, especially HIV patients, harbouring XDR strains have virtually no treatment options. New and improved methods for fast detection of drug resistance are urgently needed. This project will develop a twofold-approach system for the fast and simultaneous detection of MDR and XDR strains based on a rapid phenotypic assay and a genotypic test. Colorimetric methods, which have been previously validated by our group for first-line drug susceptibility testing, will be developed for key second-line drugs involved in XDRTB. Once set up, these methods will be further elaborated for direct application to sputum specimens. The molecular tool will be based on a modification of the novel technology named detection of immobilized amplified product in one phase system. This single step amplification method will be developed in a versatile microtitre well strip format for detection first of MDR and then of XDR strains. The tools will be then validated in different settings and prospectively evaluated in target populations. The project will contribute to the currently available armamentarium for rapid detection of drug resistant TB and will introduce new tools for the detection of the recently-described and highly-lethal XDRTB. It will also contribute to our knowledge on the mechanisms of M. tuberculosis resistance to second-line drugs.
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