Thuong Thi Vu, Son Thai Nguyen, Thanh Hoa Thi Tran, Anh Duc Dang, Huy Quang Nguyen, Hung Van Nguyen, Ngoc-Lan Nguyen, Nhung Viet Nguyen, Anne-Laure Bañuls, Van Anh Thi Nguyen, Lucie Contamin, Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), National Institute of Hygiene and Epidemiology [Hanoi, Vietnam] (NIHE), Réseau International des Instituts Pasteur (RIIP), Hanoi University of Science and Technology (HUST), Laboratoire Mixte International Drug Resistance in Southeast Asia (LMI DRISA), Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU)-Fondation Mérieux-University of sciences and technologies of hanoi (USTH)-Center of Infectiology Lao-Christophe Mérieux [Vientiane] (CILM), National Lung Hospital [Hanoi, Viet Nam], Pham Ngoc Thach Hospital, Vietnam Military Medical University, Du gène à l'écosystème (MIVEGEC-GeneSys), Pathogènes, Environnement, Santé Humaine (EPATH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), This work was supported by grants of the following projects: the PHC Lotus, the GDRI ID-BIO, the KC.10.15/06-10, the JEAI MySA, the LMI DRISA, and an ADB BIO3 USTH project. We would like to thank the Viet Nam National Tuberculosis Programme, National Lung Hospital, Pham Ngoc Thach Hospital and Hue Central Hospital for M. tuberculosis sampling. We also thank NIHE, IRD, CNRS and USTH for their support. Nguyen Quang Huy was supported by the project 911 scholarship from the Vietnamese Government., We are grateful to Elisabetta Andermarcher for editing the English., Fondation Mérieux-Center of Infectiology Lao-Christophe Mérieux [Vientiane] (CILM)-Institut Pasteur du Cambodge, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-University of sciences and technologies of hanoi (USTH)-Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU)
International audience; In Vietnam, a country with high tuberculosis (137/100.000 population) and multidrug-resistant (MDR)-TB burdens (7.8/100.000 population), little is known about the molecular signatures of drug resistance in general and more particularly of second line drug (SLD) resistance. This study is specifically focused on Mycobacterium tuberculosis isolates resistant to four first-line drugs (FLDs) that make TB much more difficult to treat. The aim is to determine the proportion of SLD resistance in these quadruple drug resistant isolates and the genetic determinants linked to drug resistance to better understand the genetic processes leading to quadruple and extremely drug resistance (XDR). 91 quadruple (rifampicin, isoniazid, ethambutol and streptomycin) FLD resistant and 55 susceptible isolates were included. Spoligotyping and 24-locus MIRU-VNTR techniques were performed and 9 genes and promoters linked to FLD and SLD resistance were sequenced. SLD susceptibility testing was carried out on a subsample of isolates. High proportion of quadruple-FLD resistant isolates was resistant to fluoroquinolones (27%) and second-line injectable drugs (30.2%) by drug susceptibility testing. The sequencing revealed high mutation diversity with prevailing mutations at positions katG315, inhA-15, rpoB531, embB306, rrs1401, rpsL43 and gyrA94. The sensitivity and specificity were high for most drug resistances (>86%), but the sensitivity was lower for injectable drug resistances (