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Resistance to Second-Line Anti-TB Drugs in Cambodia: A Phenotypic and Genetic Study

Authors Cheng S, Hide M, Pheng SH, Kerléguer A, Delvallez G, Sam S, Mao TE, Nguyen TVA, Bañuls AL

Received 6 November 2020

Accepted for publication 6 January 2021

Published 17 March 2021 Volume 2021:14 Pages 1089—1104

DOI https://doi.org/10.2147/IDR.S289907

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Héctor M. Mora-Montes


Sokleaph Cheng,1– 3 Mallorie Hide,3– 5 Sok Heng Pheng,6 Alexandra Kerléguer,2 Gauthier Delvallez,2 Sophan Sam,7 Tan Eang Mao,6 Thi Van Anh Nguyen,3,8 Anne-Laure Bañuls3– 5

1Institut Pasteur du Cambodge and Ministry of Health, Phnom Penh, Cambodia; 2Medical Biology Laboratory, Institut Pasteur du Cambodge, Phnom Penh, Cambodia; 3LMI Drug Resistance in South East Asia, Institut Pasteur du Cambodge, Phnom Penh, Cambodia; 4MIVEGEC, University of Montpellier, Institute of Research for Development, Centre National de la Recherche Scientifique, Montpellier, France; 5CREES (Centre de Recherche En Écologie Et Évolution de la Santé), Montpellier, France; 6National Center for Tuberculosis and Leprosy Control, Phnom Penh, Cambodia; 7Cambodian Health Committee, Phnom Penh, Cambodia; 8Department of Bacteriology, National Institute of Hygiene and Epidemiology, Hanoi, Martinique, Vietnam

Correspondence: Sokleaph Cheng
Institut Pasteur du Cambodge, No. 5, Monivong Boulevard, Phnom Penh 120210, Cambodia
Tel +855 12 222 684
Email [email protected]

Background: Due to the emergence of Mycobacterium tuberculosis (M.tb) clinical isolates resistant to most potent first-line drugs (FLD), second-line drugs (SLD) are being prescribed more frequently. We explore the genetic characteristics and molecular mechanisms of M.tb isolates phenotypically resistant to SLD, including pre-extensively drug-resistant (pre-XDR) and extensively drug-resistant (XDR) isolates.
Methods: Drug-resistant (DR) M.tb isolates collected from 2012 to 2017 were tested using sequencing and phenotypic drug susceptibility testing. Genotypes were determined to explore their links with SLD resistance patterns.
Results: Of the 272 DR M.tb isolates, 6 non-multidrug resistant (non-MDR) isolates were fluoroquinolones (FQ)-resistant, 3 were XDR and 16 were pre-XDR (14 resistant to FQ and 2 to second-line injectable drugs). The most frequent mutations in FQ-resistant and second-line injectable drugs resistant isolates were gyrA D94G (15/23) and rrs a1401g (3/5), respectively. Seventy-five percent of pre-XDR isolates and 100% of XDR isolates harbored mutations conferring resistance to pyrazinamide. All XDR isolates belonged to the Beijing genotype, of which one, named XDR+, was resistant to all drugs tested. One cluster including pre-XDR and XDR isolates was observed.
Conclusion: This is the first description of SLD resistance in Cambodia. The data suggest that the proportion of XDR and pre-XDR isolates remains low but is on the rise compared to previous reports. The characterization of the XDR+ isolate in a patient who refused treatment underlines the risk of transmission in the population. In addition, genotypic results show, as expected, that the Beijing family is the main involved in pre-XDR and XDR isolates and that the spread of the Beijing pre-XDR strain is capable of evolving into XDR strain. This study strongly indicates the need for rapid interventions in terms of diagnostic and treatment to prevent the spread of the pre-XDR and XDR strains and the emergence of more resistant ones.

Keywords: Mycobacterium tuberculosis, extensively drug-resistant tuberculosis, pre-extensively drug-resistant tuberculosis, fluoroquinolone, second-line injectable drugs

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