Molecular Epidemiology of Multi- and Extensively-Drug-Resistant Mycobacterium tuberculosis in Ireland, 2001-2014

The origin and spread of multi- and extensively-drug resistant (MDR/XDR) tuberculosis (TB) in Ireland are largely unknown. In this work, we performed a molecular epidemiological analysis of Mycobacterium tuberculosis complex (MTBC) isolates from cases of MDR/XDR-TB in Ireland from 2001 to 2014. Forty-two isolates were examined using phenotypic drug-susceptibility testing, Mycobacterial-Interspersed-Repetitive-Units Variable-Number Tandem-Repeat (MIRU-VNTR) genotyping and whole-genome sequencing (WGS). The lineage distribution of the MDR/XDR-TB isolates comprised 54.7% Euro-American, 33.3% East Asian, 7.2% East African Indian, and 4.8% Indo-Oceanic. A significant association was detected between the Beijing sub-lineage and the relative risk of an isolate being MDR. Seven MIRU-VNTR genotypes were identical to clusters in other European countries indicating probable cross-border spreading of MDR/XDR-TB to Ireland. Whole-genome data provided the first evidence in Ireland of in vivo microevolution of MTBC isolates from drug-susceptible to MDR, and from MDR to XDR. The katG S315T and rpoB S450L drug-resistance-associated mutations were dominant across the spectrum of MTBC lineages. In addition, a second case of MDR-TB in one patient was established as being due to re-infection with a new strain rather than reactivation of latent MDR-TB. The implications of our findings for the future prevention and monitoring of MDR-TB in Ireland are discussed.