Clinical application of whole genome sequencing to inform treatment for multi-drug resistant tuberculosis cases

Treatment of drug resistant tuberculosis cases is challenging: drug options are limited and existing diagnostics are inadequate. Whole genome sequencing (WGS) has been used in a clinical setting to investigate six cases of suspected Extensively Drug Resistant Mycobacterium tuberculosis (XDR-TB) encountered at a London teaching hospital between 2008 and 2014. 16 isolates from six suspected XDR-TB cases were sequenced; five cases were analysed in a clinically relevant timeframe with one case sequenced retrospectively. WGS identified mutations in M. tuberculosis genes associated with antibiotic resistance likely to be responsible for the phenotypic resistance. Thus an evidence base was developed to inform clinical decisions around antibiotic treatment over prolonged periods. All strains belonged to the East Asian (Beijing) lineage, and strain relatedness was consistent with expectations from case histories, confirming one contact transmission event. We demonstrate that WGS data can be produced in a clinically relevant timescale some weeks before drug sensitivity testing (DST) data is available, and actively help clinical decision making through the assessment of whether an isolate (1) has a particular resistance mutation and DST is absent or contradictory, (2) has no further resistance markers and therefore unlikely to be XDR, or (3) is identical to an isolate of known resistance (i.e. a likely transmission event). A small number of discrepancies between genotypic predictions and phenotypic DST are discussed in the wider context of interpretation and reporting of WGS results.