title: Clinical application of whole-genome sequencing to inform treatment for multidrug-resistant tuberculosis cases.
abstract: The treatment of drug-resistant tuberculosis cases is challenging, as drug options are limited, and the 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. Sixteen isolates from six suspected XDR-TB cases were sequenced; five cases were analyzed in a clinically relevant time frame, with one case sequenced retrospectively. WGS identified mutations in the M. tuberculosis genes associated with antibiotic resistance that are likely to be responsible for the phenotypic resistance. Thus, an evidence base was developed to inform the clinical decisions made around antibiotic treatment over prolonged periods. All strains in this study belonged to the East Asian (Beijing) lineage, and the strain relatedness was consistent with the expectations from the case histories, confirming one contact transmission event. We demonstrate that WGS data can be produced in a clinically relevant time scale some weeks before drug sensitivity testing (DST) data are available, and they actively help clinical decision-making through the assessment of whether an isolate (i) has a particular resistance mutation where there are absent or contradictory DST results, (ii) has no further resistance markers and therefore is unlikely to be XDR, or (iii) is identical to an isolate of known resistance (i.e., a likely transmission event). A small number of discrepancies between the genotypic predictions and phenotypic DST results are discussed in the wider context of the interpretation and reporting of WGS results.
authors: Institute for Infection and Immunity, St. George's University of London, London, United Kingdom.
authors: Adam A
authors: AA
authors: Witney
authors: Institute for Infection and Immunity, St. George's University of London, London, United Kingdom.
authors: Katherine A
authors: KA
authors: Gould
authors: Clinical Infection Unit, St. George's Healthcare NHS Trust, London, United Kingdom.
authors: Amber
authors: A
authors: Arnold
authors: Institute for Infection and Immunity, St. George's University of London, London, United Kingdom.
authors: David
authors: D
authors: Coleman
authors: Department of Microbiology, St. George's Healthcare NHS Trust, London, United Kingdom.
authors: Rachel
authors: R
authors: Delgado
authors: Institute for Infection and Immunity, St. George's University of London, London, United Kingdom.
authors: Jasvir
authors: J
authors: Dhillon
authors: Institute for Infection and Immunity, St. George's University of London, London, United Kingdom.
authors: Marcus J
authors: MJ
authors: Pond
authors: Department of Microbiology, St. George's Healthcare NHS Trust, London, United Kingdom.
authors: Cassie F
authors: CF
authors: Pope
authors: Institute for Infection and Immunity, St. George's University of London, London, United Kingdom Department of Microbiology, St. George's Healthcare NHS Trust, London, United Kingdom.
authors: Tim D
authors: TD
authors: Planche
authors: Institute for Infection and Immunity, St. George's University of London, London, United Kingdom.
authors: Neil G
authors: NG
authors: Stoker
authors: Institute for Infection and Immunity, St. George's University of London, London, United Kingdom Clinical Infection Unit, St. George's Healthcare NHS Trust, London, United Kingdom.
authors: Catherine A
authors: CA
authors: Cosgrove
authors: Institute for Infection and Immunity, St. George's University of London, London, United Kingdom.
authors: Philip D
authors: PD
authors: Butcher
authors: Institute for Infection and Immunity, St. George's University of London, London, United Kingdom Clinical Infection Unit, St. George's Healthcare NHS Trust, London, United Kingdom.
authors: Thomas S
authors: TS
authors: Harrison
authors: Institute for Infection and Immunity, St. George's University of London, London, United Kingdom jhinds@sgul.ac.uk.
authors: Jason
authors: J
authors: Hinds
mesh_terms: D001431:Bacteriological Techniques / Q000379:methods*; D054908:Extensively Drug-Resistant Tuberculosis / Q000175:diagnosis*; D005798:Genes, Bacterial; D016680:Genome, Bacterial; D005838:Genotype; D006784:Hospitals, Teaching; D006801:Humans; D008131:London; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D017422:Sequence Analysis, DNA / Q000379:methods*; D013997:Time Factors