title: Added value of whole-genome sequencing for management of highly drug-resistant TB.
abstract: OBJECTIVE
  Phenotypic drug susceptibility testing (DST) for Mycobacterium tuberculosis takes several weeks to complete and second-line DST is often poorly reproducible, potentially leading to compromised clinical decisions. Following a fatal case of XDR TB, we investigated the potential benefit of using whole-genome sequencing to generate an in silico drug susceptibility profile.
  
  
  METHODS
  The clinical course of the patient was reviewed, assessing the times at which phenotypic DST data became available and changes made to the therapeutic regimen. Whole-genome sequencing was performed on the earliest available isolate and variants associated with drug resistance were identified.
  
  
  RESULTS
  The final DST report, including second-line drugs, was issued 10 weeks after patient presentation and 8 weeks after initial growth of M. tuberculosis. In the interim, the patient may have received a compromised regimen that had the potential to select for further drug resistance. The in silico susceptibility profile, extrapolated from evolving evidence in the literature, provided comparable or superior data to the DST results for second-line drugs and could be generated in a much shorter timeframe.
  
  
  CONCLUSIONS
  We propose routine whole-genome sequencing of all MDR M. tuberculosis isolates in adequately resourced settings. This will improve individual patient care, monitor for transmission events and advance our understanding of resistance-associated mutations.
authors.affiliation: Sydney Medical School and the Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Sydney, Australia NSW Mycobacterium Reference Laboratory, Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research-Pathology West, Sydney, Australia Children's Hospital at Westmead, Sydney, Australia alexander.outhred@health.nsw.gov.au.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Outhred
authors.affiliation: NSW Mycobacterium Reference Laboratory, Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research-Pathology West, Sydney, Australia Centre for Infectious Diseases and Microbiology-Public Health, Westmead Hospital, Sydney, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Jelfs
authors.affiliation: NSW Mycobacterium Reference Laboratory, Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research-Pathology West, Sydney, Australia Centre for Infectious Diseases and Microbiology-Public Health, Westmead Hospital, Sydney, Australia.
authors.forename: Basel
authors.initials: B
authors.lastname: Suliman
authors.affiliation: Sydney Medical School and the Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Sydney, Australia.
authors.forename: Grant A
authors.initials: GA
authors.lastname: Hill-Cawthorne
authors.affiliation: Department of Respiratory and Sleep Medicine, Liverpool Hospital, Sydney, Australia.
authors.forename: Archibald B H
authors.initials: AB
authors.lastname: Crawford
authors.affiliation: Sydney Medical School and the Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Sydney, Australia Children's Hospital at Westmead, Sydney, Australia.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Marais
authors.affiliation: Sydney Medical School and the Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Sydney, Australia NSW Mycobacterium Reference Laboratory, Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research-Pathology West, Sydney, Australia Centre for Infectious Diseases and Microbiology-Public Health, Westmead Hospital, Sydney, Australia.
authors.forename: Vitali
authors.initials: V
authors.lastname: Sintchenko
mesh_terms: D000328:Adult; D024901:Drug Resistance, Multiple, Bacterial; D054908:Extensively Drug-Resistant Tuberculosis / Q000175:diagnosis* / Q000188:drug therapy / Q000382:microbiology; D016680:Genome, Bacterial; D060005:Genotyping Techniques / Q000379:methods*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests / Q000379:methods*; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification*; D017422:Sequence Analysis, DNA
keywords: MDR; XDR; extensively drug resistant; multidrug resistant