title: Implications of Failure to Routinely Diagnose Resistance to Second-Line Drugs in Patients With Rifampicin-Resistant Tuberculosis on Xpert MTB/RIF: A Multisite Observational Study.
abstract: Xpert MTB/RIF (Xpert) detects rifampicin-resistant tuberculosis (RR-tuberculosis), enabling physicians to rapidly initiate a World Health Organization-recommended 5-drug regimen while awaiting second-line drug-susceptibility test (DST) results. We quantified the second-line DST results time and proportion of patients potentially placed on suboptimal therapy.
  We included RR-tuberculosis patients detected using Xpert at the South African National Health Laboratory Services (NHLS) of the Western Cape between November 2011 and June 2013 and at Eastern Cape, Free State, and Gauteng NHLS between November 2012 and December 2013. We calculated time from specimen collection to phenotypic second-line DST results. We identified isoniazid and ethionamide resistance mutations on line probe assay and performed pyrazinamide sequencing.
  Among 1332 RR-tuberculosis patients, only 44.7% (596) had second-line DST for both fluoroquinolones and second-line injectable: 55.8% (466 of 835) in the Western Cape and 26.2% (130 of 497) in the other provinces. Patients with smear negative disease and age ≤10 years were less likely to have a result (risk ratio [RR] = 0.72; 95% CI, 0.64-0.81 and RR = 0.49; 95% CI, 0.26-0.79). Median time to second-line DST was 53 days (range, 8-259). Of the 252 patients with complete second-line DST, 101 (40.1%) potentially initiated a suboptimal regimen: 46.8% in the Western Cape and 25.3% in the other provinces.
  Many South Africans diagnosed with RR-tuberculosis by Xpert initiate a suboptimal regimen, with information to adjust therapy available in half of all patients after a median 7 weeks. Algorithm completion and time delays remain challenging.
authors.affiliation: Section of Infectious Diseases, Boston University School of Medicine, Massachusetts.
authors.forename: Karen R
authors.initials: KR
authors.lastname: Jacobson
authors.affiliation: National Health Laboratory Service, Cape Town, South Africa.
authors.forename: Marinus
authors.initials: M
authors.lastname: Barnard
authors.affiliation: Infectious Disease Prevention and Health Services Bureau, Prevention and Health Promotion Administration, Maryland Department of Health and Mental Hygiene, Baltimore.
authors.forename: Mary B
authors.initials: MB
authors.lastname: Kleinman
authors.affiliation: Department of Science and Technology/National Research Foundation Centre of Excellence in Biomedical Tuberculosis Research/South Africa Medical Research Council for Molecular Biology and Human Genetics, Stellenbosch University, Tyberberg.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Streicher
authors.affiliation: Section of Infectious Diseases, Boston University School of Medicine, Massachusetts.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Ragan
authors.affiliation: Department of Biostatistics, Boston University School of Public Health.
authors.forename: Laura F
authors.initials: LF
authors.lastname: White
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Cambridge, Massachusetts.
authors.forename: Ofer
authors.initials: O
authors.lastname: Shapira
authors.affiliation: National Health Laboratory Service, Cape Town, South Africa.
authors.forename: Tania
authors.initials: T
authors.lastname: Dolby
authors.affiliation: National Health Laboratory Service, Cape Town, South Africa.
authors.forename: John
authors.initials: J
authors.lastname: Simpson
authors.affiliation: Department of Molecular Medicine and Haematology, School of Pathology, University of the Witwatersrand and National Health Laboratory Service, National Priority Program, Johannesburg, South Africa.
authors.forename: Lesley
authors.initials: L
authors.lastname: Scott
authors.affiliation: Department of Molecular Medicine and Haematology, School of Pathology, University of the Witwatersrand and National Health Laboratory Service, National Priority Program, Johannesburg, South Africa.
authors.forename: Wendy
authors.initials: W
authors.lastname: Stevens
authors.affiliation: Department of Science and Technology/National Research Foundation Centre of Excellence in Biomedical Tuberculosis Research/South Africa Medical Research Council for Molecular Biology and Human Genetics, Stellenbosch University, Tyberberg.
authors.forename: Paul D
authors.initials: PD
authors.lastname: van Helden
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill.|Department of Epidemiology and Social Medicine and Epidemiology for Global Health Institute, University of Antwerp, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Van Rie
authors.affiliation: Department of Science and Technology/National Research Foundation Centre of Excellence in Biomedical Tuberculosis Research/South Africa Medical Research Council for Molecular Biology and Human Genetics, Stellenbosch University, Tyberberg.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Warren
mesh_terms: D000328:Adult; D024881:Drug Resistance, Bacterial; D005000:Ethionamide / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008826:Microbial Sensitivity Tests; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics; D011933:Reagent Kits, Diagnostic; D012293:Rifampin / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D013019:South Africa / Q000453:epidemiology; D013183:Sputum / Q000382:microbiology; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology*; D055815:Young Adult
chemical_list: D011933:Reagent Kits, Diagnostic; D005000:Ethionamide; D007538:Isoniazid; D012293:Rifampin
keywords: South Africa; drug resistance.; drug susceptibility; multidrug-resistant tuberculosis; tuberculosis