title: Clinical failures associated with rpoB mutations in phenotypically occult multidrug-resistant Mycobacterium tuberculosis.
abstract: METHODS
  Recently, Mycobacterium tuberculosis isolates have been described that test phenotypically susceptible to rifampicin (RMP) yet harbour genotypic rpoB mutations.
  
  
  OBJECTIVE
  1) To investigate the impact of such mutations on clinical outcomes among RMP-susceptible isolates, and 2) to determine the prevalence of rpoB mutations among isoniazid (INH) monoresistant isolates at our laboratory and to describe the association between the presence of these mutations and clinical outcomes.
  
  
  METHODS
  M. tuberculosis isolates were screened for mutations in the rpoB gene using the Cepheid Gene-Xpert® MTB/RIF assay. Clinical correlation was made by reviewing patient case notes.
  
  
  RESULTS
  Isolates from 94 patients were found to have INH-resistant, RMP-susceptible profiles. Clinical information was available for 52 patients, including three whose isolates had rpoB mutations. All three of these patients had treatment failures, compared to two of 49 patients whose isolates did not have rpoB mutations (P = 0.0005).
  
  
  CONCLUSIONS
  We demonstrate a significant association between the presence of rpoB gene mutations that are not detected at the current RMP critical concentration and treatment failure. We suggest that a review of the current RMP critical concentration is warranted to ensure that RMP is not used inappropriately for the treatment of phenotypically occult multidrug-resistant tuberculosis.
authors.affiliation: Department of Clinical Microbiology, Auckland City Hospital, Auckland, New Zealand. dwilliamson@adhb.govt.nz
authors.forename: D A
authors.initials: DA
authors.lastname: Williamson
authors.forename: S A
authors.initials: SA
authors.lastname: Roberts
authors.forename: J E
authors.initials: JE
authors.lastname: Bower
authors.forename: R
authors.initials: R
authors.lastname: Vaughan
authors.forename: S
authors.initials: S
authors.lastname: Newton
authors.forename: O
authors.initials: O
authors.lastname: Lowe
authors.forename: C A
authors.initials: CA
authors.lastname: Lewis
authors.forename: J T
authors.initials: JT
authors.lastname: Freeman
mesh_terms: D000995:Antitubercular Agents / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000235:genetics*; D004269:DNA, Bacterial / Q000235:genetics*; D012321:DNA-Directed RNA Polymerases; D005838:Genotype; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D010641:Phenotype; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000235:genetics* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004269:DNA, Bacterial; C505805:rpoB protein, Mycobacterium tuberculosis; D012321:DNA-Directed RNA Polymerases