Clinical failures associated with rpoB mutations in phenotypically occult multidrug-resistant Mycobacterium tuberculosis

SETTING: 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 GeneXpert (R) MTB/RIF assay. Clinical correlation was made by reviewing patient case notes. RESULTS: Isolates from 94 patients were found to 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). DISCUSSION: 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.