Variable ability of rapid tests to detect Mycobacterium tuberculosis rpoB mutations conferring phenotypically occult rifampicin resistance

Sci Rep. 2019 Aug 14;9(1):11826. doi: 10.1038/s41598-019-48401-z.

Abstract

We compared the ability of commercial and non-commercial, phenotypic and genotypic rapid drug susceptibility tests (DSTs) to detect rifampicin resistance (RR)-conferring 'disputed' mutations frequently missed by Mycobacterium Growth Indicator Tube (MGIT), namely L430P, D435Y, L452P, and I491F. Strains with mutation S450L served as positive control while wild-types were used as negative control. Of the 38 mutant strains, 5.7% were classified as RR by MGIT, 16.2% by Trek Sensititre MYCOTB MIC plate, 19.4% by resazurin microtiter plate assay (REMA), 50.0% by nitrate reductase assay (NRA), and 62.2% by microscopic observation direct susceptibility testing (MODS). Reducing MGIT rifampicin concentration to 0.5 µg/ml, and/or increasing incubation time, enhanced detection of disputed mutations from 5.7% to at least 65.7%, particularly for mutation I491F (from 0.0 to 75.0%). Compared with MGIT at standard pre-set time with 0.25 µg/ml ECOFF as breakpoint, we found a statistically significant increase in the ability of MGIT to resolve disputed mutants and WT strains at extended incubation period of 15 and 21 days, with 0.5 µg/ml and 1 µg/ml ECOFF respectively. MODS detected 75.0% of the I491F strains and NRA 62.5%, while it was predictably missed by all molecular assays. Xpert MTB/RIF, Xpert Ultra, and GenoscholarTB-NTM + MDRTB detected all mutations within the 81 bp RR determining region. Only GenoType MTBDRplus version 2 missed mutation L430P in 2 of 11 strains. Phenotypic and genotypic DSTs varied greatly in detecting occult rifampicin resistance. None of these methods detected all disputed mutations without misclassifying wild-type strains.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents
  • Bacterial Proteins / drug effects
  • Bacterial Proteins / genetics*
  • DNA-Directed RNA Polymerases / drug effects
  • DNA-Directed RNA Polymerases / genetics*
  • Drug Resistance, Bacterial / genetics*
  • Genes, Bacterial
  • Genotype
  • Microbial Sensitivity Tests
  • Mutation*
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / genetics*
  • Rifampin / pharmacology*

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • rpoB protein, Mycobacterium tuberculosis
  • DNA-Directed RNA Polymerases
  • Rifampin