What is resistance? Impact of phenotypic versus molecular drug resistance testing on therapy for multi-and extensively drug-resistant tuberculosis

Jan Heyckendorf, Sönke Andres, Claudio U. Köser, Ioana D. Olaru, Thomas Schön, Erik Sturegård, Patrick Beckert, Viola Schleusener, Thomas A. Kohl, Doris Hillemann, Danesh Moradigaravand, Julian Parkhill, Sharon J. Peacock, Stefan Niemann, Christoph Lange, Matthias Merkerb

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82 Scopus citations

Abstract

Rapid and accurate drug susceptibility testing (DST) is essential for the treatment of multi- and extensively drug-resistant tuberculosis (M/XDR-TB). We compared the utility of genotypic DST assays with phenotypic DST (pDST) using Bactec 960 MGIT or Löwenstein-Jensen to construct M/XDR-TB treatment regimens for a cohort of 25 consecutive M/XDR-TB patients and 15 possible anti-TB drugs. Genotypic DST results from Cepheid GeneXpert MTB/RIF (Xpert) and line probe assays (LPAs; Hain GenoType MTBDRplus 2.0 and MTBDRsl 2.0) and whole-genome sequencing (WGS) were translated into individual algorithm-derived treatment regimens for each patient. We further analyzed if discrepancies between the various methods were due to flaws in the genotypic or phenotypic test using MIC results. Compared with pDST, the average agreement in the number of drugs prescribed in genotypic regimens ranged from just 49% (95% confidence interval [CI], 39 to 59%) for Xpert and 63% (95% CI, 56 to 70%) for LPAs to 93% (95% CI, 88 to 98%) for WGS. Only the WGS regimens did not contain any drugs to which pDST showed resistance. Importantly, MIC testing revealed that pDST likely underestimated the true rate of resistance for key drugs (rifampin, levofloxacin, moxifloxacin, and kanamycin) because critical concentrations (CCs) were too high. WGS can be used to rule in resistance even in M/XDR strains with complex resistance patterns, but pDST for some drugs is still needed to confirm susceptibility and construct the final regimens. Some CCs for pDST need to be reexamined to avoid systematic false-susceptible results in low-level resistant isolates.
Original languageEnglish (US)
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number2
DOIs
StatePublished - Feb 1 2018
Externally publishedYes

Bibliographical note

Generated from Scopus record by KAUST IRTS on 2023-02-15

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology
  • Pharmacology (medical)

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