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

Heyckendorf, Jan; Andres, Sönke; Köser, Claudio U.; Olaru, Ioana D.; Schön, Thomas; Sturegård, Erik LU ; Beckert, Patrick; Schleusener, Viola; Kohl, Thomas A. and Hillemann, Doris, et al. (2018) In Antimicrobial Agents and Chemotherapy 62(2).
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... (More)

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.

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Antimicrobial Agents and Chemotherapy
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62
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2
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American Society for Microbiology
external identifiers
  • scopus:85040981340
ISSN
0066-4804
DOI
10.1128/AAC.01550-17
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English
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yes
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eb9b9d38-cb18-4104-8d88-1587ac105de1
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2018-02-06 15:13:44
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2018-09-02 04:44:48
@article{eb9b9d38-cb18-4104-8d88-1587ac105de1,
  abstract     = {<p>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.</p>},
  articleno    = {e01550-17},
  author       = {Heyckendorf, Jan and Andres, Sönke and Köser, Claudio U. and Olaru, Ioana D. and Schön, Thomas and Sturegård, Erik and Beckert, Patrick and Schleusener, Viola and Kohl, Thomas A. and Hillemann, Doris and Moradigaravand, Danesh and Parkhill, Julian and Peacock, Sharon J. and Niemann, Stefan and Lange, Christoph and Merkerb, Matthias},
  issn         = {0066-4804},
  language     = {eng},
  month        = {02},
  number       = {2},
  publisher    = {American Society for Microbiology},
  series       = {Antimicrobial Agents and Chemotherapy},
  title        = {What is resistance? Impact of phenotypic versus molecular drug resistance testing on therapy for multi-and extensively drug-resistant tuberculosis},
  url          = {http://dx.doi.org/10.1128/AAC.01550-17},
  volume       = {62},
  year         = {2018},
}