Evidence map›Paper›PMID 28545050›Full record

ArticlePloS one2017

Prevalence and extent of heteroresistance by next generation sequencing of multidrug-resistant tuberculosis.

Darwin J Operario, Alexander F Koeppel, Stephen D Turner, Yongde Bao, Suporn Pholwat, Sayera Banu, Suporn Foongladda, Stellah Mpagama, Jean Gratz, Oleg Ogarkov and 3 more

Erratum issuedAbstract read
In one paragraph

Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 50 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
50citing papers in PubMed, 3 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

50 citing papers in PubMed, 3 syntheses or guidelines pooled it.

  1. Pooled it
  2. Pooled it
  3. Pooled it
  4. Article
  5. Review
  6. Review
  7. Review
  8. Review
  9. Review
  10. Whole-Genome Sequence-Based Diversity ofPathogens (Basel, Switzerland) · 2025
    Article
  11. Article
  12. Article
  13. Article
  14. Article
  15. Spatial Distribution of Drug-ResistantPathogens (Basel, Switzerland) · 2023
    Article
  16. Article
  17. Article
  18. Review
  19. Article
  20. Relationships between Efflux Pumps and Emergence of Heteroresistance: A Comprehensive Study on the Current Findings.The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale · 2022
    Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors.

Darwin J OperarioDivision of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA, United States of America.
Alexander F KoeppelDepartment of Public Health Sciences, University of Virginia, Charlottesville, VA, United States of America.
Stephen D TurnerDepartment of Public Health Sciences, University of Virginia, Charlottesville, VA, United States of America.
Yongde BaoDepartment of Microbiology, University of Virginia, Charlottesville, VA, United States of America.
Suporn PholwatDivision of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA, United States of America.
Sayera BanuInternational Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh.
Suporn FoongladdaSiriraj Hospital, Mahidol University, Bangkok, Thailand.
Stellah MpagamaKibong'oto Infectious Diseases Hospital, Kilimanjaro, Tanzania.
Jean GratzDivision of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA, United States of America.
Oleg OgarkovScientific Centre for Family Health and Human Reproduction Problems, Irkutsk, Siberia, Russian Federation.
Svetlana ZhadovaScientific Centre for Family Health and Human Reproduction Problems, Irkutsk, Siberia, Russian Federation.
Scott K HeysellDivision of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA, United States of America.
Eric R HouptDivision of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA, United States of America.ORCID http://orcid.org/0000-0003-1085-1354

Funding

Tuberculosis Second Line Drug Susceptibility ChipR01AI093358 · NIAID · UNIVERSITY OF VIRGINIA · PI HOUPT, ERIC R · 2011 to 2015
$4.0M
Clinical Impact of Anti-TB Drug Levels and M. Tuberculosis SusceptibilityK23AI099019 · NIAID · UNIVERSITY OF VIRGINIA · PI HEYSELL, SCOTT K · 2012 to 2016
$649k
NIAID NIH HHS K23 AI099019NIAID NIH HHS R01 AI093358
6 · The paper itself

Abstract

Amplicon-based Next Generation Sequencing (NGS) is an emerging method for Mycobacterium tuberculosis drug susceptibility testing (DST) but has not been well described. We examined 158 clinical multidrug-resistant M. tuberculosis isolates via NGS of 11 resistance-associated gene regions covering 3519 nucleotides. Across these gene regions, complete resistance or heteroresistance (defined as 1%-99% mutation) was present in at least one isolate in 6.3% of loci. The number of isolates with heteroresistance was highest for gyrA codon 94, rpoB codons 526 and 531, and embB codons 306, 372 and 406 (range 11-26% of isolates exhibited heteroresistance). 57% of MDR strains had heteroresistance of one or more recognized resistance-associated mutation. Heteroresistant loci generally exhibited high or low degrees of mutation (>90% or <10%). The deep sensitivity of NGS for detecting low level pncA heteroresistance appeared to improve genotypic-phenotypic PZA susceptibility correlations over that of Sanger. NGS demonstrates that heteroresistance in TB in the regions of key genes is common and will need to be bioinformatically managed. The clinical significance of such heteroresistance is unclear, and further study of pncA should be pursued.

Indexed as

High-Throughput Nucleotide SequencingHumansMutationMycobacterium tuberculosisPhenotypeTuberculosis, Multidrug-Resistant

Identifiers

PMID28545050
PMCPMC5436647

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.