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Genotypic and phenotypic M. tuberculosis resistance: guiding clinicians to prescribe the correct regimens

Andrea Maurizio Cabibbe, Giovanni Sotgiu, Santiago Izco, Giovanni Battista Migliori
European Respiratory Journal 2017 50: 1702292; DOI: 10.1183/13993003.02292-2017
Andrea Maurizio Cabibbe
Emerging Bacterial Pathogens Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Giovanni Sotgiu
Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
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Santiago Izco
Institute of Global Health (ISGlobal), Barcelona, SpainCentro de Investigação em Saúde de Manhiça (CISM), Maputo, Mozambique
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Giovanni Battista Migliori
World Health Organization Collaborating Centre for Tuberculosis and Lung Diseases, Maugeri Care and Research Institute, IRCCS, Tradate, Italy
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  • ORCID record for Giovanni Battista Migliori
  • For correspondence: giovannibattista.migliori@icsmaugeri.it
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    FIGURE 1

    The multidrug-resistant (MDR) tuberculosis (TB) shorter regimen: schematic representation of a diagnostic algorithm. #: critical concentration not recommended. Km: kanamycin; Mfx: moxifloxacin; Pto: prothionamide; Cfz: clofazimine; Z: pyrazinamide; Hhigh-dose: high-dose isoniazid; E: ethambutol; R: rifampicin; LPA: line probe assay; R-R: rifampicin-resistant; DST: drug susceptibility testing.

Tables

  • Figures
  • TABLE 1

    Clinical interpretation of the rapid test for tuberculosis “GenoType MTBDRsl V2 (Hain Lifescience)”

    DrugFailing WT bandDeveloping mutation bandMutationClassification: final BCVsFinal interpretation for clinicians
    OFX-LFXMFXAMCMKM
    OFX
    LFX
    MFX
    gyrA WT1-
    -
    G88A
    G88C
    High
    High
    Indet
    High#
    No OFX-LFX use, not informative for MFX
    No OFX-LFX use, not informative for MFX
    gyrA WT2gyrA MUT1
    gyrA MUT2
    A90V
    S91P
    High
    High
    High
    High
    No OFX-LFX use, higher dosage of MFX?
    No OFX-LFX use, higher dosage of MFX?
    gyrA WT3gyrA MUT3A
    gyrA MUT3B
    -
    gyrA MUT3C
    gyrA MUT3D
    D94A
    D94N
    D94Y
    D94G
    D94H
    High
    High
    High
    High
    High
    High
    High
    High
    High
    Indet
    No OFX-LFX use, higher dosage of MFX?
    No use of fluoroquinolones
    No OFX-LFX use, higher dosage of MFX?
    No use of fluoroquinolones
    No OFX-LFX use, not informative for MFX
    gyrB WTgyrB MUT1
    gyrB MUT2
    N538D¶
    E540V+
    Indet
    Indet
    Indet
    Indet
    Not informative
    Not informative
    AM
    CM
    KM
    rrs WT1rrs MUT1
    -
    a1401g
    c1402t
    High
    Indet
    High
    High
    High
    High#
    No use of second-line injectables
    No CM use, not informative for AM- KM
    rrs WT2rrs MUT2g1484tHighHighHigh#No AM-CM use, not informative for KM
    KMeis WT1-g-37tMinimal#Not informative
    eis WT2eis MUT1
    -
    -
    c-14t
    c-12t
    g-10a
    High
    Minimal#
    High
    No use of kanamycin
    Not informative
    No use of kanamycin
    eis WT3-c-2aIndetNot informative

    Modified from [13]. OFX: ofloxacin; LFX: levofloxacin; MFX: moxifloxacin, AM: amikacin; CM: capreomycin; KM: kanamycin; BCVs: best confidence values; Indet: indeterminate. #: the association of these mutation is based on nominal p-values only (putative, not corrected; refer to Miotto et al. [13]); ¶: N499D; +: E501V.

    • TABLE 2

      Diagnostic accuracy and sensitivity values for anti-tuberculosis drugs (graded mutations identified by Miotto et al. [13] were used within the new classification of the World Health Organization [12]).

      Drug classDrug (genomic region targeted)Clinical interpretation of graded mutations as marker of resistance (high+moderate+minimal)
      Diagnostic accuracy %Sensitivity %
      First-lineRifampicin (rpoB)9490.5
      Isoniazid (katG, inhA-mabA, furA, mshA)80.778.3
      Second-line (group A)Ofloxacin/levofloxacin (gyrA, gyrB)
      Moxifloxacin (gyrA, gyrB)
      90.9
      94
      81.7
      89.2
      Second-line (group B)Amikacin (rrs)91.878.8
      Capreomycin (rrs, tlyA)9271.3
      Kanamycin (rrs, eis, whiB7)87.768.3
      Streptomycin (rpsL, rrs, gidB, tap, whiB7)76.461.3
      Second-line (group C)Ethionamide/prothionamide (inhA-mabA, ethA, mshA)67.548.5
      Second-line (group D)Pyrazinamide (pncA)76.853.1
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    Genotypic and phenotypic M. tuberculosis resistance: guiding clinicians to prescribe the correct regimens
    Andrea Maurizio Cabibbe, Giovanni Sotgiu, Santiago Izco, Giovanni Battista Migliori
    European Respiratory Journal Dec 2017, 50 (6) 1702292; DOI: 10.1183/13993003.02292-2017

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    Genotypic and phenotypic M. tuberculosis resistance: guiding clinicians to prescribe the correct regimens
    Andrea Maurizio Cabibbe, Giovanni Sotgiu, Santiago Izco, Giovanni Battista Migliori
    European Respiratory Journal Dec 2017, 50 (6) 1702292; DOI: 10.1183/13993003.02292-2017
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    • Article
      • Abstract
      • Introduction
      • What is the information provided by WHO-recommended tests?
      • Why is this study important?
      • How to make clinical decisions based on the results of rapid tests and DST
      • Implications to use drugs at high dose in case of drug resistance
      • Acknowledgements
      • Footnotes
      • References
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    • Respiratory infections and tuberculosis
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