RpoB Mutations Causing Discordant Rifampicin Susceptibility in Mycobacterium tuberculosis: Retrospective analysis of prevalence, phenotypic, genotypic, and treatment outcomes

Nomonde R. Mvelase, Melendhran Pillay, Wilbert Sibanda, Jacqueline N. Ngozo, James C.M. Brust, Koleka P. Mlisana

Research output: Contribution to journalArticle

Abstract

Background. Discordant genotypic/phenotypic rifampicin susceptibility testing in Mycobacterium tuberculosis is a significant challenge, yet there are limited data on its prevalence and how best to manage such patients. Whether to treat isolates with rpoB mutations not conferring phenotypic resistance as susceptible or multidrug-resistant tuberculosis (MDR-TB) is unknown. We describe phenotypic and genotypic characteristics of discordant isolates and clinical characteristics and treatment outcomes of affected patients in KwaZulu-Natal, South Africa. Methods. We analyzed clinical isolates showing rifampicin resistance on GenoType MTBDRplus while susceptible on 1% agar proportion method. We measured rifampicin minimum inhibitory concentrations (MICs) using Middlebrook 7H10 agar dilution and BACTEC MGIT 960. Sensititre MYCOTB plates were used for drug-susceptibility testing, and rpoB gene sequencing was performed on all isolates. Local MDR-TB program data were reviewed for clinical information and patient outcomes. Results. Discordant isolates constituted 4.6% (60) of 1302 rifampicin-resistant cases over the study period. Of these, 62% remained susceptible to isoniazid and 98% remained susceptible to rifabutin. Rifampicin MICs were close to the critical concentration of 1 µg/mL (0.5-2 µg/mL) for 83% of isolates. The most frequent rpoB mutations were Q513P (25.3%), D516V (19.2%), and D516Y (13.3%). Whereas 70% were human immunodeficiency virus infected, the mean CD4 count was 289 cells/mm3 and 87% were receiving antiretroviral therapy. Standard therapy for MDR-TB was used and 53% achieved successful treatment outcomes. Conclusions. Rifampicin-discordant TB is not uncommon and sequencing is required to confirm results. The high susceptibility to rifabutin and isoniazid and poor treatment outcomes with the current regimen suggest a potential utility for rifabutin-based therapy.

Original languageEnglish (US)
Article numberofz065
JournalOpen Forum Infectious Diseases
Volume6
Issue number4
DOIs
StatePublished - Apr 1 2019

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Rifampin
Mycobacterium tuberculosis
Rifabutin
Multidrug-Resistant Tuberculosis
Mutation
Isoniazid
Microbial Sensitivity Tests
Agar
CD4 Lymphocyte Count
South Africa
Therapeutics
Genotype
HIV
Pharmaceutical Preparations
Genes

Keywords

  • Discordant
  • Rifampicin
  • RpoB mutations
  • TB

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology

Cite this

RpoB Mutations Causing Discordant Rifampicin Susceptibility in Mycobacterium tuberculosis : Retrospective analysis of prevalence, phenotypic, genotypic, and treatment outcomes. / Mvelase, Nomonde R.; Pillay, Melendhran; Sibanda, Wilbert; Ngozo, Jacqueline N.; Brust, James C.M.; Mlisana, Koleka P.

In: Open Forum Infectious Diseases, Vol. 6, No. 4, ofz065, 01.04.2019.

Research output: Contribution to journalArticle

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abstract = "Background. Discordant genotypic/phenotypic rifampicin susceptibility testing in Mycobacterium tuberculosis is a significant challenge, yet there are limited data on its prevalence and how best to manage such patients. Whether to treat isolates with rpoB mutations not conferring phenotypic resistance as susceptible or multidrug-resistant tuberculosis (MDR-TB) is unknown. We describe phenotypic and genotypic characteristics of discordant isolates and clinical characteristics and treatment outcomes of affected patients in KwaZulu-Natal, South Africa. Methods. We analyzed clinical isolates showing rifampicin resistance on GenoType MTBDRplus while susceptible on 1{\%} agar proportion method. We measured rifampicin minimum inhibitory concentrations (MICs) using Middlebrook 7H10 agar dilution and BACTEC MGIT 960. Sensititre MYCOTB plates were used for drug-susceptibility testing, and rpoB gene sequencing was performed on all isolates. Local MDR-TB program data were reviewed for clinical information and patient outcomes. Results. Discordant isolates constituted 4.6{\%} (60) of 1302 rifampicin-resistant cases over the study period. Of these, 62{\%} remained susceptible to isoniazid and 98{\%} remained susceptible to rifabutin. Rifampicin MICs were close to the critical concentration of 1 µg/mL (0.5-2 µg/mL) for 83{\%} of isolates. The most frequent rpoB mutations were Q513P (25.3{\%}), D516V (19.2{\%}), and D516Y (13.3{\%}). Whereas 70{\%} were human immunodeficiency virus infected, the mean CD4 count was 289 cells/mm3 and 87{\%} were receiving antiretroviral therapy. Standard therapy for MDR-TB was used and 53{\%} achieved successful treatment outcomes. Conclusions. Rifampicin-discordant TB is not uncommon and sequencing is required to confirm results. The high susceptibility to rifabutin and isoniazid and poor treatment outcomes with the current regimen suggest a potential utility for rifabutin-based therapy.",
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AU - Mvelase, Nomonde R.

AU - Pillay, Melendhran

AU - Sibanda, Wilbert

AU - Ngozo, Jacqueline N.

AU - Brust, James C.M.

AU - Mlisana, Koleka P.

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N2 - Background. Discordant genotypic/phenotypic rifampicin susceptibility testing in Mycobacterium tuberculosis is a significant challenge, yet there are limited data on its prevalence and how best to manage such patients. Whether to treat isolates with rpoB mutations not conferring phenotypic resistance as susceptible or multidrug-resistant tuberculosis (MDR-TB) is unknown. We describe phenotypic and genotypic characteristics of discordant isolates and clinical characteristics and treatment outcomes of affected patients in KwaZulu-Natal, South Africa. Methods. We analyzed clinical isolates showing rifampicin resistance on GenoType MTBDRplus while susceptible on 1% agar proportion method. We measured rifampicin minimum inhibitory concentrations (MICs) using Middlebrook 7H10 agar dilution and BACTEC MGIT 960. Sensititre MYCOTB plates were used for drug-susceptibility testing, and rpoB gene sequencing was performed on all isolates. Local MDR-TB program data were reviewed for clinical information and patient outcomes. Results. Discordant isolates constituted 4.6% (60) of 1302 rifampicin-resistant cases over the study period. Of these, 62% remained susceptible to isoniazid and 98% remained susceptible to rifabutin. Rifampicin MICs were close to the critical concentration of 1 µg/mL (0.5-2 µg/mL) for 83% of isolates. The most frequent rpoB mutations were Q513P (25.3%), D516V (19.2%), and D516Y (13.3%). Whereas 70% were human immunodeficiency virus infected, the mean CD4 count was 289 cells/mm3 and 87% were receiving antiretroviral therapy. Standard therapy for MDR-TB was used and 53% achieved successful treatment outcomes. Conclusions. Rifampicin-discordant TB is not uncommon and sequencing is required to confirm results. The high susceptibility to rifabutin and isoniazid and poor treatment outcomes with the current regimen suggest a potential utility for rifabutin-based therapy.

AB - Background. Discordant genotypic/phenotypic rifampicin susceptibility testing in Mycobacterium tuberculosis is a significant challenge, yet there are limited data on its prevalence and how best to manage such patients. Whether to treat isolates with rpoB mutations not conferring phenotypic resistance as susceptible or multidrug-resistant tuberculosis (MDR-TB) is unknown. We describe phenotypic and genotypic characteristics of discordant isolates and clinical characteristics and treatment outcomes of affected patients in KwaZulu-Natal, South Africa. Methods. We analyzed clinical isolates showing rifampicin resistance on GenoType MTBDRplus while susceptible on 1% agar proportion method. We measured rifampicin minimum inhibitory concentrations (MICs) using Middlebrook 7H10 agar dilution and BACTEC MGIT 960. Sensititre MYCOTB plates were used for drug-susceptibility testing, and rpoB gene sequencing was performed on all isolates. Local MDR-TB program data were reviewed for clinical information and patient outcomes. Results. Discordant isolates constituted 4.6% (60) of 1302 rifampicin-resistant cases over the study period. Of these, 62% remained susceptible to isoniazid and 98% remained susceptible to rifabutin. Rifampicin MICs were close to the critical concentration of 1 µg/mL (0.5-2 µg/mL) for 83% of isolates. The most frequent rpoB mutations were Q513P (25.3%), D516V (19.2%), and D516Y (13.3%). Whereas 70% were human immunodeficiency virus infected, the mean CD4 count was 289 cells/mm3 and 87% were receiving antiretroviral therapy. Standard therapy for MDR-TB was used and 53% achieved successful treatment outcomes. Conclusions. Rifampicin-discordant TB is not uncommon and sequencing is required to confirm results. The high susceptibility to rifabutin and isoniazid and poor treatment outcomes with the current regimen suggest a potential utility for rifabutin-based therapy.

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