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Pyrazinamide resistance-conferring mutations in pncA and the transmission of multidrug resistant TB in Georgia

BACKGROUND: The ongoing epidemic of multidrug-resistant tuberculosis (MDR-TB) in Georgia highlights the need for more effective control strategies. A new regimen to treat MDR-TB that includes pyrazinamide (PZA) is currently being evaluated and PZA resistance status will largely influence the success...

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Autores principales: Sengstake, Sarah, Bergval, Indra L, Schuitema, Anja R, de Beer, Jessica L, Phelan, Jody, de Zwaan, Rina, Clark, Taane G, van Soolingen, Dick, Anthony, Richard M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506614/
https://www.ncbi.nlm.nih.gov/pubmed/28697808
http://dx.doi.org/10.1186/s12879-017-2594-3
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author Sengstake, Sarah
Bergval, Indra L
Schuitema, Anja R
de Beer, Jessica L
Phelan, Jody
de Zwaan, Rina
Clark, Taane G
van Soolingen, Dick
Anthony, Richard M
author_facet Sengstake, Sarah
Bergval, Indra L
Schuitema, Anja R
de Beer, Jessica L
Phelan, Jody
de Zwaan, Rina
Clark, Taane G
van Soolingen, Dick
Anthony, Richard M
author_sort Sengstake, Sarah
collection PubMed
description BACKGROUND: The ongoing epidemic of multidrug-resistant tuberculosis (MDR-TB) in Georgia highlights the need for more effective control strategies. A new regimen to treat MDR-TB that includes pyrazinamide (PZA) is currently being evaluated and PZA resistance status will largely influence the success of current and future treatment strategies. PZA susceptibility testing was not routinely performed at the National Reference Laboratory (NRL) in Tbilisi between 2010 and September 2015. We here provide a first insight into the prevalence of PZA resistant TB in this region. METHODS: Phenotypic susceptibility to PZA was determined in a convenience collection of well-characterised TB patient isolates collected at the NRL in Tbilisi between 2012 and 2013. In addition, the pncA gene was sequenced and whole genome sequencing was performed on two isolates. RESULTS: Out of 57 isolates tested 33 (57.9%) showed phenotypic drug resistance to PZA and had a single pncA mutation. All of these 33 isolates were MDR-TB strains. pncA mutations were absent in all but one of the 24 PZA susceptible isolate. In total we found 18 polymorphisms in the pncA gene. From the two major MDR-TB clusters represented (94–32 and 100–32), 10 of 15, 67.0% and 13 of 14, 93.0% strains, respectively were PZA resistant. We also identified a member of the potentially highly transmissive clade A strain carrying the characteristic I6L substitution in PncA. Another strain with the same MLVA type as the clade A strain acquired a different mutation in pncA and was genetically more distantly related suggesting that different branches of this particular lineage have been introduced into this region. CONCLUSION: In this high MDR-TB setting more than half of the tested MDR-TB isolates were resistant to PZA. As PZA is part of current and planned MDR-TB treatment regimens this is alarming and deserves the attention of health authorities. Based on our typing and sequence analysis results we conclude that PZA resistance is the result of primary transmission as well as acquisition within the patient and recommend prospective genotyping and PZA resistance testing in high MDR-TB settings. This is of utmost importance in order to preserve bacterial susceptibility to PZA to help protect (new) second line drugs in PZA containing regimens.
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spelling pubmed-55066142017-07-12 Pyrazinamide resistance-conferring mutations in pncA and the transmission of multidrug resistant TB in Georgia Sengstake, Sarah Bergval, Indra L Schuitema, Anja R de Beer, Jessica L Phelan, Jody de Zwaan, Rina Clark, Taane G van Soolingen, Dick Anthony, Richard M BMC Infect Dis Research Article BACKGROUND: The ongoing epidemic of multidrug-resistant tuberculosis (MDR-TB) in Georgia highlights the need for more effective control strategies. A new regimen to treat MDR-TB that includes pyrazinamide (PZA) is currently being evaluated and PZA resistance status will largely influence the success of current and future treatment strategies. PZA susceptibility testing was not routinely performed at the National Reference Laboratory (NRL) in Tbilisi between 2010 and September 2015. We here provide a first insight into the prevalence of PZA resistant TB in this region. METHODS: Phenotypic susceptibility to PZA was determined in a convenience collection of well-characterised TB patient isolates collected at the NRL in Tbilisi between 2012 and 2013. In addition, the pncA gene was sequenced and whole genome sequencing was performed on two isolates. RESULTS: Out of 57 isolates tested 33 (57.9%) showed phenotypic drug resistance to PZA and had a single pncA mutation. All of these 33 isolates were MDR-TB strains. pncA mutations were absent in all but one of the 24 PZA susceptible isolate. In total we found 18 polymorphisms in the pncA gene. From the two major MDR-TB clusters represented (94–32 and 100–32), 10 of 15, 67.0% and 13 of 14, 93.0% strains, respectively were PZA resistant. We also identified a member of the potentially highly transmissive clade A strain carrying the characteristic I6L substitution in PncA. Another strain with the same MLVA type as the clade A strain acquired a different mutation in pncA and was genetically more distantly related suggesting that different branches of this particular lineage have been introduced into this region. CONCLUSION: In this high MDR-TB setting more than half of the tested MDR-TB isolates were resistant to PZA. As PZA is part of current and planned MDR-TB treatment regimens this is alarming and deserves the attention of health authorities. Based on our typing and sequence analysis results we conclude that PZA resistance is the result of primary transmission as well as acquisition within the patient and recommend prospective genotyping and PZA resistance testing in high MDR-TB settings. This is of utmost importance in order to preserve bacterial susceptibility to PZA to help protect (new) second line drugs in PZA containing regimens. BioMed Central 2017-07-12 /pmc/articles/PMC5506614/ /pubmed/28697808 http://dx.doi.org/10.1186/s12879-017-2594-3 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Sengstake, Sarah
Bergval, Indra L
Schuitema, Anja R
de Beer, Jessica L
Phelan, Jody
de Zwaan, Rina
Clark, Taane G
van Soolingen, Dick
Anthony, Richard M
Pyrazinamide resistance-conferring mutations in pncA and the transmission of multidrug resistant TB in Georgia
title Pyrazinamide resistance-conferring mutations in pncA and the transmission of multidrug resistant TB in Georgia
title_full Pyrazinamide resistance-conferring mutations in pncA and the transmission of multidrug resistant TB in Georgia
title_fullStr Pyrazinamide resistance-conferring mutations in pncA and the transmission of multidrug resistant TB in Georgia
title_full_unstemmed Pyrazinamide resistance-conferring mutations in pncA and the transmission of multidrug resistant TB in Georgia
title_short Pyrazinamide resistance-conferring mutations in pncA and the transmission of multidrug resistant TB in Georgia
title_sort pyrazinamide resistance-conferring mutations in pnca and the transmission of multidrug resistant tb in georgia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506614/
https://www.ncbi.nlm.nih.gov/pubmed/28697808
http://dx.doi.org/10.1186/s12879-017-2594-3
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