Elucidating emergence and transmission of multidrug-resistant tuberculosis in treatment experienced patients by whole genome sequencing

Taane G. Clark, Kim Mallard, Francesc Coll, Mark Preston, Samuel Assefa, David Harris, Sam Ogwang, Francis Mumbowa, Bruce Kirenga, Denise M. O'Sullivan, Alphonse Okwera, Kathleen D. Eisenach, Moses Joloba, Stephen D. Bentley, Jerrold J. Ellner, Julian Parkhill, Edward C. Jones-López, Ruth McNerney

Research output: Contribution to journalArticle

Abstract

Background: Understanding the emergence and spread of multidrug-resistant tuberculosis (MDR-TB) is crucial for its control. MDR-TB in previously treated patients is generally attributed to the selection of drug resistant mutants during inadequate therapy rather than transmission of a resistant strain. Traditional genotyping methods are not sufficient to distinguish strains in populations with a high burden of tuberculosis and it has previously been difficult to assess the degree of transmission in these settings. We have used whole genome analysis to investigate M. tuberculosis strains isolated from treatment experienced patients with MDR-TB in Uganda over a period of four years. Methods and Findings: We used high throughput genome sequencing technology to investigate small polymorphisms and large deletions in 51 Mycobacterium tuberculosis samples from 41 treatment-experienced TB patients attending a TB referral and treatment clinic in Kampala. This was a convenience sample representing 69% of MDR-TB cases identified over the four year period. Low polymorphism was observed in longitudinal samples from individual patients (2-15 SNPs). Clusters of samples with less than 50 SNPs variation were examined. Three clusters comprising a total of 8 patients were found with almost identical genetic profiles, including mutations predictive for resistance to rifampicin and isoniazid, suggesting transmission of MDR-TB. Two patients with previous drug susceptible disease were found to have acquired MDR strains, one of which shared its genotype with an isolate from another patient in the cohort. Conclusions: Whole genome sequence analysis identified MDR-TB strains that were shared by more than one patient. The transmission of multidrug-resistant disease in this cohort of retreatment patients emphasises the importance of early detection and need for infection control. Consideration should be given to rapid testing for drug resistance in patients undergoing treatment to monitor the emergence of resistance and permit early intervention to avoid onward transmission.

Original languageEnglish (US)
Article numbere83012
JournalPLoS One
Volume8
Issue number12
DOIs
StatePublished - Dec 11 2013
Externally publishedYes

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Patient treatment
Multidrug-Resistant Tuberculosis
tuberculosis
Genes
Genome
genome
Polymorphism
Pharmaceutical Preparations
Therapeutics
Isoniazid
Rifampin
Single Nucleotide Polymorphism
Tuberculosis
Throughput
genetic polymorphism
isoniazid
sampling
drugs
rifampicin
Retreatment

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Elucidating emergence and transmission of multidrug-resistant tuberculosis in treatment experienced patients by whole genome sequencing. / Clark, Taane G.; Mallard, Kim; Coll, Francesc; Preston, Mark; Assefa, Samuel; Harris, David; Ogwang, Sam; Mumbowa, Francis; Kirenga, Bruce; O'Sullivan, Denise M.; Okwera, Alphonse; Eisenach, Kathleen D.; Joloba, Moses; Bentley, Stephen D.; Ellner, Jerrold J.; Parkhill, Julian; Jones-López, Edward C.; McNerney, Ruth.

In: PLoS One, Vol. 8, No. 12, e83012, 11.12.2013.

Research output: Contribution to journalArticle

Clark, TG, Mallard, K, Coll, F, Preston, M, Assefa, S, Harris, D, Ogwang, S, Mumbowa, F, Kirenga, B, O'Sullivan, DM, Okwera, A, Eisenach, KD, Joloba, M, Bentley, SD, Ellner, JJ, Parkhill, J, Jones-López, EC & McNerney, R 2013, 'Elucidating emergence and transmission of multidrug-resistant tuberculosis in treatment experienced patients by whole genome sequencing', PLoS One, vol. 8, no. 12, e83012. https://doi.org/10.1371/journal.pone.0083012
Clark, Taane G. ; Mallard, Kim ; Coll, Francesc ; Preston, Mark ; Assefa, Samuel ; Harris, David ; Ogwang, Sam ; Mumbowa, Francis ; Kirenga, Bruce ; O'Sullivan, Denise M. ; Okwera, Alphonse ; Eisenach, Kathleen D. ; Joloba, Moses ; Bentley, Stephen D. ; Ellner, Jerrold J. ; Parkhill, Julian ; Jones-López, Edward C. ; McNerney, Ruth. / Elucidating emergence and transmission of multidrug-resistant tuberculosis in treatment experienced patients by whole genome sequencing. In: PLoS One. 2013 ; Vol. 8, No. 12.
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abstract = "Background: Understanding the emergence and spread of multidrug-resistant tuberculosis (MDR-TB) is crucial for its control. MDR-TB in previously treated patients is generally attributed to the selection of drug resistant mutants during inadequate therapy rather than transmission of a resistant strain. Traditional genotyping methods are not sufficient to distinguish strains in populations with a high burden of tuberculosis and it has previously been difficult to assess the degree of transmission in these settings. We have used whole genome analysis to investigate M. tuberculosis strains isolated from treatment experienced patients with MDR-TB in Uganda over a period of four years. Methods and Findings: We used high throughput genome sequencing technology to investigate small polymorphisms and large deletions in 51 Mycobacterium tuberculosis samples from 41 treatment-experienced TB patients attending a TB referral and treatment clinic in Kampala. This was a convenience sample representing 69{\%} of MDR-TB cases identified over the four year period. Low polymorphism was observed in longitudinal samples from individual patients (2-15 SNPs). Clusters of samples with less than 50 SNPs variation were examined. Three clusters comprising a total of 8 patients were found with almost identical genetic profiles, including mutations predictive for resistance to rifampicin and isoniazid, suggesting transmission of MDR-TB. Two patients with previous drug susceptible disease were found to have acquired MDR strains, one of which shared its genotype with an isolate from another patient in the cohort. Conclusions: Whole genome sequence analysis identified MDR-TB strains that were shared by more than one patient. The transmission of multidrug-resistant disease in this cohort of retreatment patients emphasises the importance of early detection and need for infection control. Consideration should be given to rapid testing for drug resistance in patients undergoing treatment to monitor the emergence of resistance and permit early intervention to avoid onward transmission.",
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AU - Harris, David

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AU - Mumbowa, Francis

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AU - O'Sullivan, Denise M.

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AU - Eisenach, Kathleen D.

AU - Joloba, Moses

AU - Bentley, Stephen D.

AU - Ellner, Jerrold J.

AU - Parkhill, Julian

AU - Jones-López, Edward C.

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N2 - Background: Understanding the emergence and spread of multidrug-resistant tuberculosis (MDR-TB) is crucial for its control. MDR-TB in previously treated patients is generally attributed to the selection of drug resistant mutants during inadequate therapy rather than transmission of a resistant strain. Traditional genotyping methods are not sufficient to distinguish strains in populations with a high burden of tuberculosis and it has previously been difficult to assess the degree of transmission in these settings. We have used whole genome analysis to investigate M. tuberculosis strains isolated from treatment experienced patients with MDR-TB in Uganda over a period of four years. Methods and Findings: We used high throughput genome sequencing technology to investigate small polymorphisms and large deletions in 51 Mycobacterium tuberculosis samples from 41 treatment-experienced TB patients attending a TB referral and treatment clinic in Kampala. This was a convenience sample representing 69% of MDR-TB cases identified over the four year period. Low polymorphism was observed in longitudinal samples from individual patients (2-15 SNPs). Clusters of samples with less than 50 SNPs variation were examined. Three clusters comprising a total of 8 patients were found with almost identical genetic profiles, including mutations predictive for resistance to rifampicin and isoniazid, suggesting transmission of MDR-TB. Two patients with previous drug susceptible disease were found to have acquired MDR strains, one of which shared its genotype with an isolate from another patient in the cohort. Conclusions: Whole genome sequence analysis identified MDR-TB strains that were shared by more than one patient. The transmission of multidrug-resistant disease in this cohort of retreatment patients emphasises the importance of early detection and need for infection control. Consideration should be given to rapid testing for drug resistance in patients undergoing treatment to monitor the emergence of resistance and permit early intervention to avoid onward transmission.

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