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Volume 8, Issue 4

Transmission, distribution and drug resistance-conferring mutations of extensively drug-resistant tuberculosis in the Western Cape Province, South Africa Open Access

Abstract

Extensively drug-resistant tuberculosis (XDR-TB), defined as resistance to at least isoniazid (INH), rifampicin (RIF), a fluoroquinolone (FQ) and a second-line injectable drug (SLID), is difficult to treat and poses a major threat to TB control. The transmission dynamics and distribution of XDR () strains have not been thoroughly investigated. Using whole genome sequencing data on 461 XDR- strains, we aimed to investigate the geographical distribution of XDR- strains in the Western Cape Province of South Africa over a 10 year period (2006–2017) and assess the association between sub-lineage, age, gender, geographical patient location and membership or size of XDR-TB clusters. First, we identified transmission clusters by excluding drug resistance-conferring mutations and using the 5 SNP cutoff, followed by merging clusters based on their most recent common ancestor. We then consecutively included variants conferring resistance to INH, RIF, ethambutol (EMB), pyrazinamide (PZA), SLIDs and FQs in the cluster definition. Cluster sizes were classified as small (2–4 isolates), medium (5–20 isolates), large (21–100 isolates) or very large (>100 isolates) to reflect the success of individual strains. We found that most XDR-TB strains were clustered and that including variants conferring resistance to INH, RIF, EMB, PZA and SLIDs in the cluster definition did not significantly reduce the proportion of clustered isolates (85.5–82.2 %) but increased the number of patients belonging to small clusters (4.3–12.4 %, =0.56). Inclusion of FQ resistance-conferring variants had the greatest effect, with 11 clustered isolates reclassified as unique while the number of clusters increased from 17 to 37. Lineage 2 strains (lineage 2.2.1 typical Beijing or lineage 2.2.2 atypical Beijing) showed the large clusters which were spread across all health districts of the Western Cape Province. We identified a significant association between residence in the Cape Town metropole and cluster membership (=0.016) but no association between gender, age and cluster membership or cluster size (=0.39). Our data suggest that the XDR-TB epidemic in South Africa probably has its origin in the endemic spread of MDR and pre-XDR strains followed by acquisition of FQ resistance, with more limited transmission of XDR strains. This only became apparent with the inclusion of drug resistance-conferring variants in the definition of a cluster. In addition to the prevention of amplification of resistance, rapid diagnosis of MDR, pre-XDR and XDR-TB and timely initiation of appropriate treatment is needed to reduce transmission of difficult-to-treat TB.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): drug resistance , transmission , tuberculosis , whole genome sequencing and XDR-TB
© 2022 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution NonCommercial License.
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2022-04-26
2024-04-16
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References

  1. Cohen J. Infectious disease. Extensively drug-resistant TB gets foothold in South Africa. Science 2006; 313:1554 [View Article] [PubMed]
     [Google Scholar]
  2. Singh JA, Upshur R, Padayatchi N. XDR-TB in South Africa: no time for denial or complacency. PLoS Med 2007; 4:e50 [View Article] [PubMed]
     [Google Scholar]
  3. Gandhi NR, Moll A, Sturm AW, Pawinski R, Govender T et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006; 368:1575–1580 [View Article] [PubMed]
     [Google Scholar]
  4. World Health Organization The global MDR-TB and XDR-TB response plan 2007-2008; 2007
  5. World Health Organization Global tuberculosis report 2019; 2019
  6. de Vos M, Müller B, Borrell S, Black PA, van Helden PD et al. Putative compensatory mutations in the rpoC gene of rifampin-resistant Mycobacterium tuberculosis are associated with ongoing transmission. Antimicrob Agents Chemother 2013; 57:827–832 [View Article] [PubMed]
     [Google Scholar]
  7. Böttger EC, Springer B, Pletschette M, Sander P. Fitness of antibiotic-resistant microorganisms and compensatory mutations. Nat Med 1998; 4:1343–1344 [View Article] [PubMed]
     [Google Scholar]
  8. Billington OJ, McHugh TD, Gillespie SH. Physiological cost of rifampin resistance induced in vitro in Mycobacterium tuberculosis. Antimicrob Agents Chemother 1999; 43:1866–1869 [View Article] [PubMed]
     [Google Scholar]
  9. Sander P, Springer B, Prammananan T, Sturmfels A, Kappler M et al. Fitness cost of chromosomal drug resistance-conferring mutations. Antimicrob Agents Chemother 2002; 46:1204–1211 [View Article] [PubMed]
     [Google Scholar]
  10. Shcherbakov D, Akbergenov R, Matt T, Sander P, Andersson DI et al. Directed mutagenesis of Mycobacterium smegmatis 16S rRNA to reconstruct the in vivo evolution of aminoglycoside resistance in Mycobacterium tuberculosis. Mol Microbiol 2010; 77:830–840 [View Article] [PubMed]
     [Google Scholar]
  11. Klopper M, Heupink TH, Hill-Cawthorne G, Streicher EM, Dippenaar A et al. A landscape of genomic alterations at the root of A near-untreatable tuberculosis epidemic. BMC Med 2020; 18:24 [View Article] [PubMed]
     [Google Scholar]
  12. Valway SE, Greifinger RB, Papania M, Kilburn JO, Woodley C et al. Multidrug-resistant tuberculosis in the New York State prison system, 1990-1991. J Infect Dis 1994; 170:151–156 [View Article] [PubMed]
     [Google Scholar]
  13. van Rie A, Warren RM, Beyers N, Gie RP, Classen CN et al. Transmission of a multidrug-resistant Mycobacterium tuberculosis strain resembling “strain W” among noninstitutionalized, human immunodeficiency virus-seronegative patients. J Infect Dis 1999; 180:1608–1615 [View Article] [PubMed]
     [Google Scholar]
  14. Arnold A, Witney AA, Vergnano S, Roche A, Cosgrove CA et al. XDR-TB transmission in London: Case management and contact tracing investigation assisted by early whole genome sequencing. J Infect 2016; 73:210–218 [View Article] [PubMed]
     [Google Scholar]
  15. Shah NS, Auld SC, Brust JCM, Mathema B, Ismail N et al. Transmission of extensively drug-resistant tuberculosis in South Africa. N Engl J Med 2017; 376:243–253 [View Article] [PubMed]
     [Google Scholar]
  16. Sullivan EA, Kreiswirth BN, Palumbo L, Kapur V, Musser JM et al. Emergence of fluoroquinolone-resistant tuberculosis in New York City. Lancet 1995; 345:1148–1150 [View Article] [PubMed]
     [Google Scholar]
  17. Mlambo CK, Warren RM, Poswa X, Victor TC, Duse AG et al. Genotypic diversity of extensively drug-resistant tuberculosis (XDR-TB) in South Africa. Int J Tuberc Lung Dis 2008; 12:99–104 [PubMed]
     [Google Scholar]
  18. Dixit A, Freschi L, Vargas R, Calderon R, Sacchettini J et al. Whole genome sequencing identifies bacterial factors affecting transmission of multidrug-resistant tuberculosis in a high-prevalence setting. Sci Rep 2019; 9:5602 [View Article] [PubMed]
     [Google Scholar]
  19. Cohen KA, Abeel T, Manson McGuire A, Desjardins CA, Munsamy V et al. Evolution of extensively drug-resistant tuberculosis over four decades: whole genome sequencing and dating analysis of Mycobacterium tuberculosis isolates from KwaZulu-Natal. PLoS Med 2015; 12:e1001880 [View Article] [PubMed]
     [Google Scholar]
  20. Nelson KN, Jenness SM, Mathema B, Lopman BA, Auld SC et al. Social mixing and clinical features linked with transmission in a network of extensively drug-resistant tuberculosis cases in KwaZulu-Natal, South Africa. Clin Infect Dis 2020; 70:2396–2402 [View Article] [PubMed]
     [Google Scholar]
  21. Meehan CJ, Goig GA, Kohl TA, Verboven L, Dippenaar A et al. Whole genome sequencing of Mycobacterium tuberculosis: current standards and open issues. Nat Rev Microbiol 2019; 17:533–545 [View Article] [PubMed]
     [Google Scholar]
  22. Jamieson FB, Teatero S, Guthrie JL, Neemuchwala A, Fittipaldi N et al. Whole-genome sequencing of the Mycobacterium tuberculosis Manila sublineage results in less clustering and better resolution than mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) typing and spoligotyping. J Clin Microbiol 2014; 52:3795–3798 [View Article] [PubMed]
     [Google Scholar]
  23. Schmidt B-M, Geldenhuys H, Tameris M, Luabeya A, Mulenga H et al. Impact of Xpert MTB/RIF rollout on management of tuberculosis in a South African community. S Afr Med J 2017; 107:1078–1081 [View Article] [PubMed]
     [Google Scholar]
  24. Heupink TH, Verboven L, Warren RM, Van Rie A. Comprehensive and accurate genetic variant identification from contaminated and low-coverage Mycobacterium tuberculosis whole genome sequencing data. Microb Genom 2021; 7: [View Article] [PubMed]
     [Google Scholar]
  25. Nguyen L-T, Schmidt HA, von Haeseler A, Minh BQ. IQ-TREE: a fast and effective stochastic algorithm for estimating maximum-likelihood phylogenies. Mol Biol Evol 2015; 32:268–274 [View Article] [PubMed]
     [Google Scholar]
  26. Coll F, McNerney R, Preston MD, Guerra-Assunção JA, Warry A et al. Rapid determination of anti-tuberculosis drug resistance from whole-genome sequences. Genome Med 2015; 7:51 [View Article] [PubMed]
     [Google Scholar]
  27. Phelan JE, O’Sullivan DM, Machado D, Ramos J, Oppong YEA et al. Integrating informatics tools and portable sequencing technology for rapid detection of resistance to anti-tuberculous drugs. Genome Med 2019; 11:41 [View Article] [PubMed]
     [Google Scholar]
  28. Letunic I, Bork P. Interactive Tree Of Life (iTOL) v4: recent updates and new developments. Nucleic Acids Res 2019; 47:W256–W259 [View Article] [PubMed]
     [Google Scholar]
  29. Meehan CJ, Moris P, Kohl TA, Pečerska J, Akter S et al. The relationship between transmission time and clustering methods in Mycobacterium tuberculosis epidemiology. EBioMedicine 2018; 37:410–416 [View Article] [PubMed]
     [Google Scholar]
  30. Walker TM, Ip CLC, Harrell RH, Evans JT, Kapatai G et al. Whole-genome sequencing to delineate Mycobacterium tuberculosis outbreaks: a retrospective observational study. Lancet Infect Dis 2013; 13:137–146 [View Article] [PubMed]
     [Google Scholar]
  31. Vaziri F, Kohl TA, Ghajavand H, Kargarpour Kamakoli M, Merker M et al. Genetic diversity of multi- and extensively drug-resistant Mycobacterium tuberculosis isolates in the Capital of Iran, revealed by whole-genome sequencing. J Clin Microbiol 2019; 57:e01477-18 [View Article] [PubMed]
     [Google Scholar]
  32. McBryde ES, Meehan MT, Doan TN, Ragonnet R, Marais BJ et al. The risk of global epidemic replacement with drug-resistant Mycobacterium tuberculosis strains. Int J Infect Dis 2017; 56:14–20 [View Article] [PubMed]
     [Google Scholar]
  33. Casali N, Nikolayevskyy V, Balabanova Y, Harris SR, Ignatyeva O et al. Evolution and transmission of drug-resistant tuberculosis in a Russian population. Nat Genet 2014; 46:279–286 [View Article] [PubMed]
     [Google Scholar]
  34. Naidoo CC, Pillay M. Fitness-compensatory mutations facilitate the spread of drug-resistant F15/LAM4/KZN and F28 Mycobacterium tuberculosis strains in KwaZulu-Natal, South Africa. J Genet 2017; 96:599–612 [View Article] [PubMed]
     [Google Scholar]
  35. Welekidan LN, Skjerve E, Dejene TA, Gebremichael MW, Brynildsrud O et al. Frequency and patterns of first- and second-line drug resistance-conferring mutations in Mycobacterium tuberculosis isolated from pulmonary tuberculosis patients in a cross-sectional study in Tigray Region, Ethiopia. J Glob Antimicrob Resist 2021; 24:6–13 [View Article] [PubMed]
     [Google Scholar]
  36. Fernandes GFDS, Salgado HRN, Santos JLD. Isoniazid: a review of characteristics, properties and analytical methods. Crit Rev Anal Chem 2017; 47:298–308 [View Article] [PubMed]
     [Google Scholar]
  37. World Health Organization Guidelines for the programmatic management of drug-resistant tuberculosis, emergency update 2008; 2008
  38. Stucki D, Brites D, Jeljeli L, Coscolla M, Liu Q et al. Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages. Nat Genet 2016; 48:1535–1543 [View Article] [PubMed]
     [Google Scholar]
  39. Buu TN, van Soolingen D, Huyen MNT, Lan NTN, Quy HT et al. Increased transmission of Mycobacterium tuberculosis Beijing genotype strains associated with resistance to streptomycin: a population-based study. PLoS One 2012; 7:e42323 [View Article] [PubMed]
     [Google Scholar]
  40. Albanna AS, Reed MB, Kotar KV, Fallow A, McIntosh FA et al. Reduced transmissibility of East African Indian strains of Mycobacterium tuberculosis. PLoS One 2011; 6:e25075 [View Article] [PubMed]
     [Google Scholar]
  41. Couvin D, Rastogi NT. Tuberculosis - A global emergency: Tools and methods to monitor, understand, and control the epidemic with specific example of the Beijing lineage. Tuberculosis (Edinb) 2015; 95 Suppl 1:S177–89 [View Article] [PubMed]
     [Google Scholar]
  42. Lasunskaia E, Ribeiro SCM, Manicheva O, Gomes LL, Suffys PN et al. Emerging multidrug resistant Mycobacterium tuberculosis strains of the Beijing genotype circulating in Russia express a pattern of biological properties associated with enhanced virulence. Microbes Infect 2010; 12:467–475 [View Article] [PubMed]
     [Google Scholar]
  43. Marais BJ, Mlambo CK, Rastogi N, Zozio T, Duse AG et al. Epidemic spread of multidrug-resistant tuberculosis in Johannesburg, South Africa. J Clin Microbiol 2013; 51:1818–1825 [View Article] [PubMed]
     [Google Scholar]
  44. Nieto Ramirez LM, Ferro BE, Diaz G, Anthony RM, de Beer J et al. Genetic profiling of Mycobacterium tuberculosis “Modern” Beijing strains from Southwest Colombia. Microbiology 2019 [View Article]
     [Google Scholar]
  45. European Concerted Action on New Generation Genetic Markers and Techniques for the Epidemiology and Control of Tuberculosis Beijing/W genotype Mycobacterium tuberculosis and drug resistance. Emerg Infect Dis 2006; 12:736–743 [View Article] [PubMed]
     [Google Scholar]
  46. van der Spuy GD, Kremer K, Ndabambi SL, Beyers N, Dunbar R et al. Changing Mycobacterium tuberculosis population highlights clade-specific pathogenic characteristics. Tuberculosis (Edinb) 2009; 89:120–125 [View Article] [PubMed]
     [Google Scholar]
  47. Tuite AR, Guthrie JL, Alexander DC, Whelan MS, Lee B et al. Epidemiological evaluation of spatiotemporal and genotypic clustering of Mycobacterium tuberculosis in Ontario, Canada. Int J Tuberc Lung Dis 2013; 17:1322–1327 [View Article] [PubMed]
     [Google Scholar]
  48. Ford CB, Shah RR, Maeda MK, Gagneux S, Murray MB et al. Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis. Nat Genet 2013; 45:784–790 [View Article] [PubMed]
     [Google Scholar]
  49. Zuo TY, Liu QY, Gan MY, Gao Q. Comprehensive identification of compensatory mutations in rifampicin-resistant Mycobacterium tuberculosis strains. Zhonghua Jie He He Hu Xi Za Zhi 2018; 41:207–212 [View Article] [PubMed]
     [Google Scholar]
  50. Blaser N, Zahnd C, Hermans S, Salazar-Vizcaya L, Estill J et al. Tuberculosis in Cape Town: An age-structured transmission model. Epidemics 2016; 14:54–61 [View Article] [PubMed]
     [Google Scholar]
  51. Churchyard G, Kim P, Shah NS, Rustomjee R, Gandhi N et al. What we know about tuberculosis transmission: an overview. J Infect Dis 2017; 216:S629–S635 [View Article] [PubMed]
     [Google Scholar]
  52. Kapwata T, Morris N, Campbell A, Mthiyane T, Mpangase P et al. Spatial distribution of extensively drug-resistant tuberculosis (XDR TB) patients in KwaZulu-Natal, South Africa. PLoS One 2017; 12:e0181797 [View Article] [PubMed]
     [Google Scholar]
  53. Yang X-Y, Li Y-P, Mei Y-W, Yu Y, Xiao J et al. Time and spatial distribution of multidrug-resistant tuberculosis among Chinese people, 1981-2006: a systematic review. Int J Infect Dis 2010; 14:e828–37 [View Article] [PubMed]
     [Google Scholar]
  54. Lalor MK, Casali N, Walker TM, Anderson LF, Davidson JA et al. The use of whole-genome sequencing in cluster investigation of a multidrug-resistant tuberculosis outbreak. Eur Respir J 2018; 51:1702313 [View Article] [PubMed]
     [Google Scholar]
  55. Chirenda J, Gwitira I, Warren RM, Sampson SL, Murwira A et al. Spatial distribution of Mycobacterium Tuberculosis in metropolitan Harare, Zimbabwe. PLoS One 2020; 15:e0231637 [View Article] [PubMed]
     [Google Scholar]
  56. Peterson ML, Gandhi NR, Clennon J, Nelson KN, Morris N et al. Extensively drug-resistant tuberculosis “hotspots” and sociodemographic associations in Durban, South Africa. Int J Tuberc Lung Dis 2019; 23:720–727 [View Article]
     [Google Scholar]
  57. Gallo JF, Pinhata JMW, Simonsen V, Galesi VMN, Ferrazoli L et al. Prevalence, associated factors, outcomes and transmission of extensively drug-resistant tuberculosis among multidrug-resistant tuberculosis patients in São Paulo, Brazil: a cross-sectional study. Clin Microbiol Infect 2018; 24:889–895 [View Article]
     [Google Scholar]
  58. Perdigão J, Gomes P, Miranda A, Maltez F, Machado D et al. Using genomics to understand the origin and dispersion of multidrug and extensively drug resistant tuberculosis in Portugal. Sci Rep 2020; 10:2600 [View Article]
     [Google Scholar]
  59. Roycroft E, O’Toole RF, Fitzgibbon MM, Montgomery L, O’Meara M et al. Molecular epidemiology of multi- and extensively-drug-resistant Mycobacterium tuberculosis in Ireland, 2001-2014. J Infect 2018; 76:55–67 [View Article]
     [Google Scholar]
  60. Bainomugisa A, Lavu E, Hiashiri S, Majumdar S, Honjepari A et al. Multi-clonal evolution of multi-drug-resistant/extensively drug-resistant Mycobacterium tuberculosis in a high-prevalence setting of Papua New Guinea for over three decades. Microb Genom 2018; 4: [View Article]
     [Google Scholar]
  61. Hadifar S, Shamkhali L, Kargarpour Kamakoli M, Mostafaei S, Khanipour S et al. Genetic diversity of Mycobacterium tuberculosis isolates causing pulmonary and extrapulmonary tuberculosis in the capital of Iran. Mol Phylogenet Evol 2019; 132:46–52 [View Article] [PubMed]
     [Google Scholar]
  62. World Health Organization Meeting report of the WHO expoert consultation on the definition of extensively drug-resistant tuberculosis; 2020
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Transmission, distribution and drug resistance-conferring mutations of extensively drug-resistant tuberculosis in the Western Cape Province, South Africa
M Gen 8, 000815 (2022); https://doi.org/10.1099/mgen.0.000815
/content/journal/mgen/10.1099/mgen.0.000815
/content/journal/mgen/10.1099/mgen.0.000815
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