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Volume 9, Issue 7

Genomic epidemiology of human candidaemia isolates in a tertiary hospital Open Access

Abstract

Invasive candida infections are significant infections that may occur in vulnerable patients with high rates of mortality or morbidity. Drug-resistance rates also appear to be on the rise which further complicate treatment options and outcomes. The aims of this study were to describe the prevalence, molecular epidemiology, and genetic features of bloodstream isolates in a hospital setting. The resistance mechanisms towards the two most commonly administered antifungals, fluconazole and anidulafungin, were determined. Blood culture isolates between 1 January 2018 and 30 June 2021 positive for spp. were included. Susceptibility testing was performed using Etest. Whole-genome-sequencing was performed using Illumina NovaSeq with bioinformatics analysis performed. A total of 203 isolates were sequenced: 56 . 53 . , 44 . 36 . complex (consisting of and ), six . five . , and three . . A single cluster of azole-resistant and four clusters of isolates were observed, suggesting possible transmission occurring over several years. We found 11.3%, and 52.7 % of and , respectively, clustered with other isolates, suggesting exogenous sources may play a significant role of transmission, particularly for . The clusters spanned over several years suggesting the possibility of environmental reservoirs contributing to the spread. Limited clonality was seen for . Several sequence types appeared to be dominant for however the SNP differences varied widely, indicating absence of sustained transmission.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): Antifungal resistance , Antimicrobial resistance , Candidaemia , Genomic epidemiology and Whole-genome-sequencing
Funding
This study was supported by the:
  • National Centre of Infectious Diseases, Singapore (Award FY202012CKL)
    • Principle Award Recipient: Lip ChewKa
© 2023 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License.
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2023-07-13
2024-04-29
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References

  1. Reboli AC, Rotstein C, Pappas PG, Chapman SW, Kett DH et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007; 356:2472–2482 [View Article] [PubMed]
     [Google Scholar]
  2. Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA et al. Clinical practice guideline for the management of Candidiasis: 2016 update by the infectious diseases society of America. Clin Infect Dis 2016; 62:e1–e50 [View Article]
     [Google Scholar]
  3. Vazquez J, Reboli AC, Pappas PG, Patterson TF, Reinhardt J et al. Evaluation of an early step-down strategy from intravenous anidulafungin to oral azole therapy for the treatment of candidemia and other forms of invasive candidiasis: results from an open-label trial. BMC Infect Dis 2014; 14:97 [View Article]
     [Google Scholar]
  4. Chew KL, Octavia S, Lin RTP, Yan GZ, Teo JWP. Delay in effective therapy in anidulafungin-resistant Candida tropicalis fungaemia: potential for rapid prediction of antifungal resistance with whole-genome-sequencing. J Glob Antimicrob Resist 2019; 16:105–107 [View Article] [PubMed]
     [Google Scholar]
  5. Chew KL, Cheng JWS, Jureen R, Lin RTP, Teo JWP. ERG11 mutations are associated with high-level azole resistance in clinical Candida tropicalis isolates, a Singapore study. Mycoscience 2017; 58:111–115 [View Article]
     [Google Scholar]
  6. Chowdhary A, Prakash A, Sharma C, Kordalewska M, Kumar A et al. A multicentre study of antifungal susceptibility patterns among 350 Candida auris isolates (2009-17) in India: role of the ERG11 and FKS1 genes in azole and echinocandin resistance. J Antimicrob Chemother 2018; 73:891–899 [View Article] [PubMed]
     [Google Scholar]
  7. Escandón P, Chow NA, Caceres DH, Gade L, Berkow EL et al. Molecular epidemiology of Candida auris in Colombia reveals a highly related, countrywide colonization with regional patterns in amphotericin B resistance. Clin Infect Dis 2019; 68:15–21 [View Article] [PubMed]
     [Google Scholar]
  8. Lockhart SR, Etienne KA, Vallabhaneni S, Farooqi J, Chowdhary A et al. Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses. Clin Infect Dis 2017; 64:134–140 [View Article] [PubMed]
     [Google Scholar]
  9. Scordino F, Giuffrè L, Barberi G, Marino Merlo F, Orlando MG et al. Multilocus sequence typing reveals a new cluster of closely related Candida tropicalis genotypes in Italian patients with neurological disorders. Front Microbiol 2018; 9:679 [View Article] [PubMed]
     [Google Scholar]
  10. Thomaz DY, de Almeida JN Jr, Lima GME, Nunes M de O, Camargo CH et al. An azole-resistant Candida parapsilosis outbreak: clonal persistence in the intensive care unit of a Brazilian teaching hospital. Front Microbiol 2018; 9:2997 [View Article] [PubMed]
     [Google Scholar]
  11. Bankevich A, Nurk S, Antipov D, Gurevich AA, Dvorkin M et al. SPAdes: a new genome assembly algorithm and its applications to single-cell sequencing. J Comput Biol 2012; 19:455–477 [View Article] [PubMed]
     [Google Scholar]
  12. Harris SR. SKA: Split Kmer Analysis toolkit for bacterial genomic epidemiology. Genomics 2018bioRxiv [View Article]
     [Google Scholar]
  13. Price MN, Dehal PS, Arkin AP. FastTree: computing large minimum evolution trees with profiles instead of a distance matrix. Mol Biol Evol 2009; 26:1641–1650 [View Article] [PubMed]
     [Google Scholar]
  14. Letunic I, Bork P. Interactive tree of life (iTOL) v3: an online tool for the display and annotation of phylogenetic and other trees. Nucleic Acids Res 2016; 44:W242–W245 [View Article]
     [Google Scholar]
  15. Li H, Durbin R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 2009; 25:1754–1760 [View Article]
     [Google Scholar]
  16. Garrison E, Marth G. Haplotype-based variant detection from short-read sequencing. arXiv preprint arXiv, 1207.3907 2012
     [Google Scholar]
  17. Odds FC, Jacobsen MD. Multilocus sequence typing of pathogenic Candida species. Eukaryot Cell 2008; 7:1075–1084 [View Article]
     [Google Scholar]
  18. Odds FC, Bougnoux M-E, Shaw DJ, Bain JM, Davidson AD et al. Molecular phylogenetics of Candida albicans. Eukaryot Cell 2007; 6:1041–1052 [View Article] [PubMed]
     [Google Scholar]
  19. Borman AM, Johnson EM, Kraft CS. Name changes for fungi of medical importance, 2018 to 2019. J Clin Microbiol 2021; 59: [View Article]
     [Google Scholar]
  20. Chen YC, Lin YH, Chen KW, Lii J, Teng HJ et al. Molecular epidemiology and antifungal susceptibility of Candida parapsilosis sensu stricto, Candida orthopsilosis, and Candida metapsilosis in Taiwan. Diagn Microbiol Infect Dis 2010; 68:284–292 [View Article] [PubMed]
     [Google Scholar]
  21. Miranda-Zapico I, Eraso E, Hernández-Almaraz JL, López-Soria LM, Carrillo-Muñoz AJ et al. Prevalence and antifungal susceptibility patterns of new cryptic species inside the species complexes Candida parapsilosis and Candida glabrata among blood isolates from a Spanish tertiary hospital. J Antimicrob Chemother 2011; 66:2315–2322 [View Article] [PubMed]
     [Google Scholar]
  22. Lockhart SR, Messer SA, Gherna M, Bishop JA, Merz WG et al. Identification of Candida nivariensis and Candida bracarensis in a large global collection of Candida glabrata isolates: comparison to the literature. J Clin Microbiol 2009; 47:1216–1217 [View Article] [PubMed]
     [Google Scholar]
  23. Tan TY, Hsu LY, Alejandria MM, Chaiwarith R, Chinniah T et al. Antifungal susceptibility of invasive Candida bloodstream isolates from the Asia-Pacific region. Med Mycol 2016; 54:471–477 [View Article] [PubMed]
     [Google Scholar]
  24. Jiang C, Dong D, Yu B, Cai G, Wang X et al. Mechanisms of azole resistance in 52 clinical isolates of Candida tropicalis in China. J Antimicrob Chemother 2013; 68:778–785 [View Article] [PubMed]
     [Google Scholar]
  25. Zuza-Alves DL, Silva-Rocha WP, Chaves GM. An update on Candida tropicalis based on basic and clinical approaches. Front Microbiol 2017; 8:1927 [View Article] [PubMed]
     [Google Scholar]
  26. Tóth R, Nosek J, Mora-Montes HM, Gabaldon T, Bliss JM et al. Candida parapsilosis: from genes to the bedside. Clin Microbiol Rev 2019; 32:e00111-18 [View Article] [PubMed]
     [Google Scholar]
  27. Whaley SG, Tsao S, Weber S, Zhang Q, Barker KS et al. The RTA3 gene, encoding a putative lipid translocase, influences the susceptibility of Candida albicans to fluconazole. Antimicrob Agents Chemother 2016; 60:6060–6066 [View Article] [PubMed]
     [Google Scholar]
  28. Hassan Y, Chew SY, Than LTL. Candida glabrata: pathogenicity and resistance mechanisms for adaptation and survival. JoF 2021; 7:667 [View Article]
     [Google Scholar]
  29. Ferrari S, Ischer F, Calabrese D, Posteraro B, Sanguinetti M et al. Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence. PLoS Pathog 2009; 5:e1000268 [View Article] [PubMed]
     [Google Scholar]
  30. Simonicova L, Moye-Rowley WS. Functional information from clinically-derived drug resistant forms of the Candida glabrata Pdr1 transcription factor. PLOS Genet 2020; 16:e1009005 [View Article] [PubMed]
     [Google Scholar]
  31. Chaabane F, Graf A, Jequier L, Coste AT. Review on antifungal resistance mechanisms in the emerging pathogen Candida auris. Front Microbiol 2019; 10:2788 [View Article] [PubMed]
     [Google Scholar]
  32. Guinea J, Sánchez-Somolinos M, Cuevas O, Peláez T, Bouza E. Fluconazole resistance mechanisms in Candida krusei: the contribution of efflux-pumps. Med Mycol 2006; 44:575–578 [View Article] [PubMed]
     [Google Scholar]
  33. Pfaller MA. Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am J Med 2012; 125:S3–13 [View Article] [PubMed]
     [Google Scholar]
  34. Costa-de-Oliveira S, Marcos Miranda I, Silva RM, Pinto E Silva A, Rocha R et al. FKS2 mutations associated with decreased echinocandin susceptibility of Candida glabrata following anidulafungin therapy. Antimicrob Agents Chemother 2011; 55:1312–1314 [View Article] [PubMed]
     [Google Scholar]
  35. Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS. A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility. Antimicrob Agents Chemother 2008; 52:2305–2312 [View Article] [PubMed]
     [Google Scholar]
  36. Martí-Carrizosa M, Sánchez-Reus F, March F, Cantón E, Coll P. Implication of Candida parapsilosis FKS1 and FKS2 mutations in reduced echinocandin susceptibility. Antimicrob Agents Chemother 2015; 59:3570–3573 [View Article] [PubMed]
     [Google Scholar]
  37. Ford CB, Funt JM, Abbey D, Issi L, Guiducci C et al. The evolution of drug resistance in clinical isolates of Candida albicans. Elife 2015; 4:e00662 [View Article] [PubMed]
     [Google Scholar]
  38. Boonsilp S, Homkaew A, Phumisantiphong U, Nutalai D, Wongsuk T. Species distribution, antifungal susceptibility, and molecular epidemiology of Candida species causing candidemia in a tertiary care hospital in Bangkok, Thailand. J Fungi 2021; 7:577 [View Article] [PubMed]
     [Google Scholar]
  39. Byun SA, Won EJ, Kim MN, Lee WG, Lee K et al. Multilocus Sequence Typing (MLST) genotypes of Candida glabrata bloodstream isolates in Korea: association with antifungal resistance, mutations in mismatch repair gene (Msh2), and clinical outcomes. Front Microbiol 2018; 9:1523 [View Article] [PubMed]
     [Google Scholar]
  40. Xiao M, Fan X, Hou X, Chen SC, Wang H et al. Candida tropicalis and Candida glabrata isolates with delineation of their resistance mechanisms]]>. IDR 2018; Volume 11:155–161 [View Article]
     [Google Scholar]
  41. Biswas C, Marcelino VR, Van Hal S, Halliday C, Martinez E et al. Whole genome sequencing of Australian Candida glabrata isolates reveals genetic diversity and novel sequence types. Front Microbiol 2018; 9:2946 [View Article] [PubMed]
     [Google Scholar]
  42. O’Brien CE, Oliveira-Pacheco J, Ó Cinnéide E, Haase MAB, Hittinger CT et al. Population genomics of the pathogenic yeast Candida tropicalis identifies hybrid isolates in environmental samples. PLoS Pathog 2021; 17:e1009138 [View Article] [PubMed]
     [Google Scholar]
  43. Muñoz M, Wintaco LM, Muñoz SA, Ramírez JD. Dissecting the heterogeneous population genetic structure of Candida albicans: limitations and constraints of the multilocus sequence typing scheme. Front Microbiol 2019; 10:1052 [View Article] [PubMed]
     [Google Scholar]
  44. Zhu Y, Fang C, Shi Y, Shan Y, Liu X et al. Candida albicans multilocus sequence typing clade I contributes to the clinical phenotype of vulvovaginal candidiasis patients. Front Med 2022; 9:837536 [View Article] [PubMed]
     [Google Scholar]
  45. Pham LTT, Pharkjaksu S, Chongtrakool P, Suwannakarn K, Ngamskulrungroj P. A predominance of clade 17 Candida albicans isolated from hemocultures in a tertiary care Hospital in Thailand. Front Microbiol 2019; 10:1194 [View Article] [PubMed]
     [Google Scholar]
  46. Wang SH, Shen M, Lin HC, Sun PL, Lo HJ et al. Molecular epidemiology of invasive Candida albicans at a tertiary hospital in northern Taiwan from 2003 to 2011. Med Mycol 2015; 53:828–836 [View Article] [PubMed]
     [Google Scholar]
  47. Al-Obaid K, Asadzadeh M, Ahmad S, Khan Z. Population structure and molecular genetic characterization of clinical Candida tropicalis isolates from a tertiary-care hospital in Kuwait reveal infections with unique strains. PLoS One 2017; 12:e0182292 [View Article] [PubMed]
     [Google Scholar]
  48. Huyke J, Martin R, Walther G, Weber M, Kaerger K et al. Candida albicans bloodstream isolates in a German university hospital are genetically heterogenous and susceptible to commonly used antifungals. Int J Med Microbiol 2015; 305:742–747 [View Article] [PubMed]
     [Google Scholar]
  49. Guinea J, Mezquita S, Gómez A, Padilla B, Zamora E et al. Whole genome sequencing confirms Candida albicans and Candida parapsilosis microsatellite sporadic and persistent clones causing outbreaks of candidemia in neonates. Med Mycol 2021; 60:myab068 [View Article] [PubMed]
     [Google Scholar]
  50. Fekkar A, Blaize M, Bouglé A, Normand AC, Raoelina A et al. Hospital outbreak of fluconazole-resistant Candida parapsilosis: arguments for clonal transmission and long-term persistence. Antimicrob Agents Chemother 2021; 65: [View Article]
     [Google Scholar]
  51. Cuomo CA, Shea T, Yang B, Rao R, Forche A. Whole genome sequence of the heterozygous clinical isolate Candida krusei 81-B-5. G3 2017; 7:2883–2889 [View Article] [PubMed]
     [Google Scholar]
  52. Tan YE, Teo JQ-M, Rahman NBA, Ng OT, Kalisvar M et al. Candida auris in Singapore: genomic epidemiology, antifungal drug resistance, and identification using the updated 8.01 VITEK2 system. Int J Antimicrob Agents 2019; 54:709–715 [View Article] [PubMed]
     [Google Scholar]
  53. Chow NA, de Groot T, Badali H, Abastabar M, Chiller TM et al. Potential fifth clade of Candida auris, Iran, 2018. Emerg Infect Dis 2019; 25:1780–1781 [View Article] [PubMed]
     [Google Scholar]
  54. Forsberg K, Woodworth K, Walters M, Berkow EL, Jackson B et al. Candida auris: the recent emergence of a multidrug-resistant fungal pathogen. Med Mycol 2019; 57:e7 [View Article] [PubMed]
     [Google Scholar]
  55. Piedrahita CT, Cadnum JL, Jencson AL, Shaikh AA, Ghannoum MA et al. Environmental surfaces in healthcare facilities are a potential source for transmission of Candida auris and other Candida species. Infect Control Hosp Epidemiol 2017; 38:1107–1109 [View Article] [PubMed]
     [Google Scholar]
  56. Welsh RM, Bentz ML, Shams A, Houston H, Lyons A et al. Survival, persistence, and isolation of the emerging multidrug-resistant pathogenic yeast Candida auris on a plastic health care surface. J Clin Microbiol 2017; 55:2996–3005 [View Article] [PubMed]
     [Google Scholar]
  57. Bergin SA, Zhao F, Ryan AP, Müller CA, Nieduszynski CA et al. Systematic analysis of copy number variations in the pathogenic yeast Candida parapsilosis identifies a gene amplification in RTA3 that is associated with drug resistance. mBio 2022; 13:e0177722 [View Article] [PubMed]
     [Google Scholar]
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Genomic epidemiology of human candidaemia isolates in a tertiary hospital
M Gen 9, 001047 (2023); https://doi.org/10.1099/mgen.0.001047
/content/journal/mgen/10.1099/mgen.0.001047
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