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Volume 7, Issue 11

A species-wide genetic atlas of antimicrobial resistance in Open Access

Abstract

Antimicrobial resistance (AMR) plays an important role in the pathogenesis and spread of infection (CDI), the leading healthcare-related gastrointestinal infection in the world. An association between AMR and CDI outbreaks is well documented, however, data is limited to a few ‘epidemic’ strains in specific geographical regions. Here, through detailed analysis of 10 330 publicly-available genomes from strains isolated worldwide (spanning 270 multilocus sequence types (STs) across all known evolutionary clades), this study provides the first species-wide snapshot of AMR genomic epidemiology in . Of the 10 330 . genomes, 4532 (43.9 %) in 89 STs across clades 1–5 carried at least one genotypic AMR determinant, with 901 genomes (8.7 %) carrying AMR determinants for three or more antimicrobial classes (multidrug-resistant, MDR). No AMR genotype was identified in any strains belonging to the cryptic clades. from Australia/New Zealand had the lowest AMR prevalence compared to strains from Asia, Europe and North America (<0.0001). Based on the phylogenetic clade, AMR prevalence was higher in clades 2 (84.3 %), 4 (81.5 %) and 5 (64.8 %) compared to other clades (collectively 26.9 %) (<0.0001). MDR prevalence was highest in clade 4 (61.6 %) which was over three times higher than in clade 2, the clade with the second-highest MDR prevalence (18.3 %). There was a strong association between specific AMR determinants and three major epidemic STs: ST1 (clade 2) with fluoroquinolone resistance (mainly T82I substitution in GyrA) (<0.0001), ST11 (clade 5) with tetracycline resistance (various -family genes) (<0.0001) and ST37 (clade 4) with macrolide-lincosamide-streptogramin B (MLS) resistance (mainly ) (<0.0001) and MDR (<0.0001). A novel and previously overlooked -positive transposon designated Tn was identified, predominantly among clade 2 strains. This study provides a comprehensive review of AMR in the global population which may aid in the early detection of drug-resistant strains, and prevention of their dissemination worldwide.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): antimicrobial resistance , Clostridioides difficile and genomics
Funding
This study was supported by the:
  • Mahidol University
    • Principle Award Recipient: KorakritImwattana
  • National Health and Medical Research Council (Award APP1138257)
    • Principle Award Recipient: DanielR Knight
  • Raine Medical Research Foundation (Award RPG002-19)
    • Principle Award Recipient: DanielR Knight
© 2021 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution NonCommercial License.
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2021-11-18
2024-05-19
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References

  1. Dadgostar P. Antimicrobial resistance: implications and costs. Infect Drug Resist 2019; 12:3903–3910 [View Article] [PubMed]
     [Google Scholar]
  2. Centers for Disease Control and Prevention (CDC) Antibiotic Resistance Threats in the United States, 2013 Atlanta, GA: US: Department of Health and Human Services, CDC; 2013
     [Google Scholar]
  3. Centers for Disease Control and Prevention (CDC) Antibiotic Resistance Threats in the United States Atlanta, GA: US: Department of Health and Human Services, CDC; 2019
     [Google Scholar]
  4. Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med 2015; 372:1539–1548 [View Article] [PubMed]
     [Google Scholar]
  5. Prestinaci F, Pezzotti P, Pantosti A. Antimicrobial resistance: a global multifaceted phenomenon. Pathog Glob Health 2015; 109:309–318 [View Article] [PubMed]
     [Google Scholar]
  6. van Beurden YH, Nieuwdorp M, van de Berg P, Mulder CJJ, Goorhuis A. Current challenges in the treatment of severe Clostridium difficile infection: early treatment potential of fecal microbiota transplantation. Therap Adv Gastroenterol 2017; 10:373–381 [View Article] [PubMed]
     [Google Scholar]
  7. Banawas SS. Clostridium difficile infections: a global overview of drug sensitivity and resistance mechanisms. Biomed Res Int 2018; 2018:8414257 [View Article] [PubMed]
     [Google Scholar]
  8. Imwattana K, Knight DR, Kullin B, Collins DA, Putsathit P et al. Antimicrobial resistance in Clostridium difficile ribotype 017. Expert Rev Anti Infect Ther 2020; 18:17–25 [View Article] [PubMed]
     [Google Scholar]
  9. Kuijper EJ, de Weerdt J, Kato H, Kato N, van Dam AP et al. Nosocomial outbreak of Clostridium difficile-associated diarrhoea due to a clindamycin-resistant enterotoxin A-negative strain. Eur J Clin Microbiol Infect Dis 2001; 20:528–534 [View Article] [PubMed]
     [Google Scholar]
  10. He M, Miyajima F, Roberts P, Ellison L, Pickard DJ et al. Emergence and global spread of epidemic healthcare-associated Clostridium difficile. Nat Genet 2013; 45:109–113 [View Article] [PubMed]
     [Google Scholar]
  11. Drudy D, Harnedy N, Fanning S, Hannan M, Kyne L. Emergence and control of fluoroquinolone-resistant, toxin A-negative, toxin B-positive Clostridium difficile. Infect Control Hosp Epidemiol 2007; 28:932–940 [View Article] [PubMed]
     [Google Scholar]
  12. Curry SR, Marsh JW, Shutt KA, Muto CA, O’Leary MM et al. High frequency of rifampin resistance identified in an epidemic Clostridium difficile clone from a large teaching hospital. Clin Infect Dis 2009; 48:425–429 [View Article] [PubMed]
     [Google Scholar]
  13. Dingle KE, Didelot X, Quan TP, Eyre DW, Stoesser N et al. A role for tetracycline selection in recent evolution of agriculture-associated Clostridium difficile PCR ribotype 078. MBio 2019; 10:e02790-18 [View Article] [PubMed]
     [Google Scholar]
  14. Knight DR, Imwattana K, Kullin B, Guerrero-Araya E, Paredes-Sabja D et al. Major genetic discontinuity and novel toxigenic species in Clostridioides difficile taxonomy. eLife 2021; 10:e64325 [View Article] [PubMed]
     [Google Scholar]
  15. Imwattana K, Knight DR, Kullin B, Collins DA, Putsathit P et al. Clostridium difficile ribotype 017 - characterization, evolution and epidemiology of the dominant strain in Asia. Emerg Microbes Infect 2019; 8:796–807 [View Article] [PubMed]
     [Google Scholar]
  16. Inouye M, Dashnow H, Raven L-A, Schultz MB, Pope BJ et al. SRST2: Rapid genomic surveillance for public health and hospital microbiology labs. Genome Med 2014; 6:90 [View Article] [PubMed]
     [Google Scholar]
  17. Didelot X, Eyre DW, Cule M, Ip CLC, Ansari MA et al. Microevolutionary analysis of Clostridium difficile genomes to investigate transmission. Genome Biol 2012; 13:R118 [View Article] [PubMed]
     [Google Scholar]
  18. Toth M, Stewart NK, Smith C, Vakulenko SB. Intrinsic class D beta-lactamases of Clostridium difficile. mBio 2018; 9:e01803-18 [View Article] [PubMed]
     [Google Scholar]
  19. Khanafer N, Daneman N, Greene T, Simor A, Vanhems P et al. Susceptibilities of clinical Clostridium difficile isolates to antimicrobials: a systematic review and meta-analysis of studies since 1970. Clin Microbiol Infect 2018; 24:110–117 [View Article] [PubMed]
     [Google Scholar]
  20. Gupta SK, Padmanabhan BR, Diene SM, Lopez-Rojas R, Kempf M et al. ARG-ANNOT, a new bioinformatic tool to discover antibiotic resistance genes in bacterial genomes. Antimicrob Agents Chemother 2014; 58:212–220 [View Article] [PubMed]
     [Google Scholar]
  21. Zankari E, Hasman H, Cosentino S, Vestergaard M, Rasmussen S et al. Identification of acquired antimicrobial resistance genes. J Antimicrob Chemother 2012; 67:2640–2644 [View Article] [PubMed]
     [Google Scholar]
  22. Imwattana K, Putsathit P, Knight DR, Kiratisin P, Riley TV. Molecular characterization of, and antimicrobial resistance in, Clostridioides difficile from Thailand, 2017-2018. [Epub ahead of print]. Microb Drug Resist 2021 [View Article] [PubMed]
     [Google Scholar]
  23. Alcock BP, Raphenya AR, Lau TTY, Tsang KK, Bouchard M et al. CARD 2020: antibiotic resistome surveillance with the comprehensive antibiotic resistance database. Nucleic Acids Res 2020; 48:D25D517
     [Google Scholar]
  24. Spigaglia P. Recent advances in the understanding of antibiotic resistance in Clostridium difficile infection. Ther Adv Infect Dis 2016; 3:23–42 [View Article] [PubMed]
     [Google Scholar]
  25. He M, Sebaihia M, Lawley TD, Stabler RA, Dawson LF et al. Evolutionary dynamics of Clostridium difficile over short and long time scales. Proc Natl Acad Sci U S A 2010; 107:7527–7532 [View Article] [PubMed]
     [Google Scholar]
  26. Boekhoud IM, Hornung BVH, Sevilla E, Harmanus C, Bos-Sanders I et al. Plasmid-mediated metronidazole resistance in Clostridioides difficile. Nat Commun 2020; 11:598 [View Article] [PubMed]
     [Google Scholar]
  27. Isidro J, Santos A, Nunes A, Borges V, Silva C et al. Imipenem resistance in Clostridium difficile ribotype 017, Portugal. Emerg Infect Dis 2018; 24:741–745 [View Article] [PubMed]
     [Google Scholar]
  28. Leeds JA, Sachdeva M, Mullin S, Barnes SW, Ruzin A. In vitro selection, via serial passage, of Clostridium difficile mutants with reduced susceptibility to fidaxomicin or vancomycin. J Antimicrob Chemother 2014; 69:41–44 [View Article] [PubMed]
     [Google Scholar]
  29. Solomon K, Fanning S, McDermott S, Murray S, Scott L et al. PCR ribotype prevalence and molecular basis of macrolide-lincosamide-streptogramin B (MLSB) and fluoroquinolone resistance in Irish clinical Clostridium difficile isolates. J Antimicrob Chemother 2011; 66:1976–1982 [View Article] [PubMed]
     [Google Scholar]
  30. Tansirichaiya S, Rahman MA, Roberts AP. The Transposon Registry. Mobile DNA-UK; 2019; 10
  31. Corver J, Bakker D, Brouwer MSM, Harmanus C, Hensgens MP et al. Analysis of a Clostridium difficile PCR ribotype 078 100 kilobase island reveals the presence of a novel transposon, Tn6164. Bmc Microbiol 2012; 12:130 [View Article] [PubMed]
     [Google Scholar]
  32. Knight DR, Androga GO, Ballard SA, Howden BP, Riley TV. A phenotypically silent vanB2 operon carried on a Tn1549-like element in Clostridium difficile. mSphere 2016; 1:e00177-16 [View Article] [PubMed]
     [Google Scholar]
  33. Courvalin P. Vancomycin resistance in gram-positive cocci. Clin Infect Dis 2006; 42 Suppl 1:34
     [Google Scholar]
  34. Marin M, Martin A, Alcala L, Cercenado E, Iglesias C et al. Clostridium difficile isolates with high linezolid MICs harbor the multiresistance gene cfr. Antimicrob Agents Chemother 2015; 59:586–589 [View Article] [PubMed]
     [Google Scholar]
  35. Knight DR, Kullin B, Androga GO, Barbut F, Eckert C et al. Evolutionary and genomic insights into Clostridioides difficile sequence type 11: a diverse zoonotic and antimicrobial-resistant lineage of global one health importance. mBio 2019; 10:e00446-19 [View Article] [PubMed]
     [Google Scholar]
  36. Dang UT, Zamora I, Hevener KE, Adhikari S, XQ W et al. Rifamycin resistance in Clostridium difficile is generally associated with a low fitness burden. Antimicrob Agents Chemother 2016; 60:5604–5607 [View Article] [PubMed]
     [Google Scholar]
  37. Wasels F, Kuehne SA, Cartman ST, Spigaglia P, Barbanti F et al. Fluoroquinolone resistance does not impose a cost on the fitness of Clostridium difficile in vitro. Antimicrob Agents Chemother 2015; 59:1794–1796 [View Article] [PubMed]
     [Google Scholar]
  38. Wasels F, Spigaglia P, Barbanti F, Mastrantonio P. Clostridium difficile erm(B)-containing elements and the burden on the in vitro fitness. J Med Microbiol 2013; 62:1461–1467 [View Article] [PubMed]
     [Google Scholar]
  39. Collins DA, Putsathit P, Elliott B, Riley TV. Laboratory-based surveillance of Clostridium difficile strains circulating in the Australian healthcare setting in 2012. Pathology 2017; 49:309–313 [View Article] [PubMed]
     [Google Scholar]
  40. Li GH, Hou DJ, Fu GH, Guo JY, Guo XB et al. A review of prophylactic antibiotics use in plastic surgery in China and a systematic review. Int J Surg 2014; 12:1300–1305 [View Article] [PubMed]
     [Google Scholar]
  41. Putsathit P, Hong S, George N, Hemphill C, Huntington PG et al. Antimicrobial resistance surveillance of Clostridioides difficile in Australia, 2015-18. J Antimicrob Chemother 2021; 76:1815–1821 [View Article] [PubMed]
     [Google Scholar]
  42. Tickler IA, Obradovich AE, Goering RV, Fang FC, Tenover FC et al. Changes in molecular epidemiology and antimicrobial resistance profiles of Clostridioides (Clostridium) difficile strains in the United States between 2011 and 2017. Anaerobe 2019; 60:S1075-9964(19)30100-3 [View Article] [PubMed]
     [Google Scholar]
  43. Freeman J, Vernon J, Morris K, Nicholson S, Todhunter S et al. Pan-European longitudinal surveillance of antibiotic resistance among prevalent Clostridium difficile ribotypes. Clin Microbiol Infect 2015; 21:248–e16 [View Article] [PubMed]
     [Google Scholar]
  44. Freeman J, Vernon J, Pilling S, Morris K, Nicholson S et al. The ClosER study: results from a three-year pan-European longitudinal surveillance of antibiotic resistance among prevalent Clostridium difficile ribotypes, 2011-2014. Clin Microbiol Infect 2018; 24:724–731S1198-743X(17)30570-0 [View Article] [PubMed]
     [Google Scholar]
  45. Imwattana K, Knight DR, Riley TV. Can sequencing improve the diagnosis and management of Clostridioides difficile infection. Expert Rev Mol Diagn 2021; 21:429–431 [View Article] [PubMed]
     [Google Scholar]
  46. Foster TJ. Antibiotic resistance in Staphylococcus aureus. Current status and future prospects. Fems Microbiol Rev 2017; 41:430–449 [View Article] [PubMed]
     [Google Scholar]
  47. Wilson H, Torok ME. Extended-spectrum beta-lactamase-producing and carbapenemase-producing Enterobacteriaceae. Microb Genom 2018; 4:000197 [View Article] [PubMed]
     [Google Scholar]
  48. Galia L, Ligozzi M, Bertoncelli A, Mazzariol A. Real-time PCR assay for detection of Staphylococcus aureus, Panton-Valentine leucocidin and methicillin resistance directly from clinical samples. AIMS Microbiol 2019; 5:138–146 [View Article] [PubMed]
     [Google Scholar]
  49. Queenan AM, Bush K. Carbapenemases: The versatile beta-lactamases. Clin Microbiol Rev 2007; 20:440–458 [View Article] [PubMed]
     [Google Scholar]
  50. Carattoli A, Zankari E, Garcia-Fernandez A, Voldby Larsen M, Lund O et al. In silico detection and typing of plasmids using PlasmidFinder and plasmid multilocus sequence typing. Antimicrob Agents Chemother 2014; 58:3895–3903 [View Article] [PubMed]
     [Google Scholar]
  51. Rozwandowicz M, Brouwer MSM, Fischer J, Wagenaar JA, Gonzalez-Zorn B et al. Plasmids carrying antimicrobial resistance genes in Enterobacteriaceae. J Antimicrob Chemother 2018; 73:1121–1137 [View Article] [PubMed]
     [Google Scholar]
  52. Valiente E, Cairns MD, Wren BW. The Clostridium difficile PCR ribotype 027 lineage: a pathogen on the move. Clin Microbiol Infect 2014; 20:396–404 [View Article] [PubMed]
     [Google Scholar]
  53. Kartalidis P, Skoulakis A, Tsilipounidaki K, Florou Z, Petinaki E et al. Clostridioides difficile as a dynamic vehicle for the dissemination of antimicrobial-resistance determinants: review and in silico analysis. Microorganisms 2021; 9:1383 [View Article]
     [Google Scholar]
  54. Daigle DM, Hughes DW, Wright GD. Prodigious substrate specificity of AAC(6’)-APH(2"), an aminoglycoside antibiotic resistance determinant in enterococci and staphylococci. Chem Biol 1999; 6:99–110 [View Article] [PubMed]
     [Google Scholar]
  55. Zhang B, Ku X, Yu X, Sun Q, Wu H et al. Prevalence and antimicrobial susceptibilities of bacterial pathogens in Chinese pig farms from 2013 to 2017. Sci Rep 2019; 9:9908 [View Article] [PubMed]
     [Google Scholar]
  56. Economou V, Gousia P. Agriculture and food animals as a source of antimicrobial-resistant bacteria. Infect Drug Resist 2015; 8:49–61 [View Article] [PubMed]
     [Google Scholar]
  57. Baddour LM, Wilson WR, Bayer AS, Fowler VG, Tleyjeh IM et al. Infective endocarditis in adults: Diagnosis, antimicrobial therapy, and management of complications: A scientific statement for healthcare professionals from the American Heart Association. Circulation 2015; 132:1435–1486 [View Article] [PubMed]
     [Google Scholar]
  58. Imwattana K, Kiratisin P, Riley TV, Knight DR. Genomic basis of antimicrobial resistance in non-toxigenic Clostridium difficile in Southeast Asia. Anaerobe 2020; 66:S1075-9964(20)30146-3 [View Article] [PubMed]
     [Google Scholar]
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A species-wide genetic atlas of antimicrobial resistance in Clostridioides difficile
M Gen 7, 000696 (2021); https://doi.org/10.1099/mgen.0.000696
/content/journal/mgen/10.1099/mgen.0.000696
/content/journal/mgen/10.1099/mgen.0.000696
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