Epidemiological aspects of healthcare-associated infections and microbial genomics

  • C. MirandeEmail author
  • I. Bizine
  • A. Giannetti
  • N. Picot
  • A. van Belkum


Hospital-acquired infections (HAIs) are a cause of continuously increasing morbidity and mortality. Most of these infections are caused by a limited set of bacterial species, which share the capability to efficiently spread from patient to patient and to easily acquire antibiotic resistance determinants. This renders correct and rapid species identification and antibiotic susceptibility testing (AST) important and underscores the relevance of bacterial epidemiological typing. The latter is needed for the sensitive detection and exact tracing of nosocomial spread of these potentially multidrug-resistant microorganisms (MDRO). Many microbial typing technologies have been developed and put to some level of executive practice, but it seems that the continued evolution in methodology has currently reached an apex: there is likely to be scientific and practical consensus on the ultimate typing potential of bacterial whole-genome sequencing (WGS). The possibility to perform pan-genomic nucleotide-to-nucleotide comparisons between strains belonging to a single species and to detect even minute changes in nucleotide order will identify closely related organisms, while upon accumulation of such mutations, independent descend can be assumed. Calibration of difference levels [i.e. number of single nucleotide polymorphisms (SNPs)] into categories of inter-strain relatedness needs to be performed in order to generate robust, portable typing schemes. Here, we will briefly discuss the state of affairs regarding bacterial epidemiology based upon WGS, its relatedness with the nomenclature of former typing approaches and the continuing need for a global typing language.



We would like to acknowledge the much appreciated help of many of our colleagues from bioMérieux Microbiology Research and Development and the bioMérieux Data Analytics Unit.


No external funding was acquired in the context of the work described in the present publication.

Compliance with ethical standards

Conflict of interest

All authors were or still are employees of bioMérieux, a company developing and selling infectious disease diagnostics.

Ethics approval and informed consent

Not applicable.


  1. 1.
    Tabatabaei SM, Pour FB, Osmani S (2015) Epidemiology of hospital-acquired infections and related anti-microbial resistance patterns in a tertiary-care teaching hospital in Zahedan, Southeast Iran. Int J Infect 2:e29079Google Scholar
  2. 2.
    Dasgupta S, Das S, Chawan NS, Hazra A (2015) Nosocomial infections in the intensive care unit: incidence, risk factors, outcome and associated pathogens in a public tertiary teaching hospital of eastern India. Indian J Crit Care Med 19(1):14–20CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Quainoo S, Coolen JPM, van Hijum SAFT, Huynen MA, Melchers WJG, van Schaik W, Wertheim HFL (2017) Whole-genome sequencing of bacterial pathogens: the future of nosocomial outbreak analysis. Clin Microbiol Rev 30(4):1015–1063CrossRefPubMedGoogle Scholar
  4. 4.
    Le VTM, Diep BA (2013) Selected insights from application of whole genome sequencing for outbreak investigations. Curr Opin Crit Care 19(5):432–439CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Dheda K, Gumbo T, Maartens G, Dooley KE, McNerney R, Murray M, Furin J, Nardell EA, London L, Lessem E, Theron G, van Helden P, Niemann S, Merker M, Dowdy D, Van Rie A, Siu GKH, Pasipanodya JG, Rodrigues C, Clark TG, Sirgel FA, Esmail A, Lin H-H, Atre SR, Schaaf HS, Chang KC, Lange C, Nahid P, Udwadia ZF, Horsburgh CR Jr, Churchyard GJ, Menzies D, Hesseling AC, Nuermberger E, McIlleron H, Fennelly KP, Goemaere E, Jaramillo E, Low M, Jara CM, Padayatchi N, Warren RM (2017) The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir Med 5(4):291–360CrossRefGoogle Scholar
  6. 6.
    Chalker VJ, Smith A, Al-Shahib A, Botchway S, Macdonald E, Daniel R, Phillips S, Platt S, Doumith M, Tewolde R, Coelho J, Jolley KA, Underwood A, McCarthy ND (2016) Integration of genomic and other epidemiologic data to investigate and control a cross-institutional outbreak of Streptococcus pyogenes. Emerg Infect Dis 22(6):973–980CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Dabar G, Harmouche C, Salameh P, Jaber BL, Jamaleddine G, Waked M, Yazbeck P (2015) Community- and healthcare-associated infections in critically ill patients: a multicenter cohort study. Int J Infect Dis 37:80–85CrossRefPubMedGoogle Scholar
  8. 8.
    Magill SS, Edwards JR, Bamberg W, Beldavs ZG, Dumyati G, Kainer MA, Lynfield R, Maloney M, McAllister-Hollod L, Nadle J, Ray SM, Thompson DL, Wilson LE, Fridkin SK (2014) Multistate point-prevalence survey of health care-associated infections. N Engl J Med 370(13):1198–1208CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Zimlichman E, Henderson D, Tamir O, Franz C, Song P, Yamin CK, Keohane C, Denham CR, Bates DW (2013) Health care-associated infections: a meta-analysis of costs and financial impact on the US health care system. JAMA Intern Med 173(22):2039–2046CrossRefPubMedGoogle Scholar
  10. 10.
    Dunne MW Jr, Pouseele H, Monecke S, Ehricht R, van Belkum A (2017) Epidemiology of transmissible diseases: array hybridization and next generation sequencing as universal nucleic acid-mediated typing tools. Infect Genet Evol (in press). pii: S1567-1348(17)30324-6Google Scholar
  11. 11.
    Goering RV (2010) Pulsed field gel electrophoresis: a review of application and interpretation in the molecular epidemiology of infectious disease. Infect Genet Evol 10(7):866–875CrossRefPubMedGoogle Scholar
  12. 12.
    Singh A, Goering RV, Simjee S, Foley SL, Zervos MJ (2006) Application of molecular techniques to the study of hospital infection. Clin Microbiol Rev 19(3):512–530CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Gürtler V, Grando D (2013) New opportunities for improved ribotyping of C. difficile clinical isolates by exploring their genomes. J Microbiol Methods 93(3):257–272CrossRefPubMedGoogle Scholar
  14. 14.
    Zhu S, Zhang L, Zhang C, Chen X, Chen Q, Li Z (2014) Comparison of polymerase chain reaction ribotyping, toxinotyping and nutritional aspects of toxin production of Clostridium difficile strains. Biomed Rep 2(4):477–480CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Fawley WN, Knetsch CW, MacCannell DR, Harmanus C, Du T, Mulvey MR, Paulick A, Anderson L, Kuijper EJ, Wilcox MH (2015) Development and validation of an internationally-standardized, high-resolution capillary gel-based electrophoresis PCR-ribotyping protocol for Clostridium difficile. PLoS One 10(2):e0118150CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Wardal E, Markowska K, Żabicka D, Wróblewska M, Giemza M, Mik E, Połowniak-Pracka H, Woźniak A, Hryniewicz W, Sadowy E (2014) Molecular analysis of vanA outbreak of Enterococcus faecium in two Warsaw hospitals: the importance of mobile genetic elements. Biomed Res Int 2014:575367CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gerner-Smidt P, Scheutz F (2006) Standardized pulsed-field gel electrophoresis of Shiga toxin-producing Escherichia coli: the PulseNet Europe feasibility study. Foodborne Pathog Dis 3(1):74–80CrossRefPubMedGoogle Scholar
  18. 18.
    Maiden MC, Bygraves JA, Feil E, Morelli G, Russell JE, Urwin R, Zhang Q, Zhou J, Zurth K, Caugant DA, Feavers IM, Achtman M, Spratt BG (1998) Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms. Proc Natl Acad Sci U S A 95(6):3140–3145CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Jolley KA, Maiden MC (2010) BIGSdb: scalable analysis of bacterial genome variation at the population level. BMC Bioinf 11:595CrossRefGoogle Scholar
  20. 20.
    Bartual SG, Seifert H, Hippler C, Luzon MA, Wisplinghoff H, Rodríguez-Valera F (2005) Development of a multilocus sequence typing scheme for characterization of clinical isolates of Acinetobacter baumannii. J Clin Microbiol 43(9):4382–4390CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Da Silva GJ, Mendonça N, Batista G, Duarte A (2010) Sequence types of Portuguese carbapenem-resistant Acinetobacter baumannii isolates collected over 10 years. J Antimicrob Chemother 65(10):2254–2256CrossRefPubMedGoogle Scholar
  22. 22.
    Tomaschek F, Higgins PG, Stefanik D, Wisplinghoff H, Seifert H (2016) Head-to-head comparison of two multi-locus sequence typing (MLST) schemes for characterization of Acinetobacter baumannii outbreak and sporadic isolates. PLoS One 11(4):e0153014CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Karah N, Haldorsen B, Hermansen NO, Tveten Y, Ragnhildstveit E, Skutlaberg DH, Tofteland S, Sundsfjord A, Samuelsen Ø (2011) Emergence of OXA-carbapenemase- and 16S rRNA methylase-producing international clones of Acinetobacter baumannii in Norway. J Med Microbiol 60(4):515–521CrossRefPubMedGoogle Scholar
  24. 24.
    Grosso F, Quinteira S, Peixe L (2011) Understanding the dynamics of imipenem-resistant Acinetobacter baumannii lineages within Portugal. Clin Microbiol Infect 17(8):1275–1279CrossRefPubMedGoogle Scholar
  25. 25.
    Jaureguy F, Landraud L, Passet V, Diancourt L, Frapy E, Guigon G, Carbonnelle E, Lortholary O, Clermont O, Denamur E, Picard B, Nassif X, Brisse S (2008) Phylogenetic and genomic diversity of human bacteremic Escherichia coli strains. BMC Genomics 9:560CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Wirth T, Falush D, Lan R, Colles F, Mensa P, Wieler LH, Karch H, Reeves PR, Maiden MC, Ochman H, Achtman M (2006) Sex and virulence in Escherichia coli: an evolutionary perspective. Mol Microbiol 60(5):1136–1151CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lacher DW, Steinsland H, Blank TE, Donnenberg MS, Whittam TS (2007) Molecular evolution of typical enteropathogenic Escherichia coli: clonal analysis by multilocus sequence typing and virulence gene allelic profiling. J Bacteriol 189(2):342–350CrossRefPubMedGoogle Scholar
  28. 28.
    Lara FB, Nery DR, de Oliveira PM, Araujo ML, Carvalho FR, Messias-Silva LC, Ferreira LB, Faria-Junior C, Pereira AL (2017) Virulence markers and phylogenetic analysis of Escherichia coli strains with hybrid eaec/upec genotypes recovered from sporadic cases of extraintestinal infections. Front Microbiol 8:146CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Clermont O, Gordon D, Denamur E (2015) Guide to the various phylogenetic classification schemes for Escherichia coli and the correspondence among schemes. Microbiology 161(5):980–988CrossRefPubMedGoogle Scholar
  30. 30.
    Bae IK, Kim J, Sun JY, Jeong SH, Kim YR, Wang KK, Lee K (2014) Comparison of pulsed-field gel electrophoresis & repetitive sequence-based PCR methods for molecular epidemiological studies of Escherichia coli clinical isolates. Indian J Med Res 140(5):679–685PubMedPubMedCentralGoogle Scholar
  31. 31.
    Griffiths D, Fawley W, Kachrimanidou M, Bowden R, Crook DW, Fung R, Golubchik T, Harding RM, Jeffery KJ, Jolley KA, Kirton R, Peto TE, Rees G, Stoesser N, Vaughan A, Walker AS, Young BC, Wilcox M, Dingle KE (2010) Multilocus sequence typing of Clostridium difficile. J Clin Microbiol 48(3):770–778CrossRefPubMedGoogle Scholar
  32. 32.
    Lemee L, Dhalluin A, Pestel-Caron M, Lemeland JF, Pons JL (2004) Multilocus sequence typing analysis of human and animal Clostridium difficile isolates of various toxigenic types. J Clin Microbiol 42(6):2609–2617CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Dingle KE, Griffiths D, Didelot X, Evans J, Vaughan A, Kachrimanidou M, Stoesser N, Jolley KA, Golubchik T, Harding RM, Peto TE, Fawley W, Walker AS, Wilcox M, Crook DW (2011) Clinical Clostridium difficile: clonality and pathogenicity locus diversity. PLoS One 6(5):e19993CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Adams-Haduch JM, Onuoha EO, Bogdanovich T, Tian GB, Marschall J, Urban CM, Spellberg BJ, Rhee D, Halstead DC, Pasculle AW, Doi Y (2011) Molecular epidemiology of carbapenem-nonsusceptible Acinetobacter baumannii in the United States. J Clin Microbiol 49(11):3849–3854CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Salipante SJ, SenGupta DJ, Cummings LA, Land TA, Hoogestraat DR, Cookson BT (2015) Application of whole-genome sequencing for bacterial strain typing in molecular epidemiology. J Clin Microbiol 53(4):1072–1079CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Eyre DW, Fawley WN, Best EL, Griffiths D, Stoesser NE, Crook DW, Peto TE, Walker AS, Wilcox MH (2013a) Comparison of multilocus variable-number tandem-repeat analysis and whole-genome sequencing for investigation of Clostridium difficile transmission. J Clin Microbiol 51(12):4141–4149CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Eyre DW, Cule ML, Griffiths D, Crook DW, Peto TE, Walker AS, Wilson DJ (2013b) Detection of mixed infection from bacterial whole genome sequence data allows assessment of its role in Clostridium difficile transmission. PLoS Comput Biol 9(5):e1003059CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Eyre DW, Cule ML, Wilson DJ, Griffiths D, Vaughan A, O’Connor L, Ip CLC, Golubchik T, Batty EM, Finney JM, Wyllie DH, Didelot X, Piazza P, Bowden R, Dingle KE, Harding RM, Crook DW, Wilcox MH, Peto TEA, Walker AS (2013c) Diverse sources of C. difficile infection identified on whole-genome sequencing. N Engl J Med 369(13):1195–1205CrossRefPubMedGoogle Scholar
  39. 39.
    Janezic S, Rupnik M (2015) Genomic diversity of Clostridium difficile strains. Res Microbiol 166(4):353–360CrossRefPubMedGoogle Scholar
  40. 40.
    Zhou Y, Burnham CA, Hink T, Chen L, Shaikh N, Wollam A, Sodergren E, Weinstock GM, Tarr PI, Dubberke ER (2014) Phenotypic and genotypic analysis of Clostridium difficile isolates: a single-center study. J Clin Microbiol 52(12):4260–4266CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Knight DR, Elliott B, Chang BJ, Perkins TT, Riley TV (2015) Diversity and evolution in the genome of Clostridium difficile. Clin Microbiol Rev 28(3):721–741CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Mac Aogáin M, Moloney G, Kilkenny S, Kelleher M, Kelleghan M, Boyle B, Rogers TR (2015) Whole-genome sequencing improves discrimination of relapse from reinfection and identifies transmission events among patients with recurrent Clostridium difficile infections. J Hosp Infect 90(2):108–116CrossRefPubMedGoogle Scholar
  43. 43.
    Cairns MD, Preston MD, Lawley TD, Clark TG, Stabler RA, Wren BW (2015) Genomic epidemiology of a protracted hospital outbreak caused by a toxin A-negative Clostridium difficile sublineage PCR ribotype 017 strain in London, England. J Clin Microbiol 53(10):3141–3147CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Kumar N, Miyajima F, He M, Roberts P, Swale A, Ellison L, Pickard D, Smith G, Molyneux R, Dougan G, Parkhill J, Wren BW, Parry CM, Pirmohamed M, Lawley TD (2016) Genome-based infection tracking reveals dynamics of Clostridium difficile transmission and disease recurrence. Clin Infect Dis 62(6):746–752CrossRefPubMedGoogle Scholar
  45. 45.
    Mawer DPC, Eyre DW, Griffiths D, Fawley WN, Martin JSH, Quan TP, Peto TEA, Crook DW, Walker AS, Wilcox MH (2017) Contribution to Clostridium difficile transmission of symptomatic patients with toxigenic strains who are fecal toxin negative. Clin Infect Dis 64(9):1163–1170CrossRefPubMedGoogle Scholar
  46. 46.
    Eyre DW, Fawley WN, Rajgopal A, Settle C, Mortimer K, Goldenberg SD, Dawson S, Crook DW, Peto TEA, Walker AS, Wilcox MH (2017) Comparison of control of Clostridium difficile infection in six English hospitals using whole-genome sequencing. Clin Infect Dis 65(3):433–441CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Qin J, Dai Y, Ma X, Wang Y, Gao Q, Lu H, Li T, Meng H, Liu Q, Li M (2017) Nosocomial transmission of Clostridium difficile genotype ST81 in a general teaching hospital in China traced by whole genome sequencing. Sci Rep 7(1):9627CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Stoesser N, Eyre DW, Quan TP, Godwin H, Pill G, Mbuvi E, Vaughan A, Griffiths D, Martin J, Fawley W, Dingle KE, Oakley S, Wanelik K, Finney JM, Kachrimanidou M, Moore CE, Gorbach S, Riley TV, Crook DW, Peto TEA, Wilcox MH, Walker AS; Modernising Medical Microbiology Informatics Group (MMMIG) (2017) Epidemiology of Clostridium difficile in infants in Oxfordshire, UK: risk factors for colonization and carriage, and genetic overlap with regional C. difficile infection strains. PLoS One 12(8):e0182307CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Lewis BB, Carter RA, Ling L, Leiner I, Taur Y, Kamboj M, Dubberke ER, Xavier J, Pamer EG (2017) Pathogenicity locus, core genome, and accessory gene contributions to Clostridium difficile virulence. MBio 8(4). pii: e00885-17Google Scholar
  50. 50.
    Quesada-Gómez C, López-Ureña D, Acuña-Amador L, Villalobos-Zúñiga M, Du T, Freire R, Guzmán-Verri C, del Mar Gamboa-Coronado M, Lawley TD, Moreno E, Mulvey MR, de Castro Brito GA, Rodríguez-Cavallini E, Rodríguez C, Chaves-Olarte E (2015) Emergence of an outbreak-associated Clostridium difficile variant with increased virulence. J Clin Microbiol 53(4):1216–1226CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Dingle KE, Didelot X, Quan TP, Eyre DW, Stoesser N, Golubchik T, Harding RM, Wilson DJ, Griffiths D, Vaughan A, Finney JM, Wyllie DH, Oakley SJ, Fawley WN, Freeman J, Morris K, Martin J, Howard P, Gorbach S, Goldstein EJC, Citron DM, Hopkins S, Hope R, Johnson AP, Wilcox MH, Peto TEA, Walker AS, Crook DW; Modernising Medical Microbiology Informatics Group (2017) Effects of control interventions on Clostridium difficile infection in England: an observational study. Lancet Infect Dis 17(4):411–421CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Caspers P, Locher HH, Pfaff P, Diggelmann S, Rueedi G, Bur D, Ritz D (2017) Different resistance mechanisms for cadazolid and linezolid in C. difficile found by whole genome sequencing analysis. Antimicrob Agents Chemother 61(8). pii: e00384-17Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • C. Mirande
    • 1
    Email author
  • I. Bizine
    • 1
  • A. Giannetti
    • 1
  • N. Picot
    • 2
  • A. van Belkum
    • 3
  1. 1.Research and Development MicrobiologybioMérieuxLa Balme Les GrottesFrance
  2. 2.IP and Scientific Watch DepartmentbioMérieuxMarcy l’EtoileFrance
  3. 3.Data Analytics UnitbioMérieuxLa Balme Les GrottesFrance

Personalised recommendations