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Interplay of Virulence, Antibiotic Resistance and Epidemiology in Escherichia Coli Clinical Isolates

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Interplay of Virulence, Antibiotic Resistance and Epidemiology in Escherichia Coli Clinical Isolates Interplay of virulence, antibiotic resistance and epidemiology in Escherichia coli clinical isolates Elisabet Guiral Vilalta Aquesta tesi doctoral està subjecta a la llicència Reconeixement- NoComercial – SenseObraDerivada 4.0. Espanya de Creative Commons. Esta tesis doctoral está sujeta a la licencia Reconocimiento - NoComercial – SinObraDerivada 4.0. España de Creative Commons. This doctoral thesis is licensed under the Creative Commons Attribution-NonCommercial- NoDerivs 4.0. Spain License. Facultat de Medicina Departament de Fonaments Clínics Programa de Doctorat de Medicina i Recerca Translacional “Interplay of virulence, antibiotic resistance and epidemiology in Escherichia coli clinical isolates” Doctoranda: Elisabet Guiral Vilalta Departament de Fonaments Clínics Institut de Salut Global de Barcelona‐ Universitat de Barcelona‐ Hospital Clínic de Barcelona Directors de tesi: Dr. Jordi Vila Estapé i Dra. Sara M. Soto González Departament de Fonaments Clínics Institut de Salut Global de Barcelona‐ Universitat de Barcelona‐ Hospital Clínic de Barcelona Barcelona, Setembre 2018 El Dr. JORDI VILA ESTAPÉ, Catedràtic del Departament de Fonaments Clínics de la Facultat de Medicina de la Universitat de Barcelona, Cap del Servei de Microbiologia de l’Hospital Clínic de Barcelona i Research Professor i Director de la Iniciativa de Resistències Antimicrobianes de l’Institut de Salut Global de Barcelona (ISGlobal) i la Dra. SARA M. SOTO GONZÁLEZ, Professora Associada del Departament de Fonaments Clínics de la Universitat de Barcelona i Associate Research Professor d’ ISGlobal, CERTIFIQUEN: Que el treball de recerca titulat “Interplay of virulence, antibiotic resistance and epidemiology in Escherichia coli clinical isolates”, presentat per ELISABET GUIRAL VILALTA, ha estat realitzat al Laboratori de Microbiologia de l’ISGlobal, dins les dependències de l’Hospital Clínic de Barcelona, sota la seva direcció i compleix tots els requisits necessaris per la seva tramitació i posterior defensa davant del Tribunal corresponent. Barcelona, Setembre 2018, Dr. Jordi Vila Estapé Dra. Sara M. Soto González Codirector de la tesi doctoral Codirectora de la tesi doctoral TABLE OF CONTENTS Table of contents TABLE OF CONTENTS I. LIST OF ABBREVIATIONS .............................................................................................. 1 II. INTRODUCTION ........................................................................................................... 7 1. General characteristics of Escherichia coli .................................................................... 9 Specific features ...................................................................................................................................... 10 Discovery and applications of E. coli ....................................................................................................... 10 Niches and relationships: commensal and pathogenic E. coli ................................................................ 11 Pathogenic E. coli: virulence and antimicrobial resistance ..................................................................... 12 1.4.1 Virulence factors: Virulence factor genes and pathogenicity‐associated islands .......................... 13 1.4.2 Antimicrobial therapy and the threat of resistance ...................................................................... 14 2. E. coli as a human pathogen....................................................................................... 16 Types of E. coli in humans ....................................................................................................................... 16 2.1.1 Diarrhoeagenic E. coli (DEC) .......................................................................................................... 16 2.1.1.1 Enteropathogenic E. coli (EPEC) ........................................................................................... 17 2.1.1.2 Enterohaemorrhagic (or Shiga toxin‐producing) E. coli (EHEC/STEC) .................................. 18 2.1.1.3 Enteroaggregative E. coli (EAEC) .......................................................................................... 19 2.1.1.4 Enterotoxigenic E. coli (ETEC) ............................................................................................... 21 2.1.1.5 Enteroinvasive E. coli (EIEC) ................................................................................................. 23 2.1.1.6 Diffusely‐adherent E. coli (DAEC) ......................................................................................... 24 2.1.1.7 Diagnosis and treatment of EAEC and ETEC ......................................................................... 25 2.1.2 Extraintestinal E. coli ..................................................................................................................... 26 2.1.2.1 Commensal extraintestinal E. coli ........................................................................................ 26 2.1.2.1.1 Vaginal E. coli (VEC) .......................................................................................................... 26 2.1.2.2 Extraintestinal pathogenic E. coli (ExPEC): microbiology and virulence factors .................. 27 2.1.2.2.1 Bacteraemia or sepsis‐causing E. coli (SEPEC) ................................................................. 27 2.1.2.2.2 Uropathogenic E. coli (UPEC) ........................................................................................... 29 2.1.2.2.3 E. coli causing obstetric infections. Intra‐amniotic infection. .......................................... 31 2.1.2.2.4 Neonatal sepsis and meningitis‐causing E. coli (NMEC)................................................... 33 Table of contents 3. Antimicrobial resistance mechanisms in E. coli .......................................................... 36 Strategies of antimicrobial resistance ..................................................................................................... 37 Horizontally transferred genetic elements carrying antimicrobial resistance (AMR) mechanisms ........ 39 3.2.1 Transposable elements .................................................................................................................. 39 3.2.2 Plasmids ......................................................................................................................................... 41 3.2.3 Integrons ........................................................................................................................................ 42 Main antimicrobial agents and AMR mechanisms in E. coli .................................................................... 44 3.3.1 Aminoglycosides and AMR mechanisms ........................................................................................ 44 3.3.2 Macrolides and AMR mechanisms ................................................................................................. 45 3.3.3 Quinolones and AMR mechanisms ................................................................................................ 46 3.3.4 Rifaximin and AMR mechanisms .................................................................................................... 48 3.3.5 Thrimethoprim /sulfamethoxazole and AMR mechanisms ........................................................... 48 3.3.6 β‐lactams and AMR mechanisms ................................................................................................... 49 3.3.6.1 β‐lactamases ........................................................................................................................ 51 3.3.6.1.1 Extended spectrum beta‐lactamases (ESBLs) .................................................................. 52 3.3.6.1.1.1 CTX‐M enzymes (CTX‐M‐15) ..................................................................................... 53 4. Relationship between virulence and resistance in E. coli clinical isolates ................... 55 5. Epidemiology of E. coli ............................................................................................... 57 Epidemiological typing strategies ............................................................................................................ 57 5.1.1 Phylogenetic grouping ................................................................................................................... 58 5.1.2 Multilocus sequence typing (MLST) ............................................................................................... 60 5.1.3 Pulsed‐field gel electrophoresis (PFGE) ......................................................................................... 61 5.1.4 Other typing methods .................................................................................................................... 63 5.1.5 Comparison of E. coli typing methodologies ................................................................................. 64 E. coli high‐risk clones ............................................................................................................................. 65 III. WORK JUSTIFICATION AND HYPOTHESES ................................................................... 69 IV. OBJECTIVES ................................................................................................................ 73 Table of contents V. RESULTS ..................................................................................................................... 77 SECTION 1. Virulence in ExPEC:
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