Antimicrobial Resistant Escherichia coli Clinical - UQ eSpace

Antimicrobial Resistant Escherichia coli Clinical - UQ eSpace

Antimicrobial Resistant Escherichia coli Clinical, Epidemiological and Molecular Characteristics in the Australian Region Dr. Benjamin Alexander Roge...

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Antimicrobial Resistant Escherichia coli Clinical, Epidemiological and Molecular Characteristics in the Australian Region

Dr. Benjamin Alexander Rogers MBBS (Hons), FRACP

A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2014 School of Medicine

ABSTRACT Background Escherichia coli is the most common gram-negative bacteria to cause human infection. The pathological manifestations range from minor disease to severe life threatening sepsis. Urinary tract infection, most often caused by E. coli, is also the most common bacterial infection in humans.

Since the inception of

antimicrobial therapy in the early 20th century, E. coli has systematically developed resistance to almost all known antimicrobials, posing a challenge for the treatment of such infections. From a global perspective, the first decade of the 21st century heralded a change in the epidemiology and tempo of resistance amongst E. coli. Previously, resistance to third generation cephalosporins (3GC) was primarily associated with current or previous healthcare exposure. In the past decade however, expandedspectrum cephalosporin resistant E. coli (ESC-R-EC), usually mediated by Extended Spectrum betalactamase (ESBL) genes has spread widely within the communities of many regions, independent of healthcare associated acquisition. The latter half of this decade has led to the delineation of two further challenges amongst resistant E. coli. The first is the identification of Sequence Type 131 E. coli (ST131), a global ‘pandemic’  clone fine-tuned for resistance and virulence. This clone is now implicated in a significant proportion of community ESBL E. coli infections globally. The second challenge is the emergence of E. coli harbouring carbapenemase genes, conferring resistance to carbapenem antimicrobials used to treat severe ESBL producing E. coli infection. Methods Through several studies we have aimed to better define global and local aspects of antimicrobial resistant E. coli, in particular ESC-R-EC. The studies have included clinical and laboratory based research. Clinical research included a multi-centre case-control study of community onset ESC-R-EC infection in Australia and New Zealand, and a national survey of health services’  infection control practices pertaining to multi-resistant gram-negative bacilli and patients at risk of harbouring these. Laboratory research included molecular epidemiological investigation of E. coli from two sources. The first was isolates from the 182 participants in the case-control study, comprising a broad sample of community onset 3GC resistant and susceptible E. coli from Australia and New Zealand. The second was a collection of isolates from a previously conducted study on carriage of resistant E. coli in overseas travellers returning to Australia. Results 182 patients (91 cases and 91 controls) were recruited across six tertiary hospitals in Australia and New Zealand for the case-control study. Multivariate logistic regression identified risk factors for 3GCR-EC  

II

including birth on the Indian subcontinent (OR=11.13, 2.17-56.98, p=0.003), urinary tract infection in the past year (per infection OR=1.430, 1.13-1.82, p=0.003), travel to South East Asia, China, Indian subcontinent, Africa and the Middle East (OR=3.089, 1.29-7.38, p=0.011), prior exposure to trimethoprim+/sulfamethoxazole &/or extended spectrum cephalosporins (OR=3.665, 1.30-10.35, p=0.014) and healthcare exposure in the previous six months (OR=3.16, 1.54-6.46, p=0.02). Molecular epidemiological analysis of isolates demonstrated a predominance of CTX-M type ESBL’s, as now reported in most other regions of the world. From a global perspective, a unique distribution of ST131 E. coli was demonstrated, with a very low prevalence of ST131 amongst 3GC susceptible isolates compared with resistant isolates (7% vs. 45%). Susceptible isolates showed diversity with six MLST defined clusters of isolates. Amongst 3GCR isolates, ST131 dominated, comprising 40/89 isolates, with 88% (35/40) of ST131 being of the recently defined fimH 30 sub-clone variant. Whilst patients with ST131 were significantly more likely to have an upper rather than lower urinary tract infection (relative risk 1.8, p=0.040), they were otherwise relatively epidemiologically homogenous with other 3GCR-EC. Analysis of isolates from returned travellers gave insight into the dynamics of carriage of antimicrobial resistant E. coli in the bowel flora and supported a number of findings from the case control study. The risk of prolonged carriage after travel was lower for 3GC-resistant than ciprofloxacin or gentamicin resistant isolates and the duration of carriage was also longer for the latter resistance phenotypes (75th quartile 8 vs. 62 and 63 days respectively). In multivariate analysis, risks of prolonged carriage included antimicrobial use whilst travelling (RR 3.3, 1.3–8.4) and phylogenetic group B2 (RR 9.3, 3.4–25.6) and D (RR 3.8, 1.6–8.8). Clonality amongst longitudinal isolates from the same participant was demonstrated in 92% of participants and most marked amongst 3GC resistant isolates. ST131 was surprisingly infrequent amongst participants (3% of participants). Conclusion Within this thesis, study of a variety of aspects of antimicrobial resistant E. coli in Australia and New Zealand has revealed unique insights into this pathogen locally and globally. These insights include the delineation of risks within the community, temporality of risk and a unique molecular epidemiology. Furthermore studies completed within this thesis highlight several key future directions of research including clinical studies to investigate risk-factor modification and optimal therapy, economic impact analyses of resistant E. coli infection, and further in-depth genetic studies.

III

DECLARATION BY AUTHOR This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my research higher degree candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the General Award Rules of The University of Queensland, immediately made available for research and study in accordance with the Copyright Act 1968. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis.

 

IV

PUBLICATIONS DURING CANDIDATURE Peer-reviewed publications Paterson DL, Rogers BA. How Soon is Now? The urgent need for randomized, controlled trials evaluating multi-resistant bacterial infection. Clin Infect Dis. 2010 Dec 1;51(11):1245-7. Epub 2010 Oct 25. Rogers BA, Sidjabat HE, Paterson DL. Escherichia coli O25b-ST131: a pandemic, multiresistant, community-associated strain. J Antimicrob Chemother. 2011 Jan;66(1):1-14. PubMed PMID: 21081548. Epub 2010/11/18. Eng. Rogers BA, Aminzadeh Z, Hayashi Y, Paterson DL. Country-to-country transfer of patients and the risk of multi-resistant bacterial infection. Clin Infect Dis. 2011 Jul 1;53(1):49-56. PubMed PMID: 21653302. Epub 2011/06/10. Avent ML, Rogers BA, Cheng AC, Paterson DL. Current use of aminoglycosides: indications, pharmacokinetics and monitoring for toxicity. Intern Med J. 2011 Jun;41(6):441-9. PubMed PMID: 21309997. Epub 2011/02/12. Totsika M, Moriel DG, Idris A, Rogers BA, Wurpel DJ, Phan MD, et al. Uropathogenic Escherichia coli mediated urinary tract infection. Current drug targets. 2012 Oct;13(11):1386-99. PubMed PMID: 22664092. Epub 2012/06/06. Rogers BA, Kennedy KJ, Sidjabat HE, Jones M, Collignon P, Paterson DL. Prolonged carriage of resistant E. coli by returned travellers: clonality, risk factors and bacterial characteristics. Eur J Clin Microbiol Infect Dis. 2012 Sep;31(9):2413-20. PubMed PMID: 22391758. Epub 2012/03/07. Rogers BA, Hayashi Y. An oral carbapenem, but only now intravenous penicillin: the paradox of Japanese antimicrobials. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 2012 Dec;16(12):e830-2. PubMed PMID: 23041363. Epub 2012/10/09. Rogers BA, Sidjabat HE, Silvey A, Anderson TL, Perera S, Li J, et al. Treatment options for New Delhi

metallo-beta-lactamase-harboring

enterobacteriaceae.

Microb

Drug

Resist.

2013

Apr;19(2):100-3. PubMed PMID: 23330550. Epub 2013/01/22.

V

Rogers BA, Doi Y. Who is leading this dance? Understanding the spread of Escherichia coli sequence type 131. Infect Control Hosp Epidemiol. 2013 Apr;34(4):370-2. PubMed PMID: 23466909. Epub 2013/03/08. Williamson DA, Barrett LK, Rogers BA, Freeman JT, Hadway P, Paterson DL. Infectious complications following transrectal ultrasound-guided prostate biopsy: new challenges in the era of multidrug-resistant Escherichia coli. Clin Infect Dis. 2013 Jul;57(2):267-74. PubMed PMID: 23532481. Epub 2013/03/28. Williamson DA, Freeman JT, Roberts SA, Heffernan H, Dyet K, Paterson DL, Rogers BA et al. Rectal colonization with New Delhi metallo-beta-lactamase-1-producing Escherichia coli prior to transrectal ultrasound (TRUS)-guided prostate biopsy. J Antimicrob Chemother. 2013 Jul 3. PubMed PMID: 23825384. Epub 2013/07/05. Ingram PR, Rogers BA, Sidjabat HE, Gibson GS, Inglis TJJ. Co-selection may explain high rates of ciprofloxacin non-susceptible Eschericia coli from retail poultry reared without prior fluoroquinolone exposure, J Med Micro, 2013 62, 1743-1746. Rogers BA, Ingram PR, Runnegar N, Pitman MC, Freeman JT, Athan E, Havers S, Sidjabat H, Jones M, Gunning E, De Almeida M, Styles K, Paterson DL. Community onset Escherichia coli infection resistant to expanded-spectrum cephalosporins in low-prevalence countries. Antimicrob Agents Chemother, 2014, 58, 2126-2134 Petty NK, Ben Zakour NL, Stanton-Cook M, Skippington E, Totsika M, Forde BM, Phan MD, Gomes Moriel D, Peters KM, Davies M, Rogers BA et al. Global dissemination of a multidrug resistant

Escherichia

coli

clone.

Proc

Natl

Acad

Sci.

2014;111,

5694-9.

doi:

10.1073/pnas.1322678111. Rogers BA, Havers SM, Brown TM, Paterson DL, Predictors of use of infection control precautions for multi-resistant gram-negative bacilli in Australian hospitals: Analysis of a national survey, Am Jour Infect Cont, 2014, 42, 963-9. doi: 10.1016/j.ajic.2014.05.035 Rogers BA, Ingram PR, Runnegar N, Pitman MC, Freeman JT, Athan E, Havers S, Sidjabat H, Gunning E, De Almeida M, Styles K, Paterson DL. Sequence Type 131 fimH30 and fimH41 Subclones Amongst Escherichia coli Isolates in Australia and New Zealand, In J Antimicrob Agents, 2015, 45; 351-8, doi: 10.1016/j.ijantimicag.2014.11.015 Conference Presentations VI

Rogers BA, Silvey A, Sidjabat H, Perera S, Yam WC, Paterson D. Travelling With Friends: NDM1 and Other Resistance Genes. The Australasian Society for Infectious Diseases, Annual Scientific Meeting 2011; Lorne, Vic, Australia: ASID; 2011. (Oral Presentation) Sidjabat H, Silvey A, Yam WC, Rogers BA, Walsh TR, Vohra R, et al. C1-526 - Features of Plasmids Carrying blaNDM-1 and blaNDM-3 in Australia.

51st Interscience Conference on

Antimicrobial Agents and Chemotherapy; Chicago, IL: American Society for Microbiology; 2011. (Oral Presentation) Rogers BA, Kennedy K, Sidjabat H, Collignon P, Paterson D. P-1587 - Prolonged Gastrointestinal Carriage of Antimicrobial-Resistant Escherichia coli in International Travellers. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy; Chicago, IL, USA: American Society for Microbiology; 2011. (Oral Presentation) Rogers BA, Ingram PR, Runnegar N, Pitman MC, Freeman JT, Athan E, et al. Risk Factors for 3rd Generation Cephalosporin Resistant Community Onset E. coli Infections from Six Centres in Australia and New Zealand. Antimicrobials 2013, Australian Society for Antimcirobials Annual Scientific Meeting; Sydney, NSW, Australia: ASA; 2013. (Oral Presentation) Rogers BA, Ingram PR, Runnegar N, Freeman JT, Pitman MC, Athan E, et al. C2-689 - Risk factors for 3rd Generation Cephalosporin Resistant Community Onset E. coli Infections from Seven Centres in Low Prevalence Countries. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy; San Francisco, CA, USA: American Society for Microbiology; 2012. (Poster Presentations) Rogers BA, Havers SM, Ingram PR, Runnegar N, Athan E, Korman TM, et al. Variation in Infection Prevention Precautions for Patients Admittted to Hospital with Community Onset Infection Due to 3rd Generation Cephalosporin Resistant E. coli. Australian College for Infection Prevention and Control, National Conference; Sydney, NSW, Australia: ACIPC; 2012. (Poster Presentations)

PUBLICATIONS INCLUDED IN THIS THESIS (The contribution of individual authors is described under each publication) Chapter 1.

 

VII

1) Rogers BA, Aminzadeh Z, Hayashi Y, Paterson DL. Country-to-country transfer of patients and the risk of multi-resistant bacterial infection. Clin Infect Dis. 2011 •

BAR – Design and concept 80%, interpretation of data 80%, drafting and writing 80%, editing and revision 70%. ZA – Writing 10%, YH – Writing 10%. DLP – Design and concept 20%, interpretation of data 20%, editing and revision 30%.

Chapter 2. 1) Rogers BA, Sidjabat HE, Paterson DL. Escherichia coli O25b-ST131: a pandemic, multiresistant, community-associated strain. J Antimicrob Chemother. 2011 •

BAR – Design and concept 60%, interpretation of data 80%, drafting and writing 70%, editing and revision 70%. HES – Writing 20%. DLP – Design and concept 40%, interpretation of data 20%, drafting and writing 10%, editing and revision 30%.

Chapter 3. 1) Rogers BA, Ingram PR, Runnegar N, Pitman MC, Freeman JT, Athan E, et al. Community onset Escherichia coli infection resistant to expanded-spectrum cephalosporins in lowprevalence countries. Antimicrob Agents Chemother, 2014. •

BAR – Design and concept 90%, data collection 25%, data cleaning and entry 90%, laboratory analysis 90%, interpretation of data 100%, statistical analysis 80%, drafting and writing 100%, editing and revision 80%. DLP – Design and concept 10%, editing and revision 10%. MAJ - statistical analysis 20%. The remainder of the authors in this study contributed to data collection editing and revision of the paper.

Chapter 4. 1) Rogers BA, Ingram PR, Runnegar N, Pitman MC, et al. Sequence Type 131 fimH30 and fimH41 Sub-clones Amongst Escherichia coli Isolates in Australia and New Zealand, Int J Antimicrob Agents, 2015. •

BAR – Design and concept 90%, data collection 25%, data cleaning and entry 90%, laboratory analysis 70%, interpretation of data 100%, statistical analysis 100%, drafting and writing 100%, editing and revision 80%. DLP – Design and concept 10%, editing and revision 10%. The remainder of the authors in this study contributed to data collection editing and revision of the paper.

 

VIII

Chapter 5. 1) Rogers BA, Kennedy KJ, Sidjabat HE, Jones M, Collignon P, Paterson DL. Prolonged carriage of resistant E. coli by returned travellers: clonality, risk factors and bacterial characteristics. Eur J Clin Microbiol Infect Dis. 2012 •

BAR – Design and concept 80%, laboratory analysis 90%, interpretation of data 100%, statistical analysis 50%, drafting and writing 100%, editing and revision 70%. KJK – design and concept 5%, editing and revision 5% Sidjabat HE – laboratory analysis 10% MJ – statistical analysis 50%. PC design and concept 5%, editing and revision 5%. DLP – Design and concept 10%, editing and revision 20%

Chapter 6. 1) Rogers BA, Havers SM, Brown TM, Paterson DL. Predictors of use of infection control precautions for multi-resistant gram-negative bacilli in Australian hospitals: Analysis of a national survey, Am J Infect Control, 2014 •

BAR – Design and concept 80%, Survey construction 50% interpretation of data 100%, statistical analysis 90%, drafting and writing 90%, editing and revision 70%. SMH – design and concept 10%, statistical analysis 10%, editing and revision 10%, TMB – survey construction 50%. editing and revision 10%. DLP – Design and concept 10%, editing and revision 10%

IX

CONTRIBUTIONS BY OTHERS TO THE THESIS In addition to the contributions outlined above, Laurie Beechy assisted with data entry for the case control study. Ms Tiffany Brown assisted with data collection for the case control study. Wan Keat Yam and Dr Anna Sartor assisted with laboratory work, including genotypic and phenotypic characterisation presented in chapters 3, 4 and 5. Diane Josey (English Language Business) and Sarah Rogers assisted with proof reading of the final version of this thesis.

STATEMENT OF PARTS OF THE THESIS SUBMITTED TO QUALIFY FOR THE AWARD OF ANOTHER DEGREE None.

 

X

ACKNOWLEDGEMENTS Firstly, I would like to thank greatly my wife, Danielle, for her encouragement and support during my PhD. This has included boundless patience at home, and much support when I have had to travel, work or otherwise be absent from home. I would also like to thank our sons Eli and Jacob, for the welcome distraction and joy they have brought during this time. In addition, I would like to thank my wider family and friends for their encouragement and support in many different ways. I am greatly indebted to Prof. David Paterson, my primary supervisor, for his encouragement to undertake a PhD and his careful mentorship and guidance through the process. This includes support from an academic perspective, with respect to clinical work, and more generally from a vocation and career perspective. I would also like to thank Dr Hanna Sidjabat for her support for and guidance of, a laboratory novice, in all matters related to our laboratory. I need to acknowledge my many collaborators, without whom this research would not have been possible. All have been incredibly generous with access to isolates and data. In addition, many devoted considerable time, in addition to their already busy schedules, to conducting the clinical study in their hospitals. Furthermore, the overarching support of the Australasian Society for Infectious Diseases, Clinical Research Network was instrumental in forming the collaboration that enabled this study to form. I would like to acknowledge scholarship support from the University of Queensland, via an Australian Post Graduate Award, and directly from Prof. Paterson’s research funding. In addition, the Royal Brisbane and Women’s Hospital Foundation was generous in the provision of a research grant for part of the laboratory work presented herein.

 

XI

KEYWORDS gram-negative bacteria, Escherichia coli, antibiotic resistance, extended spectrum beta-lactamase, urinary tract infection, community onset, hospital acquired, travel.

AUSTRALIAN AND NEW ZEALAND STANDARD RESEARCH CLASSIFICATIONS (ANZSRC) ANZSRC code: 110801, Medical Bacteriology, 40% ANZSRC code: 110309, Infectious Diseases, 60%

FIELDS OF RESEARCH (FOR) CLASSIFICATION ANZSRC code: 1108, Medical Microbiology, 40% ANZSRC code: 1103, Clinical Science, 60%

XII

LIST OF ABBREVIATIONS USED IN THE THESIS

 

Abbreviation

Term

3GC

Third generation cephalosporin antimicrobial (Ceftrixaone, Cefotaxime, Ceftazidime)

3GCR-EC

Third generation cephalosporin resistant E. coli

AGAR

Australian Group on Antimicrobial Resistance

AIHW

Australian Institute of Health and Welfare

BSI

Blood stream infection

CDC

Centres for Disease Control

CGA

Clonal group A E. coli

Cip-R

Ciprofloxacin resistant isolate

CLSI CO-ESCREC

Clinical and laboratory standards institute

COOEE

Community onset ESBL and AmpC E. coli study

CP

Contact precautions

CRE

Carbapenem resistant Enterobacteriaceae

CRO-R

Ceftriaxone resistant isolate

DST

Direct antimicrobial susceptibility testing

EARS-NET

European Antimicrobial Resistance Surveillance Network

ECDC

European Centres for Disease Prevention and Control

ED

Emergency department

ESBL-EC

Extended spectrum beta-lactamase harbouring E. coli

ESC-R-EC

Expanded (or extended)-spectrum cephalosporin resistant E. coli

ExPEC

Extra intestinal pathogenic E. coli

Gent-R

Gentamic resistant isolate

GIT

Gastrointestinal tract

H30

FimH 30 subclone of ST131 E. coli

HA

Healthcare associated

ICU

Intensive Care Unit

ID

Infectious disease

IQR

Inter qurartile range

IT-patient

Patient who has undergone an international transfer

KPC

Klebsiella pneumoniae carbapenemase

LTCF

Long Term Care Facility (High-level Care Nursing Home)

MBL

Metallo beta-lactamase

MIC

Minimum inhibitory concentration

MLST

Multi-locus sequence typing

MRGNB

Multi-resistant gram-negative bacilli

MRO

Multi-resistant organism

NDM

New Delhi metallo beta-lactamase

NHMRC

National Health and Medical Research Council

non-HA

Non-healthcare associated

OR

Odds ratio

PCR

Polymerase chain reaction

PFGE

Pulse field gel electrophoresis

Community-onset expanded (or extended)-spectrum cephalosporin resistant E. coli

XIII

rep-PCR

Repetitive extragenic palindromic sequence polymerase chain reaction

RR

Relative risk

SE Asia

South East Asia

ST

Sequence type

SXT

Trimethoprim + sulfamethoxazole

TRUS biopsy

Trans-rectal ultrasound guided prostate biopsy

UK

United Kingdom

UTI

Urinary tract infection

LIST OF FIGURES & TABLE Figures Chapter

Figure

1

1

Title Schematic representation of epicenters and importations of KPC and NDM harbouring organisms

Page Number

3

1

Participant identification, recruitment and characteristics of presentation and clinical syndrome

80

3

2

Smoothed curve and discrete intervals of odds ratios for ESC resistant E. coli after healthcare contact

80

4

1

Dendrogram of 3GC susceptible E. coli

95

4

2

Dendrogram of 3GC resistant E. coli

96

4

3

4

4

Distribution of ST131 and the fimH 30 sub-clone across the study sites for 3GC susceptible and 3GC resistant E. coli. Relative contribution of clones to the burden of Fluoroquinolones and expanded-spectrum cephalosporin resistance in our population

5

1

Selection and exclusion of 102 participants for the three arms of this study

114

5

2

Kaplan-Meier survival curve comparing the duration of carriage of the three resistance phenotypes across 44 selected participants

114

5

3

Travellers representative of different patterns of carriage or resistant isolates

115

5

4

Graphical representation of the clonality of isolates amongst each individual

116

6

1

Breakdown of strategies for the use of contact precautions for ESBL-E, CRE and IT-Patients.

134-5

31

97 98

XIV

Tables

 

Chapter

Table Number

1

1

Title Factors predisposing to increased risk of infection and carriage of multi-resistant bacteria organisms in aeromedical evacuees and medical tourists

1

2

Recommendations for the management of patients who have been hospitalized internationally

28

1

3

Approach to suspected bacterial sepsis in patients previously hospitalised in another country

29

2

1

Geographical distribution and antimicrobial resistance of E. coli ST131 in humans

50-53

2

2

3

1

ESBL, AmpC and aminoglycoside-modifying enzyme genes carried by E. coli ST131 Univariate analysis of demographics, comorbidities, antimicrobial use, region of travel and birth, occupation and household exposure

3

2

Multivariate logistic regression

79

4

1

Comparison of clinical presentations within phylogenetic groups and MLST defined clones

94

5

1

Univariate analysis of risk factors for prolonged carriage of resistance

112

5

2

Multivariate analysis of risk factors for prolonged carriage

113

6

1

Infection control management of ESBL-E, CRE and internationally transferred patients (n=97)

130

6

2

6

3

Descriptive analysis of predictors of infection control management Multivariate analysis of the predictors of a permissive practice for ESBL-E, and any use of precautions for CRE and international transfer patients

Page Number

27

54

77-78

131

132

XV

TABLE OF CONTENTS CHAPTER  1.   ESCHERICHIA  COLI  AND  ANTIMICROBIAL  RESISTANCE  ....................................  5   INTRODUCTION  ................................................................................................................................................  5   EXTRA-­‐INTESTINAL  E.  COLI  INFECTION  ...........................................................................................................  6   URINARY  TRACT  INFECTION  ...............................................................................................................................................  6   BACTERAEMIA  ......................................................................................................................................................................  7   ANTIMICROBIAL  RESISTANT  E.  COLI  ................................................................................................................  7   THE  EMERGENCE  OF  COMMUNITY  ONSET  ESBL  E.  COLI  .................................................................................................  7   NOMENCLATURE  USED  TO  DESCRIBE  ESBL-­‐EC  WITHIN  THIS  THESIS  .........................................................................  8   EXTENDED  SPECTRUM  BETA-­‐LACTAMASE  HARBOURING  E.  COLI  IN  AUSTRALIAN  AND  NEW  ZEALAND  ..................  9   CARBAPENEM  RESISTANT  ENTEROBACTERIACEAE  IN  AUSTRALIA  AND  NEW  ZEALAND  ........................................  10   IMPACT  OF  ANTIMICROBIAL  RESISTANCE  .......................................................................................................................  11   INFECTION  CONTROL  MANAGEMENT  OF  ANTIMICROBIAL  RESISTANT  E.  COLI  ..........................................................  13   GLOBAL  MOVEMENT  AND  THE  SPREAD  OF  ANTIMICROBIAL  RESISTANCE  .....................................................  14   RESEARCH  PROGRAM  WITHIN  THIS  THESIS  ..................................................................................................  15   PUBLICATION:   COUNTRY-­‐TO-­‐COUNTRY   TRANSFER   OF   PATIENTS   AND   THE   RISK   OF   MULTI-­‐RESISTANT BACTERIAL  INFECTION  (CLINICAL  INFECTIOUS  DISEASES,  VOLUME  53,  JULY  2011)  ...............................  17   ABSTRACT  ..........................................................................................................................................................................  17   INTRODUCTION  ..................................................................................................................................................................  18   PATIENTS  AT  RISK  .............................................................................................................................................................  18   INFECTIONS  OF  CURRENT  CONCERN  ..............................................................................................................................  21   APPROACH  TO  THE  PATIENT  ............................................................................................................................................  24   FIGURES  AND  TABLES  .......................................................................................................................................................  27   CHAPTER  2.   THE  ESCHERICHIA  COLI  ST131  PANDEMIC  CLONE  ...........................................  32   INTRODUCTION  .............................................................................................................................................  32   PUBLICATION:   ESCHERICHIA  

COLI  

O25B-­‐ST131:  

A   PANDEMIC,   MULTIRESISTANT,   COMMUNITY-­‐

ASSOCIATED  STRAIN  (JOURNAL  OF  ANTIMICROBIAL  CHEMOTHERAPY,  VOLUME  66,  JANUARY  2011)  .....  33  

INTRODUCTION  ..................................................................................................................................................................  34   EPIDEMIOLOGY  ..................................................................................................................................................................  34   ANTIBIOTIC  RESISTANCE  .................................................................................................................................................  39   1

DETECTION  OF  O25B-­‐ST131  ........................................................................................................................................  42   VIRULENCE  .........................................................................................................................................................................  44   HUMAN  INFECTION  ...........................................................................................................................................................  45   CONCLUSION  ......................................................................................................................................................................  48   TABLES  ...............................................................................................................................................................................  50   UPDATE  ON  ESCHERICHIA  COLI  ST131  ........................................................................................................  56   EPIDEMIOLOGY  ..................................................................................................................................................................  56   CARBAPENEM  RESISTANT  ST131  ..................................................................................................................................  57   RISKS  AND  RESERVOIRS  ....................................................................................................................................................  57   H30  AND  OTHER  ST131  SUB-­‐CLONES  ..........................................................................................................................  58   ST131  IN  AUSTRALIA  AND  NEW  ZEALAND  .................................................................................................  59   CHAPTER  3.  

EPIDEMIOLOGY   OF   COMMUNITY   ONSET   ESCHERICHIA   COLI   INFECTION  

RESISTANT  TO  EXPANDED-­‐SPECTRUM  CEPHALOSPORINS.  ....................................................  61   INTRODUCTION  .............................................................................................................................................  61   PUBLICATION:   COMMUNITY   ONSET   ESCHERICHIA   COLI   INFECTION   RESISTANT   TO   EXPANDED-­‐SPECTRUM   CEPHALOSPORINS   IN   LOW-­‐PREVALENCE   COUNTRIES  

(ANTIMICROBIAL   AGENTS  

AND  

CHEMOTHERAPY,  

VOLUME  58,  APRIL  2014)  ..........................................................................................................................  63   ABSTRACT  ..........................................................................................................................................................................  64   INTRODUCTION  ..................................................................................................................................................................  65   PATIENTS  AND  METHODS  ................................................................................................................................................  65   RESULTS  .............................................................................................................................................................................  69   DISCUSSION  ........................................................................................................................................................................  73   FIGURES  AND  TABLES  .......................................................................................................................................................  77   CHAPTER  4.   MOLECULAR   EPIDEMIOLOGY   OF   COMMUNITY   ONSET   ESCHERICHIA   COLI   INFECTION  

81  

INTRODUCTION  .............................................................................................................................................  81   PUBLICATION:   SEQUENCE   TYPE   131   FIMH30   AND   FIMH41   SUB-­‐CLONES   AMONGST   ESCHERICHIA   COLI   ISOLATES   IN   AUSTRALIA   AND   NEW   ZEALAND   (INTERNATIONAL   JOURNAL   OF   ANTIMICROBIAL   AGENTS,   VOLUME  54,  2015)  .....................................................................................................................................  83   ABSTRACT  ..........................................................................................................................................................................  84   INTRODUCTION  ..................................................................................................................................................................  85   MATERIALS  AND  METHODS  .............................................................................................................................................  86    

2

RESULTS  .............................................................................................................................................................................  88   DISCUSSION  ........................................................................................................................................................................  90   FIGURES  AND  TABLES  .......................................................................................................................................................  94   CHAPTER  5.  

RETURNED  

TRAVELLERS  

AND  

CARRIAGE  

OF  

ANTIMICROBIAL  

RESISTANT  ESCHERICHIA  COLI.  ..........................................................................................................  99   INTRODUCTION  .............................................................................................................................................  99   PUBLICATION:  PR