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Lishman-H-2019-Phd-Thesis.Pdf INVESTIGATING THE ROLE OF ANTIBIOTIC EXPOSURE AND DEMOGRAPHIC/SOCIOECONOMIC FACTORS ON THE DEVELOPMENT OF BLOODSTREAM INFECTIONS IN PRIMARY CARE Hannah Lishman Imperial College London Department of Primary Care and Public Health PhD in Clinical Medicine Research (Public Health) 2019 1 | Page Declaration of Originality I, Hannah Lishman, confirm that the work presented in this thesis for examination for a PhD degree assessed and awarded by Imperial College London was carried out and written by myself, unless otherwise stated. Copyright Declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work. 2 | Page Acknowledgements “No (wo)man is an island entire of itself; every (wo)man is a piece of the continent, a part of the main…” - John Donne, 1624 There are many people who deserve my thanks in completing this piece of work. Firstly, my amazing supervisors. Professor Paul Aylin, I thank you for your keen insight and your encouragement from the beginning of my time at Imperial College to the end. Professor Alan Johnson, I thank you for your commitment to this work, your continuous guidance and your kindness. And Dr. Ceire Costelloe, my supervisor, mentor and friend, it has truly been a pleasure working with you; your endless curiosity and interest have inspired me throughout my PhD and will continue to do so as I take the next steps in my career. I would like to acknowledge the support of the National Institute for Health Research (NIHR) who have funded this work. I would like to thank the countless amazing scientists I have had the privilege of working with within the Imperial College Health Protection Research Unit in Healthcare-Associated Infections and Antimicrobial Resistance (HPRU HCAI/AMR) and in the Primary Care and Public Health (PCPH) department. This work has benefitted from the support of a wide range of epidemiologists, clinicians, pharmacists and data managers and I feel very privileged to have collaborated with so many people. I would like to thank Myriam Gharbi, Mariam Molokhia, Mahsa Mazidi, Farzan Ramzan, Kate Honeyford, Anthony Thomas and Alison Holmes in particular. I have also had the privilege of making some incredible friends within the HPRU - these brilliant, kind and fiercely funny women have got me through this experience. As part of this PhD I had the opportunity to work closely with Public Health England and I would like to thank the HCAI/AMR Surveillance Unit for their time and support, this was truly a wonderful collaborative experience for me. I would like to thank Russell Hope, Berit Muller-Pebody, Susan Hopkins, Mehdi Minaji, Miroslava Mihalkova and Sabine Bou-Antoun in particular. I would also like to acknowledge Cliodna McNulty and the PHE Primary Care Unit she leads in Gloucester for providing all the archived versions of PHE prescribing guidelines for a large portion of this work. And lastly, and perhaps most importantly, I would like to thank my wonderful friends and family for their undying support. The person who deserves the most thanks is my amazing husband – you have lifted me up in the difficult times and celebrated with me in the exciting times. I would not be where I am without your love and support. 3 | Page Abstract Background In recent years the UK has seen a rise in the incidence of Gram-negative bloodstream infections (BSIs), particularly those acquired in the community, half of which have been recorded as being preceded by a urinary tract infection (UTI) - one of the most common infections treated with antibiotics. Antibiotic resistance has been postulated as exacerbating or even partially causing the progression from a UTI to a BSI. For these reasons the UK Government has introduced a number of measures through the NHS Quality Premiums related to BSI incidence and the reduction of inappropriate antibiotic prescribing for UTIs in the community in the hope of reducing the incidence of BSIs by improving antibiotic stewardship for preceding infections. Aim To investigate whether the risk of developing a BSI following antibiotic treatment for a community-acquired UTI is affected by differing patterns of antibiotic prescribing for community-acquired UTIs. Methods For all studies a number of routinely-collected healthcare data sources linked at the national level are used. An ecological design is used to investigate the volume of GP practice antibiotic prescribing for UTI and UTI-related E. coli bacteraemia (ECB) risk, taking antibiotic susceptibility into account. An algorithm is built to determine the level of antibiotic prescribing for UTI in England was does not adhere to prescribing guidelines as well as the reasons for non-adherence at the patient-level. This algorithm is then used in a patient-level retrospective cohort study to determine whether developing a BSI is associated with guideline adherence of antibiotic treatment for a preceding UTI. Lastly, a retrospective cohort study is used to examine whether longer durations of antibiotic treatment for UTI confer a greater risk of subsequent BSI compared with shorter durations. Results The ecological study demonstrates that GP practices with higher levels of trimethoprim prescribing, after adjusting for case-mix and practice characteristics, have a higher incidence of UTI-related trimethoprim-resistant ECB than practices with lower levels. The algorithm demonstrates that the majority of antibiotic prescriptions for UTI in England do not adhere to national prescribing guidelines, mainly due to antibiotic choice or duration of treatment. The first retrospective cohort study does not find evidence of greater or lesser risk of BSI following UTI antibiotic treatment which was not in line with national prescribing guidelines. The second retrospective cohort study found weak evidence of higher risk of BSI following a longer course of trimethoprim treatment for a UTI compared with a shorter course in women with uncomplicated UTI. Conclusions Improving antibiotic prescribing for UTI in the community (through using nitrofurantoin as the first-choice antibiotic and prescribing shorter durations of treatment where appropriate) may have an effect on subsequent BSI risk, although improvements in data acquisition and linkage to overcome the limitations outlined in this work will provide further clarity to this infection pathway. 4 | Page Contents List of Tables .......................................................................................................................................8 List of Figures ................................................................................................................................... 10 Glossary............................................................................................................................................ 12 CHAPTER ONE………………………………………………………………………………………………………………………………………………….13 INTRODUCTION AND BACKGROUND - UNDERSTANDING THE INFECTION PATHWAY Introduction ................................................................................................................................. 13 1.1. What are the current challenges? ............................................................................................... 13 1.2. Hypothesis ................................................................................................................................. 15 1.3. Aims and objectives of the thesis................................................................................................ 15 1.4. Thesis overview.......................................................................................................................... 16 Background .................................................................................................................................. 19 1.5. Urinary tract infections – treatment practices and surveillance ................................................... 19 1.6. Bloodstream infections – risk factors and surveillance ................................................................ 23 1.7. Prescribing and resistance – mapping the infection pathway ...................................................... 28 1.8. How do social determinants of health fit in? ............................................................................... 31 1.9. Routinely collected data available in England ............................................................................. 32 1.10. Ethics approvals and exemptions .............................................................................................. 33 CHAPTER TWO…………………………………………………………………………………………………………………………………………………35 EXPLORING THE EFFECT OF ANTIBIOTIC PRESCRIBING ON THE INCIDENCE AND SUSCEPTIBILITY PATTERNS OF E. COLI BACTERAEMIA - AN ECOLOGICAL STUDY 2.1. Introduction ............................................................................................................................... 36 2.2. Aims and objectives ................................................................................................................... 36 2.3. Data sources and linkage ...........................................................................................................
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