An investigation into the relationship between antimicrobial prescribing and antimicrobial resistance in urinary tract infections at a population level By Dean Ironmonger A thesis submitted to The University of Birmingham for the degree of DOCTOR OF PHILOSOPHY Institute of Microbiology and Infection College of Medical and Dental Sciences University of Birmingham December 2017 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Abstract Inappropriate use of antibiotics is a key factor in the development of antimicrobial resistance (AMR). UK national guidance has been ineffective in standardising the management of infections in the community. Many community prescribers are sceptical that their actions have an effect on AMR in their locality. As part of this study, routine surveillance of AMR in a large regional population was established. To help interpret surveillance data, two surveys were undertaken: a survey of laboratory methods, and a survey of GP sampling and prescribing protocols. Using these survey results, surveillance tools were developed to provide hospital and community prescribers with data on antibiotic resistance in bacteria within their locality; and enable laboratories to compare methods for determining antibiotic susceptibility. The results of this thesis demonstrated that routine AMR surveillance can be used to monitor key antibiotic resistance, detect emergence of new or unusual resistance mechanisms, and enable the bench-marking of laboratory methods. This study was also able to demonstrate that small increases in antibiotic prescribing by individual GPs increases the number of non-susceptible bacteria isolated from specimens taken from their practice population. Results from this thesis provides supporting evidence to those developing strategies to combat AMR in the community. Dedication To Harry and Margaret Acknowledgements I am extremely grateful to my PhD supervisors, Professor Peter Hawkey and Dr. Savita Gossain for providing guidance and supporting my work during the course of this thesis. I would also like to thank Dr. Carolyne Horner for providing editorial advice and proof reading in the write-up of this study. I would like to thank all the consultant microbiologists and scientists working in West Midland diagnostic microbiology laboratories. Routine AMR surveillance would not have been possible without their cooperation and support. The studies that make up this thesis were funded by Public Health England, and I am very grateful for the additional time granted by my line managers over the period of this PhD study, namely; Dr. Obaghe Edeghere, Professor Jeremy Hawker and Dr. Susan Hopkins. I would particularly like to thank Professor Hawker for providing me the opportunity to work with the Birmingham regional epidemiology team, and allowing me the freedom to pursue various surveillance initiatives. Dr Obaghe Edeghere, Dr. Savita Gossain, Dr. Susan Hopkins and Professor Hawkey provided study design guidance and helped with the interpretation of data for the studies reported in Chapters 3 to 6. Mr. Amardeep Bains produced the SQL databases and software processes required for the development of the AmWeb surveillance application reported in Chapter 3; and also helped extract AMR data for the analysis performed in Chapter 5. Dr. Richard Loy and Professor Neil Woodford provided data from the PHE AMRHAI reference laboratory used in the analysis presented in Chapter 5. Mrs. Bridget Hilton helped with the extraction of antibiotic prescribing data and created datasheets used to build the statistical models described in Chapter 6. Mr. Neville Verlander designed the statistical models described in Chapter 6, supervised the modelling process and provided guidance in the interpretation of the statistical model results. I would also like to thank PHE colleagues in the Field Epidemiology Service and AMR/HCAI team for their continuous encouragement and support. Finally I would like to thank my family. Without their understanding this study would not have been possible. Table of Contents 1 Introduction .................................................................................................................. 1 1.1 Background............................................................................................................. 2 1.2 Antibiotics ............................................................................................................... 6 1.2.1 Discovery and development ............................................................................. 6 1.2.2 Mechanisms of action ...................................................................................... 9 1.2.3 Antimicrobial resistance ................................................................................. 15 1.3 Epidemiology of Gram-negative antimicrobial resistance ...................................... 24 1.3.1 Background ................................................................................................... 24 1.3.2 Extended spectrum beta-lactamases ............................................................. 24 1.3.3 Carbapenemases .......................................................................................... 29 1.4 Urinary Tract Infections ......................................................................................... 37 1.4.1 Definitions ...................................................................................................... 37 1.4.2 Epidemiology of UTI ....................................................................................... 38 1.4.3 Host factors ................................................................................................... 40 1.4.4 Bacterial uropathogens .................................................................................. 41 1.4.5 Diagnosis and treatment ................................................................................ 42 1.5 Antibiotic Prescribing ............................................................................................ 44 1.5.1 Background ................................................................................................... 44 1.5.2 Antimicrobial stewardship .............................................................................. 48 1.6 Surveillance of Antimicrobial Resistance ............................................................... 52 1.6.1 Surveillance systems ..................................................................................... 52 1.6.2 Interpretation of surveillance data .................................................................. 57 1.7 Study population ................................................................................................... 61 1.8 Hypothesis ............................................................................................................ 62 1.9 Aim and objectives ................................................................................................ 63 1.10 Ethics .................................................................................................................... 63 2 A survey of methodologies for the identification and antibiotic susceptibility testing of bacterial isolates from urine samples submitted to laboratories based in the West Midlands ......................................................................................................................... 65 2.1 Background........................................................................................................... 66 2.1.1 Laboratory testing protocols for urine specimens ........................................... 66 2.1.2 Initial examination .......................................................................................... 66 2.1.3 Urine culture .................................................................................................. 67 2.1.4 Identification of bacteria isolated from urine specimens ................................. 68 2.1.5 Antibiotic susceptibility tests ........................................................................... 68 2.2 Objectives ............................................................................................................. 74 2.3 Methods ................................................................................................................ 74 2.3.1 Survey protocol .............................................................................................. 74 2.3.2 Survey format ................................................................................................ 76 2.3.3 Survey follow-up questions ............................................................................ 76 2.4 Results .................................................................................................................. 79 2.4.1 Response ...................................................................................................... 79 2.4.2 Number of urines tested by