A multi-domain analysis of antimicrobial resistance In gram-negative pathogens from north-west London
File(s)
Author(s)
Rodgus, Jonah
Type
Thesis
Abstract
Gram-negative pathogens, including Klebsiella pneumoniae, cause significant morbidity and mortality as they can rapidly develop and disseminate antimicrobial resistance (AMR). Herein, three large studies were completed to determine whether integrated epidemiological and genomic data analyses can enhance the resolution of AMR surveillance in a high-acuity healthcare setting to reveal patterns of resistance emergence and transmission not evident through conventional workflows alone. Findings from a systematic narrative review of studies published between January 2020–September 2023 underscore the predominance of K. pneumoniae in intensive care units, with several clonal K. pneumoniae outbreaks described across international geographies. Analyses of antimicrobial sus ceptibility testing data for Gram-negative blood culture isolates collected across North-West London between January 2015–April 2025 show high rates of resistance to critical, last-line antimicrobials, such as carbapenems. Indeed, AMR rates in healthcare-onset K. pneumoniae infections were especially elevated compared to contemporaneous national data. 10-year time series data provide support for disaggregated modelling frameworks to capture temporal AMR trends among Gram-negative pathogens causing bloodstream infections across North-West London. Moreover, whole-genome sequencing data of 351 representative K. pneumoniae blood-culture-derived genomes show extreme genetic diversity, with 138 sequence types identified between April 2020–December 2021. Critically, four distinct carbapenemase variants (including blaNDM [n=3]) were found among these K. pneumoniae genomes, with eight blaOXA-48-like genes (blaOXA-48 [n=6] and blaOXA-181 [n=2]) as well as variants of several key hypervirulence determinants detected, some co-located on plasmids, highlighting the plasmid-mediated emergence of convergent K. pneumoniae genotypes. Without effective antimicrobials, the world risks returning to a pre-antimicrobial era marked by the resurgence of deadly bacterial infections that were once treatable. To that end, this thesis reinforces the case for integrated AMR surveillance as a tool for practical infection prevention and control, providing a foundation for future work to address challenges presented by the evolving threat of AMR.
Version
Open Access
Date Issued
2025-10-16
Date Awarded
2026-06-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Jauneikaite, Elita
Davies, Frances
Holmes, Alison
Sponsor
National Institute for Health and Care Research (NIHR)
Publisher Department
Department of Infectious Disease
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)