Evolution and Epidemiology of Multidrug-Resistant $\textit{Klebsiella pneumoniae}$ in the United Kingdom and Ireland

$\textit{Klebsiella pneumoniae}$ is a human commensal and opportunistic pathogen that has become a leading causative agent of hospital-based infections over the past few decades. The emergence and global expansion of hypervirulent and multidrug-resistant (MDR) clones of $\textit{K. pneumoniae}$ have been increasingly reported in community-acquired and nosocomial infections. Despite this, the population genomics and epidemiology of MDR $\textit{K. pneumoniae}$ at the national level are still poorly understood. To obtain insights into these, we analyzed a systematic large-scale collection of invasive MDR $\textit{K. pneumoniae}$ isolates from hospitals across the United Kingdom and Ireland. Using whole-genome phylogenetic analysis, we placed these in the context of previously sequenced $\textit{K. pneumoniae}$ populations from geographically diverse countries and identified their virulence and drug resistance determinants. Our results demonstrate that United Kingdom and Ireland MDR isolates are a highly diverse population drawn from across the global phylogenetic tree of $\textit{K. pneumoniae}$ and represent multiple recent international introductions that are mainly from Europe but in some cases from more distant countries. In addition, we identified novel genetic determinants underlying resistance to beta-lactams, gentamicin, ciprofloxacin, and tetracyclines, indicating that both increased virulence and resistance have emerged independently multiple times throughout the population. Our data show that MDR $\textit{K. pneumoniae}$ isolates in the United Kingdom and Ireland have multiple distinct origins and appear to be part of a globally circulating $\textit{K. pneumoniae}$ population. IMPORTANCE $\textit{Klebsiella pneumoniae}$ is a major human pathogen that has been implicated in infections in healthcare settings over the past few decades. Antimicrobial treatment of $\textit{K. pneumoniae}$ infections has become increasingly difficult as a consequence of the emergence and spread of strains that are resistant to multiple antimicrobials. To better understand the spread of resistant $\textit{K. pneumoniae}$, we studied the genomes of a large-scale population of extensively antimicrobial-resistant $\textit{K. pneumoniae}$ in the United Kingdom and Ireland by utilizing the fine resolution that whole-genome sequencing of pathogen genomes provides. Our results indicate that the $\textit{K. pneumoniae}$ population is highly diverse and that, in some cases, resistant strains appear to have spread across the country over a few years. In addition, we found evidence that some strains have acquired antimicrobial resistance genes independently, presumably in response to antimicrobial treatment.This publication presents independent research supported by the Health Innovation Challenge Fund (HICF-T5-342 and WT098600), a parallel funding partnership between the UK Department of Health and the Wellcome Trust. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health, Public Health England, or the Wellcome Trust. This project was also funded by a grant (098051) awarded to the Wellcome Trust Sanger Institute