PubMedmedRxiv : the preprint server for health sciences2026-11-08
Trends in incidence and antimicrobial resistance for five major causes of bacteraemia in a Canadian metropolitan area, 2006-22: a genomic and antimicrobial use cohort study.
Pham Thi Mui TM, Smith Joshua T JT, Mortimer Tatum D TD, Grad Yonatan H YH et al.
Using a population-based cohort from the Calgary Health Zone (CHZ), Canada, we integrated longitudinal antimicrobial susceptibility and prescribing data with the whole genome sequences of five major pathogens. We aimed to assess how antimicrobial resistance (AMR) responds to prescribing changes and determine which bacterial strains shape these dynamics.
We analysed antibiotic prescribing rates, clinical and genomic data from 7,271 Staphylococcus aureus , 1,609 Enterococcus faecalis , 801 Enterococcus faecium , 11,363 Escherichia coli , and 2,319 Klebsiella pneumoniae isolates, associated with bacteraemia episodes in the CHZ between 2006-2022. Genomic clusters (referred to as strains) were identified using StrainGST and assigned to known sequence types (STs) or clonal complexes (CCs). Strain-level incidence, stratified by community-onset (isolates collected ≤48h after admission) and hospital-onset (>48h after admission), AMR phenotypes, and prescribing rates were modelled using negative-binomial and binomial regression. Temporal trends were quantified using average annual percentage change (AAPC).
Between 2010-2022, fluoroquinolone prescribing declined in both community (AAPC=-6·8% [95% CI -8·1, -5·4]; p<0·0001) and hospital settings (AAPC=-5·1% [-6·5, -3·7]; p<0·0001). This was accompanied by a significant reduction in fluoroquinolone resistance among Gram-positive species. Specifically, S aureus bacteraemia resistant to clinically important antibiotics, cloxacillin, ciprofloxacin, erythromycin, and clindamycin, declined from 2006 to 2022, mostly in hospital-onset cases (AAPC=-16·0%, [-19·3%, -12·7%], p<0·0001). In E coli, ceftriaxone and ciprofloxacin resistance were clustered in ST131 and the emerging ST1193; the latter increased steadily, particularly in community-onset cases (AAPC=17·7%, [9·0%, 30·0%], p<0·0001). CTX-M-27-producing E coli ST131 strains increased (AAPC=23·8%, [17·4%, 30·5%], p<0·0001) between 2008-2022, while CTX-M-14-producing E coli ST131 declined (AAPC=-15·9%, [-21·3%, -10·2%], p<0·0001) between 2013-2022. These trends were paralleled by an increase in community cephalosporin prescribing (AAPC=7·3%, [4·2%, 10·5%], p<0·0001) between 2010-2022. For K pneumoniae , hypervirulent ST23 was most common (N=88) with an increasing trend in incidence (AAPC=2·3%, [-4·4%, 9·4%]) between 2006-2019.
The contrasting resistance trends between Gram-positive and Gram-negative species underscore the complexity of AMR control efforts. Effective strategies will require stewardship efforts targeting multiple drug classes, genomic surveillance for emerging resistant strains, and interventions extending beyond hospital settings.
This study was funded by a Large Scale Applied Research Project competition award (2017) from Genome Canada, administered via Genome Alberta. IAL is supported by an Alberta Innovates Translational Health Chair and a UCalgary Research Excellence Chair, with additional support from the Canada Foundation for Innovation (CFI-JELF 34986), the Natural Sciences and Engineering Research Council (DG 04547). Microbial isolates were prepared for analysis at the Alberta Centre for Advanced Diagnostics, which is supported by PrairiesCan (000022734). This work was also supported by federal funds from the US National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under grant number U19AI110818 to the Broad Institute. JTS is additionally supported by the NIH/NIAID F32AI179151.
Evidence before this study: We searched PubMed for articles published in English up to Dec 23, 2025, using (antibiotic[tiab] OR antimicrobial[tiab]) AND (use[tiab] OR prescribing[tiab] OR consumption[tiab]) AND (resistance[tiab] OR "multidrug resistance"[tiab]) AND (relationship[tiab] OR association[tiab] OR correlation[tiab] OR effect[tiab] OR impact[tiab] OR influence[tiab] OR regression[tiab]) AND (genomic OR genetic OR ""molecular epidemiology) AND ("Staphylococcus aureus" OR "Escherichia coli" OR "Klebsiella pneumoniae" OR "Enterococcus faecalis" OR "Enterococcus faecium") NOT animal. This search yielded 739 articles.Numerous studies have characterised the molecular epidemiology of these species over the past two decades: For Staphylococcus aureus , extensive genomic surveillance has revealed that a limited number of sequence types have dominated global infections over the past two to three decades. Pandemic hospital-associated methicillin resistant S aureus (MRSA) strains such as CC5, CC22, CC80, and CC30 were widely established in the 1990s and early 2000s, often carrying large multidrug-resistant staphylococcal cassette chromosome mec (SCCmec) elements. Since then, community-associated MRSA strains, including ST8 (CC8, USA300), ST59, and ST80, have emerged and expanded, frequently harbouring SCCmec IV or V. Livestock-associated MRSA ST398 has also become widespread, particularly in Europe and North America. While vancomycin resistance in S aureus remains rare, reduced susceptibility has been reported sporadically, especially in ST5 and ST8. Overall, the distribution of S aureus sequence types continues to shift regionally, with the spread of community-associated strains into hospitals. These patterns largely reflect data from high-income countries whereas strain distribution tends to be more heterogeneous in low-and middle-income countries. In Enterococcus faecium , genomic analyses have revealed a split population structure: clade A1 (clonal complex 17) comprises the vast majority of clinical, multidrug-resistant isolates, while clade B includes largely commensal, less drug-resistant strains circulating in the community. Globally, most clinical isolates now belong to clade A1 (CC17), which is characterised by near-universal ampicillin resistance, frequent vancomycin resistance, and additional resistance to aminoglycosides and fluoroquinolones. Since its emergence, CC17 E faecium has disseminated globally, with distinct subclones predominating in specific regions and time periods. In Europe and North America, ST17 and ST117 have become the predominant sequence types, commonly associated with vancomycin resistance and implicated in bloodstream infections. Although vancomycin resistance rates remain high in the USA and low in Canada, they have been relatively stable in recent years. Genomic epidemiology has shown that Enterococcus faecalis is more genetically diverse than E faecium , with a highly recombinogenic genome and no clear separation into distinct clades. Early vancomycin-resistant E faecalis reports in the 1990s were sporadic and genetically diverse, but by the 2000s and 2010s, expansions of hospital-associated strains such as ST6, ST87, and ST179 became more prominent, particularly in Europe and North America, frequently producing beta-lactamase and exhibiting resistance to vancomycin, and high-level gentamicin. For Klebsiella pneumoniae and Escherichia coli, studies have focused on the surveillance of extended-spectrum-beta-lactamase (ESBL) producing clones. The most common epidemic clones associated with multidrug resistance in E coli were ST131, ST1193, and ST69. The majority of ESBL-producing strains are attributed to CTX-M alleles with CTX-M-15 and CTX-M-14 being the predominant genotypes. Since 2000, the emergence of CTX-M-27, a single-nucleotide variant of CTX-M-14, has been increasingly reported. ESBL rates among hospital-associated E coli infections showed increasing trends in North America, Europe, and in many countries in Southeast and East Asia. ESBL rates varied considerably for K pneumoniae across different countries (15%-60%) with high rates primarily detected in Asia and in Southern and Eastern Europe. K pneumoniae bacteraemia was characterized by diverse strains with only a few associated with clonal outbreaks and hypervirulence, such as ST20, ST23, ST258, ST1. Only one study has comprehensively integrated clinical, genomic, and antibiotic prescribing data. Pöntinen and colleagues (2024) examined E coli bloodstream infections, showing that non-penicillin β-lactam use influenced the success of widespread multidrug-resistant, extended-spectrum beta-lactamase (ESBL)-producing E coli clones. However, no previous study has combined longitudinal clinical, genomic, and antibiotic use data across multiple major pathogens. Added value of this study: To our knowledge, this study is the first to integrate longitudinal clinical, genomic, and antibiotic prescribing data for five key bacterial pathogens for an entire region over almost two decades. This combined dataset provides a unique opportunity to analyse the impact of changing antibiotic use on antimicrobial resistance trends across multiple organisms, as well as explore how pathogen-specific strains adapt to these changes over time.Implications of all the available evidence: This study underscores the critical importance of integrated, pathogen-specific surveillance programs for guiding antimicrobial stewardship. The observed association between declining fluoroquinolone prescribing and reduced resistance among Gram-positive pathogens illustrates the potential impact of targeted prescribing interventions. At the same time, the heterogeneous responses across bacterial species to this change in practice highlight that stewardship strategies must be tailored, rather than one-size-fits-all. Continuous genomic surveillance is essential for anticipating resistance shifts and enabling timely detection and response to emerging threats, particularly from high-risk clones with the capacity for rapid dissemination. Finally, reducing antimicrobial resistance will require an integrated approach with hospital-based interventions along with coordinated efforts in the community to limit transmission and overall antibiotic exposure.