Understanding the Rising Threat of CCRE in European Healthcare

Carbapenem- and/or colistin-resistant Enterobacterales (CCRE) represent some of the most formidable pathogens in modern medicine. These bacteria, primarily species like Escherichia coli and Klebsiella pneumoniae, resist last-resort antibiotics such as carbapenems and colistin, leading to infections that are increasingly difficult to treat. In Europe, where healthcare systems handle millions of hospital admissions annually, CCRE pose a growing public health crisis. A groundbreaking multi-country study has now illuminated the extent of this challenge, revealing persistent spread and evolving resistance patterns across the continent.

The urgency stems from the fact that CCRE infections often occur in vulnerable patients—those undergoing surgery, with weakened immune systems, or in intensive care. Mortality rates can exceed 40% in some cases, far higher than for susceptible strains. This study not only quantifies the problem but underscores the pivotal role of genomic surveillance in curbing it, a field where European universities have led the charge.

The CCRE Survey: Methodology and Scope

Launched in 2019 under the European Antimicrobial Resistance Genes Surveillance Network (EURGen-Net), coordinated by the European Centre for Disease Prevention and Control (ECDC), the Carbapenem- and/or Colistin-Resistant Enterobacterales (CCRE) survey was a prospective, multicentre, cross-sectional effort. Over 300 hospitals in 36 European countries contributed data, collecting the first 10 non-duplicate isolates of carbapenem-resistant/increased exposure (R/I) or susceptible CCRE from clinical and screening samples, alongside matched susceptible comparators.

Each isolate underwent antimicrobial susceptibility testing (AST) for 19 agents per EUCAST guidelines, followed by central whole-genome sequencing (WGS) using Illumina NovaSeq at facilities like Sweden's Public Health Agency. Epidemiological details—patient demographics, hospital stay duration, prior admissions, and travel history—were pseudonymized and analyzed. This generated thousands of genomes: 548 E. coli (211 R/I) and 2,973 K. pneumoniae species complex (1,566 R/I) isolates from 156-302 hospitals.

Comparing to the 2013-2014 EuSCAPE survey, researchers used tools like Panaroo for phylogenomics, AMRFinderPlus for resistance genes, and Kleborate for K. pneumoniae virulence scoring. Universities such as the University of Oxford's Centre for Genomic Pathogen Surveillance drove the bioinformatics, while Karolinska Institutet (Sweden) and University of Groningen (Netherlands) handled sequencing and validation.

Key Findings on Escherichia coli: Warning Signs of Endemicity

For E. coli, 38.5% of 548 isolates were carbapenem-R/I, predominantly from urine (33.6%) and associated with hospital-acquired infections (73%). Five high-risk sequence types (STs)—ST131, ST410, ST38, ST167, ST648—accounted for 45.5% of R/I cases, spanning multiple countries. Alarmingly, carbapenemase genes were present in 86.3% of R/I isolates (up from 36.4% in EuSCAPE), with bla_NDM-5 surging to 34.1% (from 2%).

Phylogenetic trees revealed global clonal expansions imported into Europe, but mostly sporadic (only 4.7% closely related by ≤17 SNPs). Multidrug resistance was rampant, with 62.1% carrying extended-spectrum β-lactamases. University of Oxford researchers noted: "These trends suggest a high risk of endemicity without action."

Read the full E. coli paper in The Lancet Microbe for detailed phylogenies and ST distributions.

Persistent Circulation in Klebsiella pneumoniae: Evolving High-Risk Clones

K. pneumoniae showed even graver persistence: 89.3% of 1,566 R/I isolates carried carbapenemases (bla_OXA-48-like 31.1%, bla_KPC-3 24.8%). High-risk STs like ST258/512 (14.8%), ST101 (14.9%), and ST11 (13.3%) dominated, with emergents ST147 and ST307 expanding 2-4x since EuSCAPE. Virulence scores indicated 1.3% hypervirulent strains (up from 0.4%), mostly susceptible but acquiring resistance.

MDR reached 97.8% in R/I vs. 26.1% susceptible. Patterns varied: endemic in some regions, sporadic elsewhere. Université Libre de Bruxelles and University of Freiburg contributed key AST and genomic insights.

Access the K. pneumoniae analysis here.

European Universities at the Forefront: Collaborative Expertise

European higher education institutions were instrumental. The University of Oxford's Pandemic Sciences Institute led genomic analysis, developing tools for phylogeny and resistance prediction. Karolinska Institutet's clinical microbiology division sequenced hundreds of isolates, while University of Groningen's experts validated resistance profiles. University of Freiburg and Université Libre de Bruxelles provided epidemiological modeling, demonstrating academia's bridge between research and policy.

This pan-European effort, involving over 37 countries' labs, exemplifies how university networks like EURGen-Net foster genomic capacity. Training via ECDC's GenEpi-BioTrain equipped labs for routine WGS, a model for global AMR surveillance.

Heterogeneous Spread: Country-Level Variations and Risk Factors

Resistance patterns differed starkly: Southern Europe saw higher endemicity (e.g., Greece's ST39 clone across 12 hospitals), while Northern countries reported sporadic imports. Risk factors included prior hospitalization (43.6% R/I cases), international travel (14.2%), and ICU stays. Phylogenetic evidence pointed to hospital networks as transmission hubs, with plasmids driving gene mobility.

Early Greek detection via the survey prompted a 2022 follow-up, curbing an outbreak—proof of surveillance's value.

Implications for Public Health and Infection Control

The survey warns of a "deteriorating landscape": without enhanced infection prevention (IPC), stewardship, and genomic early-warning, CCRE could become endemic. Dr. Sophia David (Oxford) emphasized: "We need coordinated, genomic-led systems across Europe." Professor David Aanensen added urgency for global networks like CASA.

Hospitals must prioritize screening, isolation, and antibiotic audits. The ECDC report offers reference genomes for diagnostics.

Towards Routine Genomic Surveillance: CRE25 and Beyond

Building on CCRE, the CRE25 survey (ongoing) simplifies protocols for annual WGS of CRE, with rapid ECDC reporting. Supported by EU4Health and HERA, it aims for real-time tracking. Universities continue training via EURGen-RefLabCap, ensuring sustained capacity.

Challenges in Genomic AMR Tracking

Challenges include voluntary participation (69% NUTS-2 coverage), sequencing costs, and data integration. Uneven lab capacities persist, with some countries lagging in WGS. Global imports complicate containment, demanding international collaboration.

Solutions and Actionable Insights from Academia

European universities propose: standardized WGS pipelines, AI for outbreak prediction (Oxford pilots), and plasmid tracking. Enhanced stewardship reduced colistin use, curbing resistance. Policymakers should fund routine surveillance, mirroring successes in Greece.

Stakeholder Perspectives: From Labs to Policymakers

ECDC's Marc Struelens hailed genomic data's "critical role." University researchers advocate "one-health" approaches, linking human-animal-environmental surveillance. Patient groups call for transparency in hospital outbreaks.

Future Outlook: Europe's Path to AMR Mastery

With CRE25 underway, Europe leads genomic AMR surveillance. Universities like Oxford and Karolinska will drive innovations, potentially averting a post-antibiotic era. Investments in training and infrastructure promise proactive defense, safeguarding millions.

Photo by Marcus Urbenz on Unsplash