Globally Emerging Resistance Patterns of Enterobacterales

Speaker: Dr. Sasheela Ponnampalavanar, Malaysia 

Key Highlights

Introduction:

The increasing global threat posed by carbapenem-resistant Enterobacterales (CRE) is highlighted, with a focus on metallo-β-lactamases (MBLs), OXA-48-like enzymes, PBP3 mutations, and hypervirulent CRE (hv-CRKP). Data from the International Nosocomial Infection Control Consortium (2015–2022) across 630 ICUs in 45 LMICs revealed high rates of device-associated infections (7.2%). Carbapenem resistance was observed in 50% of K. pneumoniae and 20% of E. coli and Enterobacter species.

Resistance Mechanisms in CRE:

Resistance in CRE is attributed to carbapenemase production (KPC, NDM, VIM, OXA-48) and non-carbapenemase mechanisms, including efflux pumps, porin mutations, and β-lactamase combinations. PBP3 mutations are identified as an emerging concern.

Regional Surveillance Trends (ATLAS, 2018–2022):

A rise in CRE rates is noted in Asia-Pacific, Latin America, the Middle East, and Africa (from 4–5% to 10–13%). Predominant carbapenemases include NDM and OXA-48 in Asia-Pacific, KPC and NDM in Latin America, and OXA-48 in the Middle East and Africa.

U.S. Surveillance and Clinical Implications:

In the U.S. (2019–2021), a decline in KPCs (73% → 60%) and an increase in NDMs (4% → 20%) were reported. These trends influence treatment guidelines, emphasizing the need for carbapenemase identification for targeted therapy.

Challenges in Low-Resource Settings:

Limited access to rapid molecular diagnostics and newer antibiotics (e.g., ceftazidime-avibactam, cefiderocol) in LMICs complicates empirical treatment. In some hospitals, fewer than five patients per year receive these agents.

Mortality and Impact of Early Therapy:

An Italian study (2019–2022) demonstrated:

OXA-48 Evolution and Spread:

ATLAS data (2018–2021) indicated a decline in OXA-48 gene prevalence, while OXA-232, OXA-181, and OXA-244 increased. Newer variants pose detection challenges due to weak hydrolysis and misclassification.

Epidemiological Variants of OXA-48:

Diagnostic Challenges:

OXA-48 enzymes often evade standard tests. Variants like OXA-244 exhibit low MICs, leading to false susceptibility results. Horizontal and vertical transmission, including chromosomal integration, facilitates silent spread.

Multidrug Resistance in OXA-48 Producers:

OXA-48-producing strains frequently co-harbor ESBLs, NDMs, KPCs, and porin/efflux mutations, resulting in resistance to aminoglycosides and fluoroquinolones. Limited treatment options include ceftazidime-avibactam, colistin, and tigecycline.

Beta-Lactamase Inhibitor Limitations:

OXA-48 is not inhibited by vaborbactam. In vitro susceptibility does not always correlate with clinical efficacy, and CLSI/EUCAST MIC breakpoints may be unreliable for OXA-48 variants.

PBP3 Insertions: A Growing Concern:

A four-amino-acid duplication in PBP3 causes resistance to cefiderocol, aztreonam, and ceftazidime-avibactam. These mutations are detected globally, including in the U.S., India, and Europe, often co-occurring with NDM/OXA carbapenemases.

Genomic Surveillance of PBP3 Mutants:

Analysis of global data (2003–2023) revealed:

Hypervirulent Carbapenem-Resistant K. pneumoniae (hv-CRKP):

ST23 hvKP strains now carry carbapenemases (KPC, NDM, OXA-181). The WHO (2024) reported hv-CRKP in 38 countries, with mortality reaching 75%, posing a significant infection control challenge.

Conclusion:

A rapid increase in CRE is observed in LMICs. Diagnostic gaps lead to misclassification and inappropriate treatment. Affordable diagnostics and genomic surveillance are urgently needed. Infection prevention and antimicrobial stewardship remain critical for resistance control.

Tailoring Treatment to Resistant Gram-Negative Bacteria: Newer Therapeutic Approaches

Speaker: Dr. Juan P. Horcajada, Spain

Key Highlights

Overview and Focus Areas:

The session is focused on treatment strategies for extended-spectrum β-lactamases (ESBLs), carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia.

ESBL Producers:

Carbapenems (imipenem/meropenem) are considered first-line but may be overly broad. Newer options such as cefepime-enmetazobactam are shown to have similar efficacy. The ALLIUM trial demonstrated a 73% cure rate with enmetazobactam compared to 51% with piperacillin-tazobactam.

CRE: KPC and OXA-48:

Ceftazidime-avibactam is noted to be active against both KPC and OXA-48, supported by meta-analyses. Meropenem-vaborbactam is effective against KPC but not OXA-48, with high clinical success observed. Aztreonam-avibactam is recommended for MBL producers.

MBL-Producing CRE (e.g., NDM, VIM):

The combination of ceftazidime-avibactam + aztreonam is highlighted as promising, showing lower mortality than polymyxins. Cefiderocol is reported to be effective against MBLs, with a 70% clinical cure rate and 12% mortality. Avibactam-based combinations, such as aztreonam-avibactam, demonstrate strong in vitro synergy.

Dual-Action Inhibitors:

Novel inhibitors like zidebactam, nacubactam, and cerobactam are discussed, which both inhibit β-lactamases and bind PBPs, enhancing antibacterial activity. Cefepime-zidebactam is noted for its low MICs and high potency against MBL producers.

Pseudomonas aeruginosa (Difficult-to-Treat):

A tailored approach is recommended based on resistance profiles:

Acinetobacter baumannii: Cefiderocol is available but not yet first-line in EU/US guidelines. Sulbactam-durlobactam is approved in the U.S. Emerging therapies such as rifabutin and macrocyclic peptides (e.g., SPR206) are under investigation.

Stenotrophomonas maltophilia: PK/PD modeling indicates that cotrimoxazole and levofloxacin have reduced activity. Cefiderocol and aztreonam-avibactam demonstrate strong in vitro efficacy.

Novel and Adjunctive Strategies: Apotransferrin, which reduces iron availability, is explored for inhibiting bacterial regrowth. Phage therapy is under investigation for P. aeruginosa infections.

Phosphomycin & Old Drugs: Fosfomycin IV is noted to be effective for ESBLs, as seen in the FOREST trial. Temocillin is reported to be non-inferior to ertapenem in the ASTARTE trial (Spain).

OXA-48 Resistance: If resistance to ceftazidime-avibactam emerges, imipenem-relebactam or cefiderocol may be considered. Alternative options include aminoglycosides, tetracyclines, or polymyxins.

Innovative Rapid Diagnostic Methodologies for Gram-Negative Pathogens

Speaker: Dr. Laurent Dortet, France 

Key Highlights

Introduction:

The complexity of defining "innovative" and "rapid" diagnostics was highlighted, with distinctions made between community-acquired infections (requiring identification only) and hospital-acquired infections (necessitating rapid antimicrobial susceptibility testing, particularly in immunocompromised patients). Focus was placed on Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii.

Rapid Identification Tools:

Three primary diagnostic modalities were discussed:

A caution was noted against over-reliance on molecular panels due to potential omissions of pathogens like Stenotrophomonas or Citrobacter.

Rapid Detection of Resistance Mechanisms:

Key resistance mechanisms, including ESBLs, carbapenemases (KPC, NDM, VIM, OXA-48), and colistin resistance, were addressed. The following tools were emphasized:

AI-Powered Phenotypic Prediction:

AI tools such as Carba Detector were highlighted for their ability to predict carbapenemase presence (~95% sensitivity, ~90% specificity) by analyzing disk diffusion zone diameters, supporting real-time clinical decision-making.

Rapid Phenotypic AST Technologies:

Emerging platforms aiming for AST results within 2–4 hours (some directly from blood or urine) were reviewed:

Blood Culture-Free AST:

A novel approach using magnetic nanoparticle capture was described, allowing direct bacterial concentration, species identification (via hybridization), and AST on microfluidic chips. This method achieved a total turnaround time of ~12 hours—44 hours faster than conventional protocols.

Metagenomics & Whole Genome Sequencing:

These comprehensive platforms were noted for their hypothesis-free detection of pathogens and resistance genes. However, limitations such as high cost, poor genotype–phenotype correlation, and complexity in polymicrobial samples were acknowledged.

Concluding Remarks:

Key takeaways included:

It was emphasized that successful implementation depends not only on technology but also on laboratory infrastructure, trained personnel, and clinical readiness to act on rapid results.

ESCMID Global, 11–15 April 2025, Vienna