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PubMed2026

Meropenem-Colistin Combination Mitigates Porin-Associated Carbapenem Resistance Development in Ertapenem-Mono-Resistant Enterobacterales.

BACKGROUND: Non-carbapenemase-producing Enterobacterales with isolated ertapenem resistance (ETP-mono-R) may represent an early stage in the evolution toward broader carbapenem resistance, but whether further resistance induction occurs and its underlying mechanisms remain poorly understood. METHODS: Resistance induction was assessed in three Escherichia coli, four Klebsiella pneumoniae, and two Enterobacter cloacae isolates through serial exposure to subinhibitory concentrations of meropenem (MEM), imipenem, ceftazidime-avibactam, or colistin (COL), with antibiotic-free passaging for reversion. Resistance induction under MEM+COL was evaluated separately. Whole-genome sequencing (WGS), targeted porin-gene Sanger sequencing, and transcriptional analysis were used to characterize resistance mechanisms across induction stages. RESULTS: Subinhibitory MEM exposure rapidly selected for carbapenem resistance through porin-associated alterations in a species-specific manner. E. coli accumulated loop-region mutations in ompC, while K. pneumoniae predominantly developed disruptive mutations in ompK36, both accompanied by marked transcriptional downregulation. In contrast, E. cloacae retained wild-type porins but showed increased MEM MICs, suggesting a non-porin-mediated mechanism. Subinhibitory exposure to COL alone rapidly induced colistin resistance but was associated with decreased carbapenem MICs. Co-exposure to MEM and COL significantly delayed resistance development and reduced MIC increases (all P < 0.05). Targeted sequencing of 26 non-carbapenemase-producing K. pneumoniae isolates resistant to all carbapenems revealed widespread disruptive ompK36 alterations, including the S337P substitution identified experimentally, consistent with a shared permeability-loss pathway. CONCLUSIONS: In ETP-mono-R Enterobacterales, subinhibitory carbapenem exposure promotes carbapenem resistance, with porin-associated mechanisms predominating in E. coli and K. pneumoniae. Co-exposure to COL attenuates this process, suggesting a potential strategy to delay the emergence of carbapenem resistance.

Enterobacterales↗

PubMed2025

Characterization of carbapenem-resistant Pseudomonas aeruginosa in Canadian hospitals: 6 years of the CANWARD study (2018-23).

OBJECTIVES: Antimicrobial resistance in Pseudomonas aeruginosa is of increasing concern in Canada, leading to limited treatment options and poor clinical outcomes. Herein we characterized carbapenem-resistant P. aeruginosa identified through the Canadian national surveillance program CANWARD. METHODS: Antimicrobial susceptibility for 1725 P. aeruginosa isolates was assessed using broth microdilution and 2024 CLSI breakpoints. WGS of carbapenem-resistant isolates was used to identify STs, resistance and virulence markers. Genetic relatedness was further assessed using cgMLST for select STs. RESULTS: From 2018 to 2023, CANWARD collected 1725 P. aeruginosa isolates, of which 371 (21.5%) were carbapenem-resistant. The majority of carbapenem-resistant P. aeruginosa were isolated from respiratory specimens of male patients aged 18-65 years living in central Canada. Only 0.8% (n = 3) of the carbapenem-resistant isolates harboured a carbapenemase gene. WGS identified mutations associated with OprD dysfunction, MexAB-OprM efflux and AmpC overexpression in 73.6%, 1.1% and 4.9% of isolates, respectively. Most isolates (98.1%) harboured at least one of the following class D β-lactamase genes: OXA-2, OXA-5, OXA-10 or OXA-50-like subfamily. Wide genetic diversity was observed with 151 different STs identified. The most common STs were ST17 (4.6%), ST27 (4.6%) and high-risk clones ST235 (4.3%), ST244 (3.5%), ST253 (6.4%) and ST357 (2.7%). cgMLST clusters were identified amongst 34.9% of the high-risk clones, suggesting clonal dissemination. CONCLUSIONS: Currently, >20% of clinical isolates of P. aeruginosa in Canada are carbapenem-resistant. Genetic evidence indicates that clonal dissemination of high-risk clones is occurring in Canada. High-risk clones are virulent and often MDR. Continued surveillance of P. aeruginosa is important.

Pseudomonas aeruginosa↗

PubMed2025

Characterization of blaOXA-542-mediated carbapenem resistance in Acinetobacter baumannii.

BACKGROUND: Carbapenem-resistant Acinetobacter baumannii (CRAB) causes multiple anatomical site infections, representing a significant public health threat. AIM: This study reports the isolation and characterization of a carbapenem-resistant A. baumannii harbouring blaOXA-542, followed by a comprehensive investigation of its antimicrobial resistance mechanisms and genomic characteristics. METHODS: Firstly, antimicrobial susceptibility testing was performed using the broth microdilution method. Subsequently, whole-genome sequencing was employed to identify and characterize the resistance and virulence determinants. The functional validation of resistance mechanisms was performed by gene knockdown and construction of expression vectors. The fitness cost of β-lactamase expression was identified by a bacterial growth kinetic test. Molecular docking was utilized to predict potential binding sites of β-lactamase and carbapenems. Finally, the genetic characteristics of the isolates were analysed through comparative genomics analyses and phylogenetic tree construction. RESULTS AND CONCLUSIONS: The results demonstrated that blaOXA-542 confers resistance to carbapenem and penicillin in A. baumannii and Escherichia coli while exhibiting no significant impact on cephalosporins. The ability of blaOXA-542 to hydrolyze meropenem was further confirmed by modified carbapenem inactivation assay (mCIM). Expression of blaOXA-542 in E. coli BL21 showed no significant growth rate alteration. Comparative analysis of the blaOXA-542 genetic environment revealed a close association with Acinetobacter pitti. This study reports the emergence of blaOXA-542-mediated carbapenem and penicillin resistance in a novel A. baumannii lineage (ST2795Pas/ST3464Oxf), highlighting the urgent need for rational antibiotic use against specific pathogens.

Acinetobacter baumannii↗

PubMed2026

Mobilization of blaVIM genes via the Tn6292 transposon among carbapenem-resistant Enterobacter cloacae complex isolates from colonized patients in a Spanish hospital.

UNLABELLED: The aim of this study was to perform molecular characterization of the carbapenem-resistant Enterobacter cloacae complex (ECC) isolates from colonized patients in a hospital using whole-genome sequencing (WGS) technology. As part of routine surveillance for multidrug-resistant bacterial colonization, 21 ECC isolates were recovered from patients at San Carlos Hospital in Madrid (Spain) between December 2020 and November 2024. WGS was used to determine their genetic relatedness. Furthermore, species identification, sequence type (ST), resistome, plasmid content, and flanking mobile genetic elements (MGEs) of the carbapenemase genes were derived from the WGS data. The most prevalent carbapenemase gene identified was blaVIM-1 (n = 18, 85.7%), with other notable genes including blaKPC-2 (n = 1, 4.8%), blaKPC-3 (n = 1, 4.8%), and blaOXA-48 (n = 1, 4.8%). Several blaACT and blaESBL variants were also found among the carbapenem-resistant ECC isolates. All of them carried at least one blaACT gene, with blaACT-7 (11/21) and blaTEM-type (14/21) genes being the most common AmpC and ESBL-encoding genes, respectively. Additionally, two isolates exhibited the presence of the mcr-9 gene. Overall, E. hormaechei subsp. steigerwaltii (ST93), followed by E. hormaechei subsp. hoffmanii (ST78 and ST50), were the predominant species and STs circulating among the carbapenem-resistant ECC strains. The blaVIM-1 gene was part of class 1 integrons located within a Tn3-family transposon, Tn6292. blaKPC and blaOXA-48 were linked to Tn4401 and Tn1999 transposons, respectively. In conclusion, the presence of the blaVIM within a transposon Tn6292 enhances its mobility across bacterial genomes, underscoring the value of high-throughput sequencing in monitoring the spread of carbapenem-resistant ECC isolates. IMPORTANCE: This study highlights why monitoring the spread of antibiotic-resistant bacteria in hospitals is critical. By analyzing the complete DNA of carbapenem-resistant bacteria, antibiotics were considered a last line of treatment. We found that the resistance genes are not isolated. Instead, they are embedded within mobile elements called transposons. This means that they can "jump" between different bacteria, accelerating the spread of resistance. These findings emphasize the importance of high-resolution genomic technologies to track and control the spread of these dangerous bacteria in clinical settings, helping preserve the effectiveness of life-saving treatments.

Humans↗

PubMed2026

Genomic Characterisation of Carbapenem-Resistant Klebsiella pneumoniae and Enterobacter hormaechei Clinical Isolates from Nigeria: Evidence of Resistance, Virulence, and Putative Plasmid-Mediated Gene Sharing.

The global proliferation of carbapenem-resistant Enterobacterales (CRE) constitutes one of the most urgent public health threats, yet high-resolution genomic data from sub-Saharan Africa remain critically scarce. We applied whole-genome sequencing (WGS) and comparative phylogenomics to characterise antimicrobial resistance determinants, virulence genes, and mobile genetic elements (MGEs) in three carbapenem-resistant clinical isolates originating from three tertiary hospitals (selected from a broader surveillance collection spanning four facilities) in Osun State, southwestern Nigeria. We purposively selected three isolates, two Klebsiella pneumoniae subsp. pneumoniae (K22, ST411; K31, ST17) and one Enterobacter hormaechei subsp. steigerwaltii (K32, ST45) from a broader surveillance collection of 27 carbapenem-non-susceptible Enterobacterales, to represent phenotypically and genotypically divergent lineages. Resistome analysis revealed extensive plasmid-associated β-lactam and aminoglycoside resistance in K31 (including blaCTX-M-15, blaOXA-1, and blaTEM-1). K32 harboured an intrinsic chromosomal blaACT-17 AmpC gene, while IS26 and ISEcp1 insertion sequences, consistent with transposon-mediated mobilisation, flanked its acquired aminoglycoside and sulfonamide resistance cassettes. K22 lacked detected acquired carbapenemase, ESBL, or plasmid-mediated AmpC genes, indicating that its carbapenem-resistant phenotype may involve non-carbapenemase mechanisms such as porin alteration or efflux-mediated reduced susceptibility; however, this mechanism requires confirmation by direct ompK35/ompK36 sequence analysis and/or phenotypic outer membrane protein profiling. Virulome profiling identified a broader repertoire of siderophore, adhesion, and biofilm genes in both K. pneumoniae isolates than in E. hormaechei. Phylogenomic analysis demonstrated that K22 and K31 cluster within the broader K. pneumoniae population framework but represent distinct high-risk lineages (ST411 and ST17) rather than a single clonal outbreak. Analysis also identified a shared plasmid backbone between K31 and K32, supporting interspecies horizontal gene transfer. These descriptive genomic findings identify clinically relevant resistance and virulence determinants in three purposively selected carbapenem-resistant Enterobacterales from Nigerian tertiary-care hospitals. The detection of shared resistance elements between K. pneumoniae and E. hormaechei suggests possible plasmid-mediated gene sharing. Still, larger WGS studies with long-read sequencing and patient-level epidemiological data are required to define transmission and dissemination patterns.

Nigeria↗

PubMed2025

Phenotypic and genotypic profiles of clinical isolates of various Nocardia species to carbapenems and fluoroquinolones.

OBJECTIVES: To establish patterns of the antimicrobial susceptibility of Nocardia species to carbapenems and fluoroquinolones and analysis of phenotypic-genotypic correlations. METHODS: Isolates were identified to the species using 16S rRNA, secA1, or rpoB gene sequencing analysis. The antimicrobial susceptibility testing was performed using the broth microdilution method, and WGS was employed to analyse the presence of resistance genes and/or mutations of Nocardia species against carbapenems and fluoroquinolones. RESULTS: Among 143 Nocardia isolates, N. farcinica (27.27%, 39/143) and N. cyriacigeorgica (25.17%, 36/143) were the most common species, followed by N. abscessus Complex (18.88%, 27/143). The MIC90s of the seven carbapenems were 8 mg/L for doripenem, 8 mg/L for meropenem, 16 mg/L for ertapenem, 16 mg/L for biapenem, 64 mg/L for imipenem, 64 mg/L for faropenem and 128 mg/L for tebipenem, respectively. The susceptibility rates to imipenem were 76.9% and 88.9% for N. farcinica and N. cyriacigeorgica, respectively, but only 14.3% and 0% for N. otitidiscavarium and N. brasiliensis, respectively. Further, 90% of N. brasiliensis and 50% of N. otitidiscaviarum isolates were susceptible and intermediate to meropenem. WGS identified blaFAR-1 gene in N. farcinica and blaAST-1 gene in N. cyriacigeorgica, respectively. The MIC90s of the four fluoroquinolones were 1 mg/L for sitafloxacin, 4 mg/L for nemonoxacin, 4 mg/L for moxifloxacin and 16 mg/L for ciprofloxacin, respectively. The susceptibility rate of Nocardia species to ciprofloxacin was low except for N. farcinica. The resistance to fluoroquinolones arise from mutations in the gyrA gene. CONCLUSIONS: Nocardia spp. exhibited varying patterns of susceptibility to carbapenems and fluoroquinolones respectively. Importantly, different Nocardia spp. exhibited different patterns of susceptibility to carbapenems and fluoroquinolones, respectively.

Nocardia↗

PubMed2025

Emergence of carbapenem-resistant Serratia marcescens co-harboring blaNDM-1, blaKPC-2, and blaSRT-2 in bloodstream infection.

Serratia marcescens is an emerging opportunistic pathogen with high genetic diversity. The emergence and prevalence of carbapenem-resistant S. marcescens poses a major health threat due to its intrinsic resistance to multiple antibiotics, which severely restricts the selection and treatment of antibiotics for S. marcescens infection. This study presents the first documented case in China of a bloodstream infection caused by Staphylococcus epidermidis and S. marcescens strain (designated S96) co-producing blaNDM-1, blaKPC-2, and blaSRT-2. Strain S96 exhibited resistance to nearly all categories of β-lactam antimicrobials, β-lactam/inhibitor combinations, aminoglycosides, quinolones, and other clinical antibacterial agents, with the exception of tigecycline. Our main objective was to characterize the genetic mechanisms underlying its carbapenem resistance and plasmid transfer potential. Whole-genome sequencing revealed blaKPC-2 on a 44,047 bp "IncX6-like" plasmid and blaNDM-1 on a 100,081 bp IncFII(Yp)-type plasmid, alongside chromosomal blaSRT-2 and aac(6')-Ic. "IncX6-like" and IncFII(Yp)-type plasmids are widely distributed among carbapenem-resistant Enterobacteriaceae strains globally. Conjugation experiments demonstrated that the blaNDM-1-carrying plasmid could be successfully transferred to recipient Escherichia coli 600, with no significant fitness cost observed (P > 0.05). The experimental results demonstrate that carbapenem-resistant genes can disseminate among Enterobacteriaceae via plasmid-mediated horizontal transfer between bacterial cells. Comparative genomic analysis revealed plasmid structural homology with global counterparts, demonstrating IS-mediated recombination and horizontal gene transfer. The low adaptive cost of plasmid carriage and multidrug resistance phenotype pose significant challenges for clinical management. This study highlights the need for enhanced clinical surveillance and antibiotic stewardship to curb the spread of such multidrug-resistant pathogens.IMPORTANCECarbapenem resistance in Serratia marcescens is primarily mediated by Klebsiella pneumoniae carbapenemase (KPC), with New Delhi metallo-β-lactamase (NDM) being a relatively uncommon alternative resistance mechanism. KPC-2 and NDM-1 coexisting in S. marcescens is extremely rare clinically. This study reports the first clinical isolate of S. marcescens in China co-harboring blaNDM-1, blaKPC-2, and blaSRT-2. The isolate exhibits multidrug resistance to nearly all β-lactam antibiotics and β-lactam/inhibitor combinations, with low adaptive costs and high dissemination potential. The potential spread of resistance genes through mobile genetic elements poses a serious public health risk. The study underscores the need for enhanced surveillance, rational antibiotic use, and novel strategies to combat resistance. It also provides insights into the evolutionary mechanisms of bacterial resistance, emphasizing the urgent need for interventions to address the growing threat of antimicrobial resistance.

Humans↗

PubMed2025

Comparative genomics of carbapenem-resistant Acinetobacter baumannii isolated from pediatric patients in a tertiary care hospital.

Acinetobacter baumannii is a short gram-negative bacillus, notable for its intrinsic multidrug resistance and genomic plasticity, which facilitates the acquisition of additional resistance genes via mobile genetic elements. Due to its increasing carbapenem resistance, the World Health Organization has classified it as a critical priority pathogen. This study performed a comparative genomic analysis of 20 carbapenem-resistant A. baumannii clinical strains isolated from the Hospital Infantil de México Federico Gómez (CRAB-HIMFG), alongside 11 genomes from other Mexican strains. The pangenome was determined to be open, and core genome single-nucleotide polymorphism-based analysis grouped the CRAB-HIMFG strains within CC758/IC5 and CC92/IC2. A novel sequence type (ST) in the MLST-Pasteur scheme was identified, related to STPas156, and in the MLST-Oxford scheme, associated with STOxf758 and STOxf1054. Virulence and resistance genes comprised 0.61% to 2.23% of the pangenome. Oxacillinase genes and efflux pumps primarily mediated carbapenem resistance, while virulence genes included those encoding biofilm and type IV pili. Capsule typing revealed a correlation with established international clones, IC2 and IC5. Plasmids exhibited high diversity, harboring maintenance modules and toxin-antitoxin systems, with the dissemination of resistance genes linked to insertion sequences. Biofilm formation and twitching motility were not always expressed, as they depend on additional environmental factors. Our study shows that comparative genomics is an essential tool to analyze clinically and epidemiologically significant genomes, providing critical insights into gene distribution, genomic architecture, and horizontal gene transfer mechanisms in microbial populations.IMPORTANCEIn recent years, a reported increase in the mortality rate associated with infections caused by A. baumannii, along with a rise in carbapenem resistance, poses a serious clinical challenge. The WHO considered this microorganism critical for research into alternative therapies and epidemiological surveillance. Despite advances in bioinformatics, genomic studies have yet to fully elucidate the structural rearrangements and secretion systems of A. baumannii. This knowledge gap hinders our understanding of its remarkable genomic plasticity and its ability to acquire and spread resistance and virulence genes through horizontal gene transfer.

Acinetobacter baumannii↗

PubMed2026

Occurrence of blaOXA-72 in a clinical isolate of carbapenem-resistant Acinetobacter pittii ST206 in Japan.

The development of carbapenem resistance in Acinetobacter spp., which are recognized as significant opportunistic pathogens, is of critical importance as it poses challenges to therapy and the control of healthcare-associated infections in clinical settings. This study investigated the genetic characteristics of a carbapenem-resistant A. pittii clinical isolate from a university hospital using whole-genome sequencing. The A. pittii strain SU8507, which was detected in the abdominal drainage fluid of a patient, exhibited resistance to imipenem (MIC: 128 μg/mL) and meropenem (MIC: 64 μg/mL) and produced positive results by the CIMTris method. A. pittii SU8507, belonging to ST206, harbored the blaOXA-72 and new variants of intrinsic blaOXA-213-like gene blaOXA-1222, which lacks an upstream insertion sequence element, and blaADC-1-like gene blaADC-343. The blaOXA-72 gene, flanked by XerC/XerD-like recombination sites, was located on a plasmid pSU8507, sized at 10,913 bp, carrying 13 predicted protein-coding genes. Complete pSU8507 containing mobA, repB, and the yoeB-yefM toxin-antitoxin genes, showed 98.9% nucleotide sequence identity and 75% coverage with plasmid pA2702 of the A. baylyi strain A2702, but a low BLAST MAX score. SU8507 harbored virulence genes involved in biofilm formation, types II and VI secretion systems, type IV pilus system, and serum resistance. This study describes the first isolation of an OXA-72-producing, carbapenem-resistant A. pittii clinical isolate in Japan. Given that the isolation rate of carbapenem-resistant Acinetobacter spp. Remains low in Japan, it is crucial to expand the scope of rapid, accurate carbapenemase detection to include not only A. baumannii, but also non-baumannii Acinetobacter spp.

Humans↗

PubMed2026

Carbapenem-resistant Gram-negative pathogens: molecular epidemiology, diagnostic advances, and emerging therapeutic strategies.

Carbapenem-resistant Gram-negative pathogens (CR-GNPs) have become an important global health problem, contributing significantly to healthcare-associated infections, extended hospital stays, high mortality rates, and higher healthcare costs. The dissemination of carbapenem resistance is mainly attributed to the spread of carbapenemase-encoding genes, such as the Klebsiella pneumoniae carbapenemase (KPC), the New Delhi metallo-β-lactamase (NDM), the Verona integron-encoded metallo-β-lactamase (VIM), the imipenemase (IMP), and the oxacillinase-48 (OXA-48)-like enzymes associated with clinically important Gram-negative pathogens, including Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa. As well as carbapenemase production, resistance can also develop via alteration of porins, upregulation of efflux pumps, and the buildup of several resistance factors, generating highly adaptable and hard-to-treat microbes. Phenotypic resistance patterns may not predict the underlying mechanism and accurate laboratory detection remains challenging. The identification and monitoring of carbapenem-resistant organisms have undergone improvement in recent years thanks to molecular diagnostics, rapid phenotypic tests, whole-genome sequencing and metagenomics. At the same time, new drugs have been developed, such as ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol and combinations of aztreonam, offering increased treatment options, but with emerging resistance an issue. This mini review covers the molecular epidemiology of CR-GNPs, the latest developments and challenges in diagnosing these infections, new therapeutic options, and future perspectives on genomic surveillance, antimicrobial stewardship, and precision medicine strategies to address the increasing threat of carbapenem resistance.

Gram-negative pathogens↗

PubMed2025

Molecular characterization of colistin resistance in carbapenem-resistant Klebsiella pneumoniae from a tertiary hospital in China.

Colistin resistance in carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a significant global health challenge, as colistin remains the last-resort antibiotic for treating multidrug-resistant K. pneumoniae infections. This study aimed to investigate the prevalence and molecular mechanisms underlying colistin resistance in CRKP (Colr-CRKP) isolates in Henan, China, from 2021 to 2024. The minimum inhibitory concentrations of colistin for 134 K. pneumoniae isolates were determined using the broth microdilution method. Whole-genome sequencing was performed using the Illumina platform to identify carbapenemase genes and sequence types (STs). Colistin resistance mechanisms were investigated, including mutations in two-component systems (pmrA/pmrB, phoP/phoQ), inactivation of the mgrB gene, and the presence of plasmid-mediated mcr genes. Most isolates were collected from intensive care units (99/134, 73.9%), with 48.5% (59/134) of patients having no documented colistin exposure history. Notably, ST11 was the predominant sequence type among Colr-CRKP isolates (113/134, 84.3%), all of which carried blaKPC-2 as the sole carbapenemase determinant. In contrast, seven non-carbapenemase-producing isolates exhibited phenotypic resistance to carbapenems. Genomic analysis revealed inactivation or loss of the mgrB gene in 53.7% (72/134) of isolates, predominantly due to insertion mutations (54/72). Although 32.8% (44/134) of isolates carried mutations in two-component systems, these alterations did not exhibit pathway-specific clustering. Intriguingly, plasmid-mediated mcr genes were detected in only 1.5% (2/134) of cases (mcr-8.2 and mcr-1.1), while 22.4% (30/134) of colistin-resistant strains lacked identifiable resistance determinants based on current detection methods. Our findings indicate that disruption of the mgrB gene is the primary mechanism of colistin resistance in ST11 CRKP clones. The emergence of resistance in 48.5% of patients without prior colistin exposure, combined with low mcr gene prevalence (1.5%) and unexplained resistance in 22.4% of isolates, suggests complex selective pressures beyond direct antimicrobial use. These findings underscore the urgent need for strengthened antimicrobial stewardship and the development of alternative therapeutic strategies to combat this high-risk pathogen.IMPORTANCEThe global rise of colistin-resistant Klebsiella pneumoniae, particularly in carbapenem-resistant Klebsiella pneumoniae (CRKP) strains, has severely restricted treatment options for multidrug-resistant infections. Our study provides the first comprehensive molecular characterization of colistin resistance in CRKP in a large tertiary hospital in central China. We identified mgrB disruption as the predominant resistance mechanism, while plasmid-mediated mcr genes were rare. Notably, nearly half of the resistant isolates occurred in patients without prior colistin exposure, suggesting alternative selective pressures driving resistance. These findings highlight the complex dynamics of colistin resistance in CRKP and underscore the need for enhanced genomic surveillance and stewardship interventions to limit further dissemination.

Colistin↗

PubMed2026

Variations in carbapenem resistance associated with the VIM-1 metallo-β-lactamase across the Enterobacterales.

The VIM-1 metallo-β-lactamase enzyme, encoded within class 1 integrons, is found in Gram-negative clinical isolates worldwide and has been linked to outbreaks of bacterial pathogens in nosocomial settings. Six vim-1+ clinical isolates, from the genera Escherichia, Klebsiella and Enterobacter, were obtained from Kingston, Ontario, Canada. Whole-genome sequencing revealed that vim-1 was plasmid-borne in all strains and situated as the first gene in In916 or In110 integrons. Analysis of related plasmids suggested that these vim-1-containing plasmids are globally disseminated and have spread via horizontal gene transfer and autochthonous vertical spread within Ontario. Interestingly, the MICs of ertapenem and meropenem, two clinically relevant carbapenem antibiotics, against these six isolates varied more than tenfold, suggesting that the effects of VIM-1 are dependent on the genomic content of the host microbe. Introducing vim-1 into three common Enterobacterales laboratory strains was not sufficient to confer resistance to ertapenem and meropenem. Instead, adaptive laboratory evolution of the vim-1 + laboratory strains revealed that vim-1-mediated carbapenem resistance in these strains was dependent on epistatic interactions with ompC mutations, likely due to decreased outer membrane permeability to these antibiotics. Together, these results provide additional support for the role of gene epistasis in modulating the antimicrobial resistance phenotypes of acquired resistance genes, as well as previous results suggesting that the presence of a β-lactamase gene is insufficient to confer strong resistance to carbapenems without being paired with reduced outer membrane permeability.

beta-Lactamases↗

PubMed2025

Molecular insights into the persistence and co-occurrence of two different carbapenem-resistant Pseudomonas aeruginosa lineages within a hospital setting.

UNLABELLED: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) represents a critical-priority pathogen capable of causing life-threatening, multidrug-resistant infections. We performed susceptibility testing, whole-genome sequencing, and bioinformatic analyses on 137 CRPA isolates from a Guangdong hospital. We found that the major specimen types were respiratory specimens (57/137, 41.6%) and bronchoalveolar lavage (42/137, 30.7%). All isolates were carbapenem-resistant but had low resistance to polymyxin B (0.7%, 1/137). IncP-6-positive isolates exhibited ≥2- to 32-fold higher resistance to 9/12 antibiotics (P < 0.05), with no difference to imipenem and meropenem. Fifty-four sequence types and 11 O-serogroups were identified, with ST1971 (6.6%) and O11 (29.9%) being predominant. Temporal and spatial patterns suggest persistent co-occurrence of clade 1 and clade 2 isolates, indicating potential nosocomial outbreak and clonal transmission. IMPORTANCE: The prevalence of carbapenem-resistant Pseudomonas aeruginosa (CRPA) has increased rapidly in recent years, yet few genetic and epidemiological studies on CRPA isolates have been performed. We performed susceptibility testing, whole-genome sequencing, and bioinformatic analyses on hospital isolates to investigate their resistance profiles and molecular epidemiology. These findings may offer new insights for developing effective global strategies to control CRPA and reduce untreatable infections in clinical settings.

Pseudomonas aeruginosa↗

PubMed2026

Mechanisms of cefiderocol resistance in carbapenem-resistant Acinetobacter baumannii: a Swiss 2023-2025 collection.

OBJECTIVES: The numbers of infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) are increasing globally and present a significant burden on healthcare systems. This study describes the CRAB isolates received at the Swiss National Reference Centre for Emerging Antibiotic Resistance (NARA) over a 3-year period, from January 2022 to December 2025, and aimed to characterize the prevalence and mechanisms of FDC resistance. METHODS: Two-hundred and thirty-four non-duplicate CRAB isolates were submitted to NARA over the study period from hospitals and laboratories across Switzerland. Susceptibility testing was performed by disk diffusion and broth microdilution, according to EUCAST methodology. Whole-genome sequencing was performed on 11 isolates. ADC alleles were cloned into vector pVRL1 and transformed into Escherichia coli Top10. RESULTS: All isolates exhibited resistance to the carbapenems, and most were resistant to cephalosporins. Most isolates harboured an acquired class D carbapenemase, most frequently OXA-23 (181/234; 77.4%). One quarter of isolates were resistant to cefiderocol (FDC), exhibiting MICs ranging from 4->32 mg/L. Whole genome sequencing analyses, performed on 11 FDC-resistant isolates, identified that FDC resistance was due a combination of mechanisms including NDM and PER-production, mutations within the iron transporters, piuA and pirA, and the overexpression of ADC variants. CONCLUSIONS: This study showed that OXA-23 was the dominant mechanism of carbapenem-resistance in CRAB in Switzerland. Almost one quarter of CRAB isolates were resistant to "last resort" antimicrobial, FDC. The mechanisms of FDC resistance identified in this study emphasise that resistance to this antimicrobial is often complex and multifactorial, requiring high-resolution methods, including WGS, to identify.

Acinetobacter baumannii↗

PubMed2025

Isolation and characterization of strictly lytic bacteriophages against carbapenem-resistant Enterobacter cloacae complex.

UNLABELLED: The global surge of carbapenem-resistant Enterobacter cloacae complex (CR-ECC) poses a significant clinical challenge due to limited treatment options. This study aimed to isolate and characterize lytic bacteriophages (phages) targeting CR-ECC. CR-ECC CYEBC080 was used as the bacterial host for isolating lytic phages, and a comprehensive evaluation was conducted on isolated phages, including phage stability under various pH and temperature conditions, host range analysis, killing curves, and therapeutic efficacy in Galleria mellonella larvae and a murine bacteremia model. Twelve lytic phages with distinct random amplified polymorphic DNA patterns were isolated, and transmission electron microscopy confirmed their classification under the Straboviridae family within the Caudoviricetes class. All phages remained stable across pH 3-11 for up to 90 minutes, with an optimal temperature range of 25°C-37°C. Among them, CYPEBC012 exhibited the broadest host range, lysing 93.75% of 80 CR-ECC isolates, while CYPEBC006 displayed the narrowest, lysing only 65%. Whole-genome sequencing revealed 12 phages with linear double-stranded DNA genomes ranging from 177,624 to 180,648 bp. Phage treatment administered at a multiplicity of infection of 10, 1 hour post-infection, significantly improved larval survival at day 7, reaching ≥80% in most groups, except CYPEBC001 (50%) and CYPEBC004 (60%) treatment groups. In CYEBC080-infected mice, CYPEBC012 treatment resulted in 100% survival by day 3 and 80% survival through day 7. Additionally, phage-treated mice exhibited significantly reduced bacterial loads and high phage titers in blood and liver. This study demonstrates the therapeutic potential of CYPEBC012 as a promising strategy against CR-ECC infections, offering an alternative to conventional antimicrobial treatments. IMPORTANCE: This study identified and characterized lytic bacteriophages targeting carbapenem-resistant Enterobacter cloacae complex, with CYPEBC012 exhibiting the broadest host range and significantly improving survival in a murine bacteremia model. Its stability and efficacy highlight its potential for clinical application. Our findings demonstrate that phage therapy offers a promising alternative to conventional treatments to combat antibiotic-resistant infections.

Animals↗

PubMed2026

Genetic characterization of carbapenem-resistant Klebsiella pneumoniae bloodstream isolates with reduced susceptibility to cefiderocol.

OBJECTIVES: To assess cefiderocol activity against carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream isolates collected before local clinical introduction and to characterize the distribution of borderline MIC elevation across major genomic backgrounds. METHODS: We retrospectively analyzed 389 episodes of K. pneumoniae bloodstream infection at a tertiary hospital in China during 2018-2024. All 83 carbapenem-resistant isolates underwent cefiderocol broth microdilution testing and whole-genome sequencing. For epidemiological analysis, reduced susceptibility was prespecified as an MIC of 4-16 mg/L and was not intended to replace clinical breakpoint interpretation. RESULTS: CRKP accounted for 21.3% of K. pneumoniae bloodstream infections and remained associated with in-hospital mortality after adjustment for infection severity and source. By CLSI criteria, 83.1% of isolates were cefiderocol susceptible; the MIC50 and MIC90 were 4 and 8 mg/L, respectively, and 41.0% met the reduced-susceptibility definition. ST11 predominated, with KL47 and KL64 as the main capsular loci. Cefiderocol MICs were higher among KL47/KL64 and virulence-plasmid-associated isolates than among comparator backgrounds. In multivariable analysis, bla NDM-1, bla SHV-12, and the aerobactin locus remained associated with reduced susceptibility, although the findings require cautious interpretation because of limited sample size and possible effects of clonal background. No inactivating mutations were identified in cirA, fepA, or fiu. CONCLUSIONS: Borderline cefiderocol MIC elevation was present before local drug exposure and was more frequent in locally prevalent ST11-KL47/KL64 and virulence-plasmid-associated CRKP. These findings provide a bloodstream-specific pre-introduction baseline and support prospective surveillance of numerical MIC distributions and associated genomic backgrounds.

Cefiderocol↗

PubMed2026

Silent carriage of tigecycline- and carbapenem-resistant Klebsiella quasipneumoniae co-harbouring tetX(4) and blaNDM-1 in healthy individuals in China.

OBJECTIVES: To investigate the occurrence and genomic characteristics of tigecycline- and carbapenem-resistant Klebsiella quasipneumoniae isolated from healthy individuals in China. METHODS: During a nationwide screening programme, faecal samples from healthy community individuals were cultured for carbapenem-resistant Enterobacterales. Antimicrobial susceptibility testing, whole-genome sequencing and conjugation assays were performed for two K. quasipneumoniae isolates co-harbouring tet(X4) and blaNDM-1. RESULTS: Two K. quasipneumoniae strains carrying tet(X4) and blaNDM-1 were recovered from healthy individuals without recent hospitalisation or antibiotic exposure. Both isolates showed resistance to tigecycline (>8 μg/mL) and carbapenems (≥4 μg/mL). Genomic analysis demonstrated close clonal relatedness between the isolates (ST6460-1LV, KL151). The blaNDM-1 gene was located on an IncX3 plasmid associated with mobile genetic elements, whereas tet(X4) was carried by an IncX1 plasmid. Conjugation assays confirmed successful transfer of both resistance genes, which frequently co-transferred into recipient strains. CONCLUSIONS: To our knowledge, this is the first report of K. quasipneumoniae co-harbouring tet(X4) and blaNDM-1 in healthy individuals in China. The findings indicate that healthy community populations may serve as a hidden reservoir for last-resort antimicrobial resistance genes and underscore the importance of community-based surveillance within a One Health framework.

Klebsiella quasipneumoniae↗

PubMed2025

Identification of a novel phage depolymerase against ST11 K64 carbapenem-resistant Klebsiella pneumoniae and its therapeutic potential.

UNLABELLED: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a clinical pathogen with a high mortality rate, and its clinical management and infection control have become a serious challenge. Phage-encoded depolymerase cleaves the capsular polysaccharide, a major virulence factor of K. pneumoniae. This study aimed to identify a phage depolymerase targeting ST11 K64 CRKP, evaluate its antimicrobial activity and therapeutic efficacy, and provide new alternative therapeutic strategies for K64 CRKP. Phages were screened from untreated hospital sewage using clinically isolated CRKP as the host bacterium. The host range, efficiency of plaque formation, optimal multiplicity of infection, adsorption efficiency, and one-step growth curve of phage vB_KpnP_IME1309 were determined by the double-layer agar plate culture method. The morphology of the phage was observed by transmission electron microscopy. Phage nucleic acids were extracted for whole-genome sequencing, and the phage-encoded depolymerase gene ORF37 was amplified by polymerase chain reaction. Next, a recombinant plasmid was constructed to induce depolymerase expression, which was verified using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In vitro bactericidal activity was determined using a combined serum assay, and the anti-K. pneumoniae biofilm effect of depolymerase was determined by crystal violet staining. Finally, a Galleria mellonella larvae infection model was established to investigate the therapeutic effect of depolymerase on larvae in vivo. Here, we isolated and characterized a phage vB_KpnP_IME1309 targeting ST11 K64 CRKP, which featured a latent period of 20 min and a burst size of approximately 290 plaque-forming units/cell. It contained 41 predicted open reading frames, of which ORF37 encoded depolymerase. The expressed and purified depolymerase Dep37 cleaved only ST11 K64 CRKP and formed a translucent halo on the agar plate. Dep37 increased the susceptibility of K. pneumoniae B1 to serum killing, inhibited CRKP biofilm formation, and degraded mature biofilms. The combination of Dep37 and kanamycin was significantly more effective in treating CRKP biofilms compared to either Dep37 or kanamycin alone. An injection of Dep37 at 5 min and 2 h after the CRKP infection of Galleria mellonella larvae increased their survival rates by up to 73% and 53%, respectively. Depolymerase Dep37 may be used as a potential method for capsule typing of K. pneumoniae, showing great promise for the development of novel alternative therapeutic strategies against ST11 K64 CRKP. IMPORTANCE: A novel phage vB_KpnP_IME1309 targeting ST11 K64 carbapenem-resistant Klebsiella pneumoniae (CRKP) was isolated and characterized. The ORF37 encoding depolymerase gene of phage vB_KpnP_IME1309 was successfully expressed and purified. Depolymerase increases the susceptibility of CRKP to serum killing, inhibits CRKP biofilm formation, and degrades mature biofilms. The combination of depolymerase and kanamycin is significantly more effective than either depolymerase or kanamycin alone in the treatment of CRKP biofilm. Depolymerase injection at 5 min and 2 h after CRKP infection of Galleria mellonella larvae increased the survival rate of larvae by up to 73% and 53%, respectively. Depolymerase Dep37 may be used as a method for the development of novel alternative therapeutic strategies against ST11 K64 CRKP.

Klebsiella pneumoniae↗