Search Results (130)

Carbapenem-resistant Enterobacterales (CRE) are a major public health concern, yet genomic data from Bulgaria remain limited. We investigated the genomic epidemiology and genomic characteristics of clinically significant CRE recovered at University Hospital “Lozenetz”, Sofia, between 2022 and 2025. Antimicrobial susceptibility testing, phenotypic carbapenemase characterization, and PCR were combined with whole-genome sequencing of 23 purposively selected isolates chosen to capture temporal, species, carbapenemase, specimen, ward, and resistance-phenotype diversity. The proportion of CRE among all Enterobacterales remained broadly stable over the study period, and Klebsiella pneumoniae was the predominant species throughout. NDM-type carbapenemases were the most frequent overall, although VIM-, KPC-, and OXA-48-like enzymes were also detected. Among the sequenced isolates K. pneumoniae ST6260 (n = 16) was predominant. The remaining isolates included single K. pneumoniae isolates belonging to ST11, ST101, and ST258; two Enterobacter hormaechei ST114; one Proteus mirabilis ST93; and one Providencia stuartii ST46. All ST6260 isolates carried chromosomal blaNDM-5 within a conserved multidrug-resistance module with variable downstream regions, whereas blaOXA-232 was situated on a small ColKP3 plasmid within a defined subcluster. Overall, the data indicate that ST6260 is an emerging hospital-associated multidrug-resistant lineage. Full article

Carbapenem-resistant Enterobacterales (CRE) represent one of the most important antimicrobial resistance threats in Europe, particularly in healthcare settings. Their increasing epidemiological significance is driven by the dissemination of carbapenem-resistant Klebsiella pneumoniae, the emergence of high-risk clones, horizontal transfer of mobile genetic elements, and the convergence of antimicrobial resistance and hypervirulence. Despite the growing epidemiological importance of CRE, surveillance and preparedness remain heterogeneous across European countries, creating a need for a continent-wide assessment of existing surveillance systems, implementation gaps, and emerging challenges. This narrative review summarizes the current epidemiology of CRE in Europe and critically discusses the role of European and global surveillance systems in monitoring their spread. Particular attention is given to the European Antimicrobial Resistance Surveillance Network (EARS-Net), European Antimicrobial Resistance Genes Surveillance Network (EURGen-Net), Healthcare-Associated Infections Surveillance Network (HAI-Net), European Surveillance of Antimicrobial Consumption Network (ESAC-Net), Point Prevalence Survey (PPS), EpiPulse/TESSy, the Central Asian and European Surveillance of Antimicrobial Resistance (CAESAR) programme, and the World Health Organization Global Antimicrobial Resistance and Use Surveillance System (WHO GLASS). Although Europe has well-established surveillance infrastructures, substantial heterogeneity persists among countries with respect to microbiological and genomic diagnostic capacity, reporting practices, infection prevention and control (IPC), antimicrobial stewardship, healthcare infrastructure, and implementation of national policies. These differences limit data comparability and may delay the detection of colonization, outbreaks, and cross-border transmission. The available evidence indicates that effective CRE control requires integrated surveillance combining microbiological, genomic, epidemiological, and antimicrobial consumption data within a coordinated One Health framework. Further expansion of genomic surveillance, harmonization of surveillance indicators, strengthening of healthcare system preparedness, and wider implementation of antimicrobial stewardship programmes are identified as priority areas for improve CRE prevention and control across Europe. By integrating evidence across surveillance, diagnostics, infection prevention and control, and antimicrobial stewardship, this review highlights key gaps in current European approaches and provides a framework for prioritizing future surveillance and preparedness efforts. Full article

Background/Objectives: The epidemiology of carbapenem-resistant Klebsiella pneumoniae (CR-Kp) in Europe is evolving towards an increasing contribution of metallo-β-lactamases (MBLs). In particular, co-production of New Delhi metallo-β-lactamase (NDM) and OXA-48-like carbapenemases represents a major concern due to limited therapeutic options and epidemic potential. We aimed to describe temporal trends and genomic characteristics of NDM and OXA-48-like co-producing K. pneumoniae within a regional surveillance programme targeting ceftazidime-avibactam (CZA)-resistant carbapenem-resistant Enterobacterales (CRE) in the Latium Region, Italy. Methods: Between January 2019 and December 2025, CZA-resistant CRE isolates were collected through a regional surveillance network. Antimicrobial susceptibility testing and carbapenemase detection were performed, and NDM-producing K. pneumoniae (NDM-Kpn) was analysed by whole-genome sequencing (WGS). Genomic analyses included multi-locus sequence typing, assessment of clonal relatedness, and resistome/virulome profiling. Results: A total of 2752 non-repetitive CZA-resistant CRE were collected. The analysis of CZA-resistant K. pneumoniae isolates submitted to the regional surveillance network showed that the proportion of NDM producers increased markedly from 2023 onwards. In particular, NDM in association with OXA-48-like reached 26.0% in 2024 and 43.6% in 2025, becoming the predominant carbapenemase profile within this selected surveillance population. WGS of 437 NDM-Kpn revealed a structured population dominated by Sequence Type (ST)147 (63.2%), widely disseminated across 24 hospitals and characterised by a predominant NDM-1 variant and OXA-48-like co-producing profile associated with KL10/wzi420 capsular type. A subset of isolates, mainly within the ST147-KL64 subgroup, showed higher virulence scores, indicating a possible convergence of resistance and virulence. Conclusions: Our findings indicate a rapid shift towards NDM-mediated resistance among CZA-resistant K. pneumoniae submitted to the regional surveillance network, with the emergence of NDM and OXA-48-like co-producing isolates associated with a dominant ST147 clone detected across multiple hospitals. These results highlight the urgent need for coordinated genomic surveillance and infection prevention strategies. Full article

Understanding the functional potential of the gut microbiota for carbapenem-resistant Enterobacterales (CRE) decolonisation is essential for developing novel non-antibiotic strategies to promote their clearance. In a previous study, we identified distinct taxonomic signatures associated with spontaneous CRE decolonisation (DeCol). Here, we aimed to determine whether these taxonomic differences were accompanied by differences in the predicted functional potential of the gut microbiota. Patients were identified from a database of individuals colonised with CRE. We performed Illumina shotgun metagenomic sequencing on 14 persistent CRE carriage (Col) and 23 DeCol patients with OXA-48-producing isolates. Bioinformatic analysis was performed using SqueezeMeta and differential abundance of functional and metabolic genes was assessed using DESeq2. Several antimicrobial resistance genes, including blaOXA-48, were underrepresented in DeCol patients. In contrast, DeCol patients showed an overrepresentation of genes associated with motility, regulated adhesion, short-chain fatty acid (SCFA)-related pathways and alternative carbohydrate metabolism. These orthologue enrichment patterns are consistent with functions previously linked to intestinal homeostasis in the literature. Conversely, Col patients exhibited an overrepresentation of genes associated with redox defence, biofilm formation and amino acid metabolism, suggesting distinct predicted functional profiles between persistent carriage and spontaneous decolonisation. Spontaneous CRE decolonisation was associated with distinct KEGG-based functional signatures and a lower abundance of antimicrobial resistance determinants. These functional profiles were consistent with the taxonomic differences previously identified in the same cohort and generate hypotheses regarding microbiome functions that may contribute to colonisation clearance. Because these findings are based on gene-content analysis, they reflect predicted functional potential rather than direct evidence of metabolic activity. Further multi-omics and experimental studies are required to validate these observations. Full article

Background: Carbapenem-resistant Enterobacterales (CRE) are a major therapeutic challenge, particularly in settings where metallo-β-lactamases are prevalent. Aztreonam–avibactam (AZA) may provide activity against metallo-β-lactamase-producing isolates, whereas ceftazidime–avibactam (CZA) has limited activity against the isolates that harbor these enzymes. This study aimed to evaluate the in vitro activity of aztreonam–avibactam and ceftazidime–avibactam against invasive carbapenem-resistant Enterobacterales isolates and to characterize the distribution of carbapenemase genes in a tertiary-care center in Türkiye. Methods: A total of 100 non-duplicate CRE isolates recovered from blood cultures and sterile body fluids between January 2024 and January 2026 were included. Species identification and routine antimicrobial susceptibility testing were performed using MALDI-TOF MS and an automated system. CZA and AZA MICs were determined by gradient diffusion testing, whereas CZA–aztreonam synergy was assessed separately using a disk/gradient diffusion-based method. Carbapenemase genes were detected by real-time PCR. Whole-genome sequencing was performed for the two AZA-resistant Escherichia coli isolates. Results: The isolate collection was dominated by Klebsiella pneumoniae (87.0%), and most isolates were recovered from blood cultures (80.0%). CZA susceptibility was observed in 31.0% of isolates, with MIC_50/90 values of 256/256 mg/L. In contrast, AZA showed high in vitro activity, with 98.0% of isolates categorized as susceptible and MIC_50/90 values of 0.25/0.50 mg/L. CZA–aztreonam synergy was detected in 98.0% of isolates. Qualitative CZA–aztreonam synergy testing did not fully concord with direct AZA MIC-based susceptibility categorization: one AZA-resistant isolate showed a positive synergy result, whereas one synergy-negative isolate remained AZA-susceptible. Carbapenemase genes were detected in 99.0% of isolates; bla_NDM was the most frequent gene (81.0%), followed by bla_OXA-48 (72.0%), bla_KPC (14.0%), and bla_VIM (4.0%). The most common carbapenemase profile was bla_NDM + bla_OXA-48 (62.0%). bla_NDM carriage was strongly associated with CZA resistance, and CZA MICs were significantly higher among bla_NDM-positive isolates. The two AZA-resistant E. coli isolates belonged to ST500 and ST410, and both carried a YRIK insertion in PBP3; one of them additionally showed ompF disruption associated with a 4 bp insertion. Conclusions: AZA demonstrated potent in vitro activity against invasive CRE isolates in this setting, whereas CZA activity was substantially limited, likely reflecting the high prevalence of bla_NDM and frequent carbapenemase co-carriage. These findings support the potential value of AZA in regions with emerging metallo-β-lactamase predominance and highlight the importance of local molecular surveillance to guide antimicrobial strategies. Full article

Longitudinal data on carbapenem-resistant Enterobacterales (CRE) from Saudi secondary healthcare settings remain limited. This study evaluated eight-year antimicrobial resistance trends among CRE isolates to provide locally relevant evidence for antimicrobial stewardship and empiric therapy. This retrospective surveillance study analyzed Enterobacterales isolates recovered from clinical specimens between 2017 and 2024 from a Saudi healthcare setting. Isolates were deduplicated by including only the first isolate per patient per year. CRE were defined as Enterobacterales demonstrating non-susceptibility to imipenem or meropenem. Demographic data, specimen sources, species distribution, and antimicrobial resistance profiles were summarized descriptively. Temporal trends in CRE prevalence and antimicrobial non-susceptibility were evaluated using logistic regression. Factors associated with CRE were assessed using multivariable logistic regression analyses. A total of 2378 Enterobacterales isolates were identified, of which 684 (28.8%) were CRE. CRE prevalence increased significantly over the study period, rising from 9.5% in 2017 to a peak of 40.1% in 2021 before declining to 27.1% in 2024. Multivariable logistic regression demonstrated that collection year (adjusted OR 1.12, 95% CI 1.08–1.17; p < 0.0001), male sex, and specimen source were independently associated with CRE. Klebsiella pneumoniae was the predominant species. High non-susceptibility rates were observed for cephalosporins and fluoroquinolones, while aminoglycosides and tigecycline demonstrated comparatively lower resistance. Significant temporal trends in non-susceptibility were observed for cefepime, ceftazidime, ciprofloxacin, and tigecycline. CRE represented a substantial proportion of Enterobacterales isolates and demonstrated extensive antimicrobial resistance. These findings highlight the importance of continuous local surveillance to inform empirical antimicrobial therapy, support antimicrobial stewardship, and monitor evolving resistance patterns. Full article

Background: The alarming increase in the number of new bacterial defense mechanisms is exacerbating the problem of antibiotic resistance and poses a serious obstacle to the treatment of bacterial infections. Despite the approval of numerous new antibiotics by the Food and Drug Administration (FDA) and European Medicines Agency (EMA), mainly from the beta-lactam group since 2000, only some of them possess unique mechanisms of action and activity against multidrug-resistant Gram-negative bacilli (MDR GNB), including carbapenem resistance. Eravacycline (EVT), formerly known as TP-434, is a newly developed non-beta-lactam, fully synthetic tetracycline derivative, approved for the treatment of complicated intra-abdominal infections (cIAIs) in adults. Results: The analysis demonstrated significant efficacy of EVT across a wide range of in vitro and in vivo studies against MDR GNB, including carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Enterobacterales (CRE) and Gram-positive vancomycine-resistant pathogens. Conclusions: The broad spectrum of activity and favorable safety profile of EVT are well-documented in the treatment of critically ill patients. However, its efficacy against clinically relevant Gram-negative bacteria varies depending on specific species and resistance phenotypes, particularly among carbapenem-resistant and extensively drug-resistant (XDR) isolates. Full article

Background: International evidence supports early initiation of ceftazidime-avibactam (CAZ-AVI) in carbapenem-resistant Enterobacterales (CRE) infections, with superior outcomes when therapy is initiated within 72 h. The applicability of this principle to the United Arab Emirates (UAE) requires contextualization against local antimicrobial resistance epidemiology. Methods: This consensus narrative review integrates two evidence streams: (1) national AMR surveillance data from the UAE National Antimicrobial Resistance Surveillance Report 2024—encompassing 195,108 non-duplicate isolates from 318 surveillance sites across all seven Emirates—providing phenotypic susceptibility and resistance rates for key gram-negative pathogens; and (2) a structured review of the published international evidence base on CAZ-AVI clinical efficacy, outcome data, and timing, identified through PubMed searches using the terms “ceftazidime-avibactam”, “empiric therapy”, “carbapenem-resistant Enterobacterales”, and “nosocomial infections”. The risk-stratification framework was developed through expert consensus by the authoring group, informed by the integrated evidence synthesis and structured around established clinical risk factors for carbapenem-resistant gram-negative infection. Results: National carbapenem resistance among Enterobacterales remains low (imipenem 3.4%R; meropenem 1.4%R), with Klebsiella pneumoniae exhibiting the highest carbapenem non-susceptibility (imipenem 5.8% NS; meropenem 2.8% NS). Direct CAZ-AVI susceptibility testing data were available only for Pseudomonas aeruginosa at the emirate level, showing consistently high susceptibility (88–93% across Abu Dhabi, Dubai, and the Northern Emirates); dedicated CAZ-AVI susceptibility data for Klebsiella pneumoniae and Escherichia coli were not reported in any emirate-level antibiogram, representing a significant national surveillance gap. The absence of carbapenemase genotype data (OXA-48 versus NDM/MBL) in the national surveillance dataset is identified as a further critical gap. Conclusions: CAZ-AVI is not supported as a universal empiric therapy for all nosocomial pneumonia in the UAE. A risk-stratified approach is proposed: standard anti-pseudomonal beta-lactams for general nosocomial infections, and early CAZ-AVI for pre-defined high-risk CRE-suspected patients, where the timing benefit is operationally justified primarily by the international outcome evidence, given that UAE-specific CAZ-AVI phenotypic data are currently available only for P. aeruginosa. Investment in carbapenemase molecular surveillance and expanded CAZ-AVI susceptibility reporting is recommended as a national priority to enable precise empiric prescribing. Full article

Background: MDRO colonization at ICU admission may identify patients at increased risk for hospital-acquired infection (HAI), but its independent predictive value remains incompletely defined. Methods: We conducted a retrospective observational study of 560 consecutive ICU admissions (July–October 2024). Admission screening assessed colonization with extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales, carbapenem-resistant Enterobacterales (CRE), and vancomycin-resistant enterococci (VRE). The primary outcome was microbiologically confirmed HAI; the secondary outcome was in-hospital mortality. Associations were evaluated using multivariable logistic regression, ROC/AUC analysis, mediation analysis, and a sensitivity analysis restricted to first admissions. Results: Of 560 admissions, 223 were screen-positive and 283 screen-negative. HAI occurred in 49 patients (8.8%). Positive screening was associated with increased HAI odds, narrowly missing significance in the primary adjusted analysis (OR 1.81, 95% CI 0.96–3.41, p = 0.065) but reaching significance in the first-admission sensitivity analysis (OR 2.09, p = 0.034). CRE showed the strongest adjusted association with HAI (OR 2.33, 95% CI 1.21–4.51, p = 0.012). Screening alone showed poor discrimination (AUC 0.574); combined with clinical variables, discrimination improved substantially (AUC 0.788). Conclusions: MDRO admission screening was associated with increased HAI odds, particularly for CRE, though screening alone has limited predictive performance. Larger prospective studies are needed to confirm these findings. Full article

Antimicrobial resistance is a growing threat in neonatal intensive care units (NICUs) worldwide, challenging the management of neonatal sepsis for decades. The aim of this narrative review is to compare the epidemiology and resistance patterns of neonatal sepsis in NICUs between two periods, 2000–2005 and 2020–2025, and to identify key insights that may inform future practices to limit the emergence and dissemination of antimicrobial resistance in NICUs. During the early 2000s, resistant pathogens, including extended-spectrum beta-lactamases (ESBL)-producing Enterobacterales, vancomycin-resistant Enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), and coagulase-negative Staphylococci (CoNS), were increasingly reported in NICUs. The increasing prevalence of antimicrobial resistant strains was associated with the widespread use of broad-spectrum antibiotics, exerting selective pressure that contributed to the emergence of multidrug-resistant pathogens in the 2020s, including carbapenem-resistant Enterobacterales (CRE) and multidrug-resistant Acinetobacter baumannii, and to the further dissemination of resistant strains in NICUs. The evolution of antimicrobial resistance over the past twenty years highlights that preserving the effectiveness of antibiotics, through rational antibiotic use, is a key strategy to limit the emergence of resistant pathogens. This is of particular importance for the neonatal population due to the limited therapeutic options. Although antimicrobial stewardship programs have been implemented in numerous NICUs with encouraging results, optimization of antibiotic use requires the identification of biomarkers that can promptly and accurately diagnose sepsis and the development of new effective antimicrobial agents against multidrug-resistant pathogens. Future research is expected to improve diagnostic precision, therapeutic options, and stewardship strategies to limit the spread of antimicrobial resistance. Full article

Objectives: Carbapenem-resistant Enterobacterales (CRE) limit treatment options, and cefiderocol’s efficacy can be compromised by regional carbapenemases. In this study, we aimed to characterize cefiderocol susceptibility distribution among Enterobacterales in Japan—specifically endemic strains producing IMP-type carbapenemases (IMP)—and explore the effect of IMP in mediating resistance. Methods: The susceptibility of 556 evaluable Enterobacterales isolates (from an initial 560 screened) to cefiderocol was assessed using disk diffusion and broth microdilution methods based on Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) distributions across groups were compared using Kruskal–Wallis and Mann–Whitney U tests. Results: A total of 556 isolates yielded evaluable results. The cefiderocol susceptibility rate was 99.5 and 98.7% based on CLSI and European Committee on Antimicrobial Susceptibility Testing breakpoints, respectively. Notably, under both criteria, IMP-producing isolates exhibited a susceptibility rate of 99.6%, whereas non-CRE and non-extended-spectrum β-lactamase (ESBL) exhibited a susceptibility rate of 99.4%. Statistical analysis revealed that the ESBL-only group had higher MICs than the non-CRE/non-ESBL and IMP-only groups (both p < 0.001), whereas no significant difference was observed between the latter two (p = 0.083). Notably, the ESBL-only group exhibited higher MICs than those of isolates harboring both IMP and ESBL. Conclusions: These findings indicate a non-additive effect, in which the coexistence of multiple resistance enzymes does not necessarily increase cefiderocol resistance. The association between IMP and cefiderocol resistance may be limited. In specific enzyme combinations, its presence was even associated with lower MICs. Full article

Background: The COVID-19 pandemic disrupted healthcare systems and antimicrobial stewardship, potentially altering antimicrobial resistance patterns. This study characterized temporal changes in the proportions of multidrug-resistant organisms (MDROs) and identified associated factors before and during the pandemic at a tertiary care hospital in northeastern Thailand. Methods: A single-center retrospective observational study was conducted at Roi Et Hospital, including 5458 culture-confirmed MDRO cases (2017–2022), stratified into pre-pandemic (2017–2019) and pandemic (2020–2022) periods. Pathogen-specific resistance proportions were compared using odds ratios (ORs) with 95% confidence intervals (CIs). Multivariable logistic regression identified independently associated factors within each period. Results: The proportion of MDRO cases classified as hospital-acquired increased from 40.71% to 57.41% (p < 0.001). Carbapenem-resistant Acinetobacter baumannii (CRAB) increased markedly (22.87% to 76.11%; OR 10.75, 95% CI 9.43–12.26), followed by carbapenem-resistant Enterobacterales (CRE) (4.05% to 21.61%; OR 6.54, 95% CI 5.84–7.32) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) (14.32% to 27.15%; OR 2.23, 95% CI 1.87–2.65; all p < 0.001). Vancomycin-resistant Enterococcus (VRE) declined significantly (OR 0.41, 95% CI 0.25–0.68; p < 0.001). Methicillin-resistant Staphylococcus aureus (MRSA) showed a higher proportion among clinical isolates (3.28% to 6.34%; OR 2.01, 95% CI 1.42–2.83), although without a consistent annual trend. In multivariable analyses, ICU admission was independently associated with lower odds of CRE (aOR 0.52) and CRPA (aOR 0.63) and with higher odds of CRAB (aOR 2.13; all p < 0.001). Conclusions: The COVID-19 pandemic was associated with a major proportional shift toward carbapenem-resistant Gram-negative pathogens, with distinct profiles of associated factors across CRAB, CRE, and CRPA. These findings highlight the need for pathogen-specific infection prevention and antimicrobial stewardship strategies during healthcare system disruptions. Full article

Background: Carbapenem-resistant K. pneumoniae (CRKP) represents a major challenge in hospitalized patients because of its association with healthcare exposure, restricted antimicrobial options, and adverse clinical outcomes. Microbiological isolation alone does not define invasive disease; therefore, clinical interpretation requires separation of colonization, localized infection, invasive infection, and carbapenem-resistant Enterobacterales (CRE)-associated sepsis. This study evaluated epidemiological features, resistance phenotypes, treatment adequacy, and clinical outcomes among hospitalized adults with K. pneumoniae isolates, using a clinical framework that distinguishes colonization from active infection and invasive disease. Methods: This single-center retrospective observational cohort study included 157 consecutive adults admitted between January and July 2025 to a tertiary-care hospital with at least one microbiologically confirmed K. pneumoniae isolate recovered from clinical specimens and/or CRE surveillance rectal swabs. Isolates were assigned hierarchically to four mutually exclusive phenotypic groups: carbapenem-susceptible K. pneumoniae (CSKP), extended-spectrum beta-lactamase (ESBL)-producing carbapenem-susceptible K. pneumoniae (ESBL), carbapenem-resistant non-carbapenemase-producing K. pneumoniae (CRKP), and carbapenemase-producing K. pneumoniae (CP-KP). A prespecified secondary analysis compared carbapenem-resistant isolates (CRKP + CP-KP) with non-carbapenem-resistant isolates (CSKP + ESBL). Clinical adjudication distinguished colonization-only cases, non-invasive infection, bloodstream infection, device-associated infection, and CRE-associated sepsis; ventilator-associated pneumonia (VAP) was considered when source data allowed reliable attribution. Sepsis was defined according to Sepsis-3 criteria; quick Sequential Organ Failure Assessment (qSOFA) was used only as a bedside screening tool. Statistical tests were selected according to variable type, distribution, and expected cell counts. Results: The cohort comprised 157 unique patients, with a median age of 71 years (interquartile range [IQR], 61–76). Current CRE colonization was documented in 79/154 patients with available colonization status (51.3%). Complete-case in-hospital mortality was higher in the carbapenem-resistant group (CRKP + CP-KP, n = 46) than in the non-carbapenem-resistant group (CSKP + ESBL, n = 111): 11/42 (26.2%) versus 5/108 (4.6%; Fisher exact odds ratio (OR) 7.31, 95% confidence interval (CI) 2.36–22.65; p < 0.001); overall complete-case mortality was 16/150 (10.7%). Multivariable logistic regression for carbapenem resistance (N = 150; five prespecified covariates; events per variable (EPV) = 9.0) identified age 65 years or older (adjusted odds ratio [aOR] 3.78, 95% CI 1.32–10.86), recent hospitalization within 30 days (aOR 2.56, 95% CI 1.16–5.63), and current colonization (aOR 2.96, 95% CI 1.24–7.05) as independent predictors. CRE-associated sepsis was excluded a priori because of definitional circularity with the case definition. Male sex showed a non-significant protective trend (aOR 0.50, 95% CI 0.22–1.12). CRE-associated sepsis showed a strong bivariate association with carbapenem resistance (OR 9.90, 95% CI 3.91–25.09; p < 0.001), and this association is reported descriptively because the variable was excluded from the multivariable model owing to definitional circularity. Model performance was acceptable, with area under the curve (AUC) 0.77, Hosmer–Lemeshow p = 0.95, and Nagelkerke R² = 0.25. Of 99 molecularly characterized isolates, OXA-48-like was detected in 78 (78.8%), NDM in 71 (71.7%), KPC in 6 (6.1%), and NDM + OXA-48-like dual production in 54 (54.5%); VIM and IMP were uniformly negative. Conclusions: In this high-risk hospital cohort, carbapenem resistance in K. pneumoniae was associated with advanced age, recent healthcare exposure, current CRE colonization, and a pronounced unadjusted mortality signal. Interpretation of sepsis and mortality requires explicit separation of colonization from active infection and invasive disease. These findings support intensified CRE surveillance, source-specific clinical interpretation, rapid resistance detection, and risk-adapted empirical antimicrobial strategies in high-risk hospital settings. Full article

To improve clinical decision-making about Carbapenem-resistant Gram-negative bacteria (CR-GNB) infections and halt the spread of resistant microbes, quicker and less expensive diagnostic techniques are required. Thus, the purpose of this study was to thoroughly evaluate the diagnostic efficiency (sensitivity, specificity, and concordance) of direct-from-specimen multiplex lateral flow immunoassay (LFIA) across diverse raw clinical specimens and pathogen types from critically sick patients. A total of 300 non-duplicate samples were tested to detect CR-GNB. Five major Carbapenemase genes were detected directly from the specimen using carbapenem-resistant K.N.I.V.O. detection K-Set and from culture using culture-enhanced multiplex PCR. Turnaround time (TAT) of each method was calculated. The direct LFIA revealed 100% specificity for NDM, KPC, and IMP enzymes in all tested clinical matrices (blood, urine, and respiratory samples). The study demonstrated 100% sensitivity and specificity with perfect categorical agreement (κ = 1.000) for the blaKPC in the Klebsiella pneumoniae and for blaOXA-48 and blaIMP in the Acinetobacter baumannii; however, sensitivity of blaVIM was significantly diminished across all isolates and samples. TAT decreased significantly (p < 0.001) from 30 to 70 h to about 50 min. The tested direct LFIA facilitates the prompt enhancement of lifesaving tailored antibiotic treatment for severe illnesses. Full article

Carbapenem-resistant Enterobacterales (CRE) are a major therapeutic challenge because of limited treatment options and high mortality. Despite advances in resistance-targeted therapies and pharmacokinetic (PK) optimization, treatment failure remains common. This review examines how resistance mechanisms and antibiotic exposure at the infection site jointly influence therapeutic outcomes in CRE infections. A mechanistic synthesis of evidence on carbapenem PKs, bacterial resistance, and nanoparticle (NP)-based delivery systems was performed. Based on this analysis, we propose the Pre-Target Interception Model (PTIM), which describes treatment failure as the progressive loss of active antibiotic before reaching penicillin-binding proteins. Unlike conventional approaches that focus primarily on resistance determinants or drug delivery platforms, PTIM emphasizes the factors that limit effective antibiotic exposure within infected tissues. Within this framework, nanocarrier systems are assessed according to their ability to protect antibiotics, enhance tissue penetration, and improve retention under conditions of enzymatic degradation, membrane restriction, efflux activity, and biofilm-associated diffusion barriers. However, clinical translation remains limited by manufacturing challenges, variability in NP performance, and the lack of validation in CRE-specific settings. Future progress will require quantitative measurement of antibiotic exposure at infection sites, standardized evaluation of nanocarrier performance, and validation in clinically relevant models. PTIM provides a framework for the rational development of nanomedicines designed to improve antibiotic delivery in CRE infections. Full article