Search Results (42)

Background/Objectives: Immunocompromised children undergoing chemotherapy or allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic disorders face a high risk of serious, life-threatening infections caused by multidrug-resistant (MDR) bacteria. Cefiderocol is a novel siderophore cephalosporin, indicated for use in adult patients with MDR Gram-negative infections. Clinical data in immunocompromised children are limited. To report a multicenter real-life experience from the Infection Working Group of the Italian Pediatric Hematology and Oncology Association (IWG-AIEOP) on the use of cefiderocol in treating pediatric onco-hematologic patients with severe, high-risk infections. Methods: Multicenter retrospective collection of infectious episodes treated with cefiderocol, from January 2021 to December 2024, in patients 18 years or younger, after treatment for malignancies or undergoing HSCT in the AIEOP network, part of a prospective, observational study on the etiology and outcome of febrile episodes among 24 AIEOP centers (code NCT06419426). Results: Fifteen episodes of MDR, life-threatening Gram-negative infections treated with cefiderocol in 13 pediatric onco-hematologic patients were collected. There were eight males and five females, mainly affected by acute leukemia (six lymphoblastic and four myeloid, three other hematologic malignancies). The median age was 11.1 years (range 1–17.4 years), and the median weight was 37.8 kg (range 8–65). Bloodstream infection occurred in 10 of 15 episodes. Pseudomonas aeruginosa, Klebsiella pneumoniae, and Stenotrophomonas maltophilia were isolated in 11, 3, and 1 episodes, respectively. Notably, 11 of 15 isolated pathogens carried a metallo-beta-lactamase (MBL) gene (Verona integron-encoded, VIM, n = 10; New Delhi, NDM, n = 1). All patients achieved infection resolution and were alive and infection-free 90 days after infection onset. Conclusions: Cefiderocol was well tolerated and showed encouraging, favorable clinical outcomes, without serious adverse effects. Full article

Carbapenems comprise a class of β-lactam antibiotics with broad-spectrum hydrolytic activity and are often reserved as last-line agents for the treatment of serious multidrug-resistant (MDR) bacterial infections. Clinically important nosocomial MDR Gram-negative bacteria (GNB) include Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Carbapenem resistance among these organisms is predominantly mediated by the production of β-lactamases called carbapenemases, such as K. pneumoniae carbapenemase (KPC), New Delhi metallo-β-lactamase (NDM), imipenemase (IMP), Verona integron-encoded metallo-β-lactamase (VIM), and selected oxacillinase (OXA)-type carbapenemases. These enzymes degrade carbapenems, significantly compromising their clinical efficacy. To address escalating antimicrobial resistance, novel next-generation β-lactamase inhibitors (BLIs), partnered with established β-lactams (BLs), have been approved or are currently under development to inhibit carbapenemase activity. The present narrative review aims to synthesize the most current information on the major carbapenemases and discusses recently approved and investigational BL/BLI combination therapies in terms of their mechanisms of action, spectrum of activity, gaps in coverage, and available clinical and in vitro evidence. Development of resistance to novel BL/BLI combinations is also examined. Comparative analysis of inhibitory spectra and microbiological coverage indicates a continued need for metallo-β-lactamase inhibitors with direct pan-inhibitory activity, pathogen-specific BL/BLI regimens for carbapenem-resistant A. baumannii, and carbapenemase-targeted agents effective in the context of non-enzymatic resistance mechanisms. Treatment-emergent resistance to novel BL/BLIs and limitations in activity profiles underscore the critical need for continued innovation in pipeline development, vigilant global and local surveillance of carbapenemase epidemiology, and robust antimicrobial stewardship strategies to aid in preserving the efficacy of the antibacterial drug armamentarium. Full article

Antibiotic resistance remains one of the most formidable challenges to modern medicine, threatening to outpace therapeutic innovation and undermine decades of clinical progress. While resistance was once viewed narrowly as a clinical phenomenon, it is now understood as the outcome of complex ecological and molecular interactions that span soil, water, agriculture, animals, and humans. Environmental reservoirs act as silent incubators of resistance genes, with horizontal gene transfer and stress-induced mutagenesis fueling their evolution and dissemination. At the molecular level, advances in genomics, structural biology, and systems microbiology have revealed intricate networks involving plasmid-mediated resistance, efflux pump regulation, integron dynamics, and CRISPR-Cas interactions, providing new insights into the adaptability of pathogens. Simultaneously, the environmental dimensions of resistance, from wastewater treatment plants and aquaculture to airborne dissemination, highlight the urgency of adopting a One Health framework. Yet, alongside this growing threat, novel therapeutic avenues are emerging. Innovative β-lactamase inhibitors, bacteriophage-based therapies, engineered lysins, antimicrobial peptides, and CRISPR-driven antimicrobials are redefining what constitutes an “antibiotic” in the twenty-first century. Furthermore, artificial intelligence and machine learning now accelerate drug discovery and resistance prediction, raising the possibility of precision-guided antimicrobial stewardship. This review synthesizes molecular insights, environmental drivers, and therapeutic innovations to present a comprehensive landscape of antibiotic resistance. By bridging ecological microbiology, molecular biology, and translational medicine, it outlines a roadmap for surveillance, prevention, and drug development while emphasizing the need for integrative policies to safeguard global health. Full article

Carbapenemase-producing Klebsiella pneumoniae (CRKP) is a critical public health threat, particularly in Greece, where high prevalence limits therapeutic options. This retrospective study analyzed 26 CRKP isolates recovered at the General Hospital of Volos between July 2024 and January 2025, aiming to correlate carbapenemase phenotypes with clinical and epidemiological parameters. Demographic, clinical, and microbiological data were extracted from patient records, and isolates underwent phenotypic carbapenemase detection, antimicrobial susceptibility testing, and molecular characterization using real-time PCR; four isolates were further analyzed using whole-genome sequencing. CRKP was detected across multiple hospital departments, notably in the Emergency Department (n = 5) and Intensive Care Unit (n = 6). KPC producers predominated (n = 9), followed by NDM (n = 6), VIM (n = 1), and OXA-48 (n = 6). All VIM- or NDM + VIM-positive cases were associated with mortality. High-risk clones, including ST15, ST11, and ST307, were identified, with one ST15 isolate harboring bla_NDM-1, bla_VIM-1, and chromosomal colistin resistance; this is the first such report in Greece. Colistin and gentamicin were the most active agents in vitro; three isolates were pan-drug-resistant. The findings highlight significant CRKP circulation outside ICUs, the role of horizontal gene transfer in resistance dissemination, and the need to expand screening and rapid diagnostics to non-ICU settings. Enhanced molecular surveillance targeted at infection control and strengthened antimicrobial stewardship programs are essential for limiting the spread of CRKP. Full article

Acinetobacter baumannii is a Gram-negative, non-motile pathogen commonly associated with healthcare settings. It is capable of causing severe infections, particularly in immunocompromised and critically ill individuals, and is linked to poor clinical outcomes. Infections caused by carbapenem-resistant A. baumannii (CRAB) represent a major public health concern due to limited treatment options and high resistance rates. Several virulence determinants contribute to CRAB’s pathogenicity, including capsular exopolysaccharide (CPS), lipopolysaccharide (LPS), lipooligosaccharide (LOS), efflux pumps, outer membrane proteins (OMPs), pili, metal acquisition systems, two-component regulatory systems (TCSs), and secretion systems (SSs). The dominant resistance mechanism in CRAB involves the production of carbapenemases, most notably oxacillinase-23 (OXA-23) and metallo-β-lactamases (MBLs) such as Verona integron-encoded MBL (VIM) and New Delhi MBL (NDM). Accurate identification of these resistance mechanisms is crucial for guiding effective antimicrobial therapy. Potential treatment options include older agents like polymyxins, ampicillin–sulbactam, high-dose carbapenems, tigecycline, and minocycline, along with newer antimicrobials such as eravacycline, cefiderocol, and aztreonam–avibactam. This review aims to explore the virulence mechanisms and molecular pathogenesis of CRAB, while also presenting recent developments in its epidemiology and available antimicrobial therapies. Full article

Cefepime-enmetazobactam is a novel β-lactam/β-lactamase inhibitor combination showing good activity against multidrug-resistant (MDR) Gram-negative bacteria producing a variety of β-lactamases. In this systematic review, we aimed to evaluate the available data on resistance to this drug. We performed a thorough search of four databases (Embase, PubMed, Scopus, and Web of Science), as well as backward citation searching, to identify studies containing data on resistance to cefepime-enmetazobactam. The data were extracted and analyzed according to the breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Food and Drug Administration (FDA), or the specific breakpoints reported by the authors of the respective studies. Analysis based on the type of lactamases produced by the isolates was also performed. Ten studies reported in vitro susceptibility testing and mechanisms of antimicrobial resistance. The total number of isolates was 15,408. The activity of cefepime-enmetazobactam against β-lactamase-producing isolates was variable. The resistance of the studied extended-spectrum β-lactamase (ESBL)-producing and ampicillin C β-lactamase (AmpC)-producing isolates was low (0–2.8% and 0%, respectively). The resistance was higher among oxacillinase-48 β-lactamase (OXA-48)-producing and Klebsiella pneumoniae carbapenemase (KPC)-producing isolates (3.4–13.2% and 36.7–57.8%, respectively). High resistance was noted among metallo-β-^lactamase (MBL)-producing isolates (reaching 87.5% in one study), especially those producing New Delhi metallo-β-lactamase (NDM) and Verona integron-encoded metallo-β-lactamase (VIM), which had the highest rates of resistance. The high activity of cefepime-enmetazobactam against Enterobacterales and selected lactose non-fermenting Gram-negative pathogens, including ESBL-producing and AmpC-producing isolates, makes it a potential carbapenem-sparing agent. The drug should be used after in vitro antimicrobial susceptibility testing in patients with infections caused by OXA-48, KPC, and MBL-producing isolates. Full article

Background: Infections caused by carbapenem-resistant Enterobacterales have steadily multiplied over time, becoming a major threat to healthcare systems due to limited therapeutic options and high case-fatality rates. Case report: We studied a patient who, after being discharged from an ICU, developed salmonellosis caused by an antibiotic-susceptible S. enteritidis. After undergoing treatment with ciprofloxacin, the patient presented an episode of asymptomatic bacteriuria originated by a carbapenem and ciprofloxacin-resistant S. enteritidis. Results: Whole genome sequencing analysis revealed that both Salmonella isolates belonged to the same strain, and that isolate SEn_T2 acquired a plasmid carrying both bla_NDM-1 and qnrA1 genes (pIncCSEn) which was previously present in the patient’s gut in at least one Enterobacter cloacae isolate. Additionally, pIncCSEN was identified as a putatively new sub-lineage of IncC2 plasmids which lacked the first copy of the methyltransferase gene dcm and the rhs gene. The resistance genes bla_NDM-1 and qnrA1 were incorporated into a Tn21-derived transposon that included a complex class 1 integron whose genetic arrangement was: intI1- dfrA12- orfF- aadA2- qacEΔ1-sul1-ISCR1- trpF- ble- bla_NDM-1 (in reverse direction)- ISAba125-ISCR1- qnrA- cmlA1- qacEΔ1-sul1. Conclusions: Antimicrobial persistence and co-selection of antibiotic resistance play an important role in the dissemination of antimicrobial resistance genes; in this regard, a joint effort involving the infection control team, effective antibiotic stewardship, and genomic surveillance could help mitigate the spread of these multidrug resistant microorganisms. Full article

This systematic review assessed the global epidemiology of metallo-β-lactamase (MBL)-producing Acinetobacter clinical isolates and the associated antimicrobial resistance. A total of 475 relevant articles from the Cochrane Library, Google Scholar, PubMed, Scopus, and Web of Science were identified and screened as potentially eligible articles. Data from 85 articles were extracted for the analysis. Most reports on MBL-producing Acinetobacter clinical isolates originated from Asia [68/85 (80%) studies] and Africa [14/85 (16.5%) studies]. There were also scarce reports from Europe and America. The bla_VIM (in 31 studies), bla_IMP (in 29 studies), and bla_NDM (in 21 studies) genes were the most commonly identified genes. In 22 out of 28 (78.6%) studies with comparable data, the proportions of MBL-producing pathogens detected using phenotypic methods were numerically higher than those using genotypic methods. MBL-producing Acinetobacter isolates showed high resistance (up to 100%) to several antibiotic classes, including carbapenems, cephalosporins, fluoroquinolones, and monobactams. However, they showed low resistance to colistin [ranging from 0% (in six studies) to 14.3% (in one study)] and to tigecycline [0% (in three studies)]. No risk of bias assessment was conducted. The findings emphasize the global spread of MBL-producing Acinetobacter and the need for enhanced antimicrobial stewardship, infection control measures, and surveillance. Full article

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a significant opportunistic human pathogen, posing a considerable threat to public health due to its antimicrobial resistance and limited treatment options. The incidence of CRPA is high in the Philippines; however, genomic analysis of CRPA in this setting is limited. Here, we provide the phenotypic and molecular characterization of 35 non-duplicate CRPA obtained from three tertiary hospitals in Metro Manila, Philippines, from August 2022 to January 2023. Six sequence types (STs), including international high-risk clones ST111 and ST357, were identified. This article highlights the first report in the Philippines on the identification of P. aeruginosa harboring Klebsiella pneumoniae Carbapenemase-2 (KPC-2), coproduced with Verona Integron-encoded Metallo-beta-lactamase-2 (VIM-2) and Oxacillinase-74 (OXA-74). Notably, this is also the first report of KPC in the Philippines identified in P. aeruginosa. New Delhi Metallo-beta-lactamase-7 (NDM-7), coproduced with Cefotaxime-Munich-15 (CTX-M-15) and Temoneira-2 (TEM-2), was also identified from a novel ST4b1c. The relentless identification of NDM in the Philippines’ healthcare setting poses a significant global public health risk. The initial detection of the P. aeruginosa strain harboring KPC exacerbated the situation, indicating the inception of potential dissemination of these resistance determinants within P. aeruginosa in the Philippines. Full article

Extensive use of antibiotics in human healthcare as well as in agricultural and environmental settings has led to the emergence and spread of antibiotic-resistant bacteria, rendering many infections increasingly difficult to treat. Coupled with the limited development of new antibiotics, the rise of antimicrobial resistance (AMR) has caused a major health crisis worldwide, which calls for immediate action. Strengthening AMR surveillance systems is, therefore, crucial to global and national efforts in combating this escalating threat. This review explores the potential of metagenomics, a sequenced-based approach to analyze entire microbial communities without the need for cultivation, as a transformative and rapid tool for improving AMR surveillance strategies as compared to traditional cultivation-based methods. We emphasize the importance of monitoring mobile genetic elements (MGEs), such as integrons, transposons, plasmids, and bacteriophages (phages), in relation to their critical role in facilitating the dissemination of genetic resistance determinants via horizontal gene transfer (HGT) across diverse environments and clinical settings. In this context, the strengths and limitations of current bioinformatic tools designed to detect AMR-associated MGEs in metagenomic datasets, including the emerging potential of predictive machine learning models, are evaluated. Moreover, the controversial role of phages in AMR transmission is discussed alongside the potential of phage therapy as a promising alternative to conventional antibiotic treatment. Full article

Background: Carbapenemase-producing Enterobacterales (CPEs) represent a significant global health threat, particularly in the context of nosocomial infections. The current study constitutes a retrospective epidemiological survey that aimed to provide updated data on the prevalence and characteristics of carbapenemases among carbapenem-resistant Enterobacterales (CREs) in a Greek tertiary hospital in Athens during and after the COVID-19 pandemic. Results: A total of 2021 non-duplicate CPE clinical isolates were detected. A significant increase in the number of carbapenemase-positive Enterobacterales was revealed during the study period (p < 0.05). KPC remained the predominant carbapenemase type through all four years of the survey, representing 40.7%, 39.9%, 53.5%, and 45.7% of the CPE isolates, respectively. However, a rapid transition from VIM to NDM metal-β-lactamase types was revealed, changing the epidemiological image of carbapenemases in the hospital setting. Notably, among the CPEs, antimicrobial resistance rates were significantly raised in the post-COVID-19 period (2022 and 2023) compared to the first study year (2020) for almost all the tested antibiotics, including those characterized as last-resort antibiotics. Methods: CREs were identified and subjected to screening for the five most prevalent carbapenemase genes [Klebsiella pneumoniae carbapenemase (KPC), Verona integron-borne metallo-β-lactamase (VIM), New Delhi metallo-β-lactamase (NDM), imipenemase (IMP), and oxacillin-hydrolyzing (OXA-48)] using a lateral flow immunoassay, and the CREs recovered from blood cultures were analyzed using a FilmArray system. Their clinical and epidemiological characteristics, as well as their antimicrobial susceptibility profiles, were also subjected to analysis Conclusions: Given this alarming situation, which is exacerbated by the limited treatment options, the development of new, effective antimicrobial agents is needed. The continued monitoring of the changing epidemiology of carbapenemases is also imperative in order to undertake rational public health interventions. Full article

This study examines the prevalence and the mechanisms of antibiotic resistance in Pseudomonas aeruginosa isolates collected from healthcare units in Northwestern Transylvania, Romania, between 2022 and 2023. Given the alarming rise in antibiotic resistance, the study screened 34 isolates for resistance to 10 antibiotics, 46 ARGs, and integrase genes using PCR analysis. The results reveal a concerning increase in multidrug-resistant (MDR) and extensively drug-resistant (XDR) isolates over the two-year period. Notably, the prevalence of ARGs encoding resistance to sulfonamides and beta-lactams, particularly sul1 and bla_OXA-50, has shown a significant rise. Furthermore, the study detected the emergence of new resistance mechanisms in the same time interval. These include target protection and even more specific mechanisms, such as metallo-beta-lactamases or enzymes involved in the methylation of 23S rRNA. Statistical analysis further confirmed the correlation between Class I integrons and several ARGs, underscoring the role of horizontal gene transfer in the dissemination of resistance. These findings emphasize the urgent need for updated treatment strategies and monitoring programs to effectively combat the spread of ARGs in clinical settings. Full article

Background/Objectives: Carbapenem-resistant Enterobacteriaceae (CRE) are types of bacteria that need urgent attention globally. Active surveillance programs at hospitals are essential for the early identification of CRE carriers and the timely adoption of infection control measures. We aimed to analyze the epidemiology of CRE identified by multiplex RT-PCR in rectal swabs of patients upon admission to high-risk wards and to compare data obtained from both molecular and culture CRE screening. Methods: A total of 2861 rectal swabs, prospectively collected within 12–24 h of admission, underwent molecular screening for identification of K. pneumoniae carbapenemase (KPC), New Delhi metallo-β-lactamase (NDM), Verona integron-mediated metallo-β-lactamase (VIM), imipenemase (IMP), and OXA-48 (Allplex^TM Entero-DR Assay). Only samples that tested positive or invalid underwent culture testing (Agar MacConkey and CHROMID^® CARBA plates, bioMérieux, Craponne, France). Results: A total of 118 out of 2861 (about 4%) were positive for at least one carbapenem-resistant gene by a molecular approach (MA), with KPC, NDM, and VIM having the highest prevalence. Culture testing confirmed the presence of carbapenemase in 89 samples (75.4%), showing a disagreement rate of about 25% between the two methods, which, unfortunately, rises up to 60% for VIM. The dominant bacterial species were K. pneumoniae and E. coli (MALDI-TOF mass spectrometry). Conclusions: Our data underlined the need for the molecular screening of CRE carriers in order to implement active surveillance protocol in critical care settings and to improve infection control measures. Full article

The “One Health” approach provides a comprehensive framework for understanding antimicrobial resistance. This perspective is of particular importance in the study of Pseudomonas aeruginosa, as it is not only a pathogen that affects humans but also persists in environmental reservoirs. To assess evolutionary selection for niche-specific traits, a genomic comparison of 749 P. aeruginosa strains from three environments (clinical, aquatic, and soil) was performed. The results showed that the environment does indeed exert selective pressure on specific traits. The high percentage of persistent genome, the lack of correlation between phylogeny and origin of the isolate, and the high intrinsic resistance indicate that the species has a high potential for pathogenicity and resistance, regardless of the reservoir. The flexible genome showed an enrichment of metal resistance genes, which could act as a co-selection of antibiotic resistance genes. In the plasmids, resistance genes were found in multigenic clusters, with the presence of a mobile integron being prominent. This integron was identified in several pathogenic strains belonging to distantly related taxa with a worldwide distribution, showing the risk of rapid evolution of resistance. These results provide a more complete understanding of the evolution of P. aeruginosa, which could help develop new prevention strategies. Full article

Information regarding Klebsiella aerogenes haboring carbapenemase in Japan is limited. A comprehensive nationwide survey was conducted from September 2014 to December 2022, and 67 non-duplicate strains of carbapenem-resistant K. aerogenes were isolated from 57 healthcare facilities in Japan. Through genetic testing and whole-genome sequencing, six strains were found to possess carbapenemases, including imipenemase (IMP)-1, IMP-6, New Delhi metallo-β-lactamase (NDM)-1, and NDM-5. The strain harboring bla_NDM-5 was the novel strain ST709, which belongs to the clonal complex of the predominant ST4 in China. The novel integron containing bla_IMP-1 featured the oxacillinase-101 gene, which is a previously unreported structure, with an IncN₄ plasmid type. However, integrons found in the strains possessing bla_IMP-6, which were the most commonly identified, matched those reported domestically in Klebsiella pneumoniae, suggesting the prevalence of identical integrons. Transposons containing bla_NDM are similar or identical to the transposon structure of K. aerogenes harboring bla_NDM-5 previously reported in Japan, suggesting that the same type of transposon could have been transmitted to K. aerogenes in Japan. This investigation analyzed mobile genetic elements, such as integrons and transposons, to understand the spread of carbapenemases, highlighting the growing challenge of carbapenem-resistant Enterobacterales in Japan and underscoring the critical need for ongoing surveillance to control these pathogens. Full article