International Journal of Antimicrobial Agents最新文献

{"title":"Comment on “Comparison of ceftazidime-avibactam with other appropriate antimicrobial therapy for the treatment of OXA-48- or KPC-producing Enterobacterales infections in Turkiye: A multi-centre retrospective matched-cohort study”","authors":"S. Dhanya Dedeepya , Vaishali Goel , Nivedita Nikhil Desai","doi":"10.1016/j.ijantimicag.2025.107671","DOIUrl":"10.1016/j.ijantimicag.2025.107671","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 1","pages":"Article 107671"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145540066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antimicrobial peptide CATH-1 combats Streptococcus suis by targeting serine/threonine kinase","authors":"Yi Lu ,&nbsp;Xiaoying Yu ,&nbsp;Yandi Pan,&nbsp;Hang Yin,&nbsp;Qingqing Yang,&nbsp;Xin Shen,&nbsp;Xuefeng Cao,&nbsp;Zhiwei Li,&nbsp;Lianci Peng,&nbsp;Rendong Fang","doi":"10.1016/j.ijantimicag.2025.107656","DOIUrl":"10.1016/j.ijantimicag.2025.107656","url":null,"abstract":"<div><h3>Objectives</h3><div>With the increased bacterial resistance to conventional antibiotics, there is an urgent need for the development of novel antimicrobial agents. Cathelicidins belonging to the family of cationic host defense peptides (HDPs) are a critical component of the innate immune system with antimicrobial and immunomodulatory activities. Our previous study has shown that CATH-1 exhibits potent bactericidal activity against <em>Streptococcus suis</em> (<em>S. suis</em>), but the underlying mechanism is still unclear.</div></div><div><h3>Purpose</h3><div>This study investigated the effect of CATH-1 on the resistance development and antibacterial mechanisms against <em>S. suis</em>.</div></div><div><h3>Methods</h3><div>Drug resistance induction assays, time-kill curves, and Live/Dead bacterial staining were used in this study. To analyze the potential antibacterial targets of CATH-1, integrated proteomic and metabolomic analysis, scanning and transmission electron microscopy, membrane potential determination, molecular docking, GST affinity-isolation assay, cellular thermal shift assay (CETSA), and drug affinity responsive target stability assays (DARTS) were employed. Furthermore, the crucial role of STK in the antibacterial activity of CATH-1 was validated through both <em>in vitro</em> bactericidal tests and a mouse infection model.</div></div><div><h3>Results</h3><div>CATH-1 did not readily induce resistance in <em>S. suis</em>. Multi-omics analysis revealed that CATH-1 exerts its antibacterial effects by modulating multiple pathways, including those related to the cell membrane, bacterial virulence, and energy metabolism. Mechanistically, CATH-1 exhibits dual antibacterial actions by disrupting bacterial membrane integrity and targeting the STK pathway to inhibit capsular polysaccharide (CPS) synthesis. Direct binding between CATH-1 and STK was confirmed by CETSA and DARTS. Crucially, the deletion of the stk gene significantly attenuated the anti-infective efficacy of CATH-1 both <em>in vitro</em> and <em>in vivo</em>.</div></div><div><h3>Conclusion</h3><div>This study reveals a novel dual anti-bacterial mechanism of action of CATH-1, inclduing membrane disruption and inhibition of STK-mediated CPS synthesis, and identifies STK as its key functional target. These findings provide a crucial theoretical foundation and new directions for developing novel anti-infective strategies based on antimicrobial peptides.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 1","pages":"Article 107656"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145400656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two Tail Protein-Derived Capsule Depolymerases From Phage vB_KpnS_GH-K1 are Effective Against Pneumonia Caused by K2 Serotype Klebsiella pneumoniae","authors":"Guiyang Ge ,&nbsp;Hongbei Ge ,&nbsp;Jianhui Xu ,&nbsp;Bing Yue ,&nbsp;Qizhu Yang ,&nbsp;Zewei Cheng ,&nbsp;Zhimin Guo ,&nbsp;Hewen Deng ,&nbsp;Haozhe Hou ,&nbsp;Shang Shi ,&nbsp;Jiaquan Li ,&nbsp;Meng Yu ,&nbsp;Jiaming Niu ,&nbsp;Ruopeng Cai ,&nbsp;Rui Du","doi":"10.1016/j.ijantimicag.2025.107662","DOIUrl":"10.1016/j.ijantimicag.2025.107662","url":null,"abstract":"<div><h3>Objectives</h3><div>Hypervirulent <em>Klebsiella pneumoniae</em> (hvKP) poses an escalating threat to public health and animal husbandry, underscoring the urgent need for novel antimicrobial alternatives. This study aimed to isolate and characterize depolymerases from a <em>Klebsiella</em> phage and evaluate their therapeutic potential against acute pneumonia caused by the K2 serotype hvKP</div></div><div><h3>Methods</h3><div>We isolated and characterized the bacteriophage vB_KpnS_GH-K1 (GH-K1) of the “<em>KP36likevirus</em>” genus. Genomic analysis led to the identification of two putative phage-derived depolymerases: tail fiber protein (TFP41) and tail spike protein (TSP42). The enzymatic activity of the expressed and purified proteins was assessed through spot assays and mucoviscosity measurements. Their ability to enhance host immune clearance was evaluated via macrophage phagocytosis assays, analysis of mitogen-activated protein kinase (MAPK) signaling pathway activation, and cytokine profiling. The therapeutic efficacy was ultimately determined in a murine model of acute pneumonia, where survival rates, lung bacterial loads, and pathological changes were monitored following intranasal administration of the depolymerases.</div></div><div><h3>Results</h3><div>Both depolymerases exhibited potent activity in degrading the capsular polysaccharides (CPS) of K2 serotype <em>K. pneumoniae.</em> Capsule degradation by TFP41 and TSP42 enhances macrophage-mediated phagocytosis of K2 serotype strains, leading to potentiated activation of the MAPK signaling pathway. <em>In vivo</em> experiments demonstrated the exceptional therapeutic efficacy of TSP42, where a single 20 µg dose ensured over 80 % survival in mice within 12 h of intranasal infection, achieving complete survival when administered within 2 h. Importantly, TSP42 demonstrates superior therapeutic efficacy against acute pneumonia caused by K2 strains compared to other depolymerases in “<em>KP36likevirus</em>”. Although TFP41 exhibited slightly weaker efficacy, daily administration for three consecutive days also resulted in 100 % survival, and notably represents the first tail fiber depolymerase with demonstrated therapeutic efficacy in the “<em>KP36likevirus</em>” genus, expanding the functional diversity of phage-derived depolymerases beyond well-characterized tail spike proteins.</div></div><div><h3>Conclusion</h3><div>These findings underscore the potential of phage-derived depolymerases as innovative therapeutic agents against hvKP infections and position TSP42 as an exceptionally promising antibiotic alternative</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 1","pages":"Article 107662"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145458083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An easy-to-use predictive score for identifying patients at risk of suboptimal linezolid exposure and candidates for therapeutic drug monitoring","authors":"Daniel Fresán ,&nbsp;Luisa Sorlí ,&nbsp;Jaume Barceló-Vidal ,&nbsp;Ana Rodrigo-Moreno ,&nbsp;Rosana Muñoz ,&nbsp;Isaac Subirana ,&nbsp;Antoni Ferrer ,&nbsp;Camila Velasco ,&nbsp;Jason Roberts ,&nbsp;Adela Benítez-Cano ,&nbsp;Sonia Luque ,&nbsp;PK/PD of Anti-Infectives Study Group of the European Society of Clinical Microbiology and Infectious Diseases (EPASG)","doi":"10.1016/j.ijantimicag.2025.107661","DOIUrl":"10.1016/j.ijantimicag.2025.107661","url":null,"abstract":"<div><h3>Objectives</h3><div>Due to the high interindividual pharmacokinetic variability, only between 34.5–57.5% patients treated with linezolid fall within its therapeutic range with standard dosing. This study aimed to develop and validate a simple-to-use predictive score to identify patients at risk of sub- or supra-therapeutic linezolid exposure who may benefit from therapeutic drug monitoring (TDM).</div></div><div><h3>Methods</h3><div>A retrospective observational study was conducted using data from 819 patients treated with linezolid and undergoing TDM (2011–2022). Linezolid trough concentrations were classified as sub-therapeutic, therapeutic and supra-therapeutic (&lt; 2 mg/L, between 2 and 7 mg/L and &gt; 7 mg/L, respectively). A multinomial logistic regression model was used to develop a predictive score, which was externally validated in a separate cohort of 73 patients. Discrimination performance was assessed using ROC curve.</div></div><div><h3>Results</h3><div>Only 31.5% of patients achieved therapeutic concentrations. Median linezolid trough concentrations were 3.9 mg/L (range: 0.5–63.7 mg/L). Independent predictors of sub-therapeutic concentrations were a younger age, a low linezolid dose/body weight, augmented renal clearance and intensive care unit admission. Predictors of supra-therapeutic concentrations were a higher dose/body weight, renal impairment and liver cirrhosis. The predictive model showed high accuracy for identifying patients at risk of supra-therapeutic exposure (AUC 82% derivation; 90% validation), while performance was moderate for underexposure (AUC 63% derivation; 49% validation). An online calculator was implemented to facilitate score use in clinical practice.</div></div><div><h3>Conclusions</h3><div>The predictive score provides clinicians with an effective tool to support individualised linezolid therapy and guide TDM implementation, reducing the risk of toxicity or treatment failure.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 1","pages":"Article 107661"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145458666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A systematic review and meta-analysis of the global epidemiology of carbapenem-resistant Escherichia coli","authors":"Mikaela M. Walker ,&nbsp;Jason A. Roberts ,&nbsp;Yixuan Li ,&nbsp;Fekade B. Sime","doi":"10.1016/j.ijantimicag.2025.107668","DOIUrl":"10.1016/j.ijantimicag.2025.107668","url":null,"abstract":"<div><h3>Objectives</h3><div>Among drug-resistant strains, <em>Escherichia coli</em> is estimated to cause the largest number of deaths per year, globally. This study aimed to estimate the global prevalence of carbapenem-resistant <em>E. coli</em> through a systematic review and meta-analysis of the available literature.</div></div><div><h3>Methods</h3><div>Three databases, Embase, PubMed, and Scopus were screened for original research articles reporting the epidemiology of carbapenem-resistant <em>E. coli</em> between 2019 and 2023. Following data extraction, a meta-analysis was performed using the random effects model for overall prevalence and prevalence of key carbapenemase enzymes (NDM, OXA, IMP, VIM, and KPC). This systematic review was registered with PROSPERO (CRD42023433370).</div></div><div><h3>Results</h3><div>A total of 44 studies were included in this review, spanning 16 countries over five WHO regions, with a pooled global prevalence of carbapenem-resistant <em>E. coli</em> at 7 % (95 % CI 0.01; 0.31). The highest pooled prevalence was 51 % (95 % CI 43 % to 58 %) for Bangladesh, and the lowest was 0.15 % (95 % CI 0.08 % to 0.23 %) for Australia. NDM was the most frequent <em>E. coli</em> carbapenemase identified, followed by OXA, KPC, VIM, and IMP.</div></div><div><h3>Conclusions</h3><div>This study found that the prevalence of carbapenem-resistance amongst <em>E. coli</em> populations is highly variable between countries and significantly lacking in most, suggesting an increased need for robust global surveillance.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 1","pages":"Article 107668"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ceftazidime-avibactam resistance among clinical isolates of Citrobacter freundii, Morganella morganii, Providencia spp. and Serratia marcescens across five continents: Data from the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme, 2016–2023","authors":"Hao-En Jan ,&nbsp;Jiun-Ling Wang ,&nbsp;Nan-Yao Lee ,&nbsp;Shun-Chung Hsueh ,&nbsp;Yu-Tsung Huang ,&nbsp;Wen-Chien Ko ,&nbsp;Po-Ren Hsueh","doi":"10.1016/j.ijantimicag.2025.107669","DOIUrl":"10.1016/j.ijantimicag.2025.107669","url":null,"abstract":"<div><h3>Objective</h3><div>The aim of this study is to investigate the trends in ceftazidime-avibactam (CZA) resistance among clinical isolates of <em>Citrobacter freundii, Morganella morganii, Providencia</em> spp., and <em>Serratia marcescens</em> globally using the database from Antimicrobial Testing Leadership and Surveillance (ATLAS) programme, 2016–2023.</div></div><div><h3>Methods</h3><div>A total of 18,908 isolates (4,231 <em>C. freundii</em>, 4658 <em>M. morganii</em>, 3,570 <em>Providencia spp</em>., and 6449 <em>S. marcescens</em>) from five continents were analysed. Antimicrobial susceptibility testing of these isolates was conducted using the broth microdilution method.</div></div><div><h3>Results</h3><div>The CZA resistance rate was the highest in <em>Providencia</em> spp. (8.8%), followed by <em>C. freundii</em> (3.4%), <em>S. marcescens</em> (1.5%), and <em>M. morganii</em> (0.6%). An increasing resistance trend was noted in <em>C. freundii</em> (R² = 0.817) and <em>S. marcescens</em> (R² = 0.995) during the study period. The resistance rate in <em>Providencia</em> spp. peaked in 2020–2021 (R² = 0.610), while that in <em>M. morganii</em> remained sporadically low. Regionally, the biannual resistant rate of <em>C. freundii</em> rose from 6.7% to 13.0% in Asia, 0% to 7.8% in Latin America, and 0% to 7.0% in East Asia (2016–2017 vs<em>.</em> 2022–2023). Furthermore, among carbapenem-resistant isolates, CZA resistance was noted in 91.1% of <em>Providencia</em> spp., 78.8% of <em>C. freundii</em>, 34.9% of <em>S. marcescens</em>, and 60% of <em>M. morganii.</em> The predominant carbapenemase gene was <em>bla</em>_NDM in <em>Providencia</em> spp. (82.6%), <em>M. morganii</em> (69.2%), and <em>C. freundii</em> (42.0%), and <em>bla</em>_KPC in <em>S. marcescens</em> (45.3%) among carbapenemase-producing isolates.</div></div><div><h3>Conclusions</h3><div>CZA resistance is emerging across diverse Enterobacterales species, and exhibits geographic and temporal variability, and warrants continued global surveillance.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 1","pages":"Article 107669"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"International Society of Antimicrobial Chemotherapy (ISAC) News and Information Page","authors":"","doi":"10.1016/j.ijantimicag.2025.107688","DOIUrl":"10.1016/j.ijantimicag.2025.107688","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 1","pages":"Article 107688"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide insight into the evolution and global transmission of tigecycline resistant tet(X4)-carrying Klebsiella species across reservoirs","authors":"Yuye Wu ,&nbsp;Yawen Yu ,&nbsp;Xueqian He ,&nbsp;Weifang Mao ,&nbsp;Qian Tong ,&nbsp;Danni Bao ,&nbsp;Huiqiong Jia ,&nbsp;Yingying Kong ,&nbsp;Yingying Zhang ,&nbsp;Mohamed S Draz ,&nbsp;João Pedro Rueda Furlan ,&nbsp;Patrick Butaye ,&nbsp;Mohamed Elhadidy ,&nbsp;Shurong Dong ,&nbsp;Zhen Cao ,&nbsp;Xinyou Xie ,&nbsp;Shengjun Wu ,&nbsp;Zhi Ruan","doi":"10.1016/j.ijantimicag.2025.107665","DOIUrl":"10.1016/j.ijantimicag.2025.107665","url":null,"abstract":"<div><h3>Objectives</h3><div>The emergence of plasmid mediated <em>tet</em>(X4) gene compromises the clinical utility of tigecycline and underscores growing concerns regarding its environmental reservoirs and potential for interspecies transmission, particularly within <em>Klebsiella</em> species. The aim of this study is to elucidate the dissemination patterns and evolutionary relationships of <em>tet</em>(X4)-harbouring plasmids across clinical and environmental <em>Klebsiella</em> isolates.</div></div><div><h3>Methods</h3><div>We conducted a comprehensive phylogenetic analysis integrating both newly sequenced plasmids and publicly available datasets from the NCBI Plasmid database. Conjugation assays were performed to assess the horizontal transfer potential of <em>tet</em>(X4)-harbouring plasmids. Furthermore, globally sourced genomic data of <em>tet</em>(X4)-carrying <em>Klebsiella</em> strains were subjected to infer their spatiotemporal distribution, transmission dynamics, and the time to the most recent common ancestor (tMRCA) using BEAST.</div></div><div><h3>Results</h3><div>The <em>tet</em>(X4) gene was located on conjugative plasmids ranging from 5.7 kb to 19.3 kb, predominantly embedded within a conserved <em>abh-tet</em>(X4)<em>-</em>IS<em>CR2</em> structure flanked by mobile genetic elements such as IS<em>26</em> and IS<em>1</em>, which likely facilitate horizontal gene transfer and plasmid integration. These plasmids commonly co-harboured multiple ARGs, including <em>aadA1, floR</em>, and <em>tet</em>(A). The <em>tet</em>(X4)-carrying <em>Klebsiella</em> isolates exhibited substantial genetic diversity, with ST534 and ST3393 identified as the most prevalent lineages. The <em>tet</em>(X4)-carrying <em>K. pneumoniae</em> strains exhibited clonal dissemination across clinical and environmental reservoirs, with the estimated tMRCA dating back to 1873. Moreover, the co-occurrence of <em>tet</em>(X4) with carbapenemase or colistin resistance genes highlights the significant public health threat posed by these high-risk strains.</div></div><div><h3>Conclusions</h3><div>These findings highlight the urgent need for coordinated genomic surveillance under a One-Health framework to monitor and mitigate the global spread of multidrug-resistant <em>tet</em>(X4)-carrying <em>Klebsiella</em> isolates.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 1","pages":"Article 107665"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The antiarrhythmic drugs dronedarone and amiodarone exhibit potent in vitro and in vivo activity against Clostridioides difficile","authors":"Ahmed A. Abouelkhair ,&nbsp;Nader S. Abutaleb ,&nbsp;Mohamed N. Seleem","doi":"10.1016/j.ijantimicag.2025.107649","DOIUrl":"10.1016/j.ijantimicag.2025.107649","url":null,"abstract":"<div><div><em>Clostridioides difficile</em> (<em>C. difficile</em>) is the most prevalent cause of healthcare-associated diarrhea. The limited number of FDA-approved antibiotics for <em>C. difficile</em> infection (CDI), along with increasing rates of treatment failure and recurrence, highlight the critical need for new therapeutic options. Here, we report the anti-<em>C. difficile</em> activity of the antiarrhythmic drugs, dronedarone (DRO) and amiodarone (AMD). Both drugs demonstrated strong efficacy against a panel of 25 clinical isolates of <em>C. difficile</em>, with MIC₅₀ values of 4 µg/mL for DRO and 8 µg/mL for AMD. In a time-kill assay, DRO outperformed the approved drugs, vancomycin (VAN) and fidaxomicin (FDX), reducing the high bacterial inoculum below the limit of detection within 2 h. Additionally, both drugs were more effective than VAN at preventing the formation and germination of <em>C. difficile</em> spores. Mechanistic studies indicated that these drugs exert their effects by disrupting the bacterial cell membrane. Furthermore, in the <em>C. difficile</em> recurrence mouse model, both drugs showed a preventive effect comparable to that of VAN. Our findings suggest that these antiarrhythmic drugs have potential as compelling lead molecule for CDI drug discovery, warranting further investigation and potentially paving the way for new anti-<em>C. difficile</em> therapies.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 1","pages":"Article 107649"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145400709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"blaKPC-2 amplification and a novel mrcA mutation drive Cefiderocol heteroresistance in ST11 CRKP","authors":"Yuxuan Liu ,&nbsp;Hanxu Hong ,&nbsp;QianBin Dai ,&nbsp;Linping Fan ,&nbsp;Peng Liu ,&nbsp;DanDan Wei ,&nbsp;Yang Liu","doi":"10.1016/j.ijantimicag.2025.107682","DOIUrl":"10.1016/j.ijantimicag.2025.107682","url":null,"abstract":"<div><h3>Objectives</h3><div>Cefiderocol (FDC) is a promising treatment for infections caused by carbapenem-resistant <em>Klebsiella pneumoniae</em> (CRKP), but emerging heteroresistance (HR) may compromise its clinical efficacy. This study aimed to elucidate the molecular mechanisms underlying FDC heteroresistance arising during <em>in vivo</em> evolution of CRKP. <em>in vivo</em>-evolved.</div></div><div><h3>Methods</h3><div>A total of 477 clinical CRKP isolates were analyzed. FDC-heteroresistant (FDC-HR) subpopulations emerging during <em>in vivo</em> evolution were characterized using population analysis profiling, antimicrobial susceptibility testing, quantitative PCR, plasmid copy number analysis, transcriptomics, whole-genome sequencing, molecular modeling, and CRISPR-Cas9–based functional validation.</div></div><div><h3>Results</h3><div>Among the 477 CRKP isolates, 376 (78.8%) belonged to ST11-KL64, 4 (0.84%) were non-susceptible to FDC, and 12 (2.52%) exhibited an FDC-HR phenotype. Resistant subpopulations showed approximately a twofold increase in <em>bla</em>_KPC-2 plasmid copy number with upregulated expression compared with susceptible counterparts. A G652A point mutation in <em>mrcA</em> was identified and predicted to impair FDC binding. Functional validation demonstrated that the <em>mrcA</em> mutation alone increased the FDC minimum inhibitory concentration (MIC), while its combination with <em>bla</em>_KPC-2 amplification elevated the MIC from 2 to 32 mg/L, fully recapitulating the clinical heteroresistance phenotype. <em>In vivo</em> evolution reduced virulence without affecting growth.</div></div><div><h3>Conclusions</h3><div>Amplification of <em>bla</em>_KPC-2 plasmid copy number together with the <em>mrcA</em> G652A mutation drives FDC-HR in CRKP during <em>in vivo</em> evolution. This mechanism may lead to underestimation of resistance by standard susceptibility testing and increase the risk of treatment failure.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 1","pages":"Article 107682"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145668191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}