International Journal of Antimicrobial Agents最新文献

{"title":"EnvZ mutation–driven downregulation of catecholate siderophore receptors and concurrent TonB complex repression confer cefiderocol resistance in a KPC-producing ST11-KL64 hypervirulent Klebsiella pneumoniae","authors":"Danni Pu ,&nbsp;Xianxia Zhuo ,&nbsp;Rongrong Song ,&nbsp;Chunhui Wang ,&nbsp;Jiankang Zhao ,&nbsp;Bin Cao","doi":"10.1016/j.ijantimicag.2025.107693","DOIUrl":"10.1016/j.ijantimicag.2025.107693","url":null,"abstract":"<div><h3>Objectives</h3><div>Cefiderocol is an ultimate antibiotic option for Carbapenem-resistant hypervirulent <em>Klebsiella pneumoniae</em> (CR-hvKP). While resistance often involves metallo-β-lactamases, mechanisms in KPC-producing strains are unclear. This study aimed to elucidate novel cefiderocol resistance mechanisms in a clinical KPC-producing ST11-KL64 CR-hvKP isolate.</div></div><div><h3>Methods</h3><div>Cefiderocol-resistant mutants were generated through <em>in vitro</em> experimental evolution. Resistance-associated mutations were identified by whole-genome sequencing. Transcriptomic and proteomic analyses were performed to characterize global regulatory changes and were validated by qRT-PCR and targeted genetic manipulation. Additional tests examined siderophore production, intracellular iron levels, bacterial fitness, oxidative stress tolerance, and macrophage survival.</div></div><div><h3>Results</h3><div>All high-level cefiderocol-resistant mutants acquired a gain-of-function mutation in the sensor kinase EnvZ (V145G). Integrated transcriptomic and proteomic analyses showed that the <em>envZ</em> mutation drove marked downregulation of catecholate siderophore receptors (<em>cirA</em> and <em>fepA</em>), impairing cefiderocol uptake. In parallel, the TonB–ExbB–ExbD energy transduction complex was independently and stably downregulated, synergistically contributing to resistance. Notably, <em>envZ</em> mutation–associated repression of the enterobactin biosynthesis gene <em>entB</em> paradoxically increased cefiderocol susceptibility, indicating a regulatory trade-off. Resistant mutants exhibited reduced siderophore production, impaired intracellular iron accumulation, and significant fitness costs, including attenuated growth, reduced oxidative stress tolerance, and decreased survival within macrophages.</div></div><div><h3>Conclusions</h3><div>In conclusion, this work uncovers a novel cefiderocol resistance mechanism in KPC-producing ST11-KL64 CR-hvKp, initiated by the <em>envZ</em> mutation, which causes the downregulation of catecholate siderophore receptors. This receptor repression, combined with the stable downregulation of the TonB-ExbB-ExbD energy complex, severely impairs cefiderocol's “Trojan horse” active uptake. This resistance mechanism is accompanied by a fitness trade-off, providing critical insights into the evolution of these superbugs.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 2","pages":"Article 107693"},"PeriodicalIF":4.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800434","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":"In reply to the letter to editor regarding “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":"Abdullah T. Aslan ,&nbsp;Patrick N.A. Harris ,&nbsp;David L. Paterson","doi":"10.1016/j.ijantimicag.2025.107691","DOIUrl":"10.1016/j.ijantimicag.2025.107691","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 2","pages":"Article 107691"},"PeriodicalIF":4.6,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145742497","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":"Aztreonam–avibactam pharmacokinetics during extracorporeal membrane oxygenation support: First insights from a case report","authors":"Alba Pau-Parra ,&nbsp;Sònia Luque ,&nbsp;Laura Doménech ,&nbsp;María Martínez-Pla ,&nbsp;Xavier Nuvials ,&nbsp;Manuel Sosa Garay ,&nbsp;Ibai Los-Arcos ,&nbsp;Aldair Conto ,&nbsp;Fernando Lasteros ,&nbsp;Elisabet Gallart ,&nbsp;Maria Queralt Gorgas Torner ,&nbsp;Ricard Ferrer ,&nbsp;Jordi Riera","doi":"10.1016/j.ijantimicag.2025.107692","DOIUrl":"10.1016/j.ijantimicag.2025.107692","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 2","pages":"Article 107692"},"PeriodicalIF":4.6,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145742533","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":"Machine–learning and gene–synergy networks reveal interpretable drivers of antibiotic resistance in Staphylococcus aureus","authors":"Jie Xu ,&nbsp;Yuan Li ,&nbsp;Ying Wang ,&nbsp;Fang Liu ,&nbsp;Jinzhao Long ,&nbsp;Jingyuan Zhu ,&nbsp;Yuefei Jin ,&nbsp;Shuaiyin Chen ,&nbsp;Guangcai Duan ,&nbsp;Haiyan Yang","doi":"10.1016/j.ijantimicag.2025.107690","DOIUrl":"10.1016/j.ijantimicag.2025.107690","url":null,"abstract":"<div><h3>Introduction</h3><div>The evolution of antimicrobial resistance in <em>Staphylococcus aureus</em> (<em>S. aureus</em>) involves complex genotype–phenotype interactions of multiple genetic determinants acting independently.</div></div><div><h3>Objective</h3><div>In this study, we aimed to accurately predict antimicrobial resistance from genomic sequences and uncover the complex genetic interactions underlying its mechanisms, focusing on interpretability and mechanistic insights.</div></div><div><h3>Methods</h3><div>We propose a framework that elucidates antibiotic resistance by linking the genomic context with underlying gene interactions, combining a reference-agnostic gene-context 22-mer (gkmer) representation, a two-step random forest pipeline (RF1 screening/mapping; RF2 gene-level modelling), co-information-based synergy networks, and protein-structure mapping.</div></div><div><h3>Results</h3><div>Using genomic sequences from 4569 <em>S. aureus</em> strains, we successfully predicted resistance to 12 antibiotics and examined the genetic interaction networks for penicillin, ciprofloxacin, and erythromycin in detail. On the held-out 20% test set, RF2 achieved an area under the receiver operating characteristic curve (AUC) of 0.83–1.00 (median 0.90) and an F1 score of 0.58–0.99 (median 0.76); comparable performance was observed for RF1. External validation on an independent dataset including 1011 <em>S. aureus</em> isolates revealed strong generalization for ciprofloxacin, erythromycin, and penicillin (area under the receiver operating characteristic curve &gt; 0.95; F1 &gt; 0.97), while highlighting reduced performance for clindamycin and tetracycline, and failure for gentamicin and trimethoprim, thereby delineating the scope and limits of the model and its applicability. Network analysis revealed distinct structural patterns of gene cooperation, highlighting key hubs and community structures consistent with known resistance pathways.</div></div><div><h3>Conclusions</h3><div>Our findings indicate that antibiotic resistance in <em>S. aureus</em> involves distinct genetic network architectures depending on the antibiotic, highlighting the diverse regulatory pathways bacteria employ to acquire resistance. This discovery-oriented framework prioritizes interpretable determinants and generates testable mechanistic hypotheses, with prospective standardized evaluations aimed at assessing its translatability to clinical settings.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 2","pages":"Article 107690"},"PeriodicalIF":4.6,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145742502","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":"Enhanced molecular surveillance for gonococcal resistance during doxycycline post-exposure prophylaxis implementation","authors":"Ziyuan Zhao ,&nbsp;Leshan Xiu ,&nbsp;Junping Peng","doi":"10.1016/j.ijantimicag.2025.107689","DOIUrl":"10.1016/j.ijantimicag.2025.107689","url":null,"abstract":"<div><h3>Objective</h3><div>The introduction of doxycycline post-exposure prophylaxis (doxy-PEP) as a strategy to reduce the risk of bacterial sexually transmitted infections has raised concerns about the potential for rapid selection of tetracycline resistance and the emergence of ceftriaxone-resistant strains. This study aimed to develop a molecular surveillance method to monitor antimicrobial resistance (AMR) in <em>Neisseria gonorrhoeae</em> (NG) during doxy-PEP implementation.</div></div><div><h3>Methods</h3><div>We developed a high-resolution melting (HRM) analysis-based molecular assay, termed HRM-doxyPEP, to enhance surveillance of NG AMR. Validation was conducted with strains of known susceptibility profiles, and further evaluation was performed on clinical samples, comparing HRM results with quantitative PCR, whole-genome sequencing, and PCR-sequencing.</div></div><div><h3>Results</h3><div>The HRM-doxyPEP assay demonstrated high analytical specificity and a detection limit of 20 copies/reaction, enabling the detection of low levels of target DNA in clinical samples. Validation with strains of known susceptibility profiles showed 84% consistency with antimicrobial susceptibility testing results. Clinical sample testing revealed 100% sensitivity and specificity for identifying NG infection, tracking ceftriaxone-resistant FC428-like strains, and detecting <em>tetM</em> associated with tetracycline resistance.</div></div><div><h3>Conclusions</h3><div>The HRM-doxyPEP assay offers an accurate, affordable, and scalable tool for enhanced molecular surveillance of AMR in NG during doxy-PEP implementation.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 2","pages":"Article 107689"},"PeriodicalIF":4.6,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145742543","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":"Fosfomycin-based combinations against carbapenemase-producing Klebsiella pneumoniae bloodstream infections: Correlating in vitro synergy with clinical outcomes","authors":"Melike Törüyenler Coşkunpınar ,&nbsp;Güle Çınar ,&nbsp;Duygu Öcal ,&nbsp;İsmail Balık","doi":"10.1016/j.ijantimicag.2025.107687","DOIUrl":"10.1016/j.ijantimicag.2025.107687","url":null,"abstract":"<div><h3>Background</h3><div>Carbapenemase-producing <em>Klebsiella pneumoniae</em> (CP-Kp) poses a significant global health threat due to its limited treatment options and increasing resistance. Fosfomycin (FOF) has regained interest, particularly in combination therapies. This study aimed to evaluate the in vitro synergy of FOF with meropenem (MEM) and polymyxin in CP-Kp bloodstream infections (BSI) and to investigate clinical outcomes.</div></div><div><h3>Methods</h3><div>Fifty-two patients with CP-Kp BSI who received FOF-based combination therapy (FOF-C) for ≥72 h were evaluated retrospectively for clinical outcomes. Minimum inhibitor concentrations (MICs) were determined on stored isolates: FOF by agar dilution (AD) and broth microdilution, MEM and COL by broth microdilution. In vitro synergy testing of FOF with MEM and COL was performed using the checkerboard method. Data were analysed using logistic regression.</div></div><div><h3>Results</h3><div>Among 50 isolates, the FOF AD MIC_50/90 were 64/&gt;128 µg/mL. Positive in vitro interactions (synergistic or additive) were observed in 43.5% of isolates for both FOF + MEM and FOF + COL, with no antagonism. The clinical and microbiological response rates were 61.5% and 80.5%, 14- and 30-d mortality rates were 21.2% and 40.4%, respectively. Patients receiving at least one agent with in vitro positive interaction had higher clinical response, but the difference wasn’t significant (73.7% vs. 52.2% <em>P</em> = 0.153). In multivariable analysis, increased FOF AD MIC and Pitt bacteraemia score were associated with clinical nonresponse, while higher COL MIC and Pitt bacteraemia score predicted 30-d mortality.</div></div><div><h3>Conclusions</h3><div>FOF AD MIC value may have potential as a predictive marker for FOF-C treatment response in CP-Kp BSI and could aid in guiding combination therapy decisions. Larger, prospective studies using standardized synergy testing methods are needed.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 2","pages":"Article 107687"},"PeriodicalIF":4.6,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696113","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":"Effect of ibuprofen on the pharmacokinetics of intravenous flucloxacillin in healthy adults","authors":"Alison Boast ,&nbsp;Amy Legg ,&nbsp;James McCarthy ,&nbsp;Jason A Roberts ,&nbsp;Stephen YC Tong ,&nbsp;Stephen Duffull ,&nbsp;Amanda Gwee","doi":"10.1016/j.ijantimicag.2025.107684","DOIUrl":"10.1016/j.ijantimicag.2025.107684","url":null,"abstract":"<div><h3>Objective</h3><div>Ibuprofen is frequently co-administered with antibiotics for its analgesic effect when treating infections. In vitro studies have shown that ibuprofen exhibits concentration-dependent inhibition of organic anion transporters (OAT) 1 and OAT3, and therefore may reduce clearance of β-lactams, including flucloxacillin, in a similar manner to probenecid. We therefore aimed to evaluate the effect of ibuprofen on the pharmacokinetics (PK) of flucloxacillin in healthy volunteers.</div></div><div><h3>Methods</h3><div>A single-site PK study of 10 healthy adult volunteers was carried out. Over a 3-d intervention period, participants received intravenous (IV) flucloxacillin 2000 mg twice daily with oral ibuprofen 400 mg twice daily on days 2 and 3. Total and unbound flucloxacillin plasma concentrations were collected at predefined time points. A population PK model was developed using a non-linear mixed-effects modelling approach, and ibuprofen was assessed as a covariate in the final model.</div></div><div><h3>Results</h3><div>Ten participants with a median age of 24.4 y (range 18.8–54.5 y) and median weight of 68.3 kg (range 50.5–85.7 kg) were included. A median of 51.5 (range 34–52) samples was collected per participant. The final two-compartment model included saturable protein binding and allometric scaling of weight on clearance. Ibuprofen was not found to be a significant covariate on K_d (binding dissociation constant), B_max (maximum binding capacity), or clearance.</div></div><div><h3>Conclusion</h3><div>Orally administered ibuprofen had no measurable effect on plasma flucloxacillin PK in healthy adults. Given the lack of drug–drug interaction, there is no benefit to prescribing ibuprofen alongside flucloxacillin to increase flucloxacillin exposure.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 2","pages":"Article 107684"},"PeriodicalIF":4.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145668231","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":"Corrigendum to “Disrupting bacterial metabolism by targeting LDH reverses Streptococcus suis aminoglycoside resistance” [International Journal of Antimicrobial Agents 66/6 (2025) 1-16/107599]","authors":"Shuji Gao ,&nbsp;Yingying Quan ,&nbsp;Shenao Song ,&nbsp;Wenjie Jin ,&nbsp;Zhiheng Chang ,&nbsp;Baobao Liu ,&nbsp;Yuxin Wang ,&nbsp;Li Yi ,&nbsp;Yang Wang","doi":"10.1016/j.ijantimicag.2025.107631","DOIUrl":"10.1016/j.ijantimicag.2025.107631","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 6","pages":"Article 107631"},"PeriodicalIF":4.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274431","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":"2025-12-01","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}

{"title":"Title Page & Editorial Board","authors":"","doi":"10.1016/S0924-8579(25)00229-8","DOIUrl":"10.1016/S0924-8579(25)00229-8","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 6","pages":"Article 107674"},"PeriodicalIF":4.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620071","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}