International Journal of Antimicrobial Agents最新文献

{"title":"Cellular and genetic changes during and after fluconazole exposure in Cryptococcus neoformans","authors":"Samah H. Albehaijani ,&nbsp;Tien Huynh ,&nbsp;Kylie J. Boyce","doi":"10.1016/j.ijantimicag.2025.107519","DOIUrl":"10.1016/j.ijantimicag.2025.107519","url":null,"abstract":"<div><div>The validity of genome replication is fundamental to fungal survival, and errors in this process can result in ploidy changes. These changes can have negative effects, such as developmental defects or reduced fitness, or positive effects such as fungal adaptation and resilience. In the fungal pathogen <em>Cryptococcus neoformans</em>, ploidy changes have been consistently observed in clinical populations, and isolates exposed to the antifungal drug fluconazole commonly exhibit chromosome 1 aneuploidy. Chromosomal and putative metabolic function changes due to drug exposure are not well studied and are important for understanding resistance. Objectives: This study examined the fluconazole influence on <em>C. neoformans</em> transient aneuploidy and identified any potential genetic pathways that may be implicated. Methods: The study investigated 30 genes predicted to have a role in transient aneuploidy, which are related to chromosome organisation, DNA damage checkpoints and stress signalling. Other factors including ploidy status (haploid, diploid, polyploid) and species were also investigated to observe commonalities for a universal drug treatment strategy. Results: Fluconazole treatment increased DNA content, cell size and chromosomal changes in the wildtype and mutants. When fluconazole was removed, permanent changes were observed and were highly variable in the wildtypes and the 30 mutants. Additionally, some mutants lacked chromosomal changes such as <em>tel1∆, mrc1∆</em> and <em>hog1∆</em>, highlighting the potential involvement in the aneuploidy process. Conclusions: These findings highlight that fluconazole influences the entire genome rather than specific chromosomes, which increases the heterogeneity in permanent changes after fluconazole removal. This heterogeneity may result in long–term consequences, including drug resistance.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 2","pages":"Article 107519"},"PeriodicalIF":4.9,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143935954","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":"Characterisation of the genome of a Klebsiella pneumoniae clinical strain carrying a novel KPC-205 variant associated with resistance to ceftazidime/avibactam and cefiderocol","authors":"Stefano Amadesi ,&nbsp;Annarita Mazzariol ,&nbsp;Gabriele Bianco ,&nbsp;Davide Gibellini ,&nbsp;Cristina Costa ,&nbsp;Paolo Gaibani","doi":"10.1016/j.ijantimicag.2025.107514","DOIUrl":"10.1016/j.ijantimicag.2025.107514","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 2","pages":"Article 107514"},"PeriodicalIF":4.9,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917774","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":"Rising threat of metallo-β-lactamase-producing Klebsiella oxytoca complex in Taiwan, 2013–2022","authors":"Yu-Tsung Huang ,&nbsp;Carl Jay Ballena Bregente ,&nbsp;Wei-Yu Hsu ,&nbsp;Chun-Hsing Liao ,&nbsp;Yao-Wen Kuo ,&nbsp;Jia-Arng Lee ,&nbsp;Tai-fen Lee ,&nbsp;Cheng-Yen Kao ,&nbsp;Po-Ren Hsueh","doi":"10.1016/j.ijantimicag.2025.107515","DOIUrl":"10.1016/j.ijantimicag.2025.107515","url":null,"abstract":"<div><h3>Objectives</h3><div>The emergence of metallo-beta-lactamases (MBLs) within the <em>Klebsiella oxytoca</em> complex (CRKO) poses a significant challenge in Taiwan, with so far incomplete characterization of species distribution and carbapenemase variants. This study aimed to elucidate the diversity, variants, and clinical presentations of CRKO isolates collected from 2013 to 2022.</div></div><div><h3>Methods</h3><div>We analyzed production of carbapenemases by the modified carbapenem inhibitory method (mCIM) and the NG test^TM CARBA-5. Confirmation of five common carbapenemases and multilocus sequence typing were determined by polymerase chain reaction and sequencing. Nanopore whole-genome sequencing was used for the species differentiation and plasmids analysis. We also evaluated the clinical characteristics of the CRKO-infected patients.</div></div><div><h3>Results</h3><div>Three species were identified: <em>K. michiganensis</em> (n = 102), <em>K. pasteurii</em> (n = 13), and <em>K. oxytoca</em> (n = 3). A majority of isolates (91.5%, n = 108) harbored at least one MBL gene, including <em>bla</em>_VIM-1 (n = 56), <em>bla</em>_IMP-8 (n = 26), and <em>bla</em>_NDM-1 (n = 19), with six isolates carrying dual carbapenemase genes. The <em>bla</em>_NDM-1 and <em>bla</em>_IMP-8 genes were located on IncFII(Yp) and IncA/C2 plasmids, respectively. Notably, 34.7% of isolates carried kleboxymycin gene clusters (KGC). Using CLSI and EUCAST criteria, 92.4% and 82.4% of isolates, respectively, were susceptible to cefiderocol. Among 92 infected patients, the 30-day mortality rate was 21.7%, associated with female gender, higher Charlson Comorbidity Index, higher Pitt bacteremia scores, presence of bacteremia, and inversely associated with KGC.</div></div><div><h3>Conclusion</h3><div>The high prevalence of CRKO carrying MBLs and the recent surge of the ST27-<em>bla</em>_NDM-1 genotype, poses significant treatment challenges and underscores the urgent need for enhanced surveillance in Taiwan.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 2","pages":"Article 107515"},"PeriodicalIF":4.9,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917775","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":"Restoring tigecycline efficacy with lysine supplementation in tmexCD-toprJ-positive bacteria","authors":"Fulei Li ,&nbsp;Tianqi Xu ,&nbsp;Dan Fang ,&nbsp;Zhiqiang Wang ,&nbsp;Yuan Liu","doi":"10.1016/j.ijantimicag.2025.107511","DOIUrl":"10.1016/j.ijantimicag.2025.107511","url":null,"abstract":"<div><h3>Objectives</h3><div>Antimicrobial resistance is one of the most pressing challenges to global public health. Tigecycline, a last-resort antibiotic, has been undermined by the emergence of the <em>tmexCD1-toprJ1</em> gene cluster, a transferable RND-type efflux pump that confers resistance. Metabolite-enabled killing of antibiotic-resistant pathogens by antibiotics is an attractive strategy to tackle antibiotic resistance.</div></div><div><h3>Methods</h3><div>The potentiation of lysine to tigecycline was evaluated through a series of <em>in vitro</em> studies, including bacterial viability assays, time-kill kinetics analysis, persister assays, and biofilm eradication experiments, as well as <em>in vivo</em> assessment using a murine systemic infection model. The underlying mechanisms of action were further explored through transcriptomic profiling and biochemical validation.</div></div><div><h3>Results</h3><div>Herein, we show that lysine synergistically enhances the antibacterial efficacy of tigecycline against <em>tmexCD-toprJ</em>-positive bacteria. Mechanistic studies indicate that lysine supplementation promotes tigecycline uptake by upregulating ∆pH and disrupting membrane permeability. Transcriptomic analysis, coupled with phenotypic experiments, indicates that lysine not only triggers the generation of reactive oxygen species (ROS) by inhibiting hydrogen sulfide (H₂S) production but also downregulates energy metabolism pathways essential for efflux pump function. These effects promote intracellular accumulation of tigecycline, thereby overcoming <em>tmexCD-toprJ</em>-mediated resistance. In mouse infection models, the combination of lysine and tigecycline shows improved therapeutic efficacy compared to tigecycline monotherapy.</div></div><div><h3>Conclusion</h3><div>Collectively, our findings indicate that lysine can serve as a promising tigecycline booster to tackle infections caused by <em>tmexCD-toprJ</em>-positive bacteria.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 2","pages":"Article 107511"},"PeriodicalIF":4.9,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143929117","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":"Individualised amoxicillin-clavulanate dosing recommendations for critically ill children with augmented clearance after cardiac surgery","authors":"Evelyn Dhont ,&nbsp;Joseph F. Standing ,&nbsp;Emma Beel ,&nbsp;Thi V.A. Nguyen ,&nbsp;Ingrid Herck ,&nbsp;Harlinde Peperstraete ,&nbsp;Wim Vandenberghe ,&nbsp;Thierry Bové ,&nbsp;Kristof Vandekerckhove ,&nbsp;Nick Verougstraete ,&nbsp;Veronique Stove ,&nbsp;Johan Vande Walle ,&nbsp;Peter De Paepe ,&nbsp;Pieter A. De Cock","doi":"10.1016/j.ijantimicag.2025.107513","DOIUrl":"10.1016/j.ijantimicag.2025.107513","url":null,"abstract":"<div><h3>Objective</h3><div>Children who undergo cardiac surgery are prone to postoperative infections for which amoxicillin-clavulanate is a cornerstone antibiotic. Nevertheless, amoxicillin-clavulanate pharmacokinetics have not been studied in infants and children after cardiac surgery so far. Antibiotic exposure might be highly variable in this population due to the impact of growth, maturation, and specific pathophysiological and surgery-induced alterations. The objective of this study was to develop evidence-based amoxicillin-clavulanate dosing recommendations based on population pharmacokinetic analysis and probability of target attainment simulations in children after cardiac surgery.</div></div><div><h3>Methods</h3><div>Critically ill children (aged 1 day to 15 y) who underwent cardiac surgery and who were treated postoperatively with amoxicillin-clavulanate (30–60 mg/kg/6 h based on the amoxicillin component, infused in 30 min) were included. Up to five amoxicillin and clavulanate blood samples were collected per dose at predefined sampling times. Population pharmacokinetics analysis was performed using nonlinear mixed effects modelling software NONMEM.</div></div><div><h3>Results</h3><div>We collected 316 amoxicillin and 287 clavulanate blood samples from 37 patients. A three-compartment model for amoxicillin and a two-compartment model for clavulanate best described pharmacokinetics, with allometric weight scaling and maturation functions added a priori to scale for size and age. Clearance estimates were remarkably high, except in patients receiving vasopressors, which decreased clearance of amoxicillin-clavulanate by a third. Using a pharmacokinetic/pharmacodynamic target of 50%<em>f</em>T&gt;MIC of 8 mg/L, patients not on vasopressors warranted 4-hourly dosing to achieve adequate drug exposure due to augmented amoxicillin clearance. Only in patients treated with vasopressors was the standard 6-hourly dosing regimen sufficient to attain amoxicillin concentrations above the MIC for half of the dosing interval.</div></div><div><h3>Conclusions</h3><div>Current amoxicillin-clavulanate dosing regimens for critically ill children after cardiac surgery need to be updated to avoid subtherapeutic concentrations and clinical failure due to augmented clearance (ClinicalTrials.gov NCT02456974).</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 2","pages":"Article 107513"},"PeriodicalIF":4.9,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143922108","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)00073-1","DOIUrl":"10.1016/S0924-8579(25)00073-1","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 6","pages":"Article 107516"},"PeriodicalIF":4.9,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143825414","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":"Commentary on “Development and validation of a time-varying correction factor for QT interval assessment in drug-resistant tuberculosis patients”","authors":"Masoud Keikha","doi":"10.1016/j.ijantimicag.2025.107510","DOIUrl":"10.1016/j.ijantimicag.2025.107510","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 2","pages":"Article 107510"},"PeriodicalIF":4.9,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143935609","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":"Cerebrospinal fluid concentrations of ceftaroline and ceftazidime/avibactam in healthy volunteers: Pharmacokinetics and probability of target attainment","authors":"Michael Wölfl-Duchek ,&nbsp;Wisse van Os ,&nbsp;Valentin al Jalali ,&nbsp;Ulrich Rabl ,&nbsp;Peter Wohlrab ,&nbsp;Martin Bauer ,&nbsp;Edith Lackner ,&nbsp;Beatrix Wulkersdorfer ,&nbsp;Peter Marhofer ,&nbsp;Felix Bergmann ,&nbsp;Anselm Jorda ,&nbsp;Birgit Reiter ,&nbsp;Thomas Stimpfl ,&nbsp;Markus Zeitlinger","doi":"10.1016/j.ijantimicag.2025.107512","DOIUrl":"10.1016/j.ijantimicag.2025.107512","url":null,"abstract":"<div><h3>Objectives</h3><div>This study measured the penetration of ceftaroline and ceftazidime/avibactam into cerebrospinal fluid (CSF) to evaluate the potential of both drugs for treatment of central nervous system (CNS) infections.</div></div><div><h3>Methods</h3><div>In this prospective, single-centre pharmacokinetic (PK) study, 24 healthy volunteers equally divided into two groups received four doses of either 600 mg ceftaroline fosamil or 2000/500 mg ceftazidime/avibactam as intravenous infusions over 2 h at 8 h intervals for 4 doses. Plasma samples were obtained on both study days and CSF was sampled once per subject at either 2 h, 4 h or 8 h after the start of the last infusion via lumbar puncture. PK data were analysed using non-compartmental analysis, as well as using a population PK modelling approach. Monte Carlo simulations were performed to calculate probability of PK-pharmacodynamic (PK-PD) target attainment.</div></div><div><h3>Results</h3><div>Two-compartment models described the plasma PK data for all three compounds. The ratios between the estimated distribution clearances into and out of the CSF were 0.021, 0.083 and 0.071 for ceftaroline, ceftazidime and avibactam, respectively, indicating limited CSF penetration. Ceftaroline and ceftazidime PK-PD targets were not attained in CSF for minimum inhibitory concentrations around commonly used susceptibility breakpoints, but exposure appears sufficient to treat several pathogens commonly causing CNS infections. Avibactam concentrations were well below reported threshold concentrations that are required for activity.</div></div><div><h3>Conclusion</h3><div>In healthy subjects, ceftaroline, ceftazidime and avibactam poorly distribute to CSF. Nonetheless, CSF exposure of both cephalosporins might be sufficient to cover certain, but not all, pathogens causative of CNS infections.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 2","pages":"Article 107512"},"PeriodicalIF":4.9,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143935955","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.2025.107509","DOIUrl":"10.1016/j.ijantimicag.2025.107509","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"65 6","pages":"Article 107509"},"PeriodicalIF":4.9,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806860","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":"Procalcitonin-guided early cessation of antibiotics prevents gut inflammation and preserves gut microbiome: Data from the PROGRESS controlled trial","authors":"Evdoxia Kyriazopoulou ,&nbsp;Emmanouil Stylianakis ,&nbsp;Georgia Damoraki ,&nbsp;Panagiotis Koufargyris ,&nbsp;Ioannis Kollias ,&nbsp;Konstantina Katrini ,&nbsp;Elina Drakou ,&nbsp;Konstantinos Marousis ,&nbsp;Andronikos Spyrou ,&nbsp;Styliani Symbardi ,&nbsp;Nikolaos Alexiou ,&nbsp;Zoi Alexiou ,&nbsp;Malvina Lada ,&nbsp;Garyfallia Poulakou ,&nbsp;Georgios Chrysos ,&nbsp;George Adamis ,&nbsp;Evangelos J. Giamarellos-Bourboulis","doi":"10.1016/j.ijantimicag.2025.107507","DOIUrl":"10.1016/j.ijantimicag.2025.107507","url":null,"abstract":"<div><div>The PROGRESS randomised trial (ClinicalTrials.gov: NCT03333304) showed that early stopof antibiotics guided by procalcitonin (PCT) decreased the incidence of infections by multidrug-resistant organisms and/or <em>Clostridioides difficile</em> and was associated with survival benefit. This study was conducted to investigate whether this survival benefit is associated with microbiome dysbiosis. Patients with sepsis due to lung infection, acute pyelonephritis or primary bacteraemia were randomised to standard-of-care (SoC) duration of antibiotics or early stop using PCT. Faecal samples were collected before, and 7 and 28 days after randomisation and analysed using 16S rRNA Nanopore sequencing. Calprotectin was measured using an enzyme immunoassay. Median (Q₁-Q₃) antimicrobial duration was 5 (5-7.5) days in the PCT arm and 11 (8-15) days in the SoC arm (<em>P</em> &lt; 0.001). Faecal calprotectin levels were similar in the two treatment arms at baseline. By day 7, the levels of faecal calprotectin were significantly increased in the SoC arm (<em>P</em> = 0.002) but were unchanged in the PCT arm. Microbiome α- and β-diversity was similar at baseline in the PCT (n=81) and SoC (n=76) treatment arms. Shannon’s index was significantly lower in the SoC arm on day 7 compared with baseline (median [Q₁-Q₃], 2.88 [2.37-3.39] at day 1 vs. 2.24 [1.52-3.08] at day 7; <em>P</em>_t-test = 0.0013). This was not the case for the PCT arm (median [Q₁-Q₃], 2.73 [2.26-3.4] at day 1 vs. 2.43 [1.81-3.21] at day 7; <em>P</em>_t-test = 0.037, Bonferroni corrected α = 0.0125). The relative abundance of <em>Actinomycetota</em> and <em>Pseudomonadota</em> was decreased in the PCT arm by day 7 and that of <em>Bacillota</em> was increased. Early PCT-guided stop of antibiotics contributes to decreased microbiome dysbiosis by day 7.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 2","pages":"Article 107507"},"PeriodicalIF":4.9,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143934620","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}