Journal of Antimicrobial Chemotherapy最新文献

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Multidrug resistance and recurrence in urinary bacteraemia among cancer patients. 癌症患者尿菌血症的多药耐药与复发。
IF 3.6 2区 医学
Journal of Antimicrobial Chemotherapy Pub Date : 2025-09-18 DOI: 10.1093/jac/dkaf335
Ignacio Grafia, Alba Moll-Febrer, Solanche Jasmin Santillán, Clara Rodrigo, Eva Lillo, Néstor López, Berta Fidalgo, Verónica Rico-Caballero, Mateu Espasa-Soley, Daniel N Marco, Cristina Pitart, Javier Marco-Hernández, Sara Fernández, Carles Zamora, Joan Padrosa, Marta Garcia de Herreros, Sabina Herrera, Margarita Viladot, Josep Mensa, Lucía Llavata, Albert Tuca, Alex Soriano, Pedro Puerta-Alcalde
{"title":"Multidrug resistance and recurrence in urinary bacteraemia among cancer patients.","authors":"Ignacio Grafia, Alba Moll-Febrer, Solanche Jasmin Santillán, Clara Rodrigo, Eva Lillo, Néstor López, Berta Fidalgo, Verónica Rico-Caballero, Mateu Espasa-Soley, Daniel N Marco, Cristina Pitart, Javier Marco-Hernández, Sara Fernández, Carles Zamora, Joan Padrosa, Marta Garcia de Herreros, Sabina Herrera, Margarita Viladot, Josep Mensa, Lucía Llavata, Albert Tuca, Alex Soriano, Pedro Puerta-Alcalde","doi":"10.1093/jac/dkaf335","DOIUrl":"https://doi.org/10.1093/jac/dkaf335","url":null,"abstract":"<p><strong>Background: </strong>Urinary tract infections (UTI) in oncological patients can lead to bacteraemia (bUTI), increasing morbidity and mortality. This study assessed the characteristics, outcomes and recurrence of bUTI in oncological patients.</p><p><strong>Methods: </strong>A retrospective cohort study was conducted at Hospital Clinic, Barcelona, from 2008 to 2019. All episodes of bUTI in oncological patients were analysed. Multivariable regression models identified independent risk factors for multidrug-resistant (MDR) Gram-negative bacilli (GNB), recurrent bUTI and related mortality.</p><p><strong>Results: </strong>A total of 561 bUTI episodes were identified in 478 oncological patients. Urinary tract involvement due to neoplasm was present in 62.2%, and 59.4% had urinary tract instrumentation. Prior UTI-related admission without bacteraemia was reported in 63.8%. Following bUTI, oncological treatment was delayed in 47% and stopped in 33.6% of cases. GNB caused 87.3% of episodes, with Escherichia coli and Klebsiella spp. being the most common pathogens. Enterococcus spp. and Pseudomonas aeruginosa were frequent, particularly in patients with urinary instrumentation. MDR-GNB caused 19.6% of episodes, and 23.4% of cases received inappropriate empirical antibiotic therapy (IEAT). Recurrent bUTI occurred in 14.0% of patients. A simple predictive score efficiently identified patients at high risk of recurrence. Thirty-day mortality was 15.3%, and bUTI-related mortality was 10.7%, with absence of fever, septic shock and carbapenemase-producing Enterobacterales linked to higher related mortality.</p><p><strong>Conclusion: </strong>bUTI in oncological patients is predominantly caused by GNB, with high rates of MDR isolates and high mortality. IEAT is common, and recurrence is significant, highlighting the need for targeted preventive strategies and optimized empirical therapy.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091756","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}
引用次数: 0
Pharmacokinetics of aztreonam/avibactam in a critically ill patient with a class B metallo-β-lactamase producing Enterobacteriaceae and receiving continuous renal replacement therapy. 氨曲南/阿维巴坦在接受持续肾脏替代治疗的B类金属β内酰胺酶肠杆菌科危重患者中的药代动力学
IF 3.6 2区 医学
Journal of Antimicrobial Chemotherapy Pub Date : 2025-09-16 DOI: 10.1093/jac/dkaf330
Daniel Fresán, Maria Pilar Gracia-Arnillas, Aitor Iriarte Zugasti, Cristina Raich Gual, Carla Comajuán Mendoza, María Acer, Rosana Muñoz-Bermudez, María Milagro Montero, Luisa Sorlí, Sonia Luque
{"title":"Pharmacokinetics of aztreonam/avibactam in a critically ill patient with a class B metallo-β-lactamase producing Enterobacteriaceae and receiving continuous renal replacement therapy.","authors":"Daniel Fresán, Maria Pilar Gracia-Arnillas, Aitor Iriarte Zugasti, Cristina Raich Gual, Carla Comajuán Mendoza, María Acer, Rosana Muñoz-Bermudez, María Milagro Montero, Luisa Sorlí, Sonia Luque","doi":"10.1093/jac/dkaf330","DOIUrl":"https://doi.org/10.1093/jac/dkaf330","url":null,"abstract":"","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091802","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}
引用次数: 0
Azithromycin resistance in non-typhoidal Salmonella: a review. 非伤寒沙门氏菌阿奇霉素耐药性研究进展。
IF 3.6 2区 医学
Journal of Antimicrobial Chemotherapy Pub Date : 2025-09-16 DOI: 10.1093/jac/dkaf341
Zhe Zhu, Xin Hua, Yefang Ke
{"title":"Azithromycin resistance in non-typhoidal Salmonella: a review.","authors":"Zhe Zhu, Xin Hua, Yefang Ke","doi":"10.1093/jac/dkaf341","DOIUrl":"https://doi.org/10.1093/jac/dkaf341","url":null,"abstract":"<p><p>Antibiotics are crucial for controlling severe or invasive non-typhoidal Salmonella (NTS) infections. However, the high resistance or toxicity of traditionally first-line antibiotics calls for alternatives. The excellent membrane permeability, long half-life and safe to use in children render azithromycin a promising candidate. However, azithromycin resistance has been observed in NTS isolates recovered from humans, food, animals and the environment, with particularly high rates in Asia. Although azithromycin resistance remains low in Europe, the USA and Australia, an increasing tendency has been noted in the USA in recent years. Macrolide inactivation by phosphotransferases, methylation of 23S rRNA by methyltransferases, ribosomal protein alteration and efflux pumps are involved in azithromycin resistance in NTS isolates, among which phosphotransferase encoded by the mph (A) gene is the predominate mechanism. Current studies face limitations, such as the lack of a standardized azithromycin breakpoint for NTS isolates, insufficient integrated national surveillance and limited robust clinical evidence for treating NTS infections. Therefore, future studies addressing these issues are highly recommended.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091722","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}
引用次数: 0
Molecular insights into carbapenemase-producing Enterobacterales from Senegal. 塞内加尔产碳青霉烯酶肠杆菌的分子研究。
IF 3.6 2区 医学
Journal of Antimicrobial Chemotherapy Pub Date : 2025-09-16 DOI: 10.1093/jac/dkaf328
Ousmane Sow, Saoussen Oueslati, Issa Ndiaye, Océane Vanparis, Adja Bousso Gueye, Imene Mehidi, Elhadj Aly Niang, Abdoulaye Cisse, Babacar Ndiaye, Abdou Diop, Alexis Proust, Bissoume Sambe, Delphine Girlich, Laurent Dortet, Rémy A Bonnin, Abdoulaye Seck, Thierry Naas
{"title":"Molecular insights into carbapenemase-producing Enterobacterales from Senegal.","authors":"Ousmane Sow, Saoussen Oueslati, Issa Ndiaye, Océane Vanparis, Adja Bousso Gueye, Imene Mehidi, Elhadj Aly Niang, Abdoulaye Cisse, Babacar Ndiaye, Abdou Diop, Alexis Proust, Bissoume Sambe, Delphine Girlich, Laurent Dortet, Rémy A Bonnin, Abdoulaye Seck, Thierry Naas","doi":"10.1093/jac/dkaf328","DOIUrl":"https://doi.org/10.1093/jac/dkaf328","url":null,"abstract":"<p><strong>Background: </strong>Carbapenemase-producing Enterobacterales (CPE) are an urgent global health threat, especially in resource-limited countries. Here we determined the prevalence and the molecular characteristics of CPE isolated from infections in Dakar, Senegal.</p><p><strong>Method: </strong>From January 2019 to December 2020, Enterobacterales with reduced susceptibility to ertapenem (diameter < 25 mm) from infections were collected at the Pasteur Institute of Dakar. Carbapenemases were detected using biochemical and immunochromatographical assays. WGS was used to determine resistome, MLST, plasmids, virulence genes and genetic relatedness.</p><p><strong>Results: </strong>Of the 1045 Enterobacterales collected during the study period, 86 had a diameter around ertapenem of <25 mm (8%) and 19 were confirmed as CPE (2%). These included Escherichia coli (n = 6) [ST410 (n = 3), ST405 (n = 2) and ST2083], Enterobacter spp. (n = 6) [ST231 (n = 3), ST245, ST760 and ST960] and Klebsiella spp. (n = 5) (ST22, ST25, ST231, ST1535, ST4843), Citrobacter freundii ST22 (n = 1) and Citrobacter koseri with unknown ST (n = 1). blaOXA-48 (n = 7; 35%), blaOXA-181 (n = 7; 35%) and blaNDM-5 (n = 6; 30%) genes were identified. C. freundii ST22 harboured blaNDM-5, blaOXA-48 and blaCTX-M-15 genes. Some E. coli isolates belonging to the high-risk clone ST410 were closely related (<20 SNPs) to isolates recovered in France from patients returning from Senegal, suggesting transnational spread. In addition, 5/6 carbapenemase-producing E. coli isolates possessed a four amino acid insertion in PBP3, conferring reduced susceptibility to aztreonam/avibactam and cefiderocol.</p><p><strong>Conclusions: </strong>This study highlights the spread of NDM-5 and OXA-181 in Senegal, and reports the first co-occurrence of NDM-5 and OXA-48 in sub-Saharan Africa. The spread of CPE, especially in high-risk clones, underscores the urgent need for continued surveillance and targeted interventions.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091747","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}
引用次数: 0
In vitro evolution provides insights into mechanisms of Mycoplasma genitalium resistance to moxifloxacin. 体外进化提供了生殖支原体对莫西沙星耐药机制的见解。
IF 3.6 2区 医学
Journal of Antimicrobial Chemotherapy Pub Date : 2025-09-16 DOI: 10.1093/jac/dkaf324
Teck-Phui Chua, Jose L Huaman, Jennifer Danielewski, Catriona S Bradshaw, Dorothy A Machalek, Michael J McDonald, Suzanne M Garland, Gerald L Murray
{"title":"In vitro evolution provides insights into mechanisms of Mycoplasma genitalium resistance to moxifloxacin.","authors":"Teck-Phui Chua, Jose L Huaman, Jennifer Danielewski, Catriona S Bradshaw, Dorothy A Machalek, Michael J McDonald, Suzanne M Garland, Gerald L Murray","doi":"10.1093/jac/dkaf324","DOIUrl":"https://doi.org/10.1093/jac/dkaf324","url":null,"abstract":"<p><strong>Background: </strong>Current knowledge of Mycoplasma genitalium fluoroquinolone resistance is based on sequence analyses of clinical samples, an approach with limited scope. Many potential resistance mutations have been described but their impact on moxifloxacin efficacy is unclear.</p><p><strong>Objective: </strong>To investigate the impact of individual mutations on fluoroquinolone resistance through selection of moxifloxacin-resistant mutants in vitro.</p><p><strong>Methods: </strong>M. genitalium G37 was passaged sequentially in sub-inhibitory concentrations of moxifloxacin. MIC values were determined for moxifloxacin, sitafloxacin, levofloxacin and ciprofloxacin. Bacterial populations were profiled using amplicon sequencing.</p><p><strong>Results: </strong>Across three independent experiments, four moxifloxacin mutants were isolated, with mutations encoding the following protein sequence variations: (i) GyrA D99Y/ParE E468K, (ii) ParC S83I/GyrA D99Y/ParE E468K, (iii) ParC D87V/GyrB P462S and (iv) GyrA M95I/ParE E468dup. Moxifloxacin MICs were elevated 16- to 32-fold for mutants with a single GyrA or ParC variation, and 128-fold for the dual GyrA/ParC mutant. Sitafloxacin MICs were elevated but remained lower than moxifloxacin MICs. Mutations did not have a substantial impact on in vitro growth dynamics. Population analysis showed that multiple mutations attained detectable population-wide frequencies, with evidence of clonal interference dynamics, with a minority becoming fixed in the population.</p><p><strong>Conclusion: </strong>Mutations in multiple genes conferring fluoroquinolone resistance appeared with regularity in vitro. Findings of an additive effect for ParC/GyrA changes, and greater effectiveness of sitafloxacin against resistant bacteria compared with moxifloxacin, are both consistent with clinical data. Improved understanding of fluoroquinolone resistance will inform the development of diagnostic assays predicting fluoroquinolone susceptibility.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091728","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}
引用次数: 0
Population pharmacokinetic model of linezolid and its metabolite PNU-142300 in elderly patients. 利奈唑胺及其代谢物PNU-142300在老年患者体内的人群药代动力学模型。
IF 3.6 2区 医学
Journal of Antimicrobial Chemotherapy Pub Date : 2025-09-15 DOI: 10.1093/jac/dkaf329
Xianglong Chen, LiJuan Yang, Qian Zhang, Zhiwei Zhuang, TongTong Li, Yunlong Yuan, Lufen Duan, Lu Shi, Shenjia Huang, Hanzhen Zhao, Jian Lu, Jingjing Li, Jinwei Fan, Yanxia Yu, Lian Tang, Jinhui Xu
{"title":"Population pharmacokinetic model of linezolid and its metabolite PNU-142300 in elderly patients.","authors":"Xianglong Chen, LiJuan Yang, Qian Zhang, Zhiwei Zhuang, TongTong Li, Yunlong Yuan, Lufen Duan, Lu Shi, Shenjia Huang, Hanzhen Zhao, Jian Lu, Jingjing Li, Jinwei Fan, Yanxia Yu, Lian Tang, Jinhui Xu","doi":"10.1093/jac/dkaf329","DOIUrl":"https://doi.org/10.1093/jac/dkaf329","url":null,"abstract":"<p><strong>Background and objectives: </strong>Elderly patients are at an increased risk of supratherapeutic linezolid exposure, and elevated trough concentrations of linezolid and its metabolite (PNU-142300) are associated with the development of linezolid-induced thrombocytopenia. Clarifying the population pharmacokinetic (PPK) characteristics of linezolid and PNU-142300 in this population is critical for optimizing therapeutic strategies. This study aimed to develop a PPK model for linezolid and PNU-142300 in elderly patients to guide dose adjustments and mitigate thrombocytopenia risk.</p><p><strong>Methods: </strong>Patients aged ≥65 years receiving linezolid therapy were enrolled. Concentrations of linezolid and PNU-142300 were quantified using LC-MS/MS. Covariate analysis was conducted via stepwise forward inclusion and backward elimination. Model evaluation included goodness-of-fit plots, prediction-corrected visual predictive checks, and nonparametric bootstrap validation. Monte Carlo simulations were performed to identify optimal dosing regimens.</p><p><strong>Results: </strong>A total of 149 concentrations from 114 patients were analysed. Creatinine clearance (CLCr) significantly influenced the clearance of both linezolid and PNU-142300. Population mean estimates for clearance were 2.02 L/h (linezolid) and 1.57 L/h (PNU-142300), with an equal volume of distribution of 31.17 L. The model demonstrated robust stability and predictive performance. For patients with CLCr of 15-29 mL/min, 200 mg q12h achieved optimal linezolid exposure, with a 78.6% probability of maintaining PNU-142300 below the toxicity threshold. For patients with CLCr of 30-89 mL/min, 200 mg q8h provided therapeutic exposure with >80% probability of avoiding metabolite toxicity.</p><p><strong>Conclusions: </strong>This first PPK model of linezolid and PNU-142300 in elderly patients supports individualized dosing to reduce thrombocytopenia risk. Linezolid dose reduction may be necessary in elderly patients.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091716","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}
引用次数: 0
Modification of antimicrobial susceptibility testing methods. 药敏试验方法的修改。
IF 3.6 2区 医学
Journal of Antimicrobial Chemotherapy Pub Date : 2025-09-15 DOI: 10.1093/jac/dkaf332
Ian Morrissey, Jean B Patel
{"title":"Modification of antimicrobial susceptibility testing methods.","authors":"Ian Morrissey, Jean B Patel","doi":"10.1093/jac/dkaf332","DOIUrl":"https://doi.org/10.1093/jac/dkaf332","url":null,"abstract":"<p><p>The development of new antimicrobial agents is essential to combat antimicrobial resistance. Reliable antimicrobial susceptibility testing (AST) methods should be established early and thoughtfully to ensure timely patient access to these agents. The standard reference method for AST is broth microdilution (BMD) in cation-adjusted Mueller-Hinton broth (CAMHB), as defined by CLSI M07 (CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. 12th ed. CLSI Standard M07. Clinical and Laboratory Standards Institute, 2024) and ISO 20776-1 (ISO. Susceptibility Testing of Infectious Agents and Evaluation of Performance of Antimicrobial Susceptibility Test Devices-Part 1: Broth Micro-dilution Reference Method for Testing the In Vitro Activity of Antimicrobial Agents Against Rapidly Growing Aerobic Bacteria Involved in Infectious Diseases. ISO 20776-1. International Organization for Standardization, 2019). While some agents may require modifications to this method to better reflect clinical activity, such changes must be scientifically justified. Modifications aimed solely at producing lower minimal inhibitory concentration (MIC) values-or to make one antimicrobial agent appear superior to others-are not scientifically valid and are strongly discouraged. Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) caution developers that unnecessary deviations from reference AST methods can lead to increased costs, regulatory hurdles, delays in test availability and reduced clinical adoption. Until joint guidance under development by CLSI and EUCAST is finalized, early and rigorous evaluation using the reference method is essential.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091766","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}
引用次数: 0
Physiologically informed in vitro framework reveals context-dependent combinatory activity of niclosamide-colistin against Gram-negative bacteria. 生理知情的体外框架揭示了氯硝胺-粘菌素对革兰氏阴性菌的环境依赖性组合活性。
IF 3.6 2区 医学
Journal of Antimicrobial Chemotherapy Pub Date : 2025-09-08 DOI: 10.1093/jac/dkaf323
Mariana Romero-Gonzalez, Mari Park, Winnie Lin, Lindsay J Caverly, Ashlee D Brunaugh
{"title":"Physiologically informed in vitro framework reveals context-dependent combinatory activity of niclosamide-colistin against Gram-negative bacteria.","authors":"Mariana Romero-Gonzalez, Mari Park, Winnie Lin, Lindsay J Caverly, Ashlee D Brunaugh","doi":"10.1093/jac/dkaf323","DOIUrl":"https://doi.org/10.1093/jac/dkaf323","url":null,"abstract":"<p><strong>Background: </strong>Synergy between antibiotic pairs is typically discovered using chequerboard assays that assume uniform, static drug exposure; however, such conditions rarely apply in vivo. Dynamic and heterogeneous tissue environments create spatial and temporal mismatches in drug exposure that can uncouple synergistic interactions, leading to unexpected treatment failure.</p><p><strong>Objective: </strong>This study aims to develop a physiologically relevant in vitro model that integrates infection-site microenvironments and drug-specific pharmacokinetics. This platform was applied to investigate how spatial and temporal factors affect antibiotic synergy, using niclosamide and colistin as a case study for inhaled delivery to infected lung airways.</p><p><strong>Methods: </strong>Opportunistic Gram-negative bacterial species with varied susceptibility to niclosamide and colistin were tested. Synergy was assessed using microdilution chequerboard assays under both standard and physiologically altered conditions. In vitro models incorporating mucus interactions and pharmacokinetic parameters were used to examine the effects of spatial and temporal decoupling on the activity of the combination.</p><p><strong>Results: </strong>Changes in pH and cation concentration altered both individual drug potency and combination effects, consistent with the ionizable nature of niclosamide and membrane-stabilizing roles of divalent cations. Simulated rapid clearance of niclosamide reduced its contribution to synergy, suggesting that the combined effects are time-sensitive. Mucin impaired niclosamide diffusion and diminished combination efficacy, indicating that spatial separation can disrupt synergistic interactions.</p><p><strong>Conclusions: </strong>Microenvironmental complexity and drug kinetics significantly influence antibiotic synergy. Incorporating physiologically relevant spatial and temporal variables into in vitro models may improve clinical prediction and guide rational design of combination therapies.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015473","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}
引用次数: 0
Correction to: Clinical and microbiological analysis of bloodstream infections by four cefiderocol-resistant and not previously exposed NDM-producing Klebsiella pneumoniae. 更正:四种头孢地酚耐药且未暴露于ndm产生肺炎克雷伯菌的血液感染的临床和微生物学分析。
IF 3.6 2区 医学
Journal of Antimicrobial Chemotherapy Pub Date : 2025-09-04 DOI: 10.1093/jac/dkaf334
{"title":"Correction to: Clinical and microbiological analysis of bloodstream infections by four cefiderocol-resistant and not previously exposed NDM-producing Klebsiella pneumoniae.","authors":"","doi":"10.1093/jac/dkaf334","DOIUrl":"https://doi.org/10.1093/jac/dkaf334","url":null,"abstract":"","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992573","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}
引用次数: 0
Novel mutations associated with clofazimine resistance in Mycobacterium intracellulare. 胞内分枝杆菌与氯法齐明耐药相关的新突变。
IF 3.6 2区 医学
Journal of Antimicrobial Chemotherapy Pub Date : 2025-09-04 DOI: 10.1093/jac/dkaf321
Xiuzhi Jiang, Dan Cao, Yuwei Qiu, Xu Dong, Pusheng Xu, Yi Li, Xin Yuan, Yanghui Xiang, Kaijin Xu, Ying Zhang
{"title":"Novel mutations associated with clofazimine resistance in Mycobacterium intracellulare.","authors":"Xiuzhi Jiang, Dan Cao, Yuwei Qiu, Xu Dong, Pusheng Xu, Yi Li, Xin Yuan, Yanghui Xiang, Kaijin Xu, Ying Zhang","doi":"10.1093/jac/dkaf321","DOIUrl":"https://doi.org/10.1093/jac/dkaf321","url":null,"abstract":"<p><strong>Background: </strong>Clofazimine is a promising repurposed drug for treating Mycobacterium avium-intracellulare complex pulmonary disease, but its resistance mechanisms in Mycobacterium intracellulare remain poorly understood.</p><p><strong>Objective: </strong>This study aims to elucidate the resistance mechanisms of M. intracellulare to clofazimine.</p><p><strong>Methods: </strong>We isolated 36 clofazimine-resistant M. intracellulare mutants in vitro and performed whole-genome sequencing to identify resistance-associated mutations. Gene complementation was used to validate the role of the identified mutations.</p><p><strong>Results: </strong>We identified various mutations in the marR gene (WP_009952290.1) in 61% of clofazimine-resistant mutants by whole-genome sequencing. Mutations were identified in additional genes encoding ssuD (flavin-dependent oxidoreductase, C67A), lppI (membrane lipoprotein, C207 deletion), GMC oxidoreductase (glucose-methanol-choline oxidoreductase, G157 deletion), MASE1 domain-containing protein (C62G) and PPE family protein (222C deletion). Gene complementation experiments demonstrated that introducing the wild-type marR in clofazimine-resistant strain (L72) with marR mutations reduced clofazimine MIC from 1 mg/L to susceptible baseline (0.25 mg/L), confirming its critical role in clofazimine resistance. Notably, the M. intracellulare MarR lacks homology to Mycobacterium tuberculosis MarR family protein Rv0678 (MmpR) involved in clofazimine and bedaquiline resistance but is flanked by non-efflux pump genes (dhmA and doxX), and unlike M. tuberculosis, its mutation does not cause bedaquiline cross-resistance, indicating a different MarR and distinct regulatory mechanism for clofazimine resistance in M. intracellulare.</p><p><strong>Conclusions: </strong>This work highlights marR as a key determinant of clofazimine resistance in M. intracellulare and underscores the need for further mechanistic studies with implications for rapid molecular detection and effective treatment.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992663","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}
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