International Journal of Antimicrobial Agents最新文献_第5页

Superintegron of Vibrio paracholerae as a reservoir of antibiotic resistance genes 副弧菌作为抗生素抗性基因储存库的超整合子。

IF 4.6 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2025-12-30 DOI: 10.1016/j.ijantimicag.2025.107708

Sergio Mascarenhas Morgado, Erica Lourenço da Fonseca, Ana Carolina Paulo Vicente

引用次数: 0

Vancomycin clearance compared to creatinine clearance by timed urine collection in the intensive care unit 万古霉素清除率与肌酸酐清除率在重症监护病房定时收集尿液的比较。

IF 4.6 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2025-12-26 DOI: 10.1016/j.ijantimicag.2025.107704

Andrew Chantha Hean , Rinoj Mathew , Frank Chu , Linda Awdishu

Objective

Prior literature elucidating the ratio of vancomycin clearance by the kidneys to creatinine clearance is conflicting. Further studies are warranted evaluating vancomycin clearance, especially in the critically ill population.

Methods

This retrospective exploratory analysis includes data from a decade of pulmonary/medical or cardiac ICU admissions where a serum creatinine, vancomycin concentration, and 24-hour timed urine collection were obtained within a 72-hour period. Patients with dialysis prior to, or 48 hours after, urine collection were excluded. The primary outcome was the ratio of vancomycin clearance (CLv) to creatinine clearance measured by timed urine collection (mCLcr). Exploratory outcomes also included (1) P30 accuracy and bias of CLv, BSA adjusted 2021 CKD-Epidemiology Collaboration (EPI) creatinine eGFR, Jelliffe creatinine clearance, and Cockcroft-Gault creatinine clearance equations when compared to mCLcr; (2) the correlations of clearances to mCLcr; and (3) the number of patients with augmented renal clearance for each kidney function estimating equation.

Results

A total of 56 eligible subjects were analysed. The ratio of CLv to mCLcr was 0.64. Although CLv showed the lowest P30 accuracy, it was the most correlated with mCLcr along with the 2021 CKD-EPI creatinine eGFR to mCLcr.

Conclusions

In critically ill patients who warrant medical, pulmonary, or cardiac ICU admission, the ratio of total vancomycin clearance to mCLcr measured by timed urine collection may differ from other populations. CLv and the 2021 CKD-EPI creatinine equation may be more correlated to mCLcr by timed urine collection. Larger studies are needed to confirm these results.

先前的文献阐明万古霉素清除率与肌酐清除率的比例是相互矛盾的。进一步的研究评估万古霉素的清除率是必要的，特别是在危重患者人群中。方法：本回顾性探索性分析包括十年来肺部/内科或心脏重症监护病房入院患者的数据，其中在72小时内获得血清肌酐、万古霉素浓度和24小时定时尿液收集。在收集尿液前或48小时后进行透析的患者被排除在外。主要终点是万古霉素清除率（CLv）与肌酐清除率的比值，通过定时尿液收集（mCLcr）测量。探索性结果还包括：(1)与mCLcr相比，CLv的P30准确性和偏倚、体表面积调整后的2021 CKD-EPI肌酐估计肾小球滤过率（eGFR）、Jelliffe肌酐清除率和Cockcroft-Gault肌酐清除率方程的P30准确性和偏倚；(2)清除率与mCLcr的相关性；(3)每个肾功能估计方程中肾脏清除率增强的患者数量。结果：分析了56例符合条件的受试者。CLv与mCLcr之比为0.64。尽管CLv显示最低的P30准确性，但它与mCLcr以及2021 CKD-EPI肌酐eGFR与mCLcr的相关性最大。结论：在需要内科、肺部或心脏ICU住院的危重患者中，通过定时收集尿液测量的万古霉素总清除率与mccr的比值可能与其他人群不同。CLv和2021 CKD-EPI肌酐方程可能通过定时尿液收集与mCLcr更相关。需要更大规模的研究来证实这些结果。

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引用次数: 0

Development of ceftazidime–avibactam resistance driven by conversion of blaKPC-2 to blaKPC-78 during treatment of ST463 carbapenem-resistant Pseudomonas aeruginosa infection 在ST463耐碳青霉烯假单胞菌感染治疗过程中，由blaKPC-2转化为blaKPC-78驱动头孢他啶-阿维巴坦耐药性的发展

IF 4.6 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2025-12-26 DOI: 10.1016/j.ijantimicag.2025.107703

Haotian Xu , Tingjuan Zhang , Xueying Cui , Jingyi Guo , Pengpeng Min , Chengjin Wu , Xinyan Tang , Longjie Zhou , Linfang Wang , Xi Li

Objective

The emergence of ceftazidime-avibactam (CZA)-resistant carbapenem-resistant Pseudomonas aeruginosa (CRPA) poses a major clinical challenge in contemporary clinical practice. In this study, we report the first identification of bla_KPC-78, which is driven by a mutation from bla_KPC-2 in a clinical CRPA strain.

Methods

Six bla_KPC-78 CRPA isolates, along with two bla_KPC-2 strains from one patient, were subjected to antimicrobial susceptibility testing (AST), whole-genome sequencing (WGS), conjugation, and growth assays. Mechanistic investigations included structural modelling and docking, cloning experiments, efflux inhibition, and reverse transcription quantitative polymerase chain reaction (RT-qPCR).

Results

The emergence of CZA resistance in CRPA isolates was driven by a mutation from bla_KPC-2 to bla_KPC-78 during CZA therapy. The AST results showed that all KPC-78-producing CRPA exhibited a multidrug-resistant phenotype. WGS revealed that these strains belong to ST463, and bla_KPC-78 gene was located in a type I plasmid and carried by the Tn6296 transposon. Additionally, the co-occurrence of efflux pump overexpression and KPC-78 enzyme's stronger binding affinities for both ceftazidime and avibactam contributed to high-level resistance to CZA in CRPA. Moreover, despite the slower logarithmic growth of KPC-78-producing P. aeruginosa in monoculture, in vitro competitive co-culture experiments revealed that it conferred a competitive advantage over the KPC-2-producing strains.

Conclusions

We report the first identification of bla_KPC-78 in CRPA, delineate its evolutionary trajectory, and describe its genetic characteristics. The elevated hydrolytic activity of the KPC-78 producing strain, along with the overexpression of efflux pumps, contributes to its high-level resistance to CZA. Considering the widespread occurrence of ST463 CRPA in China, it is imperative to enhance the surveillance of KPC-producing CRPA.

背景：头孢他啶-阿维巴坦（CZA）耐药碳青霉烯耐药铜绿假单胞菌（CRPA）的出现是当代临床实践中的一个重大挑战。在这项研究中，我们首次在临床CRPA菌株中鉴定出由blaKPC-2突变驱动的blaKPC-78。方法：对6株blaKPC-78 CRPA分离株和1例患者的2株blaKPC-2进行抗菌药敏试验（AST）、全基因组测序（WGS）、偶联和生长试验。机制研究包括结构建模与对接、克隆实验、外排抑制和逆转录定量聚合酶链反应（RT-qPCR）。结果：CRPA分离株CZA耐药性的出现是由CZA治疗期间blaKPC-2突变为blaKPC-78引起的。AST结果显示，所有产生kpc -78的CRPA均表现出多药耐药表型。WGS结果显示，这些菌株属于ST463， blaKPC-78基因位于I型质粒上，由Tn6296转座子携带。此外，外排泵过表达和KPC-78酶对头孢他啶和阿维巴坦的结合亲和力较强，共同导致CRPA对CZA的高水平耐药。此外，尽管单培养中产生kpc -78的铜绿假单胞菌的对数生长速度较慢，但体外竞争共培养实验显示，它比产生kpc -2的菌株具有竞争优势。结论：我们首次在CRPA中发现了blaKPC-78，描绘了其进化轨迹，并描述了其遗传特征。KPC-78产生菌株的水解活性升高，以及外排泵的过度表达，有助于其对CZA的高抗性。考虑到ST463 CRPA在中国的广泛存在，加强对产kpc的CRPA的监测势在必行。

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引用次数: 0

Comments on ‘Acute kidney injury associated with colistin sulphate vs. polymyxin B sulphate therapy: A real-world, retrospective cohort study’ 《硫酸粘菌素与硫酸多粘菌素B治疗相关的急性肾损伤：一项真实世界的回顾性队列研究》评论。

IF 4.6 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2025-12-24 DOI: 10.1016/j.ijantimicag.2025.107702

Genzhu Wang

引用次数: 0

Enhancing meropenem therapy in critical care: A retrospective study of PK/PD target attainment and therapeutic drug monitoring 在重症监护中加强美罗培南治疗：PK/PD目标达成和治疗药物监测的回顾性研究。

IF 4.6 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2025-12-24 DOI: 10.1016/j.ijantimicag.2025.107697

Jingli Liao , Chao Li , Jingxian Liu , Wei Wu , Xiaohui Huang , Yanfei Mao , Lixia Li

<div><h3>Background</h3><div>Meropenem is a first-line treatment for severe infections; however, its efficacy is increasingly compromised by drug resistance. This situation underscores the urgent need to optimise dosing strategies and establish precise efficacy evaluation systems.</div></div><div><h3>Objectives</h3><div>This study aimed to evaluate the adequacy of the initial meropenem regimen by analysing factors associated with its clinical efficacy in critically ill patients, as well as to define predictive pharmacokinetic/pharmacodynamic (PK/PD) targets.</div></div><div><h3>Methods</h3><div>We conducted a retrospective analysis of 205 critically ill patients treated with meropenem. Logistic regression was employed to analyse factors influencing clinical efficacy and bacterial clearance rates, while Cox regression was utilised to assess factors affecting 30-d mortality. Receiver operating characteristic (ROC) analysis was performed to identify PK/PD targets using the first therapeutic drug monitoring (TDM) serum concentrations, and assessed the predictive performance of trough (C<sub>min</sub>) and peak (C<sub>max</sub>) concentrations concerning clinical efficacy.</div></div><div><h3>Results</h3><div>The clinical effectiveness of meropenem in critically ill patients was found to be 56.6%. Independent risk factors affecting clinical efficacy included C<sub>min</sub> (< 6 mg/L vs. ≥ 6 mg/L), urinary tract infections, tigecycline combination therapy, meropenem-sensitive vs. meropenem-resistant pathogens, sequential organ failure assessment (SOFA) scores (2–5 vs. > 5), and neutrophil counts. Notably, patients receiving prolonged infusion (≥ 2 h) achieved both significantly higher meropenem trough concentrations and better clinical efficacy than those on intermittent infusion. The bacterial clearance rate was 39.0%, which was associated with C<sub>min</sub> (< 8 mg/L vs. ≥ 8 mg/L) and the presence of meropenem-sensitive vs. resistant bacteria. The 30-d mortality rate was 20.0%, linked to age, pulmonary infections, tigecycline combination therapy, surgical history, hospital stay duration, and sequential organ failure assessment (SOFA) scores. Optimal efficacy was achieved with C<sub>min</sub> ≥ 5.3 mg/L and C<sub>max</sub> ≥ 39.4 mg/L, with higher thresholds required for bloodstream infections (C<sub>min</sub> ≥ 7.3 mg/L; C<sub>max</sub> ≥ 49.1 mg/L).</div></div><div><h3>Conclusion</h3><div>Meropenem demonstrates significant efficacy against severe infections caused by sensitive pathogens, particularly in cases of urinary tract infections. We identified that a C<sub>min</sub> of ≥ 5.3 mg/L and a C<sub>max</sub> of ≥ 39.4 mg/L are associated with optimal clinical efficacy. Based on these findings, we propose an initial dosing strategy tailored to renal function and the site of infection. Our results underscore the value of early TDM in identifying patients at risk of suboptimal exposure, which provides a crucial foundation for subsequent do

背景：美罗培南是严重感染的一线治疗药物；然而，它的功效越来越受到耐药性的影响。这种情况强调迫切需要优化给药策略和建立精确的疗效评估系统。目的：本研究旨在通过分析影响美罗培南在危重患者临床疗效的相关因素，评价美罗培南初始方案的充分性，并确定预测药代动力学/药效学（PK/PD）指标。方法：对205例使用美罗培南治疗的危重患者进行回顾性分析。采用Logistic回归分析影响临床疗效和细菌清除率的因素，采用Cox回归评估影响30天死亡率的因素。采用首次治疗药物监测（TDM）血清浓度进行受试者工作特征（ROC）分析，确定PK/PD靶点，并评估谷浓度（Cmin）和峰浓度（Cmax）对临床疗效的预测能力。结果：美罗培南治疗危重患者的临床有效率为56.6%。影响临床疗效的独立危险因素包括Cmin （< 6mg /L vs≥6mg /L）、尿路感染、替加环素联合治疗、美罗培烯敏感vs耐药病原体、SOFA评分（2-5 vs bb0 -5）和中性粒细胞计数。值得注意的是，延长输注时间（≥2h）的患者美罗培南谷浓度明显高于间歇输注的患者，且临床疗效更好。细菌清除率为39.0%，与Cmin （< 8 mg/L vs≥8 mg/L）、美罗培尼敏感菌与耐药菌的存在相关。30天死亡率为20.0%，与年龄、肺部感染、替加环素联合治疗、手术史、住院时间和SOFA评分有关。Cmin≥5.3 mg/L和Cmax≥39.4 mg/L时疗效最佳，血流感染阈值较高（Cmin≥7.3 mg/L, Cmax≥49.1 mg/L）。结论：美罗培南对敏感病原菌引起的严重感染，特别是尿路感染有显著疗效。我们发现Cmin≥5.3 mg/L和Cmax≥39.4 mg/L与最佳临床疗效相关。基于这些发现，我们提出了一个适合肾功能和感染部位的初始剂量策略。我们的研究结果强调了早期TDM在识别处于次优暴露风险的患者中的价值，这为随后的剂量调整提供了重要的基础。因此，为了优化危重患者的美罗培南治疗，实施tdm指导的策略至关重要，该策略整合了适当的剂量，延长输注方式和早期暴露评估。

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引用次数: 0

Antibiotic class comparisons for the treatment of pyelonephritis and complicated urinary tract infections: A systematic review and meta-analysis 治疗肾盂肾炎和并发尿路感染的抗生素类别比较：系统回顾和荟萃分析。

IF 4.6 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2025-12-22 DOI: 10.1016/j.ijantimicag.2025.107696

Digbijay Kunwar , Itay Zahavi , Judit Olchowski , Hagar Dallasheh , Mical Paul

Background

The relative efficacy of antibiotic classes for pyelonephritis and complicated UTI (cUTI) remains unclear, as different antibiotic classes vary in antimicrobial activity, pharmacodynamics and pharmacokinetics.

Methods

Systematic review and meta-analysis. We searched PubMed, Cochrane CENTRAL, clinical-trial registries and conference abstracts through 30 November 2025. Randomised controlled trials comparing antibiotic classes in adults with pyelonephritis/complicated UTI (cUTI) were eligible (PROSPERO CRD42023448020). Five comparisons were analysed: quinolones vs β-lactams, cephalosporins vs penicillins, aminoglycosides vs quinolones or beta-lactams, trimethoprim-sulfamethoxazole vs quinolones or beta-lactams and ESBL-active agents vs non-ESBL-active antibiotics. The primary outcome was clinical cure by day 7. We compiled risk ratios (RRs) with 95% confidence intervals (CI) using fixed-effect meta-analyses. Risk of bias was assessed with ROB 2.0 and evidence certainty using GRADE.

Results

Thirty-seven RCTs were included, comprising 7,904 mainly hospitalized participants (62.7% women). Most had some risk-of-bias concerns. No significant difference in clinical cure was observed with moderate evidence certainty, across all comparisons. Relapse increased significantly with TMP/SMX compared to quinolones or beta-lactams (RR 2.34 [1.29, 4.24]) and microbiological cure improved with ESBL-active antibiotics (RR 1.07 [1.02, 1.13], very low certainty evidence). TMP/SMX increased adverse events and aminoglycosides increased nephrotoxicity and resistance acquisition.

Conclusions

Clinical cure was comparable across all comparisons. This supports basing antibiotic selection on local resistance patterns, patient factors and toxicity profiles rather than presumed class superiority.

背景：不同种类的抗生素治疗肾盂肾炎和合并UTI （cUTI）的相对疗效尚不清楚，因为不同种类的抗生素在抗菌活性、药效学和药代动力学方面存在差异。方法：系统评价和荟萃分析。我们检索了PubMed、Cochrane CENTRAL、临床试验注册库和2025年11月30日的会议摘要。比较成人肾盂肾炎/ cUTI患者抗生素种类的随机对照试验符合条件（PROSPERO CRD42023448020）。分析了五种比较：喹诺酮类与β-内酰胺类、头孢菌素类与青霉素类、氨基糖苷类与喹诺酮类或β-内酰胺类、甲氧苄啶磺胺甲恶唑类与喹诺酮类或β-内酰胺类、esbl活性药物与非esbl活性抗生素。主要终点为第7天临床治愈。我们使用固定效应荟萃分析编制了95%置信区间的风险比（rr）。偏倚风险采用rob2.0评估，证据确定性采用GRADE评估。结果：纳入37项随机对照试验，包括7904名主要住院患者（62.7%为女性）。大多数人都有一些偏见风险的担忧。在所有比较中，没有观察到临床治愈的显著差异，证据确定性中等。与喹诺酮类或β -内酰胺类药物相比，TMP/ SMX组的复发率显著增加（RR为2.34 [1.29,4.24]），eslb活性抗生素组的微生物治愈率提高（RR为1.07[1.02,1.13]，确定性证据非常低）。TMP/ SMX增加了不良事件，氨基糖苷增加了肾毒性和耐药性获得。结论：临床治愈率在所有比较中具有可比性。这支持根据当地的耐药模式、患者因素和毒性特征来选择抗生素，而不是假设的类别优势。

{"title":"Antibiotic class comparisons for the treatment of pyelonephritis and complicated urinary tract infections: A systematic review and meta-analysis","authors":"Digbijay Kunwar , Itay Zahavi , Judit Olchowski , Hagar Dallasheh , Mical Paul","doi":"10.1016/j.ijantimicag.2025.107696","DOIUrl":"10.1016/j.ijantimicag.2025.107696","url":null,"abstract":"<div><h3>Background</h3><div>The relative efficacy of antibiotic classes for pyelonephritis and complicated UTI (cUTI) remains unclear, as different antibiotic classes vary in antimicrobial activity, pharmacodynamics and pharmacokinetics.</div></div><div><h3>Methods</h3><div>Systematic review and meta-analysis. We searched PubMed, Cochrane CENTRAL, clinical-trial registries and conference abstracts through 30 November 2025. Randomised controlled trials comparing antibiotic classes in adults with pyelonephritis/complicated UTI (cUTI) were eligible (PROSPERO CRD42023448020). Five comparisons were analysed: quinolones vs β-lactams, cephalosporins vs penicillins, aminoglycosides vs quinolones or beta-lactams, trimethoprim-sulfamethoxazole vs quinolones or beta-lactams and ESBL-active agents vs non-ESBL-active antibiotics. The primary outcome was clinical cure by day 7. We compiled risk ratios (RRs) with 95% confidence intervals (CI) using fixed-effect meta-analyses. Risk of bias was assessed with ROB 2.0 and evidence certainty using GRADE.</div></div><div><h3>Results</h3><div>Thirty-seven RCTs were included, comprising 7,904 mainly hospitalized participants (62.7% women). Most had some risk-of-bias concerns. No significant difference in clinical cure was observed with moderate evidence certainty, across all comparisons. Relapse increased significantly with TMP/SMX compared to quinolones or beta-lactams (RR 2.34 [1.29, 4.24]) and microbiological cure improved with ESBL-active antibiotics (RR 1.07 [1.02, 1.13], very low certainty evidence). TMP/SMX increased adverse events and aminoglycosides increased nephrotoxicity and resistance acquisition.</div></div><div><h3>Conclusions</h3><div>Clinical cure was comparable across all comparisons. This supports basing antibiotic selection on local resistance patterns, patient factors and toxicity profiles rather than presumed class superiority.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 2","pages":"Article 107696"},"PeriodicalIF":4.6,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827746","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

Zinc deficiency reverses biofilm azole resistance in Candida albicans 锌缺乏逆转白色念珠菌的生物膜抗唑。

IF 4.6 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2025-12-22 DOI: 10.1016/j.ijantimicag.2025.107695

Yingzhe Wang , Shigan Ye , Yuan Deng , Yingting Huang , Xiaoliang Zhu

Objective

Biofilm formation is one of the causes of azole resistance in Candida albicans. Although zinc is an essential trace element involved in biofilm regulation, its specific mechanistic role remains unclear. Here, we systematically evaluated the effects and mechanisms of zinc deficiency on biofilm formation and drug resistance.

Methods

Intracellular zinc deficiency was induced using the zinc chelator N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) and a CSR1 knockout strain, as confirmed using zinquin fluorescence. Biofilm formation and susceptibility were assessed using standardized microdilution techniques, including sessile minimum inhibitory concentration (sMIC) determinations via the XTT reduction assay, while drug interactions were assessed using a checkerboard assay. Efflux pump activity was measured using a Rhodamine 6 G assay and transcriptomic analysis was performed to elucidate underlying mechanisms. Pathogenicity was validated using a Galleria mellonella infection model.

Results

Zinc deficiency inhibited biofilm development at all stages. Low-concentration TPEN (5 µM) reduced the sessile minimum inhibitory concentration (sMIC) of fluconazole by more than 16-fold and ultimately reversed its azole resistance. This effect was mechanistically associated with the downregulation of key biofilm-related transcription factors and multidrug efflux pumps, as revealed by transcriptomic analysis, which also indicated that zinc deficiency triggered ribosomal remodelling and activated glucose metabolism. Survival analysis in the G. mellonella infection model confirmed that zinc deficiency reduced the overall pathogenicity of C. albicans biofilms.

Conclusions

These results validate zinc homeostasis as a novel therapeutic strategy against drug-resistant and recurrent fungal infections, especially those involving biofilms.

生物膜的形成是白色念珠菌耐唑的原因之一。锌是参与生物膜调控的重要微量元素，但其具体机制尚不清楚。在此，我们系统地评估了锌缺乏对生物膜形成和耐药性的影响及其机制。用锌螯合剂N，N，N‘，N’-四akis（2-吡啶基甲基）乙二胺（TPEN）和CSR1敲除菌株诱导细胞内锌缺乏，锌荧光证实了这一点。使用标准化的微量稀释技术评估生物膜形成和敏感性，包括通过XTT还原法测定无根最小抑制浓度（sMIC），而使用棋盘法评估药物相互作用。使用罗丹明6G测定法测量外排泵活性，并进行转录组学分析以阐明潜在机制。致病性用麦氏Galleria mellonella感染模型验证。结果表明，锌缺乏抑制了各阶段生物膜的发育。低浓度TPEN（5µM）可使氟康唑的sMIC降低16倍以上，并最终逆转其对唑的耐药性。转录组学分析显示，这种效应与关键生物膜相关转录因子和多药物外排泵的下调机制相关，这也表明锌缺乏引发核糖体重塑和激活葡萄糖代谢。在白念珠菌感染模型中的生存分析证实，缺锌降低了白念珠菌生物膜的整体致病性。这些结果证实锌体内平衡是一种新的治疗策略，可以对抗耐药和复发性真菌感染，特别是那些涉及生物膜的感染。

{"title":"Zinc deficiency reverses biofilm azole resistance in Candida albicans","authors":"Yingzhe Wang , Shigan Ye , Yuan Deng , Yingting Huang , Xiaoliang Zhu","doi":"10.1016/j.ijantimicag.2025.107695","DOIUrl":"10.1016/j.ijantimicag.2025.107695","url":null,"abstract":"<div><h3>Objective</h3><div>Biofilm formation is one of the causes of azole resistance in <em>Candida albicans</em>. Although zinc is an essential trace element involved in biofilm regulation, its specific mechanistic role remains unclear. Here, we systematically evaluated the effects and mechanisms of zinc deficiency on biofilm formation and drug resistance.</div></div><div><h3>Methods</h3><div>Intracellular zinc deficiency was induced using the zinc chelator N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) and a <em>CSR1</em> knockout strain, as confirmed using zinquin fluorescence. Biofilm formation and susceptibility were assessed using standardized microdilution techniques, including sessile minimum inhibitory concentration (sMIC) determinations via the XTT reduction assay, while drug interactions were assessed using a checkerboard assay. Efflux pump activity was measured using a Rhodamine 6 G assay and transcriptomic analysis was performed to elucidate underlying mechanisms. Pathogenicity was validated using a <em>Galleria mellonella</em> infection model.</div></div><div><h3>Results</h3><div>Zinc deficiency inhibited biofilm development at all stages. Low-concentration TPEN (5 µM) reduced the sessile minimum inhibitory concentration (sMIC) of fluconazole by more than 16-fold and ultimately reversed its azole resistance. This effect was mechanistically associated with the downregulation of key biofilm-related transcription factors and multidrug efflux pumps, as revealed by transcriptomic analysis, which also indicated that zinc deficiency triggered ribosomal remodelling and activated glucose metabolism. Survival analysis in the <em>G. mellonella</em> infection model confirmed that zinc deficiency reduced the overall pathogenicity of <em>C. albicans</em> biofilms.</div></div><div><h3>Conclusions</h3><div>These results validate zinc homeostasis as a novel therapeutic strategy against drug-resistant and recurrent fungal infections, especially those involving biofilms.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 2","pages":"Article 107695"},"PeriodicalIF":4.6,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827678","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

International Society of Antimicrobial Chemotherapy (ISAC) News and Information Page 国际抗微生物化疗学会（ISAC）新闻和信息页面

IF 4.6 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2025-12-20 DOI: 10.1016/j.ijantimicag.2025.107688

引用次数: 0

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 EnvZ突变驱动的儿茶酚酸铁载体受体下调和同时的TonB复合体抑制赋予产kpc的ST11-KL64高致病性肺炎克雷伯菌头孢地罗耐药。

IF 4.6 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2025-12-18 DOI: 10.1016/j.ijantimicag.2025.107693

Danni Pu , Xianxia Zhuo , Rongrong Song , Chunhui Wang , Jiankang Zhao , Bin Cao

Objectives

Cefiderocol is an ultimate antibiotic option for Carbapenem-resistant hypervirulent Klebsiella pneumoniae (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.

Methods

Cefiderocol-resistant mutants were generated through in vitro 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.

Results

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 envZ mutation drove marked downregulation of catecholate siderophore receptors (cirA and fepA), impairing cefiderocol uptake. In parallel, the TonB–ExbB–ExbD energy transduction complex was independently and stably downregulated, synergistically contributing to resistance. Notably, envZ mutation–associated repression of the enterobactin biosynthesis gene entB 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.

Conclusions

In conclusion, this work uncovers a novel cefiderocol resistance mechanism in KPC-producing ST11-KL64 CR-hvKp, initiated by the envZ 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.

头孢地罗是抗碳青霉烯高致病性肺炎克雷伯菌（CR-hvKP）的最终抗生素选择。虽然耐药性通常涉及金属β-内酰胺酶，但产生kpc的菌株的机制尚不清楚。本研究利用体外进化和多组学分析研究了临床产kpc的ST11-KL64 CR-hvKp的新型头孢地罗耐药机制。高水平头孢醚耐药突变体在双组分系统传感器激酶envZ （V145G）中都获得了功能获得突变。转录组-蛋白质组分析、qRT-PCR和基因操作显示，envZ突变主要驱动儿茶酚酸铁载体受体（cirA, fepA）的下调，从而损害头孢地酚的进入。这种作用与TonB-ExbB-ExbD能量复合物的独立下调相结合，协同赋予头孢地罗耐药性。有趣的是，共同发生的envZ突变驱动肠杆菌素生物合成基因（entB）的下调增加了头孢地罗的易感性，这表明一个复杂的调节权衡。功能分析证实，抗性突变体表现出铁载体产生减少和细胞内铁积累受损。然而，这种新的耐药机制产生了巨大的适应性代价，包括巨噬细胞生长受损、氧化应激耐受性降低和存活时间缩短。总之，这项工作揭示了kpc产生ST11-KL64 CR-hvKp的一种新的cefiderocol耐药机制，该机制由envZ突变启动，导致儿茶酚酸铁载体受体下调。这种受体抑制，加上TonB-ExbB-ExbD能量复合物的稳定下调，严重损害了头孢地罗的“特洛伊木马”主动摄取。这种抗性机制伴随着适应性的权衡，为这些超级细菌的进化提供了重要的见解。

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引用次数: 0

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” 关于“头孢他啶-阿维巴坦与其他适当抗菌药物治疗土耳其产OXA-48或kpc肠杆菌感染的比较：一项多中心回顾性匹配队列研究”的致编辑信的回复。

IF 4.6 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents

Pub Date : 2025-12-11 DOI: 10.1016/j.ijantimicag.2025.107691

Abdullah T. Aslan , Patrick N.A. Harris , David L. Paterson

引用次数: 0