Pub Date : 2026-01-07DOI: 10.1016/j.ijantimicag.2025.107705
Andrew T Nguyen , Nicita Mehta , KaiLan Mackey , Thomas Cummiskey , Edward K. Rodriguez , Jason Young
Objectives
The interest in bacteriophage therapy has significantly increased due to the rising prevalence of antibiotic-resistant bacterial infections. However, the pharmacology of bacteriophage therapy has not been systematically reviewed. This scoping review aims to summarize the current state of bacteriophage pharmacokinetics and pharmacodynamics research to identify knowledge gaps and guide future research.
Methods
Following PRISMA-ScR guidelines, we conducted a scoping review through December 18th, 2023 of MEDLINE (Ovid), PubMed, Embase (Elsevier), Web of Science Core Collection (Clarivate), and Cochrane Central. We included studies that presented original data on the pharmacokinetics and pharmacodynamics of bacteriophage therapy for in vivo infection treatment.
Results
In total, 34 in vivo studies were identified varying in multiple dimensions, including model organisms, target bacteria, delivery vehicles, modes of administration, and phage type. The scoping review maps the current research landscape of in vivo bacteriophage pharmacology.
Conclusions
Bacteriophage therapy shows notable promise as a potential alternative or therapeutic adjunct to antibiotics in clinical disease settings. Several studies of phage pharmacokinetics and pharmacodynamics have been conducted; however, these studies differ in multiple dimensions, complicating attempts to develop general principles for standardized phage administration. Further, significant gaps remain in understanding the numerous intrinsic phage and host factors that might affect the pharmacokinetics and pharmacodynamics of phage therapy in vivo.
目的：由于抗生素耐药细菌感染的流行，噬菌体治疗的兴趣显著增加。然而，噬菌体治疗的药理学尚未得到系统的综述。本文旨在总结噬菌体药代动力学和药效学研究的现状，以确定知识空白，指导未来的研究。方法：遵循PRISMA-ScR指南1，我们对MEDLINE （Ovid）、PubMed、Embase（爱思唯尔）、Web of Science Core Collection （Clarivate）和Cochrane Central进行了截止到2023年12月18日的范围综述。我们纳入了提供噬菌体治疗体内感染的药代动力学和药效学原始数据的研究。结果：总共确定了34项体内研究，这些研究在多个维度上存在差异，包括模式生物、靶菌、递送载体、给药方式和噬菌体类型。范围审查地图当前的研究景观在体内噬菌体药理学。结论：噬菌体治疗在临床疾病环境中作为抗生素的潜在替代或治疗辅助显示出显著的前景。对噬菌体的药代动力学和药效学进行了一些研究；然而，这些研究在多个方面存在差异，使制定标准化噬菌体管理的一般原则的尝试复杂化。此外，在了解许多可能影响噬菌体治疗体内药代动力学和药效学的内在噬菌体和宿主因素方面仍存在重大差距。
{"title":"Pharmacokinetics and pharmacodynamics of bacteriophage therapy: A scoping review","authors":"Andrew T Nguyen , Nicita Mehta , KaiLan Mackey , Thomas Cummiskey , Edward K. Rodriguez , Jason Young","doi":"10.1016/j.ijantimicag.2025.107705","DOIUrl":"10.1016/j.ijantimicag.2025.107705","url":null,"abstract":"<div><h3>Objectives</h3><div>The interest in bacteriophage therapy has significantly increased due to the rising prevalence of antibiotic-resistant bacterial infections. However, the pharmacology of bacteriophage therapy has not been systematically reviewed. This scoping review aims to summarize the current state of bacteriophage pharmacokinetics and pharmacodynamics research to identify knowledge gaps and guide future research.</div></div><div><h3>Methods</h3><div>Following PRISMA-ScR guidelines, we conducted a scoping review through December 18th, 2023 of MEDLINE (Ovid), PubMed, Embase (Elsevier), Web of Science Core Collection (Clarivate), and Cochrane Central. We included studies that presented original data on the pharmacokinetics and pharmacodynamics of bacteriophage therapy for in vivo infection treatment.</div></div><div><h3>Results</h3><div>In total, 34 in vivo studies were identified varying in multiple dimensions, including model organisms, target bacteria, delivery vehicles, modes of administration, and phage type. The scoping review maps the current research landscape of in vivo bacteriophage pharmacology.</div></div><div><h3>Conclusions</h3><div>Bacteriophage therapy shows notable promise as a potential alternative or therapeutic adjunct to antibiotics in clinical disease settings. Several studies of phage pharmacokinetics and pharmacodynamics have been conducted; however, these studies differ in multiple dimensions, complicating attempts to develop general principles for standardized phage administration. Further, significant gaps remain in understanding the numerous intrinsic phage and host factors that might affect the pharmacokinetics and pharmacodynamics of phage therapy in vivo.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 3","pages":"Article 107705"},"PeriodicalIF":4.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145943514","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}
Pub Date : 2026-01-04DOI: 10.1016/j.ijantimicag.2025.107709
Teng Xu , Ying Zhou , Qingqing Xu , Li Wang , Yu Zhou , Shi Wu , Haihui Huang
Objective
Metronidazole (MTZ) resistance in Clostridioides difficile is associated with decreased efficacy of MTZ. We studied the MTZ-resistant C. difficile strain sh182IR (minimum inhibitory concentration [MIC] = 32 mg/L) to characterize the role of ATP-binding cassette (ABC) family transporters in MTZ resistance in C. difficile. The strain overexpresses ABC multidrug efflux pump components.
Methods
In strain sh182IR, ClosTron mutagenesis was applied to disrupt cd17530, a gene encoding the ABC transporter ATP-binding protein, and the effects on efflux capacity and MIC of MTZ were evaluated. The upstream regulatory gene cd17520 was also sequenced.
Results
Disruption of cd17530 reduced the efflux capacity of fluorescent substrates and MIC of MTZ in C. difficile sh182IR. Repair of cd17530 successfully restored the MTZ MIC and efflux capacity of the strain. We also confirmed that the upstream TetR/AcrR family transcription factor gene cd17520 in sh182IR harbours a frameshift mutation. This mutation resulted in the loss of function of the peptide chain encoded by the gene and upregulation of cd17530-17540-17550.
Conclusions
The frameshift mutation in the transcriptional repressor cd17520, which results in the derepression of the cd17530-17540-17550 operon, contributes to ABC transporter-mediated MTZ resistance in C. difficile.
{"title":"ATP-binding cassette transporters mediate and regulate metronidazole resistance in Clostridioides difficile","authors":"Teng Xu , Ying Zhou , Qingqing Xu , Li Wang , Yu Zhou , Shi Wu , Haihui Huang","doi":"10.1016/j.ijantimicag.2025.107709","DOIUrl":"10.1016/j.ijantimicag.2025.107709","url":null,"abstract":"<div><h3>Objective</h3><div>Metronidazole (MTZ) resistance in <em>Clostridioides difficile</em> is associated with decreased efficacy of MTZ. We studied the MTZ-resistant <em>C. difficile</em> strain sh182IR (minimum inhibitory concentration [MIC] = 32 mg/L) to characterize the role of ATP-binding cassette (ABC) family transporters in MTZ resistance in <em>C. difficile</em>. The strain overexpresses ABC multidrug efflux pump components.</div></div><div><h3>Methods</h3><div>In strain sh182IR, ClosTron mutagenesis was applied to disrupt <em>cd17530</em>, a gene encoding the ABC transporter ATP-binding protein, and the effects on efflux capacity and MIC of MTZ were evaluated. The upstream regulatory gene <em>cd17520</em> was also sequenced.</div></div><div><h3>Results</h3><div>Disruption of <em>cd17530</em> reduced the efflux capacity of fluorescent substrates and MIC of MTZ in <em>C. difficile</em> sh182IR. Repair of <em>cd17530</em> successfully restored the MTZ MIC and efflux capacity of the strain. We also confirmed that the upstream TetR/AcrR family transcription factor gene <em>cd17520</em> in sh182IR harbours a frameshift mutation. This mutation resulted in the loss of function of the peptide chain encoded by the gene and upregulation of cd17530-17540-17550.</div></div><div><h3>Conclusions</h3><div>The frameshift mutation in the transcriptional repressor <em>cd17520</em>, which results in the derepression of the cd17530-17540-17550 operon, contributes to ABC transporter-mediated MTZ resistance in <em>C. difficile</em>.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 2","pages":"Article 107709"},"PeriodicalIF":4.6,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145905677","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}
Pub Date : 2026-01-03DOI: 10.1016/j.ijantimicag.2025.107710
Paula Pimenta-de-Souza , Alice Ramos-Silva , Valcieny Sandes , Patrícia Portella , Thaís Gouvêa , Fernando Fernandez-Llimos , Elisangela Costa Lima
Background
The growing prevalence of multidrug-resistant Gram-negative bacilli poses major challenges to the management of severe paediatric infections. Ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (C/T) are newer β-lactam/β-lactamase inhibitor combinations with established efficacy in adults.
Objective
To synthesize current evidence on the efficacy, effectiveness, and safety of CZA and C/T in hospitalized children with severe infections.
Methods
We conducted a systematic review, meta-analysis, and evidence map (PROSPERO CRD420251025715). Searches were performed in PubMed, Scopus, CENTRAL, Epistemonikos, LILACS, SciELO, and Web of Science. Eligible designs included randomized controlled trials (RCTs), cohort studies, case series, and case reports evaluating CZA or C/T for complicated intra-abdominal infections, complicated urinary tract infections (cUTI), pneumonia, or bacteraemia in patients aged 0–18 y. The primary outcome was 30-d mortality; secondary outcomes were clinical and microbiological cure and adverse events.
Results
Nineteen studies (4 RCTs, 9 case series, 6 case reports) involving 472 patients were included. Sixteen studies evaluated CZA and three evaluated C/T. All RCTs were phase II, industry-sponsored, and excluded critically ill children and carbapenem-resistant infections. According to the updated RoB 2 assessment, two trials had overall low risk of bias, and two presented some concerns, mainly related to missing outcome data. No deaths occurred in RCTs, whereas observational studies reported 8% mortality. Clinical and microbiological cure exceeded 80% across study designs. Adverse events were generally infrequent; neonatal events clustered in case series, but evidence was insufficient for statistical comparison across age groups. Certainty of evidence ranged from moderate (cUTI with susceptible pathogens) to very low (pneumonia and resistant infections).
Conclusions
CZA and C/T appear promising for paediatric cUTI and complicated intra-abdominal infections, but the evidence base remains narrow and largely dependent on small, industry-funded trials. Independent RCTs including critically ill children and resistant infections are urgently needed.
背景：耐多药革兰氏阴性杆菌（MDR-GNB）的日益流行给严重儿科感染的管理带来了重大挑战。头孢他啶/阿维巴坦（CZA）和头孢甲苯/他唑巴坦（C/T）是较新的β-内酰胺/β-内酰胺酶抑制剂组合，在成人中具有确定的疗效。目的：综合目前关于CZA和C/T治疗住院重症感染患儿的疗效、有效性和安全性的证据。方法：我们进行了系统评价、荟萃分析和证据图（PROSPERO CRD420251025715）。在PubMed、Scopus、CENTRAL、Epistemonikos、LILACS、SciELO和Web of Science中进行了搜索。符合条件的设计包括随机对照试验（RCTs）、队列研究、病例系列和病例报告，评估0-18岁患者的CZA或C/T治疗复杂性腹腔感染（cIAI）、复杂性尿路感染（cUTI）、肺炎或菌血症。主要结局为30天死亡率；次要结局是临床和微生物治愈和不良事件。结果：共纳入19项研究（4项随机对照试验，9个病例系列，6个病例报告），涉及472例患者。16项研究评估CZA， 3项研究评估C/T。所有随机对照试验均为II期，由行业赞助，并排除了危重儿童和碳青霉烯耐药感染。根据最新的RoB 2评估，两项试验总体偏倚风险较低，两项试验存在一些担忧，主要与缺少结局数据有关。随机对照试验中未发生死亡，而观察性研究报告死亡率为8%。临床和微生物治愈率超过80%。不良事件通常不常见；新生儿事件聚集在病例系列中，但证据不足，无法进行年龄组间的统计比较。证据的确定性范围从中等（有易感病原体的cUTI）到非常低（肺炎和耐药感染）。结论：CZA和C/T治疗儿科cUTI和cIAI似乎很有希望，但证据基础仍然狭窄，主要依赖于行业资助的小型试验。迫切需要独立的随机对照试验，包括危重儿童和耐药感染。
{"title":"Ceftazidime/avibactam and ceftolozane/tazobactam for severe paediatric infections: A systematic review, meta-analysis, and evidence map","authors":"Paula Pimenta-de-Souza , Alice Ramos-Silva , Valcieny Sandes , Patrícia Portella , Thaís Gouvêa , Fernando Fernandez-Llimos , Elisangela Costa Lima","doi":"10.1016/j.ijantimicag.2025.107710","DOIUrl":"10.1016/j.ijantimicag.2025.107710","url":null,"abstract":"<div><h3>Background</h3><div>The growing prevalence of multidrug-resistant Gram-negative bacilli poses major challenges to the management of severe paediatric infections. Ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (C/T) are newer β-lactam/β-lactamase inhibitor combinations with established efficacy in adults.</div></div><div><h3>Objective</h3><div>To synthesize current evidence on the efficacy, effectiveness, and safety of CZA and C/T in hospitalized children with severe infections.</div></div><div><h3>Methods</h3><div>We conducted a systematic review, meta-analysis, and evidence map (PROSPERO CRD420251025715). Searches were performed in PubMed, Scopus, CENTRAL, Epistemonikos, LILACS, SciELO, and Web of Science. Eligible designs included randomized controlled trials (RCTs), cohort studies, case series, and case reports evaluating CZA or C/T for complicated intra-abdominal infections, complicated urinary tract infections (cUTI), pneumonia, or bacteraemia in patients aged 0–18 y. The primary outcome was 30-d mortality; secondary outcomes were clinical and microbiological cure and adverse events.</div></div><div><h3>Results</h3><div>Nineteen studies (4 RCTs, 9 case series, 6 case reports) involving 472 patients were included. Sixteen studies evaluated CZA and three evaluated C/T. All RCTs were phase II, industry-sponsored, and excluded critically ill children and carbapenem-resistant infections. According to the updated RoB 2 assessment, two trials had overall low risk of bias, and two presented some concerns, mainly related to missing outcome data. No deaths occurred in RCTs, whereas observational studies reported 8% mortality. Clinical and microbiological cure exceeded 80% across study designs. Adverse events were generally infrequent; neonatal events clustered in case series, but evidence was insufficient for statistical comparison across age groups. Certainty of evidence ranged from moderate (cUTI with susceptible pathogens) to very low (pneumonia and resistant infections).</div></div><div><h3>Conclusions</h3><div>CZA and C/T appear promising for paediatric cUTI and complicated intra-abdominal infections, but the evidence base remains narrow and largely dependent on small, industry-funded trials. Independent RCTs including critically ill children and resistant infections are urgently needed.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 2","pages":"Article 107710"},"PeriodicalIF":4.6,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145905589","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}
Pub Date : 2025-12-30DOI: 10.1016/j.ijantimicag.2025.107708
Sergio Mascarenhas Morgado, Erica Lourenço da Fonseca, Ana Carolina Paulo Vicente
{"title":"Superintegron of Vibrio paracholerae as a reservoir of antibiotic resistance genes","authors":"Sergio Mascarenhas Morgado, Erica Lourenço da Fonseca, Ana Carolina Paulo Vicente","doi":"10.1016/j.ijantimicag.2025.107708","DOIUrl":"10.1016/j.ijantimicag.2025.107708","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 2","pages":"Article 107708"},"PeriodicalIF":4.6,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889237","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}
Pub Date : 2025-12-26DOI: 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.
{"title":"Vancomycin clearance compared to creatinine clearance by timed urine collection in the intensive care unit","authors":"Andrew Chantha Hean , Rinoj Mathew , Frank Chu , Linda Awdishu","doi":"10.1016/j.ijantimicag.2025.107704","DOIUrl":"10.1016/j.ijantimicag.2025.107704","url":null,"abstract":"<div><h3>Objective</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 2","pages":"Article 107704"},"PeriodicalIF":4.6,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850061","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}
Pub Date : 2025-12-26DOI: 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 blaKPC-78, which is driven by a mutation from blaKPC-2 in a clinical CRPA strain.
Methods
Six blaKPC-78 CRPA isolates, along with two blaKPC-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 blaKPC-2 to blaKPC-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 blaKPC-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 blaKPC-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.
{"title":"Development of ceftazidime–avibactam resistance driven by conversion of blaKPC-2 to blaKPC-78 during treatment of ST463 carbapenem-resistant Pseudomonas aeruginosa infection","authors":"Haotian Xu , Tingjuan Zhang , Xueying Cui , Jingyi Guo , Pengpeng Min , Chengjin Wu , Xinyan Tang , Longjie Zhou , Linfang Wang , Xi Li","doi":"10.1016/j.ijantimicag.2025.107703","DOIUrl":"10.1016/j.ijantimicag.2025.107703","url":null,"abstract":"<div><h3>Objective</h3><div>The emergence of ceftazidime-avibactam (CZA)-resistant carbapenem-resistant <em>Pseudomonas aeruginosa</em> (CRPA) poses a major clinical challenge in contemporary clinical practice. In this study, we report the first identification of <em>bla</em><sub>KPC-78,</sub> which is driven by a mutation from <em>bla</em><sub>KPC-2</sub> in a clinical CRPA strain.</div></div><div><h3>Methods</h3><div>Six <em>bla</em><sub>KPC-78</sub> CRPA isolates, along with two <em>bla</em><sub>KPC-2</sub> 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).</div></div><div><h3>Results</h3><div>The emergence of CZA resistance in CRPA isolates was driven by a mutation from <em>bla</em><sub>KPC-2</sub> to <em>bla</em><sub>KPC-78</sub> 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 <em>bla</em><sub>KPC-78</sub> gene was located in a type I plasmid and carried by the Tn<em>6296</em> 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 <em>P. aeruginosa</em> in monoculture, <em>in vitro</em> competitive co-culture experiments revealed that it conferred a competitive advantage over the KPC-2-producing strains.</div></div><div><h3>Conclusions</h3><div>We report the first identification of <em>bla</em><sub>KPC-78</sub> 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.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 2","pages":"Article 107703"},"PeriodicalIF":4.6,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850089","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}
Pub Date : 2025-12-24DOI: 10.1016/j.ijantimicag.2025.107702
Genzhu Wang
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Pub Date : 2025-12-24DOI: 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
{"title":"Enhancing meropenem therapy in critical care: A retrospective study of PK/PD target attainment and therapeutic drug monitoring","authors":"Jingli Liao , Chao Li , Jingxian Liu , Wei Wu , Xiaohui Huang , Yanfei Mao , Lixia Li","doi":"10.1016/j.ijantimicag.2025.107697","DOIUrl":"10.1016/j.ijantimicag.2025.107697","url":null,"abstract":"<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","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"67 2","pages":"Article 107697"},"PeriodicalIF":4.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843619","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}
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.
{"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}
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