Clinical Microbiology and Infection最新文献

{"title":"Corrigendum to Candidate anti-tuberculosis medicines and regimens under clinical evaluation.","authors":"Michael Hoelscher, David Barros-Aguirre, Masoud Dara, Norbert Heinrich, Eugene Sun, Christoph Lange, Simon Tiberi, Charles Wells","doi":"10.1016/j.cmi.2025.10.001","DOIUrl":"https://doi.org/10.1016/j.cmi.2025.10.001","url":null,"abstract":"","PeriodicalId":10444,"journal":{"name":"Clinical Microbiology and Infection","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On retiring from the role of CMI Editor-in-Chief.","authors":"Leonard Leibovici","doi":"10.1016/j.cmi.2025.10.003","DOIUrl":"https://doi.org/10.1016/j.cmi.2025.10.003","url":null,"abstract":"","PeriodicalId":10444,"journal":{"name":"Clinical Microbiology and Infection","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An introduction to Network Meta-analyses in clinical microbiology and infectious diseases.","authors":"Georgios Seitidis, Ourania Koutsiouroumpa, Roland van Rensburg, Michael McCaul, Isabelle Boutron, Dimitris Mavridis","doi":"10.1016/j.cmi.2025.09.022","DOIUrl":"https://doi.org/10.1016/j.cmi.2025.09.022","url":null,"abstract":"<p><strong>Background: </strong>Network Meta-Analysis (NMA) allows synthesizing results from studies comparing all available interventions. It uses direct evidence from studies comparing directly two interventions (say B and C) but also indirect evidence if there are studies comparing each of B and C to a common comparator (say A). By synthesizing both direct and indirect evidence, NMA allows for the comparison of multiple interventions within a single framework. Additionally, NMA enables comparing interventions that have not been directly compared, provides more precise estimates compared to pairwise meta-analysis and creates a ranking hierarchy based on any specific outcome.</p><p><strong>Objectives: </strong>We aim to provide a thorough introduction to NMA tailored for clinicians and scientists working in the fields of clinical microbiology and infectious diseases.</p><p><strong>Sources: </strong>We illustrated all steps of NMA using a published example from the field of clinical microbiology and infectious diseases. We considered cases and use examples of published NMAs.</p><p><strong>Content: </strong>We outlined the key concepts and assumptions of NMA using illustrative examples from common infectious diseases. We presented some common pitfalls and misconceptions that are frequently encountered in real-world practice. To reduce the gap between theory and practice, we applied the broad steps for conducting and interpretating an NMA to a published NMA evaluating the efficacy of different monotherapies for chronic hepatitis B infection.</p><p><strong>Implications: </strong>By clarifying methodological challenges and providing practical guidance, this paper aims to enhance infectious disease practitioners' understanding of NMA, assuring its proper application and interpretation.</p>","PeriodicalId":10444,"journal":{"name":"Clinical Microbiology and Infection","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estimating the potential economic and health impact of integrated genomic surveillance in a hospital setting.","authors":"Frederik Boetius Hertz, Karen Leth Nielsen, Dmytro Strunin, Jelena Erdmann, Martin Lucas Jørgensen, Theiss Bendixen, Roshkan Srinathan, Rasmus L Marvig, Steen Christian Rasmussen, Asger Nellemann Rasmussen, Christian Salgaard Jensen, Jenny Dahl Knudsen, Susanne Häussler","doi":"10.1016/j.cmi.2025.09.021","DOIUrl":"https://doi.org/10.1016/j.cmi.2025.09.021","url":null,"abstract":"<p><strong>Objectives: </strong>Integrated genomic surveillance, combining whole genome sequencing (WGS) of bacterial isolates with patient movement data, promises improved detection and prevention of pathogen transmission. However, evidence on its cost-effectiveness and clinical utility remains limited, not least because the full extent of transmission in hospital settings is difficult to capture.</p><p><strong>Methods: </strong>We conducted a 28-month observational study at Rigshospitalet, Copenhagen, collecting patient movement data and sequencing 18,438 bacterial isolates from 7,398 patients across diverse species, infection sites, and resistance profiles. We estimated the hypothetical benefits of implementing integrative WGS surveillance, assuming that continued transmission could be prevented when WGS information was acted upon immediately.</p><p><strong>Results: </strong>We found that 1,975 of 7,398 of culture-positive hospitalized patients (26.7 %) harboured a pathogen genetically related to another patient´s isolate. 1359 of those (68.8 %) had an epidemiological link in the hospital, with Enterococcus faecium by far being the most prevalent involved in transmissions. WGS-informed prevention could hypothetically generate net savings of €1.35 million annually if transmission was stopped once a clonal isolate was detected in a second patient. Furthermore, this approach could potentially have prevented an estimated 1,284 hospital-acquired infections over the 28-month study period, including 94 cases characterized by the recovery of bloodstream isolates.</p><p><strong>Conclusions: </strong>Our integrated genomic surveillance approach reveals previously unexplored transmission landscapes. We discovered that transmission is widespread, varies between species, and is not limited to resistant isolates. Our results emphasise the potential of integrated genomic surveillance, the identification of local transmission hotspots, potential greater savings by including susceptible isolates, and an incremental cost-effectiveness ratio classification by pathogen species.</p>","PeriodicalId":10444,"journal":{"name":"Clinical Microbiology and Infection","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Randomized clinical trial to evaluate the longitudinal HIV-1 reservoir and inflammation in treatment-naïve people starting dolutegravir/lamivudine vs. dolutegravir plus tenofovir alafenamide/emtricitabine.","authors":"Abraham Saborido-Alconchel, Ana Serna-Gallego, María Trujillo-Rodriguez, Esperanza Muñoz-Muela, Ana I Alvarez-Ríos, Cesar Sotomayor, Marta Herrero, Luis E Lopez-Cortes, Nuria Espinosa, Miguel Raffo-Marquez, Alberto Romero-Palacios, Gabriel Mariscal-Vázquez, Antonio Rivero, Cristina Roca-Oporto, Alicia Gutierrez-Valencia, Luis F López-Cortes","doi":"10.1016/j.cmi.2025.09.014","DOIUrl":"https://doi.org/10.1016/j.cmi.2025.09.014","url":null,"abstract":"<p><strong>Objective: </strong>There is limited evidence on whether dolutegravir/lamivudine (DTG/3TC) reduces the viral reservoir, immune activation, and inflammation as a three-drug regimen. This study aims to clarify possible differences in these outcomes in PHIV starting DTG plus tenofovir alafenamide/emtricitabine (DTG+TAF/F) versus DTG/3TC.</p><p><strong>Methods: </strong>A phase IV, controlled, open-label, multicenter clinical trial in which treatment-naïve PHIV were randomized to DTG+TAF/F or DTG/3TC. The primary endpoint was changes in CD4⁺ T-cells associated HIV-1-DNA and -RNA after 12 and 24 months (Intact Proviral DNA and Intact Viral RNA Assays). Secondary endpoints included immune recovery and changes in T cell phenotypes and plasma inflammatory markers.</p><p><strong>Statistics: </strong>χ², Mann-Whitney U test, and general linear model for repeated measures.</p><p><strong>Results: </strong>Sixty-six participants were randomized, of whom 30 (DTG/3TC) and 29 (DTG +TAF/F) completed follow-up. Overall, the median baseline CD4⁺/μL count was 401 (293-540), the CD4⁺/CD8⁺ ratio 0.47 (0.34-0.76), and the viral load 57,250 copies/mL (16,189-180,500) Results are reported as medians (interquartile ranges) in the DTG+TAF/F and DTG/3TC groups at baseline and month 24, respectively. Intact HIV-1-DNA: 1,210 (412-3,508) copies/10⁶ CD4⁺ and 1,230 (335-2,502), which decreased to 65 (24-236) and 71 (32-110) (F= 0.253; p= 0.691). Total defective HIV-1-DNA: 831 copies/10⁶ CD4⁺ (315-1636) and 726 (273-1770), decreasing to 143 copies/10⁶ CD4⁺ (82-368) and 266 (67-353) (F= 1.840, p= 0.201). Likewise, no significant differences were observed between the groups in immune recovery, decrease in activation, proliferation, and exhaustion markers of T-cells, as well as in the reduction of plasma levels of IL-1β, IL-6, TNF-α, IFN-γ, sCD14, and sCD163.</p><p><strong>Conclusions: </strong>These data suggest that starting treatment with DTG+TAF/F does not confer benefits over DTG/3TC.</p>","PeriodicalId":10444,"journal":{"name":"Clinical Microbiology and Infection","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Funding and geographical distribution of clinical trials in infectious diseases.","authors":"Hadrien Moffroid, Esmita Charani, Christina Blagojevic, Aliya Bryce, Aaron Ovadia, Matthew Slater, Daire Pryal, Rodrigo Escobar Careaga, Arvind Yerramilli, Nick Daneman, Steven Y C Tong, Sean W X Ong","doi":"10.1016/j.cmi.2025.09.019","DOIUrl":"https://doi.org/10.1016/j.cmi.2025.09.019","url":null,"abstract":"<p><strong>Objectives: </strong>To map funding flows in infectious disease randomized clinical trials (RCTs) by examining relationships between funding sources and trial locations in high impact journals.</p><p><strong>Methods: </strong>We conducted a secondary analysis of a previously published systematic review of 1,343 infectious disease RCTs published (2014-2023) in ten selected high-impact English language general medicine and infectious disease journals. Funding source, study site, and disease focus were extracted using a standardized data extraction form, and analysed by country income level using World Bank classifications Geographical distributions of funding and study sites were visualized using global heat maps. Funding flows between country income groups were visualized using a Sankey plot.</p><p><strong>Results: </strong>Of the 1343 trials, 1326 disclosed funding source (98.7%). Most trials identified in this review were investigator-initiated (772/1326, 58.2%), with the U.S. government as the largest contributing funder (366/1326, 27.6%), with the National Institutes of Health specifically involved in funding 258/1326 (19.5%) of trials. When disaggregated, there was a total of 1808 unique funders. These overwhelmingly originated from high-income countries (1496/1808, 82.7%) compared to upper-middle income (130/1808, 7.2%), low-middle income (35/1808, 1.9%), and low-income (8/1808, 0.4%) countries. In contrast, the 4606 disaggregated locations of study by country, were more distributed across income levels: high-income (2521/4606 61.9%), upper-middle income (918/4606, 22.5%), lower-middle income (360/4606, 8,8%), low-income (253/4606, 6.2%). Disease focus varied geographically; trials focusing on critical care, bacterial infections, sexually transmitted infections, hepatitis, influenza, and COVID-19 were underrepresented in low-income settings.</p><p><strong>Conclusion: </strong>Our study reveals skewed geographical and funding distributions in the global landscape of infectious disease RCTs published in these 10 selected English language high-impact journals. As key funders reduce funding internationally, the impact on the research landscape may disproportionately affect lower-middle income countries. Further efforts should be made to build sustainable funding models and research capacity in lower-middle income countries.</p>","PeriodicalId":10444,"journal":{"name":"Clinical Microbiology and Infection","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between COVID-19 vaccine immunogenicity and protection against infection and severe disease in clinically vulnerable patient populations: a systematic review and meta-analysis of observational studies.","authors":"Maria Danysz, Rute Cardoso De Aguiar, Hema Pindolia, Beth Stuart, Katrina Spensley, Elen Ashmore, Nicole Frumento, Nadège Haouidji-Javaux, Clare Hutchinson, Rachel Iles, Susan Lau, Jordan Rolt, Grace Uwenedi, Hollie Wagg, Eleanor Barnes, Sean H Lim, Alex Richter, Michelle Willicombe","doi":"10.1016/j.cmi.2025.09.020","DOIUrl":"https://doi.org/10.1016/j.cmi.2025.09.020","url":null,"abstract":"<p><strong>Background: </strong>The use of measured immune responses in informing risk of breakthrough COVID-19 infection and infection outcomes after vaccination against SARS-CoV-2 in clinically vulnerable patients has not been applied clinically.</p><p><strong>Objectives: </strong>Our aim was to investigate the association between measured vaccine immunogenicity and vaccine effectiveness in clinically vulnerable populations.</p><p><strong>Data sources: </strong>PubMed, MEDLINE, EMBASE, Cochrane Library.</p><p><strong>Study eligibility criteria: </strong>Studies published between 03/2020 and 01/2025, which reported data on COVID-19 vaccine immunogenicity (antibody and T-cell) and subsequent infection outcomes.</p><p><strong>Participants: </strong>Patients defined as clinically vulnerable by QCOVID criteria, who had received at least the primary course of COVID-19 vaccination.</p><p><strong>Assessment of risk of bias: </strong>The Newcastle-Ottawa quality assessment scale was used to assess risk of bias.</p><p><strong>Methods of data synthesis: </strong>A random-effects meta-analysis model was used to pool relative risks of COVID-19 breakthrough infection (BTI), hospitalisation, and death. Unadjusted data was used for the primary analysis due to a lack of adjusted data available in individual studies.</p><p><strong>Results: </strong>We identified 3305 articles, of which 45 observational studies were included in the review. Negative antibody response following COVID-19 vaccination was associated with higher risks of BTI [RR 1.82 (1.45-2.29), p<0.01, I²=84.03%], COVID-19 related hospitalisation [RR 5.88 (4.08-8.47), p<0.01, I²=25.59%] and death [RR 3.66 (1.87-7.15), p<0.01), I²=0%]. Lack of T-cell response was associated with higher risk of BTI [RR 2.08 (1.08-4.04), p=0.03, I²=65.99. Using the Newcastle-Ottawa quality assessment scale, 5 (11%) studies were of good quality, 2 (7%) of fair quality, and 37 (82%) of poor quality.</p><p><strong>Conclusions: </strong>Within the methodological limitations, this study has shown that lack of anti-spike antibody responses was associated with BTI and severe infection outcomes in clinically vulnerable populations. Further research is required to investigate the current utility of testing to inform the ongoing management of clinically vulnerable persons, such as vaccine booster schedules.</p>","PeriodicalId":10444,"journal":{"name":"Clinical Microbiology and Infection","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Faecal microbiota transplantation for urinary tract infections.","authors":"Paulína Belvončíková, Roman Gardlík","doi":"10.1016/j.cmi.2025.09.018","DOIUrl":"https://doi.org/10.1016/j.cmi.2025.09.018","url":null,"abstract":"<p><strong>Background: </strong>Recurrent urinary tract infections (rUTIs) are a major clinical burden, increasingly complicated by multidrug-resistant organisms (MDROs) and antibiotic overuse. Growing evidence implicates gut microbiota dysbiosis as a key contributor to UTI susceptibility, with the gastrointestinal tract acting as a reservoir for uropathogens.</p><p><strong>Objectives: </strong>This review examines the emerging role of faecal microbiota transplantation (FMT) as a therapeutic strategy for rUTIs. We synthesize findings from human studies and case reports, evaluate microbiological and clinical outcomes post-FMT, and discuss mechanistic insights, safety concerns, and future research directions.</p><p><strong>Sources: </strong>We reviewed peer-reviewed publications up to May 2025 using PubMed and Web of Science. Included sources comprised clinical trials, cohort studies, case reports, economic analyses, and expert reviews concerning FMT and UTIs.</p><p><strong>Content: </strong>FMT has shown promise in reducing rUTI episodes, particularly in patients with underlying gut dysbiosis or MDRO colonization. Clinical studies and case reports consistently report decreased UTI frequency, lower MDRO burden, and increased gut microbiota diversity post-FMT. Patients previously refractory to antibiotic prophylaxis achieved prolonged infection-free periods. Microbiome analyses often reveal reductions in uropathogen abundance and shifts toward donor-like microbial communities. However, outcomes vary and some patients experience persistence or transmission of uropathogens from donor stool, underscoring safety and screening concerns.</p><p><strong>Implications: </strong>FMT represents a promising microbiome-based intervention for managing rUTIs, particularly in complex or antibiotic-resistant cases. Randomized controlled trials are needed to assess efficacy, define optimal protocols, and address safety concerns. Standardized practices will be essential to integrate FMT into routine UTI care.</p>","PeriodicalId":10444,"journal":{"name":"Clinical Microbiology and Infection","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and immunogenicity of adjuvanted respiratory syncytial virus vaccine in high-risk transplant recipients: An Interventional Cohort Study.","authors":"Victoria G Hall, Adrian A Alexander, Faranak Mavandadnejad, Madeline Kern-Smith, Xiaoqing Dang, Rujun Kang, Sapna Humar, Poramed Winichakoon, Rochelle Johnstone, Meghan Aversa, Igor Novitzky-Basso, Pascal M Lavoie, Deepali Kumar, Jonas Mattsson, Victor H Ferreira","doi":"10.1016/j.cmi.2025.09.013","DOIUrl":"https://doi.org/10.1016/j.cmi.2025.09.013","url":null,"abstract":"<p><strong>Objectives: </strong>Allogeneic hematopoietic cell transplant (alloHCT) and lung transplant (LT) recipients are at highest risk for severe respiratory syncytial virus (RSV) disease, even as compared to other immunocompromised groups. Notably, these groups were excluded from published RSV vaccine clinical trials. The aim of this study was to determine the safety and immunogenicity of adjuvanted RSVPreF3 vaccine in adult alloHCT and LT recipients.</p><p><strong>Methods: </strong>Adult alloHCT (≥6 months post-transplant) and LT (≥3 months post-transplant) recipients were enrolled and administered a single dose of adjuvanted RSVPreF3 vaccine. Blood samples were collected at baseline and 4-6 weeks post-immunization to assess neutralizing antibodies (NAb), anti-RSVPreF-IgG antibody levels and RSV-specific polyfunctional T-cells. Safety was assessed through participant-led diaries and follow-up.</p><p><strong>Results: </strong>86 participants (46 alloHCT, 40 LT) were enrolled, with median follow-up of 191 days [interquartile range (IQR) 170-248]. Median age was 59 years (IQR 45.5-67.3) for LT and 64 years (IQR 59-69) for alloHCT recipients. NAb titres increased post-vaccination in both groups (alloHCT: 1.3-fold, LT: 3.0-fold; p<0.0001). Seroconversion by NAb occurred in 15/45 (33.3%) alloHCT and 19/39 (48.7%) LT recipients. IgG binding antibody levels increased significantly in both groups (3.3-fold in LT, p=0.0018; 2.3-fold in alloHCT, p=0.0015). CD4⁺ polyfunctional T-cell responses were detected in 30/42 (71.4%) alloHCT and 28/35 (80.0%) LT recipients post-vaccination. CD8⁺ T-cell responses were lower, but frequencies increased in LT recipients after vaccination (p=0.024). Overall, the vaccine was well tolerated with Grade 1 pain the most reported adverse event (54/86, 62.8%). There was no study intervention-related withdrawal. Three LT recipients developed RSV infection post vaccination; two required hospitalization.</p><p><strong>Conclusions: </strong>The adjuvanted RSVPreF3 vaccine was immunogenic and well-tolerated with modest seroconversion but robust CD4⁺ T-cell responses. These data support the benefit of RSV vaccination but underscore the need for further strategies to optimize NAb and CD8⁺ T-cell responses in this high-risk population.</p>","PeriodicalId":10444,"journal":{"name":"Clinical Microbiology and Infection","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complex pathways to ceftolozane-tazobactam resistance in clinical Pseudomonas aeruginosa isolates: a genomic epidemiology study.","authors":"Hoai-An Nguyen, Anton Y Peleg, Jiangning Song, Jessica A Wisniewski, Luke V Blakeway, Gnei Z Badoordeen, Ravali Theegala, Nhu Quynh Doan, Matthew H Parker, David L Dowe, Nenad Macesic","doi":"10.1016/j.cmi.2025.09.015","DOIUrl":"https://doi.org/10.1016/j.cmi.2025.09.015","url":null,"abstract":"<p><strong>Objectives: </strong>We aimed to conduct a comprehensive genomic analysis of ceftolozane/tazobactam (C/T) resistance mechanisms in Pseudomonas aeruginosa by combining novel institutional data with publicly available sequencing data.</p><p><strong>Methods: </strong>We analysed 1,682 P. aeruginosa isolates, comprising 339 isolates from Alfred Hospital (Melbourne, Australia) and 1,343 isolates from six public datasets. All isolates underwent whole-genome sequencing and C/T broth microdilution (BMD) susceptibility testing. We assessed previously reported intrinsic and acquired resistance mechanisms. We then conducted a genome-wide association study (GWAS) and machine learning analysis to identify novel genes associated with resistance. We then evaluated the impact of mutations in these genes on MIC values and ceftolozane binding affinity.</p><p><strong>Results: </strong>Among 1,682 P. aeruginosa isolates representing 527 distinct sequence types, 343/1,682 (20.4%) were C/T-resistant. Carbapenemase genes were detected in 206/1,682 (12.2%) isolates. Mutations in previously reported resistance-associated genes (ftsI, mpl, ampD, ampC, ampR, oprD) were more frequent in resistant isolates but were also found in almost all susceptible isolates. Successive mutations conferred additive increases in MIC. Combined GWAS and machine learning analyses a priori identified five key genes significantly associated with resistance: ftsI, ampR, ampC, PA3329, and PA4311. Molecular docking simulation revealed that the R504C mutation in penicillin-binding protein 3 (PBP3), which is encoded by ftsI, reduced binding contacts and hydrogen bonds with ceftolozane, significantly decreasing binding affinity (P=0.016).</p><p><strong>Conclusions: </strong>Our analysis of 1,682 P. aeruginosa genomes demonstrated complex pathways to C/T resistance and showed that ftsI may play an underappreciated role. We discovered two previously unidentified genes associated with C/T resistance, whose function remains to be determined.</p>","PeriodicalId":10444,"journal":{"name":"Clinical Microbiology and Infection","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}