Antimicrobial Agents and Chemotherapy最新文献

{"title":"Comparative transcriptome and proteome analysis of resistant and susceptible <i>Talaromyces marneffei</i> clinical isolates reveals a systemic multitiered defense network against azoles.","authors":"Zheng Yanqing, Peng Gaoyuan, Pang Xiaofeng, Liang Chaojuan, Luo Xiaolu, Wei Cailing, Qin Jianglong, Zou Jun, Wang Zhiyi, Pan Kaisu, Du Mingwei, Xue Peng, Liao Wanqing, Yu Mei","doi":"10.1128/aac.00293-26","DOIUrl":"10.1128/aac.00293-26","url":null,"abstract":"<p><p><i>Talaromyces marneffei</i> is a thermally dimorphic fungus causing life-threatening systemic mycosis in immunocompromised patients. The emergence of azole-resistant clinical isolates, especially those with reduced susceptibility to voriconazole (VOC) and fluconazole (FLC), presents a critical therapeutic challenge. Although target-gene alterations and efflux-related mechanisms have been reported in pathogenic fungi, the broader molecular basis distinguishing high-minimum-inhibitory concentration (MIC) and low-MIC <i>T. marneffei</i> clinical isolates remains incompletely defined. Here, we performed integrated transcriptomic (RNA-seq), proteomic (DIA-LC-MS/MS), and RT-qPCR analyses comparing four resistant and four susceptible <i>T. marneffei</i> clinical isolates. Differentially expressed genes and proteins were identified, functionally interpreted, and integrated to prioritize resistance-associated molecular candidates. The multi-omics results supported a constitutive, multitiered resistance-associated state involving transport and cell wall processes, redox-detoxification, mitochondrial metabolism, and stress regulatory adaptation. Signals involving coilin, CatA, and other discriminant features contributed to the multi-omics prioritization layer. RT-qPCR supported a 17-gene panel associated with transport, redox-detoxification, mitochondrial metabolism, and stress regulation. Five genes, PMAA_008970, PMAA_058960, PMAA_070510, PMAA_088690, and PMAA_092180, showed statistically significant R/S differences, while the remaining panel members were detectable and trend-supporting within the same functional framework. These findings refine a hierarchical azole-resistance model in <i>T. marneffei</i> and provide a focused candidate panel for future mechanistic validation.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0029326"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"L2 β-lactamase contributes to ceftolozane-tazobactam resistance in <i>Pseudomonas aeruginosa</i>.","authors":"Preeti Garai, Sophia H Nozick, Caroline C Jozefczyk, Hannah Nam, J Nicholas O'Donnell, Egon A Ozer, Alan R Hauser, Nathaniel J Rhodes","doi":"10.1128/aac.00356-26","DOIUrl":"10.1128/aac.00356-26","url":null,"abstract":"<p><p>The prevalence of non-susceptibility to ceftolozane-tazobactam (C/T) among <i>Pseudomonas aeruginosa</i> remains low, but novel mechanisms of C/T resistance are of concern. Herein, we describe a novel <i>P. aeruginosa</i> genotype associated with high-level C/T resistance (>256/4 µg/mL) in a single patient. Whole-genome sequencing of the isolate was compared to that of a susceptible isolate cultured from the same patient 2 months earlier. Analysis of the sequences revealed two different <i>P. aeruginosa</i> high-risk clones: sequence type (ST)111 followed by ST235. The C/T-resistant ST235 isolate contained five copies of a genetic element composed of an L2 β-lactamase gene (<i>bla</i>_L2) and a truncated <i>ampR</i>_L2 transcriptional regulator gene, which are commonly found together in <i>Stenotrophomonas maltophilia</i> strains and have not been reported to mediate resistance to C/T. Comparative genomic analysis with other <i>P. aeruginosa</i> isolates failed to identify alternative explanations for the observed C/T resistance. We found that exogenous expression of <i>bla</i>_L2 increased C/T minimum inhibitory concentrations (MICs) in genetically distinct <i>P. aeruginosa</i> strains. A screen of our archived isolates identified two <i>P. aeruginosa</i> clinical isolates, PS2045 and PS2046, with one and two copies, respectively, of the genetic element containing <i>bla</i>_L2 and truncated <i>ampR</i>_L2. Interestingly, disruption of the gene <i>bla</i>_L2 but not the truncated <i>ampR</i>_L2 in PS2045 led to a decrease in C/T MIC. Thus, we report a novel mechanism of C/T resistance in <i>P. aeruginosa</i> partially mediated by an L2 β-lactamase independently of its canonical regulator, AmpR_L2.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0035626"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IS<i>26</i>-mediated circular <i>bla_KPC</i> transposon in ST2483 <i>Pseudomonas aeruginosa</i>.","authors":"Mingxiao Chen, Qingqing Zhi, Miaoshan Luo, Meifang Lin, Canbo Fan, Zhuoyan Zhong, Tingting Deng, Jingyi Zhang, Qiwen Xiao, Jianqiang Zhu, Yanfen Lin, Minling Wang, Xiaobing Duan, Cong Shen, Qiang Zhou","doi":"10.1128/aac.00582-26","DOIUrl":"10.1128/aac.00582-26","url":null,"abstract":"<p><p>The global spread of carbapenem-resistant <i>Pseudomonas aeruginosa</i> (CRPA) poses a critical clinical threat, with <i>bla</i>_KPC as a key mobile carbapenem resistance gene. Here, we investigated a novel <i>bla</i>_KPC-2 genetic element and its transmission in clinical ST2483 isolate PA100 via whole-genome sequencing, molecular, and phenotypic testing, and vesicle analysis. A unique 4,746-bp IS<i>26</i>-flanked structure inserted at the chromosomal <i>InaA/pncB2</i> locus was confirmed, which forms a circular transposition intermediate through IS<i>26</i> recombination. PA100 exhibited ~40-fold higher <i>bla</i>_KPC-2 copy number and ~25-fold higher mRNA expression vs chromosomal <i>bla</i>_KPC-2 strain PA3; meropenem exposure further elevated its transcription by nearly 70-fold, far exceeding controls. PA100 showed an extensively drug-resistant phenotype with high-level carbapenem resistance, while remaining susceptible to ceftazidime-avibactam and cefiderocol. No classical conjugation or transformation was observed, while intact outer membrane vesicles (OMVs) from PA100 carried <i>bla</i>_KPC-2, supporting a non-plasmid, vesicle-associated route for transient delivery of the resistance gene under the tested conditions. The circular transposon remained genetically stable after 10 generations of passaging in PA100; however, stable maintenance in the PAO1 recipient was not detected after passage. In summary, we first report an IS<i>26</i>-driven circular <i>bla</i>_KPC-2 transposon in ST2483 <i>P. aeruginosa</i>, conferring robust overexpression and stable inheritance in the donor strain, with OMVs potentially facilitating its horizontal spread, although stable maintenance in recipient cells was not demonstrated under the current assay conditions. These data advance understanding of <i>bla</i>_KPC dissemination in CRPA and highlight clinical surveillance priorities for rare high-risk sequence types.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0058226"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In vitro</i> pharmacodynamics of the antimalarial drug cabamiquine.","authors":"Claudia Demarta-Gatsi, Julia S Wallner, Satish K Dhingra, Sunil K Narwal, Vandana Thathy, Mohamed Maiga, Alhassane B Diallo, Maike Bonsen, Emilie Mathis, Ana Rita Gomes, Matthias Jacobs, Matthias Rottmann, Laurent Dembele, David A Fidock, Julien Guizetti, Thomas Spangenberg","doi":"10.1128/aac.00802-26","DOIUrl":"10.1128/aac.00802-26","url":null,"abstract":"<p><p>Detailing the mode-of-action of novel antimalarial drugs is important to predict and optimize their treatment efficacy. To complement standardized <i>in vivo</i> studies, an <i>in vitro</i> pharmacodynamic characterization of the <i>Plasmodium</i> elongation factor 2 inhibitor cabamiquine has been undertaken on <i>Plasmodium falciparum</i>-infected red blood cells. Parasite growth arrest and killing kinetics were assessed using a MitoTracker assay, two genetically engineered luminescent parasite lines expressing firefly luciferase or NanoLuc (BRRoK assays), standard growth inhibition assays, and long-term live cell imaging. The results confirm that cabamiquine is a potent and fast-acting inhibitor of parasite protein translation, inducing complete arrest of the translational machinery within 6 h of drug exposure. Rate-of-kill assays showed a >100-fold difference in potency between the block on translation (luciferase-based BRRoK IC₅₀ = 0.9 nM) and overall parasite killing (6 h-treatment, ring-stage standard growth inhibition assay IC₅₀ > 100 nM), highlighting that translational arrest occurs well before parasite death. Prolonged inhibition of protein synthesis drives parasite exhaustion, followed by irreversible cell death within 48 h, preceding the parasite clearance observed in patients. These <i>in vitro</i> findings help contextualize why the clinically observed lag in parasite clearance may be temporally distinct from symptomatic improvement, including fever resolution. Here, cabamiquine presents itself as a fast-acting, slow clearing antimalarial drug.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0080226"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Training a phage to expand its host range: directed evolution against <i>Staphylococcus aureus</i> from diabetic foot infections.","authors":"Lucile Plumet, Chloé Magnan, Madjid Morsli, Marion Richardoz, Nadia Gaïa, Patrice François, Jean-Philippe Lavigne, Denis Costechareyre, Virginie Molle","doi":"10.1128/aac.00639-26","DOIUrl":"10.1128/aac.00639-26","url":null,"abstract":"<p><p>Diabetic foot infections (DFIs) are a major complication of diabetes frequently involving multidrug-resistant <i>Staphylococcus aureus</i>. Their persistence and therapeutic complexity underscore the urgent need for alternatives to conventional antibiotics. Phage therapy offers a promising solution, though its clinical application is often limited by the narrow host range of individual phages. Here, SAVM02, a recently characterized staphylococcal <i>Kayvirus</i>, was trained using directed evolution against DFI isolates. After 20 iterative passages on a mixed panel of susceptible and non-susceptible <i>S. aureus</i> strains, the trained phage pool (SAVM02-P20) displayed markedly enhanced activity, infecting approximately 77% of tested <i>S. aureus</i> isolates and showing partial cross-species activity against coagulase-negative staphylococci. Improved infectivity was linked to increased replication efficiency rather than adsorption. Genomic and phylogenetic analyses further suggested recurrent adaptive changes and preferential host-range expansion within genetically related lineages. <i>In vivo</i> testing in a zebrafish embryo model confirmed therapeutic efficacy against a fully susceptible strain but revealed no survival benefit against an initially poorly permissive isolate, highlighting the gap between <i>in vitro</i> adaptation and <i>in vivo</i> efficacy. These findings demonstrate both the potential and the limitations of phage training to expand therapeutic coverage and emphasize the need to integrate evolutionary approaches with physiologically relevant models to optimize phage therapy for chronic infections, such as DFIs.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0063926"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phage-first treatment results in subpopulation-driven collateral sensitivity to beta-lactams in an extensively drug-resistant <i>Pseudomonas aeruginosa</i>.","authors":"Claire Han, Karishma Patel, Haoran Gao, Jacob T Sanborn, Thomas D Nguyen, Jack F Klem, Brian M Ho, Patrick D Kenney, Yanan Zhao, Troy D Wood, Dwayne R Roach, Liang Chen, Nicholas M Smith","doi":"10.1128/aac.00048-26","DOIUrl":"10.1128/aac.00048-26","url":null,"abstract":"<p><p>Nosocomial <i>Pseudomonas aeruginosa</i> infections are among the most challenging infections to treat, and resistance to last-line agents, including polymyxins and aztreonam-based therapies, risks a future with limited or no clinical treatment options. Bacteriophages (phages) have emerged as a promising therapeutic option, both in cocktails and when given in combination with antibiotics. In this study, we show that the synergy between a lipopolysaccharide (LPS)-specific phage and antibiotics is driven by clinically relevant increases in beta-lactam permeability due to the selection of phage-resistant subpopulations. First, in the Hollow Fiber Infection Model (HFIM), we show that the combination of phage LUZ19 (pili-targeted), phage E215 (LPS-specific), and aztreonam (ATM) eradicated the laboratory host PAO1, whereas monotherapy with neither phage nor ATM could eradicate PAO1. Static time-kill studies (STKS) evaluated the LPS-specific phage PYO2 in combination with either aztreonam/avibactam (ATM/AVI) or polymyxin B (PMB) against an extensively drug-resistant clinical isolate of <i>P. aeruginosa</i> (AR-0231). PYO2 combined with ATM/AVI was determined to be synergistic, with a mean excess-over-bliss (EOB) of 0.350 (<i>P</i> < 0.05), while PYO2 with PMB was also synergistic, with a mean EOB of 0.361 (<i>P</i> < 0.05). Linear regression of STKS using sequential administration showed that, compared to antibiotic-first treatment, phage-first treatment reduced bacterial concentrations at 24 h by -6.19 log₁₀ colony-forming unit (CFU)/mL (<i>P</i> < 0.05), with statistically significant interactions estimated for each antibiotic. These results indicated that bacterial pre-selection by PYO2 improved antibiotic activity. Mass spectrometry studies showed that the PYO2-resistant AR-0231 strain exhibited a >25% increase in the outer membrane permeability surface area coefficient for all major anti-<i>Pseudomonal</i> beta-lactams, including aztreonam. Altogether, our study provides mechanistic insights into phage-induced collateral sensitivity of beta-lactams. These results show how specific beta-lactams can be prioritized and optimized in phage-antibiotic combinations to maximize the antibacterial activity.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0004826"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rigor and reproducibility of hollow-fiber infection model for antiviral pharmacokinetics/pharmacodynamics studies.","authors":"Shashikant Srivastava, Tawanda Gumbo","doi":"10.1128/aac.00969-26","DOIUrl":"10.1128/aac.00969-26","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0096926"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In vivo</i> efficacy of cefiderocol against ceftolozane/tazobactam- and ceftazidime/avibactam-resistant <i>Pseudomonas aeruginosa</i> carrying the AmpC E219K substitution.","authors":"Arianna Rodríguez-Coello, Michelle Outeda-García, Andrea García-Pose, Lucía Gonzalez-Pinto, Gabriela Alejandra Báez-Barroso, Paula Guijarro-Sánchez, Andrea Muras, Biel Taltavull, Pablo Fraile-Ribot, Isaac Alonso-Garcia, Antonio Oliver, Juan Carlos Vázquez-Ucha, Jorge Arca-Suárez, Germán Bou, Alejandro Beceiro","doi":"10.1128/aac.00724-26","DOIUrl":"10.1128/aac.00724-26","url":null,"abstract":"<p><p>Chromosomal AmpC variants selected during ceftolozane/tazobactam or ceftazidime/avibactam therapy may affect cefiderocol activity. We evaluated the impact of the E219K substitution on cefiderocol efficacy using isogenic <i>Pseudomonas aeruginosa</i> pairs in a murine bacteremia model. Cefiderocol achieved greater bacterial reductions in parental isolates than in E219K derivatives, despite susceptible MICs. Cefiderocol failed to achieve stasis against a cefiderocol-resistant isolate. E219K impaired cefiderocol efficacy <i>in vivo</i>, supporting close monitoring of cefiderocol activity against isolates carrying this variant.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0072426"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of benznidazole in the treatment of Chagas disease in children and adults: a long-term retrospective cohort study.","authors":"A Rabinovich, C Cruz, G Moscatelli, S Moroni, N González, J C Ramirez, F Garcia-Bournissen, G Ballering, H Freilij, J Altcheh","doi":"10.1128/aac.00203-26","DOIUrl":"10.1128/aac.00203-26","url":null,"abstract":"<p><p>Chagas disease, caused by <i>Trypanosoma cruzi</i>, is endemic to the Americas but has spread worldwide due to migration. Benznidazole is effective, but long-term follow-up efficacy studies are scarce and include only small numbers of patients. We analyzed data from a retrospective cohort of Chagas disease patients treated with benznidazole at a large tertiary center in Argentina (1980-2019). Treatment response was assessed through clinical, parasitological, and serological follow-up. Parasitemia was evaluated by direct visualization or PCR. Among 567 treated patients, 464 met selection criteria, including 411 children (median age: 46 months, IQR: 9.5-124 months) and 53 adults (median age: 26 years, IQR: 20-34 years). At diagnosis, 11/411 (2.68%) children and 1/53 (1.9%) adults were symptomatic; all improved after treatment. Baseline parasitemia was detected in 289/445 (64.94%) of patients, and 279/289 (96.54%) had parasitological follow-up for at least 3 years. Median benznidazole dose was 6.6 mg/kg/day in children and 5.6 mg/kg/day in adults, with treatment durations of 8 weeks and 31 days, respectively. All patients cleared parasitemia at treatment completion. Median serological follow-up was 4.8 years for children and 2.8 years for adults. At 1-year follow-up, 38.8% of patients showed >20% reduction in <i>T. cruzi</i> antibody titers, and 29.8% achieved seronegativity, with younger patients converting faster (<i>P</i> < 0.01). In this Argentinian cohort, Benznidazole achieved sustained parasitemia clearance and declining antibody titers, supporting early treatment initiation.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0020326"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of renal impairment on pharmacokinetics, safety, and tolerability of funobactam, combined with imipenem and cilastatin.","authors":"Keith A Rodvold, Grigor Mamikonyan, Yu Wang, Anastasia McRoberts, Dyal Garg, Richard Preston, Thomas Marabury, Meijie Le, Jianguo Li","doi":"10.1128/aac.00808-26","DOIUrl":"10.1128/aac.00808-26","url":null,"abstract":"<p><p>A phase 1, open-label study was conducted to investigate the effect of renal impairment (RI) on pharmacokinetics (PK) and safety of funobactam plus imipenem/cilastatin. Participants were enrolled and assigned to one of five cohorts based on renal function category: normal renal function, mild RI, moderate RI, severe RI, and end-stage renal disease (ESRD) requiring hemodialysis (HD). Participants received a single-dose of funobactam with imipenem and cilastatin by intravenous infusion administered over 60 min. Serial blood and urine samples were collected for non-compartmental PK analysis. Compared to participants with normal renal function, the geometric mean ratio (90% confidence interval) of plasma area under the curve (AUC0-∞) for funobactam, imipenem, and cilastatin increased with RI from mild (1.32 [1.04, 1.66], 1.37 [1.04, 1.79], and 1.27 [0.90, 1.78], respectively) to ESRD requiring HD (9.58 [7.59, 12.10], 2.69 [2.06, 3.52], and 15.15 [10.8, 21.3], respectively). The renal clearance for funobactam, imipenem, and cilastatin decreased progressively from normal renal function (3.93 ± 1.12 L/h, 4.95 ± 2.40 L/h, and 6.98 ± 2.75 L/h, respectively) to severe RI (0.94 ± 0.37 L/h, 1.16 ± 0.34 L/h, and 1.70 ± 0.60 L/h, respectively). Plasma clearance of funobactam, imipenem, and cilastatin correlated (r ≥0.93) with creatinine clearance and the estimated glomerular filtration rate. The treatment was well tolerated, with no deaths, severe adverse events, or discontinuation due to adverse events. Dosage adjustments of funobactam, imipenem, and cilastatin will be needed in patients with renal impairment or ESRD requiring HD.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04787562.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0080826"},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148824003","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}