Antimicrobial Agents and Chemotherapy最新文献

{"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":"https://doi.org/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":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and pharmacokinetics of CL-197, a potent compound with low cytotoxicity against HIV-1: a randomized, double-blind, placebo-controlled, first-in-human phase 1 clinical trial.","authors":"Yuming Guo, Yonggang Li, Pan Zhao, Jingfeng Bi, Chaoyun Gou, Zhengran Chuai, Shuangjie Yu, Renjie Zhang, Jinfa Du, Yi Ou, Ruonan Xu, Na Guo, Fu-Sheng Wang, Yuanyuan Li","doi":"10.1128/aac.00984-26","DOIUrl":"https://doi.org/10.1128/aac.00984-26","url":null,"abstract":"<p><p>HIV infection remains a critical global public health concern. A potential long-acting therapeutic agent, 4'-ethynyl-2-fluoroadenosine analog 1c (CL-197), was investigated in a first-in-human phase 1 clinical trial. This single-center, randomized, double-blind, dose-escalation, placebo-controlled study assessed the safety and pharmacokinetics (PKs) of five doses of CL-197 (1, 10, 30, 60, and 100 mg) in healthy adults aged 18-45 years. The 1 mg group was open-label (<i>n</i> = 4), while the other groups were randomized 4:1 to CL-197 or placebo. The primary endpoints were safety and tolerability. The PK evaluation involved the characterization of systemic exposure parameters (based on plasma drug concentrations and peripheral blood mononuclear cell [PBMC] drug concentrations) and urinary excretion parameters. CL-197 was well tolerated at all dose levels. The most frequently reported adverse reactions were sinus arrhythmia, followed by decreased apolipoprotein B, decreased blood iron, increased triglycerides, and elevated low-density lipoprotein. Plasma PKs showed dose-proportional exposure, with a mean time to maximum plasma concentration (<i>T</i>_max) of 0.50-1.00 h. As the dose increased, the elimination time was prolonged. The plasma drug concentrations were approximately dose-proportional, whereas <i>AUC</i> _0-t and <i>AUC</i> _0-∞ exhibited non-linear characteristics within the range of 1-100mg, with the mean elimination half-life (<i>t</i>_1/2) increasing from 1.39 to 10.20 h across doses. The mean <i>t</i>_1/2 in PBMCs was 61.29 h and 43.80 h in the 30 mg and 60 mg dose groups, respectively, and the median <i>T</i>_max was 12 h. In conclusion, a single administration of CL-197 demonstrated an acceptable safety profile in younger adults. The intracellular CL-197-TP in PBMCs had a long half-life, providing preliminary support for the potential use of extended dosing intervals in further development.<b>CLINICAL TRIALS</b>This study is registered with ClinicalTrials.gov as NCT05944848.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0098426"},"PeriodicalIF":4.2,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890784","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":"Reply to Srivastava and Gumbo, \"Rigor and reproducibility of hollow-fiber infection model for antiviral pharmacokinetics/pharmacodynamics studies\".","authors":"Lalitya M Sudarsono, Suzanne A M Wenker, Xuanlin Liu, Jorn Brink, Dirk-Jan van den Berg, J G C van Hasselt, Anne-Grete Märtson","doi":"10.1128/aac.00980-26","DOIUrl":"https://doi.org/10.1128/aac.00980-26","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0098026"},"PeriodicalIF":4.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886002","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":"Population pharmacokinetics of piperacillin/tazobactam in critically ill pediatric patients.","authors":"Tavey Dorofaeff, María Patricia Hernández-Mitre, Xin Liu, Yarmarly C Guerra Valero, Mark G Coulthard, Jeffrey Lipman, Steven C Wallis, Diane L Maresco-Pennisi, Suzane L Parker, Jason A Roberts","doi":"10.1128/aac.00272-26","DOIUrl":"https://doi.org/10.1128/aac.00272-26","url":null,"abstract":"<p><p>Piperacillin-tazobactam is commonly used in critically ill pediatric patients; however, standard dosing regimens may not reliably achieve maximally effective exposures in this population. To characterize the population pharmacokinetics of piperacillin-tazobactam in critically ill pediatric patients and evaluate the adequacy of commonly used dosing regimens, plasma concentrations were obtained around a single dose of piperacillin-tazobactam in critically ill pediatric patients aged 1 month to 12 years. A simultaneous population pharmacokinetic model for piperacillin and tazobactam was developed using nonlinear mixed-effects modeling. Monte Carlo simulations were performed to assess the probability of target attainment (PTA) for short, extended, and continuous infusion regimens across a range of ages and renal function states. Dosing adequacy was defined by simultaneous attainment of target drug exposures for piperacillin (100%fT > MIC) and tazobactam (85%fT > 2 mg/L). Thirty-one patients contributed 102 plasma samples, of which only 22.6% of patients achieved simultaneous piperacillin-tazobactam target exposures, considering a piperacillin MIC of 16 mg/L. Renal function and infusion duration were the primary determinants of attainment of target attainment. Standard short infusions frequently failed to achieve combined target exposures, particularly in patients with preserved renal function or augmented renal clearance (ARC). Extended infusions improved PTA, but remained suboptimal at higher MICs. Continuous infusion consistently achieved the highest target drug exposures across all simulated scenarios. Short intermittent piperacillin-tazobactam infusions and even extended infusions often result in suboptimal exposure in critically ill pediatric patients. Continuous infusion represents a rational dosing strategy to improve combined target attainment, particularly in children with preserved or ARC.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0027226"},"PeriodicalIF":4.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886034","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":"XAB06, a glyco-humanized broad-spectrum anti-<i>Pseudomonas aeruginosa</i> polyclonal antibody, protects mice in a lethal sepsis model.","authors":"Pierre-Joseph Royer, George Graur, Mehdi Varin, Bernard Vanhove, Odile Duvaux, Firas Bassissi","doi":"10.1128/aac.00277-26","DOIUrl":"https://doi.org/10.1128/aac.00277-26","url":null,"abstract":"<p><p>The global rise of antibiotic-resistant <i>Pseudomonas aeruginosa</i> (PA) necessitates the development of novel therapeutic approaches. Polyclonal antibodies constitute a promising approach, as they target multiple bacterial epitopes and functions. Moreover, they have recently demonstrated renewed clinical applicability in their humanized format. We developed a glyco-humanized polyclonal antibody (GH-pAb) targeting PA by immunization of pigs with five PA serotypes frequently encountered in clinical settings. This pentavalent GH-pAb, named XAB06, exhibited binding activity against the five serotypes used for the immunization, as well as unrelated PA serotypes. No binding activity was observed against <i>Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae,</i> or <i>Acinetobacter baumannii</i>, demonstrating the specificity of XAB06 against PA. In addition, XAB06 showed no reactivity against human blood cells. Functional assays revealed that XAB06 significantly inhibited swarming motility, biofilm formation, and pyocyanin production, indicating interference with key virulence determinants of PA. Notably, XAB06 conferred protection in a murine model of sepsis using the reference strains PAO1, PA103, and a ST235 high-risk clone. Collectively, these findings demonstrate the broad PA coverage and the protective activity of XAB06, supporting its potential as a novel therapeutic strategy against PA.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0027726"},"PeriodicalIF":4.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886074","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":"https://doi.org/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":"2026-09-03","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":"https://doi.org/10.1128/aac.00969-26","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0096926"},"PeriodicalIF":4.2,"publicationDate":"2026-09-03","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 vitro</i> activity profiles and temporal trends in reduced susceptibility to azoles in <i>Coccidioides</i> in the United States.","authors":"Nathan P Wiederhold, Charlotte Bisson, David A Stevens, Chiung-Yu Hung, Jose Lopez-Ribot, Thomas F Patterson, George R Thompson Iii","doi":"10.1128/aac.00744-26","DOIUrl":"https://doi.org/10.1128/aac.00744-26","url":null,"abstract":"<p><p>Treatment of symptomatic patients with coccidioidomycosis often involves the use of triazole antifungals. There is concern for reduced susceptibility of <i>Coccidioides</i> to fluconazole, as a high percentage of isolates were previously reported to have elevated fluconazole MICs. We reviewed our recent azole MICs against <i>Coccidioides</i> and examined temporal trends over a 20-year period. Our clinical laboratory database was queried for data against <i>Coccidioides</i> between 2006 and 2025, and trends in GM MICs and the percentage of isolates with elevated MICs to the azoles were assessed. All testing had been performed by broth dilution according to Clinical and Laboratory Standards Institute (CLSI) M38 methods. The results over the 10-year period from 2016 to 2025 were compared to those previously reported by our group from 2001 to 2015. Overall, the results between the two periods showed similar MIC parameters and distributions for fluconazole, itraconazole, posaconazole, and voriconazole, with posaconazole demonstrating the most potent activity, while fluconazole demonstrated reduced susceptibility. Isavuconazole MIC parameters were available during the second period and similar to those of voriconazole. Weak correlations were observed between fluconazole MICs and those of the other azoles. Fluctuations in GM MICs and the percentage of isolates with elevated MICs were observed with fluconazole, itraconazole, and posaconazole, with elevated values observed between 2011 and 2019. Continued surveillance is needed, and outcome data are required to determine if the consistently reduced susceptibility observed with fluconazole or in those infected with strains that have higher MICs results in poorer outcomes in patients with coccidioidomycosis.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0074426"},"PeriodicalIF":4.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886052","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":"Erratum for Chou et al., \"Novel Cytomegalovirus UL54 DNA Polymerase Gene Mutations Selected <i>In Vitro</i> That Confer Brincidofovir Resistance\".","authors":"Sunwen Chou, Ronald J Ercolani, E Randall Lanier","doi":"10.1128/aac.01024-26","DOIUrl":"10.1128/aac.01024-26","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0102426"},"PeriodicalIF":4.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683245","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":"Sorafenib enforces HIV-1 latency by selectively inhibiting PKC-driven STAT1/3 serine 727 phosphorylation.","authors":"Peipei Wang, Zhuoyue Meng, Jiasheng Zhou, Huixin Wu, Wei Wang, Zhiliang Gao, Ying Zhang, Jinfeng Cai","doi":"10.1128/aac.00540-26","DOIUrl":"10.1128/aac.00540-26","url":null,"abstract":"<p><p>Eliminating the latent HIV-1 reservoir remains a major barrier to achieving a functional cure. The \"block-and-lock\" strategy aims to enforce durable transcriptional silencing of proviruses, thereby preventing viral rebound upon interruption of antiretroviral therapy. However, the molecular mechanisms governing stable latency remain incompletely understood. Here, we identify protein kinase C (PKC)-dependent phosphorylation of STAT1 and STAT3 at serine 727 as a previously unrecognized regulatory checkpoint controlling HIV-1 transcriptional reactivation. Pharmacological inhibition of this axis using sorafenib, a clinically approved multi-kinase inhibitor, robustly suppresses HIV-1 reactivation across multiple latency models and promotes the establishment of latency in primary CD4⁺ T cells. Mechanistically, sorafenib attenuates phorbol 12-myristate 13-acetate (PMA)-induced activation of the JAK-STAT and PI3K-Akt signaling pathways, and selectively blocks PKC-mediated phosphorylation of STAT1/3 at serine 727 without affecting canonical tyrosine phosphorylation (Y701/Y705). This selective inhibition disrupts transcriptional activation at the HIV-1 long terminal repeat (<i>LTR</i>), thereby preventing viral reactivation. Importantly, sorafenib does not induce detectable cytotoxicity or alter activation and exhaustion markers in primary CD4⁺ T cells, supporting a favorable safety profile <i>in vitro</i>. Collectively, our findings define a critical role for STAT1/3 Ser727 in the regulation of HIV-1 latency and establish sorafenib as a promising latency-promoting agent for future applications in the development of a functional cure for HIV-1.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0054026"},"PeriodicalIF":4.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148663506","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}