Antimicrobial Agents and Chemotherapy最新文献

{"title":"Characterization of KPC-160, a novel Ω-loop-deleted KPC variant on a dual-copy plasmid that confers cefiderocol resistance.","authors":"Yuxuan Liu, Hanxu Hong, Qisen Huang, Linping Fan, Peng Liu, DanDan Wei, Yang Liu","doi":"10.1128/aac.01358-25","DOIUrl":"https://doi.org/10.1128/aac.01358-25","url":null,"abstract":"<p><p>The evolution of KPC-type carbapenemase variants is a major driver of resistance in <i>Klebsiella pneumoniae</i>. Cefiderocol (FDC), a next-generation siderophore cephalosporin, demonstrates potent activity against many KPC producers; however, emerging variants are compromising its efficacy. Here, we report the identification and functional characterization of a novel KPC variant, KPC-160, which confers resistance to FDC. This variant, harboring a unique two-amino acid deletion (ΔGlu167-Leu168) within the Ω-loop, was discovered in a clinical ST15-KL19 <i>Klebsiella pneumoniae</i> isolate. Antimicrobial susceptibility testing, whole-genome sequencing, and conjugation assays defined the resistance profile and genetic context, while carbapenemase activity assays, enzyme kinetics, and molecular modeling elucidated the functional mechanism. Strain K1661 exhibited FDC resistance (MIC = 8 µg/mL) alongside multidrug resistance. Genomic analysis identified the novel <i>bla</i>_KPC-160 variant carried on an IncFIB(K) plasmid in dual IS26-flanked copies, displaying efficient transfer frequencies (3.73 × 10⁻³-4.55 × 10⁻⁵). Compared with <i>bla</i>_KPC-2, <i>bla</i>_KPC-160 featured a ΔGlu167-Leu168 deletion, which markedly increased FDC MICs (16-fold higher than KPC-2) and increased its affinity for FDC. Molecular docking and dynamics simulations indicated that this deletion stabilized FDC binding within the active site, thereby facilitating resistance. Conventional carbapenemase detection assays (mCIM, GeneXpert Carba-R, and NG-Test Carba 5) successfully identified KPC-160. These findings describe <i>bla</i>_KPC-160, a deletion variant conferring clinically relevant FDC resistance via enhanced interaction and compromised inhibition. Its localization on a highly transmissible plasmid with a dual-copy architecture underscores its potential for rapid dissemination. Continuous genomic surveillance of emerging KPC variants is critical to preserving the clinical utility of FDC.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0135825"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831762","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":"A phase I study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of suraxavir marboxil: a novel oral antiviral for influenza.","authors":"Jing Zhou, Shousheng Yan, Yan Zhao, Hong Zhang, Nanya Wang","doi":"10.1128/aac.01668-25","DOIUrl":"10.1128/aac.01668-25","url":null,"abstract":"<p><p>Suraxavir marboxil (GP681, abbreviated as suraxavir) is a novel, orally active small-molecule polymerase acidic (PA) inhibitor for the treatment of influenza. Its active metabolite, GP1707D07, specifically inhibits PA endonuclease activity. Suraxavir has been approved for use in adolescents (≥12 years) and adults with uncomplicated influenza A and B. This non-randomized, open-label, parallel-group phase I clinical trial evaluated the effects of hepatic impairment on the pharmacokinetics (PK) and safety of suraxavir. Subjects with mild or moderate hepatic impairment and matched healthy controls (<i>n</i> = 8 per group) received a single oral dose of 40 mg suraxavir. PK parameters, including maximum plasma concentration (C_max), area under the plasma concentration-time curve from time 0 to last time point of measurable concentration (AUC_0-<i>t</i>), and area under the plasma concentration-time curve from time 0 to infinity (AUC_0-∞), were compared. Compared with subjects with normal hepatic function, the least-squares geometric mean ratios (90% CI) of GP1707D07 in subjects with mild hepatic impairment were 101.50% (72.63%-141.83%) for C_max, 86.98% (69.80%-108.38%) for AUC_0-<i>t</i>, and 87.06% (70.57%-107.40%) for AUC_0-∞. In subjects with moderate impairment, the corresponding ratios were 203.63% (147.50%-281.13%) for C_max, 155.23% (129.11%-186.64%) for AUC_0-<i>t</i>, and 157.26% (131.39%-188.22%) for AUC_0-∞. Mild impairment had minimal effect on GP1707D07 exposure, while moderate impairment increased C_max and AUC by ~1-fold and 0.5-fold, respectively, without resulting in clinically significant changes. A single 40-mg dose of suraxavir was safe and well tolerated in subjects with mild or moderate hepatic impairment. No dose adjustment is required for these populations.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT05814926.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0166825"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147497494","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":"Comparative <i>in vitro</i> activity of aztreonam-avibactam and aztreonam plus ceftazidime-avibactam against <i>Stenotrophomonas maltophilia</i> complex.","authors":"Ashlan J Kunz Coyne, Rachel Gray, Pavani Gonnabathula, Elizabeth S May, Pranita D Tamma, Alex Do","doi":"10.1128/aac.01456-25","DOIUrl":"10.1128/aac.01456-25","url":null,"abstract":"<p><p>Members of the <i>Stenotrophomonas maltophilia</i> complex are intrinsically multidrug-resistant pathogens that disproportionately affect critically ill patients. Aztreonam-avibactam (ATM-AVI), FDA approved in 2025, combines aztreonam (ATM; stable to L1 β-lactamase) with avibactam (AVI; an L2 β-lactamase inhibitor). Aztreonam plus ceftazidime-avibactam (ATM-CZA) has been used as a surrogate for ATM-AVI, but direct comparisons between the two regimens are lacking. Twenty-three clinical <i>S. maltophilia</i> complex isolates underwent broth microdilution (BMD) testing for ATM, ceftazidime, ATM-AVI, and ATM-CZA, with gradient diffusion performed in parallel for ATM-AVI and ATM-CZA. Static 24-h time-kill assays at humanized steady-state Cmax concentrations evaluated bactericidal activity (≥3-log₁₀ reduction). Semi-mechanistic pharmacodynamic modeling characterized growth kill dynamics by resistance determinants (<i>blaL1</i>, <i>blaL2</i>, <i>smeABC</i>). ATM-CZA and ATM-AVI MIC_50/90 values for BMD were 1/2 and 2/4 mg/L, respectively. Both regimens were bactericidal against most isolates, with a mean paired difference of 0.09 log₁₀ colony-forming units (CFU)/mL (<i>P</i> = 0.83). Isolate-level variation was evident: ATM-AVI sustained killing, whereas ATM-CZA permitted regrowth for MD17639, -4.86 vs 0.13 log₁₀ CFU/mL, <i>P</i> = 0.019; MD17061, -2.61 vs 0.64 log₁₀ CFU/mL, <i>P</i> < 0.001). Conversely, ATM-CZA achieved greater reductions in MD17662 (-3.84 vs -1.95; <i>P</i> = 0.026), MD17047 (-4.27 vs -2.64; <i>P</i> = 0.021), and UK4 (-3.47 vs -1.58; <i>P</i> = 0.017). Modeling predicted ATM-AVI benefit in <i>blaL2</i> and ATM-CZA benefit against <i>blaL1</i> or <i>smeABC</i> dominant isolates, and diminished activity of both when mechanisms coexisted. ATM-AVI and ATM-CZA show comparable <i>in vitro</i> activity against <i>S. maltophilia</i> complex. Isolate-level heterogeneity warrants further study of genotype-phenotype relationships.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0145625"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502895","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":"Bridging clinical and environmental reservoirs: antimicrobial resistance in the emerging pathogen <i>Shewanella algae</i>.","authors":"Celia García-Rivera, Juan J Roda-Garcia, Juan Carlos Rodríguez, Carmen Molina-Pardines, Iryna Tyshkovska, Jose M Haro-Moreno, Antonio Martínez-Murcia, Maria Paz Ventero, Mario López-Pérez","doi":"10.1128/aac.01891-25","DOIUrl":"10.1128/aac.01891-25","url":null,"abstract":"<p><p>The emergence of antimicrobial resistance in environmental bacteria threatens therapeutic efficacy in clinical settings. <i>Shewanella algae</i>, historically regarded as a marine saprophyte, is increasingly recognized as an emerging opportunistic pathogen. In this study, we analyzed 86 <i>S. algae</i> isolates from Spain (19 clinical and 67 environmental) and integrated them with 178 publicly available genomes to explore antimicrobial susceptibility patterns and genomic diversity. Penicillins and fosfomycin consistently showed poor activity, whereas piperacillin/tazobactam, third- and fourth-generation cephalosporins, aminoglycosides, ciprofloxacin, trimethoprim-sulfamethoxazole and several novel β-lactam-inhibitor combinations exhibited low MIC distributions. Recently introduced agents, including ceftazidime/avibactam, ceftolozane/tazobactam, and cefiderocol, also demonstrated strong <i>in vitro</i> activity. Carbapenems displayed an unusual intraclass pattern, with imipenem showing markedly higher MICs than meropenem and ertapenem. When interpreted using CLSI's \"Other Non-Enterobacterales\" criteria, clinical and environmental isolates exhibited largely overlapping susceptibility profiles, highlighting the potential role of environmental strains as reservoirs of resistance-related traits. Genomic profiling revealed a conserved intrinsic resistome (OXA-type β-lactamases, <i>qnrA</i> variants, <i>ugd</i>, and efflux regulators) together with horizontally acquired determinants. A 29 kb genomic island carrying multiple resistance genes was identified in a clinical isolate, with homologous structures detected in <i>Vibrio</i> and <i>Proteus</i>, suggesting interspecies transfer. Furthermore, plasmids harboring class 1 integrons (mobile integrons) were widespread, shared with Enterobacterales and <i>Vibrionaceae</i> across clinical and environmental settings. Overall, these findings highlight <i>S. algae</i> as both a clinically relevant pathogen and a reservoir of mobile AMR determinants and underscore the urgent need for species-specific antimicrobial susceptibility interpretive criteria to improve clinical decision-making for this emerging pathogen.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0189125"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147687591","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":"Comparative outcomes of ceftazidime-avibactam versus meropenem-vaborbactam for KPC-producing Enterobacterales infections.","authors":"Sara M Karaba, Dariusz A Hareza, Jose M Munita, Jose R W Martinez, Yehudit Bergman, Armani M Hawes, Zackery P Bulman, Sara E Cosgrove, Patricia J Simner, Pranita D Tamma","doi":"10.1128/aac.01602-25","DOIUrl":"10.1128/aac.01602-25","url":null,"abstract":"<p><p>Thirty-day mortality was similar in a propensity-score-weighted cohort of 73 patients with KPC-producing Enterobacterales infections treated with ceftazidime-avibactam or meropenem-vaborbactam. Emergence of resistance was higher in the ceftazidime-avibactam group (12% vs 0%); putative resistance mechanisms included porin mutations (<i>Klebsiella pneumoniae</i>) and R2 loop structural changes in AmpC (<i>Enterobacter cloacae</i> complex).</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0160225"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147497511","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":"Structure-guided screening of FAR-1 antagonists with multi-stage anthelmintic activity.","authors":"Juan Wen, Wenmin Qi, Jinwei Lv, Yu Lin, Fei Shen, Yu Li, Ziding Zhang, Lihua Xiao, Yaoyu Feng, Dongjuan Yuan","doi":"10.1128/aac.01226-25","DOIUrl":"10.1128/aac.01226-25","url":null,"abstract":"<p><p>Fatty acid and retinol binding proteins (FARs) are nematode-specific proteins that orchestrate lipid metabolism, development, and host immune response. Here, the antagonists of <i>Nippostrongylus brasiliensis</i> FAR-1 (<i>Nb</i>FAR-1) were identified through integrating virtual screening, fluorescent ligand binding assay, and <i>in vitro</i> egg hatching assays. An <i>in vivo</i> mouse model was employed to evaluate anthelmintic efficacy against intestine-parasitized <i>N. brasiliensis</i> and brain-parasitized <i>Angiostrongylus cantonensis</i>. Forty-eight candidates were selected by virtual screening, six of them showed more than 40% antagonism to <i>Nb</i>FAR-1 by fluorescent ligand-competition binding assay and suppressed <i>N. brasiliensis</i> egg hatching by 40%-80% at 20 μM. In mice, E002-0872 and 4340-0245 reduced intestinal <i>N. brasiliensis</i> burdens by 61.74% and 62.15%, respectively, and ameliorated intestinal damages. 4340-0245 reduced cerebral <i>A. cantonensis</i> burdens by 52.73% and alleviated meningeal bleeding and neurological signs. Moreover, treatment with 4340-0245 at 15 mg/kg shortened the body length of female worms, consistent with the higher <i>far-1</i> expression in females. Alanine scanning showed I95 of <i>Nb</i>FAR-1 as a key residue for binding fatty acid, retinol, and 4340-0245. Intraperitoneal administration of 4340-0245 at 50 mg/kg did not cause any significant toxic effects, whereas 15 mg/kg resulted in a plasma <i>C</i>_max of 56,473 ng/mL at 10 min and a half-life of ~7 h. These data provide evidence that FAR-1 is a promising target for developing anthelmintic drugs.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0122625"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147687532","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":"Contemporary antiretroviral pharmacology in the male genital tract: implications for HIV treatment and prevention.","authors":"Noah C Neverette, Jordan Winfield, Nathalia Chaparro-Cáceres, Ken S Ho, Julie B Dumond, Aaron S Devanathan","doi":"10.1128/aac.01401-25","DOIUrl":"10.1128/aac.01401-25","url":null,"abstract":"<p><p>The male genital tract (MGT) plays a critical role in HIV transmission and persistence, serving as a viral reservoir and potential site of HIV compartmentalization. While antiretroviral therapy effectively suppresses systemic viral replication, drug penetration into the MGT tissues and semen varies considerably between and within drug classes, potentially leading to subtherapeutic concentrations in the MGT. The organs comprising the MGT have anatomical barriers and express several drug-metabolizing enzymes, resulting in immune privilege, active drug efflux, and site-specific metabolism. These factors may collectively limit antiretroviral efficacy in this compartment. This review discusses the evidence of HIV persistence in MGT organs and provides insight into the anatomical, physiological, and pharmacological considerations to target this viral reservoir. Additionally, we synthesize current knowledge on contemporary antiretroviral pharmacokinetics within the MGT, highlighting differences in drug penetration between and within classes. We identify associations between drug properties (e.g., lipophilicity and protein binding) and distribution into the MGT. Finally, we forecast emerging therapeutic approaches that introduce new pharmacological opportunities and challenges, as well as advanced computational techniques to help us better understand the downstream effects of antiretroviral pharmacology at the site of action. Understanding the interplay between antiretroviral penetration, local inflammation, and viral dynamics is essential for optimizing HIV treatment and prevention strategies. Together, these insights set the stage for targeted studies to guide precision dosing based on local therapeutic exposure thresholds. Addressing remaining knowledge gaps in MGT pharmacology will be essential to overcome anatomical and physiological barriers and achieve sustained viral suppression in the MGT.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0140125"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13117926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147497475","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":"Benzoxaborole-modified azithromycins inhibit translation without inducing <i>ermC</i> expression.","authors":"Inna A Volynkina, Michael O Bortyazh, Chih-Wei Chen, Andrey G Tereshchenkov, Anastasiia O Karakchieva, Dmitrii A Lukianov, Ekaterina S Komarova, Alexey E Tupikin, Dmitry A Skvortsov, Anna N Tevyashova, Alexander S Tikhomirov, Vadim N Tashlitsky, Marsel R Kabilov, Andrey E Shchekotikhin, Olga A Dontsova, Yury S Polikanov, Petr V Sergiev","doi":"10.1128/aac.01539-25","DOIUrl":"10.1128/aac.01539-25","url":null,"abstract":"<p><p>The rapid increase in antimicrobial resistance underscores the urgent need for new antibacterial agents. One promising strategy involves designing novel compounds through targeted chemical modifications of existing antibiotics. Azithromycin (AZI), a widely used macrolide, has served as a versatile scaffold for developing numerous antibacterial candidates. However, the mechanistic consequences of such modifications remain largely unexplored. Here, we characterize the activity and mechanism of action of three AZI-benzoxaborole (AZI-BB) conjugates. We show that these compounds inhibit bacterial translation <i>in vitro</i> and remain active against a model <i>Escherichia coli</i> strain carrying an inducible <i>ermCL-ermC</i> operon, which confers resistance to macrolide antibiotics. Unlike erythromycin, these derivatives, along with AZI itself, exhibit minimal induction of ErmC expression. Structural analysis reveals that the benzoxaborole moiety of AZI-BB2 forms additional interactions with nucleotides C2441 and C2586 of 23S rRNA, likely contributing to premature ribosome stalling at the <i>ermCL</i> regulatory sequence and thereby preventing ErmC expression. Furthermore, high-throughput toeprinting analysis combined with deep sequencing (Toe-seq) demonstrates that AZI-BB2 exhibits reduced sequence specificity for canonical macrolide-sensitive stalling motifs. Altogether, these findings demonstrate that targeted chemical modification of AZI can reshape its context-specific interaction with the ribosome and attenuate the induction of macrolide resistance mechanisms.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0153925"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502877","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":"Piperacillin-tazobactam resistance in <i>Klebsiella pneumoniae</i> is often associated with IS<i>26-</i>mediated <i>bla</i>_SHV-1 amplification in a widespread <i>Klebsiella</i>-adapted plasmid.","authors":"Guilhem Royer, Maxime Danjean, Christophe Rodriguez, Vincent Fihman, Emmanuelle Gallois, Eve Tessier, Florence Reibel, Nicolas Cabanel, Philippe Glaser, Paul-Louis Woerther, Hervé Jacquier","doi":"10.1128/aac.01682-25","DOIUrl":"10.1128/aac.01682-25","url":null,"abstract":"<p><p>Piperacillin-tazobactam (TZP) resistance in <i>Klebsiella pneumoniae</i> involves diverse mechanisms with unclear prevalence and phenotypic impact. To elucidate these mechanisms, we analyzed <i>K. pneumoniae</i> clinical isolates resistant to TZP but susceptible to cefotaxime and cefepime. Among 53 isolates, 14 were further studied by MIC testing for TZP, amoxicillin-clavulanic acid (AMC), and ceftazidime (CAZ). Short-read sequencing was performed for all 14 isolates and long-read sequencing for two. Core-genome MLST showed that all were unrelated. Two had a <i>bla</i>_OXA-1 gene, one also carrying an <i>ompK35</i> porin gene mutation; two others had the same mutation in the promoter of the chromosomal copy of <i>bla</i>_SHV usually associated with overexpression. In the remaining 10, resistance correlated with plasmid-borne <i>bla</i>_SHV-1 copies. Nine isolates carried <i>bla</i>_SHV-1v1 in the same IS<i>26</i> pseudocompound transposon (PTn), corresponding to PTnSHV-L and located on a conserved IncFIB(K)_1_Kpn3 plasmid in eight. The tenth isolate carried PTnSHV-L with a distinct <i>bla</i>_SHV-1 variant on both an IncHI1B_1_pNDM-MAR plasmid and a high-copy-number Col-type plasmid. Read depth analysis confirmed that <i>bla</i>_SHV copy number correlated with TZP, AMC, and CAZ MICs. Large-scale database screening identified related IncFIB(K)_1_Kpn3 plasmids, strongly associated with <i>K. pneumoniae</i> and frequently carrying a PTnSHV-L marker. Analysis of a <i>K. pneumoniae</i> genome data set confirmed the frequent co-occurrence of this plasmid and the PTnSHV-L marker in strains with multiple <i>bla</i>_SHV copies. These findings suggest the emergence of an epidemic plasmid adapted to <i>K. pneumoniae</i> and driving TZP resistance through <i>bla</i>_SHV-1 amplification, underscoring the need for genomic surveillance to detect amplification-based resistance overlooked by standard phenotypic or PCR assays.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0168225"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502880","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":"Phase I studies assessing safety and pharmacokinetics of nacubactam administered alone or in combination with cefepime or aztreonam in Japanese healthy participants.","authors":"Jun Morita, Noriko Hida, Takuma Yonemura, Taigi Yamazaki, Hiroki Sato, Masayo Sumiya, Risako Takaya, Yuji Kumagai, Naoki Uchida","doi":"10.1128/aac.01770-25","DOIUrl":"10.1128/aac.01770-25","url":null,"abstract":"<p><p>Nacubactam is a novel developed β-lactamase inhibitor. Two randomized, double-blind, placebo-controlled phase 1 studies (OP0595-2 and -4 studies) were conducted to evaluate its pharmacokinetics and safety in healthy Japanese male participants. In the OP0595-2 study, single ascending doses (1, 2, and 4 g) and multiple doses (1 and 2 g per dose for 7 days) of nacubactam were administered intravenously over 90 min. In the OP0595-4 study, 2 g of nacubactam was administered intravenously over 60 min for 7 days in combination with cefepime or aztreonam (2 g per dose each). In both studies, participants were randomized in a 3:1 ratio to receive nacubactam or placebo. In the OP0595-2 study, exposure to nacubactam increased in a dose-dependent manner following single infusion, with steady mean trough plasma concentrations observed after Day 4 during multiple dosing. Metabolites of nacubactam were detected at low levels compared to the parent drug. Nacubactam was predominantly excreted unchanged in the urine, indicating minimal metabolic clearance. In the OP0595-4 study, administration of cefepime or aztreonam did not alter the pharmacokinetic profile of nacubactam. In both studies, nacubactam, whether administered alone or combined with cefepime or aztreonam, was generally well tolerated. These favorable findings support further clinical development of nacubactam.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0177025"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669984","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}