Antimicrobial Agents and Chemotherapy最新文献

{"title":"Pharmacokinetics and safety of TBAJ-587, a novel antimycobacterial diarylquinoline, in healthy participants.","authors":"Jerry Nedelman, Almari Conradie, Antonio Lombardi, Dean Hickman, Khalid Abd-Elaziz, Peter Dogterom, Paul Bruinenberg, Antonio J Carcas Sansuán, Elly Sakiman, Zuzana Diamant, Jolanda van Duinen, Maria Beumont, Eugene Sun","doi":"10.1128/aac.01930-25","DOIUrl":"10.1128/aac.01930-25","url":null,"abstract":"<p><p>TBAJ-587 is a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile than the first-generation bedaquiline. It is currently under development for the treatment of drug-susceptible and drug-resistant tuberculosis. A first-in-human trial of TBAJ-587, including single and multiple ascending oral doses and a dedicated food-effect cohort, was conducted in 92 healthy adults. Plasma exposures of TBAJ-587 were generally linear for AUC_tau and slightly subproportional for <i>C</i>_max, with the major circulating active metabolite, M3, remaining low relative to the parent. A high-fat meal increased the mean <i>C</i>_max and AUC_last 3.46- and 2.26-fold, respectively. TBAJ-587 accumulated with multiple dosing over the 28-day period, with mean accumulation ratios across the three tested doses ranging from 1.69 to 2.32 for <i>C</i>_max and from 2.74 to 3.73 for AUC_tau. However, steady-state conditions were not yet reached on day 28. Mean terminal half-lives after 28-day dosing of TBAJ-587 ranged from approximately 80 to 111 days. There were no deaths or serious adverse events, and TBAJ-587 was generally safe and well tolerated at single doses of 25-800 mg under fasting conditions and multiple doses of 50-200 mg once daily for 28 days after a standard breakfast. In addition, no dose- or time-dependent effects were noted for any of the other safety and tolerability parameters, including no clinically significant effects on the QTc interval. These results support further investigation of TBAJ-587 for the treatment of tuberculosis.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04890535.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0193025"},"PeriodicalIF":4.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148598108","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":"Redox-sensitive factors as targets of thiol compounds to hinder SARS-CoV-2 replication and inflammatory response.","authors":"Marta De Angelis, Gianni Gori Savellini, Elena Piselli, Gabriele Anichini, Giulia Radocchia, Sofia Masini, Francesca Monittola, Francesca Bartoccini, Michela Bruschi, Mauro Magnani, Anna Teresa Palamara, Maria Grazia Cusi, Rita Crinelli, Alessandra Fraternale, Lucia Nencioni","doi":"10.1128/aac.00518-26","DOIUrl":"10.1128/aac.00518-26","url":null,"abstract":"<p><p>SARS-CoV-2 has undergone rapid genetic evolution, leading to the emergence of new variants with distinct mutations impacting global public health. Upon infection, the virus triggers a robust inflammatory response characterized by the release of pro-inflammatory cytokines, which play a central role in lung injury. It also alters the host antioxidant response, causing oxidative stress that supports viral replication and cytokine overproduction. This study investigated key pathogenic effectors in Calu-3 and A549-ACE2/TMPRSS2 cells infected with SARS-CoV-2 variants, focusing on replication kinetics, cellular redox state, and inflammatory cytokine profile. A dramatic redox alteration in terms of glutathione (GSH) and Cysteine (Cys) was observed at 48 h p.i., along with a strong pro-inflammatory cytokine response , likely via activation of the JNK/AP-1 signaling pathway. To counteract these effects, two thiol molecules were tested: I-152, a monothiol conjugate of N-Acetyl-Cysteine (NAC) and β-mercaptoethylamine (MEA) and its dithiol derivative, I-152SdAc. Thiols restored GSH balance by enhancing the expression of Nrf2-mediated genes, such as glutamate-Cys ligase modifier subunit (GCLM), and counteracted AP-1-mediated pathway, resulting in a significant reduction of inflammation and viral replication. Antiviral and anti-inflammatory activities of thiols were confirmed in NHBE cells. These findings highlight that redox imbalance is a key pathogenetic event in SARS-CoV-2 infection. Notably, besides Nrf2 and AP-1, other redox-sensitive factors, such as the CHAC glutathione-specific gamma-glutamyl-cyclotransferase 1 (CHAC1), seem to contribute to the pathogenesis and may represent a new potential therapeutic target of redox active compounds. Therefore, the thiol-derived molecules act as broadly effective compounds by limiting virus replication and inflammation.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0051826"},"PeriodicalIF":4.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618028","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":"Case Commentary: Emergence of clinically relevant fidaxomicin-resistant <i>Clostridioides difficile</i> strains.","authors":"Kevin W Garey, Julian G Hurdle","doi":"10.1128/aac.00482-26","DOIUrl":"10.1128/aac.00482-26","url":null,"abstract":"<p><p><i>Clostridioides difficile</i> infection (CDI) has limited antibiotic treatment options, with fidaxomicin being the guideline-preferred antibiotic. C. E. Kaple, S. N. Redmond, J. L. Cadum, B. Hausman, et al. (Antimicrob Agents Chemother 0:e00130-26, 2026, https://doi.org/10.1128/aac.00130-26) describe a case of clinical failure in an elderly patient with CDI treated with a pulsed-taper fidaxomicin regimen, in which the MIC increased from 0.05 μg/mL at baseline to 32 μg/mL in isolates recovered during relapse. Relapsing symptoms were eventually resolved only after switching to oral vancomycin. This case, together with other recent clinical reports, may be the tip of the iceberg, signaling that fidaxomicin-resistant <i>C. difficile</i> can arise during treatment and contribute to clinical failure. It further challenges the assumption that high colonic drug concentrations mitigate resistance and underscores the need for improved surveillance and the development of clinically applicable molecular diagnostics to detect fidaxomicin resistance in CDI patient samples.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0048226"},"PeriodicalIF":4.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148663508","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":"Penicillin-resistant <i>Streptococcus dysgalactiae</i> subsp. <i>equisimilis</i> and the association with penicillin-binding protein mutations: a population genotypic and phenotypic study.","authors":"Ouli Xie, Aimee Tan, Thanh Binh Nguyen, Andrew J Hayes, Ravindra Dotel, Glen Carter, Matthew V N O'Sullivan, Katherine Bond, Christopher A McDevitt, Tony M Korman, Bart J Currie, David B Ascher, Steven Y C Tong, Sebastiaan J van Hal, Mark R Davies","doi":"10.1128/aac.00137-26","DOIUrl":"10.1128/aac.00137-26","url":null,"abstract":"<p><p><i>Streptococcus dysgalactiae</i> subspecies <i>equisimilis</i> (SDSE) is increasingly recognized as a cause of human disease. Despite decades of penicillin use, SDSE is near universally penicillin-susceptible. Here we report and characterize by whole genome sequencing (WGS) three penicillin-resistant SDSE isolates (minimum inhibitory concentration [MIC] ≥0.256 mg/L) isolated from blood and skin in an individual with recurrent cellulitis on penicillin prophylaxis. The isolates carried 11 penicillin-binding protein (PBP) PBP2x, five PBP1a, and one PBP2b mutations that were distinct from the only previously reported WGS-characterized penicillin-resistant SDSE isolates (<i>n</i> = 4). We then took a genotype-led approach to test the MICs of penicillin and amoxicillin for 63 isolates with PBP2x, PBP1a, and PBP2b variants selected from a well-characterized database of invasive SDSE isolates from Australia (2011-2023, <i>n</i> = 436). PBPs were highly conserved in Australian invasive SDSE genomes. Only a single isolate carrying a PBP2x variant with five mutations around the penicillin-binding cleft found in 1/436 invasive isolates demonstrated a four-fold rise in penicillin MIC, although remaining below clinical breakpoints. Strains with PBP2b and PBP1a variants alone were not associated with raised MICs. To provide broader context for PBP variants, we then examined a global database of SDSE genomes (<i>n</i> = 1,160). PBP2x mutations in isolates with raised and/or resistant penicillin MICs were found in only nine global SDSE database genomes. SDSE penicillin resistance is rare and associated with multiple PBP mutations, particularly PBP2x. WGS with phenotypic testing of novel PBP variants could be used to monitor emerging mutations associated with raised penicillin MICs.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0013726"},"PeriodicalIF":4.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148663465","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":"Antibacterial and antivirulence activities of abafungin against <i>Clostridioides difficile</i>: <i>in vitro</i> and <i>in vivo</i> studies.","authors":"Ahmed A Abouelkhair, Nader S Abutaleb, Sahar Abdelrazek, Mohamed N Seleem","doi":"10.1128/aac.00598-26","DOIUrl":"10.1128/aac.00598-26","url":null,"abstract":"<p><p><i>Clostridioides difficile</i> infection (CDI) remains a major cause of healthcare-associated diarrhea worldwide, and is classified as an urgent public health threat by the Centers for Disease Control and Prevention. Current frontline therapies, including vancomycin and fidaxomicin, are associated with disruption of the intestinal microbiota, recurrence, and emerging reduced susceptibility, underscoring the need for additional therapeutic strategies. Using a drug-repurposing approach, we identified the antifungal agent abafungin as a potent inhibitor of <i>C. difficile</i>. Abafungin is an arylguanidine antifungal with reported sporicidal activity against fungal pathogens, a property of particular relevance to CDI, given the central role of spores in disease persistence and recurrence. Herein, abafungin exhibited potent <i>in vitro</i> activity against a diverse panel of clinical <i>C. difficile</i> isolates, inhibiting 50% (MIC_5₀) and 90% (MIC_₉₀) of the tested strains at the concentrations of 0.25 μg/mL and 0.5 μg/mL, respectively, while demonstrating minimal activity against representative gut commensal bacteria. At sub-inhibitory concentrations, abafungin significantly reduced toxin production (31.8%), decreased spore formation (~4-log₁₀ reduction), and inhibited spore germination. Abafungin showed favorable gastrointestinal stability and demonstrated synergistic activity with vancomycin and metronidazole. Transcriptomic analysis revealed that abafungin disrupts metal ion transport and intracellular metal homeostasis in <i>C. difficile</i>, a mechanism supported by the antagonistic effect of Mg²⁺ supplementation on its antibacterial activity. These observations suggest a potential association between abafungin activity and metal-responsive cellular pathways. In a murine model of recurrent CDI, a combination therapy of abafungin and vancomycin significantly improved survival (83.3%) compared with vancomycin monotherapy (16.6%). Collectively, these findings establish abafungin as a potential anti<i>-C</i>. <i>difficile</i> inhibitor that suppresses <i>C. difficile</i> growth and virulence-associated processes and enhances the therapeutic efficacy of vancomycin <i>in vivo</i>. Also, these observations provide a basis for further studies exploring abafungin as a useful lead scaffold for anti<i>-C</i>. <i>difficile</i> drug discovery.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0059826"},"PeriodicalIF":4.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148720998","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":"Physiologically based pharmacokinetic (PBPK) model to predict the magnitude of drug-drug interaction between vincristine and the azole antifungals isavuconazole, posaconazole, and voriconazole in children.","authors":"Mary P Choules, Amit Desai, Laura Lynn Kovanda, Yukio Otsuka, Roger J Brüggemann, Peter L Bonate","doi":"10.1128/aac.00444-26","DOIUrl":"10.1128/aac.00444-26","url":null,"abstract":"<p><p>Invasive fungal diseases (IFDs), including invasive aspergillosis (IA) and invasive mucormycosis (IM), occur primarily in immunocompromised and/or hospitalized patients and are associated with increased morbidity and mortality. Isavuconazole and posaconazole are triazole compounds approved for the treatment of IA/IM in adults and children, while voriconazole is approved for IA treatment only. All triazole compounds inhibit CYP3A, and both isavuconazole and posaconazole inhibit the transporter P-gp. Pediatric patients being treated for leukemia with vincristine frequently experience fungal infections, requiring treatment. Vincristine is metabolized by CYP3A4 and CYP3A5 and eliminated via P-gp transport. The risk of drug-drug interactions (DDIs) between vincristine and triazole compounds is known; however, the magnitude of risk has not been quantified. In the present analysis, physiologically based pharmacokinetic (PBPK) models were built for the triazoles and vincristine in a pediatric cancer population using the Simcyp simulator and were used to predict the change in vincristine exposure following coadministration with triazoles. Different age groups and CYP3A5 phenotypes were also explored. Modeling predicted that vincristine geometric mean AUC_inf ratios in CYP3A5 poor metabolizers (PMs) ranged from 2.01- to 2.25-fold, 4.97- to 5.20-fold, and 1.43- to 1.53-fold with isavuconazole, posaconazole, and voriconazole, respectively. In CYP3A5 extensive metabolizers (EMs), vincristine AUC_inf ratios ranged from 1.22- to 1.38-fold, 1.19- to 1.24-fold, and 1.05- to 1.07-fold for isavuconazole, posaconazole, and voriconazole, respectively. The model predicted vincristine AUC_inf >100 ng·h/mL in CYP3A5 PM and <100 ng·h/mL in CYP3A5 EM; therefore, vincristine dose reduction may be required only in CYP3A5 null expressors.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0044426"},"PeriodicalIF":4.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547473","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":"Multilevel HierCC typing scheme for global genomic epidemiology and antimicrobial resistance surveillance of <i>Campylobacter jejuni</i>.","authors":"Ruochen Wu, Sandeep Kaur, Michael Payne, Li Zhang, Ruiting Lan","doi":"10.1128/aac.00310-26","DOIUrl":"10.1128/aac.00310-26","url":null,"abstract":"<p><p><i>Campylobacter jejuni</i> is the most common bacterial cause of human gastroenteritis around the world. A stable, scalable, and standardized typing scheme is essential for epidemiological and antimicrobial resistance (AMR) surveillance for prevention and control of <i>C. jejuni</i> infections. We curated, assembled, and quality-filtered a <i>C. jejuni</i> global whole-genome sequencing (WGS) data set of 63,012 publicly available Illumina short-read genomes. A <i>C. jejuni</i> global cgMLST scheme with 1,161 core loci was developed using a representative subset of 2,587 genomes. We compared the HierCC clustering of the cgMLST profiles at every allelic distance, and identified nine epidemiologically meaningful levels to form a novel multilevel HierCC typing (MHT) scheme. AMR prediction was performed for the global data set using AbritAMR and integrated with the MHT scheme. The multilevel design provides flexible typing resolution for both short- and long-term epidemiological investigations and allows natural and genetically discrete clusters to be described consistently at both global and local scales. We showcased the utility of the scheme with the identification of country- and continent-specific clusters at HC264 to HC19 levels and differentiation of farm-animal-specific (specialist) from human infection (generalist) clusters at HC264 to HC55 levels. In the U.S. dataset from 2016 to 2022, a total of 276 antibiotic-resistant clusters were identified, with 22 resistant clusters increasing in frequency in recent years. An increased prevalence of <i>C. jejuni</i> carrying <i>50S_L22</i> mutations in the USA was observed from 2016 to 2022, suggesting continuing selection pressure from macrolide use in farm animals.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0031026"},"PeriodicalIF":4.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148598110","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":"Targeting SARS-CoV-2 programmed -1 ribosomal frameshifting: structural dynamics and RNA-directed antiviral strategies.","authors":"Neha Jeena, Inshad Ali Khan","doi":"10.1128/aac.00687-26","DOIUrl":"10.1128/aac.00687-26","url":null,"abstract":"<p><p>Programmed -1 ribosomal frameshifting (-1 PRF) is a translational recoding mechanism used by many RNA viruses to regulate the expression of viral replication proteins. In coronaviruses, including SARS-CoV-2, -1 PRF is controlled by a conserved frameshift stimulation element containing a three-stemmed RNA pseudoknot located downstream of a slippery sequence. Studies have shown that conformational dynamics, mechanical stability, and structural variability of the pseudoknot influence ribosome pausing and frameshifting efficiency, identifying viral RNA structures as potential antiviral targets. This review outlines the structural organization, mechanistic basis, and conformational dynamics of viral frameshifting pseudoknots, with emphasis on the SARS-CoV-2 frameshift stimulation element. Advances in cryo-electron microscopy, single-molecule biophysics, molecular dynamics simulations, and computational modeling have identified multiple pseudoknot conformations involved in translational recoding and ribosome-RNA interactions. RNA-targeted therapeutic approaches used to suppress or modulate -1 PRF are also discussed, including small-molecule RNA binders, antisense oligonucleotides, peptide nucleic acids, and ribonuclease-targeting chimeras. These approaches act on distinct aspects of RNA structure, conformational flexibility, and stability to inhibit viral translation or promote selective RNA degradation. Major challenges include selective targeting of highly dynamic RNA structures, optimization of intracellular delivery, and minimizing off-target effects. Integration of structural biology, computational modeling, and RNA-targeted therapeutic strategies may support the development of next-generation antivirals targeting conserved viral RNA regulatory elements.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0068726"},"PeriodicalIF":4.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148663116","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":"Identification of a hypervirulent extensively drug-resistant ST383 <i>Klebsiella pneumoniae</i> sub-lineage carrying ICEKp5 in Lebanon.","authors":"Martine Abboud, Tia Clara Chaaya, Yara Daccache, Nour El Alam, Theresa Gerges, Lea Haddad, Leon Kassabian, Jame Tannous, Yara Ghanem, Judy Nabbout, Kevin Chaar, Toni Nmeir, Anthony Haddad, Charbel Al Khoury, George F Araj, Sima Tokajian","doi":"10.1128/aac.00384-26","DOIUrl":"10.1128/aac.00384-26","url":null,"abstract":"<p><p><i>Klebsiella pneumoniae</i> ST383 has emerged as a high-risk clone, characterized by carbapenem resistance and increasing detection of hypervirulence determinants. We describe a phylogenetically distinct ST383 sub-lineage in Lebanon, defined by the acquisition of ICEKp5, which carries the yersiniabactin locus. Three ST383 <i>K. pneumoniae</i> clinical isolates (LBN_CAKp91, LBN_CTKp3, and LBN_CTKp11) recovered from a Lebanese medical center were subjected to whole-genome sequencing. Comparative genomic analysis included regional ST383 strains and previously characterized Lebanese isolates. The study isolates formed a tight, monophyletic cluster (three to nine single-nucleotide polymorphisms [SNPs]) that is phylogenetically distinct from the previously reported Lebanese ST383 clone (>164 SNPs) and grouped most closely to an Egyptian ST383 strain (59-65 SNPs). All three isolates carried ICEKp5 with yersiniabactin lineage <i>ybt14</i>, a feature absent in the earlier Lebanese ST383 clone. The isolates were the only ST383 strains to harbor the full spectrum of hypervirulence determinants to date, including capsule regulators (<i>rmpA</i> and <i>rmpA2</i>), aerobactin (<i>iucABCD</i> and <i>iutA</i>), yersiniabactin, and the hypervirulence biomarker <i>peg-344</i>. All isolates carried dual carbapenemases (<i>bla</i>_OXA-48 and <i>bla</i>_NDM-5) in addition to <i>bla</i>_CTX-M-15 and <i>bla</i>_CTX-M-14b. The genetic environments of <i>bla</i>_OXA-48 and <i>bla</i>_NDM-5 were highly conserved across geographically diverse ST383 isolates, indicating common plasmid origins. This study describes a phylogenetically distinct hypervirulent extensively drug-resistant (XDR) ST383 <i>K. pneumoniae</i> sub-lineage in Lebanon. The acquisition of ICEKp5, combined with plasmid-borne hypervirulence and resistance determinants, reveals the concerning convergence of hypervirulence and XDR. Enhanced surveillance and infection control measures are urgently needed to monitor this emerging high-risk clone.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0038426"},"PeriodicalIF":4.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676875","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":"Plasma concentrations of nirmatrelvir and molnupiravir required for inhibition of SARS-CoV-2 replication differ between rhesus macaques and humans.","authors":"Ugo Avila-Ponce de Leon, Shadisadat Esmaeili, Katherine Owens, Joshua T Schiffer","doi":"10.1128/aac.00307-26","DOIUrl":"10.1128/aac.00307-26","url":null,"abstract":"<p><p>Early during the COVID-19 pandemic, non-human primate (NHP) infection models emerged as highly useful tools for preclinical screening of antiviral drugs. However, it is uncertain whether NHP models can be used to precisely inform optimal dosing in humans. We previously established and validated mathematical models, which were fit to SARS-CoV-2 viral loads from human clinical trials. These models identified that plasma drug concentrations required to inhibit viral replication by 50% in humans (<i>in vivo</i> EC50) differ substantially from <i>in vitro</i> EC50 estimates in cell culture systems. Here, we apply models to sequential viral load data from SARS-CoV-2 infected rhesus macaques (RMs) that were untreated or treated with nirmatrelvir/ritonavir, molnupiravir, or both drugs. We identify that equivalent plasma drug concentrations correspond to greater antiviral potency in the lungs compared with nasal passages for nirmatrelvir and molnupiravir. Average nirmatrelvir antiviral efficacy in RM (30% in nasal passages and 46% in the lungs) was estimated to be less than in humans (82%) due to shorter plasma drug half-life. Molnupiravir efficacy in RMs (95% in nasal and 99% in the lungs) is estimated to be similar to efficacy in humans against omicron variants. Our model estimates that 10-fold higher plasma nirmatelvir concentrations are needed in humans versus RMs to achieve 50% reduction in viral replication, whereas 20-fold lower plasma molnupiravir concentrations are needed. Our results suggest that dose optimization in humans based on modeling of NHP viral loads is limited by drug-specific differences in pharmacokinetic, pharmacodynamic, and virologic profiles, and that data from human phase 1 and 2 trials are better suited for this task.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0030726"},"PeriodicalIF":4.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676912","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}