Antimicrobial Agents and Chemotherapy最新文献

{"title":"Sterilizing activity of spectinamide MBX-4888A when replacing linezolid in the Nix-TB regimen in the relapsing BALB/c mouse model of tuberculosis.","authors":"Nathan Peroutka-Bigus, Michael S Scherman, Firat Kaya, Samanthi L Waidyarachchi, Jiuyu Liu, Joel N Rushefsky, Michelle M Butler, Terry Bowlin, Bernd Meibohm, Mercedes Gonzalez-Juarrero, Anne J Lenaerts, Matthew Zimmerman, Richard E Lee, Gregory T Robertson","doi":"10.1128/aac.01183-25","DOIUrl":"https://doi.org/10.1128/aac.01183-25","url":null,"abstract":"<p><p>Spectinamides have garnered interest as experimental tuberculosis therapeutics owing to their safety profile and efficacy as partner agents when used in conjunction with established regimens in mice. The Nix-TB regimen of bedaquiline, pretomanid, and linezolid represents a short, effective regimen recommended for treatment of pre-extensively drug-resistant tuberculosis. However, linezolid administration is associated with severe adverse events that limit its use. Here we present preclinical data comparing Nix-TB regimens anchored by either linezolid or spectinamide MBX-4888A.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0118325"},"PeriodicalIF":4.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190614","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":"Comparative effectiveness of echinocandins and liposomal amphotericin B for fluconazole-resistant <i>Candida parapsilosis</i> bloodstream infections.","authors":"Antonio Vena, Claudia Bartalucci, Marco Muccio, Giusy Tiseo, Patricia Muñoz, Mario Cesaretti, Vincenzo Di Pilato, Anna Marchese, Ramona Barbieri, Arianna Forniti, Daniele Roberto Giacobbe, Alessandro Limongelli, Antonella Lupetti, Malgorzata Mikulska, Jon Salmanton-García, Ana Soriano Martín, Lucia Taramasso, Maricela Valerio, Pilar Escribano, Jesus Guinea, Emilio Bouza, Marco Falcone, Matteo Bassetti","doi":"10.1128/aac.00355-25","DOIUrl":"https://doi.org/10.1128/aac.00355-25","url":null,"abstract":"<p><p>Current therapeutic options for fluconazole-resistant <i>Candida parapsilosis</i> (FLZR-CP) bloodstream infections (BSI) are limited to echinocandins and liposomal amphotericin B (L-AmB). To the best of our knowledge, no real-world comparative effectiveness studies have assessed these agents. This study aimed to compare the effectiveness of echinocandins and L-AmB for the treatment of FLZR-CP BSI. This retrospective, observational study was conducted in two hospitals in Italy between January 2018 and December 2022. Eligible patients were adults (≥18 years old) with microbiologically confirmed FLZR-CP BSI who received targeted therapy with either echinocandins or L-AmB. Patients were matched (2:1) based on age, Charlson comorbidity index, presence of sepsis or septic shock, time to appropriate antifungal therapy (≤48 hours or > 48 hours from diagnosis), and infection source. A total of 63 patients were included (42 in the echinocandin group and 21 in the L-AmB group). In Cox regression, targeted therapy with echinocandins was not associated with increased mortality (adjusted hazard ratio 1.40; 95% confidence interval [CI] 0.33-5.92, <i>P</i> = 0.645). An exploratory sensitivity analysis including patients who did not receive source control yielded consistent results (<i>P</i> = 0.491). Furthermore, in the multivariable regression analysis, echinocandin therapy was not associated with an increased risk of persistent fungemia (adjusted odds ratio 1.61: 95% CI 0.43-5.99, <i>P</i> = 0.476). Treatment with echinocandins and L-AmB resulted in similar 30-day mortality and persistent fungemia rates in patients with FLZR-CP BSI. These findings confirm that echinocandins are a viable treatment option for <i>C. parapsilosis</i> BSI, even for patients with fluconazole-resistant strains.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0035525"},"PeriodicalIF":4.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190667","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 first-in-human phase I study to evaluate the safety, tolerability, and pharmacokinetics of a novel anti-influenza agent suraxavir marboxil in healthy Chinese subjects.","authors":"Qingqing Wu, Lang Lv, Shousheng Yan, Yijun Wang, Qian Chen, Wenjing Xu, Yun Liu, Wei Wang, Jingying Jia, Chen Yu, Jingjing Chen, Yanmei Liu","doi":"10.1128/aac.00685-25","DOIUrl":"https://doi.org/10.1128/aac.00685-25","url":null,"abstract":"<p><p>Suraxavir marboxil (GP681) is a prodrug of a novel polymerase acidic protein inhibitor, and its metabolite GP1707D07 prevents the replication of influenza virus by selectively inhibiting the cap-dependent nucleic acid endonuclease of influenza virus. This study evaluates the safety, tolerability, and pharmacokinetics of suraxavir marboxil after a single dose and assesses the effect of a high-fat, high-calorie meal on the pharmacokinetics of suraxavir marboxil in healthy Chinese subjects. The study included two parts: single ascending-dose study (SAD) and food effect study (FE). In SAD, subjects were randomized to single-dose suraxavir marboxil (20, 40, 60, or 80 mg) or placebo. In FE, subjects (<i>n</i> = 16) were randomized to single-dose suraxavir marboxil 40 mg in fasting and fed states. Safety assessment and sample collection were in accordance with the protocol. Suraxavir marboxil was well tolerated in healthy Chinese subjects in both SAD and FE, and all adverse events recovered without treatment after discontinuation of suraxavir marboxil. In SAD, after administration of suraxavir marboxil in the dosage range of 20-80 mg, the time to maintain the clinically defined effective target blood concentration is about 72-136 h. In FE, a high-fat, high-calorie meal reduced <i>C</i>_max by approximately 19% and AUC_0-∞ by approximately 15%. Suraxavir marboxil was well tolerated in healthy Chinese subjects. Based on the safety and pharmacokinetic data, 20-80 mg single oral dosing was supported for further clinical development. Food intake may slightly reduce the rate and extent of absorption of suraxavir marboxil.The study was registered on https://classic.clinicaltrials.gov/ (registration no.: NCT04729764).</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0068525"},"PeriodicalIF":4.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190641","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":"Role of novel mutations in food vacuole transporters beyond K13-mediated artemisinin resistance in <i>Plasmodium falciparum</i>.","authors":"Iqbal Taliy Junaid, Ashutosh Panda, Arunaditya Deshmukh, Rahila Sardar, Monika Narwal, Prakhar Agrawal, Neha Prakash, Asif Akhtar, Amit Kumar Dey, Suneet Shekhar Singh, Saptarshi Mridha, Jigneshkumar Mochi, Sadaf Parveen, Mohit Kumar, Rashi Nagar, Naseem Gaur, Dinesh Gupta, Asif Mohmmed, Inderjeet Kaur, Krishanpal Karmodiya, Pawan Malhotra","doi":"10.1128/aac.00293-25","DOIUrl":"https://doi.org/10.1128/aac.00293-25","url":null,"abstract":"<p><p>Malaria remains one of the leading causes of morbidity and mortality worldwide, mainly because of the emergence of drug resistance against current antimalarials. The <i>Plasmodium falciparum</i> food vacuole (FV) proteins, <i>P. falciparum</i> chloroquine (CQ) resistance transporter (PfCRT), PfMDR1 and the cytosolic protein PfKelch13 have been linked to CQ and artemisinin resistance, respectively. Here, we aimed to identify the associations of these resistance markers with mutations in other FV transporters in several field isolates. In this study, we isolated intact <i>P. falciparum</i> FVs and carried out detailed proteome analysis to identify new FV transporters. Furthermore, we carried out co-existing mutational analysis for these transport proteins identified in the FV-enriched fraction with known PfKelch13 and PfCRT polymorphisms via single-nucleotide polymorphism (SNP) data from the Pf3K and MalariaGEN databases. Proteome analysis identified 16 transporter proteins in <i>Plasmodium</i> FVs. Comparative amino acid analysis of these transporter proteins revealed a coassociation of mutations in several transport proteins identified in the FV-enriched fraction with mutations in the PfKelch13, PfCRT, and PfMDR1 proteins. SNP data analysis of the Pf3K and MalariaGEN databases for 2,517 samples revealed the coassociation of six mutations in four transporter genes, PfCRT, PfNT1, PfCTR2, and PfMDR2, with the PfKelch13 polymorphisms (<i>P</i> < 0.0001), suggesting the contribution of additional parasite transporters to the evolution of CQ and artemisinin resistance. Furthermore, functional complementation with the wild-type PfNT1 and PfMFR5 proteins and their mutant forms (PfNT1-F394L, PfMFR5-S278T, and PfMFR5-Y570F) in <i>Saccharomyces cerevisiae</i> resulted in resistance to mutant phenotypes in the presence of dihydroartemisinin, suggesting a possible role of these mutations in the acquisition of drug resistance. Together, the genome sequence data from field isolates and yeast complementation analysis of the mutant phenotypes identified novel loci related to PfKelch13-mediated antimalarial resistance and revealed unexplored contributions of transporters to artemisinin resistance.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0029325"},"PeriodicalIF":4.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190580","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":"Synergistic effects of Cyp51 isozyme-specific azole antifungal agents on fungi with multiple <i>cyp51</i> isozyme genes.","authors":"Masaki Ishii, Kazuki Ishikawa, Kazuhiro Mikami, Koji Ichinose, Atsushi Miyashita, Takashi Yaguchi, Tsuyoshi Yamada, Shinya Ohata","doi":"10.1128/aac.00598-25","DOIUrl":"https://doi.org/10.1128/aac.00598-25","url":null,"abstract":"<p><p>Pathogenic fungi pose significant societal challenges due to limited therapeutic targets resulting from the eukaryotic nature of fungi. This limitation emphasizes the importance of enhancing susceptibility to inhibitors of Cyp51, a crucial enzyme in ergosterol biosynthesis targeted by azole antifungals. In Cyp51 isozyme deletion strains (Δ<i>cyp51A</i> and Δ<i>cyp51B</i>) of <i>Trichophyton rubrum</i>, the predominant dermatophyte species, we found that Cyp51B is essential for basal mycelial growth, while Cyp51A functions as an inducible isozyme associated with azole tolerance. Based on these differential functions, we hypothesized that each isozyme would show distinct susceptibility to azole antifungals. Our study demonstrated that most azoles exhibited increased antifungal activity against Δ<i>cyp51A</i>, while select agents demonstrated increased antifungal activity against Δ<i>cyp51B</i>. Remarkably, fluconazole, sulconazole, and imazalil exhibited relatively increased activity against Δ<i>cyp51A</i>, whereas prochloraz demonstrated increased activity against Δ<i>cyp51B</i>. Combining these isozyme-selective agents exerted synergistic effects against the wild-type strain and the parent <i>ku80</i>-knockout strain but not against individual Cyp51 knockout mutants. Our data revealed that the two Cyp51 isozymes can be selectively inhibited by different azole antifungals, resulting in a synergistic effect when combined. This synergistic effect was also observed on another fungal species, <i>Aspergillus welwitschiae</i>, which also has two Cyp51 isozymes. These data demonstrate that combining azole antifungals with different Cyp51 isozyme selectivities exerts synergistic effects against fungi possessing multiple Cyp51 isozymes. These findings advance antifungal therapeutic strategies by demonstrating that the combination of antifungals with different Cyp51 isozyme selectivities offers a promising approach for treating fungal infections, opening new avenues for isozyme-specific drug development.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0059825"},"PeriodicalIF":4.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147436","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 ritonavir as a booster of lopinavir, atazanavir, or darunavir in African children with HIV.","authors":"Lufina Tsirizani, Hylke Waalewijn, Alexander Szubert, Veronica Mulenga, Chishala Chabala, Mutsa Bwakura-Dangarembizi, Moses Chitsamatanga, Diana A Rutebarika, Victor Musiime, Mariam Kasozi, Abbas Lugemwa, Helen M McIlleron, David M Burger, Diana M Gibb, Angela Colbers, Paolo Denti, Roeland E Wasmann","doi":"10.1128/aac.00771-25","DOIUrl":"https://doi.org/10.1128/aac.00771-25","url":null,"abstract":"<p><p>Ritonavir is important in antiretroviral therapy (ART) because it is used to boost the drug exposure of its fellow protease inhibitors (PIs). While PIs are commonly used in children, ritonavir data in this population are quite scarce. We investigated the population pharmacokinetics of ritonavir given to boost exposures of lopinavir, atazanavir, or darunavir, and co-administered with nucleoside reverse transcriptase inhibitors (NRTIs) in African children, and investigated factors affecting its exposure. We conducted a pharmacokinetic sub-study within the CHAPAS-4 (ISRCTN22964075) trial, which randomized children to two NRTIs with twice-daily lopinavir/ritonavir, once-daily atazanavir/ritonavir, or once-daily darunavir/ritonavir, as second-line ART. Intensive pharmacokinetic blood samples were collected at week 6, and nonlinear mixed-effects modeling was used to identify factors affecting ritonavir pharmacokinetics. In all, 170 children were enrolled in the ritonavir-boosted PI arms of the CHAPAS-4 pharmacokinetic sub-study, with median age 10.6 (range 3.2-15.6) years and weight 26.0 (14.2-64.2) kg. Despite similar dose levels, ritonavir exposure varied widely depending on the companion PI. Compared to children on darunavir/ritonavir, those on atazanavir/ritonavir had 137% (95% CI 107%-190%) higher bioavailability and 20% (95% CI 11.3%-31.3%) faster clearance, while those on lopinavir/ritonavir had 23.4% (95% CI 8.20%-34.4%) lower bioavailability. No effect of NRTIs on ritonavir pharmacokinetics was observed. Ritonavir exposure is higher with atazanavir than with lopinavir or darunavir. These data provide greater insight into the use of ritonavir for boosting PIs in children and help reduce the knowledge gap regarding its exposure in children.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0077125"},"PeriodicalIF":4.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172609","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":"Validated antimalarial drug target discovery using genome-scale metabolic modeling.","authors":"Supannee Taweechai, Francis Isidore Garcia Totañes, David Westhead, Clara Herrera-Arozamena, Richard Foster, Glenn A McConkey","doi":"10.1128/aac.00459-25","DOIUrl":"https://doi.org/10.1128/aac.00459-25","url":null,"abstract":"<p><p>Given the rapid resistance of <i>Plasmodium falciparum</i> to antimalarial drugs, there is a continual need for new treatments. A genome-scale metabolic (GSM) model was developed with integrated metabolomics and constraint-based, experimental flux-balance data to predict genes essential for <i>P. falciparum</i> growth as drug targets. We selected the highly ranked <i>P. falciparum</i> UMP-CMP kinase (UCK) to test its necessity and the ability to inhibit parasite growth in the presence of inhibitors. Conditional deletion mutants using the DiCre recombinase system, generated by CRISPR-Cas genome editing, exhibited defective asexual growth and stage-specific developmental arrest. Based on <i>in silico</i> and <i>in vitro</i> screening, inhibitors were identified that are selective for <i>P. falciparum</i> UCK and exhibit antiparasitic activity. This study, for the first time, shows assertions from a GSM model identifying novel, validated \"druggable\" targets. These findings show a role for GSM models in antimalarial drug discovery and identify <i>P. falciparum</i> UCK as a novel, valid malaria drug target.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0045925"},"PeriodicalIF":4.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147481","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 zinc-chelating cyclic alkyl polyamine compound is efficient and safe in a murine model of multidrug-resistant <i>Candida auris</i> infection.","authors":"Takayuki Shinohara, Akira Wada, Masahiro Abe, Sayoko Oiki, Ami Koizumi, Amato Otani, Harutaka Katano, Yoshitsugu Miyazaki","doi":"10.1128/aac.00856-25","DOIUrl":"https://doi.org/10.1128/aac.00856-25","url":null,"abstract":"<p><p><i>Candida auris</i> is an emerging multidrug-resistant fungal pathogen associated with severe nosocomial outbreaks and high mortality rates worldwide. The increasing incidence of antifungal resistance underscores the urgent need for agents with novel mechanisms of action. APC6 is a zinc-chelating cyclic alkyl polyamine compound that selectively disrupts zinc homeostasis in fungal cells. We have previously reported that APC6 has antifungal activity against <i>Candida</i> spp., including <i>Candida auris</i>, and low cytotoxicity to human cells. In this study, we evaluated the <i>in vivo</i> efficacy and safety of APC6 using a neutropenic murine model of disseminated <i>C. auris</i> infection. APC6 significantly improved survival and reduced fungal burden in the liver, kidneys, and brain. At a therapeutic dose of 15 mg/kg, APC6 had similar or superior antifungal activity to that of amphotericin B. Histopathological analysis revealed a decreased number of fungal microabscesses in APC6-treated tissues. No significant adverse effects were observed following 28-day repeated intraperitoneal administration, and the Ames assay revealed no mutagenic activity. To our knowledge, this is the first study to demonstrate that a zinc-chelating compound can improve survival and reduce organ fungal burden in a mammalian model of drug-resistant <i>C. auris</i> infection. These results highlight APC6 as a promising lead compound targeting fungal zinc homeostasis and support its further development as a novel antifungal agent.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0085625"},"PeriodicalIF":4.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147766","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 nitrogen-containing diphyllin derivative C156-P1 exhibited broad-spectrum antiviral activity against <i>Flaviviridae</i> viruses by preventing endosomal acidification.","authors":"Guoquan Chen, Wanfei Li, Ka Hei Lam, Mingyue Hu, Qian Wu, Xiangyu Xu, Yunzhu Huang, Fei Tang, Guohui Cui, Ping Cui, Jianping Zuo, Linna Liu, Jun Qian, Hong-Jie Zhang, Yi-Ping Li","doi":"10.1128/aac.00527-25","DOIUrl":"https://doi.org/10.1128/aac.00527-25","url":null,"abstract":"<p><p>Dengue virus (DENV) represents a significant public health threat, with its four serotypes estimated to account for approximately 96 million symptomatic infections annually. Currently, there are no antiviral agents available for the prevention or treatment of DENV infection. Here, we initially screened 12 diphyllin derivatives and identified C156-P1, a nitrogen-containing compound, as a potent agent against DENV infection. Further, C156-P1 exhibited inhibitory effects against the viruses of the <i>Flaviviridae</i> family, including four serotypes of DENV (DENV-1 to DENV-4) in multiple human and monkey cell lines, as well as Zika virus, Japanese encephalitis virus, yellow fever virus, and hepatitis C virus. In addition, C156-P1 also showed inhibition of the infections of herpes simplex virus type 1 and vesicular stomatitis virus, but not adenovirus and Sendai virus. Mechanistic studies demonstrated that C156-P1 inhibited DENV-2 after cell entry but before the endosomal membrane fusion step. C156-P1 inhibited vacuolar-type ATPase activity by perturbing the expression of ATP6V0A2 subunit, thereby suppressing endosomal acidification. Consequently, DENV was restricted in the late endosome, inhibiting virus fusion with endosomal membranes and resulting in infection inhibition. C156-P1 treatment also suppressed both IFN-I responses and endosomal TLR3 activation induced by DENV-2 infection. Furthermore, administration of C156-P1 in AG129 mice significantly reduced DENV-2 infection and effectively increased the survival rate of the mice. Taken together, our study demonstrates that the novel nitrogen-containing diphyllin derivative C156-P1 functions as a broad-spectrum antiviral agent by inhibiting endosomal acidification, thus representing a promising host-targeting antiviral candidate for future development.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0052725"},"PeriodicalIF":4.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147770","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":"Immunocompromised patients with persistent SARS-CoV-2 viral shedding ≥8 weeks, clinical outcomes, and virological dynamics: a retrospective multicenter cohort study, 2020-2024.","authors":"Clémentine de La Porte des Vaux, Nicolas Veyrenche, Kevin Da Silva, Nathalie Chavarot, Marianne Burgard, Olivier Paccoud, Florence Runyo, Margaux Garzaro, Claire Rouzaud, Alexandra Serris, Damien Vimpere, Dany Anglicheau, Luc Mouthon, Olivier Hermine, Marie-Anne Rameix-Welti, Fanny Lanternier, Olivier Lortholary, Cléa Melenotte","doi":"10.1128/aac.00658-25","DOIUrl":"https://doi.org/10.1128/aac.00658-25","url":null,"abstract":"<p><p>Immunocompromised patients (ICPs) infected with SARS-CoV-2 are at higher risk of severe illness. Some experience persistent viral shedding beyond eight weeks, which is associated with increased mortality and invasive fungal infections. However, data on the clinical profile, treatment impact, and standardized management for these patients remain limited. We conducted a retrospective cohort study at Groupe Hospitalier Paris Centre between March 1, 2020, and February 10, 2024. We assessed symptomatic ICPs with persistent SARS-CoV-2 shedding (>8 weeks), analyzing clinical progression, time to viral clearance, and emergence of resistance mutations in relation to treatment regimens. Fifty-three patients were included: 53% were solid organ transplant (SOT) recipients, 42% had hematological malignancies (HMs), and 5% had other immunosuppressive conditions. Severe infections occurred in 32%, 91% required hospitalization, and 17% (<i>n</i> = 9) presented invasive mold infections. SOT recipients achieved clinical cure faster than HM patients (<i>P</i> < 0.01). Patients treated with direct antivirals showed significantly faster viral clearance (<i>P</i> = 0.03) than those treated with monoclonal antibodies (mAbs) or convalescent plasma. No resistance mutations emerged against remdesivir or nirmatrelvir/ritonavir. However, 54% of viral strains showed initial or acquired spike protein resistance to mAbs. Direct antiviral therapies, particularly remdesivir and nirmatrelvir/ritonavir, appear safe and effective in promoting faster viral clearance and clinical recovery in ICPs with persistent symptomatic SARS-CoV-2 infection.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0065825"},"PeriodicalIF":4.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147815","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}