Antimicrobial Agents and Chemotherapy最新文献

{"title":"Pharmacokinetics and hematologic toxicity of linezolid in children: a prospective, two-center cohort study.","authors":"Lvchang Zhu, Xinxin Zeng, Yuhang Wu, Xuben Yu, Shanshan Xu, Qiuxia Wang, Xiaoshan Zhang, Xi Zhang, Qiang Shu, Zihao Yang, Lisu Huang","doi":"10.1128/aac.00294-25","DOIUrl":"10.1128/aac.00294-25","url":null,"abstract":"<p><p>Despite the widespread pediatric use of linezolid, data on its hematologic toxicity-particularly among children exposed to anticancer chemotherapy-remain limited and inconsistent. This study aimed to evaluate linezolid-induced hematotoxicity through pharmacokinetic analysis, with an emphasis on chemotherapy-exposed pediatric patients. This dual-center prospective study assessed linezolid pharmacokinetics and clinical profiles in chemotherapy-stratified pediatric cohorts, examining associations with hematologic toxicity. Among 229 pediatric patients (65 with cancer), hematologic toxicity occurred in 43.2%, with significantly higher risks of leukopenia (hazard ratio [HR] 20.29, 95% confidence interval [CI]: 3.98-103.38), neutropenia (HR 2.60, 95% CI: 1.00-6.77), and thrombocytopenia events (HR 7.08, 95% CI: 2.19-22.92) in cancer patients. Median linezolid trough and peak concentrations were 2.60 mg/L (interquartile range [IQR] 1.42-4.06) and 12.00 mg/L (IQR 9.5-14.19), respectively. Among cancer patients, trough concentrations above 7 mg/L elevated leukopenia (HR 6.33, 95% CI: 1.36-29.42) and anemia event (HR 8.72, 95% CI: 1.98-38.37) risk. Prolonged therapy exceeding 14 days elevated the risk of anemia events (HR 2.17; 95% CI: 1.08-4.35), while durations beyond 28 days also increased the risk of neutropenia events (HR 3.58; 95% CI, 1.37-9.32). At equivalent daily doses, twice-daily dosing resulted in higher peak concentrations (19.65 vs 13.67 mg/L; <i>P</i> = 0.020) and a greater incidence of anemia events (62.50% vs 25.00%; <i>P</i> = 0.033) compared to thrice-daily regimens. Linezolid frequently causes hematologic toxicity in children, particularly in chemotherapy recipients. Risk is also driven by high concentrations (peak > 15 mg/L, trough > 7 mg/L in cancer patients), prolonged therapy, and twice-daily dosing, necessitating careful monitoring and dose optimization.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0029425"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688768","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":"Broad spectrum of β-lactamase coverage and potent antimicrobial activity of xeruborbactam in combination with meropenem against carbapenemase-producing Enterobacterales, including strains resistant to new β-lactam/β-lactamase inhibitor combinations.","authors":"Lucía Sánchez-Peña, Salud Rodríguez-Pallares, Pablo Aja-Macaya, Tania Blanco-Martín, Lucía González-Pinto, Gloria Pérez-Rodríguez, Christophe Le Terrier, Inés Portillo-Calderón, Esther Recacha, Cristina Riazzo, Juan Carlos Vázquez-Ucha, Alejandro Beceiro, Belén Aracil, Jesús Oteo-Iglesias, Luis Martínez-Martínez, Laurent Poirel, Germán Bou, Jorge Arca-Suárez","doi":"10.1128/aac.00533-25","DOIUrl":"10.1128/aac.00533-25","url":null,"abstract":"<p><p>Xeruborbactam is a broad-spectrum boronate-type β-lactamase inhibitor. We aimed to evaluate its activity in combination with meropenem and compare it with other β-lactam/β-lactamase inhibitor combinations against Enterobacterales. The following isolates were screened: (i) an isogenic collection of 94 <i>Escherichia coli</i> isolates producing β-lactamases under wild-type and low-permeability conditions, (ii) 300 genetically diverse clinical Enterobacterales isolates producing the three main carbapenemase types (KPC-like, OXA-48-like, and metallo-β-lactamases), and (iii) two collections of isolates producing mechanisms of resistance to β-lactam/β-lactamase inhibitor combinations, such as KPC variants or PBP3 insertions combined with metallo-β-lactamases (MBLs). The MICs of meropenem, meropenem/xeruborbactam, meropenem/vaborbactam, imipenem, imipenem/relebactam, cefepime, cefepime/taniborbactam, ceftazidime, ceftazidime/avibactam, aztreonam, and aztreonam/avibactam were determined by reference broth microdilution and interpreted following the European Committee on Antimicrobial Susceptibility Testing guidelines, using the breakpoint of the β-lactam alone for not yet approved combinations. Resistance mechanisms of all clinical isolates were analyzed by whole genome sequencing. Meropenem/xeruborbactam had the broadest spectrum against the isogenic collection, although higher MICs were noted for transformants producing IMP-23, SPM-1, and NDM enzymes (these latter only when produced under low-permeability conditions). Meropenem/xeruborbactam displayed the most potent activity against the collection of 300 clinical strains (MIC_50/90 ≤0.06/≤0.06 mg/L). Xeruborbactam restored meropenem activity against the strains carrying resistance mechanisms to β-lactam/β-lactamase inhibitor combinations, including strains producing KPC variants or MBLs in combination with additional chromosomal alterations (MIC range: ≤0.06-0.25 and ≤0.06-4 mg/L, respectively). Our findings highlight the potential of xeruborbactam in combination with meropenem as a promising treatment against carbapenemase-producing Enterobacterales, including strains with emerging resistance to other β-lactam/β-lactamase inhibitor combinations.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0053325"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706076","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":"<i>In vitro</i> and <i>in vivo</i> activity of quisinostat against <i>Toxoplasma gondii</i>.","authors":"Hui-Jie Qiu, Wen-Bin Zheng, Ting Zeng, Shu-Feng Yang, Dai-Ang Liu, Li-Yan Wang, Zhi-Rong Liu, Xing-Quan Zhu, Chun-Xue Zhou","doi":"10.1128/aac.01819-24","DOIUrl":"10.1128/aac.01819-24","url":null,"abstract":"<p><p><i>Toxoplasma gondii,</i> an opportunistic pathogen, poses severe threats to immunocompromised individuals and fetuses of newly infected pregnant women. The current gold-standard treatment, a combination of pyrimethamine and sulfadiazine, is limited by severe adverse events, necessitating the development of novel therapeutic agents. <i>In vitro</i>, a CCK8 assay demonstrated that quisinostat inhibited HeLa cell proliferation in a dose-dependent manner, with a CC₅₀ of 8.22 nM. Regarding <i>T. gondii</i> tachyzoites, quisinostat exhibited time-dependent inhibition of extracellular parasite activity and suppressed intracellular parasite proliferation, with an EC₅₀ of 25.84 pM, and a high selectivity index (SI = 318.11). Quisinostat disrupted the <i>T. gondii</i> lytic cycle by decreasing invasion rates, inducing G1 cell cycle arrest, reducing replication, and shrinking plaque size. Ultrastructural analysis indicated that quisinostat treatment led to membrane damage, enhanced lactate dehydrogenase (LDH) release, and apoptotic cell death in tachyzoites, whereas no significant change in reactive oxygen species (ROS) levels was detected. Proteome analysis identified 77 upregulated and 205 downregulated proteins, which were enriched in functions associated with protein dephosphorylation and ion transport, as well as pathways, such as non-homologous end-joining. Molecular docking studies revealed a strong interaction between quisinostat and <i>T. gondii</i> HDAC3. <i>In vivo</i>, treatment with quisinostat increased the survival time of mice infected with virulent RH strain. In mice infected with low-virulent ME49 tachyzoites, quisinostat treatment decreased parasite burden in multiple organs and increased the survival to 80%. Taken together, these findings demonstrate that quisinostat has potent anti-<i>Toxoplasma</i> activity both <i>in vitro</i> and <i>in vivo</i>, which offers promise for treatment of human toxoplasmosis.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0181924"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752132","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":"Pharmacokinetics, safety, and tolerability of onradivir in participants with severe renal impairment and matched healthy control participants.","authors":"Haijun Li, Xiali Yang, Jun Zhang, Lin Chen, Mingfei Zhou, Youyun Li, Xiangxing Liu, Jiyi Huang, Jufang Huang","doi":"10.1128/aac.00462-25","DOIUrl":"10.1128/aac.00462-25","url":null,"abstract":"<p><p>Onradivir is an influenza A virus RNA polymerase basic protein 2 inhibitor that is currently under development for the treatment of influenza A. Renal impairment can influence drug absorption, metabolism, and transport, potentially altering the pharmacokinetics (PK) of onradivir. This study aimed to provide guidance on clinical dosing for patients with renal impairment by evaluating the impact of renal impairment on the PK, safety, and tolerability of onradivir in a nonrandomized, parallel, single-dose study. Participants with severe renal impairment (estimated glomerular filtration rate 15-29 mL/min) along with healthy participants (<i>n</i> = eight per group) received a single oral dose of 600 mg onradivir. All participants exhibited good safety and tolerability after oral administration of onradivir, with treatment-emergent adverse events being limited to mild or moderate severity. Compared to participants with normal renal function, the maximum plasma concentration (<i>C</i>_max) of onradivir in those with severe renal impairment was similar; however, the area under the plasma concentration time curve from zero to the last quantifiable concentration (AUC_0<i>-t</i>) and the AUC from zero to infinity (AUC_0-inf) were slightly lower. The geometric mean ratios and 90% confidence intervals for <i>C</i>_max, AUC_0-<i>t</i>, and AUC_0-inf were 101.35% (63.85%-160.86%), 76.31% (52.47%-110.97%), and 76.56% (51.02%-114.90%), respectively. Severe renal impairment did not have a clinically meaningful effect on the PK, tolerability, or safety of onradivir. Therefore, no dose adjustment is necessary for patients with mild-to-severe renal impairment who are taking onradivir.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT06248567.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0046225"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774547","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":"Low isavuconazole trough levels in critically ill patients with and without extracorporeal membrane oxygenation.","authors":"Rolf Erlebach, Alix Buhlmann, Rea Andermatt, Mattia M Müller, Reto Schuepbach, Silvio D Brugger, Sascha David, Daniel A Hofmaenner","doi":"10.1128/aac.00577-25","DOIUrl":"10.1128/aac.00577-25","url":null,"abstract":"<p><p>Data on isavuconazole exposure in critically ill patients and particularly during extracorporeal membrane oxygenation (ECMO) are scarce, and therapeutic drug monitoring is not routinely performed. Critically ill patients admitted to a tertiary ECMO referral center from October 2017 to August 2024 with documented isavuconazole trough levels were retrospectively analyzed. First, measured isavuconazole trough blood levels and the occurrence of dose adjustments were analyzed in patients with and without ECMO support. Fifty-three adult patients were included, of whom 11 (21%) patients were on ECMO support at the first isavuconazole trough level measurement. Median isavuconazole trough level was overall 1.4 (interquartile range [IQR] 0.9-2.5) mg/L and did not differ between ECMO (1.3 [IQR 0.9-1.5] mg/L) and non-ECMO patients (1.6 [IQR 0.9-2.8] mg/L, <i>P</i> = 0.423). During the entire intensive care unit stay, individual doses were increased in 12 (23%) patients, of whom 5 were on ECMO support, whereas dosage was reduced or interrupted in 2 (4%) patients (both without ECMO support). Dose adjustments occurred irregularly and inconsistently after therapeutic drug monitoring, i.e., only in 6 (11%) patients after the initial therapeutic drug monitoring despite 37 (70%) drug levels being outside the target range of 2-4 mg/L. In conclusion, below targeted isavuconazole trough levels were common in critically ill patients investigated, but ECMO did not seem to have an additional negative influence. Dose adjustments appeared more frequently than previously reported, albeit irregularly performed. Regular therapeutic drug monitoring and protocolized dose adjustments should be investigated in future studies.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0057725"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688764","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":"Osh2 mediates <i>Candida</i> species resistance to miltefosine by regulating zymosterol accumulation.","authors":"Yongqin Wu, Yuanyuan Dai, Huaiwei Lu, Xiaohua Jiang, Yuanyuan Wang","doi":"10.1128/aac.00427-25","DOIUrl":"10.1128/aac.00427-25","url":null,"abstract":"<p><p>Invasive candidiasis poses a growing threat to global public health, compounded by the scarcity of effective antifungal treatments. Miltefosine exhibits broad-spectrum antifungal activity, yet its mechanisms of antifungal action and the development of resistance remain poorly understood. Here, we first generated miltefosine-resistant strains of <i>Candida glabrata</i> through stepwise exposure to increasing drug concentrations. Whole-genome sequencing revealed that nonsense mutations in the <i>OSH2</i> gene (193C > T and 3177C > A) were key drivers of resistance. Functional validation in <i>Candida albicans</i> confirmed that these <i>OSH2</i> mutations conferred miltefosine resistance, demonstrating the conserved role of Osh2 across species. Multi-omics profiling of the <i>osh2Δ/Δ</i> mutant revealed significant upregulation of ergosterol biosynthesis genes, including <i>ERG6</i> and <i>ERG11</i>, and the accumulation of zymosterol, an intermediate in the ergosterol pathway. Chemogenetic dissection further elucidated the role of sterol metabolism in resistance: <i>erg11Δ/Δ</i> mutants, which are unable to synthesize zymosterol, exhibited hypersusceptibility to miltefosine, whereas <i>erg6Δ/Δ</i> strains, which accumulate zymosterol, showed innate resistance. Exogenous supplementation of zymosterol dose dependently increased the minimum inhibitory concentration of miltefosine in <i>C. albicans</i> and <i>C. glabrata</i>, confirming that zymosterol accumulation is a key determinant of resistance. Our findings establish Osh2 as a critical regulator of membrane sterol flux and demonstrate that fungal lipid metabolic plasticity enables evasion of membrane-targeting antifungals. Therapeutic targeting of zymosterol biosynthesis enzymes may overcome such adaptive resistance mechanisms in invasive candidiasis, providing a new strategy to combat drug-resistant fungal infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0042725"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688766","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":"Emergence of carbapenem-resistant <i>Acinetobacter baumannii</i> clonal complex 2 in multiple hospitals in São Paulo state, Brazil.","authors":"Amanda Yaeko Yamada, Andreia Rodrigues de Souza, Geraldine Madalosso, Denise Brandão de Assis, Flavia Aparecida de Moraes França, Marlon Benedito Nascimento Santos, Karoline Rodrigues Campos, Claudio Tavares Sacchi, Monique Ribeiro Tiba-Casas, Eneas Carvalho, Carlos Henrique Camargo","doi":"10.1128/aac.01865-24","DOIUrl":"10.1128/aac.01865-24","url":null,"abstract":"<p><p>Carbapenem-resistant <i>Acinetobacter baumannii</i> (CRAB) is a common pathogen prevalent in Brazilian hospitals. Worldwide, dissemination of CRAB is associated with the Clonal Complex 2 (CC2); in South America, however, CC1, 15, 25, and 79 are the most prevalent clones. In July 2020, our reference laboratory received the first CC2 isolates from a COVID-19 hospital, and, in the following months, this clone was detected in 15 other Brazilian institutions. To understand the clonal structure of this emerging pathogen, we characterize 89 isolates by whole-genome sequencing and antimicrobial susceptibility testing. Disk diffusion revealed resistance to all beta-lactams, aminoglycosides, fluoroquinolones, folate pathway antagonists, and tetracyclines, but susceptibility to polymyxin B. Resistome analysis identified diverse antimicrobial resistance genes, including the <i>bla</i>_OXA-23 associated with Tn<i>2006</i>, and <i>armA</i> in AbGRI3, conferring resistance to beta-lactams and aminoglycosides, respectively. Fine-scale phylogeny based on single nucleotide polymorphisms (SNPs) revealed that Brazilian CRAB CC2 isolates were closely related, presenting up to 755 SNPs in pairwise comparison. We did not observe hospital-specific subclones, indicating multiple introductions and/or inter-hospital dissemination. This study reports the rapid arrival and spread of CRAB CC2 isolates in multiple hospitals, likely driven by infection control deficiencies experienced during the COVID-19 pandemic.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0186524"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688761","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":"Voriconazole-induced liver injury: incidence patterns and risk factors in a retrospective cohort.","authors":"Yan Lou, Yu Wang, Jing Liu, Yu-Jing Wang, Jiaqi Wang, Shuang Ma, Zong-Ming Yang, Jing-Song Li, Yun-Qing Qiu","doi":"10.1128/aac.00487-25","DOIUrl":"10.1128/aac.00487-25","url":null,"abstract":"<p><p>Voriconazole, a first-line therapy for invasive aspergillosis, carries hepatotoxicity risks lacking comprehensive epidemiological characterization. Current evidence is limited by heterogeneity in diagnostic criteria (e.g., varying thresholds for liver function abnormalities across studies), insufficient sample sizes, and inadequate adjustment for comorbidities, which compromises risk assessment accuracy. This study aims to systematically characterize the epidemiological profile of voriconazole-induced liver injury and identify modifiable independent risk factors. We analyzed 7,659 voriconazole-treated adults (2007-2020) from the First Affiliated Hospital of Zhejiang University to determine incidence and injury subtypes. Univariable and multivariable logistic regression identified risk factors, with model performance evaluated by ROC (receiver-operating characteristic) analysis; sensitivity analyses addressed potential confounders. In our results, voriconazole-induced liver injury occurred in 11.32% of patients, predominantly manifesting as hepatocellular (5.01%, 279/630), cholestatic (5.19%, 289/630), and mixed-pattern injuries (1.11%, 62/630). Key modifiable risk factors included intravenous administration (odds ratio [OR] = 1.88, 95% confidence interval [CI]: 1.43-2.46). Non-modifiable predictors comprised baseline elevated urea (OR = 1.47, 95% CI: 1.08-2.02), elevated triglycerides (TG) (cholestatic injury: OR = 1.47, 95% CI: 1.08-2.02), elevated C-reactive protein (CRP) (cholestatic injury: OR = 1.47, 95% CI: 1.08-2.02), pre-existing liver disease (liver cirrhosis, OR = 2.16, 95% CI: 1.58-2.96), diabetes (OR = 2.19, 95% CI: 1.70-2.80), and transplant status (hematopoietic stem cell transplantation, OR = 2.93, 95% CI: 1.85-4.65). Using this clinically substantial cohort (<i>n</i>=7,659), we proposed a risk-stratification framework incorporating administration route optimization and comorbidity-specific monitoring, supporting personalized risk-benefit analysis in antifungal therapy.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0048725"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752113","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":"A chlorinated diketopiperazine antibiotic targets <i>Mycobacterium tuberculosis</i>.","authors":"Libang Liang, Jeffrey Quigley, Monique Theriault, Akira Iinishi, Rachel Bargabos, Madeleine Morrissette, Megan Ghiglieri, Tom Curtis, Rachel Corsetti, Sangkeun Son, Bishwarup Sarkar, Kim Lewis","doi":"10.1128/aac.00369-25","DOIUrl":"10.1128/aac.00369-25","url":null,"abstract":"<p><p>We describe a novel macrocyclic peptide, speirobactin, produced by <i>Photorhabdus temperata</i> that selectively kills <i>Mycobacterium tuberculosis</i>. A nonribosomal peptide synthase containing two linear modules codes for the synthesis of speirobactin. The biosynthetic operon contains a pentapeptide-repeat protein as a resistance gene. Genomic analysis of speirobactin-resistant mutants of <i>M. tuberculosis</i> led to the identification of DNA gyrase as the molecular target. The mutations were recreated and show that DNA gyrase is the only target. Transcriptome analysis of <i>M. tuberculosis</i> treated with antibiotics shows that speirobactin clusters close to fluoroquinolones, supporting its action against the DNA gyrase.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0036925"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752133","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":"Population pharmacokinetics and Monte Carlo-based dosing optimization of trimethoprim-sulfamethoxazole.","authors":"Bo Chen, Yiying Chen, Ming Chen, Yunyi Mao, Yingbin Huang, Lili Zhou, Wenwei Wu, Xueyong Li, Xuemei Wu, Yu Cheng, Hongqiang Qiu","doi":"10.1128/aac.00519-25","DOIUrl":"10.1128/aac.00519-25","url":null,"abstract":"<p><p>This study aimed to develop population pharmacokinetic (PopPK) models for intravenous sulfamethoxazole (SMX) and trimethoprim (TMP) to optimize dosing regimens for the treatment of <i>Pneumocystis jirovecii</i> pneumonia using these models. A prospective study was conducted in 79 patients treated with intravenous trimethoprim-sulfamethoxazole. PopPK models were developed using nonlinear mixed-effect modeling to evaluate the effects of liver function, kidney function, and genetic polymorphisms (<i>NAT2</i> and <i>CYP2C9</i>) on pharmacokinetic parameters. Monte Carlo simulations were employed to identify the optimal dosing regimen. Pharmacokinetic analysis of SMX and TMP included 232 post-dose plasma concentrations from 79 adult patients. A one-compartment model with first-order elimination best described the data. Creatinine clearance (CrCL) was significantly correlated with the pharmacokinetic parameters of both SMX and TMP, while continuous renal replacement therapy significantly influenced only the SMX model. Liver function, <i>NAT2</i>, and <i>CYP2C9</i> genotypes did not exhibit statistically significant effects on the models. Co-trimoxazole 50 mg/kg/day in a three-times-daily divided dose regimen is feasible for patients with CrCL of <15 mL/min. However, in patients with normal renal function, the guideline-recommended 90 mg/kg/day dose demonstrates a risk of supratherapeutic exposure. This study provides critical pharmacokinetic insights into SMX and TMP for patients, highlighting the necessity for dose adjustments in those with renal dysfunction. The currently recommended dosing regimens in clinical guidelines pose a risk of excessive drug exposure. Our study offers a more precise dosing strategy to optimize treatment efficacy and safety.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0051925"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940120","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}