Antimicrobial Agents and Chemotherapy最新文献_第10页

Population pharmacokinetics of pyrazinamide and ethambutol in children with tuberculosis with or without HIV. 吡嗪酰胺和乙胺丁醇在合并或不合并HIV的结核病儿童中的群体药代动力学。

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2026-04-01 Epub Date: 2026-03-02 DOI: 10.1128/aac.00909-25

Nicole F Maranchick, Charles Martyn-Dickens, Anthony Enimil, Hongmei Yang, Aikins Kofi Amissah, Albert Dompreh, Dennis Bosomtwe, Eugenia Sly-Moore, Theresah Opoku, Augustina Frimpong Appiah, Priscilla Asiedu, Sampson Antwi, Marc H Scheetz, Charles A Peloquin, Awewura Kwara

{"title":"Population pharmacokinetics of pyrazinamide and ethambutol in children with tuberculosis with or without HIV.","authors":"Nicole F Maranchick, Charles Martyn-Dickens, Anthony Enimil, Hongmei Yang, Aikins Kofi Amissah, Albert Dompreh, Dennis Bosomtwe, Eugenia Sly-Moore, Theresah Opoku, Augustina Frimpong Appiah, Priscilla Asiedu, Sampson Antwi, Marc H Scheetz, Charles A Peloquin, Awewura Kwara","doi":"10.1128/aac.00909-25","DOIUrl":"10.1128/aac.00909-25","url":null,"abstract":"Tuberculosis (TB) is a major cause of morbidity and mortality in children globally. This study developed models to describe population pharmacokinetics (PK) of pyrazinamide (PZA) and ethambutol (EMB) in children with TB with or without human immunodeficiency virus (HIV) coinfection. Ghanaian children with TB with or without HIV coinfection receiving first-line antituberculosis therapy for at least 4 weeks had blood samples collected at time 0 (pre-dose), 1-, 2-, 4-, 8-, and 12-h post-dose. PZA and EMB concentrations were quantified using liquid chromatography tandem mass spectrometry. Nonlinear mixed-effects models were applied to describe the population PK using Monolix2024R1. Maximum concentrations (Cmax) and 24-h area under the time concentration curve (AUC0-24) were compared to published values in adults. A total of 85 children (41 TB, 44 TB/HIV) were included. The median (range) age was 5 years (0.3-14.5), and 61.2% were male. Median (range) doses for PZA and EMB were 31.6 (21.4-49.7) and 21.4 mg/kg (14.3-34.2), respectively. PZA was best described using a one-compartment model and EMB by a two-compartment model. Allometric scaling improved both model fits. Children with TB/HIV coinfection had approximately 18.5% faster PZA clearance and 25% faster EMB clearance. Optimized dosing to achieve adult-equivalent exposures required higher-than-currently recommended doses, particularly among children in the lowest weight bands and those with HIV. The population PK of PZA and EMB was well described by the final models, but the higher-than-currently recommended doses needed to achieve adult-equivalent exposures raise concerns regarding risks for drug-associated toxicities and will require further evaluation.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0090925"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13041307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324463","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}

引用次数: 0

Single-ascending and multiple-ascending dose study of the pharmacokinetics, safety, and tolerability of BV100 (rifabutin for infusion) in healthy volunteers. BV100（输注用利福布汀）在健康志愿者体内单次递增和多次递增剂量的药代动力学、安全性和耐受性研究

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2026-04-01 Epub Date: 2026-03-02 DOI: 10.1128/aac.01582-25

Christian Kemmer, Martin Hirsch, Christian Reh, Myriam Davila, Françoise Jung, Lisa Husband, Glenn E Dale

{"title":"Single-ascending and multiple-ascending dose study of the pharmacokinetics, safety, and tolerability of BV100 (rifabutin for infusion) in healthy volunteers.","authors":"Christian Kemmer, Martin Hirsch, Christian Reh, Myriam Davila, Françoise Jung, Lisa Husband, Glenn E Dale","doi":"10.1128/aac.01582-25","DOIUrl":"10.1128/aac.01582-25","url":null,"abstract":"BV100 (rifabutin for infusion) is being developed as an intravenous formulation for treating serious or life-threatening infections due to carbapenem-resistant Acinetobacter baumannii in patients with limited treatment options. Phase 1 studies were conducted to characterize the pharmacokinetics (PK), safety, and tolerability of BV100 in healthy volunteers after single and multiple doses. Single-ascending and multiple-ascending dose studies were conducted in healthy subjects to establish the PK profile of BV100. Blood samples were assayed to determine plasma concentrations of rifabutin and the major metabolite 25-O-desacetyl-rifabutin and to determine PK parameters. Subjects were assessed for safety and tolerability. The PK profile of BV100 was generally dose-proportional in the single-ascending dose studies with a t1/2 of 7.9-56.1 h, and Tmax of 1.0-1.75 h and increasing exposure with dose. A q12h versus q24h dosing interval resulted in approximately a 1.5-fold to 2-fold greater exposure of rifabutin. The 25-O-desacetyl-rifabutin metabolite represented <5% of rifabutin activity. Adverse events were more common at higher doses with q24h versus q12h dosing, and with a 60 min infusion time. The most common adverse events were infusion site events, with systemic treatment-emergent adverse events as expected for the known safety profile of rifabutin. No other treatment-related safety issues were identified. BV100 demonstrated a dose-proportional PK profile and was generally safe and well tolerated. Based on these results, BV100 doses of 200-300 mg q12h are undergoing evaluation in a Phase 2 study for treating carbapenem-resistant A. baumannii infections.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04636983 and NCT05087069.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0158225"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13041365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324498","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}

引用次数: 0

Reply to Lai and Huang, "Which beta-lactam infusion strategy is superior in ICU pneumonia? A Bayesian network meta-analysis of continuous, extended, and intermittent approaches". 回复Lai和Huang“哪种β -内酰胺输注策略在ICU肺炎中更优？”连续、扩展和间歇方法的贝叶斯网络元分析”。

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2026-04-01 Epub Date: 2026-03-16 DOI: 10.1128/aac.01859-25

Yixuan Li, Jason A Roberts, Mohd H Abdul-Aziz, Fekade B Sime

引用次数: 0

Elevated hippocampal and cortical cefepime concentrations correlate with seizures in an acute kidney injury rat model. 在急性肾损伤大鼠模型中，海马和皮质头孢吡肟浓度升高与癫痫发作相关。

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2026-04-01 Epub Date: 2026-02-17 DOI: 10.1128/aac.01005-25

Gwendolyn M Pais, Emily Lesnicki, Sylwia Marianski, Kimberly Valdez, Zoe Gibson, Jeffri Christopher, Kathy Lepard, Annette Gilchrist, Tomoyuki Mizuno, Marc H Scheetz

{"title":"Elevated hippocampal and cortical cefepime concentrations correlate with seizures in an acute kidney injury rat model.","authors":"Gwendolyn M Pais, Emily Lesnicki, Sylwia Marianski, Kimberly Valdez, Zoe Gibson, Jeffri Christopher, Kathy Lepard, Annette Gilchrist, Tomoyuki Mizuno, Marc H Scheetz","doi":"10.1128/aac.01005-25","DOIUrl":"10.1128/aac.01005-25","url":null,"abstract":"Cefepime is associated with neurotoxicity, particularly in the setting of renal impairment where drug exposure increases. This study evaluated cefepime concentrations in the brain tissue during neurotoxicity in a rat model of acute kidney injury (AKI). Male Sprague-Dawley rats (n = 18) received daily intravenous cefepime at 1,250 or 1,593 mg/kg for 5 days. Acute kidney injury was induced using folic acid (250 mg/kg on day 1, then 100 mg/kg/day prior to cefepime). Seizure activity was assessed using a modified Racine scale. Plasma samples were collected three to four times per day; the brain tissues (cerebral cortex and hippocampus) were collected at euthanasia. Cefepime concentrations were measured via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic/pharmacodynamic (PK/PD) modeling was performed using Monolix 2024R1. Rats with seizure scores >1 had significantly higher median cefepime levels in the cerebral cortex (64.2 vs 14.1 μg/g, P = 0.0014) and hippocampus (66.2 vs 15.0 μg/g, P < 0.0001). Median (IQR) estimated exposures in the cortex were AUC0-24 = 565 (161.5-1,346) mg·h/L and Cmax = 36.0 (16.3-75.6) mg/L, and in the hippocampus were AUC0-24 = 694.8 (151.5-1,152) mg·h/L and Cmax = 41.9 (13.7-62.8) mg/L. Neurotoxicity in the rat correlated with plasma AUC0-24 > 30,000 mg·h/L and brain tissue concentration of approximately 40 mg/L. Neurotoxicity was achieved via intravenous dosing of cefepime in this rat model of acute kidney injury. Cefepime concentrations were higher in the cerebral cortex and hippocampal brain tissues in animals that had seizure stages >1.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0100525"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13041311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146211989","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}

引用次数: 0

The novel second-generation triterpenoid SCY-247 maintains in vitro and in vivo activity against resistant Candida glabrata. 新型第二代三萜SCY-247在体外和体内对耐药念珠菌保持活性。

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2026-04-01 Epub Date: 2026-02-19 DOI: 10.1128/aac.01625-25

Nathan P Wiederhold, Laura K Najvar, Rosie Jaramillo, Marcos Olivo, Hoja P Patterson, Thomas F Patterson

{"title":"The novel second-generation triterpenoid SCY-247 maintains in vitro and in vivo activity against resistant Candida glabrata.","authors":"Nathan P Wiederhold, Laura K Najvar, Rosie Jaramillo, Marcos Olivo, Hoja P Patterson, Thomas F Patterson","doi":"10.1128/aac.01625-25","DOIUrl":"10.1128/aac.01625-25","url":null,"abstract":"Candida glabrata is a major cause of invasive candidiasis and is considered a high-priority fungal pathogen by the World Health Organization. SCY-247 is a second-generation IV/oral triterpenoid antifungal that targets the fungal cell wall by inhibiting glucan synthase. We evaluated the in vitro activity and in vivo efficacy of SCY-247 against echinocandin-resistant C. glabrata. Susceptibility testing was performed against 34 C. glabrata clinical strains, including 29 echinocandin non-susceptible or resistant strains, by the CLSI broth microdilution method. Neutropenic mice were infected intravenously with either an echinocandin-susceptible or resistant strain. Treatment with vehicle control, SCY-247 (16, 32, and 48 mg/kg PO BID), fluconazole (20 mg/kg PO QD), or caspofungin (5 mg/kg IP QD) was initiated 24 hours post-inoculation. Treatment continued for 7 days, and kidney and lung tissues were collected on day 8 for analysis of fungal burden. SCY-247 maintained in vitro activity against 24 of the 29 echinocandin non-susceptible/resistant strains; SCY-247 was also efficacious against echinocandin-susceptible and resistant C. glabrata invasive candidiasis. Dose-dependent reductions in kidney and lung fungal burdens were observed in mice treated with SCY-247. In contrast, neither fluconazole nor caspofungin led to reductions in fungal burden in mice infected with the resistant strain. SCY-247 concentrations measured 12 hours after the last dose increased in a dose-dependent fashion, and those within the kidneys and lungs were markedly higher than the SCY-247 MIC90 value calculated against all strains tested. These data support the potential utility of SCY-247 therapy against invasive infections caused by resistant C. glabrata.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0162525"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13041391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146225162","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}

引用次数: 0

Reply to Nishimura, "Questions regarding mortality and infection source in deep-seated infections". 答复Nishimura，“关于深层次感染的死亡率和感染源的问题”。

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2026-04-01 Epub Date: 2026-03-02 DOI: 10.1128/aac.01716-25

Nicole Slain, Ashlan J Kunz Coyne

引用次数: 0

Reply to Külls et al., "Residual confounding and outcome definition in observational comparisons of PDR-Acinetobacter baumannii therapies". 回复k<s:1> lls等人，“pdr -鲍曼不动杆菌治疗观察性比较中的残留混淆和结果定义”。

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2026-04-01 Epub Date: 2026-03-16 DOI: 10.1128/aac.00104-26

Konstantinos Pontikis, Ilias Karaiskos, Helen Giamarellou, George L Daikos

引用次数: 0

Residual confounding and outcome definition in observational comparisons of PDR-Acinetobacter baumannii therapies. pdr -鲍曼不动杆菌治疗观察性比较的残留混淆和结果定义。

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2026-04-01 Epub Date: 2026-03-16 DOI: 10.1128/aac.00084-26

Carsten Külls, Niloufar Dadashpour, Majid Golestanieraghi

引用次数: 0

Questions regarding mortality and infection source in deep-seated infections. 关于深部感染的死亡率和感染源的问题。

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2026-04-01 Epub Date: 2026-03-02 DOI: 10.1128/aac.01664-25

Sho Nishimura

引用次数: 0

Therapeutic effect of eravacycline against carbapenem-resistant hypervirulent Klebsiella pneumoniae in mouse models. 厄伐环素对耐碳青霉烯高致病性肺炎克雷伯菌小鼠模型的治疗作用。

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2026-04-01 Epub Date: 2026-02-23 DOI: 10.1128/aac.01237-25

Ruyi Zhang, Chenchen Zhang, Juan Liu, Xiaoli Kong, Shulei Zhang, Miaosu Chang, Wei Xu, Mei Zhu

{"title":"Therapeutic effect of eravacycline against carbapenem-resistant hypervirulent Klebsiella pneumoniae in mouse models.","authors":"Ruyi Zhang, Chenchen Zhang, Juan Liu, Xiaoli Kong, Shulei Zhang, Miaosu Chang, Wei Xu, Mei Zhu","doi":"10.1128/aac.01237-25","DOIUrl":"10.1128/aac.01237-25","url":null,"abstract":"Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) presents a major challenge for clinical treatment due to its characteristics of drug resistance and hypervirulence. This study aims to investigate the therapeutic effect of a novel tetracycline antibiotic, eravacycline, on CR-hvKP pneumonia. We isolated three CR-hvKP strains from clinical samples and examined their associated phenotypes. Subsequently, we infected mice with strains. The results indicated that the clinical isolates KP78, KP98, and KP100 carried multiple drug resistance genes and virulence genes, exhibiting high virulence levels and significantly resistant to neutrophil-mediated intracellular killing (P < 0.01). The body weight of infected mice decreased significantly (P < 0.0001). At the same time, the bacteria entered the blood from the lungs and spread to other organs. After the administration of eravacycline, the body weight of the mice began to increase 36 h later. The number of bacterial colonizing in the lungs was reduced (P< 0.01), the infiltration of inflammatory cells was reduced, and the interstitial vascular dilatation and congestion were alleviated. Meanwhile, eravacycline significantly suppressed the serum levels of cytokines IL-6, IL-1β, and MCP-1 (P < 0.05). Notably, eravacycline suppressed the mRNA expression of STAT1 and p-STAT1 activation in the lung tissue of mice in the treatment group. In conclusion, clinical isolates KP78, KP98, and KP100 caused severe lung injury after invading mouse lung tissues, and eravacycline attenuated the lung injury and inflammatory response induced by CR-hvKP invasion.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0123725"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13041357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147269579","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}

引用次数: 0