MULTIPLE DOSE PHARMACOKINETIC STUDY OF MEROPENEM IN YOUNG INFANTS (91 DAYS)

美罗培南多剂量小婴儿药代动力学研究（91天）

• 批准号: 8167326
• 负责人: JOHANNES NICOLAAS VAN DEN ANKER
• 金额: $ 0.1万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-20 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167326
• 关键词: Abdominal Infection; Adolescence; Adult; Age-Months; AmpC beta-lactamases; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Meningitis; Carbapenems; Childhood; Computer Retrieval of Information on Scientific Projects Database; Data; Dose; Drug Kinetics; Excretory function; Funding; Grant; Half-Life; Hour; Hydrolysis; Infant; Infection; Institution; Intra-abdominal; Intravenous; Label; Life; Meropenem; Metabolism; Multi-Drug Resistance; Penicillin Resistance; Plasma; Plasma Proteins; Protein Binding; Pseudomonas aeruginosa; Regimen; Renal function; Research; Research Personnel; Resources; Safety; Sepsis; Source; Streptococcus pneumoniae; United States National Institutes of Health; Urine; antimicrobial; antimicrobial drug; beta-Lactamase; neonate; pathogen; urinary; volunteer

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Meropenem, a carbapenem, belongs to an antibiotic class that possesses one of the broadest spectra of antimicrobial activity available, including most of the bacterial pathogens responsible for serious, life-threatening infections occurring in young (91 days) infants. Meropenem is stable against hydrolysis by most extended spectrum beta-lactamases and AmpC chromosomal beta-lactamases underscoring the drug¿¿"s activity against many antibiotic resistant Gram positive (e.g., penicillin-resistant S. pneumoniae) and Gram negative (e.g., P. aeruginosa) bacteria. Important indications for meropenem involve infections due to multi-drug resistant pathogens and polymicrobial sepsis. Meropenem is FDA-labeled for pediatric subjects from three months of age through adolescence as single agent antimicrobial therapy for bacterial meningitis and complicated intra-abdominal infections. There is substantial off-label use of meropenem in neonates and infants younger than three months of age. This off-label use occurs despite the lack of adequate meropenem pharmacokinetic, dosing, tolerability and safety data for this vulnerable subject group. The present proposal aims to determine pharmacokinetics and safety of meropenem for the treatment of suspected and complicated intra-abdominal infection in neonates and infants younger than three months of age. Metabolism in Adults: Meropenem mean peak plasma concentrations were approximately 23 ¿¿g/mL (range 14-26) for 500 mg single dose and 49 ¿¿g/mL (range 39-58) for a 1 g single dose in adult volunteers,. Following intravenous doses of 500 mg in adults mean plasma concentrations of meropenem usually decline to approximately 1 ¿¿g/mL at 6 hours after administration. In subjects with normal renal function, the elimination half-life of meropenem is approximately 1 hour. Approximately 70% of the intravenously administered dose is recovered as unchanged meropenem in the urine over 12 hours, after which little further urinary excretion is detectable. Urinary concentrations of meropenem in excess of 10 ¿¿g/mL are maintained for up to 5 hours after a 500 mg dose. No accumulation of meropenem in plasma or urine was observed with regimens using 500 mg administered every 8 hours or 1 g administered every 6 hours in volunteers with normal renal function. Plasma protein binding of meropenem is approximately 2%. There is one metabolite which is microbiologically inactive.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 对于中心来说，它不一定是研究者的机构。 美罗培南是一种碳青霉烯类抗生素，具有最广泛的抗菌活性，包括大多数导致幼年（91 天）婴儿发生的严重危及生命的感染的细菌病原体，美罗培南对水解稳定。大多数广谱 β-内酰胺酶和 AmpC 染色体 β-内酰胺酶强调了该药物的作用¿ ¿美罗培南对许多抗生素耐药性革兰氏阳性菌（例如耐青霉素肺炎链球菌）和革兰氏阴性菌（例如铜绿假单胞菌）具有活性。美罗培南的重要适应症包括多重耐药病原体和多种微生物败血症引起的感染。 FDA 标记，适用于三个月大至青春期的儿科受试者，作为细菌性脑膜炎和复杂腹内感染的单药抗菌疗法。尽管缺乏针对这一弱势群体的足够的美罗培南药代动力学、剂量、耐受性和安全性数据，但仍存在大量超说明书使用美罗培南的情况。确定美罗培南治疗新生儿和三个月以下婴儿疑似复杂腹腔内感染的药代动力学和安全性：成人代谢：美罗培南平均血浆峰浓度约为 23 ¿ g/mL（范围 14-26）对于 500 mg 单剂量和 49 ¿ ¿成人志愿者单剂量 1 g/mL（范围 39-58），成人静脉注射 500 mg 后，美罗培南的平均血浆浓度通常下降至约 1 ¿ ¿给药后 6 小时，美罗培南的消除半衰期约为 1 小时，约 70% 的静脉给药剂量在 12 小时内以原形美罗培南形式从尿液中回收。几乎没有检测到美罗培南的尿浓度超过 10 ¿ ¿肾功能正常的志愿者服用 500 mg 剂量后，每 8 小时服用 500 mg 或每 6 小时服用 1 g，未观察到美罗培南在血浆或尿液中蓄积。美罗培南的蛋白质结合率约为 2%。有一种代谢物没有微生物活性。