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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 美罗培南是一种碳青霉烯类抗生素，具有现有的最广泛的抗微生物活性，包括大多数导致幼儿(91天)发生的严重威胁生命的感染的细菌病原体。美罗培南对大多数超广谱β-内酰胺酶和AmpC染色体β-内酰胺酶的水解性很稳定，这突显了S药物对许多革兰氏阳性菌(如耐青霉素肺炎链球菌)和革兰氏阴性菌(如铜绿假单胞菌)的活性。美罗培南的重要适应症包括多重耐药病原体和多菌败血症引起的感染。美罗培南是FDA标记的，适用于从三个月大到青春期的儿科受试者，作为细菌性脑膜炎和复杂的腹内感染的单药抗菌疗法。美罗培南在新生儿和三个月以下的婴儿中有大量的标签外使用。尽管没有足够的美罗培南药代动力学、剂量、耐受性和安全性数据用于这一脆弱的受试者群体，这种标签外使用仍然发生。本提案旨在确定美罗培南治疗新生儿和3个月以下婴儿疑似和复杂的腹内感染的药代动力学和安全性。成人代谢：在成年志愿者中，单剂500毫克美罗培南的平均血药浓度约为23微克/毫升(14-26)，单剂1毫克的美罗培南平均血药浓度约为49微克/毫升(39-58)。在成人静脉注射500毫克后，美罗培南的血浆浓度通常在给药后6小时降至约1克/毫升。在肾功能正常的受试者中，美罗培南的消除半衰期约为1小时。大约70%的静脉给药剂量在12小时内在尿液中恢复为美罗培南不变，之后几乎不能检测到进一步的尿液排泄。在500毫克剂量后，美罗培南的尿药浓度超过10克/毫升，最长可维持5小时。在肾功能正常的志愿者中，每8小时给药500 mg或每6小时给药1g的方案未观察到美罗培南在血浆或尿液中的蓄积。美罗培南的血浆蛋白结合率约为2%。有一种代谢物在微生物上没有活性。

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.