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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 美罗培南是一种碳青霉烯类抗生素，具有最广泛的抗微生物活性，包括导致幼儿（91天）严重、危及生命的感染的大多数细菌病原体。美罗培南对大多数超广谱β-内酰胺酶和AmpC染色体β-内酰胺酶的水解是稳定的，这强调了该药物对许多抗生素耐药革兰氏阳性菌（例如，青霉素抗性S.肺炎）和革兰氏阴性（例如，铜绿假单胞菌）细菌。美罗培南的重要适应症包括多药耐药病原体和多微生物败血症引起的感染。美罗培南是FDA标记的用于三个月大到青春期的儿科受试者的单药抗菌治疗，用于细菌性脑膜炎和复杂的腹腔内感染。 美罗培南在新生儿和3个月以下婴儿中有大量的标签外使用。尽管缺乏该弱势受试者群体的适当美罗培南药代动力学、剂量、耐受性和安全性数据，但仍发生了这种标签外用药。本提案旨在确定美罗培南用于治疗新生儿和3个月以下婴儿可疑和复杂腹腔内感染的药代动力学和安全性。 成人代谢：在成人志愿者中，美罗培南500 mg单次给药的平均血浆峰浓度约为23 μ g/mL（范围14-26），1 g单次给药的平均血浆峰浓度约为49 μ g/mL（范围39-58）。成人静脉注射500 mg美罗培南后，平均血浆浓度通常在给药后6小时降至约1 μ g/mL。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。约70%的静脉给药剂量在12小时内以原型美罗培南形式从尿液中回收，此后几乎检测不到进一步的尿液排泄。美罗培南500 mg剂量给药后，尿中美罗培南浓度超过10 μ g/mL可维持5小时。在肾功能正常的志愿者中，使用500 mg每8小时给药一次或1 g每6小时给药一次的方案时，未观察到美罗培南在血浆或尿液中蓄积。美罗培南的血浆蛋白结合率约为2%。有一种代谢物是无微生物活性的。

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.