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.
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