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. Childhood obesity has become increasingly prevalent in both developing and developed countries. In the United States, the prevalence of being overweight has doubled in 6-11 year old children and tripled in 12-17 year old adolescents in the last 20 years (1). Obesity is associated with insulin resistance and promotes the progression of atherosclerosis by increasing the risk of type 2 diabetes (2), dyslipidemia, and hypertension, all of which are risk factors for cardiovascular disease. Hence, the long-term impact of obesity on individuals developing obesity as children may have profound consequences. Ertapenem is an established antibiotic drug for the therapy of acute lower respiratory tract and intra-abdominal infections. Ertapenem is also approved for the treatment of soft tissue infections, but its in vivo penetration into the interstitial space of skeletal muscle and subcutaneous adipose tissue in humans is presently unknown. As there is a lack of appropriate methods to directly measure tissue penetration, approval is based mainly on plasma concentration data rather than actual target tissue concentrations. Measurement of tissue concentrations and subsequent association of target site concentrations with the pharmacodynamic response to treatment, however, is crucial especially for drugs with a high plasma protein binding such as ertapenem. Based on the concept that the unbound drug concentration at the target site is directly correlated with the success of antimicrobial therapy, we will set out in the present study to determine soft tissue exposure to unbound drug concentrations following administration of a single dose ertapenem in vivo in healthy volunteers. For this purpose we will employ in vivo microdialysis an innovative bioanalytical sampling technique to measure the time versus unbound concentration profiles of ertapenem in plasma and in the interstitial space of skeletal muscle tissue following i.v. administration of 1g of the drug. The study will be carried out as a non-controlled, open-label, investigator initiated pilot trial in 3 healthy volunteers for the pilot in vivo experiments and in 6 healthy volunteers (Main study). The outcome variables are the Cmax-tissue, AUCtissue, tmax-tissue, Ctissue -MIC ratios, AUCtissue / AUCplasma ratios, as a measure of the plasma-tissue penetration of ertapenem.
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