The discovery of penicillin led to the development of natural, semi-synthetic, and synthetic antimicrobial medications. Quickly thereafter, resistant strains of microorganisms began appearing around the globe. Methicillin-resistant S. aureus, especially community-acquired MRSA, is increasingly a problem in pregnant women and in the postpartum period. The rate of MRSA infections in pregnant women, between 2000 and 2004, increased 10-fold. Postparturritional infections due to the MRSA are often serious and potentially life- threatening. Vancomycin has been the antibiotic of choice for treatment of infections caused by MRSA;however, the development of vancomycin-resistant strains of Staphylococcus aureus (VRSA) compromised its use and led to the development of its derivative telavancin. However, neither medication is approved for treatment of these infections in the pregnant patient. The hypoithesis for the proposed work is that changes in maternal physiology during pregnancy and the development of the feto-placental compartment will affect drug disposition and, consequently, pharmacokinetics (PK) and pharmacodynamics (PD) of vancomycin and telavancin. Therefore, the goal of the clinical pharmacology and translational projects proposed is to provide fundamental and necessary information that is elemental in making these 2 medications available for treatment of MRSA and VRSA infections during pregnancy. To achieve this goal, the following specific aims will be investigated: For the clinical trial-(1) The PK of vancomycin and telavancin, (2) Perinatal and maternal outcome, and (3) Neonatal outcome. For the translational project-(1) Determine the ex vivo placental transfer of the 2 antibiotics, (2) Identify the enzymes responsible for their biotransformation and the metabolites formed, (3) Determine the role and activity of placental uptake and efflux transporters and their effect on the extent of fetal exposure to the 2 antibiotics, and (4) Determine the effect of polymorphisms in the genes expressing the responsible metabolizing enzymes and transporters on their activity. The data obtained will provide the most basic information required for determination of the dose of each medication administered during pregnancy;its effect on perinatal, maternal, and neonatal outcomes;the extent to which the placenta regulates its transfer to the fetal circulation;and whether it is affected by genetic variables that could be liked to ethnicity of either the mother, fetus, or both.
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