Obstetric Pharmacology Research Units Network Center at UTMB-Galveston

描述（由申请人提供）：青霉素的发现导致了天然、半合成和合成抗菌药物的发展。此后不久，耐药的微生物菌株开始在全球出现。耐甲氧西林金黄色葡萄球菌，特别是社区获得性MRSA，越来越成为孕妇和产后的一个问题。从2000年到2004年，孕妇感染耐甲氧西林金黄色葡萄球菌的比率增加了10倍。由MRSA引起的产后感染通常很严重，甚至可能危及生命。万古霉素一直是治疗MRSA感染的首选抗生素；然而，耐万古霉素金黄色葡萄球菌（VRSA）菌株的发展损害了其使用，并导致其衍生物特拉万素的发展。然而，这两种药物都没有被批准用于治疗怀孕患者的这些感染。这项工作的假设是，怀孕期间母亲的生理变化和胎儿-胎盘间室的发育会影响药物配置，从而影响万古霉素和特拉万素的药代动力学（PK）和药效学（PD）。因此，临床药理学和转化项目的目标是提供基本和必要的信息，这些信息是使这两种药物可用于治疗妊娠期间MRSA和VRSA感染的基本信息。为了实现这一目标，将研究以下具体目标：对于临床试验-(1)万古霉素和特拉万辛的PK，(2)围产期和产妇结局，(3)新生儿结局。对于转化项目-(1)确定2种抗生素的体外胎盘转移，(2)确定负责其生物转化的酶和形成的代谢物，(3)确定胎盘摄取和排出转运体的作用和活性及其对胎儿暴露于2种抗生素程度的影响，以及(4)确定表达负责代谢酶和转运体的基因多态性对其活性的影响。获得的数据将提供确定怀孕期间使用的每种药物剂量所需的最基本信息；它对围产期、孕产妇和新生儿结局的影响；胎盘调节其向胎儿循环转移的程度；以及它是否受到遗传变量的影响，这些遗传变量可能与母亲、胎儿或两者的种族有关。

DESCRIPTION (provided by applicant): 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.