Obstetric Pharmacology Research Units Network Center at UTMB-Galveston

描述(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，抗药性的微生物菌株开始在全球范围内出现。耐甲氧西林金黄色葡萄球菌，尤其是社区获得性耐甲氧西林金黄色葡萄球菌，越来越成为孕妇和产后的问题。2000年至2004年间，孕妇感染MRSA的比率增加了10倍。由耐甲氧西林金黄色葡萄球菌引起的产后感染通常是严重的，并可能危及生命。万古霉素一直是治疗耐甲氧西林金黄色葡萄球菌(MRSA)感染的首选抗生素；然而，万古霉素耐药金黄色葡萄球菌(VRSA)的发展限制了它的使用，并导致了它的衍生物telavancin的发展。然而，这两种药物都没有被批准用于治疗孕妇的这些感染。这项拟议工作的假设是，怀孕期间母体生理的变化和胎盘间隔的发育将影响药物处置，从而影响万古霉素和替拉文星的药代动力学(PK)和药效学(PD)。因此，拟议的临床药理学和翻译项目的目标是提供基本和必要的信息，使这两种药物可用于治疗孕期MRSA和VRSA感染。为了实现这一目标，将调查以下具体目标：(1)临床试验--(1)万古霉素和替拉文星的PK；(2)围产期和母体结局；(3)新生儿结局。对于翻译项目-(1)确定两种抗生素在胎盘的体外转移，(2)确定负责其生物转化的酶和形成的代谢物，(3)确定胎盘摄取和外排转运体的作用和活性，以及它们对胎儿接触这两种抗生素的影响，以及(4)确定负责代谢酶和转运体的基因的多态性对其活性的影响。获得的数据将提供所需的最基本信息，以确定怀孕期间使用的每种药物的剂量；它对围产期、孕产妇和新生儿结局的影响；胎盘调节其转移到胎儿循环的程度；以及它是否受到遗传变量的影响，这些变量可能与母亲、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.