Trimethoprim: an overlooked contributor of trimethoprim-sulfamethoxazole idiosyncratic adverse drug reactions

项目摘要 复方抗生素甲氧苄啶-磺胺甲恶唑（TMP-SMX）是一种有效、廉价、广泛使用的抗生素， 处方，但它也导致特异质药物不良反应（IADR）在3-5%的TMP-SMX暴露 患者，这一比率远远高于大多数其他药物。特别令人担忧的是，这些IADR正在发生， 随着使用的增加而频率增加。处方医生害怕IADR，因为它们可以 导致不可预测的发病率甚至死亡率。尽管存在这些问题，TMP-SMX仍然是一个关键的 因为很少有广泛可用的替代疗法。因此 因此，有必要增加我们对TMP-SMX IADR机制的了解，以便在临床上开发 可以预测风险的相关生物标志物。 虽然TMP-SMX是由两种单独药物组分组成的组合抗生素，但IADR机制 迄今为止，研究仅限于SMX，尽管有大量临床证据表明TMP有助于这些 不希望的反应。导致TMP-SMX IADR的确切机制尚未阐明;然而， 认为母体药物生物活化为与蛋白质共价结合的化学反应性代谢物 成为IADR发展的重要启动事件。最近的数据表明，TMP是生物活化的反应性， 可以与蛋白质共价结合的代谢物。在服用TMP的儿童尿液中发现了TMP加合物 TMP-SMX，表明活性TMP中间体在体内形成。目前尚不清楚是否 发生TMP-SMX IADR的患者对SMX或TMP或两者均有反应，因此不可能 识别可能对TMP-SMX任一组分引起的IADR易感的前瞻性患者。 我们假设TMP可能是TMP-SMX暴露患者中观察到的IADR的重要贡献者。 我们将在以下具体目标中解决这一假设：1）确定用TMP治疗的个体是否 SMX在其循环中具有TMP和/或SMX蛋白加合物; 2）确定与SMX相关的免疫标记物。 与每种单独药物组分相关的TMP-SMX IADR，以及3）确定TMP代谢物是否 能够共价修饰皮肤中的蛋白质。 我们的长期目标是提高这种基本抗生素的临床安全性。这项研究将有助于 关于TMP-SMX IADR开发背后机制的关键信息。今后的研究将针对 开发一种可应用于临床的工具，以确定TMP-SMX的风险并提高安全处方。

PROJECT SUMMARY The combination antibiotic trimethoprim-sulfamethoxazole (TMP-SMX) is effective, inexpensive, and widely prescribed, yet it also causes idiosyncratic adverse drug reactions (IADRs) in 3-5% of TMP-SMX exposed patients, a rate much higher than that of most other drugs. Particularly alarming is that these IADRs are occurring with increasing frequency subsequent to increasing use. IADRs are feared by prescribers because they can result in unpredictable morbidity and even mortality. Despite these problems, TMP-SMX remains a critical mainstay therapy for treating infections worldwide because there are few widely available alternatives. Therefore it is essential to increase our mechanistic understanding of TMP-SMX IADRs in order to develop clinically relevant biomarkers that can predict risk. Although TMP-SMX is a combination antibiotic made up of two individual drug components, IADR mechanistic studies have to date been limited to SMX despite considerable clinical evidence that TMP contributes to these undesired reactions. The exact mechanism that leads to TMP-SMX IADRs has yet to be elucidated; however, bioactivation of a parent drug to a chemically reactive metabolite that covalently binds to a protein is considered to be an essential initiating event for IADR development. Recent data shows that TMP is bioactivated to reactive metabolites that can covalently bind to protein. TMP adducts have been identified in the urine of children taking TMP-SMX, suggesting that reactive TMP intermediates are formed in vivo. Currently it is not known whether patients experiencing TMP-SMX IADRs are responding to SMX, or to TMP, or to both, making it impossible to identify prospective patients who might be susceptible to an IADR caused by either component of TMP-SMX. We hypothesize that TMP may be a significant contributor to IADRs observed in TMP-SMX exposed patients. We will address this hypothesis in the following specific aims: 1) determine whether individuals treated with TMP- SMX have TMP and/or SMX protein adducts in their circulation 2) determine immunologic markers associated with TMP-SMX IADRs as related to each individual drug component and 3) determine if TMP metabolites are capable of covalently modifying proteins in the skin. Our long-term goal is to increase the clinical safety profile of this essential antibiotic. This research will contribute critical information about the mechanism behind TMP-SMX IADR development. Future studies will be directed in developing a tool that could be applied clinically to determine risk and enhance safe prescribe of TMP-SMX.