A Randomized Clinical Trial of Continuous vs. Intermittent Infusion Vancomycin: Effects on Measured GFR and Kidney Injury Biomarkers

连续与间歇输注万古霉素的随机临床试验：对测量的 GFR 和肾损伤生物标志物的影响

• 批准号: 10647236
• 负责人: Alexander H Flannery
• 金额: $ 24.96万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-20 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10647236
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Antibiotics; Benefits and Risks; Biological Markers; Clinical; Clinical Data; Clinical Research; Clinical Trials; Communicable Diseases; Continuous Infusion; Creatinine; Data; Dose; Drug Kinetics; Eligibility Determination; Glomerular Filtration Rate; Histology; Hospitalization; Hour; Infection; Infusion procedures; Injury; Injury to Kidney; Institution; Iohexol; Kidney; Measurement; Measures; Mission; Modeling; National Institute of Allergy and Infectious Disease; Patients; Pattern; Pharmaceutical Preparations; Physicians; Plasma; Randomized; Rattus; Renal function; Research; Risk; Safety; Scheme; Serum; Techniques; Testing; Time; Toxic effect; Translating; United States; Vancomycin; Work; antimicrobial; experience; improved outcome; indexing; methicillin resistant Staphylococcus aureus; nephrotoxicity; novel strategies; novel therapeutics; open label; osteopontin; pathogen; post gamma-globulins; pre-clinical; prospective; randomized, clinical trials; rat KIM-1 protein; standard of care; sulfated glycoprotein 2; tool; urinary

PROJECT SUMMARY/ABSTRACT Vancomycin is the most commonly administered antibiotic in hospitalized patients, and a mainstay treatment option for empiric and definitive therapy of gram-positive infections, particularly methicillin-resistant Staphylococcus aureus (MRSA). Patients receiving vancomycin are at risk of drug-associated acute kidney injury (DA-AKI), which occurs in 5-43% of patients. Experimental preclinical data and observational clinical data from our group indicate that the administration of vancomycin via continuous as opposed to intermittent infusion (the standard of care in most institutions) reduces urinary markers of kidney injury and leads to less DA-AKI. In order to translate these findings from the rat model, this application proposes a randomized, open- label, clinical trial of continuous versus intermittent infusion vancomycin in hospitalized patients already prescribed vancomycin by their treating physician in order to evaluate the change in kidney function and injury between the two infusion strategies. Given the known limitations of serum creatinine in assessing DA-AKI, this proposal includes measured glomerular filtration rate (mGFR) using iohexol, the gold-standard index of kidney function, and other biomarkers of kidney injury and function to work toward the overall objective of testing the impact of infusion strategy (continuous versus intermittent) on kidney function. Our central hypothesis is that vancomycin administered as a continuous versus intermittent infusion results in less DA-AKI as assessed by mGFR and kidney injury biomarkers. To test this hypothesis, the following specific aims are proposed: (1) Determine if patients randomized to receive vancomycin administered via intermittent infusion experience greater reductions in mGFR, assessed using the gold standard plasma iohexol clearance, in the 72 hours after therapy initiation compared to continuous infusion, (2) Determine if patients randomized to receive vancomycin administered via intermittent infusion demonstrate greater elevations in plasma (cystatin C) and urinary (kidney injury molecule-1, clusterin, and osteopontin) kidney biomarkers of injury and function in the 72 hours after therapy initiation compared to continuous infusion, and (3) Compare the pharmacokinetic target attainment, clinical safety, and tolerability of infusion strategy in patients randomized to receive vancomycin via continuous vs. intermittent infusion. Given the millions of patients that receive vancomycin annually in the United States for the treatment of MRSA or other gram-positive infections, the proposal aligns with NIAID’s mission of better treating infectious diseases by optimizing the risk-benefit profile of this antibiotic. Testing this hypothesis is crucial to translate the preclinical findings to patients, as well as determine if larger, definitive trials are needed to test if infusion strategy improves outcomes, including safety, with vancomycin therapy.

项目总结/摘要 万古霉素是住院患者中最常用的抗生素，也是主要的治疗方法。 革兰氏阳性菌感染，特别是耐甲氧西林的革兰氏阳性菌感染的经验性和确定性治疗的选择 金黄色葡萄球菌（MRSA）。接受万古霉素治疗的患者存在药物相关性急性肾脏病的风险 损伤（DA-AKI），发生在5-43%的患者中。实验性临床前数据和观察性临床 来自我们小组的数据表明万古霉素通过连续给药而不是间歇给药 输注（大多数机构的护理标准）可减少肾损伤的尿液标志物， 田明为了从大鼠模型中转化这些发现，本申请提出了一种随机的、开放的- 在住院患者中持续与间歇输注万古霉素的标签，临床试验已经 由其主治医生处方万古霉素，以评价肾功能和损伤的变化 两种输液策略之间的差异。鉴于血清肌酐在评估DA-AKI中的已知局限性， 一项建议包括使用碘海醇测量肾小球滤过率（mGFR），这是肾脏的金标准指数 功能，以及肾损伤和功能的其他生物标志物，以实现检测 输注策略（连续与间歇）对肾功能的影响。我们的核心假设是， 万古霉素连续输注与间歇输注相比， mGFR和肾损伤生物标志物。为了验证这一假设，提出了以下具体目标：（1） 确定随机接受万古霉素间歇性输注给药的患者是否有经验 使用金标准血浆碘海醇清除率评估的mGFR在72小时后更大的降低， 与连续输注相比，治疗开始，（2）确定患者是否随机接受万古霉素 通过间歇性输注给予的药物在血浆（胱抑素C）和尿（肾）中显示出更大的升高 损伤分子-1、簇蛋白和骨桥蛋白）肾损伤和功能的生物标志物， 与连续输注相比的治疗开始，和（3）比较药代动力学目标达到， 随机接受万古霉素连续给药的患者中输注策略的临床安全性和耐受性 vs.间歇输液鉴于美国每年有数百万患者接受万古霉素治疗， 治疗MRSA或其他革兰氏阳性感染，该提案符合NIAID的使命， 通过优化这种抗生素的风险效益来治疗感染性疾病。检验这一假设是 这对于将临床前研究结果转化为患者以及确定是否需要更大规模的确定性试验至关重要 测试输注策略是否改善万古霉素治疗的结局，包括安全性。