Clinical factors in aminoglycoside-induced ototoxicity

氨基糖苷类引起的耳毒性的临床因素

基本信息

批准号：
10206090
负责人：
Peter Stephen Steyger
金额：
$ 66.61万
依托单位：
CREIGHTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206090
关键词：
Acquired Deafness Acute Admission activity Affect Age Aminoglycoside Antibiotics Aminoglycosides Ampicillin Ampicillin Resistance Antibiotics Auditory Bacteremia Bacterial Infections Clinical Clinical Data Clinical Protocols Communication Conflict (Psychology)Data Dependence Diagnostic Diuretics Dose Early Diagnosis Early identification Enrollment Ensure Equilibrium Etiology Exhibits Frequencies Gentamicins Goals Habilitation Hearing Hearing Tests Hour Human Incidence Individual Infant Infection Inflammation Language Life Ligands Live Birth Measures Monitor Morbidity - disease rate Multi-Drug Resistance Mycoses Necrotizing Enterocolitis Neonatal Intensive Care Units Newborn Infant Organism Outcome Patients Performance Pilot Projects Pre-Clinical Model Premature Infant Quality of life Reporting Residual state Risk Risk Factors Savings Sepsis Severity of illness Site Societies Systemic infection Term Birth Testing Therapeutic United States Validation Vulnerable Populations aminoglycoside-induced ototoxicity antimicrobial beta-Lactams childhood hearing loss clinically relevant cognitive skill cohort comorbidity follow-up hearing impairment hearing loss risk hearing screening human data improved infancy infant monitoring mortality neonatal sepsis neonate novel otoacoustic emission otoprotectant ototoxicity peer power analysis pre-clinical preclinical study preservation rehabilitation strategy renal damage screening program skills socioeconomics standard of care synergism systemic inflammatory response translational study

项目摘要

SUMMARY Congenital and acquired hearing loss during infancy has lifelong, debilitating consequences. Early identification of hearing loss improves the efficacy of auditory (re)habilitation, communication outcomes and quality of life for these individuals. Systemic infections are a major cause of morbidity and mortality in neonates admitted to the neonatal intensive care unit (NICU). Bacterial infections (i.e., sepsis) are treated empirically with antibiotics, including the life-saving aminoglycosides, like gentamicin. In preclinical models, aminoglycoside treatment induces dose-dependent and frequency-selective sensorineural hearing and balance deficits (i.e., ototoxicity), as well as acute kidney damage. Systemic inflammation induced by bacterial ligands potentiates this drug-induced hearing loss. Infants with (suspected) sepsis require urgent gentamicin treatment, and appear to have a greater risk of hearing loss in pilot studies. Our long-term goal is to reduce the incidence, and extent, of drug-induced hearing loss among infants discharged from the NICU (graduates). We propose a non- interventional translational study of this vulnerable population to: Aim 1: Identify if gentamicin dose-dependently increases hearing loss in infants There is little rigorous data showing the dose-dependency and frequency-selectivity of aminoglycoside- induced hearing loss in humans. We will test the hypothesis that greater cumulative gentamicin dosing increases the degree of hearing loss in NICU graduates. Aim 2: Verify if (suspected) sepsis potentiates gentamicin-induced hearing loss in infants Pilot data suggest that NICU subjects with (suspected) sepsis and ≥5 days of gentamicin therapy have a greater risk of hearing loss compared to their age-matched peers. We will verify these pilot data by testing the hypothesis that (suspected) sepsis increases the risk, and extent, of gentamicin-induced hearing loss in NICU graduates. If gentamicin-induced hearing loss in NICU graduates is (i) dose-dependent, and/or (ii) potentiated by (suspected) sepsis, these data will predicate the need for ototoxicity monitoring prior to, and following, discharge from the NICU. If implemented, this will (i) ensure earlier detection of hearing loss, (ii) improve the efficacy of auditory (re)habilitation strategies. In addition, identifying the incidence and dose-dependency of gentamicin- induced hearing loss will facilitate subsequent studies to determine if (i) reducing ototoxic aminoglycoside dosing, and/or (ii) alternative antibiotic or otoprotective strategies, better preserve lifelong hearing in humans. These strategies will enable NICU graduates to better meet their peers’ listening and spoken language skills to fulfill their educational potential and lifelong contributions to society.

概括婴儿期的先天性和后天性听力损失会造成终生衰弱的后果。听力损失的识别可提高听力（康复）康复、沟通结果和这些人的生活质量是新生儿发病和死亡的主要原因。入住新生儿重症监护病房 (NICU) 进行细菌感染（即败血症）的经验治疗。抗生素，包括挽救生命的氨基糖苷类药物，如庆大霉素。在临床前模型中，氨基糖苷类药物。治疗会引起剂量依赖性和频率选择性的感音神经性听力和平衡缺陷（即，耳毒性）以及细菌配体引起的急性肾损伤。这种药物引起的听力损失（疑似）败血症需要紧急庆大霉素治疗，并出现。在试点研究中，我们的长期目标是降低听力损失的发生率和程度。从 NICU 出院的婴儿（毕业生）中药物引起的听力损失的情况我们建议进行非药物性听力损失研究。针对这一弱势群体的介入转化研究：目标 1：确定庆大霉素是否剂量依赖性地增加婴儿听力损失几乎没有严格的数据显示氨基糖苷类药物的剂量依赖性和频率选择性。我们将检验庆大霉素累积剂量增加会增加的假设。 NICU 毕业生的听力损失程度。目标 2：验证（疑似）败血症是否会增强庆大霉素引起的婴儿听力损失试点数据表明，患有（疑似）脓毒症且接受庆大霉素治疗≥5天的 NICU 受试者有与同龄人相比，听力损失的风险更大，我们将通过测试来验证这些试点数据。假设（疑似）脓毒症会增加 NICU 庆大霉素引起的听力损失的风险和程度毕业生。如果 NICU 毕业生庆大霉素引起的听力损失是 (i) 剂量依赖性的，和/或 (ii) 加剧的（疑似）脓毒症，这些数据将预示出院前和出院后需要进行耳毒性监测如果实施，这将 (i) 确保及早发现听力损失，(ii) 提高听力损失的效率。此外，确定庆大霉素的发病率和剂量依赖性。诱发性听力损失将有助于后续研究，以确定是否（i）减少耳毒性氨基糖苷类药物剂量，和/或 (ii) 替代抗生素或耳保护策略，更好地保护人类终生听力。策略将使 NICU 毕业生能够更好地满足同龄人的听力和口语技能，以实现他们的教育潜力和对社会的终生贡献。