Clinical factors in aminoglycoside-induced ototoxicity

氨基糖苷类引起的耳毒性的临床因素

• 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
• 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

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.

摘要 婴儿期的先天性和获得性听力损失会造成终生的、令人衰弱的后果。早些时候 听力损失的识别改善了听觉(康复)的效果、沟通结果和 这些人的生活质量。系统性感染是新生儿发病和死亡的主要原因。 住进新生儿重症监护病房(NICU)。细菌感染(即败血症)的治疗经验是 抗生素，包括挽救生命的氨基糖苷类，如庆大霉素。在临床前模型中，氨基糖苷类药物 治疗导致剂量依赖和频率选择性的感觉神经性听力和平衡障碍(即， 耳毒性)，以及急性肾脏损害。细菌配体诱导的全身炎症加剧 这种药物导致的听力损失。患有(疑似)败血症的婴儿需要紧急庆大霉素治疗，并出现 在试点研究中有更大的听力损失风险。我们的长期目标是减少发病率和范围， 从NICU出院的婴儿中药物所致听力损失的风险(毕业生)。我们提出了一个非- 对这一弱势群体的干预性翻译研究： 目的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。 在人类中导致听力损失。我们将检验这样的假设，即更大的庆大霉素累积剂量增加 NICU毕业生听力损失程度。 目的2：验证(疑似)脓毒症是否会加重庆大霉素引起的婴儿听力损失 试点数据表明，患有(疑似)脓毒症和庆大霉素治疗5天的≥的NICU患者有 与年龄匹配的同龄人相比，听力损失的风险更大。我们将通过测试 假设(疑似)脓毒症增加NICU庆大霉素所致听力损失的风险和程度 毕业生。 如果庆大霉素引起的NICU毕业生听力损失是(I)剂量依赖的，和/或(Ii)由 (疑似)脓毒症，这些数据将预示在出院前和出院后进行耳毒性监测的必要性 从NICU来的。如果实施，这将(I)确保及早发现听力损失，(Ii)提高 听觉(恢复)康复策略。此外，确定庆大霉素的发生率和剂量依赖关系- 诱发听力损失将有助于后续研究以确定(I)减少耳毒性氨基糖苷类药物的剂量， 和/或(Ii)替代抗生素或耳保护策略，更好地保护人类的终身听力。这些 策略将使NICU毕业生更好地满足同龄人的听力和口语技能要求 他们的教育潜力和对社会的终身贡献。