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.

概括 在婴儿期间，先天性和被收购的听力损失具有终生的后果。早期的 听力损失的识别可提高听觉（重新）的效率（重新），交流结果和 这些人的生活质量。全身感染是新生儿发病率和死亡率的主要原因 进入新生儿重症监护病房（NICU）。细菌感染（即败血症）经过经验治疗 抗生素，包括挽救生命的氨基糖苷，如庆大霉素。在临床前模型中，氨基糖苷 治疗诱导剂量依赖性和频率选择性的感觉性听力和平衡缺陷（即 耳毒性）以及急性肾脏损伤。细菌配体潜力引起的全身性炎症 这种药物引起的听力损失。患有败血症的婴儿需要紧急庆大霉素治疗，并且出现 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事件和程度 从NICU出院的婴儿（毕业生）的药物引起的听力损失。我们提出了一个非 对这个脆弱人群的介入翻译研究至： 目标1：确定庆大霉素剂量是否依赖性地增加婴儿的听力损失 几乎没有严格的数据显示氨基糖苷 - 剂量依赖性和频率选择性 引起人类的听力损失。我们将检验以下假设，即累积庆大霉素增加增加 NICU毕业的听力损失程度。 AIM 2：验证（惊讶）败血症潜力庆大霉素引起的婴儿的听力损失 试验数据表明，患有败血症（表面）和≥5天庆大霉素治疗的NICU受试者患有 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 假设败血症（表面）增加了庆大霉素引起的NICU听力损失的风险和程度 毕业生。 如果庆大霉素引起的NICU毕业生的听力损失是（i）剂量依赖性的，/或（ii）由 （感到惊讶）败血症，这些数据将预测对耳毒性监测的必要性，然后再出院 来自NICU。如果实施，这将（i）确保早期发现听力损失，（ii）提高效率 听觉（重新）关联策略。此外，确定庆大霉素的事件和剂量依赖性 诱导的听力损失将促进随后的研究，以确定（i）减少耳毒性氨基糖苷剂量，是否降低 和/或（ii）替代性抗生素或耳状策略，更好地保留人类终身听力。这些 策略将使NICU毕业生能够更好地满足同龄人的倾听和讲语言技能以实现 他们对社会的教育潜力和终身贡献。