Clinical factors in aminoglycoside-induced ototoxicity

总结 先天性和后天性听力损失在婴儿期有终身的，衰弱的后果。早期 听力损失的识别提高了听觉（再）障碍的疗效，沟通结果和 这些人的生活质量。全身感染是新生儿发病和死亡的主要原因 新生儿重症监护室（NICU）。细菌感染（即，脓毒症）经验性地用 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， 治疗诱导剂量依赖性和频率选择性感觉神经性听力和平衡缺陷（即， 耳毒性）以及急性肾损伤。细菌配体诱导的全身性炎症 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， 在试点研究中有更大的听力损失风险。我们的长期目标是降低发病率和程度， 从NICU出院的婴儿（毕业生）中药物性听力损失的比例。我们提出一个非- 对这一脆弱人群进行干预性转化研究，以： 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， 导致人类听力损失。我们将检验以下假设：庆大霉素累积剂量增加 新生儿重症监护病房毕业生的听力损失程度。 目的2：验证（疑似）脓毒症是否会加重庆大霉素诱导的婴儿听力损失 初步数据表明，患有（疑似）脓毒症且接受庆大霉素治疗≥5天的NICU受试者， 与同龄人相比，听力损失的风险更大。我们将通过测试 （疑似）脓毒症增加NICU中庆大霉素诱导听力损失的风险和程度的假设 毕业生 如果NICU毕业生中庆大霉素诱导的听力损失具有（i）剂量依赖性，和/或（ii） （疑似）脓毒症，这些数据将预测出院前和出院后需要进行耳毒性监测 从新生儿重症监护室如果实施，这将（i）确保早期发现听力损失，（ii）提高听力损失的有效性。 听觉（再）抑制策略。此外，确定庆大霉素的发生率和剂量依赖性- 诱导的听力损失将促进随后的研究以确定是否（i）减少耳毒性氨基糖苷类给药， 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毕业生更好地满足他们的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身贡献。

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.