Clinical factors in aminoglycoside-induced ototoxicity

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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.