Project Summary/Abstract Ototoxicity, a leading cause of acquired hearing loss from pharmacotherapeutic agents worldwide, has become an epidemic in pediatric and adult populations. National guidelines by the American Academy of Audiology and American Speech-Language-Hearing Association recommend serial monitoring of behavioral pure-tone thresholds (PTTs) and physiologic-based measures to monitor ototoxicity. However, evidence-based research shows that ototoxic monitoring is not a consistent practice for patients in US clinics, partly due to lack of physician and patient knowledge about the onset and effects of ototoxicity. Physiologic-based tests are critically needed for obtaining information about auditory function in a time-efficient manner, particularly in chronically ill patients and in pediatric populations who are unable to complete reliable PTT testing. In the US, persons with cystic fibrosis (CF) are at high risk for developing ototoxicity due their lifelong treatments with intravenous (IV) aminoglycoside (AG) antibiotics. These medications are often used because of their cost-effectiveness and high bacterial efficacy for treating life-threatening lung infections. Unfortunately, these treatments may have detrimental effects on hearing, often producing permanent high- frequency sensorineural hearing loss. Only 26% of CF clinics across the country routinely monitor hearing for ototoxicity, and protocols that do exist rely on time consuming PTT hearing assessments that may be unrealistic in this often ill population. This is an ideal cohort for which to develop an efficient, cost-effective and reliable ototoxic monitoring protocol including physiological measures, given their lifelong use of AG therapy and lack of consistent hearing monitoring. A fast, accurate physiological test to identify patients at high risk for developing ototoxicity or permanent hearing loss would address a major clinical need across all populations. National guidelines recommend a physiologic-based method to accompany behavioral testing, however a reliable measure predictive of PTT changes has not been established. Otoacoustic emissions (OAEs) are often used to determine cochlear integrity, however the magnitude of change for these responses has not shown good predictability for shifts in PTTs. Therefore, it is critical to investigate other objective clinical tests that may improve predictability of permanent hearing loss. The medial olivocochlear (MOC) system is an efferent- mediated reflex thought to control cochlear gain by modifying outer hair cell activity in frequency ranges important for processing speech. Human and preclinical evidence suggests that efferent fibers are impaired by ototoxic treatments, prior to outer hair cell loss. Preclinical (animal) research shows that (i) AGs cause dose- dependent reductions of OAE levels and (ii) loss of MOC-mediated inhibition from AGs is predictive of SNHL. The purpose of this proposal is to establish the clinical ...