Prevention of Ototoxicity with Effective Monitoring (POEM) Pharmacokinetic and Auditory Linkages

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Patients treated with life-saving aminoglycoside (AG) antibiotics may experience adverse side effects of ototoxicity – permanent hearing loss and degraded speech communication. There are critical gaps in our understanding of individual susceptibility for ototoxicity, and access to effective tests that identify those at higher risk. The objective of this proposal is to determine the effect of AG antibiotics on auditory function in relation to individual measures of drug exposure in patients with cystic fibrosis. Our long-term goal is to design improved auditory monitoring protocols to prevent hearing deficits due to ototoxicity in patients taking AG antibiotics. This project will evaluate new methods to detect onset of ototoxicity using extended high frequency (EHF) tests of inner ear function – otoacoustic emissions (OAEs) and digits in noise (DIN), in relation to individualized pharmacokinetic/dynamic (PK/PD) measures of drug exposure. Cystic fibrosis (CF) is the most common life-threatening genetic disease and causes persistent lung infections in childhood that are frequently treated with AG antibiotics, thus is an important population to target for prevention of ototoxicity. This longitudinal observational study will include CF patients treated with AG antibiotic treatments, and control persons not treated with AGs, half of whom also have CF. Our hypothesis is that these newly developed auditory tests can detect ototoxicity early and are related to the PK/PD models. Further, we hypothesize that PK/PD models can predict risk for ototoxicity. Currently, most patients at risk are not monitored for ototoxic hearing loss, primarily due to lack of availability and awareness of early detection methods, as well as treatment alternatives that can preserve hearing. Tests that can be automated or delivered remotely via the internet or through smartphones could fundamentally improve access to ototoxicity monitoring. The proposed longitudinal observational design is impactful because it will provide highly translatable auditory data in relation to advanced measures of drug exposure. The clinically relevant aims will: (1) Assess relationships over time between cumulative doses of AGs, shifts in EHF pure tone and DIN tests, and self-reported hearing difficulty and tinnitus; (2) Compare OAE tests to hearing loss shifts and determine which OAE test is more accurate to detect presence of ototoxicity; (3) Develop a clinical PK/PD tool to predict AG ototoxicity (change in audiometry, DIN or OAEs) in relation to AG tissue accumulation in CF patients. The expected outcomes will have important positive impacts because they will provide a better understanding of ototoxicity mechanisms, timing and risk factors that can be translated into improved monitoring. Future genomic studies and clinical trials to protect the inner ear would be facilitated by this expanded knowledge and by availability of improved diagnostic and monitoring tools.