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Principal Investigator: Angela Garinis
Organization: CINCINNATI CHILDRENS HOSP MED CTR
Fiscal Year: 2024
Award: $627,033
Funding agency: National Institute on Deafness and Other Communication Disorders
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.
Terms: <Address><Adverse Experience><Adverse event><Affect><Aminoglycoside Agents><Aminoglycoside Antibiotics><Aminoglycoside Drugs><Aminoglycosides><Antibiotic Agents><Antibiotic Drugs><Antibiotic Therapy><Antibiotic Treatment><Antibiotics><Assessment instrument><Assessment tool><Audiogram><Audiometric Test><Audiometry><Auditory><Bacterial Infections><Behavioral><Blood><Blood Reticuloendothelial System><Body Tissues><CF patients><Cell Phone><Cellular Phone><Cellular Telephone><Childhood><Children's Hospital><Clinical><Clinical Data><Clinical Trials><Collaborations><Communication><Consumption><Creativeness><Critical Illness><Critically Ill><Cystic Fibrosis><Data><Diagnostic><Diagnostic tests><Digit><Digit structure><Dose><Drug Exposure><Drug Kinetics><Drug Therapy><Drugs><Early Diagnosis><Effectiveness><Follow-Up Studies><Followup Studies><Fostering><Frequencies><Future><Genetic><Genetic Diseases><Genomics><Goals><Guidelines><Health><Hearing><Hearing Loss><Hearing Tests><High Frequency Deafness><High-Frequency Hearing Loss><Human><Hypoacuses><Hypoacusis><Improve Access><Individual><Individual Differences><Infection><Inner Hair Cells><Inner ear hair cells><Internal Ear><Internet><Knowledge><Labyrinth><Life><Link><Longitudinal observation study><Longitudinal, observational study><Lung infections><Measures><Medication><Methods><Miscellaneous Antibiotic><Mobile Phones><Modeling><Modern Man><Monitor><Mucoviscidosis><NIH><National Institutes of Health><Nephrotoxic><Noise><Oregon><Outcome><Outcome Study><Outer Hair Cells><Patient Self-Report><Patients><Pediatric Hospitals><Persons><Pharmaceutical Preparations><Pharmacodynamics><Pharmacogenomics><Pharmacokinetics><Pharmacotherapy><Phenotype><Physicians><Physiologic><Physiological><Population><Predicting Risk><Predisposition><Prevention><Prevention trial><Protocol><Protocols documentation><Public Health><Pure-Tone Audiometry><Reporting><Research><Ringing-Buzzing-Tinnitus><Risk><Risk Factors><Science><Self-Report><Sensorineural Deafness><Sensorineural Hearing Loss><Sensory Hearing Loss><Speech><Susceptibility><Synapses><Synaptic><Testing><Time><Time Factors><Tinnitus><Tissues><Translating><United States National Institutes of Health><Universities><WWW><adult youth><alertness><alternative treatment><aminoglycoside ototoxicity><aminoglycoside-induced ototoxicity><anti-microbial><antimicrobial><auditory tests><auditory threshold shift><bacteria infection><bacterial disease><bacterial disease treatment><bacterial infectious disease treatment><behavior response><behavioral response><clinical relevance><clinically relevant><cohort><creativity><cystic fibrosis patients><delivered remotely><design><designing><detection method><detection procedure><detection technique><dosage><drug induced hearing impairment><drug induced hearing loss><drug treatment><drug/agent><dysfunctional hearing><early awareness><early detection><forecasting risk><genetic condition><genetic disorder><hearing assessment><hearing challenged><hearing defect><hearing deficient><hearing deficit><hearing difficulty><hearing dysfunction><hearing impairment><hearing loss prevention><hearing preservation><hearing threshold shift><high risk><iPhone><improved><individuals with CF><individuals with cystic fibrosis><inner ear><innovate><innovation><innovative><kidney toxicity><nephrotoxicity><neural><neural hearing loss><novel><otoacoustic emission><ototoxic><ototoxicity><patients with CF><patients with cystic fibrosis><pediatric><permanent hearing loss><predict risk><predict risks><predicted risk><predicted risks><predicting risks><predictive risk><predicts risk><preservation><preserve hearing><prevent><prevent hearing loss><preventing><programs><prospective><pulmonary infections><remote delivery><response><risk prediction><risk predictions><sensorineural hearing impairment><side effect><smart phone><smartphone><synapse><tool><uptake><web><world wide web><young adult><young adulthood>