Antimicrobial Blue Light for the Treatment of Otitis Media

Massachusetts General Hospital, Boston MA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Otitis media (OM), the most common pediatric infection, is typically treated with systemic antibiotics. However, the rise of antibiotic resistance among otopathogens highlights a critical need for new treatment regimens. Antimicrobial blue light (aBL; 405 nm wavelength), an innovative nonpharmacological approach, has attracted increasing attention due to its prominent antibacterial activity irrespective of the antibiotic resistance profiles of bacteria. The mechanism of action of aBL relies on the photoexcitation of endogenous porphyrins in bacteria to produce cytotoxic reactive oxygen species. Due to the multitarget mode of action of aBL, bacteria are less able to develop resistance to aBL than to antibiotics. As a local treatment, aBL also avoids systemic exposure and the associated side effects that are common with systemic antibiotics. Despite the favorable features of aBL, this optical regimen remains under-explored as a treatment for OM. The objective of this R21 application is to explore the utility of aBL for treating OM. Our central hypothesis is that aBL has the potential to be an effective and safe treatment for OM. To address this hypothesis, we propose two Specific Aims. In Aim 1, we will first investigate the in vitro efficacy of aBL in killing primary otopathogens, including planktonic bacteria, monomicrobial biofilms, and polymicrobial biofilms. Following this, as the in vitro safety study, we will evaluate the side effects of aBL on human middle ear cells by exposing the cells to 1×, 5×, and 10× the aBL exposures required for significant killing of otopathogens in vitro. We will initially assess the cytotoxicity of aBL to the middle ear cells. Additionally, we will determine whether aBL affects the barrier function of the epithelial cells by measuring transepithelial electrical resistance and whether aBL influences the migratory activity of human middle ear cells by performing an in vitro scratch assay. In Aim 2, we will first evaluate the in vivo efficacy of aBL in treating OM in chinchillas. Both acute and chronic (biofilm-related) OM will be studied. We have developed a novel optical device capable of delivering aBL to the middle ear cavity. The efficacy found with aBL will be compared with that of antibiotics currently used to treat OM. Following this, we will conduct an in vivo safety study by exposing the middle ears of healthy chinchillas to aBL at 1×, 5×, and 10× the aBL exposures required for curing OM in chinchillas. We will assess the effect of aBL on the auditory function of chinchillas by measuring auditory brain response and hair cell survival in the cochlea. Additionally, we will evaluate the middle ear tissue responses to aBL (e.g., ulcerations, excess granulation tissue, tympanosclerosis, inflammation, etc.) by using histopathology. Overall, this R21 application represents an initial effort to utilize aBL for treating OM. Thus, the most important impact resides in opening a branch of study on a new treatment for OM. Successful completion of the Specific Aims in this application will establish the first preclinical evidence required to determine the effectiveness and safety of aBL in treating OM, and will help develop protocols for using this regimen.