Neutrophil-mediated delivery of antibiotics across the tympanic membrane for otitis media treatment in a preclinical model.

Abstract

Acute otitis media (AOM) is a leading cause of pediatric antibiotic prescriptions. Systemic antibiotics cause side effects and antibiotic resistance, whereas local delivery of antibiotics (directly to the middle ear) is hindered by an impermeable biological barrier, the tympanic membrane (TM). Here, we developed hydroxylated liposomes that are internalized by neutrophils recruited during AOM to transport encapsulated ciprofloxacin across the intact TM. In mice, complement opsonization of the hydroxylated liposomes increased neutrophil uptake ex vivo and in vivo. In chinchillas with AOM induced by nontypeable, a hydrogel formulation containing the hydroxylated liposomes applied topically to the TM led to middle ear concentrations of ciprofloxacin that were 36-fold higher than those achieved by liposome-free hydrogels. The pathogens were undetectable within 24 hours, which compares favorably to the current 5- to 10-day treatment using oral antibiotics. The treated TM appeared identical to the pristine ones, and auditory brainstem response thresholds in healthy animals were unchanged by the treatment. Depleting complement proteins using cobra venom factor reduced the transtympanic delivery efficiency and led to a cure rate of 25%, implicating the essential role of complement opsonization in enabling neutrophil hitchhiking. Unlike previous immune cell-based delivery approaches, our method achieves neutrophil hitchhiking through a simple topical application of hydroxylated liposomes, thereby eliminating the need for invasive neutrophil harvesting. It points to a potential low-cost and noninvasive treatment for this prevalent disease, poised to reduce pediatric antibiotic usage.