Antibiotic gel squirted into the ear could provide a one dose cure for ear infections

Middle-ear infection, or otitis media, affects 95 percent of children, prompting 12 to 16 million clinical visits per year in the U.S. alone. It's the number one reason for pediatric antibiotic prescriptions, but as parents know, getting oral antibiotics into young children several times a day for 7 to 10 days is a daunting task.

"Force-feeding antibiotics to a toddler by mouth is like a full-contact martial art," says Daniel Kohane, MD, PhD, the study's senior investigator and director of the Laboratory for Biomaterials and Drug Delivery at Boston Children's.

Children also seem to get better within a few days, so parents often stop treatment too soon. Incomplete treatment and frequent recurrence of otitis media (40 percent of children have four or more episodes) encourage the development of drug-resistant infections. And because high doses are needed to get enough antibiotic to the ear, side effects like diarrhea, rashes and oral thrush are common.

"With oral antibiotics, you have to treat the entire body repeatedly just to get to the middle ear," says Rong Yang, PhD, a chemical engineer in Kohane's lab and first author on the paper. "With the gel, a pediatrician could administer the entire antibiotic course all at once, and only where it's needed."

Penetrating the eardrum

Squirted into the ear canal, the gel quickly hardens and stays in place, gradually dispensing antibiotics across the eardrum into the middle ear. "Our technology gets things across the eardrum that don't usually get across, in sufficient quantity to be therapeutic," says Kohane.

Previously, the eardrum (also called the tympanic membrane) was an impenetrable barrier. The bioengineered gel gets drugs past it with the help of chemical permeation enhancers (CPEs), compounds FDA-approved for other uses that are structurally similar to the lipids in the stratum corneum, the eardrum's outermost layer. The CPEs insert themselves into the membrane, opening up molecular pores that allow the antibiotics to seep through.

When tested in chinchillas (rodents with a hearing range and ear structure similar to those of humans), the gel dispensed high concentrations of the antibiotic ciprofloxin in the middle ear and completely cured ear infections due to Haemophilus influenzae in 10 of 10 animals. Ordinary ciprofloxacin ear drops cleared the infection in only 5 of 8 animals by day 7.

There was no observable toxicity, and no antibiotic was detected in the animals' blood. Yang and Kohane observed a slight hearing loss, similar to that caused by earwax. Giving less of the gel alleviated the problem.

"Transtympanic delivery of antibiotics to the middle ear has the potential to enable children to benefit from the rapid antibacterial activity of antimicrobial agents without systemic exposure and could reduce emergence of resistant microbes," says Stephen Pelton, MD, a pediatric infectious disease physician at Boston Medical Center and a coauthor on the paper.

The work recently won a poster competition at the 2016 Massachusetts Life Sciences Innovation Day. Kohane has received a large, five-year NIH grant to further the work and an award from Boston Children's Hospital's Technology Development Fund to move the patented technology toward clinical use. Though further studies are needed, Kohane hopes to form a company that would begin testing the gel in patients in the next few months.

The study was done in collaboration with the Division of Pediatric Infectious Diseases at Boston Medical Center. Co-authors were Stephen Pelton and Vishakha Sabharwal of Boston Medical Center; John Rosowski of Massachusetts Eye and Ear; and Obiajulu Okonkwo, Nadya Shlykova, Rong Tong, Lily Yun Lin, Weiping Wang and Shutao Guo of Boston Children's Hospital.

Funding was provided by the Center for Integration of Medicine and Innovative Technology (U.S. Army Medical Research Acquisition Activity subcontract #W81XWH-09-2-0001), the Shereta Seelig Charitable Foundation Trust, the National Institutes of Health (DC015050) and the Department of Anesthesia at Boston Children's Hospital.