Treatment of otitis media by transtympanic delivery of antibiotics

Abstract

Otitis media is the most common reason U.S. children receive antibiotics. The requisite 7- to 10-day course of oral antibiotics can be challenging to deliver in children, entails potential systemic toxicity, and encourages selection of antimicrobial-resistant bacteria. We developed a drug delivery system that, when applied once to the tympanic membrane through the external auditory canal, delivers an entire course of antimicrobial therapy to the middle ear. A penta-block copolymer poloxamer 407–polybutylphosphoester (P407-PBP) was designed to flow easily during application and then to form a mechanically strong hydrogel on the tympanic membrane. U.S. Food and Drug Administration–approved chemical permeation enhancers within the hydrogel assisted flux of the antibiotic ciprofloxacin across the membrane. This drug delivery system completely eradicated otitis media from nontypable Haemophilus influenzae (NTHi) in 10 of 10 chinchillas, whereas only 62.5% of animals receiving 1% ciprofloxacin alone had cleared the infection by day 7. The hydrogel system was biocompatible in the ear, and ciprofloxacin was undetectable systemically (in blood), confirming local drug delivery and activity. This fast-gelling hydrogel could improve compliance, minimize side effects, and prevent systemic distribution of antibiotics in one of the most common pediatric illnesses, possibly minimizing the development of antibiotic resistance.

Getting Drugs Across Biological Barriers

“…Irritation has been defined based on in vitro cytotoxicity, [49] or in vivo reactions such as inflammation and necrosis. [3] The balance between effectiveness and irritation – however defined - is an important consideration when choosing small molecule CPEs. Indices derived from the physicochemical properties of a particular CPE (such as the cohesive energy density E c and dipole-dipole interactions δ p , see above) have been proposed as potential predictors of effectiveness and irritation.…”

“…[ 3 ] Sustained trans-tympanic drug transport has been realized with CPEs contained within a hydrogel (Figure 7). [3, 9] Peptides that can cross the TM of rats with otitis media (induced by nontypeable Haemophilus influenza ) have also been identified via phage display. [215] …”

“…[296] Increased permeability to drugs has also been observed in the tympanic membranes of animals with otitis media. [3] In a chinchilla animal model, the diffusion coefficient of the tympanic membranes with otitis increased to 10- to 15-fold of that in healthy tympanic membranes.…”

“…Transdermal drug delivery will receive special emphasis as it is the best studied and understood, and has had by far the greatest penetration into clinical practice. Delivery approaches across other barriers often derive from lessons learned from skin (e.g., CPEs to enhance drug penetration to nerve, [2] or across the tympanic membrane [3] ), or may not (e.g., receptor-mediated delivery across the blood-brain barrier [4] ). This review will cover barriers to drug delivery at the tissue/organ level; delivery into cells or cellular organelles has been reviewed elsewhere.…”

“…For example, CPEs increase drug flux across skin, [8] and the tympanic membrane, [3, 9] and dramatically enhance the local anesthetic effectiveness of tetrodotoxin in peripheral nerve. [2] However, they do not have much effect on tetrodotoxin in topical corneal anesthesia.…”