SBIR-STTR Award

Over one-quarter of all oral antibiotics is prescribed for acute otitis media in the United States. Myringotomy with tympanostomy tube insertion has become the treatment of choice for children with chronic otitis media, with more than two million tubes sold annually in the US. Tympanostomy is the most common pediatric procedure under general anesthesia in the developed world. Chronic post-tympanostomy tube otorrhea is often refractory to treatment and inflicts significant morbidity in the form of hearing loss and long-term middle ear dysfunction. The Co-investigators have confirmed that chronic middle ear infection is a mucosal biofilm disease, and this may explain why otitis media is often difficult to treat with antibiotics. Biofilm on the surface of tympanostomy tubes may be a primary factor in post-tympanostomy otorrhea, and may thus be a source of recurrent infections. Current tympanostomy tubes are ineffective in retarding bacterial attachment and biofilm development. We have discovered that a specific combination of antimicrobial/antibiotic agents incorporated in approved implant host polymers is very effective against bacterial attachment and biofilm development of organisms associated with otitis media. The goal of this study is to develop and test biofilm polymicrobial- resistant implant materials for use as tympanostomy tube implants. The Specific Aims are: 1) to develop polymeric implant materials with selected combinations of antibacterial/antibiotic agents using novel processing methods, and to study their release kinetics, 2) to evaluate bacterial attachment and biofilm development against organisms associated with otitis media, and to define the characteristics of the various antimicrobial/antibiotic combinations to determine MIC values pertaining to planktonic and biofilm inhibition, and 3) to assess the ototoxicity/cytotoxicity of the various antimicrobial/antibiotic combinations. The central innovation of this study is the development of effective implant materials by using special combinations of antimicrobial agents that could specifically retard biofilm development and minimize recurrence of disease, with emphasis on otitis media.

Thesaurus Terms:
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Over one-quarter of all oral antibiotics prescribed in the United States are for acute otitis media. Tympanostomy tube (TT) insertion has become the treatment of choice for children with recurrent or chronic otitis media, with more than two million tubes sold annually in the US. Tympanostomy is the most common pediatric procedure under general anesthesia in the developed world. Chronic post-tympanostomy tube otorrhea (PTTO) is often refractory to treatment and inflicts significant morbidity in the form of hearing loss and long-term middle ear dysfunction. The Co-investigators have confirmed that chronic middle ear infection is a mucosal biofilm disease, and this may explain why otitis media is often difficult to treat with antibiotics. Biofilm growth on the TT surface and on middle ear mucosa may be a source of recurrent infections, and thus may also be a primary contributor. Between 10% and 50% of children with tubes experience otorrhea, and approximately 25% of children with a primary set of tubes will have to go on to have a second set of tubes. Based on prior studies, we believe that we can reduce the number of episodes and episode duration of PTTO by creating antimicrobial eluting ear tubes based on developing novel materials. We have designed a combination therapy that will provide broad-spectrum activity against planktonic and biofilm-forming species associated with otitis media. The antimicrobials selected will also reduce the likelihood of the development of resistant strains. We have demonstrated in Phase I that we can suppress biofilm formation and planktonic growth of Pseudomonas aeruginosa and Staphylococcus aureus for an extended period of time. By modifying the release kinetics, we believe we can increase this time period of efficacy even further. Our data also suggests that we have a synergistic interaction between antimicrobials. We have also demonstrated that we can make materials which are not cytotoxic to rabbit fibroblasts. The Specific Aims of this Phase II study are: 1) to optimize the release kinetics of our new materials and to injection mold TTs, 2) to confirm our in vitro studies with Haemophilus influenzae and Streptococcus pneumoniae, and quantify synergy and monitor for the development of resistant strains, 3) to assess ototoxicity, sensitivity and irritation in animal models, and 4) to compare the ability of experimental tubes with control tubes to treat and prevent PTTO in the chinchilla model of otitis media.

Public Health Relevance:
In Phase I, we developed a combination of antimicrobial/antibiotic compounds incorporated in host polymers that significantly inhibits bacterial attachment and biofilm development of organisms associated with otitis media. We plan to develop tympanostomy tube materials using such combination strategies and test their safety in an established animal model.

Thesaurus Terms:
0-11 Years Old; 2,6-Diacetyl-7,9-Dihydroxy-8,9b-Dimethyl-1,3(2h,9bh)-Dibenzofurandione; 3-Quinolinecarboxylic Acid, 1-Cyclopropyl-6-Fluoro-1,4-Dihydro-4-Oxo-7-(1-Piperazinyl)-; Acetates; Acute; Address; Adhesions; Adverse Effects; Affect; Animal Model; Animal Models And Related Studies; Animals; Antibiotic Agents; Antibiotic Drugs; Antibiotics; Aspiration Of Middle Ear; Auditory Brainstem Responses; Cavia; Chemicals; Child; Child Youth; Childhood; Children (0-21); Chinchilla; Chinchilla (Genus); Chronic; Ciprofloxacin; Clinical Trials, Phase Ii; Combined Modality Therapy; Communities; Complex; D. Pneumoniae; D.Pneumoniae; Data; Development; Diplococcus Pneumoniae; Disease; Disorder; Drainage; Drainage Procedure; Dysfunction; Eff; Ear; Ear Structure; Eardrum; Elements; Equipment; Fibroblasts; Functional Disorder; Fungi, Filamentous; General Anesthesia; Generalized Growth; Genomics; Growth; Guinea Pigs; H. Influenza; H. Influenzae; H.Influenza; H.Influenzae; Haemophilus Influenzae; Health Care Costs; Health Costs; Healthcare Costs; Hearing; Hearing Loss; Human, Child; Hypoacuses; Hypoacusis; Implant; In Vitro; Infection; Injection Of Therapeutic Agent; Injections; Investigators; Kinetic; Kinetics; Liquid Substance; Longitudinal Studies; Mrsa; Mammals, Guinea Pigs; Mammals, Rabbits; Measures; Membrana Tympanica; Methicillin Resistant S. Aureus; Methicillin Resistant Staphylococcus Aureus; Methods; Microbial Biofilms; Microorganisms, General; Middle Ear Implant; Middle Ear Paracentesis; Miscellaneous Antibiotic; Modeling; Molds; Monitor; Morbidity; Morbidity - Disease Rate; Mucosa; Mucosal Tissue; Mucous Membrane; Multimodal Therapy; Multimodal Treatment; Multimodality Treatment; Myringostomy; Myringotomy; Oral; Organism; Oryctolagus Cuniculus; Ostamer; Otitis Media; Otorrhea; Outcome Measure; P. Aeruginosa; P.Aeruginosa; Paracentesis Of Tympanum; Pellethane; Phase; Phase 2 Clinical Trials; Phase Ii Clinical Trials; Physiopathology; Plastics; Play; Pneumococcus; Polyisocyanates; Polymers; Polyurethanes; Procedures; Process; Pseudomonas Aeruginosa; Pseudomonas Pyocyanea; Public Health; Rabbit, Domestic; Rabbits; Recurrence; Recurrent; Refractory; Research Personnel; Researchers; Resistance; Resistance Development; Resistant Development; Responses, Auditory Brainstem; Role; S. Aureus; S. Pneumoniae; S.Aureus; Safety; Science; Solutions; Source; Staphylococcus Aureus; Streptococcus Pneumoniae; Surface; System; System, Loinc Axis 4; Technology; Testing; Time; Tissue Growth; Treatment Side Effects; Tube; Tympanic Membrane; Tympanic Membrane Structure; Tympanocentesis; Tympanostomy; Tympanostomy Tube Insertions; Tympanotomy; United States; Anti-Microbial; Antimicrobial; Base; Biofilm; Children; Cohort; Combination Therapy; Combined Modality Treatment; Combined Treatment; Copolymer; Cytotoxic; Cytotoxicity Test; Design; Designing; Developing Resistance; Disease/Disorder; Ear Drum; Ear Infection; Effusion; Experience; Fluid; Hearing Impairment; Hearing Perception; Implant Material; Irritation; Liquid; Living System; Long-Term Study; Medical Implant; Methicillin Resistant Staphylococcus Aureus (Organism); Microorganism; Middle Ear; Model Organism; Multimodality Therapy; New Technology; Novel; Ontogeny; Ototoxicity; Pathogen; Pathophysiology; Pediatric; Phase 2 Study; Phase 2 Trial; Phase Ii Trial; Prevent; Preventing; Primary Outcome; Protocol, Phase Ii; Public Health Medicine (Field); Public Health Relevance; Resistant; Resistant Strain; Side Effect; Social Role; Sound Perception; Stem; Study, Phase Ii; Therapy Adverse Effect; Treatment Adverse Effect; Usnic Acid; Youngster