Trans-tympanic delivery of antibiotics to treat otitis media
Rong Yang, Daniel Kohane
Harvard Medical School, Children’s Hospital Boston
Otitis media (OM) is a major child health burden in the United States. Twelve to 16 million physician visits per year in the United States are attributed to OM, making it the most common specifically treated childhood disease.[1, 2] Acute otitis media (AOM) has a prevalence of 90% within the first 5 years of life and is the most common reason for antimicrobial prescribing in US children. Frequent recurrences of this highly prevalent disease (1/3 of all children in the U.S. having 6 or more episodes of AOM by age 7)[4, 5] are believed to be partially responsible for the ongoing increase in antibiotic resistance among pathogenic bacteria as current therapy for AOM typically consists of a 10-day course of broad spectrum oral antibiotics [6, 7]. The annual impact of antibiotic-resistant infections on the U.S. economy have ranged as high as $20 billion in excess direct health care costs, and as much as $35 billion in lost productivity from hospitalizations and sick days.
Local, sustained delivery of active therapeutics directly to the middle ear for the treatment of OM could potentially minimize systemic exposure and allow for much higher middle ear drug concentrations than from systemic administration. However, the tympanic membrane (TM), while only about 100 μm thick, presents a barrier that is largely impermeable to all but the smallest lipophilic molecules due to its keratin- and lipid-rich stratum corneum.
We successfully designed and synthesized a non-invasive trans-tympanic OM treatment platform that produces sustained and sufficient drug flux across the TM to treat acute OM in chinchillas. A multicomponent hydrogel with reverse thermal gelation was applied in situ. Design of the molecular structure of the hydrogel was directed by two principles: 1) enhance the gelation process, particularly in the presence of small molecules that enhance the drug flux across the TM; and 2) improve adherence of the gel to TM. One simple chemical modification leads to faster gelation rate and considerably improved mechanical properties of the gel formed in situ. We chose ciprofloxacin as the antibiotic because a) it is small (331 da), moderately hydrophobic (log P = 0.28), can be dissolved at relatively high concentration in aqueous solution at acidic pH (pKa = 6.16), and has a broad antibacterial spectrum, b) it is currently used successfully clinically to treat acute otorrhea in children with tympanostomy tubes. The effects of small molecule additives on the mechanical properties of the hydrogel were investigated systematically and can be used as important reference for the design of future multicomponent polymeric systems. As a proof-of-concept, as designed multicomponent formulation was applied in single application to chinchillas infected with non-typable Haemophilus influenzae (NTHi) and was sufficient to provide high concentrations of antibiotics localized to the middle ear, resulting in eradication of bacterial OM without the systemic exposure of oral therapy. Additionally, application of the formulation can alleviate the formation of biofilm, which has been implicated in the pathogenesis and persistence of OM.
(1) Berman, S. Otitis media in children. N Engl J Med 1995, 332, 1560-5.
(2) Fried, V. M.; Makuc, D. M. Rooks, R. N. Ambulatory health care visits by children: principal diagnosis and place of visit.; 137; Washington, D.C.: Government Printing Office, 1998.: 1998.
(3) Teele, D. W.; Klein, J. O. Rosner, B. Epidemiology of otitis media during the first seven years of life in children in greater Boston: a prospective, cohort study. J Infect Dis 1989, 160, 83-94.
(4) Faden, H.; Duffy, L. Boeve, M. Otitis media: back to basics. Pediatr Infect Dis J 1998, 17, 1105-12; quiz 1112-3.
(5) Lanphear, B. P.; Byrd, R. S.; Auinger, P. Hall, C. B. Increasing prevalence of recurrent otitis media among children in the United States. Pediatrics 1997, 99, E1.
(6) Bluestone, C. D. Klein, J. O., in Otitis media in infants and children, BC Decker, Hamilton, Ontario, Canada 2006.
(7) Bluestone, C. D. Klein, J. O., in Otitis media in infants and children, BC Decker, Hamilton, ON 2007.
(8) Antibiotic / Antimicrobial Resistance. http://www.cdc.gov/drugresistance/
(9) Doyle, W. J.; Alper, C. M.; Seroky, J. T. Karnavas, W. J. Exchange rates of gases across the tympanic membrane in rhesus monkeys. Acta Otolaryngol 1998, 118, 567-73.