Effects of an enrofloxacin–silver sulfadiazine emulsion in the ears of rabbits with perforated tympanic membranes

Fiona L. Bateman 1Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

Search for other papers by Fiona L. Bateman in
Current site
Google Scholar
PubMed
Close
 BVSc
,
Shannon G. M. Kirejczyk 2Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

Search for other papers by Shannon G. M. Kirejczyk in
Current site
Google Scholar
PubMed
Close
 DVM, MPH
,
Georgina V. Stewart 1Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

Search for other papers by Georgina V. Stewart in
Current site
Google Scholar
PubMed
Close
 BVSc
,
Daniel C. Cutler 1Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

Search for other papers by Daniel C. Cutler in
Current site
Google Scholar
PubMed
Close
 DVM
,
Laura L. Quilling 1Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

Search for other papers by Laura L. Quilling in
Current site
Google Scholar
PubMed
Close
 DVM
,
Elizabeth W. Howerth 2Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

Search for other papers by Elizabeth W. Howerth in
Current site
Google Scholar
PubMed
Close
 DVM, PhD
, and
Joerg Mayer 1Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

Search for other papers by Joerg Mayer in
Current site
Google Scholar
PubMed
Close
 DVM, MS

Abstract

OBJECTIVE

To determine whether an enrofloxacin–silver sulfadiazine emulsion (ESS) labeled for treatment of otitis externa in dogs has ototoxic effects in rabbits following myringotomy.

ANIMALS

6 healthy adult New Zealand White rabbits.

PROCEDURES

Rabbits were anesthetized for brainstem auditory-evoked response (BAER) tests on day 0. Myringotomy was performed, and BAER testing was repeated. Saline (0.9% NaCl) solution and ESS were then instilled in the left and right middle ears, respectively, and BAER testing was repeated prior to recovery of rabbits from anesthesia. Application of assigned treatments was continued every 12 hours for 7 days, and rabbits were anesthetized for BAER testing on day 8. Rabbits were euthanized, and samples were collected for histologic (6 ears/treatment) and scanning electron microscopic (1 ear/treatment) examination.

RESULTS

Most hearing thresholds (11/12 ears) were subjectively increased after myringotomy, with BAER measurements ranging from 30 to 85 dB in both ears. All day 8 hearing thresholds exceeded baseline (premyringotomy) values; results ranged from 30 to 85 dB and 80 to > 95 dB (the upper test limit) in saline solution–treated and ESS-treated ears, respectively. All ESS-treated ears had heterophilic otitis externa, epithelial hyperplasia of the external ear canal, various degrees of mucoperiosteal edema, and periosteal new bone formation on histologic examination. Scanning electron microscopy revealed that most outer hair cells in the ESS-treated ear lacked stereocilia or were absent.

CONCLUSIONS AND CLINICAL RELEVANCE

Results supported that ESS has ototoxic effects in the middle ear of rabbits. Further research is needed to confirm these findings. Myringotomized laboratory rabbits may be useful to study ototoxicity of drugs used in human medicine.

Abstract

OBJECTIVE

To determine whether an enrofloxacin–silver sulfadiazine emulsion (ESS) labeled for treatment of otitis externa in dogs has ototoxic effects in rabbits following myringotomy.

ANIMALS

6 healthy adult New Zealand White rabbits.

PROCEDURES

Rabbits were anesthetized for brainstem auditory-evoked response (BAER) tests on day 0. Myringotomy was performed, and BAER testing was repeated. Saline (0.9% NaCl) solution and ESS were then instilled in the left and right middle ears, respectively, and BAER testing was repeated prior to recovery of rabbits from anesthesia. Application of assigned treatments was continued every 12 hours for 7 days, and rabbits were anesthetized for BAER testing on day 8. Rabbits were euthanized, and samples were collected for histologic (6 ears/treatment) and scanning electron microscopic (1 ear/treatment) examination.

RESULTS

Most hearing thresholds (11/12 ears) were subjectively increased after myringotomy, with BAER measurements ranging from 30 to 85 dB in both ears. All day 8 hearing thresholds exceeded baseline (premyringotomy) values; results ranged from 30 to 85 dB and 80 to > 95 dB (the upper test limit) in saline solution–treated and ESS-treated ears, respectively. All ESS-treated ears had heterophilic otitis externa, epithelial hyperplasia of the external ear canal, various degrees of mucoperiosteal edema, and periosteal new bone formation on histologic examination. Scanning electron microscopy revealed that most outer hair cells in the ESS-treated ear lacked stereocilia or were absent.

CONCLUSIONS AND CLINICAL RELEVANCE

Results supported that ESS has ototoxic effects in the middle ear of rabbits. Further research is needed to confirm these findings. Myringotomized laboratory rabbits may be useful to study ototoxicity of drugs used in human medicine.

Contributor Notes

Dr. Bateman's present address is Animal Dermatology Clinic, 1453 Terrell Mill Rd SE, #119, Marietta, GA 30067.

Dr. Kirejczyk's present address is Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329.

Dr. Stewart's present address is Summit Veterinary Referral Center, 2505 South 80th St, Tacoma, WA 98409.

Dr. Quilling's present address is Gulf Coast Veterinary Specialists, 1030 Wirt Rd, Houston, TX 77055.

Address correspondence to Dr. Bateman (fbateman@adcmg.com).
  • 1. Csomos R, Bosscher G, Mans C, et al. Surgical management of ear diseases in rabbits. Vet Clin North Am Exot Anim Pract 2016;19:189204.

  • 2. Flatt RE, Deyoung DW, Hogle RM. Suppurative otitis media in the rabbit: prevalence, pathology and microbiology. Lab Anim Sci 1977;27:343347.

    • Search Google Scholar
    • Export Citation
  • 3. Matz G, Rybak L, Roland PS, et al. Ototoxicity of ototopical antibiotic drops in humans. Otolaryngol Head Neck Surg 2004;130(suppl 3):S79S82.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Roland PS, Rybak L, Hannley M, et al. Animal ototoxicity of topical antibiotics and the relevance to clinical treatment of human subjects. Otolaryngol Head Neck Surg 2004;130(suppl 3):S57S78.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Brummett RE, Harris RF, Lindgren JA. Detection of ototoxicity from drugs applied topically to the middle ear space. Laryngoscope 1976;86:11771187.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Jakob T, Wright CG, Robinson K, et al. Ototoxicity of topical ticarcillin and clavulanic acid in the chinchilla. Arch Otolaryngol Head Neck Surg 1995;121:3943.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Paterson S. Brainstem auditory evoked responses in 37 dogs with otitis media before and after topical therapy. J Small Anim Pract 2018;59:1015.

  • 8. Jang CH, Park H, Cho YB, et al. Evaluating the ototoxicity of topical piperacillin-tazobactam. Int J Pediatr Otorhinolaryngol 2008;72:18151821.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Kavanagh KR, Parham K, Schoem SR. Auditory function after a prolonged course of ciprofloxacin-dexamethasone otic suspension in a murine model. Arch Otolaryngol Head Neck Surg 2009;135:238241.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10. Phillips JS, Yung MW, Burton MJ, et al. Evidence review and ENT-UK consensus report for the use of aminoglycoside-containing ear drops in the presence of an open middle ear. Clin Otolaryngol 2007;32:330336.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11. Serin GM, Ciprut A, Baylançiçek S, et al. Ototoxic effect of Burow solution applied to the guinea pig middle ear. Otol Neurotol 2007;28:605608.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Harris AS, Elhassan HA, Flook EP. Why are ototopical aminoglycosides still first-line therapy for chronic suppurative otitis media? A systematic review and discussion of aminoglycosides versus quinolones. J Laryngol Otol 2016;130:27.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13. Macfadyen CA, Acuin JM, Gamble C. Systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations. Cochrane Database Syst Rev 2006;25:CD005608.

    • Search Google Scholar
    • Export Citation
  • 14. Macfadyen C, Gamble C, Garner P, et al. Topical quinolone vs. antiseptic for treating chronic suppurative otitis media: a randomized controlled trial. Trop Med Int Health 2005;10:190197.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15. Bruyette DS, Lorenz MD. Otitis externa and otitis media: diagnostic and medical aspects. Semin Vet Med Surg (Small Anim) 1993;8:39.

    • Search Google Scholar
    • Export Citation
  • 16. Morris DO. Medical therapy of otitis externa and otitis media. Vet Clin North Am Small Anim Pract 2004;34:541555.

  • 17. Stieve M, Mojallal H, Winter M, et al. Normative auditory brainstem response data for hearing threshold in the rabbit. Audiol Neurootol 2006;11:310317.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18. Mujica-Mota MA, Bezdjian A, Salehi P, et al. Assessment of ototoxicity of intratympanic administration of Auralgan in a chinchilla animal model. Laryngoscope 2015;125:14441448.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19. Rask-Andersen H, Schrott-Fischer A, Pfaller K, et al. Perilymph/modiolar communication routes in the human cochlea. Ear Hear 2006;27:457465.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20. Zine EA, Romand R. Expression of alpha-actinin in the stereocilia of hair cells of the inner ear: immunohistochemical localization. Neuroreport 1993;4:13501352.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21. Becvarovski Z, Bojrab DI, Michaelides EM, et al. Round window gentamicin absorption: an in vivo human model. Laryngoscope 2002;112:16101613.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22. Helal A. Aminoglycoside eardrops and ototoxicity. CMAJ 1997;156:10561058.

  • 23. Bath AP, Walsh RM, Bance ML, et al. Ototoxicity of topical gentamicin preparations. Laryngoscope 1999;109:10881093.

  • 24. Marais J, Rutka JA. Ototoxicity and topical eardrops. Clin Otolaryngol Allied Sci 1998;23:360367.

  • 25. Macfadyen CA, Acuin JM, Gamble CL. Topical antibiotics without steroids for chronically discharging ears with underlying eardrum perforations. Cochrane Database Syst Rev 2005;19:CD004618.

    • Search Google Scholar
    • Export Citation
  • 26. Samarei R. Comparison of local and systemic ciprofloxacin ototoxicity in the treatment of chronic media otitis. Glob J Health Sci 2014;6:144149.

    • Search Google Scholar
    • Export Citation
  • 27. Lemke LE, McGee DDH, Prieskorn DM, et al. Safety of ciprofloxacin and dexamethasone in the guinea pig middle ear. Arch Otolaryngol Head Neck Surg 2009;135:575580.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28. Daniel SJ, Munguia R. Ototoxicity of topical ciprofloxacin/dexamethasone otic suspension in a chinchilla animal model. Otolaryngol Head Neck Surg 2008;139:840845.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29. Lanvers-Kaminsky C, Zehnhoff-Dinnesen AA, Parfitt R, et al. Drug-induced ototoxicity: mechanisms, pharmacogenetics, and protective strategies. Clin Pharmacol Ther 2017;101:491500.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30. Brummett RE, Fox KE. Aminoglycoside-induced hearing loss in humans. Antimicrob Agents Chemother 1989;33:797800.

  • 31. Rastogi V, Puri N, Arora S, et al. Artefacts: a diagnostic dilemma—a review. J Clin Diagn Res 2013;7:24082413.

  • 32. Njaa BL. The ear. In: Zachary J, ed. Pathologic basis of veterinary disease. 6th ed. St Louis: Elsevier Health Sciences, 2017;12231264.

    • Search Google Scholar
    • Export Citation
  • 33. Schafer KA, Bolon B. Special senses—ear. In: Wallig MA, Haschek WM, Rousseaux CG, et al, eds. Fundamentals of toxicologic pathology. 3rd ed. St Louis: Elsevier Health Sciences, 2018;729747.

    • Search Google Scholar
    • Export Citation
  • 34. Raphael Y, Altschuler RA. Scar formation after drug-induced cochlear insult. Hear Res 1991;51:173183.

  • 35. Martin L. Models related to hearing loss. In: Suckow MA, Stevens KA, Wilson RP, eds. The laboratory rabbit, guinea pig, hamster, and other rodents. St Louis: Elsevier Health Sciences, 2012;10171023.

    • Search Google Scholar
    • Export Citation
  • 36. Lansdown AB, Williams A, Chandler S, et al. Silver absorption and antibacterial efficacy of silver dressings. J Wound Care 2005;14:155160.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37. García AA, Rodríguez Martin AM, Serra Baldrich E, et al. Allergic contact dermatitis to silver in a patient treated with silver sulphadiazine after a burn. J Eur Acad Dermatol Venereol 2016;30:365366.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38. Fuller FW. The side effects of silver sulfadiazine. J Burn Care Res 2009;30:464470.

  • 39. Fisher NM, Marsh E, Lazova R. Scar-localized argyria secondary to silver sulfadiazine cream. J Am Acad Dermatol 2003;49:730732.

  • 40. Perez R, Freeman S, Sohmer H, et al. Vestibular and cochlear ototoxicity of topical antiseptics assessed by evoked potentials. Laryngoscope 2000;110:15221527.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41. Emami N, Daniel SJ. Ototoxicity of olive oil in a chinchilla animal model. Laryngoscope 2013;123:20092012.

  • 42. Al-Jarallah A, Akinpelu OV, Citra D, et al. Ototoxicity of baby oil in a chinchilla animal model. Int J Pediatr Otorhinolaryngol 2012;76:564568.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43. Peleva E, Mourad S, Citra D, et al. Assessment of the ototoxicity of almond oil in a chinchilla animal model. Laryngoscope 2011;121:26612664.

  • 44. Nader ME, Saliba I. Ototoxicity of intratympanic docusate sodium and mineral oil in the guinea pig. Otolaryngol Head Neck Surg 2012;146:455460.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45. Morizono T. Toxicity of ototopical drugs: animal modeling. Ann Otol Rhinol Laryngol Suppl 1990;148:4245.

  • 46. Schuknecht H, Gulya A. Anatomy of the temporal bone with surgical implications. Philadelphia: Lea & Febiger, 1986.

  • 47. Brown OE, Wright CG, Meyerhoff WL. Workshop on Chronic Suppurative Otitis Media: Etiology and Management. August 29–30, 1985, Pittsburgh, Pennsylvania. Proceedings. Ann Otol Rhinol Laryngol Suppl 1988;131:3840.

    • Search Google Scholar
    • Export Citation
  • 48. Baytril Otic [package insert]. Shawnee Mission, Kan: Bayer HealthCare LLC, 2017.

Advertisement