Skip to main content
SpringerLink
Log in
Book cover

Cell and Molecular Biology of the Ear pp 157–164Cite as

Mechanism and Prevention of Aminoglycoside-Induced Hearing Loss

  • Chapter

Abstract

Today, aminoglycoside antibiotics are the most commonly used antibiotics worldwide because of their high efficacy combined with low cost. However, toxicity to the kidney (nephrotoxicity) and the inner ear (ototoxicity) are two major side effects. This review presents a novel hypothesis of aminoglycoside ototoxicity and reports on a successful approach to its prevention.

Aminoglycoside antibiotics chelate iron, and the resulting iron-aminoglycoside complex is redox-active, catalyzing the formation of free radicals. Free radicals cause tissue damage while endogenous antioxidant systems limit the extent of toxicity. Consequently, ototoxicity can be prevented through the administration of antioxidants and iron chelators. Both hearing loss and vestibular dysfunction induced by several aminoglycosides were significantly attenuated by antioxidant therapy in guinea pigs without compromising the antibacterial efficacy of the drugs. This finding may lead to a safe and effective way to eliminate the threat of ototoxicity by this indispensable class of antibiotics.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Black, F.O., and Pesznecker, S.C. (1993). Vestibular ototoxicity: Clinical considerations. Otolaryngol. Clin. North. Am. 26, 713–736.

    CAS  Google Scholar 

  • Clerici, W.J., Hensley, K., DiMartino, D.L., and Butterfield, D.A. (1996). Direct detection of ototoxicant-induced reactive oxygen species generation in cochlear explants. Hear. Res. 98, 116–124.

    CAS  Google Scholar 

  • Crann, S.A., Huang, M.Y., McLaren, J.D., and Schacht, J. (1992). Formation of a toxic metabolite from gentamicin by a hepatic cytosolic fraction. Biochem. Pharmacol. 43, 1835–1839.

    CAS  Google Scholar 

  • de Groot, J.C., Meeuwsen, E, Ruizendaal, W.E., and Veldman, J.E. (1990). Ultrastructural localization of gentamicin in the cochlea. Hear. Res. 50, 35–42.

    Google Scholar 

  • Doelman, C.J., and Bast, A. (1990). Oxygen radicals in lung pathology. Free Radic. Biol. Med. 9, 381–400.

    CAS  Google Scholar 

  • Dulon, D., Zajic, G., Aran, J.M., and Schacht, J. (1989). Aminoglycoside antibiotics impair calcium-entry but not viability and motility of cochlear outer hair cells. J. Neurosci. Res. 24, 338–346.

    Article  PubMed  CAS  Google Scholar 

  • Fantone, J.C., and Ward, P.A. (1985). Polymorphonuclear leukocyte-mediated cell and tissue injury: Oxygen metabolites and their relations to human disease. Hum. Pathol. 16, 973–978.

    CAS  Google Scholar 

  • Federspil, P. (1979). Antibiotikaschäden des Ohres, pp. 86–89. Barth, Leipzig. Forge, A. (1985). Outer hair cell loss and supporting cell expansion following chronic gentamicin treatment. Hear. Res. 19, 171–182.

    Google Scholar 

  • Forge, A., and Fradis, M. (1985). Structural abnormalities in the stria vascularis following chronic gentamicin treatment. Hear. Res. 20, 233–244.

    CAS  Google Scholar 

  • Forge, A., and Schacht, J. (2000). Aminoglycoside antibiotics. Audiol. Neuro-Otol. 5, 3–22.

    Article  CAS  Google Scholar 

  • Fu, D.M. (1985). Survey of 1583 deaf mutes. Qinghai Med. J. 1, 22–23.

    Google Scholar 

  • Garcia-Quiroga, J., Norris, C.H., Glade, L., Bryant, G.M., Tachibana, M., and Guth, P.S. (1978). The relationship between kanamycin ototoxicity and glucose transport. Res. Comm. Chem. Pathol. Pharmacol. 22, 535–547.

    CAS  Google Scholar 

  • Hawkins, J.E. (1976). Drug ototoxicity. In Handbook of Sensory Physiology, (eds. W.D. Keidel, and W.D. Neff) pp. 707–748. Springer-Verlag. New York.

    Google Scholar 

  • Hinshaw, H.C., and Feldman, W.H. (1945). Streptomycin in treatment of clinical tuberculosis: a preliminary report. Proc. Mayo. Clinic. 20, 313–318.

    Google Scholar 

  • Hirose, K., Hockenbery, D.M., and Rubel, E.W. (1997). Reactive oxygen species in chick hair cells after gentamicin exposure in vitro. Hear. Res. 104,1–14.

    CAS  Google Scholar 

  • Hoffman, D.W., Whitworth, C.A., Jones-King, K.L., and Rybak, L.P. (1988). Potentiation of ototoxicity by glutathione depletion. Ann. Otol. Rhinol. Laryngol. 97, 36–41.

    PubMed  CAS  Google Scholar 

  • Huang, M.Y., and Schacht, J. (1990). Formation of a cytotoxic metabolite from gentamicin by liver. Biochem. Pharmacol. 40, R11–R14.

    CAS  Google Scholar 

  • Hulka, G.F., Prazma, J., Brownlee, R.E., Pulver, S., and Pillsbury, H.C. (1993). Use of poly-l-aspartic acid to inhibit aminoglycoside cochlear ototoxicity. Am. J. Otol. 14, 352–356.

    PubMed  CAS  Google Scholar 

  • Kanno, H., Yamanobe, S., and Rybak, L.P. (1995). The ototoxicity of deferoxamine mesylate. Am. J. Otolaryngol. 16,148–152.

    Article  PubMed  CAS  Google Scholar 

  • Kohlhepp, S.J., McGregor, D.N., Cohen, S.J., Kohlhepp, M.E., and Gilbert, D.N. (1992). Determinants of the in vitro interaction of polyaspartic acid and aminoglycoside antibiotics. J. Pharmacol. Exp. Ther. 263,1464–1470.

    PubMed  CAS  Google Scholar 

  • Kuhn, R.J., and Nahata, M.C. (1985). Therapeutic management of cystic fibrosis. Clin. Pharmacy 4, 555–565.

    CAS  Google Scholar 

  • Lautermann, J., McLaren, J., and Schacht, J. (1995). Glutathione protection against gentamicin ototoxicity depends on nutritional status. Hear. Res. 86, 15–24.

    CAS  Google Scholar 

  • Lodhi, S., Weiner, N.D., Mechigian, I., and Schacht, J. (1980). Ototoxicity of aminoglycosides correlated with their action on monomolecular films of polyphosphoinositides. Biochem. Pharmacol. 29, 597–6601.

    CAS  Google Scholar 

  • Lu, Y.F. (1987). Cause of 611 deaf mutes in schools for deaf children in Shanghai. Shanghai Med. J. 10, 159.

    Google Scholar 

  • Moore, R.D., Smith, C.R., and Lietman, P.S. (1984). Risk factors for the development of auditory toxicity in patients receiving aminoglycosides. J. Infect. Dis. 149, 23–30.

    Article  PubMed  CAS  Google Scholar 

  • Mulherin, D., Fahy, J., Grant, W, Keogan, M., Kavanagh, B., and Fitzgerald, M. (1991) Aminoglycoside induced ototoxicity inpatients with cystic fibrosis. Irish J. Med. Sci. 160,173–175.

    CAS  Google Scholar 

  • Peterson, C.M., Graziano, J.H., Grady, R.W., Jones, R.L., Markenson, A., Lavi, U., Canale, V., Gray, G.F., Cerami, A., and Miller, D.R. (1979). Chelation therapy in beta-thalassemia major: a one-year double blind study of 2,3-dihydroxybenzoic acid. Exp. Hematol. 7, 74–80.

    CAS  Google Scholar 

  • Prezant, T.R., Agapian, J.V., Bohlman, M.C., Bu, X., Oztas, S., Qiu, W.Q., Arms, K.S., Cortopassi, G.A., Jaber, L., and Rotter, J.I. (1993). Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nature Genetics. 4, 289–94.

    Article  PubMed  CAS  Google Scholar 

  • Priuska, E., and Schacht, J. (1995). Formation of free radicals by gentamicin and iron and evidence for an iron/gentamicin complex. Biochem. Pharmacol. 50,1749–1752.

    CAS  Google Scholar 

  • Priuska, E., Clark, K., Pecoraro, V., and Schacht, J. (1998). NMR spectra of iron-gentamicin complexes and the implications for aminoglycoside toxicity. Inorg. Chim. Acta, 273, 85–91.

    CAS  Google Scholar 

  • Pullan, L.M., Stumpo, R.J., Powel, R.J., Paschetto, K.A., and Britt, M. (1992). Neomycin is an antagonist at a polyamine site in the N-methyl-D-aspartate receptor. J. Neurochem. 59, 2087–2093.

    Article  PubMed  CAS  Google Scholar 

  • Ryals, B., Westbrook, E., and Schacht, J. (1997). Morphological evidence of ototoxicity of the iron chelator deferoximine. Hear. Res. 112, 44–48.

    CAS  Google Scholar 

  • Schacht, J. (1993). Biochemical basis of aminoglycoside ototoxicity. Otolaryngol. Clin. North. Am. 26, 845–856.

    CAS  Google Scholar 

  • Schacht, J. (1979). Isolation of an aminoglycoside receptor from guinea pig inner ear tissues and kidney. Arch. Otorhinolaryngol. 224, 129–134.

    Article  CAS  Google Scholar 

  • Schatz, A., Bugie, E., and Waksman, S.A. (1944). Streptomycin, a substance exhibiting antibiotic activity against gram-positive and gram-negative bacteria. Proc. Soc. Exp. Biol. Med. 55, 66–69.

    CAS  Google Scholar 

  • Seiler, N., Hardy, A., and Moulinoux, J.P. (1996). Aminoglycosides and polyamines: Targets and effects in the mammalian organism of two important groups of natural aliphatic polycations. Progr. Drug Res. 46, 183–241.

    CAS  Google Scholar 

  • Sha, S.-H., and Schacht, J. (1999a). Formation of reactive oxygen species following bioactivation of gentamicin. Free Radi. Biol. Med. 26, 341–347.

    CAS  Google Scholar 

  • Sha, S.H., and Schacht, J. (1999b) Salicylate attenuates gentamicin-induced ototoxicity. Lab. Invest. 79, 807–813.

    CAS  Google Scholar 

  • Sha, S.H., and Schacht, J. (2000). Antioxidants attenuate gentamicin-induced free-radical formation in vitro and ototoxicity in vivo: D-methionine is a potential protectant. Hear. Res. 142, 34–40.

    CAS  Google Scholar 

  • Sha, S.-H., Zajic, G., and Schacht, J. (1997). Transgenic mice overexpressing copper-zinc superoxide dismutase are protected from kanamycin-induced ototoxicity. Assoc. Res. Otolaryngol. 20,122.

    Google Scholar 

  • Shafer, R.W., Chirgwin, K.D., Glatt, A.E., Dandouh, M.A., Landesman, S.H., and Suster, B. (1991). HIV prevalence, immunosuppression, and drug resistance in patients with tuberculosis in an area endemic for AIDS. AIDS 5, 399–406.

    Article  PubMed  CAS  Google Scholar 

  • Song, B.-B., Anderson, D.J., and Schacht, J. (1997). Protection from gentamicin ototoxicity by iron chelators in guinea pig in vivo. J. Pharmacol. Exp. Ther. 282, 369–377.

    PubMed  CAS  Google Scholar 

  • Song, B.-B., and Schacht, J. (1996). Variable efficacy of radical scavengers and iron chelators to attenuate gentamicin ototoxicity in guinea pig in vivo. Hear. Res. 94, 87–93.

    CAS  Google Scholar 

  • Song, B.-B., Sha, S.-H., and Schacht, J. (1998). Iron chelators protect from aminoglycoside-induced cochleo-and vestibulo-toxicity. Free Rad. Biol. Med. 25, 189–195.

    CAS  Google Scholar 

  • Sudre, P, ten Dam, G., and Kochi, A. (1992). Tuberculosis: a global overview of the situation today. Bull. WHO 70,149–159.

    PubMed  CAS  Google Scholar 

  • Usami, S., Abe, S., Tono, T., Komune, S., Kimberling, W.J., and Shinkawa, H. (1998). Isepamicin sulfate-induced sensorineural hearing loss in patients with the 1555 A -* G mitochondrial mutation. ORL 60,164–169.

    Article  PubMed  CAS  Google Scholar 

  • Usami, S., Hjelle, O.P., and Ottersen, O.P. (1996). Differential cellular distribution of glutathione-an endogenous antioxidant-in the guinea pig inner ear. Brain Res. 743, 337–340.

    Article  PubMed  CAS  Google Scholar 

  • Walker, P.D., and Shah, S.V. (1987). Gentamicin enhanced production of hydrogen peroxide by renal cortical mitochondria. Am. J. Physiol. 253, C495–C499.

    PubMed  CAS  Google Scholar 

  • Wang, B.M., Weiner, N.D., Takada, A., and Schacht, J. (1984). Characterization of aminoglycoside-lipid interactions and development of a refined model for ototoxicity testing Biochem Pharmacol 33, 3257–3262.

    CAS  Google Scholar 

  • Warchol, M.E., Lambert, PR., Goldstein, B.J., Forge, A., and Corwin, J.T. (1993). Regenerative prolifer-ation in inner ear sensory epithelia from adult guinea pigs and humans. Science 259,1619–1622.

    Article  PubMed  CAS  Google Scholar 

  • Ward, P.A., Till, G.O., Kunkel, R., and Beauchamp, C. (1983). Evidence for role of hydroxyl radical in complement and neutrophil-dependent tissue injury. J. Clin. Invest. 72, 789–801.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Kresge Hearing Research Institute, Department of Otolaryngology, University of Michigan, Ann Arbor, MI, USA

    Su-Hua Sha & Jochen Schacht

Authors
  1. Su-Hua Sha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jochen Schacht
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. House Ear Institute, Los Angeles, California, USA

    David J. Lim

Rights and permissions

Reprints and permissions

Copyright information

© 2000 Kluwer Academic/Plenum Publishers, New York

About this chapter

Cite this chapter

Sha, SH., Schacht, J. (2000). Mechanism and Prevention of Aminoglycoside-Induced Hearing Loss. In: Lim, D.J. (eds) Cell and Molecular Biology of the Ear. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4223-0_12

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-4223-0_12

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-6896-0

  • Online ISBN: 978-1-4615-4223-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation