Adverse outcome pathway for aminoglycoside ototoxicity in drug-resistant tuberculosis treatment

  • Hyejeong HongEmail author
  • Kelly E. Dooley
  • Laura E. Starbird
  • Howard W. Francis
  • Jason E. Farley
Organ Toxicity and Mechanisms


Individuals treated for multidrug-resistant tuberculosis (MDR-TB) with aminoglycosides (AGs) in resource-limited settings often experience permanent hearing loss. However, AG ototoxicity has never been conceptually integrated or causally linked to MDR-TB patients’ pre-treatment health condition. We sought to develop a framework that examines the relationships between pre-treatment conditions and AG-induced hearing loss among MDR-TB-infected individuals in sub-Saharan Africa. The adverse outcome pathway (AOP) approach was used to develop a framework linking key events (KEs) within a biological pathway that results in adverse outcomes (AO), which are associated with chemical perturbation of a molecular initiating event (MIE). This AOP describes pathways initiating from AG accumulation in hair cells, sound transducers of the inner ear immediately after AG administration. After administration, the drug catalyzes cellular oxidative stress due to overproduction of reactive oxygen species. Since oxidative stress inhibits mitochondrial protein synthesis, hair cells undergo apoptotic cell death, resulting in irreversible hearing loss (AO). We identified the following pre-treatment conditions that worsen the causal linkage between MIE and AO: HIV, malnutrition, aging, noise, smoking, and alcohol use. The KEs are: (1) nephrotoxicity, pre-existing hearing loss, and hypoalbuminemia that catalyzes AG accumulation; (2) immunodeficiency and antioxidant deficiency that trigger oxidative stress pathways; and (3) co-administration of mitochondrial toxic drugs that hinder mitochondrial protein synthesis, causing apoptosis. This AOP clearly warrants the development of personalized interventions for patients undergoing MDR-TB treatment. Such interventions (i.e., choosing less ototoxic drugs, scheduling frequent monitoring, modifying nutritional status, avoiding poly-pharmacy) will be required to limit the burden of AG ototoxicity.


Aminoglycoside Ototoxicity Sensorineural hearing loss Tuberculosis 



Research reported in this manuscript was funded by the National Institute of Allergy and Infectious Disease (R01 AI104488-01A1 to J. Farley), the National Institute of Nursing Research (F31 NR016910-01A1 to H. Hong) of the National Institutes of Health, Sigma Theta Tau International Global Nursing Research Grant, Sigma Theta Tau International/Association of Nurses in AIDS Care Grant, Global Korean Nursing Foundation Scientific Award, Dr. Scholl Foundation Dissertation Scholarship, the Johns Hopkins Center for Global Health Established Field Placements Grant. We would like to express our appreciation to Martin Blair for his editorial support. The content is solely the responsibility of the authors and does not necessarily represent the official views of the aforementioned organizations/institutions. The authors declare that they have no conflict of interest.

Supplementary material

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  1. Abi-Hachem RN, Zine A, Van De Water TR (2010) The injured cochlea as a target for inflammatory processes, initiation of cell death pathways and application of related otoprotectives strategies. Recent Pat CNS Drug Discov 5(2)147–163CrossRefPubMedGoogle Scholar
  2. Aladag I, Guven M, Songu M (2016) Prevention of gentamicin ototoxicity with N-acetylcysteine and vitamin A. J Laryngol Otol 130(5):440–446. CrossRefPubMedGoogle Scholar
  3. Albano E (2006) Alcohol, oxidative stress and free radical damage. Proc Nutr Soc 65(3):278–290CrossRefPubMedGoogle Scholar
  4. Alford RL, Arnos KS, Fox M et al (2014) American college of medical genetics and genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss. Genet Med 16(4):347–355. CrossRefPubMedGoogle Scholar
  5. Alomar MJ (2014) Factors affecting the development of adverse drug reactions (Review article). Saudi Pharm J 22(2):83–94. CrossRefPubMedGoogle Scholar
  6. Anema A, Vogenthaler N, Frongillo EA, Kadiyala S, Weiser SD (2009) Food insecurity and HIV/AIDS: current knowledge, gaps, and research priorities. Curr HIV/AIDS Rep 6(4):224–231CrossRefPubMedPubMedCentralGoogle Scholar
  7. Ankley GT, Bennett RS, Erickson RJ et al (2010) Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem 29(3):730–741. CrossRefPubMedGoogle Scholar
  8. Aran JM, Darrouzet J (1975) Observation of click-evoked compound VIII nerve responses before, during, and over seven months after kanamycin treatment in the guinea pig. Acta Oto-laryngol 79(1–2):24–32CrossRefGoogle Scholar
  9. Ariano RE, Zelenitsky SA, Kassum DA (2008) Aminoglycoside-induced vestibular injury: maintaining a sense of balance. Ann Pharmacother 42(9):1282–1289. CrossRefPubMedGoogle Scholar
  10. Aukrust P, Luna L, Ueland T et al (2005) Impaired base excision repair and accumulation of oxidative base lesions in CD4+ T cells of HIV-infected patients. Blood 105(12):4730–4735. CrossRefPubMedGoogle Scholar
  11. Avent ML, Rogers BA, Cheng AC, Paterson DL (2011) Current use of aminoglycosides: indications, pharmacokinetics and monitoring for toxicity. Intern Med J 41(6):441–449. CrossRefPubMedGoogle Scholar
  12. Bächinger D, Horvath L, Eckhard A et al (2018) Neuronal erythropoietin overexpression is protective against kanamycin-induced hearing loss in mice. Toxicol Lett 291:121–128. CrossRefPubMedGoogle Scholar
  13. Bankaitis AE, Keith RW (1995) Audiological changes associated with HIV infection. Ear Nose Throat J 74(5):353–359PubMedGoogle Scholar
  14. Bareggi R, Grill V, Narducci P, Zweyer M, Tesei L, Russolo M (1990) Gentamicin ototoxicity: histological and ultrastructural alterations after transtympanic administration. Pharmacol Res 22(5):635–644CrossRefPubMedGoogle Scholar
  15. Bartlett J, Gallant J, Pham P (2012) Medical Management of HIV infection. Knowledge Source Solutions, LLC., DurhamGoogle Scholar
  16. Basile AS, Huang JM, Xie C, Webster D, Berlin C, Skolnick P (1996) N-methyl-d-aspartate antagonists limit aminoglycoside antibiotic-induced hearing loss. Nat Med 2(12):1338–1343CrossRefPubMedGoogle Scholar
  17. Benhar M, Dalyot I, Engelberg D, Levitzki A (2001) Enhanced ROS production in oncogenically transformed cells potentiates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and sensitization to genotoxic stress. Mol Cell Biol 21(20):6913–6926. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Benhar M, Engelberg D, Levitzki A (2002) ROS, stress-activated kinases and stress signaling in cancer. EMBO Rep 3(5):420–425. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Bisaso KR, Owen JS, Ojara FW et al (2014) Characterizing plasma albumin concentration changes in TB/HIV patients on anti retroviral and anti–tuberculosis therapy. In Silico Pharmacol 2:3. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Bitner-Glindzicz M, Pembrey M, Duncan A et al (2009) Prevalence of mitochondrial 1555A→G mutation in European children. N Engl J Med 360(6):640–642. CrossRefPubMedGoogle Scholar
  21. Blot SI, Pea F, Lipman J (2014) The effect of pathophysiology on pharmacokinetics in the critically ill patient-concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev 77:3–11. CrossRefPubMedGoogle Scholar
  22. Bodmer D, Brors D, Bodmer M, Ryan AF (2002) Rescue of auditory hair cells from ototoxicity by CEP-11 004, an inhibitor of the JNK signaling pathway. Laryngo-rhino-otologie 81(12):853–856. CrossRefPubMedGoogle Scholar
  23. Bosch J, Lebeko K, Nziale JJ, Dandara C, Makubalo N, Wonkam A (2014) In search of genetic markers for nonsyndromic deafness in Africa: a study in Cameroonians and Black South Africans with the GJB6 and GJA1 candidate genes. Omics 18(7):481–485. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Calza L, Trapani F, Tedeschi S et al (2011) Tenofovir-induced renal toxicity in 324 HIV-infected, antiretroviral-naive patients. Scand J Infect Dis 43(8):656–660. CrossRefPubMedGoogle Scholar
  25. Campbell KC, Martin SM, Meech RP, Hargrove TL, Verhulst SJ, Fox DJ (2016) d-methionine (d-met) significantly reduces kanamycin-induced ototoxicity in pigmented guinea pigs. Int J Audiol 55(5):273–278. CrossRefPubMedGoogle Scholar
  26. Cernada M, Pérez-Aytes A, Vento M, Millán JM (2014) The genetics of aminoglycoside-related deafness. NeoReviews 15(10):e449–e457. CrossRefGoogle Scholar
  27. Chandrasekhar SS, Siverls V, Sekhar HK (1992) Histopathologic and ultrastructural changes in the temporal bones of HIV-infected human adults. Am J Otol 13(3):207–214PubMedGoogle Scholar
  28. Choi DW (1992) Excitotoxic cell death. J Neurobiol 23(9):1261–1276. CrossRefPubMedGoogle Scholar
  29. Clerici WJ, Hensley K, DiMartino DL, Butterfield DA (1996) Direct detection of ototoxicant-induced reactive oxygen species generation in cochlear explants. Hear Res 98(1–2):116–124CrossRefPubMedGoogle Scholar
  30. Corns LF, Jeng JY, Richardson GP, Kros CJ, Marcotti W (2017) TMC2 modifies permeation properties of the mechanoelectrical transducer channel in early postnatal mouse cochlear outer hair cells. Front Mol Neurosci 10:326. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Cox EC, White JR, Flaks JG (1964) Streptomycin action and the ribosome. Proc Natl Acad Sci USA 51:703–709CrossRefPubMedGoogle Scholar
  32. Cui H, Kong Y, Zhang H (2012) Oxidative stress, mitochondrial dysfunction, and aging. J Signal Transduct 2012:646354. CrossRefPubMedGoogle Scholar
  33. Dai CF, Mangiardi D, Cotanche DA, Steyger PS (2006) Uptake of fluorescent gentamicin by vertebrate sensory cells in vivo. Hear Res 213(1–2):64–78. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Davies J, Anderson P, Davis BD (1965) Inhibition of protein synthesis by spectinomycin. Science 149(3688):1096–1098CrossRefPubMedGoogle Scholar
  35. de Grey ADNJ (1999) The mitochondrial free radical theory of aging. R.G. Landes Company, AustinGoogle Scholar
  36. de Pee S, Semba RD (2010) Role of nutrition in HIV infection: review of evidence for more effective programming in resource-limited settings. Food Nutr Bull 31(4):S313–S344CrossRefPubMedGoogle Scholar
  37. de Jager P, van Altena R (2002) Hearing loss and nephrotoxicity in long-term aminoglycoside treatment in patients with tuberculosis. Int J Tuberculosis lung disease: the official journal of the International Union against Tuberc Lung Dis 6(7):622–627Google Scholar
  38. Dogan M, Polat H, Yasar M et al (2017) Protective role of misoprostol in prevention of gentamicin ototoxicity. Int J Pediatr Otorhinolaryngol 96:140–144. CrossRefPubMedGoogle Scholar
  39. Donohue JF (2006) Ageing, smoking and oxidative stress. Thorax 61(6):461–462. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Elias A, Nelson B, Oputiri D, Geoffrey OBP (2013) Antiretroviral toxicity and oxidative stress. Am J Pharmacol Toxicol 8(4):187–196. CrossRefGoogle Scholar
  41. Esterberg R, Linbo T, Pickett SB et al (2016) Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death. J Clin Investig 126(9):3556–3566. CrossRefPubMedGoogle Scholar
  42. Farris HE, LeBlanc CL, Goswami J, Ricci AJ (2004) Probing the pore of the auditory hair cell mechanotransducer channel in turtle. J Physiol 558(Pt 3):769–792. CrossRefPubMedPubMedCentralGoogle Scholar
  43. Fetoni AR, Sergi B, Ferraresi A, Paludetti G, Troiani D (2004) alpha-Tocopherol protective effects on gentamicin ototoxicity: an experimental study. Int J Audiol 43(3):166–171CrossRefPubMedGoogle Scholar
  44. Fiume G, Vecchio E, De Laurentiis A et al (2012) Human immunodeficiency virus-1 Tat activates NF-kappaB via physical interaction with IkappaB-alpha and p65. Nucleic acids Res 40(8):3548–3562. CrossRefPubMedGoogle Scholar
  45. Fox DJ, Cooper MD, Speil CA et al (2016) d-Methionine reduces tobramycin-induced ototoxicity without antimicrobial interference in animal models. J Cyst Fibros 15(4):518–530. CrossRefPubMedGoogle Scholar
  46. Fraisse T, Gras aygon C, Paccalin M et al (2014) Aminoglycosides use in patients over 75 years old. Age Ageing 43(5):676–681. CrossRefPubMedGoogle Scholar
  47. Freed EO, Martin MA (2007) HIVs and their replication. Lippincott, Williams & Wilkins, PhiladelphiaGoogle Scholar
  48. Garcia-Alcantara F, Murillo-Cuesta S, Pulido S et al (2017) The expression of oxidative stress response genes is modulated by a combination of resveratrol and N-acetylcysteine to ameliorate ototoxicity in the rat cochlea. Hear Res 358:10–21. CrossRefPubMedGoogle Scholar
  49. Garetz SL, Altschuler RA, Schacht J (1994) Attenuation of gentamicin ototoxicity by glutathione in the guinea pig in vivo. Hear Res 77(1–2):81–87CrossRefPubMedGoogle Scholar
  50. Gonzalez LS III, Spencer JP (1998) Aminoglycosides: a practical review. Am Fam Physician 58(8):1811–1820PubMedGoogle Scholar
  51. Hamasaki K, Rando RR (1997) Specific binding of aminoglycosides to a human rRNA construct based on a DNA polymorphism which causes aminoglycoside-induced deafness. Biochemistry 36(40):12323–12328. CrossRefPubMedGoogle Scholar
  52. Hashino E, Shero M (1995) Endocytosis of aminoglycoside antibiotics in sensory hair cells. Brain research 704(1):135–140CrossRefPubMedGoogle Scholar
  53. Hayashida T, Nomura Y, Iwamori M, Nagai Y, Kurata T (1985) Distribution of gentamicin by immunofluorescence in the guinea pig inner ear. Arch Oto-rhino-laryngol 242(3):257–264CrossRefGoogle Scholar
  54. Henderson D, Bielefeld EC, Harris KC, Hu BH (2006) The role of oxidative stress in noise-induced hearing loss. Ear Hear 27(1):1–19. CrossRefPubMedGoogle Scholar
  55. Hill AB (1965) The environment and disease: association or causation? Proc R Soc Med 58(5):295–300Google Scholar
  56. Hirose K, Hockenbery DM, Rubel EW (1997) Reactive oxygen species in chick hair cells after gentamicin exposure in vitro. Hear Res 104(1–2):1–14CrossRefPubMedGoogle Scholar
  57. Hirose K, Li S-Z, Ohlemiller KK, Ransohoff RM (2014) Systemic Lipopolysaccharide induces cochlear inflammation and exacerbates the synergistic ototoxicity of kanamycin and furosemide. JARO J Assoc Res Otolaryngol 15(4):555–570. CrossRefPubMedGoogle Scholar
  58. Hobbie SN, Akshay S, Kalapala SK, Bruell CM, Shcherbakov D, Bottger EC (2008) Genetic analysis of interactions with eukaryotic rRNA identify the mitoribosome as target in aminoglycoside ototoxicity. Proc Natl Acad Sci USA 105(52):20888–20893. CrossRefPubMedGoogle Scholar
  59. Hong H, Budhathoki C, Farley JE (2018) Increased risk of aminoglycoside-induced hearing loss in MDR-TB patients with HIV coinfection. Int J Tuberc Lung Dis 22(6):667–674. CrossRefPubMedPubMedCentralGoogle Scholar
  60. Hood ML (2013) A narrative review of recent progress in understanding the relationship between tuberculosis and protein energy malnutrition. Eur J Clin Nutr 67(11):1122–1128. CrossRefPubMedGoogle Scholar
  61. Hu W, Wu J, Jiang W, Tang J (2018) MicroRNAs and presbycusis. Aging Dis 9(1):133–142. CrossRefPubMedPubMedCentralGoogle Scholar
  62. Huth ME, Ricci AJ, Cheng AG (2011) Mechanisms of aminoglycoside ototoxicity and targets of hair cell protection. Int J Otolaryngol. CrossRefPubMedPubMedCentralGoogle Scholar
  63. Hyde GE, Rubel EW (1995) Mitochondrial role in hair cell survival after injury. Otolaryngol Head Neck Surg 113(5):530–540. CrossRefPubMedGoogle Scholar
  64. Imamura S, Adams JC (2003) Distribution of gentamicin in the guinea pig inner ear after local or systemic application. J Assoc Res Otolaryngol JARO 4(2):176–195. CrossRefPubMedGoogle Scholar
  65. Isik B, Ceylan A, Isik R (2007) Oxidative stress in smokers and non-smokers. Inhal Toxicol 19(9):767–769. CrossRefPubMedGoogle Scholar
  66. Ivanov AV, Bartosch B, Isaguliants MG (2017) Oxidative Stress in Infection and Consequent Disease. Oxid Med Cell Longev 2017:3496043. CrossRefPubMedPubMedCentralGoogle Scholar
  67. Ivers LC, Cullen KA, Freedberg KA, Block S, Coates J, Webb P (2009) HIV/AIDS, undernutrition and food insecurity. Clin Infect Dis 49(7):1096–1102. CrossRefPubMedPubMedCentralGoogle Scholar
  68. Iwai H, Baba S, Omae M, Lee S, Yamashita T, Ikehara S (2008) Maintenance of systemic immune functions prevents accelerated presbycusis. Brain Res 1208:8–16. CrossRefPubMedGoogle Scholar
  69. Jiang M, Karasawa T, Steyger PS (2017) Aminoglycoside-Induced Cochleotoxicity: A Review. Front Cell Neurosci 11:308. CrossRefPubMedPubMedCentralGoogle Scholar
  70. Jin S, Kim MH, Park JH et al (2015) The incidence and clinical characteristics of acute serum creatinine elevation more than 1.5 mg/dL among the patients treated with tenofovir/emtricitabine-containing HAART regimens. Infect Chemother 47(4):239–246. CrossRefPubMedPubMedCentralGoogle Scholar
  71. Kabahuma RI, Ouyang X, Du LL et al (2011) Absence of GJB2 gene mutations, the GJB6 deletion (GJB6-D13S1830) and four common mitochondrial mutations in nonsyndromic genetic hearing loss in a South African population. Int J Pediatr Otorhinolaryngol 75(5):611–617. CrossRefPubMedPubMedCentralGoogle Scholar
  72. Kalinec GM, Lomberk G, Urrutia RA, Kalinec F (2017) Resolution of Cochlear Inflammation: Novel Target for Preventing or Ameliorating Drug-, Noise- and Age-related Hearing Loss. Front Cell Neurosci 11:192. CrossRefPubMedPubMedCentralGoogle Scholar
  73. Karasawa T, Wang Q, David LL, Steyger PS (2010) CLIMP-63 is a gentamicin-binding protein that is involved in drug-induced cytotoxicity. Cell Death Dis 1(11):e102. CrossRefPubMedPubMedCentralGoogle Scholar
  74. Keene M, Hawke M, Barber HO, Farkashidy J (1982) Histopathological findings in clinical gentamicin ototoxicity. Arch Otolaryngol 108(2):65–70CrossRefGoogle Scholar
  75. Kelly P, Musonda R, Kafwembe E, Kaetano L, Keane E, Farthing M (1999) Micronutrient supplementation in the AIDS diarrhoea-wasting syndrome in Zambia: a randomized controlled trial. AIDS (London England) 13(4):495–500CrossRefGoogle Scholar
  76. Kenyon C, Wearne N, Burton R, Meintjes G (2011) The Risks of concurrent treatment with tenofovir and aminoglycosides in patients with HIV-associated tuberculosis South Afr J HIV Med 12(1):43–45CrossRefPubMedPubMedCentralGoogle Scholar
  77. Khare M, Mohanty C, Das BK, Jyoti A, Mukhopadhyay B, Mishra SP (2014) Free radicals and antioxidant status in protein energy malnutrition. Int J Pediatr 2014:254396. CrossRefPubMedPubMedCentralGoogle Scholar
  78. Kim SH, Kim UK, Lee WS et al (2011) Albumin-like protein is the major protein constituent of luminal fluid in the human endolymphatic sac. PloS One 6(6):e21656. CrossRefPubMedPubMedCentralGoogle Scholar
  79. Kim S, McClave SA, Martindale RG, Miller KR, Hurt RT (2017) Hypoalbuminemia and clinical outcomes: What is the mechanism behind the relationship? Am Surg 83(11):1220–1227PubMedGoogle Scholar
  80. Kim CW, Han JH, Wu L, Choi JY (2018) microRNA-183 is essential for hair cell regeneration after neomycin injury in zebrafish. Yonsei Med J 59(1):141–147. CrossRefPubMedGoogle Scholar
  81. Kirkwood NK, O’Reilly M, Derudas M et al (2017) d-tubocurarine and berbamine: alkaloids that are permeant blockers of the hair cell’s mechano-electrical transducer channel and protect from aminoglycoside toxicity. Front Cell Neurosci 11:262. CrossRefPubMedPubMedCentralGoogle Scholar
  82. Koethe JR, Chi BH, Megazzini KM, Heimburger DC, Stringer JS (2009) Macronutrient supplementation for malnourished HIV-infected adults: a review of the evidence in resource-adequate and resource-constrained settings. Clin Infect Dis 49(5):787–798. CrossRefPubMedPubMedCentralGoogle Scholar
  83. Kohler JJ, Hosseini SH, Hoying-Brandt A et al (2009) Tenofovir renal toxicity targets mitochondria of renal proximal tubules. Lab Investig 89(5):513–519. CrossRefPubMedGoogle Scholar
  84. Koo JW, Quintanilla-Dieck L, Jiang M et al (2015) Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity. Sci Transl Med 7(298):298ra118. CrossRefPubMedPubMedCentralGoogle Scholar
  85. Krause KH, Michalak M (1997) Calreticulin Cell 88(4):439–443. CrossRefPubMedGoogle Scholar
  86. Krause KM, Serio AW, Kane TR, Connolly LE (2016) Aminoglycosides: An Overview. Cold Spring Harbor Perspect Med 6(6):a027029. CrossRefGoogle Scholar
  87. Ladrech S, Eybalin M, Puel JL, Lenoir M (2017) Epithelial-mesenchymal transition, and collective and individual cell migration regulate epithelial changes in the amikacin-damaged organ of Corti. Histochem Cell Biol 148(2):129–142. CrossRefPubMedGoogle Scholar
  88. Lasisi AO, Bademci G, Foster J II, Blanton S, Tekin M (2014) Common genes for non-syndromic deafness are uncommon in sub-Saharan Africa: a report from Nigeria. Int J Pediatr Otorhinolaryngol 78(11):1870–1873. CrossRefPubMedPubMedCentralGoogle Scholar
  89. Le Prell CG, Ojano-Dirain C, Rudnick EW et al (2014) Assessment of nutrient supplement to reduce gentamicin-induced ototoxicity. J Assoc Res Otolaryngol JARO 15(3):375–393. CrossRefPubMedGoogle Scholar
  90. Lecain E, Omri B, Behar-Cohen F, Tran Ba Huy P, Crisanti P (2007) The role of PKCzeta in amikacin-induced apoptosis in the cochlea: prevention by aspirin. Apoptosis 12(2):333–342. CrossRefPubMedGoogle Scholar
  91. Lee K-Y (2013) Pathophysiology of Age-Related Hearing Loss (Peripheral and Central). Korean J Audiol 17(2):45–49. CrossRefPubMedPubMedCentralGoogle Scholar
  92. Lemasters JJ (2005) Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res 8(1):3–5CrossRefPubMedGoogle Scholar
  93. Lenoir M, Puel JL (1987) Dose-dependent changes in the rat cochlea following aminoglycoside intoxication. II. Histological study. Hear Res 26(2):199–209CrossRefPubMedGoogle Scholar
  94. Lesniak W, Pecoraro VL, Schacht J (2005) Ternary complexes of gentamicin with iron and lipid catalyze formation of reactive oxygen species. Chem Res Toxicol 18(2):357–364. CrossRefPubMedGoogle Scholar
  95. Marcotti W, van Netten SM, Kros CJ (2005) The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano-electrical transducer channels. J Physiol 567(Pt 2):505–521. CrossRefPubMedPubMedCentralGoogle Scholar
  96. Marí M, Morales A, Colell A, García-Ruiz C, Fernández-Checa JC (2009) Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal 11(11):2685–2700. CrossRefPubMedPubMedCentralGoogle Scholar
  97. Marks SM, Flood J, Seaworth B et al (2014) Treatment practices, outcomes, and costs of multidrug-resistant and extensively drug-resistant tuberculosis, United States, 2005–2007. Emerg Infect Dis 20(5):812–821. CrossRefPubMedPubMedCentralGoogle Scholar
  98. Marra CM, Wechkin HA, Longstreth WT Jr, Rees TS, Syapin CL, Gates GA (1997) Hearing loss and antiretroviral therapy in patients infected with HIV-1. Arch Neurol 54(4):407–410CrossRefPubMedGoogle Scholar
  99. McNaghten AD, Wan PC, Dworkin MS (2001) Prevalence of hearing loss in a cohort of HIV-infected patients. Arch Otolaryngol Head Neck Surg 127(12):1516–1518CrossRefPubMedGoogle Scholar
  100. Michaels L (2012) Ear, nose and throat histopathology. In: Ototoxic damage to the inner ear. Springer-Verlag, BerlinGoogle Scholar
  101. Miller ME, Makary C, Lopez IA, Ishiyama A (2010) Endolymphatic hydrops in otologic syphilis: a temporal bone study. Otology & neurotology: official publication of the American Otological Society. Otol Neurotol 31(4):681–686. CrossRefPubMedGoogle Scholar
  102. Mingeot-Leclercq MP, Glupczynski Y, Tulkens PM (1999) Aminoglycosides: activity and resistance. Antimicrob Agents Chemother 43(4):727–737CrossRefPubMedPubMedCentralGoogle Scholar
  103. Mohamed-Hussein A, Salama S, Khalil M, Eid S (2016) Malnutrition in tuberculosis: value of fat-free mass and creatinine-height index. Egypt J Bronchol 10(1):58–63. CrossRefGoogle Scholar
  104. Mörike K, Schwab M, Klotz U (1997) Use of Aminoglycosides in Elderly Patients. Drugs Aging 10(4):259–277. CrossRefPubMedGoogle Scholar
  105. Mostafa BE, Tawfik S, Hefnawi NG, Hassan MA, Ismail FA (2007) The role of deferoxamine in the prevention of gentamicin ototoxicity: a histological and audiological study in guinea pigs. Acta Oto-laryngol 127(3):234–239. CrossRefGoogle Scholar
  106. Murphy MP (2013) Mitochondrial dysfunction indirectly elevates ROS production by the endoplasmic reticulum. Cell Metab 18(2):145–146. CrossRefPubMedGoogle Scholar
  107. Nakamagoe M, Tabuchi K, Uemaetomari I, Nishimura B, Hara A (2010) Estradiol protects the cochlea against gentamicin ototoxicity through inhibition of the JNK pathway. Hear Res 261(1–2):67–74. CrossRefPubMedGoogle Scholar
  108. Nishida I, Takumida M (1996) Attenuation of aminoglycoside ototoxicity by glutathione. ORL 58(2):68–73CrossRefPubMedGoogle Scholar
  109. Nordstrom L, Ringberg H, Cronberg S, Tjernstrom O, Walder M (1990) Does administration of an aminoglycoside in a single daily dose affect its efficacy and toxicity? J Antimicrob Chemother 25(1):159–173CrossRefPubMedGoogle Scholar
  110. OECD (2012) Proposal for a template and guidance on developing and assessing the completeness of adverse outcome pathways. Organisation for Economic Co-operation and Development, ParisGoogle Scholar
  111. OECD (2013) Guidance document on developing and assessing adverse outcome pathways, vol 184. Organisation for Economic Co-operations and Development, ParisGoogle Scholar
  112. Op de Beeck K, Schacht J, Van Camp G (2011) Apoptosis in acquired and genetic hearing impairment: the programmed death of the hair cell. Hear Res 281(1–2):18–27. CrossRefPubMedGoogle Scholar
  113. Owens KN, Cunningham DE, MacDonald G, Rubel EW, Raible DW, Pujol R (2007) Ultrastructural analysis of aminoglycoside-induced hair cell death in the zebrafish lateral line reveals an early mitochondrial response. J Comp Neurol 502(4):522–543. CrossRefPubMedGoogle Scholar
  114. Pagkalis S, Mantadakis E, Mavros MN, Ammari C, Falagas ME (2011) Pharmacological considerations for the proper clinical use of aminoglycosides. Drugs 71(17):2277–2294. CrossRefPubMedGoogle Scholar
  115. Park YH, Chung J, Lee MY, Lee DY, Kim YH (2018) Cochlear damage caused by the striking noise of titanium head golf driver. Clin Exp Otorhinolaryngol. CrossRefPubMedPubMedCentralGoogle Scholar
  116. Patel R, McKinnon BJ (2018) Hearing loss in the elderly. Clin Geriatr Med 34(2):163–174. CrossRefPubMedGoogle Scholar
  117. Prasad HKC, Bhojwani KM, Shenoy V, Prasad SC (2006) HIV manifestations in otolaryngology. Am J Otolaryngol 27(3):179–185. CrossRefPubMedGoogle Scholar
  118. Prezant TR, Agapian JV, Bohlman MC et al (1993) Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat Genet 4(3):289–294. CrossRefPubMedGoogle Scholar
  119. Priuska EM, Schacht J (1995) Formation of free radicals by gentamicin and iron and evidence for an iron/gentamicin complex. Biochem Pharmacol 50(11):1749–1752CrossRefPubMedGoogle Scholar
  120. Puel JL, Ladrech S, Chabert R, Pujol R, Eybalin M (1991) Electrophysiological evidence for the presence of NMDA receptors in the guinea pig cochlea. Hear Res 51(2):255–264CrossRefPubMedGoogle Scholar
  121. Rajopadhye SH, Mukherjee SR, Chowdhary AS, Dandekar SP (2017) Oxidative stress markers in tuberculosis and HIV/TB co-infection. J Clin Diagn Res JCDR 11(8):Bc24–Bbc28. CrossRefPubMedGoogle Scholar
  122. Ricci AJ, Kennedy HJ, Crawford AC, Fettiplace R (2005) The transduction channel filter in auditory hair cells. J Neurosci 25(34):7831–7839. CrossRefPubMedGoogle Scholar
  123. Roche M, Rondeau P, Singh NR, Tarnus E, Bourdon E (2008) The antioxidant properties of serum albumin. FEBS Lett 582(13):1783–1787. CrossRefPubMedGoogle Scholar
  124. Rzewnicki I, Olszewska E, Rogowska-Szadkowska D (2012) HIV infections in otolaryngology. Med Sci Monit 18(3):RA17–RA21. CrossRefPubMedPubMedCentralGoogle Scholar
  125. Saitoh Y, Hosokawa M, Shimada A et al (1994) Age-related hearing impairment in senescence-accelerated mouse (SAM). Hear Res 75(1–2):27–37CrossRefPubMedGoogle Scholar
  126. Scherzer R, Estrella M, Li Y et al (2012) Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS (Lond Engl) 26(7):867–875. CrossRefGoogle Scholar
  127. Sha SH, Schacht J (1999a) Salicylate attenuates gentamicin-induced ototoxicity. Lab Investig 79(7):807–813PubMedGoogle Scholar
  128. Sha SH, Schacht J (1999b) Stimulation of free radical formation by aminoglycoside antibiotics. Hear Res 128(1–2):112–118CrossRefPubMedGoogle Scholar
  129. Shokolenko I, Venediktova N, Bochkareva A, Wilson GL, Alexeyev MF (2009) Oxidative stress induces degradation of mitochondrial DNA. Nucleic Acids Res 37(8):2539–2548. CrossRefPubMedPubMedCentralGoogle Scholar
  130. Simdon J, Watters D, Bartlett S, Connick E (2001) Ototoxicity associated with use of nucleoside analog reverse transcriptase inhibitors: a report of 3 possible cases and review of the literature. Clin Infect Dis 32(11):1623–1627. CrossRefPubMedGoogle Scholar
  131. Sitar ME, Aydin S, Cakatay U (2013) Human serum albumin and its relation with oxidative stress. Clin Lab 59(9–10):945–952PubMedGoogle Scholar
  132. Son Y, Kim S, Chung H-T, Pae H-O (2013) Reactive Oxygen Species in the Activation of MAP Kinases. In: Cadenas E, Packer L (eds) Methods in enzymology. 528. Academic Press, New York 27–48Google Scholar
  133. Staal FJ, Ela SW, Roederer M, Anderson MT, Herzenberg LA, Herzenberg LA (1992) Glutathione deficiency and human immunodeficiency virus infection. Lancet 339(8798):909–912CrossRefPubMedGoogle Scholar
  134. Stepanyan RS, Indzhykulian AA, Velez-Ortega AC et al (2011) TRPA1-mediated accumulation of aminoglycosides in mouse cochlear outer hair cells. J Assoc Res Otolaryngol JARO 12(6):729–740. CrossRefPubMedGoogle Scholar
  135. Sturdy A, Goodman A, Jose RJ et al (2011) Multidrug-resistant tuberculosis (MDR-TB) treatment in the UK: a study of injectable use and toxicity in practice. J Antimicrob Chemother 66(8):1815–1820. CrossRefPubMedGoogle Scholar
  136. Torre P III, Hoffman HJ, Springer G et al (2015a) Hearing loss among HIV-seropositive and HIV-seronegative men and women. JAMA Otolaryngol Head Neck Surg 141(3):202–210. CrossRefPubMedPubMedCentralGoogle Scholar
  137. Torre P, Hoffman HJ, Springer G et al (2015b) Hearing loss among hiv-seropositive and hiv-seronegative men and women. JAMA Otolaryngol Head Neck Surg 141(3):202–210. CrossRefPubMedPubMedCentralGoogle Scholar
  138. Tunstall MJ, Gale JE, Ashmore JF (1995) Action of salicylate on membrane capacitance of outer hair cells from the guinea-pig cochlea. J Physiol 485(Pt 3):739–752CrossRefPubMedPubMedCentralGoogle Scholar
  139. Tysome JRKR (2016) Hearing: an introduction and practical guide. CRC Press, Taylor & Francis Group, LLC, Baca RatonGoogle Scholar
  140. van Lettow M, Fawzi WW, Semba RD (2003) Triple trouble: the role of malnutrition in tuberculosis and human immunodeficiency virus co-infection. Nutr Rev 61(3):81–90CrossRefPubMedGoogle Scholar
  141. Vandebona H, Mitchell P, Manwaring N et al (2009) Prevalence of mitochondrial 1555A–>G mutation in adults of European descent. N Engl J Med 360(6):642–644. CrossRefPubMedGoogle Scholar
  142. Vinken M (2013) The adverse outcome pathway concept: a pragmatic tool in toxicology. Toxicology 312:158–165. CrossRefPubMedGoogle Scholar
  143. Wanchu A, Rana SV, Pallikkuth S, Sachdeva RK (2009) Short communication: oxidative stress in HIV-infected individuals: a cross-sectional study. AIDS Res Hum Retrovir 25(12):1307–1311. CrossRefPubMedGoogle Scholar
  144. Wang Q, Steyger PS (2009) Trafficking of systemic fluorescent gentamicin into the cochlea and hair cells. J Assoc Res Otolaryngol JARO 10(2):205–219. CrossRefPubMedGoogle Scholar
  145. Wang J, Van De Water TR, Bonny C, de Ribaupierre F, Puel JL, Zine A (2003) A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss. J Neurosci 23(24):8596–8607CrossRefPubMedGoogle Scholar
  146. Wang A, Hou N, Bao D, Liu S, Xu T (2012) Mechanism of alpha-lipoic acid in attenuating kanamycin-induced ototoxicity. Neural Regen Res 7(35):2793–2800. CrossRefPubMedPubMedCentralGoogle Scholar
  147. Weder S, Senn P, Caversaccio M, Vibert D (2013) Cochleovestibular deficit as first manifestation of syphilis in a HIV-infected patient. Case Rep Neurol 5(1):62–67. CrossRefPubMedPubMedCentralGoogle Scholar
  148. Weinstein JR, Anderson S (2010) The aging kidney: physiological changes. Adv Chronic Kidney Dis 17(4):302–307 CrossRefPubMedPubMedCentralGoogle Scholar
  149. Wersall J, Hawkins JE Jr (1962) The vestibular sensory epithelia in the cat labyrinth and their reactions in chronic streptomycin intoxication. Acta Oto-laryngol 54:1–23CrossRefGoogle Scholar
  150. WHO (2003a) Nutrient Requirements for People living with HIV/AIDS: Report of a technical consultation.
  151. WHO (2003b) Nutrition and HIV/AIDS. World Health Organization.
  152. WHO (2012) Social determinants of health: What are social determinants of health? World Health Organization. In.
  153. WHO (2016a) Global tuberculosis report 2016. World Health Organization, GenevaGoogle Scholar
  154. WHO (2016b) WHO treatment guidelines for drug-resistant tuberculosis, 2016 updates. World Health Organization, GenevaGoogle Scholar
  155. Wonkam A, Bosch J, Noubiap JJ, Lebeko K, Makubalo N, Dandara C (2015) No evidence for clinical utility in investigating the connexin genes GJB2, GJB6 and GJA1 in non-syndromic hearing loss in black Africans. S Afr Med J 105(1):23–6CrossRefPubMedGoogle Scholar
  156. Wu CY, Lee HJ, Liu CF, Korivi M, Chen HH, Chan MH (2015) Protective role of l-ascorbic acid, N-acetylcysteine and apocynin on neomycin-induced hair cell loss in zebrafish. J Appl Toxicol JAT 35(3):273–279. CrossRefPubMedGoogle Scholar
  157. Yu X, Fan Z, Han Y et al (2018) Paeoniflorin reduces neomycin-induced ototoxicity in hair cells by suppression of reactive oxygen species generation and extracellularly regulated kinase signalization. Toxicol Lett 285:9–19. CrossRefPubMedGoogle Scholar
  158. Zorov DB, Juhaszova M, Sollott SJ (2014) Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev 94(3):909–950. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Johns Hopkins University School of NursingBaltimoreUSA
  2. 2.Johns Hopkins University School of Nursing, The REACH InitiativeBaltimoreUSA
  3. 3.Divisions of Clinical Pharmacology and Infectious DiseaseJohns Hopkins University School of MedicineBaltimoreUSA
  4. 4.Center for Health PolicyColumbia University School of NursingNew YorkUSA
  5. 5.Division of Head and Neck Surgery and Communication SciencesDuke University School of MedicineDurhamUSA

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