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

Hyejeong Hong, Kelly Elise Dooley, Laura E. Starbird, Howard W. Francis, Jason Farley

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalArchives of Toxicology
DOIs
StatePublished - Jan 1 2019

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Multidrug-Resistant Tuberculosis
Aminoglycosides
Audition
Hearing Loss
Oxidative stress
Pharmaceutical Preparations
Oxidative Stress
Mitochondrial Proteins
Therapeutics
Cells
Wiskott-Aldrich Syndrome
Hypoalbuminemia
Africa South of the Sahara
Poisons
Inner Ear
Cell death
Nutritional Status
Transducers
Malnutrition
Noise

Keywords

  • Aminoglycoside
  • Ototoxicity
  • Sensorineural hearing loss
  • Tuberculosis

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Adverse outcome pathway for aminoglycoside ototoxicity in drug-resistant tuberculosis treatment. / Hong, Hyejeong; Dooley, Kelly Elise; Starbird, Laura E.; Francis, Howard W.; Farley, Jason.

In: Archives of Toxicology, 01.01.2019.

Research output: Contribution to journalArticle

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