Debilitating Gentamicin Ototoxicity: Case Report and Recommendations Against Routine Use in Surgical Prophylaxis.

INTRODUCTION: Aminoglycoside antibiotics such as gentamicin are bactericidal and effective against gram negative organisms and act synergistically against gram positive organisms, including Staphylococcus aureus. However, they have serious adverse effects such as nephrotoxicity and ototoxicity. Gentamicin ototoxicity may occur after a single dose and results in decreased vestibular function, which is frequently debilitating and often permanent. OBJECTIVE: To emphasize the risk of gentamicin ototoxicity and suggest alternative antibiotics in penicillin-allergic patients undergoing surgery. CASE SUMMARY: We present a case of a woman with preexisting Meniere's Disease who received gentamicin 400 mg perioperatively for a sigmoidectomy due to a penicillin allergy listed in the patient's medical record. The patient developed severe ototoxicity preventing her from working or driving. Physical examination was remarkable for a broad-based gait requiring assistance to walk and bilateral corrective saccades. Vestibular testing revealed high-grade bilateral vestibular loss associated with all semicircular canals, a considerable decline compared to her function 3 years prior. DISCUSSION: Gentamicin is indicated for surgical prophylaxis when a patient has a true allergy to penicillins and cannot receive cephalosporins, though alternatives exist. True allergies include IgE-mediated illness (anaphylaxis, bronchospasm, or urticaria 30-60 minutes after administration) or exfoliative reactions (Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis). The authors encourage more prudent use of gentamicin, especially in patients susceptible for debilitating otologic insults, and offer recommendations for alternative agents prior to using gentamicin.

Decreased expression of synaptic genes in the vestibular ganglion of rodents following subchronic ototoxic stress.

The vestibular ganglion contains primary sensory neurons that are postsynaptic to the transducing hair cells (HC) and project to the central nervous system. Understanding the response of these neurons to HC stress or loss is of great interest as their survival and functional competence will determine the functional outcome of any intervention aiming at repair or regeneration of the HCs. We have shown that subchronic exposure to the ototoxicant 3,3'-iminodipropionitrile (IDPN) in rats and mice causes a reversible detachment and synaptic uncoupling between the HCs and the ganglion neurons. Here, we used this paradigm to study the global changes in gene expression in vestibular ganglia using RNA-seq. Comparative gene ontology and pathway analyses of the data from both model species indicated a robust downregulation of terms related to synapses, including presynaptic and postsynaptic functions. Manual analyses of the most significantly downregulated transcripts identified genes with expressions related to neuronal activity, modulators of neuronal excitability, and transcription factors and receptors that promote neurite growth and differentiation. For choice selected genes, the mRNA expression results were replicated by qRT-PCR, validated spatially by RNA-scope, or were demonstrated to be associated with decreased expression of the corresponding protein. We conjectured that decreased synaptic input or trophic support on the ganglion neurons from the HC was triggering these expression changes. To support this hypothesis, we demonstrated decreased expression of BDNF mRNA in the vestibular epithelium after subchronic ototoxicity and also downregulated expression of similarly identified genes (e.g Etv5, Camk1g, Slc17a6, Nptx2, Spp1) after HC ablation with another ototoxic compound, allylnitrile. We conclude that vestibular ganglion neurons respond to decreased input from HCs by decreasing the strength of all their synaptic contacts, both as postsynaptic and presynaptic players.

The auditory and vestibular toxicities induced by antiepileptic drugs.

INTRODUCTION: Epilepsy is a chronic medical disease in one third of patients and is associated with comorbid adverse somatic conditions due to epilepsy itself or its long-term treatment with antiepileptic drugs (AEDs). Data from experimental, cross-sectional and prospective studies have evidence for the deleterious effect of some AEDs on the auditory and vestibular systems. These abnormalities may be reversible or irreversible. Areas covered: This article review the evidence that long-term treatment with some antiepileptic drugs (AEDs) [e.g. carbamazepine, phenytoin, valproate, lamotrigine, gabapentin, vigabatrin and oxcarbazepine] (even in therapeutic drug doses) may result in tinnitus, phonophobia, sensorineural hearing loss, dizziness, ataxia, disequilibrium, imbalance, nystagmus, abnormalities in saccadic and pursuit eye movements and delayed conduction within the cochlea, auditory nerve and brainstem auditory pathways evidenced by abnormalities in Brainstem auditory evoked potentials and nystagmography recordings indicating auditory and central and/or peripheral vestibular dysfunctions. Expert opinion: Identification of monitoring of patients at high risk for developing audio-vestibular manifestations is necessary for appropriate preventive and therapeutic measures.

Strain and Sex Differences in the Vestibular and Systemic Toxicity of 3,3'-Iminodipropionitrile in Mice.

The nitrile 3,3'-iminodipropionitrile (IDPN) causes a loss of hair cells in the vestibular epithelium of the inner ear in several species of both mammals and nonmammals. It is of interest as a model compound in ototoxicity and vestibular regeneration research, but its effects on the mouse, including the potential relevance of strain and sex differences for susceptibility, have not yet been thoroughly characterized. In this study, we compared the vestibular toxicity of IDPN in dose-response studies (0, 8, 12, 16, and 24 mmol/kg IDPN p.o.) in males and females of 2 different mouse strains (RjOrl:Swiss/CD-1 and 129S1/SvImJ). 3,3'-Iminodipropionitrile caused a dose-dependent loss of vestibular function in all sex and strain groups, as assessed by a specific battery of behavioral tests. However, large differences in systemic toxicity were recorded, with high systemic toxicity in 129S1 mice of both sexes compared to limited effects on the Swiss mice. Both male and female Swiss mice showed a marked increase of hindlimb stride width after exposure. The Swiss, but not the 129S1, mice treated with IDPN showed hyperactivity in the open field. The dose-response relationships in the behavioral effects were matched by the extent of hair cell loss assessed by scanning electron microscopy. Altogether, the data demonstrated prominent strain-dependent differences in the systemic toxicity of IDPN between 129S1 and Swiss mice, in contrast to no differences between the strains and small differences between the sexes in its vestibular toxicity. These results support the use of Swiss mice exposed to IDPN as a mouse lesion model for research in vestibular therapy and regeneration.

The Protective Effect of Epigallocatechin-3-Gallate Against Gentamicin Vestibular Ototoxicity in Type I Vestibular Hair Cell of Guinea Pig / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: Gentamicin (GM) is well known for its vestibulotoxicity. There have been many reports about vestibulotoxicity, however, its mechanism is still unclear. So far, it is known that GM affects the voltage-dependent K+ current and nitric oxide (NO) production. Epigallocatechin-3-gallate (EGCG) is the major component of green tea and is known to have anti-oxidative and anti-toxic effect. This study was undertaken to investigate the protective effect of EGCG against gentamicin on vestibular hair cell (VHC). MATERIALS AND METHOD: White guinea pigs (200-250 g) were rapidly decapitated and the temporal bones were immediately removed. Under a dissecting microscope, the crista ampullaris was obtained. The dissociated VHCs were transferred into a recording chamber mounted onto an inverted microscope. Whole-cell membrane currents and potentials were recorded using standard patch-clamp techniques. In addition, measurements of NO production were obtained using the NO-sensitive dye, 4,5-diamino-fluorescein diacetate (DAF-2DA). RESULTS: Type I VHCs Voltage-dependent K+ current was activated from low depolarizing stimulation. As the stimulation increased, higher current was detected. Voltage-dependent K+ current in type I VHCs was decreased when GM (200 microM) was administrated and GM effects of K+ current inhibition was significantly blocked by EGCG. Extracellular GM-induced an increase in DAF-2DA fluorescence, which thus indicates NO production in VHCs. Also, the GMinduced NO production was inhibited by EGCG. CONCLUSION: GM inhibits voltage-dependent K+ current by releasing NO in isolated type I VHCs. EGCG blocks this inhibitory effects, suggesting a protective role on GM vestibulotoxicity.

Vestibulotoxic properties of potential metabolites of allylnitrile.

This study addressed the hypothesis that epoxidation of the double bond in allylnitrile mediates its vestibular toxicity, directly or after subsequent metabolism by epoxide hydrolases. The potential metabolites 3,4-epoxybutyronitrile and 3,4-dihydroxybutyronitrile were synthesized and characterized. In aqueous solutions containing sodium or potassium ions, 3,4-epoxybutyronitrile rearranged to 4-hydroxybut-2-enenitrile, and this compound was also isolated for study. Male adult Long-Evans rats were exposed to allylnitrile or 3,4-epoxybutyronitrile by bilateral transtympanic injection, and vestibular toxicity was assessed using a behavioral test battery and scanning electron microscopy (SEM) observation of the sensory epithelia. Overt vestibular toxicity was caused by 3,4-epoxybutyronitrile at 0.125 mmol/ear and by allylnitrile in some animals at 0.25 mmol/ear. Additional rats were exposed by unilateral transtympanic injection. In these studies, behavioral evidences and SEM observations demonstrated unilateral vestibular toxicity after 0.125 mmol of 3,4-epoxybutyronitrile and bilateral vestibular toxicity after 0.50 mmol of allylnitrile. However, 0.25 mmol of allylnitrile did not cause vestibular toxicity. Unilateral administration of 0.50 mmol of 3,4-dihydroxybutyronitrile or 4-hydroxybut-2-enenitrile caused no vestibular toxicity. The four compounds were also evaluated in the mouse utricle explant culture model. In 8-h exposure experiments, hair cells completely disappeared after 3,4-epoxybutyronitrile at concentrations of 325 or 450µM but not at concentrations of 150µM or lower. In contrast, no difference from controls was recorded in utricles exposed to 450µM or 1.5mM of allylnitrile, 3,4-dihydroxybutyronitrile, or 4-hydroxybut-2-enenitrile. Taken together, the present data support the hypothesis that 3,4-epoxybutyronitrile is the active metabolite of allylnitrile for vestibular toxicity.