Ototoxicity

1
Ototoxicity

• Russell D. Briggs, M.D.
• Arun K. Gadre, M.D.

2
Introduction

• Definition
• Damage to the cochlea or vestibular apparatus
  from exposure to a chemical source
• Many sources
• Mercury
• Herbs
• Streptomycin (1944)
• Dihydrostreptomycin (1948)
• Gentamicin (1965)
• Others

3
Aminoglycosides

• Streptomycin, kanamycin, neomycin, amikacin,
  gentamicin, tobramycin, sisomycin, netilmicin
• Enter into inner ear by unknown mechanism
• Secreted into the perilymph by spiral ligament or
  endolymph by stria vascularis
• Diffuse through round window membrane
• Eliminated by kidney

4
Aminoglycosides

• Cochlear toxicity
• Amikacin, kanamycin, neomycin, netilmicin
• Vestibular toxicity
• Streptomycin, gentamicin, sisomycin
• Can occur simultaneously

5
Aminoglycosides

• Cochlear toxicity
• Increase of 10-20 dB in thresholds of one or more
  frequencies
• Incidence (6-13), netilmicin lowest
• Risk factors
• Diuretics, renal failure, prolonged treatment,
  old age, preexisting SNHL
• Infants less affected, once daily dosing

6
Aminoglycosides

• Cochlear toxicity
• Outer hair cell loss first in basal turn then to
  apex
• Inner hair cell loss later

7
Aminoglycosides
8
Aminoglycosides

• Cochlear toxicity presentation
• High frequency SNHL first, then lower frequencies
  to profound loss
• Not reversible
• Damage usually heralded by tinnitus

9
Aminoglycosides

• Cochlear toxicity
• Can be familial form of nonsyndromic HL maternal
  inheritance
• Associated with mtDNA 1555A to G point mutation
  in 12S ribosomal RNA gene causes increased
  binding to ribosome

10
Aminoglycosides

• Vestibular toxicity
• Assessment is difficult
• Dynamic posturography can detect
• Pathologically
• Type I hair cells more sensitive
• Cristae ampullaris then utricle and saccule
• Clinically (ambulatory vs. bedridden)
• Ataxic gait, lose balance when turning
• Bobbing oscillopsia

11
Aminoglycosides
12
Aminoglycosides

• Prevention
• Pharmacological
• Clinical
• Consider less ototoxic drugs (netilmicin)
• Identify high-risk patients
• Audiogram before and weekly after starting
• ENG prior if possible
• History and physical exam daily (Romberg, VA)
• Adjust doses or switch drugs if toxic

13
Macrolides

• Discovered erythromycin 1952 (McGuire)
• Mintz (1972) first report of ototoxicity
• Reversible 50-55 dB losses in two cases
• Clinically
• Hearing loss with/without tinnitus 2 days
• All frequencies, recovery after stopping
• Rarely permanent (hepatic)
• Incidence unknown

14
Macrolides

• Mechanism unknown
• Azithromycin and clarithromycin can cause similar
  findings in animals

15
Other antibiotics

• Vancomycin
• Believed to be ototoxic (no data)
• Penicillin, sulfonamides, cephalosporins
• May have topical toxicity in middle ear
• Nucleoside analog reverse transcriptase
  inhibitors
• Poor study

16
Loop Diuretics

• Ethacrinic acid, furosemide, bumetaside
• Clinically (6-7)
• Usually tinnitus, temporary and reversible SNHL,
  rare vertigo within minutes
• High doses can cause permanent SNHL
• Highest risk coadministration of aminoglycosides

17
Loop Diuretics

• Pathologically
• Edema of stria vascularis
• Ionic gradient changes
• Inhibition of adenylate cyclase and G-proteins

18
Salicylates and NSAIDS

• Most common OTC drugs in US
• Mechanism
• Normal histology (no hair cell loss)
• Decreased blood flow, decreased enzymes
• Clinically
• Tonal, high frequency tinnitus (7-9 kHz)
• Reversible mild to moderate SNHL (usually high
  frequency) rarely permanent

19
Salicylates and NSAIDs
20
Quinine

• Similar clinical findings with aspirin
• Usage up for leg cramps
• Clinically
• High-pitched tinnitus
• Reversible, symmetric SNHL
• Occasional vertigo
• Mechanism
• Decreased perfusion, direct damage to outer hair
  cells, biochemical alterations

21
Antineoplastic Agents

• Cisplatin
• Incidence is high (62-81)
• Pathologically
• Outer hair cell degeneration
• Clinically
• Bilateral symmetric SNHL, usually high frequency
  not reversible, cumulative
• Risks factors age extremes, cranial irradiation,
  high dose therapy, high cumulative dose

22
Antineoplastic Drugs
23
Antineoplastic Drugs

• Cisplatin
• Prevention
• Probenecid, WR 2721, DDTC, diuretics, calcium
  supplements not effective
• L-N-acetyl-cysteine protective in vitro

24
Topical Antimicrobials

• Commonly prescribed for otorrhea after tubes and
  CSOM
• Controversial subject
• Agents may enter middle ear and gain access to
  membranous labyrinth
• Animal testing reveals irrefutable evidence of
  severe ototoxicity

25
Topical Antimicrobials

• Polymixin B (Brummett)
• Chloramphenicol (Patterson)
• Neomycin (Brummett)
• Gentamicin (Webster)
• Ticarcillin (Jakob)
• Vasocidin (Brown)
• Ciprofloxacin (Lenarz)

26
Topical Antimicrobials

• Differences in humans
• Round window is not exposed
• Round window thicker
• Mucosal membrane protective
• Mucosal edema with or without exudates typically
  present
• Widespread usage with few side effects
• One in ten thousand

27
Topical Antimicrobials

• Remains a possibility in humans
• Patient education important
• Prescribe for only necessary duration
• Avoid in healthy ear
• Caution with prexisting vestibular defects

28
Case Presentation

• 68 yowf presents to clinic with complaint of
  ringing in my ears

29
Case Presentation

• 68 yowf presents to clinic with complaint of
  ringing in my ears
• Described as high pitched in both ears, onset was
  5 days prior and worsening, not able to sleep

30
Case Presentation

• 68 yowf presents to clinic with complaint of
  ringing in my ears
• Described as high pitched in both ears, onset was
  5 days prior and worsening, not able to sleep
• Long history of mild hearing loss, now worsening
  also
• Denies vertigo or dysequilibrium

31
Case Presentation

• Has prior history of significant noise exposure
  (worked in factory)
• No recent or prior antibiotic use
• No prior otologic history except mild HL

32
Case Presentation

• PMH HTN (controlled with medications), CRI (no
  change- creatinine 2.0)
• PSH none

33
Case Presentation

• PMH HTN (controlled with medications), CRI (no
  change- creatinine 2.0), arthritis, back pain
• PSH none
• Medications clonidine tid, lasix bid, vitamins
  qd, aspirin qid, ibuprofen prn

34
Case Presentation

• PMH HTN (controlled with medications), CRI (no
  change- creatinine 2.0), arthritis, back pain
• PSH none
• Medications clonidine tid, lasix bid, vitamins
  qd, aspirin qid, ibuprofen prn
• SH/FH noncontributory

35
Case Presentation

• PMH HTN (controlled with medications), CRI (no
  change- creatinine 2.0), arthritis, back pain
• PSH none
• Medications clonidine tid, vitamins qd, aspirin
  qid, ibuprofen prn
• SH/FH noncontributory
• ROS leg swelling worsening, DOE, anterior neck
  pain, arthritis worsening

36
Case Presentation

• PE H/N normal except ?left TVC paresis on IDL,
  tender nodules on pinna
• Neurologic exam normal
• Remainder exam normal except decreased ROM
  fingers, tender proximal joints

37
Case Presentation

• Labs CBC normal, Cr3.5, remainder nl

38
Case Presentation

• Labs CBC normal, Cr3.5, remainder nl
• Rheumatoid factor positive

39
Case Presentation

• Labs CBC normal, Cr3.5, remainder nl
• Rheumatoid factor positive

40
Case Presentation

• Labs CBC normal, Cr3.5, remainder nl
• Rheumatoid factor positive
• Salicylate level 20

41
Case Presentation

• Labs CBC normal, Cr3.5, remainder nl
• Rheumatoid factor positive
• Salicylate level 20