Title: Aminoglycoside Ototoxicity: The Need to Consider More Than Auditory Status
1Aminoglycoside Ototoxicity The Need to Consider
More Than Auditory Status
- Jaynee A. Handelsman, Ph.D.
- ASHA Convention
- November 20, 2008
2Ototoxicity
- Damage to the inner ear from toxic agents
- Negative consequence of the availability and use
of medications that prolong life through
treatment of serious infections and cancer - Chemotherapy agents
- Antibiotics
- Result is damage to cochlear and/or the
vestibular end organs - Evidence suggests that there are no safe levels
3Session Objectives
- Discuss clinical features of auditory and
vestibular system damage - Discuss the challenges involved in monitoring for
auditory and vestibular system changes - Discuss our experience in monitoring patients
with CF during aminoglycoside exposure - Propose guidelines for monitoring auditory and
vestibular function during and following exposure
4Factors Determining Individual Ototoxicity
- Individual tolerance including genetic
predisposition - Impaired renal function
- Hyperthermia
- Prior or concomitant exposure to other ototoxic
agents - Dosing strategy perhaps, although recent evidence
suggests this might not be the case - Age
5Aminoglycosides
- Selective cochlear and/or vestibular toxic agents
- Readily absorbed from intramuscular and
subcutaneous sites poorly absorbed from
intestinal tract - From blood, about 50 is excreted unchanged in
24 hours - With renal insufficiency, blood levels may remain
high for many days - Distributed to all extra-cellular fluids (e.g.
endolymph and perilymph)
6Mechanisms of Ototoxicity
- It appears that ototoxicity is not caused by
accumulation of the substance in the ear - Rather, it appears to be caused by the drugs
penetration into compartments from which the
half-life of distribution is extremely long - Likely results from rapid uptake, early
saturation, and long exposure of the inner-ear
tissues to the drug
7Clinical Features of Ototoxicity on Audition
- Tinnitus
- Hearing loss
- Difficulty understanding speech in noise
- Sensorineural, usually bilateral, symmetric
- Progresses from high to low frequencies
- Symptoms can be delayed days, months
- Usually permanent but some recovery may occur
8Clinical Features of Ototoxicity on Vestibular
Function
- Acute bilateral vestibular loss
- Ataxia of stance
- Ataxia of gait
- Saccadic eye movements with rapid head turns
- Changes in visual acuity with head shaking or
nodding - Acute unilateral vestibular loss
- Vertigo, nausea, unsteadiness
- May have changes in visual acuity with head
movement
9Onset May be Acute or Insidious
- dramatic onset of severe imbalance and loss of
orientation in space - vertigo
- illusion of tilting
- slowly increasing unsteadiness of gait and
imbalance - oscillopsia
- frequent use of contact cues in darkness or when
walking on uneven ground
10Definition of Symptoms
- Oscillopsia an illusory movement of viewed
stationary objects or surrounds occurring with
head movement - Gait ataxia uncoordinated wide-based gait that
is commonly associated with a variety of
disorders including cerebellar disease and
bilateral peripheral vestibular loss
11Vestibular System is Responsible for Sensing and
Controlling Motion
- Receptors located within the labyrinth of each
inner ear transduce information about angular and
linear acceleration as well as gravity - Information combined with visual and
somatosensory signals on neurons in vestibular
nuclei - Integration of sensory signals produces
information required to control vestibulo-ocular
reflex (VOR) and the vestibulo-spinal reflex (VSR)
12Responsibilities of VOR and VSR
- VOR facilitates maintenance of binocular
fixation, thereby stabilizing gaze during rapid,
short-duration head movements - Reflexes move the eyes in the correct direction
and by the precise angle required to offset the
effects of head movements - VSR enables person to maintain desired head and
body positions with respect to gravity, even
following imposed movement of the head or trunk
13Explanation of Symptoms
- Oscillopsia is a direct result of the loss of the
VOR, which is responsible for maintaining foveal
vision when the head is moving, especially at
relatively high speeds - Quick movements of the head are associated with
saccadic gaze readjustments rather than smooth
compensatory eye movements - Ataxic gait is due to loss of vestibular input
and the need to rely on visual and proprioceptive
information for maintenance of postural control
14Challenges - Audition
- Complaints of ototoxic damage on hearing are
uncommon until communication problem becomes
significant - How much change at how many frequencies is
significant - Difficult to predict ototoxic damage
- Relationship to drug dosage, peak serum levels,
and other toxicities is variable
15Challenges - Vestibular
- The symptoms of vestibular loss are not
appreciated by physicians - Belief among many that monitoring blood levels
and using safe levels will prevent loss - When ototoxicity follows a long illness, symptoms
may be attributed to deconditioning - There are no accepted protocols for monitoring
function
16Factors Determining Oscillopsia in Bilateral
Vestibular Loss
- Age at onset
- Severity of semicircular canal dysfunction
- Extent of otolithic dysfunction
- Individual compensatory faculties
17Evaluation Protocol for Ototoxicity Things to
Consider
- Define the purpose of the monitoring protocol
- Define the target population
- Create a referral base by communicating with
physicians - Select the monitoring tools
- Test schedule
- Definition of significant change
- Communicate results
- Education, Counseling, and Rehabilitation
18Purpose of Monitoring
- Early Identification and Prevention
-
- Should we care about early changes enough to
take the time to measure them? -
19Rationale for Monitoring Hearing
- Hearing loss within 2 to 9 kHz range is
clinically significant for children - Some impact of high frequency loss on speech
understanding, even in adults - The use of amplification to remediate hearing
loss above 5 kHz is problematic - Continued damage may affect more of the critical
speech frequencies
20Reasons to Monitor Cochlear and Vestibular
Function
- Cochlear function is affected by almost all
aminoglycosides - Even slight ototoxic cochlear dysfunction is
noticeable, particularly via high frequency
audiometry and otoacoustic emissions - Slowly progressive vestibular dysfunction may go
undetected for some time - Vestibular ototoxicity is variable in terms of
onset and progression
21Benefits of Monitoring
- Early detection may prevent hearing damage that
requires amplification/rehabilitation - If change observed, treatment modification can
prevent further hearing loss - If no change observed, continued treatment is
warranted - Provides an opportunity for counseling and
rehabilitation during and post treatment - It is the basis for informed medical decision
making
22Target Patient Population
- Receiving highly ototoxic drugs
- Very old and very young people
- Poor medical condition
- Poor renal function
- Poor hydration status
- Familial tendency for susceptibility
(aminoglycoside antibiotics) - Receiving more than one ototoxic drug
- Receiving large or multiple doses
23At- Risk Populations
- Diabetic patients may be more profoundly affected
by bilateral vestibular loss due to concurrent
loss of vision and proprioception - Renal patients are more susceptible to
aminoglycoside ototoxicity because drugs are
metabolized by the kidneys - Dialysis patients are frequently at increased
risk of infection, and may be more likely to have
repeated exposure to aminoglycosides - Patients with cystic fibrosis are frequently
treated with aminoglycosides
24Incidence is Difficult to Define
- Patient population differences
- Different risk factors
- Methodological differences
- Established baseline
- No standard monitoring techniques
- Criteria
- Frequency range tested for hearing change
25Ototoxic Medications
- Antineoplastic Agents
- Cisplatin
- Carboplatin
- Vinblastine
- Vincristine
- Vinorelbine
- Difluoromethylornithine (DFMO)
- Nitrogen mustard
- Methotrexate
- Dactinomycin
- Bleomycin
- Loop diuretics
- Furosemide
- Ethacrynic acid
- Bumetanide
- Torsemide
- Limited evidence of ototoxicity
26Ototoxic Medications
- Aminoglycosides
- Gentamicin
- Sisomicin
- Kanamycin
- Neomycin
- Paromomycin
- Tobramycin
- Streptomycin
- Amikacin
- Dibekacin
- Netilimicin
- Other Antibiotics
- vancomycin
27Most Vestibulotoxic Aminoglycosides in Humans
- Gentamicin
- Streptomycin
- Tobramycin
28Evaluation Tools
- Pure-tone thresholds
- near upper frequency hearing limit (for example
ultra-high frequency audiometry) - Otoacoustic emissions
- High frequency ABR
- Tests of high frequency responses are likely to
be the most sensitive indicators of early change
29Criteria for Hearing Change
- Always referenced to baseline measures
- Criteria from ASHA 1994 guidelines
- gt 20 dB change at any one test frequency
- gt 10 dB change at any two consecutive test
frequencies - Loss of response at three consecutive test
frequencies where responses were previously
obtained. - Hearing change by any of these criteria was
confirmed by retest
30ASHA Change Criteria
- Normal variability in pure-tone thresholds occurs
at random frequencies - Threshold shifts at adjacent test frequencies
indicate more systematic change - Threshold shifts on repeated tests are also a
stronger indication of a true threshold change
31Extended High Frequency Audiometry - Sensitivity
- High- to low- frequency progression
- High-frequency testing is reliable
- Studies have shown the efficacy of high-frequency
monitoring - Studies have shown testing in 1/6-octave
intervals provides earlier detection - Individualized protocols targeting the highest
frequencies a person can hear
32Extended High Frequency Audiometry - Problems
- There are no normative high-frequency sensitivity
(threshold) standards due to lack of
standardization in - Calibration
- Instrumentation
- Methodological procedures
- There is a high degree of inter-subject
variability in sensitivity - Threshold variability increases with age and with
higher frequencies
33Does it Matter for Monitoring?
- The key to serial monitoring is intra-subject
(test-retest) reliability - High-frequency test-retest threshold variability
is within a clinically acceptable range ( 10 dB) - As a result, monitoring near individuals
high-frequency hearing limit is effective
34ABR Sensitivity
- Elongation of latency and/or disappearance of
click-evoked wave V following administration of
ototoxic drugs - Ultra-high frequency tone bursts (8-14 kHz) have
been shown to be more sensitive than clicks
35Problem Frequency Specificity
- Two problems at high stimulus levels
- Increased spectral splatter (stimulus energy
spreads) - Response could be due to tails of off-frequency
neurons - Pertains to all measures of auditory function
with all kinds of stimuli - Evoked potentials, behavioral measures
- Clicks, tone bursts, pure tones
-
36Problem Change Criteria
- There is no broadly accepted ABR latency change
criteria - Adults
- Children
- Neonates
37ABR Advantages
- Good test-retest reliability
- Can be performed at bedside
- Can estimate thresholds (magnitude of
ototoxicity-induced hearing loss) - Can obtain in patients with substantial
pre-existing hearing loss (up to severe to
profound)
38ABR Disadvantages
- Time consuming
- Limited frequency specificity (depending on how
performed) - Limited high-frequency output
- Response interpretation at high frequencies
- Subject noise, hearing loss may preclude
measurement - Infants children may require sedation
39DPOAE Advantages
- Highly selective to outer hair cell function
- Most ototoxic drugs attack outer hair cells
- Might provide earliest detection of ototoxicity
- It is frequency specific and can include a wide
frequency range - Objective and can be performed at bedside
- Good test-retest reliability
- Rapid
40Aminoglycoside Ototoxicity Outer hair cells and
otoacoustic emissions
- Distortion product otoacoustic emissions test
protocol - Intensity L1 65 dB SPL L2 55 dB SPL
- f2/f1 ratio 1.20
- Frequency range 500 or 1000 Hz to gt 8000 Hz
- Newer equipment now available clinically for
higher frequencies - Frequencies/octave 5 to 8
James W. Hall III, Ph.D.
41Problems Change Criteria
- Greater than or equal to 6 dB change
- Based on test-retest variability in normal
subjects - 6 dB change was more than variability in about
95 of subjects tested--so likely to be real
change - Confirm by re-test to decrease false positive
rates - Change at two adjacent frequencies would decrease
false positive rates - Each clinic should establish its own change
criteria
42DPOAE Disadvantages
- Limited high-frequency (gt 6 kHz) measurements
typical for clinical systems - DPOAE amplitudes are linked to hearing
sensitivity only for losses lt 50-60 dB - Hearing loss may preclude measurable responses at
baseline - Depends on normal middle ear function
43DPOAEs Essentials of Analysis and Interpretation
- Verify that noise floor is low
- below upper limit for a normal population
- Verify the presence of reliable OAEs for each
frequency - amplitude gt 6 dB above noise floor
- Interpret amplitudes for each frequency relative
to the normal region - OAEs within normal limits normal
- OAEs present but below normal limits
abnormal - OAEs lt 6 dB above noise floor (OAE NF lt 6
dB) absent
James W. Hall III, Ph.D.
44Relation Between OAE Amplitude and Hearing Loss
DPOAE 65/55 dB SPL TEOAE 80 dB SPL
WNL (Amplitude gt 95ile)
OAE Amplitude
Normal
Present but not normal
No OAE
No OAE (OAE NF lt 6 dB)
-10 0 10 20 30 40
50 60
Hearing Level in dB HL
James W. Hall III, Ph.D.
45Laboratory Tests for Monitoring Vestibular
Ototoxicity
- Dynamic visual acuity testing
- Caloric testing
- Rotational testing
- Dynamic posturography
46Rotational Testing Has Value
- Caloric testing evaluates only very low frequency
function (lt.003 Hz) - Rotational testing tests mid- to high frequency
function (.01-.64 Hz) - Testing the VOR at lowest rotational frequencies
may provide early signs of vestibular dysfunction
47Dynamic Posturography
- Useful for quantifying ataxia
- Useful for evaluating patients ability to use
visual and proprioceptive information to maintain
postural stability following bilateral loss of
vestibular function - In patients with CF, some have abnormal function
even when they deny problems
48Bedside Tests of Vestibular Function
- Head thrust
- Testing of dynamic visual acuity
- Romberg, tandem walking, stepping test
49Cystic Fibrosis Project
- First aim of the project is to establish the
prevalence of vestibular system involvement in
patients treated with aminoglycosides for
pulmonary exacerbations secondary to CF - Secondary aim is to determine whether incremental
changes in function can be detected reliably over
time - Hope is to develop guidelines for optimal
monitoring protocol
50Original Plan with CF Patients
- Patients admitted into the hospital for
initiation of aminoglycoside antibiotics - Test vestibular function while inpatient when
possible, ideally within a couple of days of
initiation of treatment - Completion of Dizziness Handicap Inventory (DHI)
- Also complete audiological testing when possible
- Test patients again at their three month
follow-up appointment with pulmonologist
51Categories of Vestibular Loss
- Non-lateralized vestibular system involvement
- Unilateral vestibular loss
- Bilateral peripheral vestibular paresis
52Non-lateralized Vestibular Involvement
- Significant spontaneous, positional, or post head
shaking nystagmus - Increased phase leads in sinusoidal rotational
testing - Short time constants in rotational step testing
- Patient may not be symptomatic
53Unilateral Involvement
- Significant unilateral weakness in caloric
testing - During the acute phase, might have spontaneous
nystagmus and asymmetries in rotational testing - Patient more likely to describe vertigo and
unsteadiness, although oscillopsia is possible
54Bilateral Vestibular Loss
- Significant bilateral caloric reduction
- Significant gain reductions in sinusoidal
rotational tests - Significant gain reductions in rotational step
testing - Gait instability and oscillopsia are common
symptoms
55Data Trends to Date
- We have completed vestibular testing on 49
patients to date - We do not have audiological test data on 11 of
those individuals - Testing was attempted with minimal results
obtained on additional patients - 18 have evidence of non-lateralized vestibular
involvement - 5 have significant unilateral loss
- 14 have bilateral peripheral vestibular paresis
- 4 have documented normal hearing and vestibular
function, with 5 others without hearing tests
56Data Trends to Date
- We have completed serial monitoring on a subset
of patients - When comparing individual patient data for
absolute caloric and rotational chair values, it
appears that sub-clinical but consistent changes
are occurring over time - From normal calorics to an eventual significant
unilateral weakness - From evidence of non-lateralizing findings to
bilateral involvement - From mild bilateral involvement to severe
bilateral loss
57Pragmatic Issues to Consider
- Not all patients will tolerate vestibular testing
- It is unrealistic to conduct serial testing as
often as we had anticipated - When patients are admitted for initiation of
aminoglycosides, there are time and scheduling
constraints - Patients and parents are generally not well
informed about the importance of monitoring
function over time - Physicians, parents, and patients may not want to
know when damage occurs
58Acknowledgement
- N008681-385013 Vestibular and Auditory Sensory
Loss in CF Patients - W. Michael King, Ph.D., Jaynee Handelsman, Ph.D.
and Samya Nasr, M.D. - Cystic Fibrosis Foundation Therapeutics, Inc.
59Test Battery for Monitoring and Diagnosis
University of Florida
- Diagnosis of auditory dysfunction
- Distortion product otoacoustic emissions
- Aural immittance measurement
- Tympanometry
- Acoustic reflexes
- Pure tone audiometry
- Conventional audiometric frequencies
- High frequencies (10 K to 20 K Hz)
- Speech audiometry
- Word recognition (10 most difficult words first)
- Speech-in-noise (as indicated by history)
James W. Hall III, Ph.D.
60Hearing Findings in Patients with Cystic
Fibrosis University of Florida
OAEs
100
Audio lt 8K Hz
80
60
Audio gt 8K Hz
57 (N 33)
Abnormal Findings in
50 (N 2)
43
40
30
25
20
20
Children (N 15)
Adults (N 81)
James W. Hall III, Ph.D.
61Vestibular Rehabilitation is Effective in Aiding
Patients with Unilateral and Bilateral Vestibular
Loss
- Therapy aimed at fostering the substitution of
visual and somatosensory cues for lost vestibular
function - Gaze stabilization exercises
- Balance retraining exercises
62Adaptive and Compensatory Mechanisms Involved in
Stabilization of Eye Movements
- Adaptation of saccadic eye and head movement
- Use of neck and other somatosensory afferents
- Enhanced eye tracking
- Centrally preprogrammed eye movements
- Central suppression of undesired image movement
across the retina
63Functional Adaptations Build within One Year
- Gaze stabilization most improved through
centrally preprogrammed slow eye movements during
active (predictable) head movement - During unpredictable head movements,
cervico-ocular reflexes and increased fixation
may yield best stabilization - Strongest suppression of oscillopsia achieved by
central adaptive rearrangements
64Compensatory Mechanisms Effective in Suppressing
Oscillopsia
- Only one third of adult patients with acquired
bilateral vestibular loss of function suffer from
permanent oscillopsia - This underlines the paramount biological
importance of maintaining clear vision during
locomotion
65Roles of Vision and Propriception
- Patients are able to use vision and somatosensory
input to maintain postural control in the absence
of vestibular function - When circumstance prevent their use (e.g. in
darkness or when walking on uneven or
compressible surfaces), gait ataxia persists for
almost every patient
66Bilateral Vestibular Loss - Practical Implications
- Oscillopsia, which results in visual blurring or
bobbling - may prevent patients from driving,
or even walking unassisted - Because patients rely on vision and
proprioception to maintain postural control while
ambulating, darkness combined with compressible
or uneven support surfaces result in increase
risk of falling
67Vestibular Rehabilitation The Good News
- Research supports the fact that responses of a
partially functioning vestibular system can be
modified - For patients with some residual function, VR is
focused on optimizing the use of the remaining
VOR, as well as increasing the effectiveness of
the COR - For all patients with bilateral vestibular loss,
increasing the use of vision and proprioception
is a goal
68Variables Affecting Therapy Outcome
- Extent of the vestibular loss
- The presence of coexisting disease that may
impact sensory system function - Overall patient heath and fitness
- Patient motivation and compliance with program
69Pharmacologic Protection from Aminoglycoside
Induced Ototoxicity
70Proposed Otoprotective Agentsfor Aminoglycoside
Ototoxicity
- Lipoic Acid
- N-acetylcysteine (NAC)
- Aspirin
- Iron chelators
- Caspase inhibitors
- Gene therapies
- D-methionine (D-met)
Kathleen C.M. Campbell, Ph.D
71D-methionine (D-met)
- Provides excellent but not complete protection
against aminoglycoside-induced hearing loss in
animal studies to date. - Excellent protection from noise-induced hearing
loss for pre/peri- and even post exposure
administration. - Also effective in preventing NIHL,
cisplatin-induced ototoxicity, and radiation
induced oral mucositis in studies to date. - Some patients are exposed to a combination of
these factors.
Kathleen C.M. Campbell, Ph.D
72Current Status of D-met Research
- FDA approved ISUs Investigational New Drug
Application January 2005 for D-met protection
from radiation induced oral mucositis. - FDA approved Clinical Trials in progress
- Phase II clinical trials for cisplatin in
progress in India. - Looking for US patient populations.
- In discussions with military for NIHL protection.
- More bench work also needed. Currently performing
additional basic research to go to clinical
trials for aminoglycoside otoprotection.
Kathleen C.M. Campbell, Ph.D
73Protection from Amikacin Induced Ototoxicity by
D-methionine Klemens and Campbell
- Three Groups 5 albino guinea pigs each
- Amikacin 200 mg/kg/day subcutaneously for 28
days - D-methionine 300mg/kg/day ip 30 minutes prior to
the amikacin - Control animals given equal volume saline
Kathleen C.M. Campbell, Ph.D
74D-met Protection from Aminoglycoside Induced
Hearing Loss
- D-met provides partial but significant protection
against amikacin-induced hearing loss. - Planning further studies on dosing protocols and
additional aminoglycosides
Kathleen C.M. Campbell, Ph.D
75Sha and Schacht Two Studies Published in 2000
- Both Studies used pigmented male guinea pigs and
19 day administration of amikacin - Study 1
- 100 mg/kg histidine combined w/gent
- 3) 200 mg/kg D-met combined w/gent
- 4) saline only
- 5) D-met only
- 6) histidine only
- Study 2200 mg/kg d-met twice daily
- First dose combined with 120mg gentamicin
- Second dose of D-met injected 7 hours later
Kathleen C.M. Campbell, Ph.D
76Conclusions
- D-methionine can protect against aminoglycoside
induced ototoxicity. - More work needs to be done on dosing protocols.
- More work needs to be done on nephroprotection
- More work needs to be done to be done to ensure
lack of interference with the aminoglycosides
antimicrobial activity
Kathleen C.M. Campbell, Ph.D
77Current Work D-met and Aminoglycosides
- Thanks to NIH/NIDCD
- The group at ISU is performing the translational
research laboratory studies to prepare for FDA
approved clinical trials. - Studies include developing D-met protection for
gentamicin, amikacin, and tobramycin. - Performing dosing studies (i.e. fractionated
versus daily dosing, dose response curves) - Performing antimicrobial interference studies.
- Collecting control data on patients currently on
aminoglycosides to establish data base for
clinical trials.
Kathleen C.M. Campbell, Ph.D
78Summary
- Ototoxicity not only relates to hearing, but to
vestibular system function - Bilateral vestibular loss can be devastating,
causing ataxia and oscillopsia - Unilateral loss is possible as well
- There is a need to monitor closely patients at
risk for vestibular loss - Vestibular rehabilitation should be considered in
all cases of uncompensated vestibular system
involvement - Future Outlook Protective Drugs May Limit
Aminoglycoside Ototoxicity