Intratympanic gentamicin as a treatment for drop attacks in

patients with meniere's disease.

Hypothesis/Objective: Vertigo attacks in most cases of Meniere's disease are
successfully treated with lifestyle changes and medication However! appro"imately #$
of patients with Meniere's %isease develop drop attacks! a potentially life&threatening
condition 'raditional treatment for drop attacks has been surgical labyrinthecctomy
'he objective of this study was to assess the effectiveness of intratympanic gentamicin
for drop attacks in patients with Meniere's %isease (tudy %esign: )etrospective charts
review Methods: *ll charts were reviewed from Meniere drop attack patients at our
hospital during the +,&year period from -,,-&-,+- who had been treated with
intratympanic gentamicin and had been followed for at least + year afterwards )esults:
'wenty&four ears fulfilled inclusion criteria 'he time for manifestation of drop attacks
varied from +&-, years after diagnosis .mean +, years/0 122$ of ears with intractable
Meniere's %isease and drop attack achieved complete symptom control of drop attacks
after the first intratympanic gentamicin cycle! and 341$ after further injections *mong
patients with no drop attacks recurrence by the end of the study follow&up! the
symptom&free interval varied from +-&+-, months .mean: 524 mos/ *ll fifteen patients
with 6-5 mos follow&up were still free of drop attacks 7levated or absent V7M8
thresholds were more common in drop attack than in contralateral ears! and hearing
loss was not a major complication of the treatment 9onclusion: :ntratympanic
gentamicin treatment appears to be a long&lasting and effective treatment for Meniere's
%isease with drop attacks
Chemical and Physical Properties
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Color/Form
WHITE AMORPHOUS POWDER
from HSDB
Melting Point
102-108 DEG C
from HSDB
Solubilities
FREEL SOL I! WATER" SOL I! PRIDI!E# DIMETHLFORMAMIDE $ I! ACIDIC
MEDIA WITH SALT FORMATIO!" MODERATEL SOL I! METHA!OL# ETHA!OL#
ACETO!E" PRACTICALL I!SOL I! %E!&E!E# HALOGE!ATED HDROCAR%O!S
from HSDB
Spectral Properties
SPECIFIC OPTICAL ROTATIO!' (1)* DEG + 2, DEG C-D
from HSDB
Side effects
'hese aminoglycosides are to"ic to the sensory cells of the ear! but they vary greatly in their relative
effects on hearing versus balance ;entamicin is a vestibuloto"in! and can cause permanent loss of
e<uilibrioception! caused by damage to the vestibular apparatus of the inner ear! usually if taken at
high doses or for prolonged periods of time! but there are well documented cases in which
gentamicin completely destroyed the vestibular apparatus after three to five days * small number of
affected individuals have a normally harmless mutation in their mitochondrial )=* .m+444 *>;/!
that allows the gentamicin to affect their cells 'he cells of the ear are particularly sensitive to this!
sometimes causing complete hearing loss However! gentamicin is sometimes used intentionally for
this purpose in severe M?ni@re's disease! to disable the vestibular apparatus 'hese side effects are
most common when the drug is administered via drops directly to the ear
;entamicin can also be highly nephroto"ic! particularly if multiple doses accumulate over a course of
treatment Aor this reason gentamicin is usually dosed by ideal body weight Various formulae e"ist
for calculating gentamicin dosage *lso trough and peak serum levels of gentamicin are monitored
during treatment! generally before and after the third dose is infused
;entamicin! like other aminoglycosides! causes nephroto"icity by inhibiting protein synthesis in renal
cells 'his mechanism specifically causes necrosis of cells in thepro"imal tubule! resulting in acute
tubular necrosis which can lead to acute renal failure
B1C
(ide effects of gentamicin to"icity vary from patient to patient (ide effects may become apparent
shortly after or up to months after gentamicin is administered (ymptoms of gentamicin to"icity
include:
Dalance difficulty
Douncing! unsteady vision
)inging in the ears .tinnitus/
%ifficulty multi&tasking! particularly when standing
8sychiatric symptoms related to gentamicin can occur 'hese include anore"ia! confusion!
depression! disorientation and visual hallucinations :mmediate professional help should be sought if
any of these symptoms or others appear after administration of aminoglycosides
Many medical practitioners freely administer gentamicin as an antibiotic without advising patients of
the severe and permanent potential ramifications of its use ;entamicin is well known to be a cheap!
low&cost yet old medicine when compared with modern alternatives! and is typically E(F2G# per
dosage less than modern alternatives
Many people recover from gentamicin to"icity naturally over time if the drug is discontinued! but they
recover slowly and usually incompletely (ometimes the to"icity of gentamicin can still increase over
months after the last dose Epon cessation of gentamicin therapy symptoms such as tinnitus and
imbalance may become less pronounced (ensori&neural hearing loss caused by gentamicin to"icity
is permanent however
Gentamicin is an aminoglycoside antibiotic ('he term aminoglycoside refers to a
recogniHed medicinal and bacteriologic category of traditional ;ram&negative antibacterial
therapeutic agents that inhibit protein synthesis and contain as a portion of the molecule an amino&
modified glycoside.sugar/0 the term can also refer more generally to any organic molecule that
contains aminosugar substructures /
What is Gentamicin Toxicity?
Gentamicin is a commonly used antibiotic medication. Gentamicin toxicity is the most common single
known cause of bilateral vestibulopathy, accounting for ! to !"# of all cases. $ilateral
vestibulopathy, discussed in more detail here, occurs when the balance portions of both inner ears are
damaged. The symptoms typically include imbalance and visual symptoms. The imbalance is worse in the
dark, or in situations where footing is uncertain. Spinning vertigo is unusual. The visual symptoms, called
oscillopsia, only occur when the head is moving. %uick movements of the head are associated with
transient visual blurring. This can cause difficulties with seeing signs while driving, or recogni&ing faces
while walking.
When a person has bilateral vestibular damage, such as may result from Gentamicin toxicity,
they may experience oscillopsia. When the head is moving, ob'ects blur. When driving, one
may be unable to see signs clearly on a bumpy road.(ther than gentamicin, there are
numerous other ototoxins, but most maily affect hearing.
Gentamicin is spelled with a terminal micin, unlike several other drugs in the same aminoglycoside
family, that end with mycin. The difference in spelling from other aminoglycosides, such as streptomycin,
reflects the different species of origin of this antibiotic.
)earing ototoxicity reportedly occurs about ! to "# of the time that gentamicin is given intravenously or
during peritoneal dialysis. )owever, hearing in humans is generally affected only for high fre*uencies
+approximately ,,""" to -,""" )&. or not at all. This differs from the situation in most animals.
Typical audiogram of person exposed to
gentamicin. )earing is commonly normal through /""" )&, and then falls off at higher fre*uencies.
(ften, persons with significant vestibular damage from gentamicin do not notice any change in their
hearing.
0ore importantly, the vestibular system can be damaged with gentamicin. The exact incidence of
vestibulotoxicity when gentamicin is administered in humans is presently uncertain. 1ot only have very
few prospective studies of vestibular function been done, but it is also difficult to detect vestibular damage
until it is profound. 2t seems likely that significant vestibular damage does not occur as fre*uently as the
subtle hearing impairment reported above +! to "#.. The author3s best estimate is that between ".# and
# of all two4week courses of gentamicin result in vestibular toxicity. This is only a guess, and we hope
that a prospective study is done to answer this *uestion at some point.
The current prevailing view is that aminoglycoside toxicity is associated with death of inner ear hair cells
one to two days after exposure, while spiral ganglion cell loss occurs three to fifteen days post4exposure
+5lhara&neh et al -", 6ilberstein et al -"-.. The auditory ganglion is spared.
Why 7o (nly Some 8eople 7evelop Gentamicin Toxicity?
5s discussed above, gentamicin toxicity is certainly not the rule, even for month4long courses of
gentamicin. Why do some people react with ototoxicity and others don3t? The following factors may affect
toxicity9
dose
potentiating medications
genetic susceptibility
7ose
(ne possibility is that the dose was too small. 2t is very uncommon for gentamicin ototoxicity to develop
with less than one week of treatment. 2t is possible to develop bilateral vestibular toxicity from
gentamicin, even when the level of the drug is not too high ifit is given for a long period. The risk may be
especially high if there are other drugs being given +see below., or in certain individuals with genetic
predisposition +see below..
:ecent studies suggest that gentamicin ototoxicity is most closely related to total dose, rather than having
inappropriately high levels. ;onventionally, gentamicin is given three times per day, with a total dose per
day ranging from < mg=kg to ! mg=kg. These doses may need to be modified for special situations such as
when kidney function is impaired. 5 recent study found a strong correlation between aminoglycoside dose
fre*uency and severity of hearing loss +Tokgo& et al -""..
5 recent trend is to administer gentamicin on a once per day schedule because bacterial killing is a
stronger function of concentration than time. 7etails about how this is done using a nomogram, called
the )artford 1omogram, is found in in a paper written by 1icolau et al. 5 thorough discussion of dosage
and monitoring is discussed by :oberts and associates +-"-. .8eak levels are expected to be *uite high,
and targets for three time per day dosing as discussed above are inappropriate for once per day dosing.
2nstead, levels drawn at known times from the administration are used to ad'ust the interval of dosing
using a nomogram. 5ccording to :oberts et al. +-"-., trough levels are not necessarily needed for once4
daily dosing. >vidence suggests that ototoxicity is less for once=day dosing than more fre*uent dosing
+Tokgo& et al -"".. This line of evidence suggests that high4peak levels are not necessarily ototoxic, but
rather it is the total dose that is important. 2t is also possible that toxicity might be related to a
combination of peak dose and total dose. The studies done to date are not powerful enough to clearly
distinguish between the two possibilities.
8otentiating 0edications
There may be increased risk of ototoxicity from gentamicin, if other ototoxic drugs such as cisplatin +a
chemotherapy agent. and vancomycin +another antibiotic. are given at the same time. There also appears
to be a synergistic effect of loop diuretics, such as furosemide or ethacrynic acid +7ing et al -""., and
also loud noise +?i @ Steyger -""A., when combined with gentamicin. The potentiating effect of loop
diuretics is likely related to a more rapid entry of gentamicin into the ear. Gentamicin is probably also
toxic to the ear of the developing fetus, as related drugs +such as. streptomycin. have been shown to have
this problem +Touw et al -""A.. >ar drops containing gentamicin, as well as related substances, may
be ototoxic if given over a prolonged time to individuals with perforated ear drums.
Genetic Susceptibility
2t has been found that in some individuals there is unusual susceptibility to gentamicin or streptomycin
ototoxicity related to a mutation of mitochondria +0uyderman et al -"-, %ian @ Guan -""A.. This
susceptibility is passed on genetically through the mother and occurs in as many as B# of individuals
with hearing loss after aminoglycoside exposure. Cestibular abnormalities have been demonstrated in an
animals with dysfunctional mitochondria +%uintana et al -""., and human pedigrees have been reported
with both sensorineural deafness and aminoglycoside sensitivity+:ahman et al -"-.. )earing loss is also
common in Dearns4Sayre, a disorder with mitochondrial 715 and other mitochondrial disorders.
What is the 8rognosis of Gentamicin Toxicity?
2n general the message is not very encouraging. 8eople do recover, but the process is slow and usually
incomplete. The ma'ority of the improvement occurs at high fre*uencies on rotatory chair testing E high4
fre*uency gain may return to normal, but remain depressed for lower fre*uencies. 8rogression of
vestibulotoxicity can occur for months after the last dose, and recovery can be measured out to a year or
even longer +$lack et al, -"".. :ecovery likely is related to a combination of several factors9
. Some FsickG inner ear hair cells get better. 1obody knows exactly how many inner ear hair cells
are sick rather than being dead, but it seems reasonable to assume that they are not all deadH some
remain but are not functioning at top efficiency. 5s gentamicin persists in the ear for somewhere
between ," days and a year, recovery from this process might reasonably stretch over the same time
frame.
-. The brain adapts to the missing inner ear information. ;ertainly people adapt to missing sensory
input using plasticity, substitution and behavioral changes.
<. There may be regeneration occurring. $irds can regenerate their hair cells. 2t was felt for a long
time that people can3t do thisH however, there is a small amount of evidence that some regeneration
does occur.
/. 1erve axons sprout and innervate surviving hair cells.
;urrent research has shown that vestibular hair cell regeneration may be possible with gene therapy +5lbu
@ 0uresanu -"-..
8lease see our $ilateral Cestibulopathy 8age for further information regarding diagnosis, treatment,
prognosis, and research efforts related to ototoxicity in general and gentamicin toxicity in particular.