Second Meeting of the Subcommittee of the Expert Committee on the

Selection and Use of Essential Medicines

Geneva, 29 September to 3 October 2008

Gentamicin - Ototoxicity in children

Summary
Aminoglycosides have good activity against many multi-drug resistant Gram negative
bacilli and are therefore important for treating serious infections due to these
organisms in adults and children including neonates. Use of these drugs can result in
ototoxicity and nephrotoxicity. Ototoxicity is irreversible and may result in cochlear
damage, vestibular damage or both. Incidence of cochlear and vestibular toxicity is
low in children and neonates. There is no significant difference in the incidence of
ototoxicity between once daily dosing and multiple doses per day. Limited available
data show that aminoglycoside induced hearing loss contributes to only a small
proportion of the deafness in the community. Individuals with certain identifiable
mutations have higher susceptibility to aminoglycoside induced hearing loss.
Nephrotoxicity is largely reversible and its incidence is also low in children.
However, aminoglycosides are to be used only when there is a definite indication and
for the minimum duration required. Monitoring of drug levels and for toxicity is
recommended.
Most trials in children have used gentamicin. Cost of gentamicin is less than that of
other aminoglycosides. Amikacin has almost similar spectrum and is also safe in
children. It may be effective against some gentamicin resistant bacteria and so is more
suitable for hospital settings where gentamicin resistance rates are high.
Introduction
Aminoglycosides are narrow spectrum antibiotics which act mainly on aerobic Gram
negative bacilli including many multi drug resistant ones. They are recommended for
use in children including neonates for several serious infections like septicaemia,
caused by these bacteria. However, aminoglycoside use can result in ototoxicity and
nephrotoxicity. Other adverse events like antibiotic associated diarrhoea and
hypersensitivity are rare [1]. Although gentamicin and amikacin have similar

indications for use and safety profile in children, most reported experience is with
gentamicn. It is also less expensive (International Drug Price Indicator Guide).
Ototoxicity
Animal and human studies show that aminoglycosides progressively accumulate in
endolymph and perilymph of inner ear and that the half life in these fluids is 5 to 6
times greater that that of plasma half life [1]. Back-diffusion is dependent on
concentration of the drug in plasma and hence, ototoxicity is more likely to occur in
patients with persistently elevated concentrations in plasma. However, even single
doses can cause ototoxicity.
Vestibular and cochlear sensory cells are susceptible to damage by aminoglycosides
and the changes are largely irreversible. Hence ototooxicity can be cochlear and/or
vestibular damage. Although all aminoglycosides are capable of affecting cochlear
and vestibular functions, some preferential toxicity is evident. For example,
gentamicin causes more vestibular damage while amikacin causes more auditory
damage. Auditory damage is better recognised and often erroneously used
synonymously with ototoxicity
Hearing loss (Cochlear toxicity)
By audiometry, about 25% of patients on aminoglycoside therapy develop toxicity
[1]. Most studies in infants and children from different parts of the world however,
show that hearing loss is a rare complication of aminoglycoside therapy [2-7].
Neither ototoxicity nor nephrotoxicity were noted in a Cochrane review [2] done to
assess safety and efficacy of once daily (OD) dosing of gentamicin, based on 11
studies (n= 574) in neonates with sepsis. Pharmacokinetic properties were better with
OD regime in that it achieved higher peak levels while avoiding toxic trough levels.
Only one study enrolled infants less than 32 wks gestation.
Another meta-analyses [3] of 24 RCTs in children published between 1991 and 2003,
found that the pooled toxicity rates by auditory testing were 2.3% (10 of 436 cases)
with OD and 2.0% (8 of 406 cases) with multiple doses per day (MD) schedules.
There were no cases of clinical hearing impairment (OD and MD 114 cases each).
Hearing abnormalities were infrequent in neonates treated with aminoglycosides [4].
2.3% of low birth weight and very low birth weight infants on gentamicin had
probable hearing abnormalities as detected using brainstem auditory response signals
(ALGO screen). 0.9% neonates in the control group also had a similar finding [8].

With amikacin no neonate had abnormalities in the brainstem auditory evoked

potentials in one study on 40 neonates [9] and no difference from control neonates
were observed in another [10]. Only one RCT in a metaanalyses of gentamicin
therapy of UTI in children looked for toxicity by audiometry and none of the 172
children had this complication [5].
Measurements were done in the immediate post treatment periods for most of these
studies. Although gentamicin is used widely in neonates, reports on hearing loss in
such children in later life are scanty. This probably suggests relative absence of this
problem. Limited data do not show any significant hearing loss in gentamicin and
kanamicin treated infants on four year follow up [11]. In a clinic and school based
survey in Nicaragua done to identify causes of deafness, earlier gentamicin use was
recorded as a possible risk factor in a small number of children. However, most of
these children had other risk factors also like meningitis and familial hearing loss
[12]. A family history of hearing loss was the most frequent risk factor in this survey.
Some individuals have genetic predisposition for developing hearing loss and they can
develop permanent hearing loss with therapeutic concentrations and even single doses
of aminoglycosides [13]. About quarter of individuals with aminoglycoside induced
hearing loss have maternal relatives with drug related hearing loss. Most common
predisposing mutation identified is m.1555A>G, which is a mitochondrial DNA
mutation and hence exclusively maternally inherited [13]. This mutation is seen in up
to 50% of aminoglycoside related hearing loss. No large scale data for its prevalence
is available. In the US 1/1161 neonates had this mutation and in a report from New
Zealand 1/206 random blood samples showed this mutaion. In the UK, 1/1000
children are born deaf and 2-5% of them have this mutation. Epidemiological studies
suggest that probability of becoming deaf is very high if individuals with this
mutation are exposed to aminoglycosides. Hence to prevent aminoglycoside related
hearing loss, one possibility is to screen for this mutation[13]. However the test is
expensive, not easily available and can cause delays in initiating therapy. Asking for
history of deafness in maternal relatives is more practical.
Damage is mediated by reactive oxygen species that trigger mechanisms causing cell
death. Antioxidants show promise in protecting inner ear from damage in
experimental animals [14]. One double-blind, placebo controlled clinical trial showed
that aspirin can reduce the incidence of aminoglycoside induced hearing loss in
human beings [14].

Vestibular toxicity
Vestibular function is much more sensitive to aminoglycosides than hearing [15].
Most individuals with vestibular toxicity do not develop hearing loss [16] and these
cases are usually missed. Manifestations include gait imbalance and head movement
induced oscillopsia[17]. Vertigo may or may not be present. This damage is also
permanent [15].
This toxicity also appears to be rare in children and neonates. No vestibular toxicity
was documented among 209 OD and 206 MD patients [3] in a metaanalyses of dosing
schedules. 30 children aged between 3.1 and 32.9 m, who had received gentamcin in
the neonatal period did not show increase frequency of spontaneous eye movements
as compared to children without gentamicin exposure in neonatal period [18].
Nephrotoxicity
Approximately 8% to 26% of patients who receive aminoglycosides for more than 710 days (Australian Medicines Handbook) develop mild renal impairment which is
almost always reversible [1]. It usually presents as gradually worsening non oliguric
renal failure. Severe acute tubular necrosis may occur rarely.
Nephrotoxicity is also uncommon in children. The Cochrane review did not identify
any nephrotoxicity [2]. Other meta-analyses found low incidences of this toxicity [35]. There was no significant difference between OD (15 of 955 cases, 1.6%) and MD
(15 of 923 cases, 1.6%) schedules in causing elevated creatinine levels or in reducing
creatinine clearance in children. Urinary excretion of protein or phospholipids
occurred in 3 of 69(4.4%) cases on OD compared to 11 of 69 cases (5.9%) on MD
(statistically significant RR 0.33, 95% CI: 0.12-0.89) [3]. In one RCT, of the 172
evaluable cases (between 1m to 9yrs) 1.2% on OD and 2.3% on MD schedule had
nephrotoxicity [5]. NAG/creatinine ratio was abnormal in 2/13 (15%) and 5/11 (45%)
children in another RCT in the same meta-analysis [5]. No nephrotoxicity, as defined
using creatinine levels, was recorded in 148 and 162 malnourished children on OD
and MD gentamicin regimes [19]. Nephrotoxicity was not observed in 90 infants and
children receiving gentamicin and vancomycin together for a mean duration of 9
days[20].
Aminoglycosides can impair neuromuscular transmission. These are not to be given to
children with myasthenia (BNF C 2006).

Since toxicity correlates with elevated concentrations of drug in plasma, it is

important to monitor drug levels. This is especially important in neonates and infants
since half life is longer and can vary during this period. In children with normal renal
function, drug levels are to be measured initially after 3-4 doses for the MD regimes
(BNF C 2006). Children with renal impairment will require earlier and more frequent
measurements. Monitoring for ototoxicity and nephrotoxicity is also recommended.
Loading and maintenance doses are to be calculated based on weight and renal
function. Dose and interval between doses need to be adjusted in renal impairment
(BNF C 2006). Interval between doses in neonates on OD regime may require to be
prolonged to more than 24 hrs, based on trough levels (BNF C 2006). Duration of
therapy should be kept to the minimum, usually less than 7 days. BNF C 2006
recommends that aminoglycoside should preferably not be given with potentially
ototoxic diuretics like furosemide. If concurrent use is unavoidable, the gap while
administering the two should be as wide as possible.
Table Comparative information on toxicity (Australian Medicines Handbook)
Vestibular

Cochlear

Nephro

Neuromuscular

Amikacin

++

++

Gentamicin

++

++

++

Streptomycin

+++

++

Tobramycin

++

++

++

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4.
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