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 7-

10 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 [3-

5]. 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 ++ ++ ++ +

References 1. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th Edition, ed. L.L. Brunton, et al. 2006. 2. Rao, S.C., M. Ahmed, and R. Hagan, One dose per day compared to multiple

doses per day of gentamicin for treatment of suspected or proven sepsis in neonates. Cochrane Database Syst Rev, 2006(1): p. CD005091.

3. Contopoulos-Ioannidis, D.G., et al., Extended-interval aminoglycoside administration for children: a meta-analysis. Pediatrics, 2004. 114(1): p. e111-8.

4. Nestaas, E., et al., Aminoglycoside extended interval dosing in neonates is safe and effective: a meta-analysis. Arch Dis Child Fetal Neonatal Ed, 2005. 90(4): p. F294-300.

5. Shahid, M. and R. Cooke, Is a once daily dose of gentamicin safe and effective in the treatment of uti in infants and children? Arch Dis Child, 2007. 92(9): p. 823-4.

6. Darmstadt, G.L., et al., Determination of extended-interval gentamicin dosing for neonatal patients in developing countries. Pediatr Infect Dis J, 2007. 26(6): p. 501-7.

7. McCracken, G.H., Jr., Aminoglycoside toxicity in infants and children. Am J Med, 1986. 80(6B): p. 172-8.

8. Lundergan, F.S., et al., Once-daily gentamicin dosing in newborn infants. Pediatrics, 1999. 103(6 Pt 1): p. 1228-34.

9. Kotze, A., P.R. Bartel, and D.K. Sommers, Once versus twice daily amikacin in neonates: prospective study on toxicity. J Paediatr Child Health, 1999. 35(3): p. 283-6.

10. Langhendries, J.P., et al., Once-a-day administration of amikacin in neonates: assessment of nephrotoxicity and ototoxicity. Dev Pharmacol Ther, 1993. 20(3-4): p. 220-30.

11. Finitzo-Hieber, T., et al., Ototoxicity in neonates treated with gentamicin and kanamycin: results of a four-year controlled follow-up study. Pediatrics, 1979. 63(3): p. 443-50.

12. Saunders, J.E., et al., Prevalence and etiology of hearing loss in rural Nicaraguan children. Laryngoscope, 2007. 117(3): p. 387-98.

13. Bitner-Glindzicz, M. and S. Rahman, Ototoxicity caused by aminoglycosides. Bmj, 2007. 335(7624): p. 784-5.

14. Rybak, L.P. and V. Ramkumar, Ototoxicity. Kidney Int, 2007. 72(8): p. 931-5. 15. Seemungal, B.M. and A.M. Bronstein, Aminoglycoside ototoxicity: Vestibular

function is also vulnerable. Bmj, 2007. 335(7627): p. 952. 16. Dobie, R.A., et al., Hearing loss in patients with vestibulotoxic reactions to

gentamicin therapy. Arch Otolaryngol Head Neck Surg, 2006. 132(3): p. 253-7.

17. Ishiyama, G., et al., Gentamicin ototoxicity: clinical features and the effect on the human vestibulo-ocular reflex. Acta Otolaryngol, 2006. 126(10): p. 1057-61.

18. Aust, G. and D. Schneider, [Vestibular toxicity of gentamycin in newborn infants]. Laryngorhinootologie, 2001. 80(4): p. 173-6.

19. Khan, A.M., et al., Extended-interval gentamicin administration in malnourished children. J Trop Pediatr, 2006. 52(3): p. 179-84.

20. Nahata, M.C., Lack of nephrotoxicity in pediatric patients receiving concurrent vancomycin and aminoglycoside therapy. Chemotherapy, 1987. 33(4): p. 302-4.

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