The World Health Organization (WHO) has produced guidelines for the management of common illnesses in hospitals with limited resources. This series reviews the scientific evidence behind WHO's recommendations. The WHO guidelines, and more reviews are available at http://www.ichrc.org.

This review addresses the question: What is the evidence for the safety of gentamicin use in children?

Gentamicin is widely advocated throughout the WHO Pocketbook of Hospital Care for Children in the treatment of serious bacterial infection (including meningitis, pneumonia and various infections with enteric flora).

Introduction

Infection is the commonest cause of infant and child mortality worldwide [1]. As there is such an overlap between the clinical presentations of bacterial infection, an empirical combination of antibiotics are often used to cover the commonest and most serious micro-organisms.

Gentamicin, an aminoglycoside, is relatively cheap and widely available, and is bactericidal against most aerobic Gram-negative and some Gram-positive organisms: as a result, it is often included in empirical treatments, as it is in the WHO Pocketbook. It is also particularly useful in the co-treatment of infection with Streptococcus, Listeria species or Pseudomonas infections [2].

Aminoglycosides act by preventing bacterial protein synthesis, and act synergistically with antibiotics that prevent cell wall formation [2], reducing the problem of resistance, and increasing efficacy.

Aminoglycosides are not absorbed from the gastrointestinal tract, hence they must be administered by injection. Most of that is excreted by the kidney unchanged and the therapeutic index is narrow; therefore, if renal function is inhibited, toxicity can rapidly occur. On these grounds, serum levels should be monitored where possible.

Few alternatives to gentamicin are available, particularly in countries with limited resources, where more expensive drugs are not obtainable. In some instances, such as in the treatment of severe pneumonia, the WHO Pocketbook recommends chloramphenicol as an alternative, for which clinical outcome should be similar [3].

Gentamicin is associated with dose-related (trough serum concentrations >2 µg ml−1 [4]) nephro- and ototoxicity [2]. Nephrotoxicity is usually reversible on termination of gentamicin treatment, but ototoxicity can lead to permanent sensori-neural deafness and vestibular disturbance. If serum gentamicin levels are monitored, safety can be improved, but this is not always possible in countries where the pocketbook would be used. It is on these grounds that the safety profile of gentamicin needs to be established: what is the evidence of safety of gentamicin use in children?

Methodology

The PubMed Clincal Queries search filters were employed. (http://www.ncbi.nlm.nih.gov/entrez/query/static/clinical.shtml).

Clinical Study category ‘therapy’ ((gentamicin OR gentamycin) AND (child OR neonate OR infant OR paediatric OR pediatric)) AND (randomized controlled trial [Publication Type] OR (randomized [Title/Abstract] AND controlled [Title/Abstract] AND trial [Title/Abstract])) identified 176 Randomized Control Trials (RCTs) and Reviews.

A keyword search (Gentamicin OR Aminoglycosides) AND (Child OR Infant OR Pediatric) AND (Safety OR toxicity) identified one further Systematic Review.

A MeSH search [‘Gentamicins’ (MeSH) OR ‘Aminoglycosides’ (MeSH)] AND [‘Child’ (MeSH) OR ‘Infant’ (MeSH) OR ‘Pediatric Nursing’ (MeSH)] AND [‘Safety’ (MeSH) OR ‘toxicity’ (Subheading)] identified another relevant review.

All abstracts were read, and articles sourced fully where relevant. Articles were excluded if the article did not concern paediatric patients, if the safety of gentamicin had not been investigated, if the research did not include systemic treatment, or if doses were altered on the basis of serum gentamicin levels. Articles involving other aminoglycosides were included where deemed appropriate. Much of the available research into the toxicity of gentamicin was in the comparison of multiple versus once daily dosing: only once daily figures were considered, as this is the dosing strategy recommended in the WHO Pocketbook.

Results

Using the methodology described 14 RCTs, 2 systematic reviews and 1 meta-analysis were identified as relevant. It should be noted that ototoxicity was measured by a variety of means [including brain-stem-evoked responses (BER), audiological testing and clinical impression], all of which are used to detect deafness. Nephrotoxicity was also defined differently between studies: either by reduced creatinine clearance, raised serum creatinine or β2-microglobulinuria. Each case of nephrotoxicity mentioned below will be defined according to the parameters set in each individual study.

A Cochrane systematic review identified no difference between oto- and nephrotoxicity in once daily and multiple daily dosing of gentamicin, but the figures for each were not given [5].

Trials that monitored nephrotoxicity are as follows: none was noted in six RCTs [6–11], and one reported a clinically insignificant but potential gentamicin-induced nephrotoxicity [12]. One meta-analysis reported primary nephrotoxicity in 1.6% and secondary nephrotoxicity in 4.4% [13]. Occurrence of nephrotoxicity (1.2% and 15%) was found in a further two RCTs [14, 15]. Another reported laboratory nephrotoxicity in 1.5%, but none was detectable clinically [16].

Assessment of ototoxicity: a systematic review of aminoglycosides reported that with the exception of one study, ototoxicity occurred less frequently in aminoglycoside-treated patients than it did untreated control patients. It concluded that the lack of reports on aminoglycoside-associated toxic effects in children suggests that these compounds are safe and well tolerated in this age group [17]. A meta-analysis reported ototoxicity in 2.3% of cases, with no evidence of disturbed vestibular function [13]. An RCT that looked at the effect on hearing concluded that aminoglycosides are unlikely to cause ototoxicity [18]. No ototoxicity was noted in three RCTs [6, 14, 15].

Two studies in ototoxicity over a longer time scale (4 years) concluded that there was no hearing loss that could be attributed to the use of aminoglycosides [19, 20]. One study emphasized the importance of long-term follow-up of hearing, as there is a high incidence of transient auditory abnormalities which lead to no higher incidence of sensori-neural deafness than those without antibiotic treatment [21].

Discussion

Many studies are relatively small scale but the consistency of results suggests they are reliable, particularly in the case of nephrotoxicity. Evidence relating to ototoxicity is less convincing: perhaps larger scale studies would need to be included, although none could be obtained in this instance. Research indicates that nephro- and ototoxicity are relatively uncommon, and is a risk worth taking in the context of a life-threatening infection.

Alternatives such as chloramphenicol and β-lactams (such as penicillin) would need to be investigated in terms of safety before being used confidently as a first line treatment: chloramphenicol is known to cause agranulocytosis and ‘grey baby syndrome’ in newborns, and β-lactams are recognized as causing hypersensitivity reactions as well as exhibiting high levels of resistance against them.

In all the studies reviewed, the duration for which aminoglycosides were administered was relatively short (usually about a week): perhaps with longer administration toxicity is more likely to develop [12].

Summary

Based on the evidence available, short-term gentamicin administration at the recommended doses is an appropriate antibiotic, even without serum gentamicin level monitoring.

References

1
The World Health Report 2004: Changing History.
2004
24 April 2008, date last accessed
Geneva, Switzerland
World Health Organisation
 
2
Rang
HP
Dale
MM
Ritter
JM
, et al.  . 
Pharmacology
 , 
2003
5th
Bath, UK
Churchill Livingstone
3
Duke
T
Poka
H
Dale
F
, et al.  . 
Chloramphenicol versus benzylpenicillin and gentamicin for the treatment of severe pneumonia in children in Papua New Guinea: a randomised trial
Lancet
 , 
2002
, vol. 
359
 (pg. 
474
-
80
)
4
Mattie
H
Craig
WA
Pechere
JC
Determinants of efficacy and toxicity of aminoglycosides
J Antimicrobial Chemother
 , 
1989
, vol. 
24
 (pg. 
281
-
93
)
5
Tan
K
Bunn
H
Once daily versus multiple daily dosing with intravenous aminoglycosides for cystic fibrosis.
[update in Cochrane Database Syst Rev 2006;3:CD002009; PMID: 16855982]. Cochrane Database Syst Rev 2000;(4):CD002009
 
6
Bass
KD
Larkin
SE
Paap
C
, et al.  . 
Pharmacokinetics of once-daily gentamicin dosing in pediatric patients
J Pediatr Surg
 , 
1998
, vol. 
33
 (pg. 
1104
-
7
)
7
Khan
AM
Ahmed
T
Alam
NH
, et al.  . 
Extended-interval gentamicin administration in malnourished children
J Trop Pediatr
 , 
2006
, vol. 
52
 (pg. 
179
-
84
)
8
Krishnan
L
George
SA
Gentamicin therapy in preterms: a comparison of two dosage regimens
Indian Pediatr
 , 
1997
, vol. 
34
 (pg. 
1075
-
80
)
9
Hayani
KC
Hatzopoulos
FK
Frank
AL
, et al.  . 
Pharmacokinetics of once-daily dosing of gentamicin in neonates
J Pediatr
 , 
1997
, vol. 
131
 (pg. 
76
-
80
)
10
Landers
S
Berry
PL
Kearns
GL
, et al.  . 
Gentamicin disposition and effect on development of renal function in the very low birth weight infant
Dev Pharmacol Ther
 , 
1984
, vol. 
7
 (pg. 
285
-
302
)
11
Marks
S
Marks
MI
Dupont
C
, et al.  . 
Evaluation of three antibiotic programs in newborn infants
Can Med Assoc J
 , 
1978
, vol. 
118
 (pg. 
659
-
62
)
12
English
M
Mohammed
S
Ross
A
, et al.  . 
A randomised, controlled trial of once daily and multi-dose daily gentamicin in young Kenyan infants
Arch Dis Child
 , 
2004
, vol. 
89
 (pg. 
665
-
9
)
13
Contopoulos-Ioannidis
DG
Giotis
ND
Baliatsa
DV
, et al.  . 
Extended-interval aminoglycoside administration for children: a meta-analysis
Pediatrics
 , 
2004
, vol. 
114
 (pg. 
e111
-
8
)
14
Chong
CY
Tan
AS
Ng
W
, et al.  . 
Treatment of urinary tract infection with gentamicin once or three times daily
Acta Paediatr
 , 
2003
, vol. 
92
 (pg. 
291
-
6
)
15
Itsarayoungyuen
S
Riff
L
Schauf
V
, et al.  . 
Tobramycin and gentamicin are equally safe for neonates: results of a double-blind randomized trial with quantitative assessment of renal function
Pediatr Pharmacol
 , 
1982
, vol. 
2
 (pg. 
143
-
55
)
16
Tapaneya-Olarn
C
Tapaneya-Olarn
W
Pitayamornwong
V
, et al.  . 
Single daily dose of gentamicin in the treatment of pediatric urinary tract infection
J Med Assoc Thai
 , 
1999
, vol. 
82
 
Suppl 1
(pg. 
S93
-
7
)
17
McCracken
GH
Jr
Aminoglycoside toxicity in infants and children
Am J Med
 , 
1986
, vol. 
80
 (pg. 
172
-
8
)
18
Zorowka
P
Schmitt
HJ
Eckel
HE
, et al.  . 
Serial measurements of transient evoked otoacoustic emissions (TEOAEs) in healthy newborns and in newborns with perinatal infection
Int J Pediatr Otorhinolaryngol
 , 
1993
, vol. 
27
 (pg. 
245
-
54
)
19
Robertson
CM
Tyebkhan
JM
Peliowski
A
, et al.  . 
Ototoxic drugs and sensorineural hearing loss following severe neonatal respiratory failure
Acta Paediatr
 , 
2006
, vol. 
95
 (pg. 
214
-
23
)
20
Finitzo-Hieber
T
McCracken
GH
Jr
Roeser
RJ
, et al.  . 
Ototoxicity in neonates treated with gentamicin and kanamycin: results of a four-year controlled follow-up study
Pediatrics
 , 
1979
, vol. 
63
 (pg. 
443
-
50
)
21
Finitzo-Hieber
T
McCracken
GH
Jr
Brown
KC
Prospective controlled evaluation of auditory function in neonates given netilmicin or amikacin
J Pediatr
 , 
1985
, vol. 
106
 (pg. 
129
-
36
)

Author notes

Section Editors: Trevor Duke and Julian Kelly.
For more information on this project to evaluate the evidence behind the WHO Hospital Care for Children, see J Trop Pediatr 2006;52:1–2. If you would like suggest a topic or contribute a review, please contact Dr Julian Kelly. E-mail <julian.kelly@rch.org.au>.

Comments

0 Comments