What is the evidence of safety of gentamicin use in children?


Primary Reviewer: Anna McGlone1, Secondary Reviewer: Noel Cranswick2

1 University of Manchester, UK
2 Royal Children's Hospital, Melbourne, Australia

The World Health Organization 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.who.int/child-adolescent-health/publications/CHILD_HEALTH/PB.htm

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 contaminations with enteric flora).


Introduction:

Infection is the commonest cause of infant and child mortality worldwide [1]. As there is such overlap between the clinical presentations of bacterial infection, an empirical combination of antibiotics are often used to cover the commonest and most serious microorganisms. 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 so must be administered by injection. Most 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 [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 strategy developed by Haynes RB et al was employed: 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 brainstem 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 β-2-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 6 RCTs [6][7][8][9][10][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 2 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 3 RCTs [6][14][15].

 Two studies into ototoxicity over a longer timescale (4 years) concluded 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 beta-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 beta-lactams are recognised 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. Geneva, Switzerland, World Health Organisation, 2004. Available at: http://www.int/whr/2004/en/ 
  1. Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology. 5th ed. Bath, UK: Churchill Livingstone; 2003 
  1. Duke T, Poka H, Dale F, Michael A, Mgone J, Wal T. Chloramphenicol versus benzylpenicillin and gentamicin for the treatment of severe pneumonia in children in Papua New Guinea: a randomised trial. Lancet. 2002 Feb 9; 359(9305):474-80 [Medline]
  1. Mattie H, Craig WA, Pechere JC. Determinants of efficacy and toxicity of aminoglycosides. J Antimicrobial Chemother. 1989;24:281-93 [Medline]
  1. 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 of Systematic Reviews. (4):CD002009, 2000 [Medline]
  1. Bass KD, Larkin SE, Paap C, Haase GM.  Pharmacokinetics of once-daily gentamicin dosing in pediatric patients. J Pediatr Surg. 1998 Jul;33(7):1104-7 [Medline]
  1. Khan AM, Ahmed T, Alam NH, Chowdhury AK, Fuchs GJ. Extended-interval gentamicin administration in malnourished children. J Trop Pediatr. 2006 Jun;52(3):179-84. Epub 2005 Aug 26 [Medline]
  1. Krishnan L, George SA.  Gentamicin therapy in preterms: a comparison of two dosage regimens. Indian Pediatr. 1997 Dec;34(12):1075-80 [Medline]
  1. Hayani KC, Hatzopoulos FK, Frank AL, Thummala MR, Hantsch MJ, Schatz BM et al. Pharmacokinetics of once-daily dosing of gentamicin in neonates. J Pediatr. 1997 Jul;131(1 Pt 1):76-80 [Medline]
  1. Landers S, Berry PL, Kearns GL, Kaplan SL, Rudolph AJ.  Gentamicin disposition and effect on development of renal function in the very low birth weight infant. Dev Pharmacol Ther. 1984;7(5):285-302 [Medline]
  1. Marks S, Marks MI, Dupont C, Hammerberg S. Evaluation of three antibiotic programs in newborn infants. Can Med Assoc J. 1978 Mar 18;118(6):659-62 [Medline]
  1. English M, Mohammed S, Ross A, Ndirangu S, Kokwaro G, Shann F et al. A randomised, controlled trial of once daily and multi-dose daily gentamicin in young Kenyan infants. Arch Dis Child. 2004 Jul;89(7):665-9[Medline]

  1. Contopoulos-Ioannidis DG, Giotis ND, Baliatsa DV, Ioannidis JP. Extended-interval aminoglycoside administration for children: a meta-analysis. Pediatrics. 2004 Jul; 114(1):e111-8[Medline]

  2. Chong CY, Tan AS, Ng W, Tan-Kendrick A, Balakrishnan A, Chao SM.  Treatment of urinary tract infection with gentamicin once or three times daily. Acta Paediatr. 2003;92(3):291-6   [Medline]

  3. Itsarayoungyuen S, Riff L, Schauf V, Hamilton L, Otrembiak J, Vidyasagar D. Tobramycin and gentamicin are equally safe for neonates: results of a double-blind randomized trial with quantitative assessment of renal function. Pediatr Pharmacol (New York). 1982;2(2):143-55[Medline]

  4. Tapaneya-Olarn C, Tapaneya-Olarn W, Pitayamornwong V, Petchthong T, Tangnararatchakit K.  Single daily dose of gentamicin in the treatment of pediatric urinary tract infection. J Med Assoc Thai. 1999 Nov;82 Suppl 1:S93-7[Medline]

  5. McCracken GH Jr. Aminoglycoside toxicity in infants and children. American Journal of Medicine. 1986 Jun 30; 80(6B):172-8[Medline]

  6. Zorowka P, Schmitt HJ, Eckel HE, Lippert KL, Schonberger W, Merz E. Serial measurements of transient evoked otoacoustic emissions (TEOAEs) in healthy newborns and in newborns with perinatal infection. Int J Pediatr Otorhinolaryngol. 1993 Oct;27(3):245-54[Medline]

  7. Robertson CM, Tyebkhan JM, Peliowski A, Etches PC, Cheung PY.  Ototoxic drugs and sensorineural hearing loss following severe neonatal respiratory failure. Acta Paediatr. 2006 Feb;95(2):214-23[Medline]

  8. Finitzo-Hieber T, McCracken GH Jr, Roeser RJ, Allen DA, Chrane DF, Morrow J.  Ototoxicity in neonates treated with gentamicin and kanamycin: results of a four-year controlled follow-up study. Pediatrics. 1979 Mar; 63(3):443-50[Medline]

  9. Finitzo-Hieber T, McCracken GH Jr, Brown KC.  Prospective controlled evaluation of auditory function in neonates given netilmicin or amikacin. J Pediatr. 1985 Jan;106(1):129-36[Medline]