Published online March 1, 2005
PEDIATRICS Vol. 115 No. 3 March 2005, pp. 827-828 (doi:10.1542/10.1542/peds.2004-2425)

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Extended-Interval Aminoglycosides in Children: More Guidance Is Needed

E. J. Best, MBChB
P. Palasanthiran, MD, FRACP
School of Women's and Children's Health,
University of New South Wales,
New South Wales 2031, Australia,
Immunology and Infectious Diseases,
Sydney Children's Hospital,
New South Wales 2031, Australia

M. Gazarian, MBBS, MSc(ClinEpi), FRACP
School of Women's and Children's Health,
University of New South Wales,
New South Wales 2031, Australia,
Clinical Pharmacology and Therapeutics,
Sydney Children's Hospital,
New South Wales 2031, Australia

To the Editor.—

We read with interest the article by Contopoulos-Ioannidis et al in the July 2004 issue of Pediatrics.¹ We welcome this collation of pediatric data on the efficacy and safety of extended-interval aminoglycoside dosing (EIAD), given the lack of clear consensus about whether the existing evidence justifies a change in standard practice.² This meta-analysis of the available evidence demonstrates that efficacy, and probably nephrotoxicity, is at least equivalent between EIAD and multiple daily-dosing regimens. More importantly, however, it identifies gaps in our knowledge about (1) the incidence of ototoxicity, (2) the appropriate dose (which varied from 4 to 7.5 mg/kg per 24 hours in included trials), and (3) the role and appropriate mode of therapeutic drug monitoring with EIAD, issues that are crucial to the pediatrician considering adopting EIAD. In contrast to adults, EIAD is not standard practice in pediatrics currently; a recent survey of US hospitals revealed that only 23% of respondents used EIAD in children.³ Critical evaluation of evidence about the risk/benefit ratio of any medicine is essential to guide treatment decisions. However, when evaluating evidence about safety, randomized, controlled trials (RCTs) and meta-analyses of RCTs have inherent limitations that which need to be highlighted. RCTs are designed to evaluate drug efficacy in a much more rigorous and complete way than safety,⁴ and there may also be an overestimate of benefits versus risks due to selective reporting in published RCTs.⁵ Finally, to detect low prevalence ototoxicity, as is thought to be the case in pediatric aminoglycoside use,⁶ large sample sizes are needed with near-complete follow-up of participants. Only about half of the RCTs in this meta-analysis assessed hearing by using objective auditory testing rather than clinical assessment. Most had either incomplete follow-up and/or were underpowered to detect differences in ototoxicity outcomes. The pooled incidence of ototoxicity, although less than that reported in adults, was 2% even among these "low-risk children" on relatively short-course therapy. If ototoxicity occurs independent of dosing regimen, then issues of minimizing toxicity by careful selection of patient group and/or monitoring are even more important.

Acknowledging the current limitations of meta-analyses of RCTs in evaluating safety, evidence is accumulating for equivalent efficacy of EIAD in pediatrics as demonstrated by Contopoulos-Ioannidis et al. Because EIAD regimens seem to be more convenient and are increasingly used despite the incomplete evidence base,³ clinicians are left with more questions about optimal dosage, therapeutic drug monitoring, and determining which groups of children can receive EIAD safely (neonates, children with cystic fibrosis, or all children?). There is an ongoing and significant need to delineate the true incidence of ototoxicity with EIAD in children and obtain more conclusive data on the usefulness of therapeutic drug monitoring in predicting or minimizing this toxicity, issues that we are currently researching.⁷ At this stage, we cannot be reassured that EIAD minimizes ototoxicity nor confidently recommend universal change in aminoglycoside dosing for children based on the evidence summarized in this meta-analysis.

REFERENCES

1. Contopoulos-Ioannidis DG, Giotis ND, Baliatsa DV, Ioannidis JP. Extended-interval aminoglycoside administration for children: a meta-analysis. Pediatrics. 2004;114(1) . Available at: www.pediatrics.org/cgi/content/full/114/1/e111
2. Brown GH, Bertino JS Jr, Rotschafer JC. Single daily dosing of aminoglycosides—a community standard? Clin Infect Dis. 2000;30 :440 –441[CrossRef][Web of Science][Medline]
3. Chuck SK, Raber SR, Rodvold KA, Areff D. National survey of extended-interval aminoglycoside dosing. Clin Infect Dis. 2000;30 :433 –439[CrossRef][Web of Science][Medline]
4. Ioannidis JP, Lau J. Completeness of safety reporting in randomized trials: an evaluation of 7 medical areas. JAMA. 2001;285 :437 –443[Abstract/Free Full Text]
5. Chan AW, Hrobjartsson A, Haahr MT, Gotzsche PC, Altman DG. Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. JAMA. 2004;291 :2457 –2465[Abstract/Free Full Text]
6. Kahlmeter G, Dahlager JI. Aminoglycoside toxicity—a review of clinical studies published between 1975 and 1982. J Antimicrob Chemother. 1984;13(suppl A) :9 –22[Medline]
7. Best EJ, Gazarian M, Palasanthiran P, Cohn R, Wilkinson M. Once daily gentamicin in infants and children: an evaluation of safety and the role of therapeutic drug monitoring in minimising toxicity [abstract]. Clin Exp Pharmacol Physiol. 2004;31(suppl 1) :A130[CrossRef]

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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics

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