Recurrence up to 3.5 years after antibiotic treatment of acute otitis media in very young Dutch children: survey of trial participants

Journal Club

Recurrence up to 3.5 years after antibiotic treatment of acute otitis media in very young Dutch children: survey of trial participants

22 October 2014

Facilitated by Research Fellow Malene Plejdrup Hansen

Background
Acute otitis media (AOM) in children is a common community-acquired infection and up to 80% of children aged three years have had at least one episode of AOM. It is one of the most common indications for antibiotics in primary care, despite the fact that children almost invariably recover without treatment, and antibiotics only shortens symptoms by half- to one-day. Little is known about the long term effect of antibiotics such as the duration of middle ear effusion and concomitant hearing impairment or the recurrence rate of AOM. It is important to gain more knowledge about the long term effect and possible harms of antibiotic treatment of AOM as guidelines are changing and recommend withholding antibiotics in most cases.

Paper presented
Bezáková et al1 did a prospective three year follow-up study within the framework of a double blind, randomised, placebo controlled trial. The original trial 2 took place in the Netherlands between 1996 and 1998 and followed children clinically diagnosed with AOM actively for six months. Approximately three and a half years after the start of the trial the parents to the participating children were sent a questionnaire, asking them about episodes of recurrent AOM; referral to secondary care; and ear, nose, and throat surgery.

The PICO principle was used to identify the question of this paper:

Participants: Children with acute otitis aged 6 month to 2 years

Intervention: Amoxicillin

Comparison: Placebo

Outcome (s): Recurrence of acute otitis media; referral to secondary care; and ear, nose, and throat surgery

Timeframe: 3.5 years

The “RAMbo tool” was used to critically appraise the trial/survey:

Randomisation

  • Randomised, placebo controlled, double blind trial
  • Computerised two-block randomisation
  • Primary care setting
  • The diagnosis of AOM was based on the presence of acute signs of infection and otoscopy
  • Baseline similarity between the two groups of children participating in the questionnaire survey. The characteristics were similar to those initially randomised.

Attrition

  • Of the 240 participants originally randomised in the trial, 168 participants returned the questionnaire (70%)
  • No information on subsequent antibiotic treatments (after the six months)
  • Analyses are on an intention to treat basis

Measurements – blinded? or objective?

  • About 95% of the 168 parents were still blinded to the original treatment when they filled in the questionnaire
  • Self-reported outcomes

The results were:

Three years after randomization…

  • Acute otitis media had recurred in 63% children in the amoxicillin group compared with 43% children in the placebo group (risk difference 20%, 95% confidence intervals 5% to 35%).
  • A total of 31% children in the amoxicillin group and 30% in the placebo were referred to secondary care (risk difference 0%, 95% confidence intervals -14% to 14%).
  • 21% of the children in the amoxicillin group compared with 30% in the placebo group had ear, nose, and throat surgery (risk difference -9%, 95% confidence intervals -23% to 4%).

Discussion

Interestingly, recurrent AOM occurred more often in children originally treated with amoxicillin. However, the corresponding confidence intervals are wide and the results should be interpreted with caution. It is necessary to conduct similar long term follow-up studies to gain more knowledge about the long term effect and possible harms of antibiotic treatment.
The authors identified possible confounders such as sex, allergy, and history of recurrent AOM. It might have been relevant to ask the parents “Has your child had antibiotics since after the trial”, and taken this possible confounder into account as well. The article does not give any information on subsequent antibiotic use after the first six months of the post-trial follow-up period. Sensitivity analysis for the primary outcome measure, comparing only children in each group who did not receive antibiotics in the first 6 months of the post-trial follow-up period, showed a risk difference of 32% (95% confidence intervals 13% to 51%).A sensitivity analysis, comparing those who were treated with antibiotics after the six months with those who did not receive any antibiotics after the six months follow-up period, could also have been performed.
A Cochrane review on antibiotic treatment of children with AOM3 did not find any differences in AOM recurrence in children treated with antibiotics versus placebo (risk ratio 0.93 95% confidence intervals 0.78-1.10). The included trials in the review all had shorter follow-up periods – up to one year.
An update of this Cochrane review should preferably include this present study by Bezáková et al as a long term outcome of antibiotic treatment.
As the authors state, the use of antibiotics early in an episode of AOM may impair the natural immune response and weaken the protection against further episodes or may cause an unfavourable shift towards colonisation with resistant pathogens, which are likely to promote recurrence of infection.  However, for the first six months of follow-up, recurrence rates in the amoxicillin and placebo group were similar (51% vs 50%, risk difference 1%, 95% confidence intervals -12% to 15%).We find it hard to believe that previous antibiotic treatment of AOM causes late recurrences of AOM – but not early recurrences. It is worthwhile conducting a similar study of both the long (up to one year) and very long (several years) term effects, as more information is needed both of the possible long term benefits and harms of antibiotic treatment of children with AOM.

References

  1. Bezáková N, Damoiseaux RA, Hoes AW, et al. Recurrence up to 3.5 years after antibiotic treatment of acute otitis media in very young Dutch children: survey of trial participants. BMJ (Clinical research ed). 2009;338:b2525.
  2. Damoiseaux RA, van Balen FA, Hoes AW, et al. Primary care based randomised, double blind trial of amoxicillin versus placebo for acute otitis media in children aged under 2 years. BMJ (Clinical research ed). 2000;320(7231):350-354.
  3. Venekamp RP, Sanders S, Glasziou PP, et al. Antibiotics for acute otitis media in children. The Cochrane database of systematic reviews. 2013;1:Cd000219.