Elsevier

The Lancet

Volume 348, Issue 9029, 14 September 1996, Pages 713-716
The Lancet

Articles
Double-blind randomised trial of co-amoxiclav versus placebo for persistent otitis media with effusion in general practice

https://doi.org/10.1016/S0140-6736(96)02511-1Get rights and content

Summary

Background

The treatment of persistent otitis media with effusion (OME) remains controversial, but this condition is the commonest reason for children to require ear, nose, and throat (ENT) surgery. Trials of antibiotics are inconclusive, are often weak methodologically, and have not been done in general practice. Our aim was a trial of an antibiotic for OME in such a population.

Methods

433 children, aged 6 months to 6 years, with OME from 57 general practices entered a 3–month watchful waiting period. Of 223 (52%) with persistent bilateral OME, 162 were randomised double-blind to receive co–amoxiclav suspension (20 mg/kg amoxicillin, 5 mg/kg clavulanate potassium) or matching placebo, orally three times a day for 14 days. All cases also received xylometazoline 0·25% decongestant nosedrops thrice daily. Of the 61 not randomised, 13 children were referred to an ENT surgeon and parents refused consent in 48 cases. The main outcome measures were persistent OME in both ears and in one or both ears, as assessed clinically and by tympanometry. Analysis was by intention-to-treat.

Findings

79 children in the treatment group and 70 in the placebo group were analysed for efficacy. 3 withdrew in the co-amoxiclav group (2 lost to follow-up, 1 due to side-effects); 6 withdrew in the placebo group (5 and 1, respectively). In addition, 4 tympanograms were uninterpretable in the controls. Compliance was over 90% in both groups. Persistent OME in both ears and in one or both ears were found at significantly lower rates in the co-amoxiclav group than in the controls at the 2-week follow-up: 53 vs 84% and 77 vs 93%, respectively. Odds ratios adjusted for sex, history of adenoidectomy, and upper respiratory tract infection at follow-up were 0·25 (95% CI 0·11, 0·58, p=0·001) and 0·30 (0·10, 0·89, p=0·03), respectively. Parents of children in the co-amoxiclav group reported significantly more side-effects than those of control children (44 vs 22%, p=0·03). Side-effects were mostly gastrointestinal and mild.

Interpretation

Our study in a general–practice setting confirmed the positive short-term effect of antibiotic treatment for persistent middle-ear infection. Before referral to an ENT surgeon, children with persistent OME presenting to general practitioners could be considered for such treatment, depending on the individual child and possible adverse sequelae.

Introduction

Otitis media with effusion (OME) incurs great morbidity and costs in children.1 The treatment of first choice remains controversial. There is agreement on watchful waiting before active treatment, but not for how long.1, 2, 3 Both US2 and Dutch4 guidelines include watchful waiting for 3 months, after which treatment options are medical or surgical. Medical treatment could be started by the general practitioner which might lead to fewer referrals, thereby reducing the high costs of surgery.5 Decongestants and antihistamines are ineffective.6 Treatment with corticosteroids is still under discussion.7, 8

The rationale underlying antimicrobial therapy is based on the observation that pathogenic bacteria can be recovered from the middle-ear effusion in a third of all cases.9, 10 The microorganisms most frequently found are Streptocococcus pneumonia, Haemophilus influenzae, and Moraxella catarrhalis.11, 12 Two meta–analyses13, 14 show a positive short-term effect from antibiotics. Amoxicillin, used alone or with clavulanate potassium, produced a uniform, statistically significant effect in three placebo–controlled randomised trials,15, 16, 17 but not in one other.18 Randomised studies in which the antibiotic was given for 14 days showed a positive effect, but none was carried out in general practice.

We therefore studied the efficacy of co-amoxiclav (amoxicillin and clavulanate potassium) in persistent bilateral OME in a general-practice population of children. To minimise the number of refusals, non-compliance, and loss to follow-up, antibiotic treatment was given for 14 days. In the Netherlands it is not common to treat OME with antimicrobial drugs, so long treatment courses are not feasible in general practice.

OME was defined as the presence of fluid in the middle-ear cavity behind an intact tympanic membrane without signs or symptoms of acute infection. Persistent OME was defined as the presence of effusion for at least 3 months. The presence of OME was based on the findings of tympanometry by the examining general practitioner. In the Netherlands, a modified version of Jerger's classification (table 1) is most commonly used.19, 20 The presence of middle-ear effusion was defined by the B and C2 curves, because of their high positive predictive values (88% and 54%, respectively).21 A child with an A or C1 curve was considered not to have middle-ear effusion.

General practitioners working within 150 km of our department were asked to participate. All participants received training in tympanometry and in the classification of tympanograms according to the modified Jerger classification.21 Post-training assessment showed that all 57 doctors performed tympanometry faultlessly. The interobserver agreement was high (κ=0·63).

Middle-ear effusion may go unnoticed in many cases. To include as many cases with bilateral effusion as possible, the doctors were asked to carry out otoscopy and tympanometry in all children aged 6 months to 6 years with the presence of one or more of the following: objective or subjective hearing loss, language or speech problems, mouth breathing, history of recurrent (six episodes in the past 12 months, each episode not exceeding 4 weeks) upper respiratory tract infections (URTI), history of recurrent otitis media among the parents or siblings (positive family history), or an episode of acute otitis media within the past 6 weeks (table 2). The duration of effusion before recruitment was not known, children with bilateral OME were asked to return for follow-up after 3 months (figure), because middle-ear effusion is less likely to resolve spontaneously after this.20 During this watchful waiting, they received no treatment for their ear problems. If, after 3 months, tympanometry still showed the presence of bilateral OME, informed consent was asked for from the parents. After informed consent had been obtained, the children were allocated to 14 days of antibiotic treatment or of placebo. Children were excluded from the study for any of the following: antimicrobial therapy within 4 weeks preceding the trial, penicillin allergy, compromised immunity, referral to an ear, nose, and throat (ENT) surgeon at time of inclusion, craniofacial abnormalities, Down's syndrome, or cystic fibrosis. Approval was granted by the Utrecht University Hospital ethics committee.

Because in the Netherlands most patients with middle-ear effusion receive decongestant nosedrops (one drop of xylometazoline 0·25%, three times a day), these drops were given to all included children. The study groups were randomised to treatment with a suspension of co-amoxiclav, at a daily dose of 20 mg/kg amoxicillin with 5 mg/kg clavulanate potassium, or a placebo suspension with the same colour and taste, both in three daily doses for 14 days. The suspensions were dispensed to participating general practitioners in a double-blind fashion with computerised four-block randomisation. Throughout the study, doctor and patient remained blinded. Parents were given enough suspension for only 1 week, after which they were asked to return the empty bottle and were given the rest of the suspension. At the follow-up after 2 weeks, all remaining suspension had to be returned. Parents were asked to keep a diary for the duration of the study, recording the amount of the suspension given and any observed side-effects. Compliance was measured by our secretary by examination of the diaries and measurement of the amount of suspension that remained in the bottles.

At the baseline visit, the doctor documented the patient's history and the presence or absence of risk factors for middle-ear disease, and did an ENT examination that included tympanometry. The results of the tympanometry were printed. At the follow-up 2 weeks after the start of the trial, the doctor recorded the present and interval occurrence of URTIs and middle-ear disease, the findings of the ENT examination, tympanometry results, and any side-effects. At this visit the doctor was free in his or her choice of treatment, but was asked to record this.

All tympanograms were also classified by a second well-trained general practitioner (FvB).22 In cases of disagreement between the study doctor and FvB, a team of experts was consulted. If they could not agree, the tympanogram was classified as uninterpretable. In the Netherlands it is advised to treat only cases with persistent bilateral middle-ear effusion. To be able to generalise the results to all cases with persistent OME, two measures of outcome were defined at the follow-up visit: persistent OME in both ears and persistent OME in one or both ears.

The difference in treatment outcome was calculated as rate differences. Odds ratios were calculated by multivariate logistic regression analysis to control for possible confounders and effect modifiers. The results are given with 95% CI for the odds ratios. Analysis was by intention-to-treat in those patients who returned at 2 weeks.

Section snippets

Results

Between December, 1992, and August, 1994, 433 children with one or more entry criteria and bilateral OME were enrolled (figure). 223 (52%) had persistent bilateral OME. At the request of parents, 13 children were referred to the ENT surgeon at the 3 month visit, and parents of 48 children refused consent. The remaining 162 children were included: 82 received co-amoxiclav and 80 placebo. The groups were similar except for sex, the placebo group having more boys (table 2). In the youngest age

Discussion

We found that for children aged 6 months to 6 years, with at least 3 months of persisting bilateral OME, treatment with co-amoxiclav for 2 weeks led to higher rates of resolution at end of therapy than placebo. Side-effects were more frequent in the treated group, although they were mild and mainly gastrointestinal. A 2–4 weeks' course with antimicrobial drugs is feasible in general practice because at the follow-up visit most doctors, who were still blinded, gave antibiotic treatment when OME

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