Introduction

Acute otitis media is the most frequently diagnosed illness in children and the most commonly cited indication for antimicrobial therapy in children. Recommendations vary regarding immediate antimicrobial treatment versus watchful waiting for children younger than 2 years of age with acute otitis media depending on the severity of the condition.

Aim

To determine the extent to which amoxicillin–clavulanate treatment affects the course of both symptoms and signs of acute otitis media among children 6 to 23 months of age

Patient Profile

291 children aged between 6 to 23 months with acute otitis media onset, Acute Otitis Media Severity of Symptoms (AOM-SOS) score of at least 3, the presence of middle-ear effusion, and moderate or marked bulging of the tympanic membrane or slight bulging accompanied by either otalgia or marked erythema of the membrane

Method

Study Design

• Randomized placebo-controlled trial
• Patients were randomised to either amoxicillin–clavulanate at a daily dose of 90 mg of amoxicillin per kilogram of body weight combined with 6.4 mg of clavulanate per kilogram, or placebo for 10 days (two doses per day)
• Children with clinical failure were treated with a standardized 10-day regimen of orally administered amoxicillin, at a dose of 90 mg per kilogram per day, and cefixime, at a dose of 8 mg per kilogram per day

  Endpoints

• Primary outcome:

• Time to resolution of symptoms (the time to the first recording of an AOM-SOS score of 0 or 1 and the time to the second of two successive recordings of that score)
• Symptom burden over time (mean AOM-SOS score in the two groups each day over the first 7 days of follow-up and the groups' weighted mean scores for that period)
  • Secondary outcomes: Overall clinical efficacy, the use of acetaminophen, the occurrence of adverse events, nasopharyngeal colonization rates, and the use of health care resources.

Results

Efficacy

• Amoxicillin–clavulanate therapy achieved initial resolution of symptoms by day 2 in 35%, by day 4 in 61%, and by day 7 in 80% as compared to placebo which achieved initial resolution of symptoms in 28%, 54%, and 74%, respectively (overall P = 0.14)
• Amoxicillin–clavulanate led to sustained resolution of symptoms by day 2 in 20%, by day 4 in 41%, and by day 7 in 67% versus placebo in 14%, 36%, and 53%, respectively (overall P = 0.04)
• The mean AOM-SOS scores over the first 7 days were lower with amoxicillin–clavulanate therapy versus placebo at each time point (P = 0.02) and at the 10–12 day visit (1.59 vs. 2.46; P = 0.003)
• The 7-day weighted mean AOM-SOS score was also significantly lower in the amoxicillin–clavulanate group than in the placebo group (2.79 vs. 3.42; P = 0.01)
• The degree of difference between the two treatment groups varied according to the severity of the children's baseline symptoms: for initial AOM-SOS score <8, the values were 2.21 vs. 2.58 (P = 0.14), and initial AOM-SOS score >8, the values were 3.59 vs. 4.50 (P = 0.02)
• The rate of clinical failure (at/before day 4–5 visit was either a lack of substantial improvement in symptoms, a worsening of signs on otoscopic examination, or both and at day 10–12 visit was the failure to achieve symptom and otoscopic sign resolution) was lower among the children treated with amoxicillin–clavulanate versus those on placebo (4% vs. 23% at/before the visit on day 4–5; P<0.001 and 16% vs. 51% at/before the visit on day 10–12; P<0.001)
• The mean scores at the day 4–5 visit were 5.0 among children who met the criteria and 2.2 among children who did not meet the criteria for clinical failure at that visit; the corresponding values at the day 10–12 visit were 3.7 and 1.2
• At day 10 to 12, the clinical results were less favorable among children who were exposed to >3 children for at least 10 hours per week than among children who were not (P = 0.007), among children with higher AOM-SOS scores at entry than among those with lower scores (P = 0.004), among children with bilateral acute otitis media than among children with unilateral acute otitis media (P = 0.002), and among children with more bulging of the tympanic membrane than among children with less bulging (P<0.001)
• The rates of clinical failure at/before the day 10–12 visit were lower among those receiving amoxicillin–clavulanate (19% and 14%) vs. among those receiving placebo (61% and 43%) in children with severe and non-severe illness, respectively
• Children 18 to 23 months of age who received amoxicillin–clavulanate had a higher rate of clinical failure than did children 12 to 17 months of age and children 6 to 11 months of age (38% vs. 12% and 11%, respectively)
• At the day 21–25 visit, lesser children in the amoxicillin–clavulanate group had middle-ear effusion vs. those in the placebo group (50% vs. 63%, P = 0.05)
• No significant changes in either group in the rates of nasopharyngeal colonization with non-susceptible Streptococcus pneumoniae

Figure 1: Effect of amoxicillin-clavulanate on sustained resolution of symptoms as compared to placebo

Safety 

• Mastoiditis developed in one child who received placebo
• Diarrhea and diaper-area dermatitis were more common among children who received amoxicillin–clavulanate.

Conclusion

• Amoxicillin–clavulanate treatment for 10 days in children (6 to 23 months of age) with acute otitis media, reduced the time to resolution of symptoms and reduced the overall symptom burden and the rate of persistent signs of acute infection on otoscopic examination
• Amoxicillin–clavulanate treatment provided a measurable short-term benefit, irrespective of the apparent severity of the illness.

N Engl J Med. 2011; 364(2): 105–115