Introduction

Amoxicillin-clavulanate (A/C) is currently the most effective oral antimicrobial in treating children with acute otitis media (AOM), but the standard dosage (90 mg amoxicillin/6.4 mg clavulanate/kg of body weight/day) has been commonly associated with diarrhea (25% - 48% rates). The available standard formulation provided children with almost twice the clavulanate dose in use for adults. A reduction in the total effective dose of clavulanate and in the number of daily doses has been associated with reduced rates of diarrhea.

Aim

To examine whether a pediatric formulation of A/C containing lower concentrations of clavulanate would result in lower rates of diarrhea while maintaining plasma levels of amoxicillin and clavulanate adequate to eradicate Haemophilus influenzae and Moraxella catarrhalis from the middle ear and to achieve clinical success in children with AOM

Patient Profile

• 40 children (aged 6 to 23 months) with AOM in phase 1 and 72 children in phase 2

Method

Study Design

• Open-label study

   

• In phase 1, 40 children were treated with a reduced-clavulanate A/C formulation providing 90 mg amoxicillin/3.2 mg clavulanate/kg/day in two divided doses for 10 days
• In phase 2, 72 children were treated with the same formulation at a dosage of 80 mg amoxicillin/2.85 mg clavulanate/kg/day in two divided doses for 10 days

Endpoints

• Primary outcome: proportion of children developing protocol defined diarrhea (PDD)
• Secondary outcomes:

1. a comparison of the phase 1 standard dosing regimen of amoxicillin-clavulanate to the reduced clavulanate regimen used in phase 2, regarding the proportion of children who experienced diaper dermatitis occasioning prescription of an antifungal cream
2. clinical failure at the day 12 to 14 visit
3. the symptom burden over time and the proportion of children whose symptomatic response was considered satisfactory (greater than 50% decrease in AOM-SOS scores from baseline)

Results

Efficacy

• No significant differences were observed in the outcomes in children receiving the reduced-clavulanate formulation (90 mg amoxicillin/3.2 mg clavulanate/kg of body weight/day) for 10 days (phase 1) compared with the historical children (on standard formulation of 90 amoxicillin/6.4 mg clavulanate/kg/day for 10 days)

• Children receiving the reduced-clavulanate formulation (80 mg amoxicillin/2.85 mg clavulanate/kg/day) for 10 days (phase 2) had a lower rate of PDD than historical control children (17% vs. 26%, respectively; P = 0.10)
• The reduced-clavulanate formulation significantly lowered the rate of diaper dermatitis (21% vs. 33%; P = 0.04), and reduced the rate of temporary or permanent discontinuation of study medication because of PDD and/or diaper dermatitis as compared to the historical children (1% vs. 10%; P < 0.05)
• The corresponding rates of AOM treatment failure (12% vs. 16%; P = 0.44) and symptomatic responses did not differ significantly between regimens
• Parental satisfaction with the therapy given to their children was significantly higher among the phase 2 children than among the historical controls (on a scale of 1 to 5, mean, 4.75 vs. 4.47, P = 0.02)
• Satisfactory plasma levels of both amoxicillin and clavulanate to inhibit beta-lactamase activity were maintained in both phase 1 and phase 2 children

Conclusion

In young children with AOM, reduced-clavulanate formulation of A/C (600 mg amoxicillin/21.5 mg clavulanate/5 ml) with a dosing regimen of 80 mg amoxicillin/2.85 mg

clavulanate/kg/day for 10 days provided an improved safety profile while maintaining plasma levels and clinical efficacy.

Antimicrob Agents Chemother 2017; 61(7): e00238-17