Reduced-Concentration Clavulanate for Young Children with Acute Otitis Media

Abstract

Amoxicillin-clavulanate (A/C) is currently the most effective oral antimicrobial in treating children with acute otitis media (AOM), but the standard dosage of 90 mg amoxicillin/6.4 mg clavulanate/kg of body weight/day commonly causes diarrhea. We examined whether an A/C formulation containing lower concentrations of clavulanate would result in less diarrhea while maintaining plasma levels of amoxicillin and clavulanate adequate to eradicate middle-ear pathogens and to achieve clinical success. We conducted an open-label study in children with AOM who were 6 to 23 months of age. In phase 1, we treated 40 children with a reduced-clavulanate A/C formulation providing 90 mg amoxicillin/3.2 mg clavulanate/kg/day for 10 days. In phase 2, we treated 72 children with the same formulation at a dosage of 80 mg amoxicillin/2.85 mg clavulanate/kg/day for 10 days. We compared the rates of protocol-defined diarrhea (PDD), diaper dermatitis, and AOM clinical response in these children with rates we had reported in children who received the standard A/C regimen, and we obtained plasma levels of amoxicillin and clavulanate at various time points. Outcomes in phase 1 children and in children who had received the standard regimen did not differ significantly. Rates of PDD in children receiving phase 2 and standard regimens were 17% and 26%, respectively (P = 0.10). The corresponding rates of diaper dermatitis were 21% and 33% (P = 0.04) and of AOM treatment failure were 12% and 16% (P = 0.44). Symptomatic responses did not differ significantly between regimens; both gave clavulanate levels sufficient to inhibit β-lactamase activity. In young children with AOM, clavulanate dosages lower than those currently used may be associated with fewer side effects without reducing clinical efficacy. (This study has been registered at ClinicalTrials.gov under registration no. NCT02630992.).

Keywords: acute otitis media; amoxicillin-clavulanate; antimicrobial treatment.

Copyright © 2017 American Society for Microbiology.

Figures

FIG 1

Percentages of children with protocol-defined diarrhea according to day of treatment and amoxicillin-clavulanate dosage regimen.

FIG 2

Population plasma concentration versus time curves for children receiving the reduced-clavulanate formulation of amoxicillin-clavulanate using various dosage regimens during phase 1 (90/3.2 mg/kg/day) and phase 2 (80/2.85 mg/kg/day). Plasma concentrations (Conc.) for time points 6, 8, 10, and 12 h were extrapolated on the basis of the elimination rate constant calculated from data collected up to 4 h. Data points up to 4 h without a standard deviation bar indicate that the assessment was available for only one child.

FIG 3

Images of tympanic membranes.