# P-1241. Pharmacokinetic Comparison of Augmentin ES-600 and a Reduced Concentration Clavulanate Formulation in Young Children; Modeling of amoxicillin/clavulanic acid in vitro effects on bacterial growth and killing and in vivo exposure evaluation

## TL;DR

This study explores whether reducing clavulanic acid in a children's antibiotic could maintain effectiveness while reducing side effects like diarrhea.

## Contribution

The study uses model-informed approaches to evaluate a reduced clavulanate dose for pediatric antibiotic therapy.

## Key findings

- Simulated exposures suggest a reduced clavulanate dose maintains therapeutic effectiveness in middle ear fluid.
- Current formulations may cause excessive clavulanate exposure in children, raising safety concerns.
- In vitro data supports the potential for a lower dose to achieve bacterial stasis and reduction.

## Abstract

Amoxicillin/clavulanic acid is currently the most effective antimicrobial for the treatment of children with acute otitis media and recurrent otitis media. While the FDA-approved pediatric formulation, Augmentin ES-600® (amoxicillin/clavulanic acid at 45/3.2 mg/kg), is highly effective, it is also known to cause problematic diarrhea, delaying children and their parents from resuming daily activities. A reduced clavulanic acid dose may mitigate these side effects without compromising therapeutic efficacy

. In our study, we employed a model-informed approach to estimate amoxicillin/clavulanic acid exposure in middle ear fluid (MEF) and evaluated the suitability of a lower clavulanic acid dose (1.425 mg/kg) based on in vitro exposure-response (E-R) data. Using established pediatric PK models for oral amoxicillin/clavulanic acid, we simulated drug exposures in MEF for a virtual pediatric population (ages 3-24 months) derived from the NHANES database. In vitro bacterial growth and killing data against five isolates of Haemophilus influenzae were used to determine effective AUC/MIC metrics, which were then compared with the simulated exposures in MEF.

Our results suggest that the simulated mean AUC0-24 exceeds the in vitro AUC0-24/MIC required to achieve net bacterial stasis and 1-log 10 CFU/mL reduction against an isolate with an MIC of 0.5 mg/L in children 3-24 months of age. These findings indicate that a reduced clavulanic acid dose may provide effective therapeutic exposure in MEF while potentially mitigating adverse events.

The significantly elevated clavulanic acid exposure associated with Augmentin ES-600 exceeds adult recommendations and raises questions about currently marketed amoxicillin: clavulanate ratios, suggesting the need to reassess dosing strategies to optimize efficacy and safety in young children

Keith Dewedoff, n/a, Kaizen Biosciences: Board Member|Kaizen Biosciences: Ownership Interest|Kaizen Biosciences: Stocks/Bonds (Private Company) Alejandro Hoberman, MD, Kaizen Biosciences: Advisor/Consultant|Kaizen Biosciences: Stocks/Bonds (Private Company)