Population pharmacokinetic of Intravenous Amoxicillin and Clavulanic acid in critically ill dogs

Abstract

Background – Data regarding antimicrobial pharmacokinetics (PK) in critically ill dogs is lacking and likely differs from healthy dogs.

Hypothesis/Objectives —To describe a population PK model for intravenous amoxicillin clavulanic acid (AMC) in both healthy and sick dogs and to simulate a range of clinical dosing scenarios to compute PK/PD cut-offs for both populations.

Animals – 12 client-owned dogs university teaching hospital hospitalized in the intensive care unit (ICU) and 12 healthy beagles

Methods – Prospective clinical trial. Clinical dogs received IV AMC 20mg/kg every 8 hours (0.5h infusion) during a minimum of 48 hours. Blood samples were collected at pre-determined times, including 4 trough samples. Clinical covariates and outcome were recorded, including survival to discharge and bacteriologic clinical failure. Satellite PK data was generated de-novo from 12 healthy beagles. Non-linear mixed effect model was used to estimate the PK parameters (and the effect of health upon them) together with variability within- and between-subjects. Monte Carlo simulation were performed with 7 dosage regimens (standard and increased doses). Correlation between model-derived drug exposure and clinical covariates were tested with Spearman nonparametric correlation analysis.

Results – Tri-compartmental model best described the data. Amoxicillin clearance was reduced by 56% in sick dogs (0.147 L/kg/h) compared to healthy dogs (0.336 L/kg/h). Intercompartmental clearance was also decreased. No clinical data covariates were significantly correlated with individual exposure. PK/PD cut-off values of 8 mg/L could be reached in sick dogs by extending the infusion to 3h or doubling the dose.

Conclusions and clinical importance –Our study allows to generate hypotheses with regards to higher AMC exposure in clinical dogs.