Population Pharmacokinetics of Intravenous Amoxicillin Combined With Clavulanic Acid in Healthy and Critically Ill Dogs

Vegas Cómitre, Maria; Cortellini, Stefano; Devreese, Mathias; Roques, Beatrice; Bousquet-Melou, Alain; Toutain, Pierre-Louis; Pelligand, Ludovic

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.

Citation

Vegas Cómitre, M., Cortellini, S., Devreese, M., Roques, B., Bousquet-Melou, A., Toutain, P., & Pelligand, L. (2021). Population Pharmacokinetics of Intravenous Amoxicillin Combined With Clavulanic Acid in Healthy and Critically Ill Dogs. Journal of Veterinary Medicine, https://doi.org/10.3389/fvets.2021.770202

• Journal Article Type: Article
• Acceptance Date: Oct 18, 2021
• Publication Date: Nov 15, 2021
• Deposit Date: Aug 5, 2021
• Publicly Available Date: Jul 14, 2022
• Print ISSN: 2356-7708
• Electronic ISSN: 2314-6966
• Publisher: Hindawi
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.3389/fvets.2021.770202
• Keywords: Antimicrobial, ICU, VetCAST, PK/PD, NLME, MIC