Population pharmacokinetic meta-analysis to support dosing regimen in dogs for surgical antimicrobial prophylaxis

Abstract

The Pharmacokinetic/Pharmacodynamic of antimicrobial drugs (AMD) for surgical prophylaxis has been poorly studied, hampering evidence-based decision making around AMD dosing and timing. Our objective is to use PK/PD principles to inform (i) the timing of administration and (ii) the interval for re-administration of AMD used peri-operatively in dogs. Raw plasma concentrations of cefazolin, cefuroxime, cephalexin, amoxicillin and ampicillin were retrieved from original intravenous studies performed in dogs. Staphylococci and E. coli were identified as possible intraoperative contaminants and their Epidemiological cutoffs (ECOFF) were retrieved from the EUCAST database. Individual PK data were refitted with non-linear mixed effect models (Phoenix). We performed Monte Carlo simulation to compute i) the 95th percentile of time of peak concentration in the peripheral compartment (informing timing between administration and first incision) and ii) the duration for which at least 90% of dogs maintain a free plasma concentration above ECOFF (informing timing of re-administration: 1.5 to 4h). Cefazolin (22-25 mg/kg), cefuroxime (20 mg/kg) and amoxicillin (16.7 mg/kg) reached peak peripheral concentrations within 30 minutes, but cephalexin (15 mg/kg) and ampicillin (20 mg/kg) required 45 and 90 minutes, respectively. For staphylococci, cefazolin and cefuroxime require re-administration every 2h, whereas cephalexin and both amoxicillin and ampicillin can be readministered every 3 and 4 hours, respectively. For E. coli, only cefazolin provided adequate perioperative coverage with 2-hourly administration, where cefuroxime and cephalexin failed uniformly. Alternatively, ampicillin and amoxicillin (sick dogs) may cover E. coli contaminations, but only if readministered every 1.5h. These PK-derived conclusions provide a rationale for perioperative AMD administration timing