Population pharmacokinetic meta-analysis of five beta-lactams antibiotics to support dosing regimens in dogs for surgical antimicrobial prophylaxis

The Pharmacokinetic/Pharmacodynamic (PK/PD) relationship 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 (1) the timing of administration and (2) the interval for re-administration of AMD used peri-operatively in dogs. Raw plasma concentrations of cefazolin, cefuroxime, cefalexin, amoxicillin and ampicillin were retrieved from original intravenous studies performed in dogs. E. coli and methicillin-susceptible staphylococci were identified as possible intraoperative contaminants and their epidemiological cut-offs (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 (22-25mg/kg), cefuroxime (20mg/kg), cefalexin (15mg/kg) and amoxicillin (16.7mg/kg) reached peak peripheral concentrations within 30min, but ampicillin (20mg/kg) required 82min, respectively. For methicillin-susceptible staphylococci, cefazolin and cefuroxime require re-administration every 2h, whereas cefalexin and both amoxicillin and ampicillin can be readministered every 3 and 4h, respectively. For E. coli, only cefazolin provided adequate perioperative coverage with 2-hourly administration, where cefuroxime and cefalexin failed uniformly. Alternatively, ampicillin and amoxicillin (critically ill 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.