Population Pharmacokinetic Study of Cefazolin Used Prophylactically in Canine Surgery for Susceptibility Testing Breakpoint Determination

This study aimed to determine the population pharmacokinetic (Pop PK) parameters of cefazolin administered prophylactically at 25 mg/kg intravenously (IV) 30 min before surgery in a canine population of 78 dogs and assess whether covariates, such as sex, age, body weight (BW), breed, health status, creatinine level, and surgery time, have an influence on cefazolin disposition. The ultimate goal was to compute PK/PD cut off values and subsequently establish a specific clinical breakpoint (CBP) for the development of an antimicrobial susceptibility test (AST) of cefazolin in dogs according to the VetCAST approach. Two to 11 blood samples were collected from each dog from 5 to 480 min after cefazolin administration. A two-compartment model was selected, and parameterization was in terms of serum clearance (CL), intercompartmental CL(s) (Q) and volume(s) of distribution (V). The percentage of cefazolin binding to serum protein was 36.2 ± 5.3%. Population primary parameter estimates V1, V2, CL, and Q were (typical value ± SE) 0.116 ± 0.013 L/kg, 0.177 ± 0.011 L/kg, 0.0037 ± 0.0002 L/kg/min, and 0.0103 ± 0.0013 L/kg/min, respectively. Cefazolin presented rapid distribution and elimination half-lives (mean ± SE) 4.17 ± 0.77 min and 57.93 ± 3.11 min, respectively. The overall between-subject variability (BSV) for estimated primary parameters ranged from 36 to 42%, and none of the seven explored covariates were able to reduce this variability by an amplitude clinically relevant. By Monte Carlo simulation, the probability of a PK/PD target attainment (here to achieve a free serum concentration exceeding the MIC for 50% of the dosing interval in 90% of dogs) was computed with a dosage of 25 mg/kg administered IV every 6 h for 4 administrations in 24 h. The computed PK/PD cut off value was 2 mg/L. In conclusion, cefazolin administered prophylactically in surgical dogs at 25 mg/kg IV every 6 h was deemed effective against pathogens with a MIC value ≤ 2 mg/L and from a PK/PD perspective, can be recommended in a wide range of canine patient populations with no necessary dose adjustment for special dog subpopulations.