Population pharmacokinetics of cefazolin and metronidazole in patients undergoing elective colorectal surgery

Cefazolin and metronidazole are recommended for surgical prophylaxis in colorectal surgery. This study characterised the pharmacokinetics of both agents and evaluated the adequacy of current dosing regimens.

Patients undergoing elective colorectal surgery received 2 g of cefazolin and 500 mg metronidazole. Serial plasma and subcutaneous adipose tissue samples were collected perioperatively. Total and unbound cefazolin, and total metronidazole and hydroxymetronidazole concentrations were quantified. Population pharmacokinetic models were developed using nonlinear mixed-effects modelling, and Monte Carlo simulations assessed the probability of target attainment (PTA) against epidemiological cut-off values.

Twelve patients were included. A two-compartment model with saturable protein binding best described cefazolin pharmacokinetics, with total body weight (TBW) retained as a covariate on the central volume of distribution. Cefazolin tissue exposure was 27% of plasma exposure, with high variability. A two-compartment model described metronidazole and hydroxymetronidazole pharmacokinetics, with TBW retained as a covariate on clearance and peripheral volume of distribution. Median tissue penetration of metronidazole was 9% of plasma exposure. Simulations showed that 2 g cefazolin achieved >90% PTA for organisms with MIC ≤2 mg/L for up to 6 h, but fell below this target at MIC 4 mg/L beyond 4 h. A single 500 mg dose of metronidazole achieved >90% PTA for organisms with MIC ≤4 mg/L for up to 6 h.

Current cefazolin and metronidazole regimens provide adequate prophylactic coverage in patients ≤100 kg undergoing elective colorectal surgery. Redosing of cefazolin at 4 h is appropriate. Additional intraoperative dosing of metronidazole is not required within 6 h.