Population pharmacokinetic models for cefuroxime and metronidazole used in combination as prophylactic agents in colorectal surgery: Model-based evaluation of standard dosing regimens

The antibiotics used for prophylaxis in colorectal surgery must maintain appropriate plasma concentrations during the entire surgery to avoid surgical site infections caused by aerobes and anaerobes; cefuroxime plus metronidazole is one of the combinations used. The aim of this study was to evaluate the adequacy of cefuroxime plus metronidazole administration as prophylaxis in colorectal surgery. In total, 63 patients electively undergoing rectal or colon surgery were administered 1500 mg of cefuroxime and 1500 mg of metronidazole in 15-min and 1-h infusions, respectively, prior to surgery. Blood samples were withdrawn during and after surgery for determination of plasma concentrations by high-performance liquid chromatography. Population pharmacokinetic models were developed using NONMEM 7.2.0. Pharmacokinetic/pharmacodynamic (PK/PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. Pharmacokinetics for both antibiotics were best described by a two-compartment model. Elimination of cefuroxime was conditioned by creatinine clearance (CLCr). The half-life of cefuroxime was 1.5 h for patients with normal renal function and 4.9 h in patients with renal impairment. Elimination and distribution of metronidazole were affected by patient body weight (BW). PK/PD analysis revealed that a single-dose protocol of 1500 mg of cefuroxime and metronidazole is adequate in short surgeries (≤2 h). However, for longer surgeries, recommendations are suggested depending on the patient's CLCr and BW. Additional doses of cefuroxime are needed for patients with moderate renal impairment or those presenting normal renal function. For metronidazole, an additional dose is needed for patients with a BW of 90 kg.