title: Population pharmacokinetic models for cefuroxime and metronidazole used in combination as prophylactic agents in colorectal surgery: Model-based evaluation of standard dosing regimens.
abstract: 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 1500mg of cefuroxime and 1500mg 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 Blood samples were withdrawn during and after surgery for determination of plasma concentrations by high-performance liquid chromatography.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 1.5h for patients with normal renal function and 4.9h 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 1500mg of cefuroxime and metronidazole is adequate in short surgeries (≤2h). 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 90kg.
authors.affiliation: Pharmacokinetics, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain; Centro de Investigación Lascaray ikergunea, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Asín-Prieto
authors.affiliation: Pharmacokinetics, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain; Centro de Investigación Lascaray ikergunea, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain.
authors.forename: Amaia
authors.initials: A
authors.lastname: Soraluce
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Pamplona, Spain.
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Trocóniz
authors.affiliation: Service of General Surgery, University Hospital of Alava, Vitoria-Gasteiz, Spain.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Campo Cimarras
authors.affiliation: Service of General Surgery, University Hospital of Alava, Vitoria-Gasteiz, Spain.
authors.forename: Jaione
authors.initials: J
authors.lastname: Sáenz de Ugarte Sobrón
authors.affiliation: Pharmacokinetics, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain; Centro de Investigación Lascaray ikergunea, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Rodríguez-Gascón
authors.affiliation: Pharmacokinetics, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain; Centro de Investigación Lascaray ikergunea, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain. Electronic address: arantxa.isla@ehu.eus.
authors.forename: Arantxazu
authors.initials: A
authors.lastname: Isla
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019072:Antibiotic Prophylaxis / Q000379:methods*; D002444:Cefuroxime / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D003107:Colorectal Surgery; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008795:Metronidazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D015233:Models, Statistical; D010949:Plasma / Q000737:chemistry; D011446:Prospective Studies; D013530:Surgical Wound Infection / Q000517:prevention & control*
chemical_list: D000900:Anti-Bacterial Agents; D008795:Metronidazole; D002444:Cefuroxime
keywords: Cefuroxime; Colorectal surgery; Metronidazole; NONMEM; PK/PD analysis; Population pharmacokinetics; Prophylaxis