title: Continuous versus short-term infusion of cefuroxime: assessment of concept based on plasma, subcutaneous tissue, and bone pharmacokinetics in an animal model.
abstract: The relatively short half-lives of most β-lactams suggest that continuous infusion of these time-dependent antimicrobials may be favorable compared to short-term infusion. Nevertheless, only limited solid-tissue pharmacokinetic data are available to support this theory. In this study, we randomly assigned 12 pigs to receive cefuroxime as either a short-term or continuous infusion. Measurements of cefuroxime were obtained every 30 min in plasma, subcutaneous tissue, and bone. For the measurements in solid tissues, microdialysis was applied. A two-compartment population model was fitted separately to the drug concentration data for the different tissues using a nonlinear mixed-effects regression model. Estimates of the pharmacokinetic parameters and time with concentrations above the MIC were derived using Monte Carlo simulations. Except for subcutaneous tissue in the short-term infusion group, the tissue penetration was incomplete for all tissues. For short-term infusion, the tissue penetration ratios were 0.97 (95% confidence interval [CI], 0.67 to 1.39), 0.61 (95% CI, 0.51 to 0.73), and 0.45 (95% CI, 0.36 to 0.56) for subcutaneous tissue, cancellous bone, and cortical bone, respectively. For continuous infusion, they were 0.53 (95% CI, 0.33 to 0.84), 0.38 (95% CI, 0.23 to 0.57), and 0.27 (95% CI, 0.13 to 0.48) for the same tissues, respectively. The absolute areas under the concentration-time curve were also lower in the continuous infusion group. Nevertheless, a significantly longer time with concentrations above the MIC was found for continuous infusion up until MICs of 4, 2, 2, and 0.5 μg/ml for plasma and the same three tissues mentioned above, respectively. For drugs with a short half-life, like cefuroxime, continuous infusion seems to be favorable compared to short-term infusion; however, incomplete tissue penetration and high MIC strains may jeopardize the continuous infusion approach.
authors.affiliation: Department of Orthopaedic Surgery, Horsens Regional Hospital, Horsens, Denmark Orthopaedic Research Unit, Aarhus University Hospital, Aarhus, Denmark mikkel.tottrup@clin.au.dk.
authors.forename: Mikkel
authors.initials: M
authors.lastname: Tøttrup
authors.affiliation: Department of Biostatistics, Aarhus University, Aarhus, Denmark.
authors.forename: Bo M
authors.initials: BM
authors.lastname: Bibby
authors.affiliation: Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Tore F
authors.initials: TF
authors.lastname: Hardlei
authors.affiliation: Department of Orthopaedic Surgery, Horsens Regional Hospital, Horsens, Denmark Orthopaedic Research Unit, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Mats
authors.initials: M
authors.lastname: Bue
authors.affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Kerrn-Jespersen
authors.affiliation: Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Kurt
authors.initials: K
authors.lastname: Fuursted
authors.affiliation: Orthopaedic Research Unit, Aarhus University Hospital, Aarhus, Denmark Department of Orthopaedic Surgery, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Kjeld
authors.initials: K
authors.lastname: Søballe
authors.affiliation: Orthopaedic Research Unit, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Hanne
authors.initials: H
authors.lastname: Birke-Sørensen
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D002444:Cefuroxime / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D007262:Infusions, Intravenous; D008826:Microbial Sensitivity Tests; D023421:Models, Animal; D011897:Random Allocation; D050151:Subcutaneous Fat / Q000378:metabolism*; D040521:Subcutaneous Tissue / Q000378:metabolism*; D013552:Swine
chemical_list: D002444:Cefuroxime