Target Attainment and Population Pharmacokinetics of Cefazolin in Patients with Invasive <i>Staphylococcus aureus</i> Infections: A Prospective Cohort Study
Severin Bausch,
Sarah Dräger,
Panteleimon Charitos-Fragkakis,
Adrian Egli,
Stephan Moser,
Vladimira Hinic,
Richard Kuehl,
Stefano Bassetti,
Martin Siegemund,
Katharina M. Rentsch,
Laura Hermann,
Verena Schöning,
Felix Hammann,
Parham Sendi,
Michael Osthoff
Affiliations
Severin Bausch
Division of Internal Medicine, University Hospital Basel, 4031 Basel, Switzerland
Sarah Dräger
Division of Internal Medicine, University Hospital Basel, 4031 Basel, Switzerland
Panteleimon Charitos-Fragkakis
Division of Internal Medicine, University Hospital Basel, 4031 Basel, Switzerland
Adrian Egli
Division of Clinical Bacteriology and Mycology, University Hospital Basel, 4031 Basel, Switzerland
Stephan Moser
Division of Internal Medicine, University Hospital Basel, 4031 Basel, Switzerland
Vladimira Hinic
Division of Clinical Bacteriology and Mycology, University Hospital Basel, 4031 Basel, Switzerland
Richard Kuehl
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, 4031 Basel, Switzerland
Stefano Bassetti
Division of Internal Medicine, University Hospital Basel, 4031 Basel, Switzerland
Martin Siegemund
Intensive Care Unit, Department of Acute Medicine, University Hospital Basel, 4031 Basel, Switzerland
Katharina M. Rentsch
Department of Laboratory Medicine, University Hospital Basel, 4031 Basel, Switzerland
Laura Hermann
Division of Clinical Pharmacology & Toxicology, Department of Internal Medicine, University Hospital Bern, 3010 Bern, Switzerland
Verena Schöning
Division of Clinical Pharmacology & Toxicology, Department of Internal Medicine, University Hospital Bern, 3010 Bern, Switzerland
Felix Hammann
Division of Clinical Pharmacology & Toxicology, Department of Internal Medicine, University Hospital Bern, 3010 Bern, Switzerland
Parham Sendi
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, 4031 Basel, Switzerland
Michael Osthoff
Division of Internal Medicine, University Hospital Basel, 4031 Basel, Switzerland
This study aimed to determine cefazolin target attainment in patients with invasive Staphylococcus aureus (S. aureus) infections and to develop a population pharmacokinetic (PK) model. Adult patients with invasive S. aureus infections treated with cefazolin bolus infusions were included. Unbound and total trough and mid-dose cefazolin concentrations were measured, and strain-specific MICs were determined. The primary outcome was the proportion of patients attaining 100% fT>MIC at all time points evaluated. A population PK model was developed, using non-linear mixed-effects modelling. Overall, 51 patients were included, with a total of 226 unbound and total cefazolin concentrations measured (mean: 4.4 per patient). The median daily dosage in patients with an estimated glomerular filtration rate of >60 mL/min/m2 was 8 g. The median age was 74 years (interquartile range (IQR) 57–82) and 26% were female. A history of chronic kidney disease and acute kidney injury were present in 10/51 (19.6%) and 6/51 (11.7%), respectively. Achievement of 100% fT>MIC occurred in 86% of the patients and decreased to 45% when a target of 100% fT>4xMIC was evaluated. The mean unbound cefazolin fraction was 27.0% (standard deviation (SD) 13.4). Measured and estimated mean cefazolin trough concentrations differed significantly [13.1 mg/L (SD 23.5) vs. 7.4 mg/L (SD 7.9), p < 0.001]. In the population PK model, elevated estimated creatinine clearance and bolus instead of continuous application were covariates for target non-attainment. In conclusion, cefazolin target achievement was high, and the measurement of the unbound cefazolin concentration may be favored. The Monte Carlo simulations indicated that target attainment was significantly improved with continuous infusion.
