title: Population Pharmacokinetics of Cefazolin in Serum and Tissue for Patients with Complicated Skin and Soft Tissue Infections (cSSTI).
abstract: BACKGROUND
  Cefazolin is commonly used to treat complicated skin and soft tissue infections (cSSTI) caused by methicillin-susceptible Staphylococcus aureus (MSSA) and Enterobacteriaceae. We aimed to determine the variability of cefazolin exposure in interstitial fluid (ISF) of tissue and evaluate its dosing recommendations.
  
  
  METHODS
  Population pharmacokinetics were performed to co-model serum and ISF concentration data from six patients enrolled in a previous in vivo microdialysis study. A 5,000 patient Monte Carlo simulation was then conducted for 1 and 2 g every 8 h (q8h) regimens to calculate the penetration ratio and probability of target attainment (PTA) at 30% and 50% of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (fT > MIC) in ISF of tissue.
  
  
  RESULTS
  A three-compartment model, with one of the compartments representing ISF concentrations, fits the data best. The final model resulted in the mean ± SD parameter values: Clearance = 3.8 ± 2.1 L/h, volume of distribution in central compartment = 8.6 ± 6.4 L and volume of distribution in ISF = 36.6 ± 17.9 L. The mean ± SD and median penetration ratios were 1.36 ± 4.57 and 0.80, respectively. At the MIC90 for MSSA of 1 mg/L, PTAs for the 1 g q8h dose in ISF were 96% and 91% for 30% and 50% fT > MIC targets, respectively, which decreased to 87% and 71% at 2 mg/L. For the same respective targets, a 2 g q8h dosing regimen increased PTA to 96% and 91% at 2 mg/L.
  
  
  CONCLUSIONS
  Cefazolin penetration into the ISF of a lower limb infection varied across this simulated patient population. Based on these data, a 1 g q8h regimen should be sufficient to obtain 30% fT > MIC exposure against most MSSA causing cSSTI. However, a 2 g q8h dose is required to obtain 50% fT > MIC pharmacodynamic targets at the current breakpoint for Enterobacteriaceae (2 mg/L).
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
authors.forename: Wonhee
authors.initials: W
authors.lastname: So
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kuti
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA. david.nicolau@hhchealth.org.|Division of Infectious Diseases, Hartford Hospital, Hartford, CT, USA. david.nicolau@hhchealth.org.
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
keywords: Cefazolin; Diabetic wound; Microdialysis; Tissue pharmacokinetics; cSSTI