Yukihiro Hamada1, Joseph L Kuti2, David P Nicolau3. 1. Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA Aichi Medical University Hospital School of Medicine, Aichi, Japan. 2. Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA. 3. Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA Division of Infectious Diseases, Hartford Hospital, Hartford, CT, USA david.nicolau@hhchealth.org.
Abstract
OBJECTIVES: Vancomycin is a common treatment for complicated skin and skin structure infections (cSSSIs) caused by MRSA. This analysis aimed to understand the variability of vancomycin tissue exposure at the site of infection. METHODS: Vancomycin serum and interstitial tissue fluid concentration data for nine patients with cSSSI and normal renal function were derived from an in vivo microdialysis study. Using Pmetrics, the non-parametric population modelling package for R, we co-modelled serum and tissue concentration data. A 5000-patient Monte Carlo simulation was conducted for 1 g of vancomycin every 12 h and every 8 h to calculate the penetration distribution (AUCtissue/fAUCserum) and probability of target attainment (PTA) at an fAUC/MIC target of ≥200 in tissue fluid. RESULTS: A three-compartment model fitted the data best. The mean (SD) and median penetration ratios into tissue of the simulated population were 1.91 (4.56) and 0.85, respectively, which were consistent with observed values in the original patients. PTAs for 1 g of vancomycin every 12 h and every 8 h in tissue fluid were 39.6% and 56.6% at an MIC of 1 mg/L. Serum trough concentrations (R(2) = 0.06) and serum AUC exposure (R(2) = 0.002) were poor predictors of vancomycin AUC tissue exposure. CONCLUSIONS: Standard dosages of vancomycin provide a low likelihood of obtaining target pharmacodynamic exposure in the tissue of a lower limb infection. This low likelihood is due to wide variability in vancomycin penetration in the interstitial tissue fluid, which could not be predicted by serum concentrations.
OBJECTIVES:Vancomycin is a common treatment for complicated skin and skin structure infections (cSSSIs) caused by MRSA. This analysis aimed to understand the variability of vancomycin tissue exposure at the site of infection. METHODS:Vancomycin serum and interstitial tissue fluid concentration data for nine patients with cSSSI and normal renal function were derived from an in vivo microdialysis study. Using Pmetrics, the non-parametric population modelling package for R, we co-modelled serum and tissue concentration data. A 5000-patient Monte Carlo simulation was conducted for 1 g of vancomycin every 12 h and every 8 h to calculate the penetration distribution (AUCtissue/fAUCserum) and probability of target attainment (PTA) at an fAUC/MIC target of ≥200 in tissue fluid. RESULTS: A three-compartment model fitted the data best. The mean (SD) and median penetration ratios into tissue of the simulated population were 1.91 (4.56) and 0.85, respectively, which were consistent with observed values in the original patients. PTAs for 1 g of vancomycin every 12 h and every 8 h in tissue fluid were 39.6% and 56.6% at an MIC of 1 mg/L. Serum trough concentrations (R(2) = 0.06) and serum AUC exposure (R(2) = 0.002) were poor predictors of vancomycin AUC tissue exposure. CONCLUSIONS: Standard dosages of vancomycin provide a low likelihood of obtaining target pharmacodynamic exposure in the tissue of a lower limb infection. This low likelihood is due to wide variability in vancomycin penetration in the interstitial tissue fluid, which could not be predicted by serum concentrations.
Authors: Carl T Gustafson; Felix Boakye-Agyeman; Cassandra L Brinkman; Joel M Reid; Robin Patel; Zeljko Bajzer; Mahrokh Dadsetan; Michael J Yaszemski Journal: PLoS One Date: 2016-01-13 Impact factor: 3.240