Session: Poster Session: Human Pharmacokinetics/Dynamics
Monday, October 27, 2008: 12:00 AM
Room: Hall C
Background: Antibiotic penetration into the infection site is critical for obtaining a good clinical outcome. However, few studies have evaluated the penetration of β-lactam agents in the lung, as measured by the epithelial lining fluid (ELF), & these studies have typically involved non-infected pts. This study examines the penetration & pharmacodynamics of meropenem (MER) in the ELF among pts with ventilator-associated pneumonia. Methods: Plasma & ELF concentration-time data for MER were obtained from a multicenter clinical trial. All subjects received MER 2 g IV as a 3-hour infusion, Q8H. Plasma and ELF PK data were available on 56 and 17 pts, respectively. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer (BigNPAG). Monte Carlo simulation of 9999 subjects was performed to calculate the ELF/plasma penetration ratios by estimating the AUCELF and free AUCPlasma from zero to infinity (AUC0-inf) after a single dose of MER 2 g. The fraction of simulated subjects who achieved 30% T>MIC for both the plasma (free drug) and ELF (total drug) were calculated for the range of MIC values from 0.1 to 40 mg/L. Results: The model fit the data well overall with slopes & intercepts of the predicted versus observed concentration plots for plasma and ELF very close to the ideal values of 1.0 and 0.0, respectively. The median AUCELF/AUCPLASMA penetration ratio was 25.6%, & the 25th and 75th percentiles were 9.1% and 70.5%, respectively. In the ELF, the probability of acheiving 30% T>MIC was >90% at 1 mg/L, 80% at 2 mg/L, 70% at 4 mg/L and 56% at 8 mg/L. Conclusions: In infected patients, the median AUCELF is approximately 25% of free AUCPLASMA & there was a >90% probability of achieving 30% T>MIC in the ELF for MIC <= 1 mg/L.