Antibiotic penetration to the infection site is critical for obtaining a good clinical outcome in patients with ventilator-associated pneumonia (VAP). Surprisingly few studies have quantified the penetration of -lactam agents into the lung, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUC ELF /AUC plasma ratio). These have typically involved noninfected patients. This study examines the penetration and pharmacodynamics of meropenem in the ELF among patients with VAP. Meropenem plasma and ELF concentration-time data were obtained from patients in a multicenter clinical trial. 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 (big nonparametric adaptive grid [BigNPAG]). A Monte Carlo simulation was performed to estimate the range of ELF/ plasma penetration ratios one would expect to observe in patients with VAP, as measured by the AUC ELF / AUC plasma ratio. The range of AUC ELF /AUC plasma penetration ratios predicted by the Monte Carlo simulation was large. The 10th percentile of lung penetration was 3.7%, while the 90th percentile of penetration was 178%. The variability of ELF penetration is such that if relatively high ELF exposure targets are required to attain multilog kill or resistance suppression for bacteria like Pseudomonas aeruginosa, then even receiving the largest licensed dose of meropenem with an optimal prolonged infusion may not result in target attainment for a substantial fraction of the population.Ventilator-associated pneumonia (VAP) remains a frequent cause of morbidity and mortality among intensive care unit patients despite advances in antimicrobial therapy, better supportive care modalities, and the use of a wide range of preventive measures (1, 26). Prompt delivery of empirical therapy for patients likely to have VAP is of paramount importance, since delays in appropriate antibiotic therapy have been associated with deleterious outcomes (1,18,19,24,25). An important consideration when selecting empirical therapy for VAP is the agent's ability to adequately penetrate the infected site and achieve sufficient concentrations for the desired endpoint. For extracellular respiratory tract pathogens, the determination of drug concentration in epithelial lining fluid (ELF) currently provides the best estimate for ascertaining the degree of antibiotic exposure for these organisms in patients with 12,[15][16][17]21,25,27,28).While it is well established that the efficacy of an antibiotic regimen largely depends on its penetration in the infection site, relatively few studies have focused on the penetration of antibiotics into the ELF (3-8, 12, 15-17, 21, 23, 25, 27, 28). Of those available, most have been among patients treated with fluoroquinolones and macrolides (12,15,16,23,27,28). A surprisingly small body of data is available for the penetration of -lactam agents into the ELF. In the older li...