Frédéric Frippiat1, Flora Tshinanu Musuamba2, Laurence Seidel3, Adelin Albert3, Raphaël Denooz4, Corinne Charlier4, Françoise Van Bambeke5, Pierre Wallemacq6, Julie Descy7, Bernard Lambermont8, Nathalie Layios8, Pierre Damas8, Michel Moutschen9. 1. Department of Infectious Diseases and General Internal Medicine, University Hospital of Liège, Liège, Belgium f.frippiat@chu.ulg.ac.be. 2. School of Pharmacy, University College, London, UK. 3. Department of Biostatistics, University Hospital of Liège, Liège, Belgium. 4. Department of Toxicology, University Hospital of Liège, Liège, Belgium. 5. Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium. 6. Louvain Centre for Toxicology and Applied Pharmacology, Université catholique de Louvain, Brussels, Belgium. 7. Department of Microbiology, University Hospital of Liège, Liège, Belgium. 8. Intensive Care Unit, University Hospital of Liège, Liège, Belgium. 9. Department of Infectious Diseases and General Internal Medicine, University Hospital of Liège, Liège, Belgium.
Abstract
OBJECTIVES: The objective of this study was to propose an optimal treatment regimen of meropenem in critically ill patients with severe nosocomial pneumonia. PATIENTS AND METHODS: Among 55 patients in intensive care treated with 1 g of meropenem every 8 h for severe nosocomial pneumonia, 30 were assigned to intermittent infusion (II; over 0.5 h) and 25 to extended infusion (EI; over 3 h) groups. Based on plasma and epithelial lining fluid (ELF) concentrations determined at steady-state, pharmacokinetic modelling and Monte Carlo simulations were undertaken to assess the probability of attaining drug concentrations above the MIC for 40%-100% of the time between doses (%T > 1-fold and 4-fold MIC), for 1 or 2 g administered by either method. RESULTS: Penetration ratio, measured by the ELF/plasma ratio of AUCs, was statistically higher in the EI group than in the II group (mean ± SEM: 0.29 ± 0.030 versus 0.20 ± 0.033, P = 0.047). Considering a maximum susceptibility breakpoint of 2 mg/L, all dosages and modes of infusions achieved 40%-100% T > 1-fold MIC in plasma, but none did so in ELF, and only the 2 g dose over EI achieved 40%-100% T > 4-fold MIC in plasma. CONCLUSIONS: The optimum regimen to treat severe nosocomial pneumonia was 2 g of meropenem infused over 3 h every 8 h. This regimen achieved the highest pharmacodynamic targets both in plasma and in ELF.
OBJECTIVES: The objective of this study was to propose an optimal treatment regimen of meropenem in critically illpatients with severe nosocomial pneumonia. PATIENTS AND METHODS: Among 55 patients in intensive care treated with 1 g of meropenem every 8 h for severe nosocomial pneumonia, 30 were assigned to intermittent infusion (II; over 0.5 h) and 25 to extended infusion (EI; over 3 h) groups. Based on plasma and epithelial lining fluid (ELF) concentrations determined at steady-state, pharmacokinetic modelling and Monte Carlo simulations were undertaken to assess the probability of attaining drug concentrations above the MIC for 40%-100% of the time between doses (%T > 1-fold and 4-fold MIC), for 1 or 2 g administered by either method. RESULTS: Penetration ratio, measured by the ELF/plasma ratio of AUCs, was statistically higher in the EI group than in the II group (mean ± SEM: 0.29 ± 0.030 versus 0.20 ± 0.033, P = 0.047). Considering a maximum susceptibility breakpoint of 2 mg/L, all dosages and modes of infusions achieved 40%-100% T > 1-fold MIC in plasma, but none did so in ELF, and only the 2 g dose over EI achieved 40%-100% T > 4-fold MIC in plasma. CONCLUSIONS: The optimum regimen to treat severe nosocomial pneumonia was 2 g of meropenem infused over 3 h every 8 h. This regimen achieved the highest pharmacodynamic targets both in plasma and in ELF.
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