title: Efficacy of High-Dose Meropenem (Six Grams per Day) in Treatment of Experimental Murine Pneumonia Induced by Meropenem-Resistant Pseudomonas aeruginosa.
abstract: High-dose meropenem (MEPM; 6 g/day) has been approved as a treatment for purulent meningitis; however, little is known regarding its in vivo efficacy in refractory lower respiratory tract infections. The purpose of this study was to evaluate the efficacy of MEPM at 6 g/day in a murine model of severe pneumonia caused by MEPM-resistant Pseudomonas aeruginosa Experimental pneumonia induced by MEPM-resistant P. aeruginosa was treated with normal-dose MEPM (150 mg/kg of body weight, simulating a 3-g/day regimen in humans) or high-dose MEPM (500 mg/kg, simulating a 6-g/day regimen in humans). Mice treated with high-dose MEPM showed significantly restored survival relative to that of untreated mice and tended to show a survival rate higher than that of mice treated with normal-dose MEPM. The viable bacterial counts (of two clinical isolates) in the lungs decreased significantly in mice treated with high-dose MEPM from those for untreated mice (P < 0.001) or mice treated with normal-dose MEPM (P, <0.01 and <0.05). The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) was also significantly lower in mice treated with high-dose MEPM than in untreated mice. The free MEPM concentration in the epithelial lining fluid (ELF) exceeded 16 μg/ml for 85 min in mice treated with high-dose MEPM, but not for mice treated with normal-dose MEPM. Our results demonstrate that high-dose MEPM (6 g/day) might provide better protection against pneumonia caused by MEPM-resistant strains of P. aeruginosa than the dose normally administered (less than 3 g/day).
authors: Leading Program, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.|Unit of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.|Department of Respiratory Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors: Kazuhiro
authors: K
authors: Oshima
authors: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan shigekinak@nih.go.jp.
authors: Shigeki
authors: S
authors: Nakamura
authors: Department of Respiratory Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors: Naoki
authors: N
authors: Iwanaga
authors: Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan.
authors: Koji
authors: K
authors: Takemoto
authors: Unit of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.|Department of Respiratory Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors: Taiga
authors: T
authors: Miyazaki
authors: Department of Laboratory Medicine, Nagasaki University Hospital, Nagasaki, Japan.
authors: Kastunori
authors: K
authors: Yanagihara
authors: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Yoshitsugu
authors: Y
authors: Miyazaki
authors: Department of Respiratory Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors: Hiroshi
authors: H
authors: Mukae
authors: Department of Respiratory Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors: Shigeru
authors: S
authors: Kohno
authors: Unit of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors: Koichi
authors: K
authors: Izumikawa
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development; D020545:Respiratory Mucosa / Q000187:drug effects / Q000382:microbiology; D016019:Survival Analysis; D013845:Thienamycins / Q000493:pharmacokinetics* / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem
keywords: high dose; meropenem; meropenem-resistant Pseudomonas aeruginosa; pharmacokinetics/pharmacodynamics