title: In vivo efficacy of biapenem with ME1071, a novel metallo-β-lactamase (MBL) inhibitor, in a murine model mimicking ventilator-associated pneumonia caused by MBL-producing Pseudomonas aeruginosa.
abstract: ME1071, a maleic acid derivative, is a novel, specific inhibitor of metallo-β-lactamases (MBLs). In vitro, ME1071 can potentiate the activity of carbapenems against MBL-producing Pseudomonas aeruginosa. To confirm the clinical efficacy of ME1071 in ventilator-associated pneumonia (VAP) caused by MBL-producing P. aeruginosa, a mouse model that mimics VAP by placement of a plastic tube in the bronchus was used. Biapenem (100 mg/kg) or ME1071 plus biapenem (each 100 mg/kg) was administered intraperitoneally every 12 h beginning at 12 h after inoculation. Survival was evaluated over 7 days. At 30 h post infection, mice were sacrificed and the numbers of viable bacteria in the lungs and bronchoalveolar lavage fluid (BALF) were compared. Histopathological analysis of lung specimens was also performed. The pharmacokinetics of ME1071 was analysed after initial treatment. The ME1071 plus biapenem combination group displayed significantly longer survival compared with the control and biapenem monotherapy groups (P<0.05). Furthermore, the number of viable bacteria in the lungs was significantly lower in the combination group (P<0.05). Histopathological examination of lung specimens indicated that progression of lung inflammation was prevented in the combination group. Furthermore, total cell and neutrophil counts, as well as cytokine levels, in BALF were significantly decreased (P<0.05) in the combination group. The percentage time above the MIC (%T>MIC) for biapenem without ME1071 was 0% in plasma; however, this value was elevated to 10.8% with ME1071. These results suggest that ME1071 is potent and effective for treatment of VAP caused by MBL-producing P. aeruginosa.
authors.affiliation: Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Yamada
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yanagihara
authors.forename: Norihito
authors.initials: N
authors.lastname: Kaku
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Harada
authors.forename: Yohei
authors.initials: Y
authors.lastname: Migiyama
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nagaoka
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Morinaga
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nakamura
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Imamura
authors.forename: Taiga
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Koichi
authors.initials: K
authors.lastname: Izumikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kakeya
authors.forename: Hiroo
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Akira
authors.initials: A
authors.lastname: Yasuoka
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000276:immunology; D004359:Drug Therapy, Combination; D007249:Inflammation / Q000188:drug therapy; D008168:Lung / Q000382:microbiology; D008298:Maleates / Q000627:therapeutic use*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009504:Neutrophils / Q000276:immunology; D053717:Pneumonia, Ventilator-Associated / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000401:mortality; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013534:Survival; D013845:Thienamycins / Q000627:therapeutic use*; D016896:Treatment Outcome; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; C587494:ME1071; D008298:Maleates; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; C409201:beta-lactamase IMP-1; D001618:beta-Lactamases; C065257:biapenem
keywords: ME1071; Metallo-β-lactamase; Pseudomonas aeruginosa; Ventilator-associated pneumonia