title: Potency of DX-619, a novel des-F(6)-quinolone, in haematogenous murine bronchopneumonia caused by methicillin-resistant and vancomycin-intermediate Staphylococcus aureus.
abstract: In this study, the potency of DX-619, a novel des-fluoro(6)-quinolone agent, was compared with that of vancomycin (VCM) in a murine model of haematogenous bronchopneumonia infection caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate S. aureus (VISA). The minimum inhibitory concentrations (MICs) of DX-619 and VCM against MRSA were 0.03 microg/mL and 1.0 microg/mL, respectively, whilst the MICs against VISA were 0.125 microg/mL and 8.0 microg/mL, respectively. Treatment with DX-619 resulted in a significant decrease in the number of viable bacteria in the MRSA infection model (mean+/-standard error of the mean for control, VCM and DX-619 groups: 7.97+/-0.32, 7.19+/-0.33 and 2.91+/-0.60 log(10) colony-forming units/lung, respectively). For infection with VISA, mice were pre-treated with cyclophosphamide. The survival rate of mice treated with DX-619 (90% survival) was significantly higher than survival rates in the other two groups (45% both for VCM and control groups; P<0.05). Histopathological examination revealed that inflammatory changes in the DX-619-treated group were less marked than in the other two groups. The parameters in lung tissue for the area under the concentration-time curve/MIC ratio both for MRSA and VISA were higher in the DX-619 group than in the VCM group. Our results emphasise the potency of DX-619 against MRSA and VISA murine haematogenous pulmonary infection.
authors.affiliation: Second Department of Internal Medicine, Nagasaki University Graduate School of Pharmaceutical Sciences, Nagasaki University Graduate School of Medical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. kyana-ngs@umin.ac.jp
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yanagihara
authors.forename: Masafumi
authors.initials: M
authors.lastname: Seki
authors.forename: Koichi
authors.initials: K
authors.lastname: Izumikawa
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Higashiyama
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Hirakata
authors.forename: Kazunori
authors.initials: K
authors.lastname: Tomono
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mizuta
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsukamoto
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D008168:Lung / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008297:Male; D008712:Methicillin / Q000494:pharmacology; D016106:Methicillin Resistance; D051379:Mice; D011023:Pneumonia, Staphylococcal / Q000188:drug therapy / Q000382:microbiology* / Q000473:pathology; D011759:Pyrrolidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D015363:Quinolones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D013047:Specific Pathogen-Free Organisms; D013211:Staphylococcus aureus / Q000187:drug effects*; D014640:Vancomycin / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; C505440:DX 619; D011759:Pyrrolidines; D015363:Quinolones; D014640:Vancomycin; D008712:Methicillin