title: In vivo efficacies and pharmacokinetics of DX-619, a novel des-fluoro(6) quinolone, against Streptococcus pneumoniae in a mouse lung infection model.
abstract: DX-619 is a novel des-fluoro(6) quinolone with potent activity against gram-positive pathogens. The in vivo activity of DX-619 against Streptococcus pneumoniae was compared with those of fluoro(6) quinolones, sitafloxacin, and ciprofloxacin in a mouse model. Two strains of S. pneumoniae were used: a penicillin-sensitive S. pneumoniae (PSSP) strain and a penicillin-resistant S. pneumoniae (PRSP) strain. Furthermore, these strains showed intermediate susceptibilities to ciprofloxacin. In murine lung infections caused by PSSP, the 50% effective doses (ED50s) of DX-619, sitafloxacin, and ciprofloxacin were 9.15, 11.1, and 127.6 mg/kg of body weight, respectively. Against PRSP-mediated pneumonia in mice, the ED50s of DX-619, sitafloxacin, and ciprofloxacin were 0.69, 4.84, and 38.75 mg/kg, respectively. The mean +/- standard error of the mean viable bacterial counts in murine lungs infected with PSSP and treated with DX-619, sitafloxacin, ciprofloxacin (10 mg/kg twice daily), and saline (twice daily) were 1.75 +/- 0.06, 1.92 +/- 0.23, 6.48 +/- 0.28, and 7.57 +/- 0.13 log10 CFU/ml, respectively. Furthermore, the numbers of viable bacteria in lungs infected with PRSP and treated with the three agents and not treated (control) were 1.73 +/- 0.04, 2.28 +/- 0.17, 4.61 +/- 0.59, and 5.54 +/- 0.72 log10 CFU/ml, respectively. DX-619 and sitafloxacin significantly decreased the numbers of viable bacteria in the lungs compared to the numbers in the lungs of ciprofloxacin-treated and untreated mice. The pharmacokinetic parameter of the area under the concentration-time curve (AUC)/MIC ratio in the lungs for DX-619, sitafloxacin, and ciprofloxacin were 171.0, 21.92, and 1.22, respectively. The AUC/MIC ratio in the lungs was significantly higher for DX-619 than for sitafloxacin and ciprofloxacin. Our results suggest that DX-619 and sitafloxacin are potent against both PSSP and PRSP in our mouse pneumonia model.
authors.affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Fukuda
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yanagihara
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ohno
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Higashiyama
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsukamoto
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: Takayoshi
authors.initials: T
authors.lastname: Tashiro
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D004195:Disease Models, Animal; D008171:Lung Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008813:Mice, Inbred ICR; D011008:Pneumococcal Infections / Q000188:drug therapy* / Q000378:metabolism; D011759:Pyrrolidines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015363:Quinolones / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013296:Streptococcus pneumoniae
chemical_list: D000890:Anti-Infective Agents; C505440:DX 619; D011759:Pyrrolidines; D015363:Quinolones