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: Yuichi Fukuda, Katsunori Yanagihara, Hideaki Ohno, Yasuhito Higashiyama, Yoshitsugu Miyazaki, Kazuhiro Tsukamoto, Yoichi Hirakata, Kazunori Tomono, Yohei Mizuta, Takayoshi Tashiro, Shigeru Kohno
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 50 Issue 1 Pg. 121-5 (Jan 2006) ISSN: 0066-4804 [Print] United States
• PMID: 16377676 (Publication Type: Journal Article)

Chemical References

• Anti-Infective Agents
• DX 619
• Pyrrolidines
• Quinolones

Topics

• Animals
• Anti-Infective Agents (blood, pharmacokinetics, therapeutic use)
• Area Under Curve
• Disease Models, Animal
• Lung Diseases (drug therapy, metabolism, microbiology)
• Mice
• Mice, Inbred ICR
• Pneumococcal Infections (drug therapy, metabolism)
• Pyrrolidines (blood, pharmacokinetics, therapeutic use)
• Quinolones (blood, pharmacokinetics, therapeutic use)
• Streptococcus pneumoniae