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Antimicrobial Agents and Chemotherapy, January 2006, p. 121-125, Vol. 50, No. 1
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.1.121-125.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

In Vivo Efficacies and Pharmacokinetics of DX-619, a Novel Des-Fluoro(6) Quinolone, against Streptococcus pneumoniae in a Mouse Lung Infection Model

Yuichi Fukuda,^1, Katsunori Yanagihara,^1,2*, Hideaki Ohno,¹ Yasuhito Higashiyama,¹ Yoshitsugu Miyazaki,¹ Kazuhiro Tsukamoto,^1,2 Yoichi Hirakata,¹ Kazunori Tomono,¹ Yohei Mizuta,¹ Takayoshi Tashiro,¹ and Shigeru Kohno^1,3

Second Department of Internal Medicine,¹ Department of Pharmacotherapeutics, Nagasaki University Graduate School of Pharmaceutical Sciences,² Division of Molecular & Clinical Microbiology, Department of Molecular Microbiology & Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan³

Received 6 April 2005/ Returned for modification 17 May 2005/ Accepted 30 September 2005

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.

Y. Fukuda and K. Yanagihara contributed equally to this work.

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