Vol.56 No.S-1 April 2008

In vitro and in vivo antibacterial activity of sitafloxacin

Hiroko Kanda¹⁾, Yuichi Kurosaka¹⁾, Katsuko Fujikawa¹⁾, Megumi Chiba¹⁾, Shinichiro Yamachika¹⁾, Ryo Okumura¹⁾, Yoshinori Kashimoto¹⁾, Saori Uoyama¹⁾, Kazuki Hoshino¹⁾, Mayumi Tanaka²⁾ and Tsuyoshi Otani¹⁾

¹⁾Biological Research Laboratories IV, Daiichi Sankyo Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo, Japan
²⁾Global Project Management Group, Daiichi Sankyo Co., Ltd.

Abstract

The in vitro and in vivo antibacterial activity of sitafloxacin(STFX), a quinolone, was compared to that of other quinolones: levofloxacin, ciprofloxacin(CPFX), moxifloxacin, and tosufloxacin. STFX showed the most potent antibacterial activity against clinical isolates of both Gram-positive and Gram-negative bacteria, including quinolone-resistant strains, Mycoplasma pneumoniae, and Chlamydiaceae. MIC₉₀ of STFX against Streptococcus pneumoniae, a major respiratory tract infection pathogen was 0.06 μg/mL, and was 4- to 64-fold more active than those of other quinolones tested. MIC₉₀ of STFX against Escherichia coli, major urinary tract infection pathogen, was 1 μg/mL, and was 16- to 32-fold more active than those of other quinolones tested. In systemic infection caused by major pathogens in mice, STFX showed a protective effect reflecting its potent in vitro antibacterial activity. STFX also showed higher in vitro activity against Pseudomonas aeruginosa than that of CPFX. In a model of complicated urinary tract infection caused by P. aeruginosa in the rat, the therapeutic efficacy of STFX was greater than that of CPFX. A study on the inhibitory effect against DNA gyrase and topoisomerase IV purified from S. pneumoniae and E. coli showed that STFX had higher inhibitory activity than other quinolones tested against both wild- and mutant enzymes, which has single or double amino-acid replacement(s) in the quinolone-resistance-determining region(QRDR). The inhibitory activity of STFX against mutant DNA gyrase and topoisomerase IV, which has single amino-acid replacement in QRDR, corresponded roughly to those of other comparable quinolones against wild-type enzymes.
In an in vitro pharmacokinetic model simulating serum concentrations of STFX following 50 mg twice-daily and 100 mg twice-daily oral administration, STFX was shown to be bactericidal against Staphylococcus aureus, S. pneumoniae, E. coli, P. aeruginosa, Haemophilus influenzae, and Moraxella catarrhalis. Even at lower doses, STFX was bactericidal against S. pneumoniae, H. influenzae, and M. catarrhalis, for which MIC of STFX corresponded to MIC₉₀ of clinical isolates. A study focusing on AUC, the major pharmacokinetic parameter correlated with pharmacodynamics of quinolones, showed that STFX, with simulated human serum AUC in the mouse, was shown to be highly effective in a model of pneumonia due to penicillin-resistant S. pneumoniae.

Key word

sitafloxacin, antibacterial activity

Received

November 5, 2007

Accepted

January 8, 2008

Jpn. J. Chemother. 56 (S-1): 1-17, 2008