Sitafloxacin の細菌学的評価  [in Japanese] In vitro and in vivo antibacterial activity of sitafloxacin  [in Japanese]

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新規キノロン系抗菌薬sitanoxacin (STFX) は, 各種細菌の臨床分離株を用いた感受性試験において, 既存キノロン系抗菌薬耐性菌を含むグラム陽性菌ならびに陰性菌, さらには<I>Mycoplasma pneumoniae</I>および<I>Chlamydiaceae</I>などに対して, levofloxacin, ciprofloxacin (CPFX), moxifloxacinおよびtosufloxacinと比較して, 最も高い抗菌活性を示した。特に, 呼吸器感染症主要原因菌である<I>Strepfococcus pneumoniae</I>および尿路感染症主要原因菌である<I>Escherichia coli</I>に対して, それぞれ0.06および1μg/mLのMIC<SUB>90</SUB>を示し, 対照キノロン系抗菌薬と比較してそれぞれ4~64倍および16~32倍以上強い抗菌力を有していた。これらを含む主要菌種によるマウス敗血症モデルにおいて, STFXは, 高い<I>in vitro</I>抗菌活性を反映した強い感染防御効果を示した。また, 本薬は, <I>Pseudomonas aeruginosa</I>に対してCPFXを上回る抗菌活性を示し, ラットを用いた複雑性尿路感染症モデルにおいても, CPFXより高い治療効果を示した。作用機作解析の結果では, STFXは, <I>S.pneumoniae</I>ならびに<I>E.coli</I>由来のDNAジャイレースおよびトポイソメラーゼIVの野生型ならびにキノロン耐性決定領域の1あるいは2カ所にアミノ酸置換を有する変異型酵素に対し, 対照キノロン系抗菌薬と比較して高い阻害活性を示した。本薬の一変異型酵素に対する阻害活性は, 対照キノロン系抗菌薬の野生型標的酵素に対する阻害活性と同等であった。<BR><I>in vitro</I>シミュレーションシステムを用いたヒト常用量 (50mg1日2回) および最高用量 (100mg1日2回) 経口投与時の血清中濃度推移での殺菌効果の検討では, STFXは<I>Staphylococcus aureus, S.pneumoniae, E.coli, P.aeruginosa, Haemophilus influenzae</I>および<I>Moraxella catarrhalis</I>に対して優れた殺菌効果を示した。特に, <I>S.pneumoniae, H.influenzae, M.catarrhalis</I>に対しては, ヒト常用量投与モデルで, MIC<SUB>90</SUB>値に相当するMICを示す菌株に対しても強い殺菌効果を示した。さらに, キノロン系抗菌薬の薬効発現に関与する主要な薬物動態パラメータであるAUCに着目し, ヒトと同程度の血中AUCをマウスにて再現した結果, STFXはペニシリン耐性<I>S.pneumoniae</I>によるマウス肺炎モデルにおいて高い治療効果を示した。

The <I>in oitro</I> and <I>in vivo</I> 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, <I>Mycoplasma pneumoniae</I>, and <I>Chlamydiaceae</I>. MIC<SUB>90</SUB> of STFX against <I>streptococcus pneumoniae</I>, a major respiratory tract infection pathogen was 0.06μg/mL, and was 4-to 64-fold more active than those of other quinolones tested. MIC<SUB>90</SUB> of STFX against <I>Escherichia coli</I>, major urinary tract infection pathogen, was 1μg/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 <I>in vitro</I> antibacterial activity. STFX also showed higher <I>in vitro</I> activity against <I>Pseudomonas aeruginosa</I> than that of CPFX. In a model of complicated urinary tract infection caused by <I>P. aeruginosa</I> 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 <I>S.pneumoniae</I> and <I>E. coli</I> showed that STFX had higher inhibitory activity than other quinolones tested against both wild-and mutant enzymes, which has single or double aminoacid 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.<BR>In an <I>in vitro</I> pharmacokinetic model simulating serum concentrations of STFX following 50mg twicedaily and 100mg twice-daily oral administration, STFX was shown to be bactericidal against staphylococcas aureus, <I>S.pneumoniae, E.coli, P. aeruginosa, Haernophilus influenzae</I>, and <I>Moraxella catarrhalis</I>. Even at lower doses, STFX was bactericidal against <I>S. pneumoniae, H. influennzae</I>, and <I>M. catarrhalis</I>, for which MIC of STFX corresponded to MIC<SUB>90</SUB> of clinical isolates. A study focusing on AUC, the malor 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 <I>S.pneumoniae</I>.



    CHEMOTHERAPY 56, 1-17, 2008-04-10 

    Japanese Society of Chemotherapy

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