Table 1. MICs of fosfomycin and other antibiotics determined by agar dilution method against Pseudomonas aeruginosa FOM: fosfomycin, PIPC: piperacilli

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1 Key words: Pseudomonas aeruginosa, fosfomycin, ofloxacin,

2 Table 1. MICs of fosfomycin and other antibiotics determined by agar dilution method against Pseudomonas aeruginosa FOM: fosfomycin, PIPC: piperacillin, CAZ: ceftazidime, IPM/CS: imipenem/cilastatin, GM: gentamicin, EM: erythromycin, OFLX: ofloxacin, NFLX: norfloxacin, CPFX: ciprofloxacin

3 FOM: fosfomycin, PIPC: piperacillin, CAZ: ceftazidime, IPM/CS: imipenem/cilastatin, GM: gentamicin, EM: erythromycin, OFLX: ofloxacin Fig. 1. Combined effects of fasfomycin and various antibiotics on Pseudomonas aeruginosa PRC-72. FOM: fosfomycin, OFLX: ofloxacin, NFLX: norfloxacin, CPFX: ciprofloxacin Fig. 2. Combined effects of fosfomycin and new quinolones on Pseudomonas aeruginosa PRC-72.

4 r g. 3. Combined effects of FOM and new quinolones at several concentrations of fosfomycin on Pseudomonas aeruginosa PRC-72. FOM: fosfomycin, OFLX: ofloxacin Fig. 5. Correlation between the combined effects and MICs of fosfomycin and new quinolones on Pseudomonas aeruginosa. Fig. 4. Combined effects of fosfomycin and new quinolones at several dose intervals of quinolones on Pseudomonas aeruginosa PRC-72.

5 VOL. 43 NO.8 各 種抗菌 薬 の殺菌力 にお よぼすFOMの Table 739 影讐 2. Influence of fosfomycin on cell-surface in Pseudomonas aeruginosa PRC-72 hydrophobicity 治 療 に は 限界 が あ り,併 用 療 法 の対 象菌 種 と考 え られ て い る3,7 9) ま た,併 用療 法 は,抗 菌 力 の 増 大,耐 性 化 の 防 止,副 作 用 の軽 減 な どを 図 る手 段1川 と して注 目 され て い る Paen岬Ssに MIC)を Fig. 6. Scanning PRC-72 electron exposed micrographs to fosfomycin 対 してFOM(1/2MIC)と (1/2 作 用 させ る と,単 独 で は 静 菌 的 に推 移 後 再 増 of P. aeruginosa 殖 し,併 用 に お い て は,FOM添 ofloxacin. さ せ る と同 時 添 加 と比 較 し,よ and NFLX 加 後 にNFLXを 作用 り殺 菌 的 な 作 用 を示 し た1nと の報 告 が あ る に 示 し た FOM は,菌 12.5μg/mlを 単 独 作 用 さ せ た場 合 で の 球 形 化 お よ び バ ル ジ 構 造 が 観 察 さ れ, 3.13μg/ml単 独 さ せ た 場 合 に は,菌 観 察 さ れ た 一 方,FOM FOMを 除 き, OFLX3. は,各 OFLX の若干 の伸 長化 が 作用 させた場 合 に EM,OFLX, 0.78μg/ml作 よびCPFXを GM, 作 用 させ る こ と に キ ノ ロ ン剤 に つ い て は,単 剤 作 用 と比 較 OFLXを 併 用 す る こ と に よ り,各 単 剤 の作 用 と比 較 し数 多 くの溶 菌 像 が観 察 され,形 態 学 的 に も併 用効 果 が 認 め られ た 3.13お よび 用 させ た と き の 影 響 を示 し た 併 用 効 果 果 の で な い 濃 度0.78μg/mlを 作 用 さ せ た と き とを比 較 用効 用 効 果 の で る 濃 度 を 作 用 さ せ た と き の 方 が, 菌 体 表 層 を 疎 水 性 に 傾 け た ま た, 12.5μg/mlを0.5,1,2お よ び4時 FOM 間作 用 させ た と き を(B)に 示 し た そ の 結 果,FOMを1時 間以上 の作 用 さ キ ノ ロ ン の取 り込 み はMg2+で る12)こ とが い われ て い る また,FOMは 強 い 陽 イ オ ンで あ る燐 を持 っ て い る た め,燐 イ オ ン が 外 膜 の電 位 の バ ラ ンス を崩 し,Mg2+に 影 響 を与 え て い る こ とが 考 え られ る 一 方,MRSAに 対 しFOMを1/16MIC作 せ る こ と に よ り菌 体 表 層 を 疎 水 性 に 変 化 さ せ る こ と が 認 め られ た お い て も失 わ れ るPBP画 III.考 P.aeruginosaは,一 察 対 し て は感 染 力 を発 の 病 態 は 難 治 性 に 移 行 し や す く,単 用 させ る II'の 産 生 が 少 な くな り,ま た,グ ラ ム 陰 性 菌 に 分 が 認 め られ る13)とい う報 告 が あ る 般 に そ の 病 原 性 は 低 い もの と さ れ て い る が,Compromisedhostに 阻 害 され,脱 共 役 剤 な どで プ ロ トン駆 動 力 を解 消 す る と取 り込 み 量 が 増 加 す とPBP 揮 し,そ IPM/CS, 示 し た (A)に は,FOMを12.5, 作 用 さ せ た と き,併 約10 70倍 NFLXお に よ り,特 CAZ, 菌 体 表 層 の疎 水 性 に 及 ぼす 影 響 の検 討 結 果 を の み ら れ る 濃 度12.5μg/mlを す る と,併 理 菌 に対 し, PIPC, 子 顕 微 鏡 に よ る観 察 に お い て は,FOMと 体 表 層 の 疎 水 性 の 違 い と併 用 効 果 の 検 討 FOMの 前処理す る ことに し,顕 著 に殺 菌 力 の増 強 が認 め られ た また,走 査 型 電 溶 菌像 が 観 察 さ れ た Table2に にFOMを 対 す る FOMと よ る影 響 に つ い て検 討 した FOM処 単 剤 の 作 用 に 比 べ て 数 多 くの 球 形 化 し た 菌 お よ び 7.菌 各 種 薬 剤 との併 用効 果,特 間作 用後 12.5μg/mlを2時 13μg/mlを そ こで 今 回 我 々 は,P.aeruginosaに 剤 におけ る この よ うなFOMの 作 用 機 作 に よ り,各 種 抗 菌 薬 の 菌 体 内 へ の取 り込 み が 高 め られ 殺 菌 力 の 増 強 が 認 め られ た もの と推 察 さ れ る

6 cancer patients. Am J Med 80 (Suppl 5 C): 96 ` 100, ) Hill M. Yu V L, Sharp J, Zuravleff J, Korvick J A, Murder R R: Antibiotic therapy 6) Hirai K, Aoyama H, Suzue S, Irikura T, lyobe S, Mituhashi S: Isolation and Characterization of Norfloxacin-Resistant Mutants of Escherichia coil K-12. Antimicrobial Agents and Chemotherapy 30: 248 `253, ) de Jough C A, Joshi J H, Newman K A, Moody M R, Wharton R, Standiford H C, Schimpff S C: Antibiotic synergism and response in gram-negative bacteremia in granulocytopenic for Pseudomonas aeruginosa bacteremia, Outcome correlations in a prospective stuby of 200 patients. Am J Med 87: 540 `546, ) Godfrey A J, Bryan L E: Cell Surfaec Changes in Pseudomonas aeruginosa PAO 4069 in Response to Treatment with 6-Aminopenicillanic Acid. Antimicrobial Agents and Chemotherapy 33: 1435

7 Influence of fosfomycin on the bactericidal activity of various antibiotics against Pseudomonas aeruginosa Yumiko Kanno, Toshihiko Takata, Toshie Sugano, Takashi Yoshida Meiji Seika Kaisha, Ltd., Pharmaceutical Research Center, 760 Morooka-cho, Kohoku-ku, Yokohama 222, Japan We examined in vitro the synergistic effect of fosfomycin (FOM) and other antibiotics against Pseudomonas aeruginosa under various conditions. The results were as follows. 1) In combination with FOM and other antibiotics, the bactericidal activities against P. aeruginosa pretreated with sub MIC of FOM were greater than those of non-pretreated bacteria, and these synegistic effects increased with increasing concentrations of sub-mic of FOM. 2) In FOM and other antibiotic combinations, good synergism was found when an antibiotic was added for less than 1 hours after the removal of FOM for the pretreatment of cells. No apparent synergism was observed when the antibiotic was added for more than 1 hour later after FOM was removed. 3) We did not observe a correlation between these synergistic bactericidal effects and the antipseudomonal susceptibilities of each antibiotic. 4) In the test strains that revealed synergistic effects the cell surface of P. aeruginosa became more hydrophobic than without FOM treatment. 5) The combination of FOM and ofloxacin (OFLX) induced lysis at higher frequencies than that either FOM or OFLX alone according to morphorogical observation by scanning electron microscope.

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