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CHEMOTHERAPY MAY 1988 Table 1 Media used for preculture and MIC determination *BHIB: Brain heart infusion broth (Difco), B-NAD: B-Nicotinamide adenine dinucleotide (Sigma chemical Co.), GAMB GAM broth (Nissui), STB: Sensitivity test broth (Nissui), BHIA: Brain heart infusion agar (Thfco), GAMA: GAM agar (Nissui), STA: Sensitivity test agar (Nigsui).

Fig. 1 Antibacterial activity against S. aurcus (100 strains) Table 2 Antibacterial spectra

CHEMOTHERAPY MAY.1988 Fig. 4 Antibacterial activity against S. pyogenes (79 strains) Fig. 2 Antibacterial activity against S. epidermidis (79 strains) (5) E. faecalis (3) S. pneumoniae Fig. 5 Antibacterial activity against E. faecalis (49 strains) Fig. 3 Antibacterial activity against S. pneumoniae (24 strains)

Fig. 6 Antibacterial activity against E. coli (91 strains) Fig. 8 Antibacterial activity against K,arytoca (50 strains) Fig. 7 Antibacterial activity against K. pneurnoniae (49 strains) Fig. 9 Antibacterial activity against C. freundii (79 strains) Fig. 10 Antibacterial activity against P. mirabilis (54 strains)

CHEMOTHERAPY MAY. 1988 Fig. 13 Antibacterial activity against P. rettgeri (53 strains) Fig. 11 Antibacterial activity against P. vulgaris (54 strains) Fig. 14 Antibacterial activity against M. morganii (81 strains) Fig. 12 Antibacterial activity against P. inconstans (54 strains)

Fig. 15 Antibacterial activity against E. cloacae (77 strains) Fig. 18 Antibacterial activity against B. fragilis (27 strains) Fig. 16 Antibacterial activity against S. marcescens (80 strains) Fig. 17 Antibacterial activity against H. influenzae ( 54 strains)

CHEMOTHERAPY MAY. 1988 Table 3 Influence of medium ph on antibacterial activity Table 4 Influence of horse serum on antibacterial activity

VOL. 36 S-1 CHEMOTHERAPY Table 5 Influence of inoculum size on antibacterial activity Table 6 Bactericidal effect * :fl-lactamase-producing strains.

CHEMOTHERAPY MAY. 1988 Fig. 19 Time-kill curves against S. aureus FDA 209PJC-1 R.3763 CCL T.2525 Fig. 20 Time-kill curves against E. coil NIHJ JC-2 R-3763 CCL T-2525

VOL 36 S-1 CHEMOTHERAPY Fig. 21 Time kill curves against K. pneumoniae GN6445 R-3763 CCL 1-2525 Table 7 f3-lactamase stability - Not tested.

CHEMOT 12 Fig. 22 HERAPY MAY.1988 Competition of R-3763 with 14C-PCG for binding to PBPs (A) (B) (A) : S. aureus FDA 209PIC-1. (B): E. coli NIHJ JC-2 らに わ ず か な が ら もT-2588を Table 8 Competition of R-3763 and CCL with 14C-PCG binding to PBPs 上 廻 りCFIXと ほ ぼ同 for 等 の 成 績 で あ った 特 に既 存 のCEX,CDX,CCL AMPCな どのED50値 が>100mg/kgと さない β-lactamase産 治 療 効 果 を示 生性 のS.marcescensL-65株 に よ る感 染症 に対 して も,CS-807は 優 れ た治 療 効果 を 示 した のが 特 長 で あ った III. 考 CS-807の S. aureus FDA 209PJC-I 察 生体 内活 性 代 謝 物R-3763は 7位 にa-methoxyiminoaminothiazole基 セ フェ ム環 の を持 ち, い わ ゆ る 第 三 世 代 セ フ ェム 系 抗 生 剤 と よ ば れ る cefotaxime,ceftizoxime,cefmenoximeな ど と共 通 の構 造 を有 して い る 今 回の 実 験 成 績 か らR-3763は これ ら第 三 世 代 セ フ ェム剤 と同様 グ ラム 陽性 菌,グ ラム 陰性 菌 に幅 広 い抗 菌 スペ ク トル を有 し,か つ強 力 な抗 菌 活性 を示 した と くに 現在 臨 床 使 用 され て い る経 口 用 β-lactam抗 E. coli NIHJ JG2 freundii,イ 等 でCE)LCDX,CFIXを coli 生剤CE)らCDX,CCLAMPCな ganii,e-cloacae,s.marcescensに GN644馬P.mir- 菌 力 を発 現 した またR-3763は abilis GN4754,S.nuarcescens の 惹 起 す る感 染 に 対 し てCS-807は L-65な どグ ラム陰 性菌 小 さ いED5 値 を示 した そ の 治 療 効 果 は 既 存 の 薬 剤 よ り も優 れ て お り,さ CSaseに 生 性 のC. ン ドール 陽 性 のProteus属,M.mor- 上 廻 る 成 績 で あ っ た E. ML4707,K.pneumoniae どの 抗 菌 力 が 及 ば な か っ た β-lactamase産 も比 鮫的 良 好 な抗 各 菌 種 由来 のPCase, 高 い安 定 性 を有 して お り,こ の こ とが 上 記 菌 種 にR-3763が 良 好 な抗 菌活 性 を示 す 一 因 で あ ろ う さ ら にR-3763はS.auremsのPBPs1,3,4な らび

Table 9 Protective effect on intraneritoneal infections in mice

CHEMOTHERAPY MAY. 1988 antibacterial 1) BILL, N. J. & J. A. WASHINGTON : Comparison of in vitro activity of cephalexin, cephradine, and cefaclor. Antimicrob. Agents Chemother. 11: 470-471, 1977. 2) NEU, H. C. & K. P. Fu : Cefatrizine activity compared with that of other cephalosporins. Antimicrob. Agents Chemother. 15: 209-212, 1979 5) KOMAI, T.; K. FUJIMOTO, M. IWATA, M. SEKINE & H. MASUDA : CS-807, a new orally active cephalosporin. II. Absorption-excretion studies in experimental animals. Program Abstr. Intersci. Conf. Antimicrob. Agents Chemother. 26, abstr. no. 593, 1986 6) SUGAWARA, S. ; M. IWATA, M. TAJIMA, T. MAGAR- IBUCHI, H. YANAGISAWA, H. NAKAO, J. KUMAZAWA & S. KUWAHARA : CS-807, a new orally active cephalosporin. I. In vitro and in vivo Conf. Antimicrob. no. 592, 1986 activities. Program Abstr. Intereci. Agents Chemother. 26, abstr. 9) Ross,-G. W. ; K. V. CHANTER, A. M. HARRIS, S. KIRBY, M. J. MARSHALL & C. H. O'CHALLAGHAN: Comparison of assay technique for beta -lactamase activity. Anal. Biochem. 54: 9-16, 1973 10) WALEY, S. G.: A spectrophotometric assay of fl -lactamase action on penicillins. Biochem. J. 139: 780-789, 1974 11) SPRATT, B. G. & A. B. PARDEE : Penicillin-binding proteins and cell shape in E. coll. Nature 254: 516-517, 1975

ANTIBACTERIAL ACTIVITIES OF CS-807, A NEW ORAL CEPHALOSPORIN YUKIO UTSUI, MATSUHISA INOUE* and SUSUMU MITSUHASHI Episome Institute, Laboratory of Drug Resistance in Bacteria, School of Medicine, Gunma University*, Maebashi The antibacterial activities of CS-807, a new orally absorbable cephalosporin, were compared with those of cephalexin (CEX), cefadroxil (CDX), cefaclor (CCL), amoxicillin (AMPC), cefixime (CFIX), and T-2588. The results are as follows. 1) R-3763, active compound of CS-807, possessed broad antibacterial spectra together with potent activities against both Gram-positive and Gram-negative pathogens, namely, C. freundii, indole-positive Proteus sp., M. morganii, E. cloacae, and S. marcescens insusceptible to CEX, CDX, CCL, and AMPC. Moreover, R -3763 was very active against S. pneumoniae, S. pyogenes, and H. influenzae. 2) The activity of R-3763 was scarcely influenced by changes in ph of medium or co-existence of horse serum in medium, but was slightly affected by an increase in inoculum size. 3) R-3763 showed the potent bactericidal activity (MBC/MIC) against various species of bacteria including potent bactericidal activity of R-3763 at concentrations above the MIC level. 4) R-3763 was highly resistant to hydrolysis by Ĉ-lactamases from various organisms, and its Ĉ-lactamase stability was much higher than that of CEX, CDX, CCL, and AMPC. 5) R-3763 showed high affinity for penicillin-binding proteins (PBPs) 1, 3, 4 of S. aureus, and PBPs 1A, 1 Bs, 3 of E. coli. 6) The therapeutic efficacy of CS-807 against experimental intraperitoneal infections caused by Gram -positive cocci such as S. pneumoniae and S. pyogenes, and Gram-negative bacilli was superior to that of CEX, CDX, CCL, and AMPC. In addition, CS-807 was very active against systemic infection caused by S. marcescens, a Ĉ-lactamase-producing strain, on which orally available fl-lactam antibiotics were not effective.

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