43 Acontum apoiense

17 19581147 1988 17 2001 A4 A4 H17. 4.20. 3. 1012 131421 IT 50 10,340 11,521 2 3 8 9 9 10 10 15 19 20 21 21 1617 22 23

1904 1928 1940 Nature MRSA MRCNS VREVRSA PRSP BRNAR MDRP ESBL)MBL AmpC Qnr 20MRSA MRSA - - - Extended-spectrum -lactamase: ESBL - --MBL - MBL MBL MRSA - PC-1 1970 MRSA1997 2001 SENTRY MRSA 70%MRSA VRSA VRE1997 VRE VER vanc Enterococcus faecalis, Enterococcus faecium

Enterococcus aviumvanc vanavanb CorynebacteriumLactococcusBacillus E. faecalis vanatn1546 PRSP S R SR1928 SR S RS 1994 DNA PBP PBP PBP PBP - AmblerA BCD A CD ESBLAD ESBL ESBL ESBL ESBL TEM-SHV- A- S. sanguis S. oralis

ESBL ESBLCTX-M- Toho- ESBL CTX-M-- CTX-M- Kluyvera KluyveraCTX- M-99% CTX-M- Kluyvera ESBL ESBLESBL ESBL CTX-M-- ESBL - CTX- M- CTX-M- X- CTX-M- 1940-65 - -PBP - PBP - et al

MBLB MBL MBL MBL 200260 MBL 2% MBL2002 MBL MBL MBL MBL () 3 Clinical and Laboratory Standards Institute MBL MBL MBL Qnr DNA QRDR DNA Qnr Qnr Qnr et al BamSphSmaKpnEcoHind ClaI; EcoXba

ant pneumococci. Microb Drug Resist 1: 29-34. Crook, D. W., and B. G. Spratt. 1998. Multiple antibiotic resistance in Streptococcus pneumoniae. Br Med Bull 54: 595-610. Feil, E. J., and B. G. Spratt. 2001. Recombination and the population structures of bacterial pathogens. Annu Rev Microbiol 55: 561-90. Spratt, B. G. 1994. Resistance to antibiotics mediated by target alterations. Science 264: 388-93. Bradford, P. A. 2001. Extended-spectrum -lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin Microbiol Rev 14: 933-51, table of contents. Bush, K., G. A. Jacoby, and A. A. Medeiros. 1995. A functional classification scheme for -lactamases and its correlation with molecular structure. Antimicrob Agents Chemother 39: 1211-33. Frere, J. M. 1995. -lactamases and bacterial resistance to antibiotics. Mol Microbiol 16: 385-95. Knox, J. R. 1995. Extended-spectrum and inhibitor-resistant TEM-type -lactamases: mutations, specificity, and three-dimensional structure. Antimicrob Agents Chemother 39: 2593-601. Matagne, A., A. Dubus, M. Galleni, and J. M. Frere. 1999. The -lactamase cycle: a tale of selective pressure and bacterial ingenuity. Nat Prod Rep 16: 1-19. Matagne, A., J. Lamotte-Brasseur, and J. M. Frere. 1998. Catalytic properties of class A -lactamases: efficiency and diversity. Biochem J 330 (Pt 2) : 581-98. Nordmann, P., and L. Poirel. 2002. Emerging carbapenemases in Gram-negative aerobes. Clin Microbiol Infect 8: 321-31. Walsh, T. R., M. A. Toleman, L. Poirel, and P. Nordmann. 2005. Metallo--lactamases: the quiet before the storm? Clin Microbiol Rev 18: 306-25. Bonten, M. J., R. Willems, and R. A. Weinstein. 2001. Vancomycin-resistant enterococci: why are they here, and where do they come from? Lancet Infect Dis 1: 314-25. Menichetti, F. 2005. Current and emerging serious Grampositive infections. Clin Microbiol Infect 11 Suppl 3: 22-8. Patel, R. 2003. Clinical impact of vancomycin-resistant enterococci. J Antimicrob Chemother 51 Suppl 3: iii13-21. Coffey, T. J., C. G. Dowson, M. Daniels, and B. G. Spratt. 1995. Genetics and molecular biology of b-lactam-resist- Alba, J., C. Bauvois, Y. Ishii, M. Galleni, K. Masuda, M. Ishiguro, M. Ito, J. M. Frere, and K. Yamaguchi. 2003. A detailed kinetic study of Mox-1, a plasmid-encoded class C -lactamase. FEMS Microbiol Lett 225: 183-8. Alba, J., Y. Ishii, M. Galleni, J. M. Frere, M. Ito, and K. Yamaguchi. 2002. Cefcapene inactivates chromosomeencoded class C -lactamases. J Infect Chemother 8: 207-10. Ibuka, A., A. Taguchi, M. Ishiguro, S. Fushinobu, Y. Ishii, S. Kamitori, K. Okuyama, K. Yamaguchi, M. Konno, and H. Matsuzawa. 1999. Crystal structure of the E166A mutant of extended-spectrum -lactamase Toho-1 at 1.8 A resolution. J Mol Biol 285: 2079-87. Ibuka, A. S., Y. Ishii, M. Galleni, M. Ishiguro, K. Yamaguchi, J. M. Frere, H. Matsuzawa, and H. Sakai. 2003. Crystal structure of extended-spectrum -lactamase Toho-1: insights into the molecular mechanism for catalytic reaction and substrate specificity expansion. Biochemistry 42: 10634-43. Ishii, Y., S. Kimura, J. Alba, K. Shiroto, M. Otsuka, N. Hashizume, K. Tamura, and K. Yamaguchi. 2005. Extended-spectrum -lactamase-producing Shiga toxin gene (Stx1)-positive Escherichia coli O26: H11: a new concern. J Clin Microbiol 43: 1072-5. Ishii, Y., A. Ohno, H. Taguchi, S. Imajo, M. Ishiguro, and H. Matsuzawa. 1995. Cloning and sequence of the gene encoding a cefotaxime-hydrolyzing class A -lactamase isolated from Escherichia coli. Antimicrob Agents Chemother 39: 2269-75. Kimura, S., J. Alba, K. Shiroto, R. Sano, Y. Niki, S. Maesaki, K. Akizawa, M. Kaku, Y. Watanuki, Y. Ishii, and K. Yamaguchi. 2005. Clonal diversity of metallo-lactamase-possessing Pseudomonas aeruginosa in geographically diverse regions of Japan. J Clin Microbiol 43: 458-61. Kimura, S., M. Ishiguro, Y. Ishii, J. Alba, and K. Yamaguchi. 2004. Role of a mutation at position 167 of CTX-M-19 in ceftazidime hydrolysis. Antimicrob Agents Chemother 48: 1454-60. Kojima, A., Y. Ishii, K. Ishihara, H. Esaki, T. Asai, C. Oda, Y. Tamura, T. Takahashi, and K. Yamaguchi. 2005. Extended-Spectrum--Lactamase-Producing Escherichia coli Strains Isolated from Farm Animals from 1999 to

2002: Report from the Japanese Veterinary Antimicrobial Resistance Monitoring Program. Antimicrob Agents Chemother 49: 3533-7. Ma, L., J. Alba, F. Y. Chang, M. Ishiguro, K. Yamaguchi, L. K. Siu, and Y. Ishii. 2005. Novel SHV-derived extendedspectrum b-lactamase, SHV-57, that confers resistance to ceftazidime but not cefazolin. Antimicrob Agents Chemother 49: 600-5. Ma, L., Y. Ishii, F. Y. Chang, K. Yamaguchi, M. Ho, and L. K. Siu. 2002. CTX-M-14, a plasmid-mediated CTX-M type extended-spectrum -lactamase isolated from Escherichia coli. Antimicrob Agents Chemother 46: 1985-8. Ma, L., Y. Ishii, M. Ishiguro, H. Matsuzawa, and K. Yamaguchi. 1998. Cloning and sequencing of the gene encoding Toho-2, a class A -lactamase preferentially inhibited by tazobactam. Antimicrob Agents Chemother 42: 1181-6. Ma, L., H. Matsuo, Y. Ishii, and K. Yamaguchi. 2002. Characterization of cefotaxime-resistant Escherichia coli isolates from a nosocomial outbreak at three geriatric hospitals. J Infect Chemother 8: 155-62. Mercuri, P. S., Y. Ishii, L. Ma, G. M. Rossolini, F. Luzzaro, G. Amicosante, N. Franceschini, J. M. Frere, and M. Galleni. 2002. Clonal diversity and metallo--lactamase production in clinical isolates of Stenotrophomonas maltophilia. Microb Drug Resist 8: 193-200. Shimamura, T., A. Ibuka, S. Fushinobu, T. Wakagi, M. Ishiguro, Y. Ishii, and H. Matsuzawa. 2002. Acyl-intermediate structures of the extended-spectrum class A lactamase, Toho-1, in complex with cefotaxime, cephalothin, and benzylpenicillin. J Biol Chem 277: 46601-8. Takenouchi, T., Y. Ishii, and K. Yamaguchi. 2002. Properties of extended-spectrum -lactamases constructed by site-directed mutagenesis. J Infect Chemother 8: 211-7. 195814 1981 1981 1991 1991 1995 1999 2000 200210 American Society for Microbiology Infection Control Doctor 37 UCLA Pardridge Journal of Nuclear Medicine 20042152 200412 195946 5,700 BBB Pardridge2002 2004 10 BBB BBB

12 274-8555 Tel 047-465-2129 Fax 047-465-2158 URL http://www.pha.nihon-u.ac.jp e-mail nyushi@pha.nihon-u.ac.jp 18 30 30 1815 100 171119 10410 2020 300 1,000 101 18112 102 18 1 103 1811 2 100 4-8-24 JR A20 1730 18 1,000

13 1011 171030 11:0011:30 1-4-1 TEL: 03-5423-7000 12,000 1 1 2122 27485557-7-1 E-mail: t-suzuki@pha.nihon-u.ac.jp TEL&FAX047-465-5877 17 1711 11 500 171120 13 TEL03-3261-9921 22 171126 330 TEL03-3261-9921 TEL047-465-39544027 345 3 TDM CRO PK (Pharmacokinetics)/PD (Pharmacodynamics) TDM

6 649 18 17 43 47 11 30 19 311 18 82 Tubaki System OB 14 ALS 312 17

14 27 29 1126 314 4 17 4 14 T 315 134 17 17 1412 1783 km12km!?

321 29 324 1714 4 2 2 2 325 11

525 10 FDA 211019 1614 1522 11100 535 17 11 10 34 10 1253 170km 18 616 19

14 30 28 LBM 645 1410 D1M2M1 34

1713301630 11322119 40 4 4535 1731 2001728 77 7335

7276 1711 12 17 10 1115 30 MT M 12 M T 1126

1712113 13 126 11 5256 50 267 85 5256 525626 1719 21 1

8 1719 40 52 40 10 18 DVD 16

24 273 78 1718 81 23 36 51 63 The Huges-Tubaki-Barron System 10Centenary Fellow Keisuke TubakiSuperstar

171725 3051260 16 17 12 42 23 1727 34 63 17 13 10 14 12 21 18 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 15 21 10 15 12 19 13 20 14 25 21 30 2005 10 12 21 10 21 12 17 21 14 21 21 16 17

171731 2000,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 4000 6000 10000,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 12000, 20000,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 30000 50000 70000 16 1,,,,,,,,,,,,,,,, 16 16

15,,,, 16, 17 15,, 16, 17,,,,,, 16,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 17,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 15,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 16,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 17,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 171015 TEL 0332678056 771 274-8555 FAX 0474651478 00140053798