600mg 600mg CTD 2 2.5

2.5 Page 3 2.5...7 2.5.1...7 2.5.2...27 2.5.3...28 2.5.4...42 2.5.5...55 2.5.6...79 2.5.7...97

2.5 Page 5 73 67 31 48 48A 102 104 105 106 ALP ALT(GPT) AST(GOT) AUC AUEC BID BUN CCDS CE CL C max C 12 COSTART CYP EOT ESRD FDA F-U GCP γ-gtp ITT IV LLN MAO(I) MDRSP ME ME-MRSA MIC MRSA MRSE MRSS MSSA PK PO M/1260/0073 M/1260/0067 M/1260/0031 M/1260/0048 M/1260/0048A 766-INF-0026-102 766-INF-0026-104 766-INF-0026-105 766-INF-0026-106 Alkaline phosphatase Alanine aminotransferase (Glutamic-pyruvic transaminase) Aspartate aminotransferase (Glutamic-oxaloacetic transaminase) 1 2 Blood urea nitrogen Company Core Data Sheet Clinically Evaluable 12 Coding Symbols for Thesaurus of Adverse Reaction Terms FDA Cytochrome P450 P450 End of Treatment End-stage renal disease Food and Drug Administration Follow-Up Good Clinical Practice γ-glutamyl transpeptidase γ- Intent-to-Treat 1 Lower limit of normal Monoamine oxidase (inhibitor) Multidrug-resistant Streptococcus pneumoniae Microbiologically Evaluable MRSA Minimum inhibitory concentration Methicillin - resistant Staphylococcus aureus Methicillin - resistant Staphylococcus epidermidis Methicillin - resistant Staphylococcus Species Methicillin - susceptible Staphylococcus aureus Pharmacokinetics

2.5 Page 6 PRSP PSUR t 1/2 t max TDM ULN V VISA VRE VRSA WBC Penicillin-resistant Streptococcus pneumoniae Periodic Safety Update Report Therapeutic Drug Monitoring Upper limit of normal Vancomycin-intermediate Staphylococcus aureus Vancomycin-resistant Enterococci Vancomycin-resistant Staphylococcus aureus White Blood Cell

2.5.1 Page 7 2.5 2.5.1 2.5.1.1 2.5.1.1.1 PNU-100766/PNU-100766SS 1 Kalamazoo 1 (S)-N-3- -5- -2-1987 E. I. dupont de Nemours and Co., Inc. 5- -2- DuP 105 (s)-[3-(4-(methylsulfinyl)phyenyl)-2-oxo-5-oxazolidinyl]methyl acetamide DuP 721 (s)- [3-(4-acetylphenyl)-2-oxo-5-oxazolidinyl]methyl acetamide 5- -2-1990 eperezolid PNU-100592 linezolid PNU-100766 1 2 eperezolid in vitro 50S 70S 1) 2) 3) 2

2.5.1 Page 8 2-1 4) in vitro MRSA MRSE VRE PISP PRSP 4 µg/ml 1 5 MRSA: Methicillin-resistant Staphylococcus aureus MRSE: Methicillin-resistant Staphylococcus epidermidis VRE: Vancomycin-resistant Enterococcus faecium PISP: Penicillin-intermediate Streptococcus pneumoniae PRSP: Penicillin-resistant Streptococcus pneumoniae

2.5.1 Page 9 1 MIC µg/ml MIC 50 MIC 90 Staphylococcs aureus 0.5 2 0.5 2 1 2 1 2 Staphycoccus epidermidis 1 1 1 2 2 4 Enterococcus faecalis 1 2 1 2 0.5 4 0.5 4 Enterococcus faecium 1 2 1 2 1 2 1 2 0.5 2 1 2 Streptococcus pneumoniae 1 2 2 1 1 2 Streptococcus agalactiae 1 2 1 2 Streptococcus pyogens 1 2 1 2 5 1 3 MRSA 2.7.3.5.3 21 MRSA MIC 2.5.1.1.2 MRSA 1929 A. Fleming 1941 β- MRSA MRSE VRE PRSP 3 100 MRSE 4 耐性化率 (%) 80 60 40 20 0 MRSE 1 MRSA 1 1 PRSP 2 VRE 1 1 GISA 3 1975 1980 1985 1990 1995 2000 1997 // // // // // MRSA 5 PRSP 6 2 // VRE 7 GISA 8 VRSA 9 3 1: National Nosocomial Infection Surveillance (NNIS) 2: TRUST2 project 3: MMWR, (1997) 4, 5, 7: NNISS (2003), 6: McCormick AW et al. (2003), 8: Chang S et al. (2003) 9: MMWR, (2004)

2.5.1 Page 10 MRSA 1 4 β- 2000 1999 65% 6) 1980 MRSA JANIS MRSA 92.6% 2001 7) 2003 1 3.8 8) 4 MRSA MRSA 感染症報告総数 25,000 20,000 15,000 10,000 5,000 0 報告総数月あたり定点あたり 4.00 3.50 3.00 2.50 2.00 1.50 1.00 0.50 0.00 MRSA 感染症の月あたり一定点当たり報告数 1999 2000 2001 2002 2003 4 JANIS MRSA JANIS MRSA MRSA MSSA compromised host β- MRSA MRSA MRSA MRSA 50% 48 25% 9) MSSA Methicillin-susceptible Staphylococcus aureus

2.5.1 Page 13 VISA 1 21), 22) 2002 VRSA 2 23) VRSA 3 24), 25) 2004 VRSA VRSA, VRE MRSA 100% MRSA 2.5.1.2 2.5.1.2.1 Time above MIC MRSA MIC 4 µg/ml 100% 31% P450 MAO MRSA MRSA 1 VISA Vancomycin-intermediate Staphylococcus aureus 2 VRSA Vancomycin-resistant Staphylococcus aureus VRSA 3 meca vana 3 128 µg/ml 64 µg/ml, 64 µg/ml