ICAAC. Key words: antibacterial agent development approval. linezolid β. chloramphenicol tetracycline colistin mupirocin teicoplanin

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1 β ICAAC Key words: antibacterial agent development approval Fig. 1 β β β 40 chloramphenicol tetracycline colistin mupirocin teicoplanin linezolid β

2 Numbers of agents cumulative AB BLA CHEM ML AG AB CHEM AG TB ML BLA BLA: -Lactams ML: Macrolides AG: Aminoglycosides AB: Various antibiotics CHEM: Chemotherapeutics TB: Anti-tuberculotic agents Fig. 2. Composition of antibacterial agents currentlyusedinjapan TB BLA: -Lactams CHEM: Chemotherapeutics AB: Various antibiotics ML: Macrolides AG: Aminoglycosides TB: Anti-tuberculotic agents Fig. 1. Transition of antibacterial agents introduced into clinics in Japan nalidixic acid 6 tetracycline minocycline cephalothin cefotaxime 1981 kanamycin 1958 dibekacin 1975 amikacin 1977 erythromycin clarithromycin 1991 clarithromycin ampicillin lenampicillin Fig. 2 β I Fig. 3 Fig

3 Antibacterial agents Antifungal agents Antiviral agents Antiprotozoal agents Numbers of agents Fig. 3. Approval of anti-infective agents in Japan ; Total 66 agents Antibacterial agents Antifungal agents Antiviral agents Antiprotozoal agents 8 Numbers of agents Fig. 4. Approval of anti-infective agents in Japan ; Total 44 agents β β aztreonam imipenem arbekacin clarithromycin roxithromycin

4 Antibacterial agents Antifungal agents Antiviral agents Antiprotozoal agents 9 Numbers of agents Fig. 5. Approval of anti-infective agents in the USA ; Total 53 agents 1998 GCP HIV 10 Fig HIV HIV 200 HIV Fig β β norfloxacin 2 ofloxacin FDA ICH II

5 Japan; 19 agents USA; 17 agents QL AB Misc ML BL QL Misc BL AB ML BL: -Lactams ML: Macrolides AB: Various antibiotics QL: Fluoroquinolones Misc: Other agents Fig. 6. Comparison of approved antibacterial agents between Japan and the USA FDA MRSA VRE FDA 1999 dalfopristin quinupristin 2000 linezolid 2003 daptomycin MRSA MRSA daptomycin MRSA 2 Enterococcus faecalis vancomycin telithromycin 6 3 β 2002 ertapenem

6 Table 1. New antibacterial agents currently under development in Japan Class Agent Formula Phase Company Doripenem S-4661 NDA Shionogi Carbapenem ME1036 CP5609 CS-023 R P-II P-I Meiji Seika Sankyo ME1211 L-084 Oral P-II Meiji Seika Moxifloxacin Bay Oral NDA Bayer Sitafloxacin DU-6859a Oral P-III Daiichi Fluoroquinolone Garenoxacin T-3811E Oral P-III P-I Toyama Chemical DX-619 P-I Daiichi Tetracycline Tigecycline P-I Wyeth NDA: New Drug Application gemifloxacin 2003 FDA 5 10 III Table Table Table FDA Wyeth tigecycline FDA Washington Times Wall Street Journal FDA Wyeth

7 Table 2. New antibacterial agents currently under development in the USA and Europe Class Agent phase; company Cephem Carbapenem Macrolide Streptogramin Tetracycline Glycopeptide / Lipopeptide Rifamycin Fluoroquinolone Peptide deformylase inhibitor Dehydrofolate reductase inhibitor -Lactamase inhibitor BAL5788 P-II; Basilea RWJ P-I; Johnson & Johnson PPI-0903 P-I; Peninsula Doripenem P-III; Peninsula R-1558 = CS023; P-I; Roche OPT-80 P-I; Optimer XRP2868 P-I; Aventis Tigecycline P-III; Wyeth-Ayerst BAY = PTK0796; P-I; Bayer Oritavancin NDA; InterMune Dalbavancin P-II; Vicuron Telavancin P-II; Theravance Ramoplanin P-III; Genome Therapeutics Rifalazil P-II; ActiBiotics Sitafloxacin P-III; Daiichi Garenoxacin P-III; Schering ABT-492 =WQ-3034; P-II; Abbott AVE-6971 P-I; Aventis DX-619 P-I; Daiichi LMB415 P-I; Novartis Iclaprim P-II; Arpida AM-112 P-I; Amura FDA minocycline MRSA VRE tigecycline FDA FDA 2001 Wyeth 4,000 4,000 8,000 Wyeth FDA tigecycline 2004 Table PhRMA IDSA Bristol-Myers Squibb Eli Lilly Abbott Wyeth IDSA Bartlett IV

8 Table 3. Ongoing clinical trials of tigecycline Subject Trial Comparator Study site Community acquired pneumonia; hospitalized cases Randomized, double-blind Pareteral levofloxacin USA: 25 hospitals in 17 States Europe: 39 hospitals in 14 countries Nosocomial pneumonia Randomized, double-blind Imipenem/ cilastatin USA: 23 hospitals in 13 States Serious infections caused by MRSA and VRE Randomized, double-blind Vancomycin or linezolid USA: 30 hospitals in 18 States Complicated intra-abdominal infections Randomized, double-blind Imipenem/ cilastatin USA: 38 hospitals in 25 States Canada and Central/South America: 26 hospitals in 7 countries Serious infections caused by resistant Gram-negative bacteria Open-label, non-comparative None USA: 25 hospitals in 17 States -Lactams Macrolides Peptides Table 4. New antibacterial agents presented at the ICAAC during recent 5 years Miscellaneous antibiotics Pyridone carboxylates Oxazolidinones Miscellaneous antibacterials 1999 a Total Average/year New antibacterial agents: those of pre-ind investigational new drug application ICAAC: Interscience conference on antimicrobial agents and chemotherapy a The numbers include those presented in previous years ASM Interscience Conference on Antimicrobial Agents & Chemotherapy ICAAC ICAAC 1960 cefazolin piperacillin 1980 ICAAC in vitro Vicuron LBM 415 Novartis Paratek PKT0796 Bayer 5 ICAAC Table 4 5 β 13 8 linezolid Chemical Library

9 Combinatorial Chemistry High Throughput Screening Mur A Mra Y t-rna CoA MRSA BLNAR V MRSA PRSP

10 Status and prospects for antibacterial agent development Morimasa Yagisawa Japan Antibiotics Research Association, Kamiosaki, Shinagawa-ku, Tokyo, Japan In the 58 years since penicillin was clinically introduced, 238 antibacterial agents have been used in Japan. Through the alternation of generation and selection, 154 are available today. The majority of current agents are 65 β -lactams and 24 synthetic chemotherapeutics including fluoroquinolones. Taking a general view of approval of antibacterial agents during the last 2 decades, 46 of different classes were approved in the first decade but only 19 of limited classes in the second. Such low activity suggests the need to develop novel antibacterial agents with potential for coping with the alteration of infectious diseases within 5-10 years. Current development of medicinal products including antibacterial agents is conducted globally, simultaneously, and cooperatively. Novel agents created in Japan are often evaluated simultaneously in clinics in Japan, the US and Europe. Unlike Japan, however, the approval of agents in the US in last 10 years is recognized to be preferred to those possessing activity against defined resistant bacteria and being applied to a narrow spectrum of infectious diseases. Philosophies on development of antibacterial agents differ in Japan and the west, i.e., carbapenems and fluoroquinolones dominate over those under development in Japan, while glycopeptide, rifamycin, and others are extensively developed in the US and Europe. Industries involved in the development of antibacterial agents also differ, i.e., are limited to megapharma firms in Japan but, in the US, small industries called biopharma are creating novel agents with novel mechanism of action under unique approaches. The US megapharm firms may take them to clinical development when they have completed their preliminary evaluation. Such novel agents have been evaluated at ICAAC annual meetings sponsored by the American Society for Microbiology, and a great deal of information the trends in development of antibacterial agents is available at the conference.