The Complete Guide to Anti-infectives

Therapeutic

The total global anti-infective market is currently estimated at $25 billion, and it is expected to grow in the next few years. From 1999-2004 a number of patents on leading antibacterial products will expire, making the marketplace highly competitive. In addition, the continuing increase in antimicrobial drug resistance and the emergence of new pathogens underline the need for new agents. It is essential that all companies involved in the anti-infective market are prepared for these developments.


The Complete Guide to Anti-infectives provides all the information you need to address both current and future market trends. It is written by Gerry Halls, a leading expert with over 13 years experience in the anti-infective field, which included his creation of the IMS Hospital Anti-Infective Audit.


This report will enable you to:


Price: �995/$1,995/�239,000
Published: July 1999
Pages: 200+
Ref: BS1022E



CONTENTS
LIST OF TABLES
LIST OF FIGURES
ACKNOWLEDGEMENTS
EXECUTIVE SUMMARY
ES.1 Introduction
ES.2 Bacterial infection, resistance and treatment guidelines
ES.3 The antibiotic pipeline
ES.4 The antifungal market
ES.5 The antiviral market
ES.6 Pharmacokinetics, pharmacodynamics and evolving regulatory requirements
ES.7 The market structure
ES.8 Company profiles
ABBREVIATIONS AND GLOSSARY


CHAPTER 1 INTRODUCTION
1.1 Resistance to antimicrobials
1.2 Emergence of opportunistic infections

CHAPTER 2 BACTERIAL INFECTIONS
2.1 Aerobic pathogenic bacteria
2.1.1 Gram-positive bacterial pathogens
2.1.1.1 Staphylococci
2.1.1.2 Enterococci
2.1.1.3 Streptococci
2.1.1.4 Mycobacteria
2.1.2 Gram-negative bacterial pathogens
2.1.2.1 Haemophilus influenzae
2.1.2.2 Moraxella catarrhalis
2.1.2.3 Borrelia burgdorferi
2.1.2.4 Enterobacteriaceae
2.1.2.5 Pseudomonas aeruginosa
2.1.2.6 Other non-fermenting Gram-negative bacilli
2.1.2.7 Helicobacter pylori
2.1.2.8 Legionellae
2.1.2.9 Chlamydiae
2.2 Anaerobic pathogenic bacteria
2.3 Mycoplasmas
2.4 Bacterial resistance
2.4.1 Resistance mechanisms
2.5 Clinical guidelines
2.5.1 Pneumonia
2.5.2 Acute exacerbations of chronic bronchitis/obstructive pulmonary disease
2.5.3 Acute otitis media
2.5.4 Fever of unknown origin in neutropaenic patients
2.5.5 Vancomycin usage

CHAPTER 3 ANTIBIOTIC RESEARCH PIPELINE
3.1 Tetracyclines
3.1.1 Introduction
3.1.2 Mechanism of action and resistance
3.1.3 New molecules
3.1.3.1 GAR-936 (Wyeth-Ayerst)
3.1.3.2 WAY 152,288 (Wyeth-Ayerst)
3.2 Cephalosporins
3.2.1 Introduction
3.2.2 Mechanism of action and resistance
3.2.3 New molecules
3.2.3.1 MC-02479 (Microcide, Johnson & Johnson)
3.2.3.2 Ro-639141 (Roche)
3.2.3.3 TOC-50, TOC-39 (Taiho)
3.2.3.4 PGE-7119699 and PGE-7594630 (Proctor & Gamble)
3.2.3.5 CKD-604 (Chong Kun Dang, Korea Institute of Science and Technology)
3.2.3.6 LB-10522 (LG Chemical)
3.3 Macrolides and similar compounds
3.3.1 Introduction
3.3.2 Mechanism of action and resistance
3.3.3 New molecules
3.3.3.1 Telithromycin (formerly HMR-3647, ketolide, Hoechst Marion Roussel)
3.3.3.2 CP-544372 (erythromycylamine, Pfizer)
3.3.3.3 CP-279107 (erythromycylamine, Pfizer)
3.3.3.4 ABT-773 (formerly A-165600, ketolide, Abbott)
3.3.3.5 A-179796 (3-descladinosyl macrolide, Abbott)
3.3.3.6 TEA-0769 (acylide, Taisho)
3.4 Quinolones and analogues
3.4.1 Introduction
3.4.2 Mechanism of action and resistance
3.4.3 Structure-activity relationships: activity and toxicity
3.4.3.1 Activity
3.4.3.2 Toxicity and safety profile
3.4.4 New fluoroquinolones: recently launched and pipeline products
3.4.4.1 Levofloxacin (Cravit, Daiichi; Levaquin, Johnson & Johnson; Tavanic, Hoechst Marion Roussel)
3.4.4.2 Grepafloxacin (Lungaskin, Otsuka; Raxar, Glaxo Wellcome)
3.4.4.3 Trovafloxacin (Trovan, Pfizer)
3.4.4.4 Moxifloxacin (Avelox, Bayer)
3.4.4.5 Gatifloxacin (Tequin, Kyorin, Gr�nenthal, Bristol-Myers Squibb)
3.4.4.6 Prulifloxacin (Quisnon, Nippon Shinyaku, Meiji Seika, undisclosed licensee in Europe)
3.4.4.7 Pazufloxacin (Pasil, Toyama, Yoshitomi)
3.4.4.8 Clinafloxacin (Warner-Lambert)
3.4.4.9 LB-20304a (LG Chemical)/SB-265805 (SmithKline Beecham)
3.4.4.10 Sitafloxacin (Daiichi, Beijing General)
3.4.4.11 DW-116 (Dong Wha)
3.4.4.12 HSR-903 (Knoll)
3.4.4.13 Caderofloxacin (CS-940, Ube, Sankyo)
3.4.4.14 T-3811 (Toyama, Bristol-Myers Squibb)
3.4.4.15 DC-756 (Daiichi)
3.4.4.16 CFC-222 (Cheil Jedang)
3.4.4.17 WQ-3034 (Wakunaga)
3.4.4.18 WQ-2743 (Dainippon)
3.4.4.19 A-165753, A-170568 (Abbott)
3.4.4.20 Y-34867 (Yoshitomi)
3.4.4.21 CJ-13136 (Pfizer)
3.4.4.22 S-34109 (Kaken)
3.5 Aminoglycosides
3.5.1 Introduction
3.5.2 New developments
3.5.2.1 MiKasome (liposomal amikacin, NeXstar)
3.5.2.2 DepoFoam amikacin (DepoTech)
3.5.2.3 TOBI (tobramycin solution, PathoGenesis)
3.6 Glycopeptides
3.6.1 Introduction
3.6.2 Mechanism of action and resistance
3.6.3 New molecules
3.6.3.1 Daptomycin (Cubist)
3.6.3.2 Ramoplanin (Biosearch Italia)
3.6.3.3 LY-333328 (Eli Lilly)
3.7 Other (-lactams
3.7.1 Introduction
3.7.2 New molecules
3.7.3 Carbapenems
3.7.3.1 MK-826 (L-749345, Merck & Co)
3.7.3.2 S-4661 (Shionogi)
3.7.3.3 CS-834 (Sankyo)
3.7.3.4 L-084 (American Home Products)
3.7.3.5 OCA-983 (American Home Products)
3.7.3.6 KR-21056 (Korean Chemical Research Institute)
3.7.3.7 J-111225, J-114870, J-114871 (Banyu, Merck & Co)
3.7.4 Monobactams
3.7.4.1 PA-1806 (Bristol-Myers Squibb, PathoGenesis)
3.7.5 Penems
3.7.5.1 Ritipenem (Pharmacia & Upjohn, Tanabe Seiyaku)
3.7.5.2 Faropenem (Suntory, Yamanouchi)
3.7.5.3 SB-206999-Z (SmithKline Beecham)
3.7.6 Trinems
3.7.6.1 GV-143253 (Glaxo Wellcome)
3.7.6.2 SR-15402 (SRI International)
3.8 Other Gram-positive antibiotics
3.8.1 Streptogramins
3.8.1.1 Quinupristin/dalfopristin (Synercid), Rh�ne-Poulenc Rorer
3.8.2 Oxazolidinones
3.8.2.1 Linezolid (Zyvox, Pharmacia & Upjohn)
3.8.2.2 Eprezolid (Pharmacia & Upjohn)
3.8.2.3 Other oxazolidinones
3.8.3 Everninomicins
3.8.3.1 Sch-27899 (Ziracin, Schering-Plough)
3.9 Other Gram-negative antibiotics
3.9.1 (-lactamase inhibitors
3.9.1.1 Introduction
3.9.1.2 Syn-2190 (SynPhar)
3.9.1.3 J-110441 (Banyu, Merck & Co)
3.9.1.4 SB-252619 (SmithKline Beecham)
3.9.1.5 Research Corporation Technologies
3.10 Peptide antibiotics
3.10.1 Introduction
3.10.2 Mechanism of action and resistance
3.10.3 Classes of peptides
3.10.4 Spectrum of activity
3.10.5 New molecules
3.10.5.1 Pexiganan acetate (Locilex, Magainin)
3.10.5.2 rBPI-21 (Neuprex, Xoma)
3.10.5.3 MBI-226 (Micrologix Biotech)
3.10.5.4 IB-367 (IntraBiotics, Pharmacia & Upjohn)
3.10.5.5 Nisin (AMBI, AstraZeneca, Azwell)
3.10.5.6 Defensins (Biosource Technologies)
3.10.5.7 WAP-8294A2 (Wakamoto Pharmaceuticals, Nippon Medical Research)
3.10.5.8 M-636 (Ramot)
3.10.5.9 Loloatin-B (Ocean)
3.10.5.10 Other peptide agents
3.11 Rifampicin/rifamycin and other antimycobacterials
3.11.1 Introduction
3.11.2 New molecules
3.11.2.1 Rifalazil (Kaneka)
3.11.2.2 Perillyl alcohol (Wisconsin Genetics (Endorex))
3.11.2.3 SPA-S-565 (SPA, Glaxo India)
3.11.2.4 T-9 (NIHFI)
3.11.2.5 PA-824 (PathoGenesis)
3.11.2.6 ABT-255 (Abbott)
3.11.2.7 BM-212 (University of Cagliari)
3.11.2.8 Other research leads
3.12 New targets
3.12.1 Two-component systems (R W Johnson)
3.12.2 Efflux pump inhibitors (Microcide)
3.12.3 Mur ligases (Versicor)
3.12.4 femABX genes (Bayer)
3.12.5 SecA (Cubist and Wyeth-Ayerst)
3.12.6 Coenzyme A reductase (Maxygen Inc)
3.12.7 RNase P (Cubist)
3.12.8 ppGpp metabolism (RiboGene)
3.12.9 Dihydroneopterin aldolase (Roche)
3.12.10 Deformylase inhibition (Versicor)
3.12.11 Aminoacyl tRNA synthetase inhibitors
3.12.12 Protease inhibitors (Siga)
3.12.13 Quorum sensing

CHAPTER 4 FUNGAL INFECTIONS AND FUNGAL PATHOGENS
4.1 Dermatophytes
4.2 Yeasts
4.2.1 Candida species
4.2.2 Cryptococcus neoformans
4.2.3 Pneumocystis carinii
4.3 Dimorphic fungi
4.3.1 Histoplasma capsulatum
4.3.2 Coccidioides immitis
4.3.3 Blastomyces dermatitidis
4.3.4 Paracoccidioides brasiliensis
4.3.5 Sporothrix schenckii
4.4 Filamentous moulds
4.5 Dematiaceous fungi
4.6 Zygomycoses
4.7 Mechanisms of action and resistance
4.8 Development of existing compounds
4.8.1 Lipid formulations of amphotericin B
4.8.1.1 Amphotericin B lipid complex (Ablecet; The Liposome Company)
4.8.1.2 Amphotericin B colloidal dispersion (Amphotec, Sequus)
4.8.1.3 Liposomal amphotericin B (AmBisome, NeXstar)
4.8.1.4 Health economics issues with lipid formulations
4.8.2 Terbinafine in systemic mycosis
4.9 Clinical guidelines for the management of fungal infections
4.9.1 Invasive aspergillosis
4.9.1.1 Prevention
4.9.1.2 Diagnosis and screening
4.9.1.3 Treatment
4.10 Pipeline compounds: new antifungal agents
4.10.1 Triazoles
4.10.1.1 Voriconazole (Pfizer)
4.10.1.2 Sch-56592 (Schering-Plough)
4.10.1.3 BMS-207147/ER-30346 (Bristol-Myers Squibb/Eisai)
4.10.1.4 Syn-2869 (SynPhar (Taiho))
4.10.1.5 UR-9825 (Uriach)
4.10.1.6 Z-11679D (Zambon)
4.10.1.7 SSY-726 (SSP, Yoshitomi)
4.10.1.8 TAK-187 (Takeda)
4.10.1.9 (2R,4S)-itraconazole (Sepracor)
4.10.2 (-1,3-glucan synthetase inhibitors
4.10.2.1 MK-991 (Merck & Co)
4.10.2.2 LY-303366 (Eli Lilly)
4.10.2.3 FK-463 (Fujisawa)
4.10.2.4 FR-901469 (Fujisawa)
4.10.3 Other new antifungal agents
4.10.3.1 Nikkomycin Z (SP-920704; Shaman Pharmaceuticals)
4.10.3.2 GM-222712 (Glaxo Wellcome)
4.10.3.3 Cepacidine A (Cheil Jedang)
4.10.3.4 YM-170320 (Yamanouchi)
4.10.4 New polyenes
4.10.4.1 3874-H3 (Hoechst Marion Roussel)
4.10.4.2 Amphotericin B conjugate (Hadassah University)
4.10.5 New formulations
4.10.5.1 Liposomal nystatin (Nyotran; Aronex Pharmaceuticals, Abbott)
4.10.6 New targets
4.10.6.1 Sterol methyltransferase
4.10.6.2 D-cecropin B
4.10.6.3 BAY-10-8888 (Bayer)
4.10.6.4 (-1,6-glucan synthesis inhibitors (Alpha-Beta Technology)
4.10.6.5 Cell wall assembly inhibitors (Alpha-Beta Technology)
4.10.6.6 Cell wall integrity inhibitors (Mitotix)
4.10.6.7 Cell wall synthesis inhibitors (Oxford GlycoSciences)
4.10.6.8 Conjugated styryl ketones
4.10.6.9 CAN-296 (IGG International)

CHAPTER 5 VIRUSES
5.1 Viruses and viral infections
5.2 Herpes and similar viruses
5.2.1 Herpes simplex and varicella zoster
5.2.2 Cytomegalovirus
5.2.3 Epstein-Barr virus
5.3 Hepatitis
5.3.1 Hepatitis A
5.3.2 Hepatitis B
5.3.3 Hepatitis C
5.3.4 Hepatitis D
5.3.5 Hepatitis E
5.3.6 Hepatitis G
5.4 Human immunodeficiency virus
5.4.1 Recent trends
5.4.2 Epidemiology
5.4.3 Treatment guidelines: starting therapy
5.4.4 Treatment guidelines: changing therapy that is failing
5.4.5 Treatment in the developing world
5.5 Influenza
5.6 Respiratory syncytial virus
5.7 Picornaviruses
5.7.1 Enteroviruses
5.7.2 Rhinoviruses
5.7.3 Coronaviruses
5.8 Antivirals: mechanism of action and resistance
5.8.1 DNA polymerase inhibitors
5.8.1.1 Inhibitors of herpesvirus DNA polymerases
5.8.2 Antiretrovirals
5.8.2.1 Nucleoside reverse transcriptase inhibitors
5.8.2.2 Non-nucleoside reverse transcriptase inhibitors
5.8.2.3 Protease inhibitors
5.8.3 Resistance to antiretrovirals
5.9 HIV: pipeline products
5.9.1 Nucleoside reverse transcriptase inhibitors
5.9.1.1 Ziagen (abacavir; Glaxo Wellcome)
5.9.1.2 Triple combination Epivir/Retrovir/Ziagen (Glaxo Wellcome)
5.9.1.3 Coviracil (emtricitabine (FTC), Triangle Pharmaceuticals)
5.9.1.4 Lodenosine (US Bioscience)
5.9.1.5 Phosfazid (Viscount Pharma)
5.9.1.6 BCH-10652 (dOTC; BioChem Pharma)
5.9.1.7 D-DF4C (Emory University)
5.9.2 Nucleotide reverse transcriptase inhibitors
5.9.2.1 Preveon (adefovir dipivoxil; Gilead Sciences)
5.9.2.2 GS-4331 (bis (POC) PMPA; Gilead Sciences)
5.9.3 Non-nucleoside reverse transcriptase inhibitors
5.9.3.1 Efavirenz (Sustiva/Stocrin; Merck & Co, DuPont)
5.9.3.2 MKC-442 (Coactinon; Mitsubishi Chemical, Triangle)
5.9.3.3 AG-1549 (formerly S-1153; Shionogi, Agouron)
5.9.3.4 GW-420867 (Glaxo Wellcome)
5.9.3.5 PNU-142721 (Pharmacia & Upjohn)
5.9.3.6 Calanolide A (NIH, MediChem Research, Vita-Invest)
5.9.3.7 PETT compounds (Medivir AB, Abbott)
5.9.3.8 DMP-961, DMP-963 (DuPont)

5.9.4 Protease inhibitors
5.9.4.1 Amprenavir (Agenerase; Vertex Pharmaceuticals, Glaxo Wellcome, Kissei)
5.9.4.2 Tipranavir (PNU-140690; Pharmacia & Upjohn)
5.9.4.3 ABT-378 (Abbott)
5.9.4.4 DMP-450 (Triangle)
5.9.4.5 BMS-232632 (Bristol-Myers Squibb)
5.9.4.6 PD-178390 (Parke-Davis)
5.9.4.7 AG-1776 (Japan Energy, Agouron)
5.9.4.8 Fosamprenavir and third-generation protease inhibitors (Vertex)
5.9.5 Other approaches
5.9.5.1 Remune (AG-1661; Immune Response, Agouron)
5.9.5.2 Hydroxyurea (Bristol-Myers Squibb)
5.9.6 New targets
5.9.6.1 Pentafuside (Trimeris)
5.9.6.2 Zintevir (Aronex)
5.9.6.3 Integrase inhibitor (Agouron)
5.9.6.4 Antisense nucleotides (ISIS Pharmaceuticals)
5.9.6.5 HIV gene therapy (Intracel)
5.9.6.6 Intrabodies (Chiron)
5.9.6.7 Anti-HIV fusion protein (Idun)
5.9.6.8 CCR5 antagonists
5.9.6.9 CI-1012 (Parke-Davis)
5.10 Herpes and similar viruses: pipeline products
5.10.1 Genvir (aciclovir, Micropump; Flamel Technologies)
5.10.2 Valganciclovir (Roche)
5.10.3 GEM-132 (Hybridon)
5.10.4 Maribavir (Glaxo Wellcome)
5.10.5 ABT-606 (Medivir AB, Abbott)
5.10.6 GS-930 (Gilead Sciences)
5.10.7 ISIS-13312 (ISIS Pharmaceuticals)
5.10.8 Aciclovir (ES-Gel; Bioglan Laboratories)
5.10.9 NNU-023 (Nippon Kayaku)
5.10.10 SR-3775 (SRI International)
5.10.11 Ro-32-4397 (Roche)
5.10.12 BILS 45 BS (Bio-Mega)
5.10.13 T-157602 (Tularik)
5.10.14 Monobactams (Boehringer Ingelheim)
5.10.15 IE inhibitors (Signal)
5.11 Respiratory syncytial virus: pipeline products
5.11.1 RD3-0028 (Kuraray)
5.11.2 T-786 (Trimeris)
5.12 Influenza: pipeline products
5.12.1 Relenza (zanamivir; Glaxo Wellcome)
5.12.2 Oseltamivir (Roche)
5.12.3 VP-14221 (ViroPharma)
5.13 Picornaviruses: pipeline products
5.13.1 Pleconaril (ViroPharma)
5.14 Rhinoviruses: pipeline products
5.14.1 AG-7088 (rhinovirus protease inhibitor; Agouron)
5.15 Hepatitis B: pipeline products
5.15.1 Zeffix (lamivudine; Glaxo Wellcome)
5.15.2 Coviracil (emtricitabine (FTC), Triangle Pharmaceuticals)
5.15.3 BMS-200475 (Bristol-Myers Squibb)
5.15.4 DAPD (Triangle Pharmaceuticals)
5.15.5 L-FMAU (Triangle Pharmaceuticals)
5.15.6 DW-471 (Dong Wha)
5.15.7 Famciclovir

5.16 Hepatitis C: pipeline products
5.16.1 VX-497 (Vertex)
5.16.2 Ro-326167 (Roche)
5.16.3 HCV protease and helicase inhibitors (Vertex)

CHAPTER 6 ESTABLISHING COMPETITIVE ADVANTAGE: RECENT AND EMERGING TRENDS AND REGULATORY ASPECTS
6.1 Pharmacokinetics and pharmacodynamics
6.1.1 Area under the inhibitory curve
6.2 Rapid susceptibility testing
6.3 Recent developments in regulatory aspects
6.3.1 US guidance
6.3.2 European guidance
6.3.2.1 Antibacterial agents
6.3.2.2 Antiviral agents
6.3.2.3 Additional considerations for antiretrovirals for HIV infections

CHAPTER 7 MARKET STRUCTURE
7.1 The antibacterial market
7.1.1 Sales and growth
7.1.2 Market structure
7.1.3 Leading antibiotic products
7.1.4 Leading pharmaceutical companies
7.1.5 Leading antibiotic classes
7.1.5.1 Hospitals
7.1.5.2 Primary care antibiotic usage
7.1.6 Leading diagnoses for antibiotics
7.1.6.1 Community-acquired pneumonia
7.1.6.2 Otitis media
7.1.6.3 Leading diagnoses in hospitals
7.1.7 Forecasts for the antibiotic market
7.1.7.1 Pipeline products: winners and losers
7.2 Antifungal market structure
7.2.1 Sales and growth
7.2.2 Forecasts
7.3 Antiviral market
7.3.1 Sales potential
7.3.2 The HIV market
7.3.2.1 Nucleoside reverse transcriptase inhibitors
7.3.2.2 Non-nucleoside reverse transcriptase inhibitors
7.3.2.3 Protease inhibitors
7.3.3 The HIV market: forecasts: pipeline products
7.3.3.1 Nucleoside reverse transcriptase inhibitors
7.3.3.2 Non-nucleoside reverse transcriptase inhibitors
7.3.3.3 Protease inhibitors
7.3.3.4 Other approaches: Remune

CHAPTER 8 COMPANY PROFILES
8.1 Abbott Laboratories
8.1.1 Marketed anti-infectives
8.1.2 Licensing contacts
8.2 American Home Products
8.2.1 Marketed anti-infectives
8.2.2 Licensing contacts
8.3 Bayer AG
8.3.1 Marketed anti-infectives
8.3.2 Licensing contact
8.4 Bristol-Myers Squibb
8.4.1 Marketed anti-infectives
8.4.2 Licensing contact
8.5 Cheil Jedang Corporation
8.5.1 Marketed anti-infectives
8.5.2 Licensing contact
8.6 Cubist Pharmaceuticals Inc
8.7 Daiichi Pharmaceutical
8.7.1 Marketed anti-infectives
8.7.2 Licensing contact
8.8 DuPont Pharmaceuticals
8.8.1 Marketed anti-infectives
8.8.2 Licensing contact
8.9 Eisai Co Ltd
8.9.1 Marketed anti-infectives
8.9.2 Licensing contacts
8.10 Fujisawa Pharmaceutical Co Ltd
8.10.1 Marketed anti-infectives
8.11 Gilead Sciences Inc
8.11.1 Licensing contact
8.12 Glaxo Wellcome
8.12.1 Marketed anti-infectives
8.12.2 Licensing contact
8.13 Hoechst Marion Roussel AG
8.13.1 Marketed anti-infectives
8.13.2 Licensing contact
8.14 Johnson & Johnson
8.14.1 Marketed anti-infectives
8.14.2 Licensing contacts
8.15 LG Chemical Ltd
8.15.1 Licensing contact
8.16 Eli Lilly
8.16.1 Marketed anti-infectives
8.16.2 Licensing contact
8.17 Magainin Pharmaceuticals
8.17.1 Licensing contact
8.18 Merck & Co
8.18.1 Marketed anti-infectives
8.19 Microcide Pharmaceuticals Inc
8.19.1 Licensing contact
8.20 Novartis
8.20.1 Marketed anti-infectives
8.21 PathoGenesis Corporation
8.21.1 Licensing contact
8.22 Pfizer Inc
8.22.1 Marketed anti-infectives
8.23 Pharmacia & Upjohn
8.23.1 Marketed anti-infectives
8.23.2 Licensing contact
8.24 Procter & Gamble
8.24.1 Marketed anti-infectives
8.24.2 Licensing contact
8.25 Ramot
8.25.1 Licensing contact
8.26 Rh�ne-Poulenc Rorer
8.26.1 Marketed anti-infectives
8.26.2 Licensing contacts
8.27 RiboGene
8.27.1 Licensing contact
8.28 Roche
8.28.1 Marketed anti-infectives
8.28.2 Licensing contacts
8.29 Sankyo
8.29.1 Marketed anti-infectives
8.29.2 Licensing contact
8.30 Schering-Plough
8.30.1 Marketed anti-infectives
8.30.2 Licensing contacts (for prescription pharmaceuticals)
8.31 Scriptgen Pharmaceuticals
8.31.1 Licensing contact
8.32 Sepracor
8.32.1 Versicor
8.33 SmithKline Beecham
8.33.1 Marketed anti-infectives
8.33.2 Licensing contacts
8.34 Taiho Pharmaceutical Co
8.34.1 Licensing contact
8.35 Takeda
8.35.1 Marketed anti-infectives
8.35.2 Licensing contact
8.36 Toyama
8.36.1 Marketed anti-infectives
8.36.2 Licensing contact
8.37 Uriach
8.37.1 Licensing contact
8.38 Warner-Lambert
8.38.1 Marketed anti-infectives
8.38.2 Licensing contact
8.39 Zambon
8.39.1 Licensing contact
APPENDIX I DIRECTORY OF COMPANIES
APPENDIX II CONFERENCE CALENDAR
REFERENCES

LIST OF TABLES
Table 2.1 Susceptibility of MRSA to antibiotics other than glycopeptides
Table 2.2 Prevalence of methicillin resistance in S. aureus
Table 2.3 Pathogen prevalence in bloodstream infections in Europe
Table 2.4 Susceptibility of enterococci causing endocarditis in UK
Table 2.5 Susceptibility of S. pneumoniae in Spain (1996-1997)
Table 2.6 Annual incidence of meningococcal and Hib invasive disease in Spain
Table 2.7 Simplified classification of (-lactamases
Table 2.8 ATS treatment guidelines for pneumonia
Table 2.9 IDSA treatment guidelines for pneumonia
Table 2.10 Risk class mortality rates in CAP
Table 2.11 Proposed new guidelines for management of AECOPD
Table 2.12 Definition of neutropaenic FUO
Table 2.13 Pathogen prevalence in microbiologically-defined infection in neutropaenic patients
Table 3.1 Principal properties of cephalosporins by generation
Table 3.2 Classification of cephalosporins by generation
Table 3.3 New cephalosporins in preclinical development
Table 3.4 Classification of macrolides
Table 3.5 Macrolide development pipeline
Table 3.6 Marketed quinolones
Table 3.7 Quinolone development pipeline
Table 3.8 Primary targets of quinolones
Table 3.9 Quinolone structure-activity relationships
Table 3.10 Relative in vitro potency of new quinolones versus S. pneumoniae
Table 3.11 Comparative hospital formulary acceptance levels in the US
Table 3.12 Glycopeptide resistance in enterococci: the 'van alphabet'
Table 3.13 Glycopeptide development pipeline
Table 3.14 (-lactam development pipeline
Table 3.15 (-lactamase inhibitor research leads
Table 3.16 Classes of cationic peptides
Table 3.17 Development status of antibacterial peptides
Table 3.18 Antitubercular product pipeline
Table 4.1 Classification of fungal infections and causative organisms
Table 4.2 Typical duration of treatment for dermatophyte infections
Table 4.3 Species distribution of Candida bloodstream isolates - US
Table 4.4 Species distribution of Candida bloodstream isolates - US, Canada, South America
Table 4.5 Incidence of candidaemia in French hospitals, 1995
Table 4.6 Distribution of endemic mycoses
Table 4.7 Impact of amphotericin B-induced nephrotoxicity on hospital costs
Table 4.8 Clinical and economic comparison of ABLC and amphotericin B
Table 4.9 Comparative representative pharmacokinetic parameters of investigational triazoles
Table 4.10 Triazole development pipeline
Table 4.11 Clinical response to voriconazole in neutropaenic invasive aspergillosis
Table 4.12 Development pipeline for (-1,3-glucan synthetase inhibitors and other antifungals
Table 4.13 Susceptibility of yeasts to MK-991 from Phase II trials
Table 5.1 HIV/AIDS: the global epidemic
Table 5.2 HIV/AIDS by region
Table 5.3 Age distribution of AIDS cases in the US
Table 5.4 AIDS rates per million population, Europe
Table 5.5 Classes of NRTIs
Table 5.6 NRTI development pipeline
Table 5.7 Marketed NNTRIs - the pill count
Table 5.8 NNRTI development pipeline
Table 5.9 Cumulative risk of developing lipodystrophy on PI therapy
Table 5.10 Effect of PI-containing regimens on serum cholesterol
Table 5.11 Marketed protease inhibitors - the pill count and dietary restrictions
Table 5.12 Interactions of protease inhibitors
Table 5.13 The protease inhibitor development pipeline
Table 5.14 Antivirals for herpesvirus and cytomegalovirus development pipeline
Table 5.15 Hepatitis B antiviral development pipeline
Table 5.16 Hepatitis C antiviral development pipeline
Table 6.1 Classification of antibiotics by kill-type
Table 6.2 Relationship between AUIC and response rates
Table 6.3 Comparative AUICs for new fluoroquinolones versus S. pneumoniae, corrected for protein binding
Table 6.4 Example of a SPC stating susceptible organisms and range of resistance in EU
Table 6.5 Added value for 'approval under exceptional circumstances' of antiretrovirals
Table 7.1 Leading therapy classes, 1998
Table 7.2 The anti-infective market ($ billion)
Table 7.3 Top 10 selling anti-infectives, 1998
Table 7.4 Top 10 anti-infective companies, 1998 sales
Table 7.5 Leading antibiotic products ranked on 1998 sales
Table 7.6 Patent expiry dates for leading antibiotics
Table 7.7 Importance of antibiotics to leading companies, 1998
Table 7.8 Antibiotic usage in US hospitals, 1998
Table 7.9 Antibiotic usage in German hospitals, 1998
Table 7.10 Population standardised hospital antibiotic usage, US and Germany, 1998
Table 7.11 Systemic antibiotic prescriptions in the US
Table 7.12 Hospitalisation of pneumonia patients
Table 7.13 Leading diagnoses for antibiotics in US hospitals, 1998
Table 7.14 Leading diagnoses for antibiotics in German hospitals, 1998
Table 7.15 Extent of early discharge on antibiotic therapy in Europe (1990/1991)
Table 7.16 Sales estimates and pipeline potential for quinolones
Table 7.17 Sales estimates and pipeline potential for macrolides
Table 7.18 Sales estimates and pipeline potential for other (-lactams
Table 7.19 Sales estimates and pipeline potential for Gram-positive antibiotics
Table 7.20 Estimated sales of leading antifungals ($ million)
Table 7.21 Patent expiry dates for leading antifungals
Table 7.22 Sales estimates and pipeline potential for antifungals
Table 7.23 The HIV market sales, 1990-1998
Table 7.24 Sales of NRTIs ($ million), 1990-1998
Table 7.25 Sales of NNRTIs ($ million), 1996-1998
Table 7.26 Sales of protease inhibitors ($ million), 1996-1998
Table 7.27 Sales estimates and pipeline potential for selected NRTIs
Table 7.28 Sales estimates and pipeline potential for NNRTIs
Table 7.29 Sales estimates and pipeline potential for protease inhibitors
Table 7.30 Sales estimates for Remune
Table 8.1 Abbott's financial performance ($ million)
Table 8.2 AHP's financial performance ($ million)
Table 8.3 Bayer's financial performance (DM million)
Table 8.4 Bristol-Myers Squibb's financial performance ($ million)
Table 8.5 Cheil Jedang's financial performance (Won billion)
Table 8.6 Cubist's financial performance ($ 000)
Table 8.7 Daiichi's financial performance (� million )
Table 8.8 DuPont's financial performance ($ million)
Table 8.9 Eisai's financial performance (� million)
Table 8.10 Fujisawa's financial performance (� million)
Table 8.11 Gilead's financial performance ($ 000)
Table 8.12 Glaxo Wellcome's financial performance (� million)
Table 8.13 Hoechst Group's financial performance (DM million)
Table 8.14 Johnson & Johnson's financial performance ($ million)
Table 8.15 LG Chemical's financial performance ($ million)
Table 8.16 Eli Lilly's financial performance ($ million)
Table 8.17 Magainin's financial performance ($ 000)
Table 8.18 Merck & Co's financial performance ($ million)
Table 8.19 Microcide's financial performance ($ million)
Table 8.20 Novartis' financial performance (SFr million)
Table 8.21 PathoGenesis' financial performance ($ 000)
Table 8.22 Pfizer's financial performance ($ million)
Table 8.23 Pharmacia & Upjohn's financial performance ($ million)
Table 8.24 Procter & Gamble's financial performance ($ million)
Table 8.25 Rh�ne-Poulenc Rorer's financial performance (FFr million)
Table 8.26 RiboGene's financial performance ($ 000)
Table 8.27 Roche's financial performance (SFr million)
Table 8.28 Sankyo's financial performance (� million)
Table 8.29 Schering-Plough's financial performance ($ million)
Table 8.30 Sepracor's financial performance ($ 000)
Table 8.31 SmithKline Beecham's financial performance (� million)
Table 8.32 Taiho's financial performance (� million)
Table 8.33 Takeda's financial performance (� million)
Table 8.34 Toyama's financial performance (� million)
Table 8.35 Uriach's financial performance (Pst million)
Table 8.36 Warner-Lambert's financial performance ($ million)
Table 8.37 Zambon's financial performance (L million)


LIST OF FIGURES
Figure 3.1 Quinolone structure
Figure 3.2 Structure of T-3811
Figure 5.1 Deaths due to AIDS in the US, 1992-1997
Figure 5.2 Deaths due to AIDS by race/ethnicity in the US
Figure 5.3 Percentage of deaths due to AIDS by race/ethnicity in the US
Figure 5.4 Mechanism of action of DNA polymerase inhibitors
Figure 5.5 Structure of adefovir
Figure 6.1 Area under the curve
Figure 6.2 Comparative benefit of an AUIC ratio of ( 250


EXECUTIVE SUMMARY
ES.1 Introduction
Resistance is probably the most important issue in antimicrobial chemotherapy. Although 'superbugs' have been headline stories in the lay media, the inexorable advance in resistance in community pathogens, as well as nosocomial pathogens, is driving the development of new antimicrobials, but also leading to pressures to restrain prescribing. The research pipeline that will reach the market in the next 2-5 years is, for the most part, composed of new products from existing classes of antibiotics, antifungals and antivirals. This will put pressure on the current market leaders, only some of which are facing patent expiry in that time frame. It will also make the task of successfully introducing the later-entry products even more challenging as possibilities for product differentiation are anticipated by the earlier entrants.


The future generations of antimicrobials will be directed at targets identified by genomics and will avoid cross-resistance with existing classes, but in the short term, the spectre of untreatable infection - effectively a return to the pre-penicillin era for some infections - is still a possibility. This, together with efforts to constrain costs, has led to the development of treatment guidelines which may become treatment protocols, making product differentiation and inclusion in formularies and guidelines even more important and challenging.


ES.2 Bacterial infection, resistance and treatment guidelines
Resistance that has recently emerged raises the prospect of a return to the pre-antibiotic era. Chapter 2 reviews the important bacteria involved. These include staphylococci (especially methicillin-resistant Staphylococcus aureus (MRSA), streptococci (especially Streptococcus pneumoniae in meningitis) and enterococci among the Gram-positive bacteria. The Gram-negative bacteria of medical importance include Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Acinetobacter and Enterobacteriaceae, implicated with resistance to extended spectrum cephalosporins in intensive care units (ICUs), together with Haemophillus influenzae and Escherichia coli, which are involved with infections in the community.


The relatively recent recognition of the bacteria responsible for atypical pneumonia - Legionella pneumophilia, Chlamydia pneumoniae and mycoplasmas - has led to the updating of guidelines on the treatment of community-acquired pneumonia (CAP). Other guidelines evolving in response to epidemiology, outcomes measures and the trials of new agents, as well as post-marketing data, include the management of fever in neutropaenic patients. Guidelines to reduce inappropriate use of glycopeptides (vancomycin and teicoplanin) have only been partially successful.


ES.3 The antibiotic pipeline
Although the 1980s was the decade of the cephalosporins, the 1990s have been the decade of the quinolones, in terms of both market growth and R&D activity, a pattern expected to continue through to 2002. The sequence starting with Levaquin (levofloxacin), Raxar (grepafloxacin) and Trovan (trovafloxacin) will be closely followed by Bayer's Avelox (moxifloxacin, the first of the 8-methoxy quinolones, which is being launched relatively close to the patent expiry of ciprofloxacin), SmithKline Beecham's Factive (gemifloxacin), Parke-Davis's clinafloxacin, Bristol-Myers Squibb's Tequin (gatifloxacin) and Daiichi's sitafloxacin.


After an interval of three years, it is likely that the novel quinolone, T-3811, will be the first to be licensed for paediatric use, followed by Daiichi's DC-756 towards the middle of the next decade, which has activity against quinolone-resistant bacteria (including ciprofloxacin-resistant MRSA).
Perhaps the most eagerly awaited antibiotics are the new Gram-positive agents active against MRSA and vancomycin-resistant enterococci (VRE): Rh�ne-Poulenc Rorer's Synercid, Pharmacia & Upjohn's Zyvox (linezolid) and Schering-Plough's everninomicin, Ziracin. Chapter 3 covers the antibiotic classes by therapy class sequence, including the new peptide antibiotics that suffered a setback when the US Food and Drug Administration (FDA) declined to approve Magainin's Locilex (pexiganan acetate) for diabetic ulceration. This situation is likely to be only temporary, however, as Xoma's Neuprex is in Phase III trials as monotherapy for meningococcal sepsis. Some of the new targets for antibiotics are also explored, including the novel bacterial signalling, termed quorum sensing.


ES.4 The antifungal market
In fungi, the problem of resistance is principally intrinsic. Chapter 4 covers the main pathogenic fungi and the infections they cause, from skin infections to the emerging moulds that are causing fatal infections in heavily immunosuppressed patients. The development pipeline is heavily biased towards more active and broader-spectrum triazoles, which will be competing with the lipid formulations of amphotericin B in the most severe infections, and with the existing triazoles for the increasingly prevalent, less-susceptible, non-Candida albicans species. The new category of cell wall-active fungicidal agents is led by Merck & Co's pneumocandin. This may be the first well-tolerated cidal agent that does not act on the fungal cell membrane. These introductions may place further pressure on the lipid formulations of amphotericin B, which are restricted to refractory patients and those with failing renal function due to cost issues. Health economic studies examining total costs are also reviewed.


ES.5 The antiviral market
In terms of market size, as well as classification, the antiviral market can be divided between HIV and other viral infections. Chapter 5 describes the most important viruses, the infections they cause - for which antiviral drugs are marketed or are in development - and treatment guidelines. The development of resistance, especially class resistance, is more problematic than for antifungals. This has been well publicised with the durability of effect of current antiretrovirals used to treat HIV.

Toxicity is even more of a concern when treating viral rather than fungal infections, as viruses rely on host cell metabolic processes for their replication cycle. This is demonstrated for example by the appearance of lipodystrophy and other metabolic disorders associated with protease inhibitors, which only three years ago (1996) at the 11th International AIDS Conference were being described as possibly curative. Treatment protocols have been reassessed. These are reviewed, together with pipeline HIV products, including those for new targets.


Among the developments for viral infections other than HIV are treatments for hepatitis B virus, which has a target similar to HIV and for which the first HIV antiretroviral for hepatitis B - lamivudine - will soon be introduced as Zeffix by Glaxo Wellcome. New targets specific to hepatitis B virus are further away but the market potential is considerable as so many chronic carriers of hepatitis will develop fibrosis and cirrhosis. Hepatitis is one of the leading causes of liver transplantation, and an even larger number of chronic hepatitis patients are carriers of hepatitis C.

This virus is an RNA virus, and while specific agents are being developed, these are further away. Also in development with potentially even larger patient populations are treatments for influenza, which are close to marketing, and the common cold. These will have implications for healthcare resources leading to likely increases in patient co-payments.


ES.6 Pharmacokinetics, pharmacodynamics and evolving regulatory requirements
Pharmacokinetics and pharmacodynamics have now come of age. Chapter 6 discusses the main aspects that are being incorporated into development programmes and into pre-marketing communications to demonstrate competitive advantage where, previously, minimal inhibitory concentration (MIC) and half-life data used to be the battleground. The predictive value of the exposure of the pathogen to an antimicrobial and the time course of in vivo concentrations to maximise efficacy in relation to possible side effects has also led to evolving regulatory requirements. This is especially the case in the US where these factors may now enable new antimicrobial agents to be developed more quickly and which require fewer pivotal studies, resulting in clear cost implications. In Europe, Summaries of Product Characteristics (SPCs) will only be able to include lists of susceptible pathogens in approved indications and they must indicate the approximate proportion that demonstrate resistance. The attitude of European agencies to 'fast tracking' is also reviewed.


ES.7 The market structure
Chapter 7 describes the market structure in total and by each of the three main markets (bacterial, fungal and viral), in terms of leading products, companies involved and the importance of antimicrobials to company revenue. Six of the top 10 selling anti-infectives are antibiotics, three are antifungals and only one is an antiviral - perhaps, surprisingly, not an antiretroviral for HIV infection. Zovirax, for herpesvirus infections, is ranked eighth. There are five antimicrobials with sales estimated to exceed $1 billion in 1998. Two companies each have two products in the top 10, but none has two antibiotics in the top 10. Two companies have more than 30% of total company pharmaceutical sales in antibiotics. Only one company in the top 10 and four companies in the top 20 (excluding the Japanese companies) do not have marketed antibiotics in their portfolios.

Novartis is the only company in the top 15 without an antibiotic but it has the ninth ranked antimicrobial, which occupies second position in the antifungal rankings. Although the market is mature in terms of volume, opportunities do exist for innovation. Two of the top 10 ranking antibiotics and the top two ranking antifungals were introduced in the early 1990s. Usage of antimicrobials in hospitals in the US and Germany are compared, together with epidemiology - including data for pneumonia and otitis media.


With so many products in the pipeline, many of them later entries in existing classes, the question of which will be winners is discussed. The prospects for the pipeline products - sales potentials, rather than forecasts or predictions - and the existing market leaders are reviewed in the context of patent expiry as well as competition from the new agents and the pressure from the spread of resistance.

ES.8 Company profiles
The leading companies marketing anti-infective agents are profiled in Chapter 8, together with selected smaller companies whose technology has produced some of the innovative products that these major corporations have licensed. Appendix I contains contact details for companies mentioned in this report. Appendix II provides a conference calendar for forthcoming meetings of interest.

© PJB Publications Ltd. 2000
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