ANTIBIOTICS: TECHNOLOGIES AND GLOBAL MARKETS

Transcription

1 ANTIBIOTICS: TECHNOLOGIES AND GLOBAL MARKETS PHM025D March 2016 Neha Maliwal Project Analyst ISBN: BCC Research 49 Walnut Park, Building 2 Wellesley, MA USA (toll-free within the USA), or (+1) information@bccresearch.com

2 TABLE OF CONTENTS CHAPTER 1 INTRODUCTION 2 STUDY GOALS AND OBJECTIVES 2 REASONS FOR DOING THE STUDY 2 SCOPE OF REPORT 3 INTENDED AUDIENCE 3 RESEARCH METHODOLOGY 4 ANALYST'S CREDENTIALS 5 RELATED BCC RESEARCH REPORTS 5 BCC RESEARCH WEBSITE 5 DISCLAIMER 5 CHAPTER 2 EXECUTIVE SUMMARY 7 SUMMARY TABLE GLOBAL ANTIBIOTICS MARKET BY CLASS, THROUGH 2020 ($ SUMMARY FIGURE GLOBAL ANTIBIOTICS MARKET BY CLASS, 2015 AND 2020 ($ 8 8 CHAPTER 3 MARKET OVERVIEW 10 INTRODUCTION 10 BACTERIA 10 TABLE 1 DIFFERENCES BETWEEN GRAM-NEGATIVE AND GRAM-POSITIVE BACTERIA 11 GRAM-POSITIVE BACTERIA 12 GRAM-NEGATIVE BACTERIA 12 Mycobacterium 13 TABLE 2 CLASSIFICATION OF BACTERIA BY SHAPE 13 BACTERIAL INFECTIONS 14 RESPIRATORY TRACT INFECTIONS 15 Upper Respiratory Tract Infection 15 TABLE 3 PRINCIPLES FOR JUDICIAL USE OF ANTIBIOTICS 15 TABLE 4 INCIDENCE OF UPPER RESPIRATORY TRACT INFECTIONS CAUSED BY STREPTOCOCCUS BY COUNTRY, 2010 (NUMBER/%) Lower Respiratory Tract Infection 17 PNEUMONIA 17 TABLE 5 COMMON CAUSATIVE MICROBES OF COMMUNITY AND HOSPITAL-ACQUIRED PNEUMONIA Community-acquired Pneumonia 18 Hospital-acquired Pneumonia 18 TABLE 6 PREFERRED PHARMACOTHERAPY FOR MICROORGANISMS CAUSING BACTERIAL PNEUMONIA TABLE 7 INCIDENCE OF COMMUNITY-ACQUIRED PNEUMONIA BY COUNTRY, 2010 (NUMBER/%) TUBERCULOSIS 20 URINARY TRACT INFECTIONS (UTI) 20 TABLE 8 INCIDENCE OF URINARY TRACT INFECTIONS CAUSED BY STREPTOCOCCUS BY COUNTRY, 2010 (NUMBER/%) SKIN AND SKIN STRUCTURE INFECTIONS

3 TABLE 9 INCIDENCE OF BACTERIAL SKIN AND SKIN STRUCTURE INFECTIONS CAUSED BY STREPTOCOCCUS BY COUNTRY, 2010 (NUMBER/%) Cellulitis and Erysipelas 22 Folliculitis 22 Impetigo and Ecthyma 23 Abscesses 23 Carbuncles and Furuncles 23 GYNECOLOGICAL INFECTIONS 23 TABLE 10 INCIDENCE OF BACTERIAL VAGINOSIS INFECTIONS CAUSED BY STREPTOCOCCUS BY COUNTRY, 2010 (NUMBER/%) DEFINITION OF ANTIBIOTIC 24 CLASSIFICATION OF ANTIBIOTICS 24 FIGURE 1 CLASSIFICATION OF ANTIBIOTICS 25 HISTORY OF ANTIBIOTICS AND CURRENT STATUS 25 PRE-ANTIBIOTIC ERA 25 ANTIBIOTIC ERA 26 TABLE 11 U.S. LIFE EXPECTANCY AT BIRTH, (YEARS) 26 TABLE 12 ANTIBIOTICS: YEAR OF INTRODUCTION, MODE OF ACTION AND TARGET SPECIES ANTIBIOTIC-RESISTANT BACTERIA 28 MECHANISM OF RESISTANCE 29 TABLE 13 ANTIBIOTICS: MODE OF ACTION 30 Mechanisms of Antimicrobial Resistance 30 TABLE 14 ESTIMATED DEATHS PER YEAR CAUSED BY AMR BY REGION, 2050 (NUMBER) Methods for the Dissemination of Antimicrobial Resistance Genes 32 Resistance to B-Lactam Antibiotics 32 Tetracycline Resistance 32 Chloramphenicol Resistance 32 Aminoglycoside Resistance 33 Quinolone Resistance 33 Macrolide, Lincosamide, and Streptogramin (MLS) Resistance 33 Glycopeptide Resistance 33 Sulfonamides and Trimethoprim Resistance 34 Multidrug Resistance 34 TABLE 15 TYPES OF ANTIBIOTICS AND METHODS OF RESISTANCE 34 TABLE 16 CURRENT AND EMERGING ANTIBIOTIC-RESISTANT BACTERIA 35 EMERGENCE OF POST-ANTIBIOTIC ERA 36 TABLE 17 BIOCHEMICAL MECHANISM OF ANTIBIOTIC RESISTANCE 37 FIGURE 2 CDC LIST OF HIGHLY CONCERNING BACTERIA, ACCORDING TO THREAT LEVEL TABLE 18 ADDITIONAL COST AND LENGTH OF STAY DUE TO ANTIBIOTIC-RESISTANT BACTERIA BY REGION Limitation of Antibiotics 39 Some Antibiotics are Active against Only Certain Kinds of Bacteria Some Bacteria are Virulent and Can Kill Quickly 40 Some Bacteria Grow in Biofilms that cannot be Easily Penetrated by Antibiotics

4 DRIVERS RESTRAINTS AND OPPORTUNITIES 40 DRIVERS 40 Growth of the Global Pharmaceutical Market Driven by Antibiotics 40 Aging Population Propels the Growth of the Antibiotics Market 41 FIGURE 3 INCREASE IN AGING POPULATION, 2011 AND Public-Private Partnerships Encourage Antibiotic Development 42 Increasing Prevalence of Hospital-Acquired Infections Triggers Market Growth RESTRAINTS 43 Antibiotic Resistance 43 Declining R&D Investment Poses Long-Term Barrier to Market Growth 44 Genericization of Antibiotics Restrains Market Growth 44 OPPORTUNITIES 44 Market Expansion into Emerging Countries 44 Multidrug-Resistant Pathogens Provide an Opportunity to Develop Novel Antibacterial Agents BURNING ISSUE 46 New Antibiotic Discovered From Soil 46 MARKET SHARES OF KEY COMPANIES 46 FIGURE 4 GLOBAL MARKET SHARES FOR ANTIBIOTIC COMPANIES, 2014 (%) 46 VALUE CHAIN OF ANTIBIOTICS 48 CHINA IS A BECOMING A CENTER FOR MICROBIAL THREATS 49 REGULATORY ISSUES 50 FDA AND INTERNATIONAL REGULATORY AGENCIES 50 RECENT REGULATORY REFORMS 51 KETEK CASE STUDY 51 KEY TRENDS AFFECTING THE MARKET 52 NEVER EVENTS 52 Impact on the Use of Antibiotics 53 FUNDING FOR NEW ANTIBIOTICS 53 United States 53 Infectious Diseases Society of America 53 NIH Funding 54 Public-Private Partnerships 54 Europe 55 Innovative Medicines Initiative 55 EMERGING DRUGS WITH NOVEL MECHANISMS OF ACTION 56 PharmaSea Project 56 Combination of Different Antibiotics 56 Others CHAPTER 4 ANTIBIOTIC RESEARCH AND DEVELOPMENT 59 REASONS FOR LACK OF INNOVATION IN ANTIBIOTIC RESEARCH 59 FIGURE 5 REASONS FOR LACK OF INNOVATION IN ANTIBIOTIC RESEARCH 60 LOW RETURN ON INVESTMENT 60 STRICT REGULATORY ENVIRONMENT 61 SCIENTIFIC CHALLENGES 62 STRATEGIES TO PROMOTE ANTIBIOTIC RESEARCH 62

5 FIGURE 6 STRATEGIES TO PROMOTE ANTIBIOTIC RESEARCH 62 PUSH STRATEGIES 63 Increasing Access to Research 63 Increasing the Number of Scientific Personnel 64 Direct Funding of Research 64 Translational Research 66 Tax Incentives 66 Product Development Partnerships 67 PULL STRATEGIES 67 Monetary Awards 67 Advance Market Commitments 68 Legal and Regulatory Initiatives 69 Clinical Trials 69 Accelerated Regulatory Review 70 Intellectual Property Rights Strategies 70 Increasing the Term of IP Protection and Data Exclusivity 71 Wildcard Patent Extension 71 Patent Buyouts 72 Pricing and Reimbursement 72 Other Legal/Regulatory Strategies 72 COMBINED PULL AND PUSH INCENTIVES 73 ORPHAN DRUG STATUS 73 TABLE 19 COMPARISON OF U.S. AND EU ORPHAN DRUG LEGISLATION AND PROCESS Delinkage of Antibiotics 74 TABLE 20 LIST OF DELINKAGE MODELS 75 TABLE 21 LIST OF HYBRID MODELS CHAPTER 5 ANTIBIOTICS MARKET BY TYPE 80 MARKET SIZE ESTIMATION 80 MARKET SHARE ESTIMATION 80 GLOBAL ANTIBIOTICS MARKET BY CLASS 81 TABLE 22 GLOBAL ANTIBIOTICS MARKET BY CLASS, THROUGH 2020 ($ 81 TABLE 23 GLOBAL ANTIBIOTICS MARKET BY REGION, THROUGH 2020 ($ 81 FIGURE 7 ANTIBIOTICS BY CLASS 81 BETA-LACTAM ANTIBIOTICS 82 TABLE 24 GLOBAL MARKET FOR BETA-LACTAM ANTIBIOTICS BY TYPE, THROUGH 2020 ($ TABLE 25 GLOBAL MARKET FOR BETA-LACTAM ANTIBIOTICS BY REGION, THROUGH 2020 ($ Extended Spectrum Beta-Lactamase 84 Metallo-Beta-Lactamases 85 FIGURE 8 TYPES OF BETA-LACTAM ANTIBIOTICS 85 Penicillins 85 TABLE 26 GLOBAL MARKET FOR PENICILLIN BY REGION, THROUGH 2020 ($ Types of Penicillin 87 TABLE 27 TYPES OF PENICILLIN BY BRAND NAME AND APPROVAL DATE

6 Cephalosporins 88 Side Effects 89 TABLE 28 GLOBAL MARKET FOR CEPHALOSPORIN BY REGION, THROUGH 2020 ($ Teflaro Driving the Cephalosporin Market 90 Generations of Cephalosporins 90 TABLE 29 GENERATIONS OF CEPHALOSPORIN 90 First-Generation Cephalosporins 91 TABLE 30 LIST OF FIRST-GENERATION CEPHALOSPORINS 91 Second-Generation Cephalosporins 92 TABLE 31 LIST OF SECOND-GENERATION CEPHALOSPORINS 92 Third-Generation Cephalosporins 92 Antipseudomonal Cephalosporins 93 TABLE 32 LIST OF THIRD-GENERATION CEPHALOSPORINS 93 Fourth-Generation Cephalosporins 94 TABLE 33 LIST OF FOURTH-GENERATION CEPHALOSPORINS 94 Fifth-Generation Cephalosporins 94 TABLE 34 LIST OF FIFTH-GENERATION CEPHALOSPORINS 95 Carbapenems 95 TABLE 35 GLOBAL MARKET FOR CARBAPENEM BY REGION, THROUGH 2020 ($ TABLE 36 TYPES OF CARBAPENEMS 96 QUINOLONES AND FLUOROQUINOLONES 96 TABLE 37 DEVELOPMENT HISTORY OF FLUOROQUINOLONES 98 TABLE 38 GLOBAL MARKET FOR FLUOROQUINOLONES BY GENERATION, THROUGH 2020 ($ TABLE 39 GLOBAL MARKET FOR FLUOROQUINOLONES BY REGION, THROUGH 2020 ($ Generations of Quinolones 99 First-Generation Quinolones 99 Second-Generation Fluoroquinolones 99 TABLE 40 GLOBAL MARKET FOR SECOND-GENERATION FLUOROQUINOLONES BY REGION, THROUGH 2020 ($ Third-Generation Fluoroquinolones 100 TABLE 41 GLOBAL MARKET FOR THIRD-GENERATION FLUOROQUINOLONES BY REGION, THROUGH 2020 ($ Levofloxacin: A Major Driver of the Market for Third-Generation Fluoroquinolones Fourth-Generation Fluoroquinolones 101 TABLE 42 GLOBAL MARKET FOR OTHER QUINOLONES BY REGION, THROUGH 2020 ($ TABLE 43 TYPES OF QUINOLONES 102 TETRACYCLINE 103 TABLE 44 GLOBAL MARKET FOR TETRACYCLINE BY REGION, THROUGH 2020 ($ TABLE 45 TYPES OF TETRACYCLINE 104 MACROLIDES 105 TABLE 46 GLOBAL MARKET FOR MACROLIDE BY REGION, THROUGH 2020 ($

7 Ketolides 106 Ketek 107 TABLE 47 TYPES OF MACROLIDES/KETOLIDES 107 OTHER ANTIBIOTICS 107 Pseudomonas Aeruginosa 107 TABLE 48 GLOBAL MARKET FOR OTHER ANTIBIOTICS BY REGION, THROUGH 2020 ($ 108 CHAPTER 6 VETERINARY ANTIBIOTICS MARKET 111 INTRODUCTION 111 TABLE 49 DIFFERENCES BETWEEN ANTIBIOTIC USAGE IN ANIMALS AND HUMANS 111 TABLE 50 GLOBAL MARKET FOR VETERINARY ANTIBIOTICS BY APPLICATION, THROUGH 2020 ($ VETERINARY APPLICATIONS 112 FEED APPLICATION 112 FDA to Phase out Antibiotics from Food Production 113 THERAPEUTIC APPLICATIONS 114 TABLE 51 GLOBAL MARKET FOR VETERINARY THERAPEUTIC ANTIBIOTICS BY TYPE, THROUGH 2020 ($ TABLE 52 GLOBAL MARKET FOR VETERINARY THERAPEUTIC ANTIBIOTICS BY ANIMAL TYPE, THROUGH 2020 ($ OTHER APPLICATIONS CHAPTER 7 COMPANY PROFILES 118 ASTRAZENECA 118 FINANCIALS 118 TABLE 53 ASTRAZENECA REVENUES AND R &D EXPENDITURES, ($ MILLIONS/%) DEVELOPMENTS 119 TABLE 54 ASTRAZENECA DEVELOPMENTS 119 BAYER HEALTHCARE AG 120 FINANCIALS 120 TABLE 55 BAYER REVENUES AND R &D EXPENDITURES, ($ MILLIONS/%) 120 DEVELOPMENTS 120 CUBIST PHARMACEUTICALS 120 DEVELOPMENTS 121 TABLE 56 CUBIST PHARMACEUTICAL DEVELOPMENTS 121 GLAXOSMITHKLINE 122 FINANCIALS 122 TABLE 57 GSK REVENUES AND R & D EXPENDITURES, ($ MILLIONS/%) 122 DEVELOPMENTS 123 TABLE 58 GSK DEVELOPMENTS 123 JOHNSON & JOHNSON 124 FINANCIALS 124 TABLE 59 JOHNSON & JOHNSON REVENUES AND R &D EXPENDITURES, ($ MILLIONS/%) DEVELOPMENTS 125 TABLE 60 JOHNSON & JOHNSON DEVELOPMENTS 125 MERCK & CO

8 FINANCIALS 125 TABLE 61 MERCK & CO. REVENUES AND R &D EXPENDITURES, ($ MILLIONS/%) DEVELOPMENTS 126 TABLE 62 MERCK & CO.DEVELOPMENTS 126 PFIZER 126 FINANCIALS 127 TABLE 63 PFIZER REVENUES AND R &D EXPENDITURES, ($ MILLIONS/%) 127 DEVELOPMENTS 127 TABLE 64 PFIZER DEVELOPMENTS 127 RECENT MERGERS AND ACQUISITIONS 128 TABLE 65 LIST OF OTHER COMPANIES IN THE ANTIBIOTICS MARKET CHAPTER 8 CLINICAL TRIALS ON ANTIBIOTICS 133 FIGURE 9 ANTIBIOTICS IN PHASES I-III CLINICAL TRIALS, 2015 (%) 134 TABLE 66 ANTIBIOTIC COMPOUNDS IN PHASE III CLINICAL TRIALS, ANTIBIOTICS IN PHASE II CLINICAL TRIALS 136 TABLE 67 ANTIBIOTIC COMPOUNDS IN PHASE II CLINICAL TRIALS, ANTIBIOTICS IN PHASE I CLINICAL TRIALS 137 TABLE 68 ANTIBIOTIC COMPOUNDS IN PHASE I CLINICAL TRIALS, TABLE 69 NATURAL PRODUCTS IN CLINICAL TRIALS FOR ANTIBIOTIC ACTIVITY THAT REPRESENT NEW CHEMICAL CLASSES, CHAPTER 9 OVERVIEW OF BACTERIA TYPES 142 DISEASE ORGANISMS, DIAGNOSTICS, CLINICAL MANIFESTATIONS AND TREATMENTS TABLE 70 LIST OF GRAM-POSITIVE BACTERIA 142 TABLE 71 LIST OF GRAM-NEGATIVE BACTERIA 146 TABLE 72 LIST OF GRAM-NEGATIVE COCCI 151 TABLE 73 LIST OF GRAM-NEGATIVE RODS RELATED TO RESPIRATORY TRACT INFECTIONS TABLE 74 LIST OF GRAM-NEGATIVE RODS RELATED TO THE ENTERIC TRACT 155 TABLE 75 LIST OF GRAM-NEGATIVE SPIROCHETES 159 TABLE 76 LIST OF GRAM-NEGATIVE OBLIGATE INTRACELLULAR PARASITES 161 TABLE 77 LIST OF MISCELLANEOUS BACTERIA CHAPTER 10 LIST OF ACRONYMS 166 LIST OF ACRONYMS 166

9 LIST OF TABLES TABLE HEADING SUMMARY TABLE GLOBAL ANTIBIOTICS MARKET BY CLASS, THROUGH 2020 ($ TABLE 1 DIFFERENCES BETWEEN GRAM-NEGATIVE AND GRAM-POSITIVE BACTERIA 11 TABLE 2 CLASSIFICATION OF BACTERIA BY SHAPE 13 TABLE 3 PRINCIPLES FOR JUDICIAL USE OF ANTIBIOTICS 15 TABLE 4 INCIDENCE OF UPPER RESPIRATORY TRACT INFECTIONS CAUSED BY STREPTOCOCCUS BY COUNTRY, 2010 (NUMBER/%) TABLE 5 COMMON CAUSATIVE MICROBES OF COMMUNITY AND HOSPITAL-ACQUIRED PNEUMONIA TABLE 6 PREFERRED PHARMACOTHERAPY FOR MICROORGANISMS CAUSING BACTERIAL PNEUMONIA TABLE 7 INCIDENCE OF COMMUNITY-ACQUIRED PNEUMONIA BY COUNTRY, 2010 (NUMBER/%) TABLE 8 INCIDENCE OF URINARY TRACT INFECTIONS CAUSED BY STREPTOCOCCUS BY COUNTRY, 2010 (NUMBER/%) TABLE 9 INCIDENCE OF BACTERIAL SKIN AND SKIN STRUCTURE INFECTIONS CAUSED BY STREPTOCOCCUS BY COUNTRY, 2010 (NUMBER/%) TABLE 10 INCIDENCE OF BACTERIAL VAGINOSIS INFECTIONS CAUSED BY STREPTOCOCCUS BY COUNTRY, 2010 (NUMBER/%) TABLE 11 U.S. LIFE EXPECTANCY AT BIRTH, (YEARS) 26 TABLE 12 ANTIBIOTICS: YEAR OF INTRODUCTION, MODE OF ACTION AND TARGET SPECIES TABLE 13 ANTIBIOTICS: MODE OF ACTION 30 TABLE 14 ESTIMATED DEATHS PER YEAR CAUSED BY AMR BY REGION, 2050 (NUMBER) TABLE 15 TYPES OF ANTIBIOTICS AND METHODS OF RESISTANCE 34 TABLE 16 CURRENT AND EMERGING ANTIBIOTIC-RESISTANT BACTERIA 35 TABLE 17 BIOCHEMICAL MECHANISM OF ANTIBIOTIC RESISTANCE 37 TABLE 18 ADDITIONAL COST AND LENGTH OF STAY DUE TO ANTIBIOTIC-RESISTANT BACTERIA BY REGION TABLE 19 COMPARISON OF U.S. AND EU ORPHAN DRUG LEGISLATION AND PROCESS 73 TABLE 20 LIST OF DELINKAGE MODELS 75 TABLE 21 LIST OF HYBRID MODELS 77 TABLE 22 GLOBAL ANTIBIOTICS MARKET BY CLASS, THROUGH 2020 ($ 81 TABLE 23 GLOBAL ANTIBIOTICS MARKET BY REGION, THROUGH 2020 ($ 81 TABLE 24 GLOBAL MARKET FOR BETA-LACTAM ANTIBIOTICS BY TYPE, THROUGH 2020 ($ TABLE 25 GLOBAL MARKET FOR BETA-LACTAM ANTIBIOTICS BY REGION, THROUGH 2020 ($ TABLE 26 GLOBAL MARKET FOR PENICILLIN BY REGION, THROUGH 2020 ($ TABLE 27 TYPES OF PENICILLIN BY BRAND NAME AND APPROVAL DATE 88 TABLE 28 GLOBAL MARKET FOR CEPHALOSPORIN BY REGION, THROUGH 2020 ($ TABLE 29 GENERATIONS OF CEPHALOSPORIN 90 TABLE 30 LIST OF FIRST-GENERATION CEPHALOSPORINS 91 TABLE 31 LIST OF SECOND-GENERATION CEPHALOSPORINS 92 TABLE 32 LIST OF THIRD-GENERATION CEPHALOSPORINS 93 TABLE 33 LIST OF FOURTH-GENERATION CEPHALOSPORINS

10 TABLE HEADING TABLE 34 LIST OF FIFTH-GENERATION CEPHALOSPORINS 95 TABLE 35 GLOBAL MARKET FOR CARBAPENEM BY REGION, THROUGH 2020 ($ TABLE 36 TYPES OF CARBAPENEMS 96 TABLE 37 DEVELOPMENT HISTORY OF FLUOROQUINOLONES 98 TABLE 38 GLOBAL MARKET FOR FLUOROQUINOLONES BY GENERATION, THROUGH 2020 ($ TABLE 39 GLOBAL MARKET FOR FLUOROQUINOLONES BY REGION, THROUGH 2020 ($ TABLE 40 GLOBAL MARKET FOR SECOND-GENERATION FLUOROQUINOLONES BY REGION, THROUGH 2020 ($ TABLE 41 GLOBAL MARKET FOR THIRD-GENERATION FLUOROQUINOLONES BY REGION, THROUGH 2020 ($ TABLE 42 GLOBAL MARKET FOR OTHER QUINOLONES BY REGION, THROUGH 2020 ($ TABLE 43 TYPES OF QUINOLONES 102 TABLE 44 GLOBAL MARKET FOR TETRACYCLINE BY REGION, THROUGH 2020 ($ TABLE 45 TYPES OF TETRACYCLINE 104 TABLE 46 GLOBAL MARKET FOR MACROLIDE BY REGION, THROUGH 2020 ($ TABLE 47 TYPES OF MACROLIDES/KETOLIDES 107 TABLE 48 GLOBAL MARKET FOR OTHER ANTIBIOTICS BY REGION, THROUGH 2020 ($ TABLE 49 DIFFERENCES BETWEEN ANTIBIOTIC USAGE IN ANIMALS AND HUMANS 111 TABLE 50 GLOBAL MARKET FOR VETERINARY ANTIBIOTICS BY APPLICATION, THROUGH 2020 ($ TABLE 51 GLOBAL MARKET FOR VETERINARY THERAPEUTIC ANTIBIOTICS BY TYPE, THROUGH 2020 ($ TABLE 52 GLOBAL MARKET FOR VETERINARY THERAPEUTIC ANTIBIOTICS BY ANIMAL TYPE, THROUGH 2020 ($ TABLE 53 ASTRAZENECA REVENUES AND R &D EXPENDITURES, ($ MILLIONS/%) TABLE 54 ASTRAZENECA DEVELOPMENTS 119 TABLE 55 BAYER REVENUES AND R &D EXPENDITURES, ($ MILLIONS/%) 120 TABLE 56 CUBIST PHARMACEUTICAL DEVELOPMENTS 121 TABLE 57 GSK REVENUES AND R & D EXPENDITURES, ($ MILLIONS/%) 122 TABLE 58 GSK DEVELOPMENTS 123 TABLE 59 JOHNSON & JOHNSON REVENUES AND R &D EXPENDITURES, ($ MILLIONS/%) TABLE 60 JOHNSON & JOHNSON DEVELOPMENTS 125 TABLE 61 MERCK & CO. REVENUES AND R &D EXPENDITURES, ($ MILLIONS/%) TABLE 62 MERCK & CO.DEVELOPMENTS 126 TABLE 63 PFIZER REVENUES AND R &D EXPENDITURES, ($ MILLIONS/%) 127 TABLE 64 PFIZER DEVELOPMENTS 127 TABLE 65 LIST OF OTHER COMPANIES IN THE ANTIBIOTICS MARKET 129 TABLE 66 ANTIBIOTIC COMPOUNDS IN PHASE III CLINICAL TRIALS, TABLE 67 ANTIBIOTIC COMPOUNDS IN PHASE II CLINICAL TRIALS, TABLE 68 ANTIBIOTIC COMPOUNDS IN PHASE I CLINICAL TRIALS,

11 TABLE HEADING TABLE 69 NATURAL PRODUCTS IN CLINICAL TRIALS FOR ANTIBIOTIC ACTIVITY THAT REPRESENT NEW CHEMICAL CLASSES, 2015 TABLE 70 LIST OF GRAM-POSITIVE BACTERIA 142 TABLE 71 LIST OF GRAM-NEGATIVE BACTERIA 146 TABLE 72 LIST OF GRAM-NEGATIVE COCCI 151 TABLE 73 LIST OF GRAM-NEGATIVE RODS RELATED TO RESPIRATORY TRACT INFECTIONS TABLE 74 LIST OF GRAM-NEGATIVE RODS RELATED TO THE ENTERIC TRACT 155 TABLE 75 LIST OF GRAM-NEGATIVE SPIROCHETES 159 TABLE 76 LIST OF GRAM-NEGATIVE OBLIGATE INTRACELLULAR PARASITES 161 TABLE 77 LIST OF MISCELLANEOUS BACTERIA

12 LIST OF FIGURES FIGURE TITLE SUMMARY FIGURE GLOBAL ANTIBIOTICS MARKET BY CLASS, 2015 AND 2020 ($ FIGURE 1 CLASSIFICATION OF ANTIBIOTICS 25 FIGURE 2 CDC LIST OF HIGHLY CONCERNING BACTERIA, ACCORDING TO THREAT LEVEL FIGURE 3 INCREASE IN AGING POPULATION, 2011 AND FIGURE 4 GLOBAL MARKET SHARES FOR ANTIBIOTIC COMPANIES, 2014 (%) 46 FIGURE 5 REASONS FOR LACK OF INNOVATION IN ANTIBIOTIC RESEARCH 60 FIGURE 6 STRATEGIES TO PROMOTE ANTIBIOTIC RESEARCH 62 FIGURE 7 ANTIBIOTICS BY CLASS 81 FIGURE 8 TYPES OF BETA-LACTAM ANTIBIOTICS 85 FIGURE 9 ANTIBIOTICS IN PHASES I-III CLINICAL TRIALS, 2015 (%)