Antibiotics and Drug Resistance 2008

Table of Contents

Executive Summary

1 INTRODUCTION

• 1.1 Background
• 1.2 Antibiotic Resistance
• 1.3 Resistance Mechanisms
• 1.4 The Resistome
• 1.5 Pathogenomics
• 1.6 Antibiotics, Strategies and Targets
• 1.7 The Cost of Antibiotic Resistance
• 1.8 Global Surveillance
• 1.9 This Report

2 ANTIBIOTIC RESISTANCE: GLOBAL FIGURES AND TRENDS

• Summary
• 2.1 Antibiotic Resistance
• 2.2 Europe
  • 2.2.1 Escherichia coli
  • 2.2.2 Streptococcus pneumoniae
  • 2.2.3 Staphylococcus aureus
  • 2.2.4 Enterococci
  • 2.2.5 Klebsiella pneumoniae
  • 2.2.6 Pseudomonas aeruginosa
• 2.3 England and Wales
  • 2.3.1 Gram-positive cocci
  • 2.3.2 Gram-negative bacilli
  • 2.3.3 Other pathogens
• 2.4 Other countries
• 2.5 China
• 2.6 USA
• 2.7 Kuwait
• 2.8 Discussion

3 FULLY LAUNCHED ANTI-BACTERIALS

• 3.1 Current Anti-Infectives
• 3.2 Anti-bacterials
• 3.3 Bacterial Cell Wall Inhibitors
• 3.4 Immune Stimulators
• 3.5 30S/50S Ribosomal Subunit Inhibitors
• 3.6 DNA Gyrase/Topoisomerase Inhibitors
• 3.7 Other Antibiotics
• 3.8 Discussion

4 PIPELINE ANTI-BACTERIALS

• 4.1 Pipeline Anti-Infectives
• 4.2 Developmental Stage
• 4.3 Mechanisms of Action
• 4.4 Phase III and Beyond (Late Stage)
• 4.5 Pre-Clinical to Phase II (Early Stage)
  • 4.5.1 Established Classes
  • 4.5.2 New Classes
• 4.6 Anti-bacterial Groups
  • 4.6.1 Immune-acting agents
  • 4.6.2 Cell wall inhibitors
  • 4.6.3 DNA topoisomerase ATP hydrolysing inhibitors
  • 4.6.4 Protein 50S ribosomal subunit inhibitors
  • 4.6.5 Protein 30S ribosomal subunit inhibitors
  • 4.6.6 Protein synthesis antagonists
  • 4.6.7 DNA directed DNA polymerase inhibitors
  • 4.6.8 DNA antagonists
  • 4.6.9 DNA topoisomerase IV inhibitors
  • 4.6.10 B anthracis protective antigen inhibitors
  • 4.6.11 Chelating agents
  • 4.6.12 Defensin agonists
  • 4.6.13 Deformylase inhibitors
  • 4.6.14 General pump inhibitors
  • 4.6.15 FABI inhibitors
  • 4.6.16 Membrane integrity antagonists
  • 4.6.17 Membrane permeability enhancers
  • 4.6.18 Dihydrofolate reductase inhibitors
  • 4.6.19 DNA synthesis inhibitors
  • 4.6.20 Lactamase-A inhibitors
  • 4.6.21 Adenosinetriphosphate synthase inhibitors
  • 4.6.22 Deg protease inhibitors
  • 4.6.23 Fab F inhibitors
  • 4.6.24 Gene expression inhibitors
  • 4.6.25 Glutamate racemase inhibitors
  • 4.6.26 Glycosyl transferase inhibitors
  • 4.6.27 Heat shock protein 90 antagonists
  • 4.6.28 Kinase inhibitors
  • 4.6.29 Lipoteichoic acid antagonists
  • 4.6.30 PcrV inhibitors
  • 4.6.31 Peptidyltransferase inhibitors
• 4.7 Notable pipeline candidates
  • 4.7.1 Pre-registered and Registered
  • 4.7.2 Phase III
  • 4.7.3 Early-stage
• 4.8 Discussion

5 EMERGING ANTI-BACTERIALS

• 5.1 Patents
• 5.2 Antibiotic Classes
  • 5.2.1 Macrolide
  • 5.2.2 Beta-lactam
  • 5.2.3 Peptides
  • 5.2.4 Cephalosporins
  • 5.2.5 Combined antimicrobiols
  • 5.2.6 Carbapenems
  • 5.2.7 Quinolones
  • 5.2.8 General
  • 5.2.9 Vaccines (therapeutic)
  • 5.2.10 Lytics
  • 5.2.11 Bioenhancers
  • 5.2.12 Lactamase inhibitors
  • 5.2.13 Oxazolidinones
  • 5.2.14 Tetracyclines
  • 5.2.15 Natural products
  • 5.2.16 Aminoglycosides
  • 5.2.17 Quorum sensing
  • 5.2.18 Rifamycins
  • 5.2.19 ABC transporter modulator
  • 5.2.20 Glycopeptides
  • 5.2.21 Other technologies
  • 5.2.22 Patent filings organisations
• 5.3 Discussion

6 COMBATING RESISTANCE MECHANISMS

• 6.1 Background
• 6.2 New Targets and Mechanisms
• 6.3 Multiple Activities
• 6.4 Circumventing Resistance
• 6.5 Resistance Mutations
• 6.6 Virulence
• 6.7 Other Technologies
• 6.8 Discussion

CHAPTER 7 COMPANIES AND ORIGINATORS

• 7.1 Companies

FIGURES

• Figure 2.1 Escherichia coli: Combined resistance (fluoroquinolones, third-generation cephalosporins and aminoglycosides) by country 2001-2005. Only countries that reported 20 isolates or more per year for at least 3 years were included. The arrows indicate significant trends (Source: EARSS).
• Figure 2.2 Streptococcus pneumoniae: Dual resistance to penicillin and erythromycin by country, 1999-2005. Only countries that reported 20 isolates or more per year for at least 3 years were included. The arrows indicate significant trends (Source: EARSS).
• Figure 2.3 Staphylococcus aureus: Resistance to methicillin by country, 1999-2005. Only countries that reported 20 isolates or more per year for at least 3 years were included. The arrows indicate significant trends (Source: EARSS).
• Figure 2.4 Staphylococcus aureus: MRSA levels in England and Wales, 1992-2005. (Source UK Health Protection Agency, Trends in Antimicrobiol Resistance in England and Wales, 2004-2005).
• Figure 2.5 Enterococcus faecalis: Trends in high aminoglycoside resistance by country 2001-2005. Only countries that reported 20 isolates or more per year for at least 3 years were included. The arrows indicate significant trends (Source: EARSS).
• Figure 2.6 Klebsiella pneumoniae: Trends in high aminoglycoside resistance by country in 2002 and 2005. Only countries that reported 20 isolates or more per year for at least 3 years were included (Source: EARSS).
• Figure 2.7 Pseudomonas aeruginosa: Trends in high aminoglycoside resistance by country in 2002 and 2005. Only countries that reported 20 isolates or more per year for at least 3 years were included (Source: EARSS).
• Figure 2.8 Antibiotic resistance of gram-positive cocci in England and Wales, 2004-2005 (Source: UK Health Protection Agency, Trends in Antimicrobiol Resistance in England and Wales, 2004-2005.
• Figure 2.9 Antibiotic resistance of gram-negative bacilli in England and Wales, 2004-2005 (Source: UK Health Protection Agency, Trends in Antimicrobiol Resistance in England and Wales, 2004-2005.
• Figure 2.10 Antibiotic resistance of other bacteria in England and Wales, 2004-2005 (Source: UK Health Protection Agency, Trends in Antimicrobiol Resistance in England and Wales, 2004-2005).
• Figure 2.11 Antibiotic resistance of Staphylococcus, Streptococcus, Escherichia coli and Enterococcus in the US, Egypt and Tunisia (Source: Frimodt-Møller et al., Danish Medical Bulletin Vol. 54, May 2007)
• Figure 3.1 Current, fully launched anti-infectives (Independent Research, Pharmaprojects 2007)
• Figure 3.2 Categories of fully approved anti-bacterial therapeutics (Independent Research, Pharmaprojects 2007)

TABLES

• Table 2.1 EARSS surveillance programme: countries and country codes
• Table 3.1a. Fully launched antibiotics - bacterial cell wall inhibitors (β-lactams) (Source: Company Research May 2007, Pharmaprojects May 2007)
• Table 3.1b. Approved antibiotics - bacterial cell wall inhibitors (β-lactams) (Source: Company Research May 2007, Pharmaprojects May 2007)
• Table 3.2a. Approved antibiotics - Immune Stimulators/Modulators (Source: Company Research May 2007, Pharmaprojects May 2007)
• Table 3.2b. Approved antibiotics - Immune Stimulators/Modulators (Source: Company Research May 2007, Pharmaprojects May 2007)
• Table 3.3 Approved antibiotics - Protein 30S/50S Ribosomal Subunit Inhibitors (Source: Company Research May 2007, Pharmaprojects May 2007)
• Table 3.4 Approved antibiotics - DNA topoisomerase ATP hydrolysing inhibitor (Source: Company Research May 2007, Pharmaprojects May 2007)
• Table 3.5a Approved antibiotics - Other antibiotics (Source: Company Research May 2007, Pharmaprojects May 2007)
• Table 3.5b Approved antibiotics - Other antibiotics (Source: Company Research May 2007, Pharmaprojects May 2007)
• Table 3.5c Approved antibiotics - Other antibiotics (Source: Company Research May 2007, Pharmaprojects May 2007)
• 3.8 Discussion
• Table 4.1 Pipeline Anti-Infectives (Source: Company Research May 2007, Pharmaprojects May 2007)
• Table 4.2 Pipeline Anti-infectives (Source: Company Research May 2007, Pharmaprojects May 2007)
• Table 4.3 Pipeline Anti-Infectives (Source: Company Research May 2007, Pharmaprojects May 2007)
• Figure 7.1 The top 20 companies with fully launched anti-bacterials (Source: Independent Research, Pharmaprojects 2007)
• Figure 7.2 The top 20 anti-bacterial development companies, representing candidates in the development pipeline (pre-clinical to Phase III/initial launch) (Source: Independent Research, Pharmaprojects 2007)
• Figure 7.3 The top 20 anti-bacterial patent filing organisations of 340 patents selected for analysis in this report. (Source: Delphion)

APPENDICES

• Appendix 1 Escherichia coli: trends of aminopenicillin resistance by country, 2001-2005. Only countries that reported 20 isolates or more per year for at least 3 years were included. The arrows indicate significant trends. See page X for country codes (Source: EARSS).
• Appendix 2 Escherichia coli: trends in 3rd generation cephalosporin resistance by country, 2001-2005. Only countries that reported 20 isolates or more per year for at least 3 years were included. The arrows indicate significant trends. See page X for country codes (Source: EARSS).
• Appendix 3 Escherichia coli: trends of fluoroquinolones resistance by country, 2001-2005. Only countries that reported 20 isolates or more per year for at least 3 years were included. The arrows indicate significant trends. See page X for country codes (Source: EARSS).
• Appendix 4 Escherichia coli: trends of aminoglycoside resistance by country, 2001-2005. Only countries that reported 20 isolates or more per year for at least 3 years were included. The arrows indicate significant trends. See page X for country codes (Source: EARSS).
• Appendix 5 Streptococcus pneumoniae: Resistance to penicillin by country, 1999-2005. Only countries that reported 20 isolates or more per year for at least 3 years were included. The arrows indicate significant trends. See page X for country codes (Source: EARSS).
• Appendix 6 Streptococcus pneumoniae: Resistance to erythromycin by country, 1999-2005. Only countries that reported 20 isolates or more per year for at least 3 years were included. The arrows indicate significant trends. See page X for country codes (Source: EARSS).
• Appendix 7 Anti-bacterials on the drug development pipeline (Source: Company Research May 2007, Pharmaprojects May 2007)
• Appendix 8 Patent Application for Antibiotics and Anti-bacterials 2002-2007 (Source: Delphion, WIPO)