Antibiotics and Drug Resistance 2008

Content

• Chapter 1 Introduction
  • This Chapter Gives An Outline And Background On Antibiotic Resistance, Global Surveillance, Resistance Mechanisms And Antibiotics And Identifies Areas That Are Discussed In More Detail Later In The Report. Summary
  • 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
• Chapter 2 Antibiotic Resistance: Global Figures And Trends
  • This Chapter Gives Detailed Recently Published Figures On Antibiotic Resistance, From More Than 35 Countries. These Data Were Obtained From The European Antimicrobial Resistance Surveillance System (Earss) In Europe, The Health Protection Agency In The Uk, The Active Bacterial Core Surveillance (Abcs) Project In The Us, China's National Center For Antimicrobial Resistance And Other Sources. These Data Are Discussed In Terms Of Current Antibiotics And Global Healthcare/Human Costs. 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
• Chapter 3 Fully Launched Anti-Bacterials
  • This Chapter Identifies And Tabulates All Currently Approved Antibiotics (Around 200), Discussed In Relation To Antibiotic Resistance, Including Company, Pharmacological Mechanism, Use And Other Areas. This Includes New Recently Introduced Antibiotics. Summary
  • 3.1 Current Anti-Infectives
  • 3.2 Anti-Bacterials
  • 3.3 Bacterial Cell Wall Inhibitors
  • 3.4 Immune Stimulators
  • 3.5 30s/50s Ribosomal Inhibitors
  • 3.6 Dna Gyrase/Topoisomerase Inhibitors
  • 3.7 Other Antibiotics
  • 3.8 Discussion
• Chapter 4 Pipeline Anti-Bacterials
  • This Chapter Identifies And Tabulates All Pipeline Anti-Bacterials (Around 370), Discussed In Relation To Antibiotic Resistance, Developmental Stage (Pre-Clinical To Phase Iii/Initial Launch), Pharmacological Mechanism, Company And Other Areas. This Includes The Identification And Discussion Of The Most Promising Pipeline Antibiotics. Summary
  • 4.1 Pipeline
  • 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
• Chapter 5 Emerging Anti-Bacterials
  • This Chapter Identifies And Tabulates Patents On Anti-Bacterials (Around 340) Which Were Published Between Jan 2002 And May 2007. These Were Selected From More Than 1800 ""Anti-Infectives"" Patents Published Over The Same Time. Discussion Includes Pharmacological Mechanisms, Antibiotic Types, Patent Numbers, Companies, Originators And Other Areas. Important Candidates Are Selected For Discussion In Relation To Current Needs And The Combating Of Antibiotic Resistance. Summary
  • 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
• Chapter 6 Combating Antibiotic Resistance
  • Based On The Candidates, Technologies And Strategies Discussed In Chapter 2-5, This Chapter Reviews Current Antibiotics, Thinking, Strategies And Technologies Relating To The Combating Of Antibiotic Resistance Mechanisms, Citing Developmental Examples. Summary
  • 6.1 Background
  • 6.2 New Targets
  • 6.3 Multiple Activities
  • 6.4 Circumventing Resistance
  • 6.5 Mutations
  • 6.7 New Strategies
  • 6.8 Virulence
  • 6.9 Dissemination Of Traits
  • 6.10 Predicting Resistance
  • 6.11 Pathogenomics And The Resistome
  • 6.12 The Future
• Chapter 7 Companies
  • This Final Chapter Identifies And Discusses The Companies, Innovators And Research Groups With Existing Fully Approved Antibiotics, Developmental Or Research-Stage Candidates And Technologies.
  • 7.1 Companies
  • 7.2 Discussion

• 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-Mller Et Al., Danish Medical Bulletin Vol. 54, May 2007)
  • Figure 3.1 Current, Fully Launched Anti-Infectives
  • Figure 3.2 Categories Of Fully Approved Anti-Bacterial Therapeutics
• Tables
  • Table 2.1 Earss Surveillance Programme: Countries And Country Codes
  • Table 3.1a Fully Launched Antibiotics - Bacterial Cell Wall Inhibitors (-Lactams)
  • Table 3.1b Approved Antibiotics - Bacterial Cell Wall Inhibitors (-Lactams)
  • Table 3.2a Approved Antibiotics - Immune Stimulators/Modulators
  • Table 3.2b Approved Antibiotics - Immune Stimulators/Modulators
  • Table 3.3 Approved Antibiotics - Protein 30s/50s Ribosomal Subunit Inhibitors
  • Table 3.4 Approved Antibiotics - Dna Topoisomerase Atp Hydrolysing Inhibitor
  • Table 3.5a Approved Antibiotics - Other Antibiotics
  • Table 3.5b Approved Antibiotics - Other Antibiotics
  • Table 3.5c Approved Antibiotics - Other Antibiotics
• 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 (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 (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 (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 (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 (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 (Source: Earss).
    • Appendix 7 Anti-Bacterials On The Drug Development Pipeline
    • Appendix 8 Patent Applications For Antibiotics And Anti-Bacterials 2002-2007 (Source: Delphion, Wipo)
• This Report
  • This Report Reviews New Drug Innovation And Strategy To Combat Antibiotic Resistance Mechanisms. This Embraces Current Research-Stage Activities, Patents Published In The Last Five Year, The Entire Pharmaceutical Development Pipeline And Today's Existing Armoury Of Anti-Bacterial Drugs. The Report Reviews 370+ Pipeline Antibiotics And Anti-Bacterial Technologies (From Pre-Clinical To Phase Iii/Initial Launch), 340+ Antibiotic Patents Published Between Jan 2002 To May 2007 And More Than 200 Fully Launched Antibiotics. It Identifies And Discuss New Antibiotics, Technologies And Strategies At The Anti-Bacterial Mechanistic Level, That Are Specifically Being Developed To Combat Resistance Mechanisms. The Opportunities Which They Potentially Offer In Tackling The Increasing Global Threat Of Antibiotic Resistance, Are Discussed. The Report Looks In Depth At Current Developments And Thinking On How Antibiotic Resistance Can Be Tackled Technically And Strategically, From Improvements To Existing Drugs And Drug Combinations, To Completely Novel Molecules, New And More Promising Drug Targets And Approaches To Tackling Resistance At Its Source.
• Examples Of Key Findings
  • Antibiotic Resistance: The Need For Drugs That Combat Or Circumvent Antibiotic Resistance Mechanisms Is Now Pivotal To The Development Of New Anti-Bacterial Agents. The Nature Of Bacterial Resistance Mechanisms Means That The Activities Of New Anti-Bacterials At The Bactericidal Mechanistic Level Is A Fundamental Consideration And New Drugs Must Target Bacterial Pathogens In New Ways, Compared With Many Long-Established Antibiotics. A New Drug Discovery Era Is Emerging, Based On The Development Of Agents That Directly Combat Or Circumvent Antibiotic Resistance Mechanisms.
  • Current Antibiotics: Four Antibiotic Classes ( Lactams, Quinolones, Aminoglycosides And Macrolides), Against Which There Is Rapidly Developing Resistance, Represent Almost Three-Quarters Of All Currently Available Drugs. Whilst These Remain Important First-Line Antibiotics And Others Such As Vancomycin And More Recently Zyvox (Pfizer), Tigecycline (Wyeth) And Daptomycin (Cubist) Are Important In The Treatment Of Some Difficult Infections, Resistance Is Developing Against These Agents Too. Today's Armoury
  • Antibiotics And Drug Resistance, Biopharm Reports August 2007
  • Of Antibiotics Is Substantially Reliant On Antibiotics That Have Been Used For Many Years And There Is Increasing Dependency On A Small Number Of Drugs, Some Of Which Have Only Recently Entered The Market.
  • Development Pipeline: Currently There Are Around 370 Anti-Bacterials In The Development Pipeline, Around 60% Of Which Are At The Pre-Clinical Stage. Whilst A Number Of Promising Developmental Compounds Are In Late-Stage Development Such As Pfizer's Ramoplanin And Gsk's Retapamulin, Around Three Quarters Of Late Stage Candidates Are Based On Or Closely Related To Existing Fully Launched Drugs. Of The 315 Candidate Anti-Bacterials At The Pre-Clinical To Phase Ii Stages, Around 40% Are Closely Related To Established Classes Of Anti-Bacterials. In Contrast, 60% Of Pre-Clinical To Phase Ii Candidates Can Be Categorised As Novel Or Recently Developed. The Current Development Pipeline Shows Substantial Reliance On Anti-Bacterial Classes That Are Similar To Those Already In Use And Against Which Resistance Is Continuing To Rise, And A High Proportion Of Novel Candidates Are Still At The Pre-Clinical Stage.
  • Targeting Resistance Mechanisms: Many New Approaches Are Being Developed To Directly Target Bacterial Resistance Mechanisms. These Include New Target Identification, The Identification Of Targets Which May Preclude Or Circumvent Genomic/Phenotypic Adaptation By Bacteria Or Where This Is Considered More Difficult, Unique Combined-Activity Molecules, Inhibitors Of The Mutational Emergence Of Resistance Genes In Response To Synthetic Antibiotics, Novel Anti-Bacterial Technologies, New Targeting Strategies And Synthetic Or Semi-Synthetic Approaches Vs. Drugs Of Natural Origin. Other Areas Include Virulence Targeting And Novel Technologies.
  • Research And Patents: Analysis Of Global Patent Filings For The Period Jan 2002 To May 2007, Shows That More Than 1800 Documents Citing The Terms ""Antibiotic"" Or ""Anti-Bacterial"" Were Published During This Period, Under Ipc Class Coding A61k. Of These, 340 Were Selected For Further Examination In This Report And Show Important Areas Of Innovation Relating To The Combating Of Antibiotic Resistance.
  • Antibiotics And Drug Resistance, Biopharm Reports August 2007
  • Global Surveillance: Surveillance Data From More Than 35 Countries Show That Antibiotic Resistance Levels Continue To Rise Globally. In The Us It Is Reported That Between 50-60% Of All Hospital-Acquired Infections Are Caused By Antibiotic Resistant Bacteria, However Some Experts Believe That The Vast Majority Of Hospital-Acquired Infections Are The Result Of Drug Resistant Pathogens.
  • Deaths From Hospital-Acquired Infections In The Us Were 13,300 In 1992, Compared With Around 100,000 Today. This Shows Around A 700% Increase Over The Following Decade, Equivalent To Around A 20% Annual Growth During That Time. This Report Estimates That Healthcare Costs Due To Hospital-Acquired Infections In The Developed World, Exceed $30 Billion.
• From This Report
  • From: Section 6.5 Mutations
  • In The Past, Gene Mutation Has Been Attributed To Errors In Dna Replication, Through Mispairing Of Bases And Failed Dna Repair. Now, It Is Believed That Cells Themselves, Both Prokaryotes And Eukaryotes, Are Involved In The Mutational Process. Research On Escherichia Coli, Pioneered At The Scripps Research Institute By Prof. Floyd Romesberg, Has Shown That Under The Stress Of Being Exposed To Man-Made Antibiotics, Bacteria Up-Regulate Genes Which Code For Error-Prone Polymerases, Which Lead To The Emergence Of New Bacterial Mutations.
  • Resistance To Antibiotics Of Natural Origin (E.G. The Lactams) Is Commonly Due To Long-Established Bacterial Genes. However, In The Case Of Man-Made Antibiotics Such As Trimethoprim, The Quinolones And Sulfonamides, Antibiotic Resistance Is Thought To Rely On Mutations To Existing Genes, Which Subsequently Confer Survival Phenotypes. For Examples, Resistance To The Quinolone Antibiotic Ciprofloxacin Occurs Through Mutations In The Genes Coding For Gyrase (Gyra And Gyrb) Or Topoisomerase Iv (Parc And Pare).
  • Studies By Romesberg And His Colleagues Demonstrated (Cirz Et Al., Plos Biol 3(6): 2005) That When Escherichia Coli Were Treated With Ciprofloxacin And Rifampicin, Pathways Were Switched On Which Resulted In The Rapid Development Of Resistant Strains. A Protein Called
  • Lex A, A Serine Protease, Is An Important Mediator In This Process And The Scripps Groups Have Found That The Inhibition Of Lexa Prevented The Development Of Resistant Strains. Inhibitors Of Lexa Are Now Being Actively Researched As Potential Therapeutics To Block The Development Of Resistance In This Way. These Activities Are Being Carried Out In Collaboration With Achaogen Inc.
  • This Strategy, To Block The Ability Of Bacteria To Mutate In Response To Man-Made Antibiotics, May Offer Possibilities For Dual-Action Drugs Which Contain I) A Man-Made Bactericidal Agent And Ii) Molecules Which Inhibit The Development Of Resistance Through Stress-Induced Mutation (E.G. By The Inhibition Of Lexa).
  • From: Section 6.4 Circumventing Resistance
  • Broadly, Bacteria Develop Resistance In Two Ways; Either By Preventing The Antibiotic From Reaching The Target (Efflux, Blocking The Movement Of The Drug To The Target, Changing The Target) Or By Changing The Antibiotic In Some Way (E.G. Inactivation Of -Lactams By Lactamases).
  • One Example Of How Bacteria Are Able To Protect Themselves By Changing The Target Is Seen In The Case Of Vancomycin Resistance, Due To The Vana Gene Cluster. This Adaptive Change Results From A Relatively Minor Modification Of Lipid Ii, A Molecule Which Is Involved In The Delivery Of The Building Blocks Of Cell Wall Synthesis (Breukink Et Al., J. Biol. Chem., Vol. 278, No 22, 19898-19903, 2003). Vancomycin Works By Blocking The Delivery Of These Building Blocks. However, This Minor Adaptive Change In Lipid Ii Is Able To Block The Activity Of The Antibiotic, Without Loss Of Its Function In Cell Wall Synthesis.
  • An Important Factor Here Is That The Vana Gene Cluster Allows The Adaptive Change Of Lipid Ii. But What If Man-Made Antibiotics Were Designed To Target Bacterial Viability-Critical Molecules Which Could Not Change In This Way? Does This Offer A Better Strategy For Ensuring That These Kinds Of Bacterial Adaptations Cannot Take Place, Or Are Much More Difficult For The Organism? A Possible Example Of Such A Strategy Is Seen In The Case Of Peptide Antibiotic Nisin.
  • Nisin Is An Anti-Bacterial Polycyclic Peptide That Is Used As A Food Preservative. This Molecule Is The First Reported Example Of An Antibiotic That Kills Bacteria By Targeted Pore Formation And Substantially Targets Lipid Ii (Hasper Et Al., Biochemistry (2004) 43: 11567-75). Since Lipid Ii Is Integral To The Synthesis Of Bacterial Cells Wall, Substantial Adaptive Changes To This Molecule (I.E. To Block The Activity Of Nisin) Would Be Likely To Be Difficult. More Specifically, Nisin Binds To The Pyrophosphate Grouping Of Lipid Ii, Changes To Which Would Very Likely Undermine The Ability Of The Bacterium To Synthesise Its Own Cell Wall. As Such, Nisin Might Allow Resistance To Be Circumvented In Certain Pathogens And Such Strategies Offer The Prospect Of Developing Antibiotics To Which Certain Pathogens Cannot Adapt.
  • Pfizer's Ramoplanin, Which Is Currently In Phase Iii Clinical Development, Is Another Example Of An Antibiotic That Targets A Site Which May Circumvent Adaptation By The Bacterium. Ramoplanin's Cellular Target Is The Transglycosylation Step Of Peptidoglycan Biosynthesis (Fang Et Al., Mol. Biosyst., 2006, 2, 69-76). It Is Thought That It Will Be More Difficult Or Impossible For The Bacterium To Evolve Resistance, Since It Would Require Changes To The Way Bacteria Make Their Cell Walls.