Pandemic Control: Resistant Organisms and Emerging Threats

Introduction
Study Goal And Objectives

Reasons For Doing The Study

Contributions Of The Study And For Whom

Scope And Format

Methodology

Information Sources

Analyst's Credentials

Related Bcc Work Credentials, Including Work Done By Other Authors

Bcc On-Line Services

Disclaimer

Summary
Summary Table:
Markets For 'New Antibiotics,' And Hiv/Aids Drugs By Category, Worldwide, Through 2009 ($ Millions)

Summary Figure:
Markets For 'New Antibiotics,' And Hiv/Aids Drugs By Category, Worldwide, 2001-2009 ($ Millions)

Overview
A Brief History Of Bugs And Man

Trends In Mortality From Infectious Diseases

Table 1 Trends In Mortality From Infectious Diseases: 1900-1990

Spanish Influenza Pandemic

Pathogenic Microbes And Infectious Diseases Recognized Between 1973 And 1997

Table 2 Disease-Causing Bacteria, Parasites And Viruses Identified Since 1973

Table 2 (Continued)

Setting The Stage For Pandemic Infectious Diseases

The Rapid Evolution Of Microbes

A Paradigm For A New Pandemic

Current Technologies For Addressing Potential Pandemic Threats

Table 3 Technologies To Address Potential Pandemic Threats

The New Antibiotic Market
The Greatest Challenge Facing The Anti-Infective Drug Market-Drug Resistance

The Crisis Of Antibiotic Resistance

The Microbiology Of Bacterial Resistance

Mechanisms Of Resistance

Beta-Lactamase Production

Importing Resistance Genes From Other Organisms

Alteration Of Binding Sites To Circumvent Anti-Infective Effectiveness

Antibiotic Efflux

Geographic Snapshot Of Resistance

The Primary Reasons For The Development Of Antibiotic Resistance

Broad Spectrum Prescriptions

Patient Pressure

Healthcare Policy

International Efforts To Address Microbial Resistance

Efforts By The World Health Organization

Efforts By The U.S. Congress

Strategies Implemented In The United Kingdom

No Advocates For Multidrug-Resistant Bacterial Diseases

The Impact Of Thinning Pipelines

The Impact Of Thinning Pipelines (Continued)

The Effect Of Drug Shortages

The Role Of Counterfeit Drugs

Insurers Get Involved

Resistance By Class Of Antibiotic

Fluoroquinolones

Mrsa Correlation

Expanded-Spectrum Fluoroquinolones

Median Mic90 Values Of Gram-Negative Organisms To Selected Fluoroquinolones

Table 4 Median Mic90 (Microgram/Ml) Values Of Gram-Negative Organisms To Selected Marketed And Development-Stage Fluoroquinolones

Table 5 Median Mic90 (Microgram/Ml) Values Of Gram-Positive Organisms To Selected Marketed And Development-Stage Fluoroquinolones

Macrolides

Prescription Use In Selected Countries

Table 6 Annual Macrolide Prescriptions Per 1,000 Inhabitants In Six Countries In 1980 And 1990

Antibiotic Use And Rate Of Macrolide-Resistant Streptococcus Pneumoniae In Selected Countries.

Table 7 Total Macrolide Use And Rate Of Macrolide-Resistant S. Pneumoniae In Selected Countries

Antibiotic Use And The Rate Of Macrolide-Resistant Streptococcus Pyogenes In Selected Countries

Table 8 Total Macrolide Use And Rate Of Macrolide-Resistant S. Pyogenes In Selected Countries

Penicillins

Table 9 Annual Beta-Lactam Prescriptions Per 1,000 Inhabitants In Six Countries In 1980 And 1990

Table 10 Total Antibiotic Use And Rate Of Penicillin-Nonsusceptible S. Pneumoniae In Selected Countries

Table 10 (Continued)

Selected Other Agents

Table 11 Percent Resistance To Ceftazidime, Ciprofloxacin, Imipenem And Piperacllin In P. Aeruginosa Isolates From Blood: San Francisco County, California, 1996-1999 (%)

The Leading Drug-Resistant Bacteria

Hospital And Community-Acquired Bacterial Pathogens In The U.S.

Table 12 Annual Incidence Of Infections Caused By Hospital- And Community-Acquired Bacterial Pathogens: U.S.

Disease Incidence By Bacterial Pathogen In U.S.

Table 13 Disease Incidence By Bacterial Pathogen (U.S.)

Selected Resistant Bacteria

Table 14 Selected Organisms And Agents To Which They Have Developed Resistance

Table 14 (Continued)

Enterococcal Infections

Vancomycin Resistance

Variant Esp Gene Vancomycin-Susceptible E. Faecium

Biofilm-Formation Capacity

Ampicillin Resistance

Table 15 Resistance Patterns Among Enterococcal Organisms Isolated From Bloodstream Infections

Escherichia Coli

Helicobacter Pylori

Hemophilus Influenzae

Klebsiella Pneumoniae

Pneumococcus

Pseudomonas Aeruginosa

Table 16 In Vitro Susceptibility Of P. Aeruginosa Isolates From Patients With Lower Respiratory Tract Infections

Staphylococcus Aureus

Mrsa

Community-Acquired Mrsa

Nursing Homes

Intensive Care Units And Medical Devices

Vancomycin Resistance

Streptococcal Infections

Streptococcus Pneumoniae

Penicillin And Other Drug Resistances

Geographic Specificity

Cephalosporin Resistance

Table 17 Comparison Of Percent Of Streptococcus Pneumoniae Isolates Nonsusceptible To Third-Generation Cephalosporins By Site: Antibiograms Versus Abcs

Erythromycin Resistance

Table 18 Comparison Of Percent Of Streptococcus Pneumoniae Isolates Nonsusceptible To Erythromycin By Site: Antibiograms Versus Abcs

Penicillin Resistance

Table 19 Comparison Of Percent Of Streptococcus Pneumoniae Isolates Nonsusceptible To Penicillin By Site: Antibiograms Versus Abcs

Serotype 3

New Developments

Foodborne Pathogens

Drug Resistance In Selected Diseases

Dysentery

Pneumonia

Leading Causes

Table 20 Frequency Of Occurrence Of Bacterial Pathogens Implicated In Pneumonia In Hospitalized Patients, Us.

Bacterial Versus Viral Infections

Penicillin-Resistant Cases In Selected Countries

Table 21 Percentage Of Hospitalized Patients In Selected Countries Infected With Penicillin-Resistant Pneumococci

Demand For Broad-Spectrum Drugs

Community-Acquired Pneumonia

Salmonella Infection

Tuberculosis

Tuberculosis (Continued)

The Who's Global Project On Anti-Tuberculosis Drug Resistance Surveillance

Geographic Specificity

Table 22 Percentage Of Drug-Resistant Strains Among New Cases Of Tuberculosis In Selected Countries, 2000

Geographic Specificity (Continued)

2004 Update On The Problem Of Mdr Tuberculosis

Applying Effective Treatment

The Dots Plan

Developing Effective Diagnostics For Detection Of Mdr Tuberculosis

Current Methods

Strategies To Combat Bacterial Resistance In The Hospital Setting

Development Of Narrow-Spectrum Agents

Avoidance Of Underdosing

Rotating Antibiotic Agents

Surgical Prophylaxis

Antibiograms

The Ideal Antibiotic

The Relationship Of Drug Resistance To The Use Of Antibiotics In Agriculture

Factors Contributing To Overuse Of Antimicrobials In Food Animals

Screening For Antibiotics In Food Animal Products

Drug-Resistant Bacteria In Livestock

Fluoroquinolone Resistance

Vancomycin Resistance

Avoparcin

Aquaculture

Government Regulation

Global Efforts To Address Antimicrobial Usage In Agriculture

Microbes In Livestock Manure

Technological Strategies To Combat Resistance

Efflux Pump Inhibitors

Mechanism

Efficacy

Research

Adverse Effects

Prions

Quorum Sensing

Quorum Sensing (Continued)

Sequencing Of Bacterial Genomes

The Market For Selected 'New Antibiotic' Products

Table 23 Worldwide Sales And Year Of Fda Approval Of Selected 'New Antibiotic' Prdocuts, Through 2009 ($ Millions)

Table 24 The Markets For Selected New Antibiotics And Existing Antibiotics, By Category: Worldwide Sales, Through 2009 ($ Millions)

Figure 1 The Markets For Selected New Antibiotics And Existing Antibiotics, By Category: Worldwide Sales, 2001-2009 ($ Millions)

Market Share By Company For New Antibiotics

Figure 2 Market Share By Company For New Antibiotics: 2004 And 2009 (%)

Products Targeted At Antibiotic Resistance

Products Introduced In 2001, 2002 And 2003

Table 25 Antibacterial Product Approvals, U.S.: 2001-2003

Table 25 (Continued)

Table 25 (Continued)

Selected Products Approved In 2001, 2002 And 2003

Cubicin

Mechanism

Indications

Market

Factive

Invanz

Levaquin

Spectracef

Tequin

Vigamox

Zithromax

Mechanism And Efficacy

Market

Zithromax Single Dose, Tri-Pak And Ivvial-Mate

Zosyn

Zymar

Zyvox

Selected Products Projected To Be Introduced In 2004 And 2005

Table 26 Projected Antibacterial Product Approvals, U.S.: 2004-2005

Table 26 (Continued)

Table 26 (Continued)

Table 26 (Continued)

Abt-773

Augmentin Xr

Choleragarde

Cubicin

Dalbavancin

Doripenem

Faropenem

Floxin Otic

Gracevit

Helicide

Iclaprim

Isv-401

Ketek

Ketek (Continued)

Mbi-226

Merrem I.V.

Oritavancin

Ramoplanin

Rifaximin

Segard

Staphvax

Tifacogin

Tigecycline

Zithromax

Selected Promising Products In Earlier Stages Of Development

Altastaph

Glycodendriprotein

Iseganan

Lysostaphin

Oligosaccharides

Oxazolidinones

Zyvox

Streptogramins

Synercid

Synercid (Continued)

Innovative Technologies In Early Research
Antibiotic-Producing Bacteria

Bacteriophages

Bacteriophages (Continued)

Q Beta

Natural Protective Mechanisms Of Bacteria

Natural Protective Mechanisms Of Bacteria (Continued)

Nubiotics

Peptide Drugs

Peptide Deformylase Inhibitors

Viral Pandemic Threats
What Is A Virus?

The Viral Pandemic Of 2004 - Human Immunodeficiency Virus (Hiv) Infection And Acquired Immune Deficiency Syndrome (Aids)

The Viral Pandemic Of 2004.. (Continued)

Transmission Of Hiv

Early Symptoms And Progress Of Hiv Infection

The Expanded Definition Of Aids

The Pandemic

Hiv And Aids In Africa - A Timeline Of Death

Leading Causes Of Death

Table 27 Leading Causes Of Death In Africa: 2000

Life Expectancy

Table 28 Life Expectancy In Selected African Countries: 1950-2000

Table 28 (Continued)

Hiv And Aids In The Ex-Soviet Bloc-An Africa In The Making?

Mathematical Models For The Aids Epidemic

Mathematical Models For The Aids Epidemic (Continued)

Hiv And Aids Statistics

Number Of Hiv/Living With Aids Cases In 2003 By Geographic Region

Table 29 Estimated Number Of Persons Infected With Hiv/Living With Aids, Adults And Children, By Geographic Region: 2003

Geographic Region 2003 Percentage Of Global Hiv Cases By Geographic Region

Table 30 Percent Of Global Hiv Cases By Geographic Region: 2003

New Hiv Cases In 2003 By Region

Table 31 Estimated Number Of People Newly Infected With Hiv, Adults And Children, By Geographic Region: 2003

Increase Of Hiv Cases By Region From 1999 To 2002

Table 32 Increase In Number Of People Newly Infected With Hiv, Adults And Children, By Geographic Region: 1999-2002

2003 Aids Deaths By Region

Table 33 Estimated Number Of Deaths From Aids, Adults And Children, By Geographic Region: 2003

Estimated Number Of Hiv Cases By Country In 2002 And 2010

Table 34 Estimated Number Of People Infected With Hiv In Selected Countries: 2002 And 2010

Hiv Infection And Aids Cases In The U.S.

The Dire Need For Better Access To Treatment

Table 35 Percent Of Patients By Geographic Region Receiving Antiretroviral Treatment For Hiv Infection

The Impact Of The Availability Of Antiretroviral Therapy

The Introduction Of Haart

Table 36 Number Of Deaths From Aids In The U.S., 1988-2002

Efforts To Reduce The Cost Of Hiv Drugs In The Developing World

Boehringer Ingelheim And Glaxosmithkline Sign Agreements

Aids Healthcare Foundation Lawsuit

Government Lawsuits

Sub-Saharan Africa Generic Production Agreement

Merck Announces Reduction Of The Cost Of Stocrin

Council Of Ministers Program Slow To Recruit Participants

Efforts To Make Generic Hiv Drugs Available In Developing Countries

The World Trade Organization Steps In

Generic Manufacturers Make A Bold Play

A Strategy To Gain A Foothold In The World Market

The Bush Administration Moves To Restrict Access To Generic Hiv Drugs

Clinton Foundation Negotiates Lower Drug Prices For Poor Countries

Other Struggles To Gain Access To Generic Hiv Drugs

'The 3 By 5 Initiative'

Near-Term Objectives

Main Plan Objectives

Drug Resistance In Hiv/Aids

Definition Of Antiviral Drug Resistance

How Resistance Develops

Locations Of Mutations

Current Status Of Resistance

2003 Catch Study

Resistance Among Hiv Cases In Europe

Table 37 Resistance Among Hiv-Positive Patients In Europe As Determined By The Catch Study

Conclusions

Acute Infection And Early Disease Research Program

2nd International Aids Society Conference

San Francisco Study Of Pockets Of Resistance Epidemics

Epidemic Control Recommendations

Types Of Drug Resistance Testing

Genotypic And Phenotypic Testing

Table 38 Protease Mutations

Table 39 Reverse Transcriptase Mutations

Genotypic And Phenotypic Testing (Continued)

Table 40 Advantages And Disadvantages Of Genotypic Versus Phenotypic Testing

Reimbursement For Hiv Drug Resistance Testing

Guidelines For Hiv Drug Resistance Testing

The Special Case Of Protease Inhibitors

The Rationale For Genotypic Testing For Hiv-I Drug Resistance

Available Hiv Drug Resistance Tests

New Saliva Test Approved To Detect Hiv

Cost Of Hiv/Aids Treatment

Table 41 Estimated Annual Costs For Haart In U.S. And Sub-Saharan Africa

Abbott Increases The Cost Of Norvir Five-Fold

Table 42 Comparison Of Average Annual Cost Of Boosted* Protease Inhibitor-Based Hiv Treatment Regimens Before And After Norvir Price Increase

Available Products For The Treatment Of Hiv Infection And Aids

Table 43 Fda-Approved Drugs For The Treatment Of Hiv Infection/Aids

Table 43 (Continued)

Products For The Prevention/Treatment Of Antiviral Diseases Introduced In 2001, 2002 And 2003

Table 44 Antiviral And Vaccine Product Introductions, U.S.: 2001-2003

Table 44 (Continued)

Table 44 (Continued)

The Market For Products To Treat Hiv Infection And Aids

Table 45 The Market For Selected Hiv/Aids Therapeutics: Worldwide Sales, Through 2009 ($ Millions)

Table 46 The Market For Selected Hiv/Aids Therapeutics By Product Category: Worldwide Sales, Through 2009 ($ Millions)

Figure 3 The Market For Selected Hiv/Aids Therapeutics By Product Category: Worldwide Sales, 2001-2009 ($ Millions)

Figure 4 Market Share Of Hiv/Aids Drugs By Product Category, Worldwide Sales, 2003 And 2009 ($ Millions)

The U.S. Market For Hiv/Aids Drugs

Table 47 The Market For Selected Hiv Therapeutics: U.S. Sales, Through 2009 ($ Millions)

Combination Products Emerge As Preferred Treatment

Leading Marketers Of Hiv/Aids Drugs

Leaders In The Nucleoside Reverse Transcriptase Inhibitor Class

Categories Of Drugs Available For The Treatment Of Hiv/Aids

Entry Inhibitors, Fusion Inhibitors And Receptor Inhibitors

Entry Inhibitors, Fusion Inhibitors And Receptor Inhibitors (Continued)

Immunotherapies

Nonnucleoside Reverse Transcriptase Inhibitors

Nucleoside Reverse Transcriptase Inhibitors

Nucleotide Reverse Transcriptase Inhibitors

Protease Inhibitors

Selected Hiv/Aids Drugs Introduced To The U.S. Market In 2001, 2002 And 2003

Fusion Inhibitors

Nonnucleoside Reverse Transcriptase Inhibitors

Sustiva

Nucleoside Reverse Transcriptase Inhibitors

Emtriva

Nucleotide Reverse Transcriptase Inhibitors

Protease Inhibitors

Lexiva/Telzir

Reyataz

Reyataz (Continued)

Kaletra

Table 48 Protease Inhibitor Prescription Market Share, By Product, June 1, 2003 To November 30, 2003: U.S.

Dosing And Compliance Challenges

Table 49 Daily Dosage Requirements For Selected Hiv/Aids Therapies

Table 50 Relationship Between Compliance And Dosing Frequency

The Ideal Treatment Regimen

The Number Of Salvage Patients Continues To Increase

Drugs In Development For The Treatment And/Or Prevention Of Hiv Infection And Aids

Table 51 Products In Phase Ii Or Later Development For The Treatment And/Or Prevention Of Hiv Infection/Aids

Table 51 (Continued)

The Four Main Targets For Antiretroviral Drugs

Entry Mechanisms

Integrase

Protease

Reverse Transcriptase

Antiviral Products Projected To Be Introduced In 2004 And 2005

Table 52 Projected Product Introductions To Address Viral Diseases: 2004-2005

Table 52 (Continued)

C31g 1% Vaginal Gel

Capravirine

Remune

Viread/Emtriva Combination Product

Other Products In Late-Stage Development

Tmc-114

Tipranavir

Other Selected Products In Earlier Development

Ccr5 Antagonists

Hiv-Hemopurifier

Pro-542

Vgx-410

Viread

Aids Vaccines In Development

Status Of Selected Products

Table 53 Selected Hiv And Aids Vaccines In Development

Table 53 (Continued)

Class And Vector Of Selected Products

Table 54 Vaccine Type And Vectors For Hiv Vaccines In Phase I/Ii Trials

Development Strategies

Barriers

Vaccine Candidates And Target Market

Results Of Early Trials With Hiv/Aids Vaccines

Aidsvax

Alvac Hiv

Gp120 Vaccines

Gp160 Vaccines

Live Virus Hiv Vaccine

Other Emerging Viral Disease Threats
Dengue Virus

Ebola Virus

Outbreak Locales

Infection And Transmission

Recovery Factors

Diagnosis

Treatment

Enteroviruses

Hantaviruses

Influenza

The Algorithm Of The Pandemic

Avian Influenza

The Concern About The H5n1 Subtype

Influenza Type A

Progress Made Since The 1918-1919 Pandemic

Diagnostic And Therapeutic Products For Influenza

Flumadine

Relenza

Symmetrel

Tamiflu

Vaccines

Marburg Virus

Outbreak Locales

Infection And Transmission

Diagnosis

Recovery Factors

Treatment

Nipah Virus

Outbreak Locales

Infection And Transmission

Treatment

Norwalk Virus

Severe Acute Respiratory Syndrome

Variant Creutzfeldt-Jakob Disease

Infection And Transmission

Mbm And Export Bans

Outbreak Locales

West Nile Virus

Yellow Fever

Infection And Transmission

Outbreak Locales

Recovery Factors

Diagnosis

Treatment

Company Profiles
Avant Immunotherapeutics, Inc.

Business Overview

Financial Information

Products

Table 55 Avant Immunotherapeutics' Product Pipeline

Corporate Strategy

Biosynexus, Inc.

Business Overview

Products

Corporate Strategy

Bristol-Myers Squibb

Business Overview

Financial Information

Products

Corporate Strategy

Chiron Corp.

Business Overview

Financial Information

Products

Table 56 Selected Vaccines And Biopharmaceuticals In Chiron's Product Pipeline

Corporate Strategy

Cubist Pharmaceuticals, Inc.

Business Overview

Financial Information

Products

Products (Continued)

Corporate Strategy

Gilead Sciences, Inc.

Business Overview

Financial Information

Products

Table 57 Gilead's Product Pipeline

Corporate Strategy

Glaxosmithkline Plc

Business Overview

Financial Information

Table 58 Glaxosmithkline's Antibacterial And Hiv/Aids Product Sales, 2002 And 2003 ($ Millions)

Products

Table 59 Glaxosmithkline's Antibacterial, Hiv/Aids Drugs And Antiviral Vaccine Product Pipeline

Corporate Strategy

Intermune, Inc.

Business Overview

Financial Information

Products

Corporate Strategy

Micrologix Biotech Inc.

Business Overview

Financial Information

Products

Table 60 Micrologix's Product Pipeline

Company Strategy

Oscient Pharmaceuticals, Inc. (Formerly Genome Therapeutics Corp.)

Business Overview

Financial Information

Products

Table 61 Oscientoscient Pharmaceuticals' Product Pipeline

Corporate Strategy

Table 62 Oscient Pharmaceuticals' Corporate Partnerships

Pfizer Corp.

Business Overview

Financial Information

Products

Corporate Strategy

Salix Pharmaceuticals, Inc.

Business Overview

Financial Information

Products

Corporate Strategy

Vicuron, Inc.

Business Overview

Financial Information

Products

Table 63 Vicuron's Product Pipeline

Corporate Strategy

Virologic, Inc.

Business Overview

Financial Information

Products

Corporate Strategy