Download Dr Dennix Dixon, National Institute of Allergy and Infectious Disease

NIAID Antimicrobial Resistance
Research Efforts: Opportunities
for the Global Community
Dennis M. Dixon, PhD
Chief, Bacteriology and Mycology Branch
Division of Microbiology and Infectious
Diseases
NIAID, NIH, DHHS
November 26, 2013
• Basic Research
• Translational
Research/
Product
Development
• Clinical
Research
NIAID Research Agenda:
Comprehensive and Sustainable
• Basic Research
– Generation and
vetting of novel
scientific concepts
• Translational
– Reduction of concepts
to practical
implementation
• Clinical
– Rigorous safety and
efficacy testing of
candidate products
and practices
• Prevention
• Diagnosis
• Treatment
Interagency Task Force on Antimicrobial
Resistance
• Created in 1999
• Co-chaired by CDC, FDA, NIH
• A Public Health Action Plan to Combat
Antimicrobial Resistance
– Published in 2001
– Updated in 2011
– CDC has lead on Surveillance and Prevention
sections
– NIH/NIAID has lead on Research Section
– FDA has lead on Product Development
Section
Trans Atlantic Task Force on
Antimicrobial Resistance - TATFAR
• US and EU membership
• Objective: Promote
information exchange,
coordination and cooperation between the
US and the EU
• 2011 Report: 17
recommended areas for
further collaboration
EU-US Summit –November 2009
Basic Research at NIAID
Basic Research Leads to Next
Generation Interventions
NIAID/DMID Genomics Program
Proteomics
Sequencing
Functional
Genomics
Structural
Genomics
Systems
Biology
Bioinformatics
Genomic Research Resources
Genomic/Omics Data Sets, Databases, Bioinformatics Tools, Biomarkers, 3D Structures, Protein Clones, Predictive Models
To address key questions
in microbiology and
infectious disease
Translational Research at NIAID
• Vaccines
• Diagnostics
• Therapeutics
Partnerships Program
• Encourages partnerships formed by academic and
industrial investigators to accelerate the translational
research
• Focuses on preclinical product development
activities of candidate therapeutics, vaccines,
adjuvants, diagnostics, and related platform
technologies
• Clearly delineated Product Development Strategy
Vaccines to Reduce Antibacterial
Resistance: 2 Examples
• Strategy 1: Prevent Bacterial Infections
– Support for Staphylococcus aureus vaccines
• Investigator-initiated R01s and SBIRs
• Preclinical services to advance product
development
• 2010 and 2013 workshops to advance the field
• Strategy 2: prevent viral respiratory
infections
– Basic, translational and clinical support for
influenza and RSV vaccines
Importance of Diagnostics: Delay in
early detection of infection
Conventional Diagnosis
Symptoms
Appropriate
Inappropriate
Isolate and Susceptibility
drug drug
Culture IDdetermined
initiated
discontinued?
Empiric Therapy
Onset
DELAY
Days & Weeks
Diagnostics to Guide Treatment
• Nine targeted funding opportunities since 2010
addressing:
• Healthcare-Associated Infections
• POC Technologies
• Drug-Resistant Bacteria and Parasites
• 2011 TATFAR Workshop: Challenges and
Solutions in the Development of New Diagnostic
Tests to Combat Antimicrobial Resistance
• Capacity to support diagnostic validation through
the VTEU network
New Therapeutics for Resistant Pathogens:
Early to Mid-stage Development
• Small business grant program (SBIR)
• Partnerships Program, e.g., novel approaches
to treating Gram-negative bacterial infections:
– Novel antibacterial compounds with low resistance
potential
– Novel approaches to blocking efflux
– Novel drug delivery mechanism
– Disrupting Biofilms
– Disrupting signaling (quorum sensing; SOS response)
– Novel β-lactamase inhibitors
New Therapeutics for Resistant
Pathogens: Advanced Development
• Representative, recent contracts for the
development of novel broad-spectrum
antibacterials:
– β-lactamase inhibitor for treatment in conjunction with
the cephalosporin β-lactam-class of licensed
antibiotics
– new pyrimidoindole
– bicyclolide
– tetracycline
– inhalable, broad spectrum antibiotic based on the
potent anti-infective property of gallium citrate
– dual target antibiotics
Lowering Risk with Overlapping Funding
Mechanisms
Basic
Translational
Clinical (Product Development)
Licensed
Products
Grants
SBIR
Commercial
Development
Activities
Cooperative
Agreements
Phase IV
Contracts
NIAID
Scientific
Activities
Phase II
Preclinical and Clinical Services
DMID Resources for Researchers
Search Term: DMID Resources
NIAID Preclinical Services
• In vitro Assessment for Antimicrobial Activity
• Animal Models of Infectious Diseases
• Therapeutics Development Services
– Lead identification and development
– Chemistry and manufacturing
– In vitro microbiological services
– In vitro and in vivo preclinical safety, toxicology
and pharmokinetics
– Preclinical development, planning and
evaluation
DMID preclinical services enable private
sector support
S. aureus MAb
Basic Research
Translational
Novel Mab
demonstrating
activity against
S. aureus
Performed GLP
acute toxicity
study in
support of IND
submission
DMID service activity
Investigator activity (R01 support)
Company activity
Product Development
Licensed to Sanofi-Aventis
• Successful Phase I trial
• Phase II trial planned
FDA
Licensure
Clinical Research at NIAID
DMID general clinical research networks
• Vaccine and Treatment Evaluation Units
(VTEUs)
– Phase I-IV clinical trials
– Prevention and Treatment
– All DMID pathogens
• Phase I Clinical Trial Units for
Therapeutics
– Phase I clinical trials of new drugs
Vaccine and Treatment Evaluation
Units and Phase I Clinical Trial Units
Phase I
VTEUs
Trials to Assess Novel Methods to Prevent
Infection
Decontamination
of endotracheal
tubes
Gram-negative
sepsis vaccine
Evaluation of a
new product for
MRSA
decolonization
Decolonization of
MRSA in NICU
Comparison of
standard bathing
vs. MRSA
decolonization +
chlorhexadine
bathing
Optimal Utilization: Colistin
Problem: Utilization studies on Colistin are necessary both to limit
toxicity and to prevent the emergence of resistance.
Post-Marketing Studies
DMID service activity
NIAID-supported
investigator activity
PK/PD of colistin in MDR
Gram-negative bacterial
infections with Acinetobacter
and Pseudomonas
Parallel EU activity
Colistin PK following
inhalational
administration
Colistin alone versus
colistin used in
combination for
treatment of MDR Gramnegative infections
Investigator-Initiated R01
Table 3: Suggested loading dose
Loading Dose
All patient categories
Equation 9:
Loading dose of CBA (mg) =
colistin Css,avg targetb x 2.0 x
body wt (kg).c See caveat in
footnote c. First
maintenance dose should be
given 24 h later.
Targeted Clinical Trials to Reduce
the Risk of Antimicrobial Resistance
•
•
•
•
Do off-patent drugs work for CA-MRSA SSTI?
Is drug necessary for drainable abscesses?
Can treatment for pediatric UTI be shortened?
Can treatment for staphylococcal BSI be
shortened?
• Can treatment for AOM be shortened?
• Do combinations of drugs work better than single
drugs against BSI and HAP caused by GNB?
• Can a pharmacodynamically optimized regimen
improve the outcome of gram-negative VAP?
New: NIAID Antibacterial Resistance
Leadership Group (ARLG)
• PIs: Vance Fowler, M.D., Duke, and Henry
Chambers, M.D., UCSF, consortium of 20+
investigators
• Purpose: develop, design, implement and
manage a clinical research agenda to increase
knowledge of and mitigate the important
factors that drive antibiotic resistance
• Four priority areas:
• Gram-negative bacterial infections
• Gram-positive bacterial infections
• Diagnostics and devices
• Stewardship and infection prevention
ARLG
Thank You
… For listening