1. 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

2. Basic Research Translational Research/ Product Development Clinical Research

3. 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

4. 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

5. Trans Atlantic Task Force on Antimicrobial Resistance - TATFAR EU-US Summit –November 2009 US and EU membership Objective: Promote information exchange, coordination and co- operation between the US and the EU 2011 Report: 17 recommended areas for further collaboration

6. Basic Research at NIAID

7. Basic Research Leads to Next Generation Interventions

8. NIAID/DMID Genomics Program SequencingFunctional Genomics Proteomics Structural Genomics Systems Biology Bioinformatics To address key questions in microbiology and infectious disease Genomic Research Resources Genomic/Omics Data Sets, Databases, Bioinformatics Tools, Biomarkers, 3D Structures, Protein Clones, Predictive Models

9. Translational Research at NIAID Vaccines Diagnostics Therapeutics

10. 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

11. 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

12. Importance of Diagnostics: Delay in early detection of infection Onset Symptoms Conventional Diagnosis Days & Weeks DELAY Empiric Therapy Isolate and Culture ID Susceptibility determined Inappropriate drug discontinued? Appropriate drug initiated

13. 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

14. 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

15. 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

16. Basic Translational Clinical (Product Development) Lowering Risk with Overlapping Funding Mechanisms Commercial Development Activities Licensed Products NIAID Scientific Activities Grants SBIR Cooperative Agreements Contracts Phase II Phase IV Preclinical and Clinical Services

17. DMID Resources for Researchers Search Term: DMID Resources

18. 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

19. FDA Licensure Basic Research Translational Product Development DMID preclinical services enable private sector support Performed GLP acute toxicity study in support of IND submission Investigator activity (R01 support) DMID service activity Novel Mab demonstrating activity against S. aureus Licensed to Sanofi-Aventis Successful Phase I trial Phase II trial planned Company activity S. aureus MAb

20. Clinical Research at NIAID

21. 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

22. Vaccine and Treatment Evaluation Units and Phase I Clinical Trial Units Phase I VTEUs

23. Decontamination of endotracheal tubes Evaluation of a new product for MRSA decolonization Trials to Assess Novel Methods to Prevent Infection Gram-negative sepsis vaccine Decolonization of MRSA in NICU Comparison of standard bathing vs. MRSA decolonization + chlorhexadine bathing

24. Post-Marketing Studies Optimal Utilization: Colistin Problem: Utilization studies on Colistin are necessary both to limit toxicity and to prevent the emergence of resistance. Colistin PK following inhalational administration Colistin alone versus colistin used in combination for treatment of MDR Gram- negative infections PK/PD of colistin in MDR Gram-negative bacterial infections with Acinetobacter and Pseudomonas NIAID-supported investigator activity DMID service activity Parallel EU activity

25. Investigator-Initiated R01 Table 3: Suggested loading dose Loading DoseAll patient categories Equation 9: Loading dose of CBA (mg) = colistin C ss,avg target b x 2.0 x body wt (kg). c See caveat in footnote c. First maintenance dose should be given 24 h later.

26. 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? Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance

27. 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

28. ARLG

29. Thank You … For listening