The U.S. National Antimicrobial Resistance Monitoring System: Achievements and Challenges Patrick McDermott, Ph.D. Director, NARMS U.S. Food & Drug Administration Center for Veterinary Medicine Office of Research Laurel, MD USA
The Golden Age of Antibiotics Began in 1933, when an antibiotic called sulfanilamide cured a 10-month old German infant dying of a bloodstream staphylococcal infection. Gerhard Domagk, sulfa drug pioneer. Nobel Prize, 1939
The Golden Age of Antibiotics For most of the infectious diseases on the wards of Boston City Hospital in 1937, there was nothing that could be done beyond bed rest and good nursing care. Then came the explosive news of sulfanilamide, and the start of the real revolution in medicine. I remember the astonishment when the first cases of pneumococcal and streptococcal septicemia were treated in Boston in 1937. The phenomenon was almost beyond belief. Here were moribund patients, who would surely have died without treatment, improving within a matter of hours and feeling entirely well within the next day we became convinced, overnight, that nothing lay beyond reach for the future. Lewis Thomas. Notes of a Medicine Watcher. 83. Viking Press Albert Lasker Award Member of the NAS National Book Award
The Golden Age of Antibiotics 1952
Words of Caution The Nobel Prize in Physiology or Medicine 1945 "for the discovery of penicillin and its curative effect in various infectious diseases" Sir Alexander Fleming Sir Howard Florey Ernst Chain Sir Alexander Fleming Nobel Lecture, December 11, 1945 It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body.
Impact of Resistance 1. More expensive/toxic drugs 2. Additional diagnostic testing 3. Extended length of stay in the hospital 4. Costs to patient/family-time from work, increased mortality 5. Resistance genes remain a problem for the future the hospital/farm as reservoir
Summary of International Activities TATFAR created in 2009 to promote cooperation and info exchange between US and EU on human and animal aspects of AMR GHSA AMR action package Surveillance, one health, and R&D working groups WHO GAP 2015 requests the Member States to effectively address the problem by strengthening their national systems Surveillance GLASS PAHO addressing AMR G7 - under the 2015 German Presidency suggested convening an experts group includes Japan G20 China plans to make AMR a subject for their presidency in 2016 7
The US National Action Plan March 2015 Outlines steps for implementing the National Strategy on Combating Antibiotic- Resistant Bacteria and addressing the policy recommendations of the President s Council of Advisors on Science and Technology (PCAST) report on Combating Antibiotic Resistance. Five goals: 1. Slow the emergence of resistant bacteria and prevent the spread of resistant infections. 2. Strengthen national one-health surveillance efforts to combat resistance. 3. Advance development and use of rapid and innovative diagnostic tests for identification and characterization of resistant bacteria. 4. Accelerate basic and applied research and development for new antibiotics, other therapeutics, and vaccines. 5. Improve international collaboration and capacities for antibiotic-resistance prevention, surveillance, control, and antibiotic research and development. Includes information sharing, surveillance (drug use and resistance), stewardship initiatives, risk assessments, and more. 8
Level of concern depends on pathogen and type of resistance Urgent Threats Clostridium difficile Carbapenem-resistant Enterobacteriaceae (CRE) Drug-resistant Neisseria gonorrhoeae Serious Threats Multidrug-resistant Acinetobacter Fluconazole-resistant Candida (a fungus) Vancomycin-resistant Enterococcus (VRE) Multidrug-resistant Pseudomonas aeruginosa Drug-resistant Salmonella Typhi Drug-resistant Shigella Methicillin-resistant S. aureus Drug-resistant Streptococcus pneumoniae Drug-resistant tuberculosis Drug-resistant Campylobacter Drug-resistant Non-typhoidal Salmonella ESBL + Enterobacteriaceae Concerning Threats Vancomycin-resistant S. aureus (VRSA) Erythromycin-resistant Group A Streptococcus Clindamycin-resistant Group B Streptococcus
FDA Center for Veterinary Medicine Strategy to Limit Resistance Multipronged strategy designed to limit or reverse resistance arising from the use of antibiotics in food-producing animals, while continuing to ensure the availability of safe and effective antibiotics for use in animals and humans The National Antimicrobial Resistance Monitoring System 1996 Extralabel use prohibition of fluoroquinolones and glycopeptides 1997 Revised safety assessment process (GFI #152) 2003 Withdrawal enrofloxacin in poultry 2005 Revised judicious use guidance (GFI #209) 2012 Cephalosporin extralabel use prohibition 2012 Industry guidance on eliminating production uses (GFI #213) 2013 Enhanced annual summary of antibiotic sales data 2014 Update on veterinary feed directive (GFI #120) 2015 Collaboration with international partners (WHO, OIE, Codex)
What is integrated surveillance of antimicrobial resistance in foodborne bacteria? The coordinated sampling and testing of bacteria from food animals, foods, and clinically ill humans; and the subsequent evaluation of antimicrobial resistance trends throughout the food production and supply chain using harmonized methods. Source: WHO-AGISAR report
Purpose of Integrated Surveillance 1. Baselines - Document resistance levels in different reservoirs 2. Spread - Describe the spread of resistant bacterial strains and resistance genes 3. Trends - Identify temporal and spatial trends in resistance 4. Attribution - Generate hypotheses about sources and reservoirs of resistant bacteria 5. Risk analysis - Understand links between use practices and resistance 6. BOI - Identify risk factors and clinical outcomes of infections caused by AMR bacteria 7. Education - Provide data for education on current and emerging hazards 8. Policy - Guide evidence-based policies and guidelines to control antimicrobial use in hospitals, communities, agriculture, aquaculture, and veterinary medicine 9. Regulations Pre-harvest - Support risk analysis of foodborne antimicrobial resistance hazards Post-harvest - Identify interventions to contain resistance and evaluate their effectiveness 10. Evaluate interventions - 11. Go back to #1 12
Challenges of Integrated Surveillance for Antimicrobial Resistance 1. Gathering accurate information and bacterial isolates is expensive and laborious 2. Burden of illness and food consumption data are needed for design and prioritization of pathogens and commodities 3. Sound sampling scheme along the food chain is critical for valid trend analysis 4. Combining resistance and use data in a meaningful way 5. Cooperation, collaboration, good communication and data sharing between a. agriculture, industry and public health sectors b. microbiologists & epidemiologists within and across sectors
Challenges of Integrated Surveillance for Antimicrobial Resistance 6. Political/financial support - Requires recognition of the public health issues and the need for ongoing risk assessments 7. Establish a process for review and enhancement 8. Remain flexible in order to stay current 9. Adapt to changing technologies 10. Understanding the implications of the data and the need for research 11. Publishing often very complex findings to different audiences in a timely manner 12. Using the data to formulate sound public health policy 13. International harmonization and cooperation
Bacteria Tested Human - CDC Non-Typhoidal Salmonella (1996) Campylobacter (1997) E. coli 0157:H7 (1996) Salmonella Typhi (1999) Shigella (1999) Vibrio Enterococcus (2001) E. coli (2004) Animal - USDA Non-Typhoidal Salmonella (1997) Campylobacter (1998) E. coli (2000) Enterococcus (2003) Retail Meats - FDA (2002) Non-Typhoidal Salmonella Campylobacter Enterococcus E. coli
NARMS Objectives 1. Monitor trends in antimicrobial resistance among foodborne bacteria from humans, retail meats, and animals 2. Disseminate timely information on antimicrobial resistance to promote interventions that reduce resistance among foodborne bacteria 3. Conduct research to better understand the emergence, persistence, and spread of antimicrobial resistance 4. Assist the FDA in making decisions related to the approval of safe and effective antimicrobial drugs for animals
NARMS Strategic Plan Goal 1: To develop, implement and optimize a shared database, with advanced data acquisition and reporting tools Goal 2: To make sampling more representative and more applicable to trend analysis Goal 3: To strengthen collaborative research projects to address high risk food safety issues 2012-2016 Goal 4: To support international activities which promote food safety, and mitigate the spread of antimicrobial resistance
1. Monitor Trends: Sampling Strategy 18
Human isolated testing - CDC Bacteria isolated at the state laboratory and sent to CDC for susceptibility testing and additional analyses Non-typhoidal Salmonella- all 50 states submit every 20th isolate Campylobacter- 10 FoodNet sites submit every 2nd, 3rd, or 5th isolate More details at www.cdc.gov/narms
Retail meat testing - FDA 14 sites total since 2013 2002- mid 2015 each site collected 40 meats/month (10 each of chicken parts, ground turkey, pork chop, and ground beef) Beginning mid 2015 each site collects 80 meats/month (40 chicken parts, 20 ground turkey, 10 pork chop, and 10 ground beef) All sites culture for Salmonella (all meat types) and Campylobacter (poultry) Four sites culture for E. coli and Enterococcus Isolates are sent to FDA for analysis Sample total = 6,720 per annum 13,440
History of NARMS - USDA 1. In Plant FSIS PR/HACCP samples Western Lab Midwestern Lab Eastern Lab ARS Eastern Lab received Salmonella isolates Old System (HACCP) Pathogen Swine Cattle Chicken Turkeys Campylobacter Salmonella x x x x x Chicken carcasses Campylobacter, E coli, Enterococcus Samples taken by FSIS veterinarians and inspectors at FSIS-regulated plants and establishments Cecal samples better reflect animal status and less confounded by plant events A randomized, nationally representative testing of slaughterhouses Ability to distinguish production classes Complete microbiology for all animal species E. coli x Enterococcus Pathogen New System (Cecal) Swine hogs, sows Cattle dairy, beef steers, heifers x Chicken Turkeys Campylobacter x x x x Salmonella x x x x E. coli x x x x Enterococcus x x x x
History of NARMS USDA 2. On-Farm Collaboration with USDA- Agricultural Research Service (ARS) and University partners Examining resistance on farm and differences between farm and slaughter Looking for rare phenotypes (early detection) Interventions Drug use information 22
NARMS Highlights 2013 About 80% of human Salmonella isolates are not resistant to any of the tested antibiotics, a finding that has not changed in the past 10 years. Further, resistance to ceftriaxone, azithromycin, and quinolones, three important drugs used to treat human Salmonella isolates, remains below 3%. Salmonella multi-drug resistance (resistance to three or more classes of antibiotics) in human, cattle, and chicken isolates has not changed or declined in the last decade, CipR C. jejuni resistance was at its lowest level in retail chicken to date (11%). 23
Multidrug resistance (MDR) in human isolates of a common Salmonella serotype (l 4,[5],12:i:-) continues to rise. Resistance has more than doubled from 18% in 2011 to 46% in 2013. NARMS Highlights 2013 An increase in MDR and ceftriaxone resistance was also observed in Salmonella serotype Dublin isolated from cattle and human sources. 24
Resistance in Salmonella from Humans: 1948-1990s 25
Resistance in Salmonella from Humans: 1996-2011 26
Resistance in Salmonella from Humans: 1948-2011 27
1. Monitor Trends: Laboratory Methods 28
Antimicrobial Susceptibility Testing NCCLS Quality Control Organisms (ug/ml) Antimicrobial Resistant NARMS #wells Ranges S. aureus E. faecalis E. coli P. aeruginosa Within breakpoint /plate ug/ml 29213 29212 25922 27853 CLSI QC cefoxitin >=32 7 0.5-32 1-4 1-4 yes azithromycin >=16 8 0.125-16 0.25-2 64-256 0.5-4 1-4 yes chloramphenicol >=32 5 2-32 2-8 4-16 2-8 yes tetracycline >=16 4 4-32 0.12-1 8-32 0.5-2 8-32 yes ceftriaxone >=4 8 0.5-64 1-8 0.03-0.12 8-64 yes amoxicillin/clavulanate >=32/16 6 1-32 0.12-0.5 0.25-1 2/1-8/4 yes ciprofloxacin >=4 9 0.015-4 0.12-0.5 0.25-2 0.004-0.015 0.25-1 yes gentamicin >=16 7 0.25-16 0.12-1 4-16 0.25-1 0.5-2 yes nalidixic acid >=32 7 0.5-32 1-4 yes ceftiofur >=8 7 0.12-8 0.25-1 0.25-1 16-64 yes sulfamethoxazole >=512 6 16-512 32-128 32-128 8-32 yes trimethoprim/sulfa >=4/76 6 0.12-4 <0.5/9.5 <0.5/9.5 <0.5/9.5 8/152-32/608 yes kanamycin >=64 4 8-64 1-4 16-64 1-4 yes ampicillin >=32 6 1-32 0.25-1 0.5-2 2-8 yes streptomycin none 2 32-64 None positive control 3 negative control 1 Total # wells 96 in CLSI QC range 29
Drug selection Important in veterinary medicine (e.g. tetracycline) Important in human medicine (e.g. carbapenems) Important in both human and veterinary medicine (e.g. cephalosporins, fluoroquinolones) Epidemiologic markers (e.g. chloramphenicol) Harmonized with CIPARS 30
Added Value of NARMS Understanding the sources of resistance also helps with strain attribution in BOI estimates Outbreak detection PulseNet (NARMS PulseNet database has >12,000 data entries) 8,380 Salmonella 3,439 Campylobacter 547 E. coli 69 Vibrio Phylogenetics Evolution of MDR Virulence Trend analysis Method development Emerging trends Networked of trained and dedicated laboratory personnel and epidemiologists Infrastructure for targeted studies Opportunity to serve broader FDA food safety priorities
Additional Analyses Source: CDC 32
2. Reporting: Disseminate timely information 33
Human Population Physician Visit Local Lab State Lab Retail Meats Random stratified sampling in 14 States ORA Imported Foods Grocery Stores Chicken Ground turkey Ground beef Pork chop Farm Pilots Farm to Slaughter Drug use data point Animals Random sampling of national production at slaughter Chickens, Turkeys, Cattle, Swine HACCP 2013-present HACCP 1997-2013 Chicken only Other pathogens surveyed Campylobacter Salmonella Enterococcus E. coli Data Integration Integrated Report
Integrated NARMS Report 35
Integrated NARMS Report cont d 36
Integrated NARMS Report cont d 37
Antimicrobial Drugs Approved for Use in Food-Producing Animals: 2011 Sales and Distribution Data Reported by Drug Class Antimicrobial Class Annual Totals (kg) Domestic Aminoglycosides 214895 Cephalosporins 26,611 Ionophores 4,123,259 Lincosamides 190,101 Macrolides 582,836 Penicillins 880,163 Sulfas 371,020 Tetracyclines 5,642,573 NIR 1,510,572 Export Tetracyclines 15,321 NIRE 185,333 38
Conduct Research 39
Added Value of Integrated Surveillance Source attribution is useful in burden of illness estimates Database of strain relatedness for outbreak detection Phylogenetics Evolution of MDR Virulence Method development Emerging trends Networked of trained and dedicated laboratory personnel and epidemiologists Infrastructure for targeted studies Welch TJ, Fricke WF, McDermott PF, et al. Multiple antimicrobial resistance in plague:an emerging public health risk. PLoS One. 2007 Mar 21;2(3):e309. Opportunity to serve broader food safety priorities
NARMS Research: Filling the Gaps in Surveillance 1. Standardize and validate in vitro antimicrobial susceptibility testing methods 2. Measure the effects of veterinary antimicrobials on emergence of resistance in zoonotic foodborne bacteria in target animals 3. Examine the role of animal feeds (rendered products, dried commodities, complete feeds) in the ecology of resistance 4. Risk factors and clinical outcomes infections caused by AR pathogens 5. Characterize and compare molecular mechanisms of resistance 6. Develop rapid methods to identify/characterize resistant bacteria (WGS)
Assist the FDA 42
Qualitative Risk Assessment: Components and Procedures Hazard Characterization Qualitative Risk Assessment Release Assessment probability that resistant bacteria are present in target animal as a consequence of drug use (rank as High, Medium, or Low ) Exposure Assessment probability for humans to ingest bacteria in question from the relevant food commodity (rank as High, Medium, or Low ) Consequence Assessment probability that human exposure to resistant bacteria results in an adverse health consequence (rank as High, Medium, or Low ) Overall Risk Estimate: Integration of release, exposure and consequence assessments. (rank as High, Medium, or Low ) Risk Estimation
Where can we use NARMS Data? Release Assessment Parameters: Mechanism of Activity Class of Drug, targeted action Spectrum of Activity Gram +/- activity, susceptibility data Resistance mechanisms Structural, efflux, gene Resistance Transfer chromosomal, mobile element Selection Pressure co-selection Exposure Assessment Parameters: Consumption of commodity Prevalence of zoonotic pathogens in commodity Prevalence of resistance in zoonotic pathogens 44
Consequence Assessment Describes human health consequence of exposure to resistant bacteria based on importance of drug (or related drugs) to humans (ranking of antimicrobials) Drug Ranking Examples Critically Important 3 rd Generation cephalosporins (Ceftriaxone), macrolides (Erythromycin), fluoroquinolones (Ciprofloxacin). Highly Important 4 th Generation cephalosporins, aminoglycosides, clindamycin Important 1 st & 2 nd Generation cephalosporins, monobactams, quinolones
Examples of Risk Management Tools Approval conditions Marketing status Category 1 (H) Category 2 (M) Category 3 (L) Rx Rx/VFD Rx/VFD/OTC Extra-label use ELU restriction Restricted in some cases ELU permitted Extent of use Low Low/Medium Low, Medium, High Advisory committee review Post-approval monitoring YES In certain cases NO NARMS NARMS NARMS GFI #152, Table 8, pp. 25
Withdrawal of Approval of Fluoroquinolones for Poultry In 2000, CVM proposed the withdrawal of the approval of the new animal drug applications for fluoroquinolone use in poultry. Abbott Laboratories withdrew their application for sarafloxacin. Bayer Corp. requested a hearing to address the safety of Baytril, the trade name for enrofloxacin. CVM research validated a standardized AST method for Campylobacter to evaluate the resistance data being reported CVM research conducted in vivo treatment studies with Campylobacter infected broilers The Final Decision of the FDA Commissioner to withdraw the approval became effective September 12, 2005. 47
Extra-Label Use Prohibition of Certain Cephalosporins Effective April 5, 2012 FDA prohibits unapproved uses of 3rd gen. cephalosporins in cattle, swine, chickens and turkeys. The prohibited uses include: using cephalosporin drugs at unapproved dose levels, frequencies, durations, or routes of administration; using cephalosporin drugs in cattle, swine, chickens or turkeys that are not approved for use in that species (e.g., cephalosporin drugs intended for humans or companion animals); using cephalosporin drugs for disease prevention. 48
Impact of GFI #209 Removes production claims for medically important antimicrobials used in food-producing animals Places other feed and water drugs under veterinary control Begins in January 2017 Sensitivity of NARMS to measure impact will be tested 49
The future of integrated antimicrobial resistance monitoring 50
Surveillance Today Isolate pure cultures from samples obtained from animals, foods & people Ship them to central laboratories to conduct a small number of expensive and labor intensive assays in batch using specialized reagents Humans Chicken Breast Ground Turkey Cattle Swine 1 Typhimurium Typhimurium Hadar Montevideo Typhimurium 2 Enteritidis Kentucky Heidelberg Dublin Derby 3 Newport Heidelberg Saintpaul Muenster Johannesburg 4 Heidelberg Enteritidis Reading Newport Infantis 5 I 4,[5],12:i:- Montevideo Schwarzengrund Mbandaka Anatum 6 Javiana I 4,[5],12:i:- Senfternberg Typhimurium Saintpaul 7 Muenchen Hadar Agona Cerro Adelaide 8 Montevideo Mbandaka Minnesota Anatum London 9 Tennessee Oranienburg Albany Agona Hadar 10 Mississippi Other I 4,5,12:r:- Meleagridis Agona 11 Oranienburg Muenchen Infantis Muenchen 12 Braenderup Other Other Other 13 Agona AST, PFGE, Serotyping Present aggregated phenotype data over time in an integrated fashion Perform research projects to more fully characterize and compare strains, and publish the results months-years later. Phage typing, plasmid typing, MLST, CRISPR, virulence typing, R-gene sequencing, etc. 51
Surveillance tomorrow Next generation sequencing technology is changing the science of infectious disease. It has the potential to serve as the single assay of NARMS surveillance in the future and to supplant multiple methods, saving time and money. 1. Classical serotyping 2. PFGE and other strain typing methods 3. In vivo antimicrobial susceptibility testing 4. Piecemeal PCR gene detection and plasmid typing And to provide: 1. Genome/nucleotide surveillance 2. Virulence profiles 3. Molecular phage typing 4. Markers for source attribution 5. Better understanding of emerging trends 6. Costs savings - $20 - $60 per isolates 7. Resistance to drugs not tested 8. Integration with drug use information 9. Metagenomic surveillance and CIDT
34/P aph(2 )-Ig teto aad9* aade sat4 53
Surveillance tomorrow Separate microbial surveillance systems based on and limited by methodology (PulseNet, NARMS, HACCP, NSS, hospital programs) will eventually contribute to and share a common, mobile, database. New opportunities for additional sample sources as costs continue to drop ($20-60/isolate) resulting in better trend analysis and greater sensitivity to changing patterns. Ability to address resistance in other ecosystems involving zoonotic and environmental spread Companion animals, other (minor) food animal sources, imported products, environmental, produce, etc. Other pathogens and bacteria Real time data collection and analysis Better informed and more rapid public health response 54
NARMS Objectives with WGS 1. Monitor trends in antimicrobial resistance among foodborne bacteria from humans, retail meats, and animals 2. Disseminate timely information on antimicrobial resistance to promote interventions that reduce resistance among foodborne bacteria 3. Conduct research to better understand the emergence, persistence, and spread of antimicrobial resistance 4. Assist the FDA in making decisions related to the approval of safe and effective antimicrobial drugs for animals 1. Monitor genomes in antimicrobial resistant foodborne bacteria from humans, retail meats, food animals, companion animals, feral animals and the environment. 2. Disseminate timely information on changes in the resistome to promote interventions that reduce resistance among foodborne bacteria and to prevent emerging resistances from becoming widespread 3. Conduct in vivo research to better understand the emergence, persistence, and spread of antimicrobial resistance under different conditions 4. Assist the FDA in making decisions related to the approval of safe and effective antimicrobial drugs for animals
Strengths of NARMS Comprehensive susceptibility data for managing risks associated with food animal antibiotic use, including pre-approval review of new animal antibiotics and post-approval safety monitoring of adverse events Most extensive program of its kind in the word, suitable to the large US food productions systems Excellent example of federal collaboration and federal-state partnership CDC-FoodNet, CDC-PulseNet, USDA-FSIS, USDA-ARS, USDA-APHIS, FDA-ORA,FDA-CFSAN, NIH, Universities, Industry. Is a recognized model for international capacity building and technical standards Robust and targeted research programs Well characterized isolates are a rich source of information on FBP Infrastructure in place for ad hoc food hazard analyses Exceptional staff of well-trained and dedicated microbiologists, epidemiologists, veterinarians, database managers, molecular biologists, bioinformaticians, statisticians. NARMS assists FDA in decision making on approving safe and effective antimicrobial drugs, and supports the Agency s mission as a science-based regulatory agency
Challenges Communication of complex data sets in a clear way to different audiences Providing timelier data generation, analysis and reporting Examining other pathogens and commodities as needed without compromising core functions. Professional development and training on emerging technologies Resources for research Future Needs Detailed drug use information in food producing animals Additional retail food isolates for better trend analysis Continued progress on linking databases on food safety Exploiting other sources of data on AR (e.g., hospitals and clinics) Collecting and incorporating import data into NARMS as needed IT and computing infrastructure for WGS
Acknowledgements USDA-ARS Eileen Thacker Paula Fedorka-Cray Jovita Haro USDA-APHIS Dave Dargatz Bruce Wagner USDA-FSIS Uday Dessai Emilio Esteban Alice Thayer Bill Cray Jodie Plumblee FDA/CVM Jason Abbott Sherry Ayers Sonya Bodeis-Jones Emily Crarey Sharon Friedman Stuart Gaines Michael Grabenstein David Heller Claudine Kabera Claudia Lam Melissa Warren Crystal Rice-Trujillo Jonathan Sabo Heather Tate Thu Thuy-Tran Shenia Young Shaohua Zhao CDC Cindy Friedman Jean Whichard Beth Karp Jason Folster Allison O Donnell Jared Reynolds Julian Grass Felicita Medalla FDA/CFSAN Eric Brown Mark Allard Ruth Timme Errol Strain Mary Torrence Non-federal partners Public health and veterinary diagnostic laboratories FoodNet EIP funded sites
Thank you 59