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The National Antimicrobial Resistance Monitoring System (NARMS) Dr. David G. White Center for Veterinary Medicine U.S. FDA Science Board to the FDA NARMS Program Subcommittee Meeting April 10th, 2007
Slide 2 Background In food animals, antimicrobials are used for the control, prevention and treatment of infectious bacterial diseases as well as for enhancing growth and feed efficiency purposes An undesired consequence of this use is the potential development of antimicrobial resistant zoonotic bacterial pathogens and subsequent transmission to humans Recognizing this potential health hazard, WHO, FAO and OIE recommend that countries implement monitoring programs aimed at determining the occurrence of antimicrobial resistance in bacteria from animals, foods and humans
Slide 3 CVM Strategy Aimed at assessing relationships between antimicrobial use in agriculture and potential human health consequences - Pathogens (Salmonella, Campylobacter, E. coli)            - commensal bacteria (e.g., Enterococcus, E. coli) Multi-pronged approach that includes: - Education/outreach activities - Participation in international activities - Expanded research activities - Revised safety assessment process - Enhanced surveillance activities
Slide 4 NARMS The National Antimicrobial Resistance Monitoring System (NARMS) is a national collaborative network between the FDA, CDC and USDA as well as public health laboratories in all 50 states and local health departments in three major cities NARMS was developed to monitor changes in susceptibility/resistance of select zoonotic bacterial pathogens and commensal organisms recovered from animals, retail meats and humans to antimicrobial agents of human and veterinary importance  NARMS monitors susceptibility/resistance phenotypes using three testing sites including: FDA/CVM (retail meat and poultry) CDC (humans) USDA (animal/slaughter)
Slide 5 NARMS History NARMS became operational in 1996 Salmonella of animal and human origin was initial organism selected Sources and types of isolates have expanded over time Campylobacter was added in 1998 Enterococcus and E. coli in 2000 Retail arm in 2002 Each year, samples are collected from numerous origins and tested to determine if there have been changes in the susceptibility/resistance of certain enteric bacteria to selected antimicrobial drugs The antimicrobial drugs tested annually are selected based on their importance in human and veterinary medicine
Slide 6 NARMS – 1996 to Present Interagency Program - CDC - USDA-ARS - USDA-FSIS - USDA-APHIS - FDA Funded through an FDA IAG with: - Human Arm (CDC) - Animal Arm (USDA)
Slide 7 Goals of NARMS Program Provide descriptive data and trends on antimicrobial susceptibility/resistance patterns in zoonotic foodborne bacterial pathogens and select commensal organisms Respond to unusual or high levels of bacterial drug resistance in humans, animals and retail meats in order to contain or mitigate resistance dissemination Design follow-up epidemiology and research studies to better understand the emergence and transfer of antimicrobial resistance Assist the FDA in decision making on approving safe and effective drugs for humans and animals, as well as promote prudent and judicious use of antimicrobial drugs
Slide 8 NARMS Methods Animal, human, retail lab testing comparable Methods meetings in 2002, 2003 Annual meeting Same antimicrobial susceptibility testing methods Broth microdilution methods Sensititre System – Salmonella, E. coli, Enterococcus 2005, Campylobacter  Same antimicrobial plate formats Same isolate handling procedures Quality Assurance Internal and external programs CLSI/NCCLS standards 2003 International - WHO EQAS
Slide 9 Bacteria Tested Human Non-Typhi Salmonella E. coli 0157:H7 Enterococcus Campylobacter S. Typhi Shigella Listeria Vibrio Animal Non-Typhi Salmonella E. coli 0157:H7 when available Enterococcus Campylobacter Retail meats Non-Typhi Salmonella E. coli Enterococcus Campylobacter
Slide 10 NARMS Methods Salmonella and E. coli  Tested by broth microdilution (Sensititre?, Trek Diagnostic Systems, Westlake, OH) 1997-present, core antimicrobials tested include amikacin, amoxicillin-clavulanic acid, ampicillin, ceftiofur, ceftriaxone, chloramphenicol, ciprofloxacin, gentamicin, kanamycin, nalidixic acid, streptomycin, tetracycline, and trimethoprim-sulfamethoxazole Sulfamethoxazole 1997-2003; sulfisoxazole 2004-present Ticarcillin 1997-1998 Apramycin 1997-2001 Florfenicol 1999 Imipenim 2001 Cephalothin 1997-2003 Cefoxitin 2000-present Antimicrobial dilutions tested have improved over time to include full ranges including appropriate CLSI/NCCLS QC and interpretive criteria E. coli ATCC 25922, S. aureus ATCC 29213, E. faecalis ATCC 29212, and P. aeruginosa ATCC 27853
Slide 11 NARMS Methods 2007 Salmonella/E. coli Plates ß-lactams ampicillin amoxicillin/clavulanic acid cefoxitin ceftiofur ceftriaxone Quinolones nalidixic acid ciprofloxacin Folic acid inhibitors sulfisoxazole trimethoprim/sulfamethoxazole Aminoglycosides streptomycin* kanamycin gentamicin amikacin Other chloramphenicol tetracycline CMV1AGNF 15 antimicrobials
Slide 12 Supplemental NARMS AST Plates ESBL panel Antimicrobial aztreonam cefepime cefotaxime cefotaxime/clavulanic acid* cefquinome* ceftazidime ceftazidime/clavulanic acid* imipenem piperacillin/tazobactam FQ panel Antimicrobial ciprofloxacin danofloxacin difloxacin enrofloxacin gatifloxacin levofloxacin marbofloxacin orbifloxacin
Slide 13 NARMS Methods Enterococcus Tested by broth microdilution (Sensititre?, Trek Diagnostic Systems, Westlake, OH) 2000-present, core antimicrobials tested include chloramphenicol, ciprofloxacin, erythromycin, flavomycin, gentamicin, kanamycin, lincomycin, linezolid, nitrofurantoin, penicillin, streptomycin, Q/D, tetracycline, tylosin, vancomycin Salinomycin 2000-2003 Bacitracin     2000-2005 Daptomycin 2004-present Tigecycline  2005-present Antimicrobial dilutions tested have improved over time to include full ranges including appropriate CLSI/NCCLS QC and interpretive criteria E. faecalis ATCC 29212, E. faecalis ATCC 51299
Slide 14 NARMS Methods 2007 Enterococcus Plate Production drugs flavomycin lincomycin tylosin tartrate Aminoglycosides streptomycin kanamycin gentamicin Other vancomycin daptomycin linezolid penicillin Q/D ciprofloxacin nitrofurantoin erythromycin chloramphenicol tetracycline tigecycline            CMV2AGPF            17 antimicrobials
Slide 15 Antimicrobial Susceptibility Testing Methods - Campylobacter Campylobacter surveillance was added in 1998 at USDA and CDC E-test was used to determine susceptibilities to 8 antimicrobials 1998- 2004  Azithromycin Clindamycin Erythromycin Nalidixic acid Ciprofloxacin Gentamicin Chloramphenicol Tetracycline NARMS Retail began in 2002 using CLSI/NCCLS approved agar dilution susceptibility testing method and E-test for Campylobacter Ciprofloxacin Doxycycline Erythromycin Gentamicin Meropenem
Slide 16 Campylobacter Broth Microdilution Method Different methods and lack of reproducibility for some drugs led to the development of a new CLSI/NCCLS approved broth microdilution method for Campylobacter in 2004 C. jejuni ATCC 33560 The QC MIC limits for AST of Campylobacter were accepted by the CLSI (January 2005) and have been published in CLSI M-45 document This broth method is much easier to use than agar dilution, and is amenable to semi-automation, and has QC ranges for 14 antimicrobial agents NARMS began using broth microdilution for Campylobacter in mid-2005
Slide 17 NARMS Methods 2005 Campylobacter Plate Macrolides and Lincosamides azithromycin erythromycin clindamycin Quinolones nalidixic acid ciprofloxacin Ketolides telithromycin Other florfenicol gentamicin tetracycline Campy 9 antimicrobials
Slide 18 Genotyping Methods Used by NARMS Pulsed Field Gel Electrophoresis (PFGE) - Genomic DNA is cut with an enzyme and resulting resultant fragments of differential sizes can indicate mutations or insertions - Partner with PulseNet National program that assists investigations and improves outbreak detection (through rapid linking of cases by comparing bacterial DNA fingerprinting patterns) - USDA VetNet - Isolates can be used for future research projects Biosource tracking experiments Virulence studies Antimicrobial resistance studies
Slide 19 Genotyping Methods Used by NARMS Journal of Clinical Microbiology, July 2006, p. 2449-2457 Vol. 44, No.7 009-1137/06, 08,00+0 doi:10.1128 JCM.00019-06 Comparison of Multilocus Sequence Typing, Pulsed-Field GelElectrophoresis, and Antimicrobial Susceptibility Typing forCharacterization of Salmonella enterica Serotype Newport Isolates H.Harbottle, D.G White, P.F McDermott, R.D. Walker, and S. Zhao Division of Animal and Food Microbiology, Office of Research, Center for Veterinary Medicine, U.S Food and Drug Administration, Laurel, Maryland 20708 Journal of Clinical Microbiology, Oct. 2006, p. 3569-3577 Vol. 44, No.10 0095-1137/06, 08,00+0 doi:10.1128 JCM.00745-06 Comparison of Subtyping Methods for Differentiating Salmonella EntericaSerovar Typhimurium Isolates Obtained from Food Animal Sources Steven L. Foley,1,2. David G. White3 Patrick F. McDermott,3 Robert D. Walker,3 Bobbie Rhodes,2 Paula J. Fedorka-Cary,4 Shabbir Simjee,3 and Shaohua Zhao3 National Farm Medicine Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin1; Division of Animal and Food Microbiology, Office of Research, Center for Veterinary Medicine, U.S Food and Drug Admininistration, Laurel, Maryland2; Bacterial Epidemiology and Antimicrobial Resistance Research Unit, Agriculture Research Service, United States Department of Agriculture, Athens, Georgia4; and Department of Biology, University of Centeral Arkansas Conway, Arkansas2 Applied and Environmental Micorbiolog-y, Oct 2006, p. 6368-6374 Vol. 71, No. 100099-2240/05/08,00+0 doi: 10.1128/AFM.71.10.6368-6374.2005 Differentiate of Campylobacter Populations as Demonstrated by Flagellin Short Variable Region Sequences Richard J. Meinersmann,1 Robert W. Phillips,1 Kelli L. Hiett,2 and Paula Fedorka-Cray3 Poultry Processing and Meat Quality Research Unit,1 Poultry Microbiological Safety Research Unit,2 and Antimicrobial Resistance Research Unit,3 Agriculture Research Service, Athens, Georgia 30604
Slide 20 NARMS Research Enterococcus aminoglycoside-modifying enzymes Salmonella antimicrobial resistance microarray Class 1 integrons in Salmonella Plasmid mediated quinolone resistance in Salmonella
Slide 21 NARMS Research
Slide 22 NARMS International Developing safe food and drugs internationally is a priority of the FDA NARMS supports the work of international organizations involved in foodborne disease surveillance and monitoring Interactions with other surveillance networks - DANMAP - CIPARS - ResistVet PulseNet International Training scientists Global Salm-Surv (GSS)
Slide 23 NARMS and GSS Has helped confirm the role of imported foods to antimicrobial resistance in the U.S. and other countries - Spread of Multiple Antimicrobial Resistant Salmonella Schwarzengrund from Thailand to Denmark and the USA through the International Trade of Food Products. F.M. Aarestrup, P.F. McDermott, D.G. White, ET AL Emerging Infectious Diseases, Accepted for publication, EID Coordination of surveillance design for better international data comparison Strong support from the FDA Expert Review Panel, June 2005 Also supports priority action items of phase II (international issues) of the  Public Health Action Plan to Combat Antimicrobial Resistance
Slide 24 Steering Committee WHO Global Salm-Surv
Slide 25 The ResistVet Project: A Network for Monitoring Antimicrobial Resistance in Foodborne Pathogens From Humans, Retail Meats and Animals in Mexico
Slide 26 NARMS Annual Reports More details and data are available on the FDA-CVM webpage and links to CDC, USDA and CVM annual reports http://www.fda.gov/cvm/narms_pg.html CDC – Human origin FDA/CVM – Retail meats USDA – Animal origin
Slide 27 NARMS Executive Reports First Executive NARMS report released - summarizes 2003 data from FDA, USDA, CDC in single report Link on CVM’s Web site - www.fda.gov/cvm Working on 2004 report
Slide 28 NARMS Executive Report Salmonella Data 1. Salmonella Isolates Tested Table 3. Total Numbers of Salmonella Typhl, Isolates Tested, by Source and Year, 1996 - 2003  Source Year 1996 1997 1998 1999 2000 2001 2002 2003 Human 1324 1301 1460 1498 1377 1419 2008 1865 Chicken Breasts 60 83 Bround Turkey 74 114 Ground Beef 9 10 Pork Chops 10 5 Chickens 214 561 1436 1173 1307 1500 1158 Turkeys 107 240 713 518 550 244 262 Cattle 24 284 1610 1388 893 1008 670 Swine 111 793 676 451 418 379 211 Table 10. Number of Salmonella (non-typhl) isolates from Humans and Foods Animals Resistant to Nalldixic Aicd, by year 1996- 2003   1996 1997 1998 1999 2000 2001 2002 2003 Humans 5 12 20 16 34 37 36 43 Chickens 0 1 3 6 0 12 5 Turkeys 5 5 38 28 28 13 10 Cattle 0 1 1 6 4 4 3 Swine 0 0 0 1 0 1 0
Slide 29 How NARMS Data can be Used GFI 152, Evaluating the safety of antimicrobial new animal drugs with regard to their microbiological effects on bacteria of human health concern Release Assessment Part of human food safety evaluation on antimicrobial use impacts on resistant pathogenic, zoonotic bacteria (e.g. Salmonella, E. coli, Campylobacter, etc.). October 23, 2003 Exposure Assessment Risk Estimation Human exposure through ingestion of animal-derived food Consequence Assessment Risk Management Qualitative risk assessment approach Based on OIE Ad Hoc Group on Antimicrobial Resistance process Possible risk management steps range from denying the drug approval application to approving the application under various use conditions that assure the safe use of the product
Slide 30 Public Health Action Plan to Combat Antimicrobial Resistance A blueprint for specific coordinated federal action to address the emerging threat of antimicrobial resistance Interagency Task Force created in 1999 Input from many partners: - state and local health agencies, universities, professional societies, pharmaceutical companies, health care organizations, food producers, consumer groups, & etc. Implemented over time, building on existing public health infrastructure
Slide 31 NARMS Review Outside expert review in 2005 Looked at key elements, established goals NARMS expert review transcripts located at http://www.fda.gov/cvm/narms_pg.html Improved sampling (e.g. retail and human Campylobacter isolates) and isolate testing methods over time Improved coordination of research activities and publications among the 3 NARMS components Working to strengthen data reporting and harmonization 1st executive report recently published Improving timeliness of annual reports Looking at antimicrobial susceptibility trends among bacteria under surveillance by source, year, etc.
Slide 32 NARMS Review Continue to collaborate with international surveillance partners Global village NARMS is a very strong program and is an important part of national public health surveillance in the United States  It has broad support from diverse sectors and numerous stakeholders It has matured since its inception in 1996 and would benefit from the input of the FDA Science Board on its key elements and future directions - Sampling - Epidemiological and microbiological research - Harmonization of data reporting - Coordination with international surveillance
Slide 33 NARMS COMPONENTS USDA Animal arm (clinical & slaughter, healthy animal isolates) Dr. Paula Fedorka-Cray   CDC Human arm (53 participating public health departments submit isolates) Dr. Tom Chiller Dr. Ezra Barzilay   CVM Retail Meat Arm CDC/FoodNet sites Dr. Patrick McDermott

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