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STATENS SERUM INSTITUT Spread of Resistant E.coli and Resistance Genes from Animals to Humans Anette M. Hammerum National Center for Antimicrobials and Infection Control Statens Serum Institut, Copenhagen, Denmark STATENS SERUM INSTITUT Agenda • Danmap- brief history • Olaquindox Resistance in Indicator E. coli from Animals and Humans • Normat-study • Comparison of Indicator E. coli from Pigs, Pork and Humans • Detection of sul genes in pig, pork and humans • Flouroquinolones in animals and humans • TRAINAU STATENS SERUM INSTITUT DANMAP – brief history • The Danish Integrated Antimicrobial Resistance Monitoring and Research Programme (DANMAP) was established by the Danish Ministry of Food, Agriculture and Fisheries and the Danish Ministry of Health in 1995 Statens Serum Institut • Since 1996, DANMAP reported annually on the occurrence of antimicrobial resistance in pathogenic and indicator bacteria from animals, foods and humans in Denmark STATENS SERUM INSTITUT DANMAP Danish Integrated Antimicrobial Monitoring and Research Programme DANMAP pdf-files: www.danmap.org STATENS SERUM INSTITUT http://www.danmap.org http://www.strama.se/news.asp http://www.vetinst.no/Arkiv/Zoonosesenteret/ NORM_NORM-VET_2003.pdf http://www.swab.nl STATENS SERUM INSTITUT Consumers are increasingly concerned about food safety Animal to human transfer of bacteria (or resistance determinants) carrying resistance to antimicrobials considered critically important in human medicine National Center for Antimicrobials STATENS SERUM INSTITUTand Infection Control Transfer of antimicrobial resistance between animals and humans Statens Serum Institut Environment Direct contact STATENS SERUM INSTITUT Public Health Concerns Salmonella & E. coli Enterococci, Fluroquinolones Streptococci, 3rd Gen. Cephalosporins Staphylococci Aminoglycosides Vancomycin Sulphonamides Streptogramins Campylobacter Fluroquinolones Macrolides Most G- Concerns relate to the THERAPEUTIC use of antibiotics in food animals Most G+ concerns relate to the GROWTH PROMOTER use of antibiotics STATENS SERUM INSTITUT Antimicrobial Growth Promoters (AGP) Antimicrobial substances used as a supplement in animal feed in sub-therapeutic concentrations Avoparcin (G+) Spiramycin (G+) Bacitracin (G+) Avilamycin (G+) Virginiamycin (G+) Flavomycin (G+) Tylosin (G+) Carbadox (G-) Olaquindox (G-) STATENS SERUM INSTITUT Olaquindox Resistance in Indicator E. coli from Animals and Humans • It has recently been shown that olaquindox resistance is encoded by oqxA and oqxB (efflux pump system) Hansen et al. 2005 AAC • This system has been found in E. coli isolates from pigs. STATENS SERUM INSTITUT Olaquindox resistence in E. coli isolates from humans • Olaquindox resistance can been found in persons with close contact to animals and in person with no contact to pigs STATENS SERUM INSTITUT AGP for Finisher pigs and broilers terminated 250 AGP for Weaner pigs terminated 200 150 100 50 Therapeutic AGPs 20 04 20 03 20 02 20 01 20 00 19 99 19 98 19 97 19 96 19 94 Profit on therapeutics reduced 19 92 0 19 90 Tonnes (active component) Trends in consumption of antimicrobials in food animals in Denmark STATENS SERUM INSTITUT Effect of the AGP Stop on Antimicrobial Consumption and Occurrence of Resistance in Food Animals in Denmark • Total antimicrobial consumption in animals reduced by >50% from 1994 to 2002 • Slow increase in consumption of antimicrobials for therapy in pigs - No increase in broilers • Substantial quantitative reduction of antimicrobial resistance in bacteria from animals and food STATENS SERUM INSTITUT DANMAP - data flow Diagnostic submission Veterinary practice Data Samples Private Laboratories Isolates Data Danish Institute for Food and Veterinary research Data Data Slaughter plants Samples Isolates Regional Food Control Laboratories Regional hospital laboratories Danish Zoonosis Centre Data Isolates Data Data Statens Serum Institut Data Samples General practice Data Samples Danish Medicines Agency VetStat Data STATENS SERUM INSTITUT -16 counties in DK -15/16 clinical microbiology laboratories delivered data in 2004 North Jutland Bornholm Viborg Aarhus Frederiksborg Ringkoebing Copenhagen County Vejle Ribe West Zealand Copenhagen Municipality Frederiksberg Municipality Funen South Jutland Roskilde Storstroem STATENS SERUM INSTITUT Data Included in the DANMAP Integrated surveillance Origin Humans Indicator Pathogens Consumption of bacteria antimicrobials + + + Pigs (and pork) + + + Poultry (and poultry meat) + + + Cattle (and beef) + + + Fish - - + STATENS SERUM INSTITUT Indicator bacteria Gram+ : E. faecium / E. faecalis Gram - : E. coli • Easily obtained from various animal species as well as from humans • Good ability to acquire resistance to various antimicrobial substances • Easily obtained from healthy individuals STATENS SERUM INSTITUT Indicator Bacteria in DANMAP • E. coli (and Enterococcus faecalis og Enterococcus faecium) from meat and healthy animals has been sampled since 1996, whereas a continuously sampling of faces from nonhospitalized persons was initiated in 2002 STATENS SERUM INSTITUT Normal Flora Study at SSI Methods: • Volunteers were found through the Danish Civil Registry system, which is a continuously updated register of all residents in DK. • The scientific ethics committee for Copenhagen and Frederiksberg municipalities approved the protocol • Age and gender profile of the invited volunteers were in compliance with the total Danish population STATENS SERUM INSTITUT Selection of persons via CPR (DZC) 1st Letter: Invitation + Declaration of consent Declaration of consent to DZC 2nd Letter: Material for faeces sample + questionnaire (with code) Faeces sample sent to SSI NOR-MAT, 2002-ongoing One random E. coli, E. faecium and E. faecalis isolate / sample MIC determination (Sensititre) for growth promoters and antibiotics used for therapy A selective method to detect vancomycin res. enterococci Presence of enteric pathogens E-mail to DZC with code Identification and testing Database (DZC) Telephone interview / web STATENS SERUM INSTITUT Respons rate Year Invitered Answars Respons rate 2002 (from Marts) 760 111 14.6 % 2003 1055 130 12.3 % 2004 988 119 12.0 % STATENS SERUM INSTITUT NOR-MAT: Results, 2002-2003 • From March 2002 to December 31, 2003, 1815 individuals were invited to participate in the study • 248 (13.7%) responded to the letter • In total, 93 E. faecium isolates, 119 E. faecalis isolates, and 195 E. coli isolates were obtained STATENS SERUM INSTITUT NOR-MAT: Results, 2002-2003 • A single E. faecalis isolate was gentamicin-resistant and one vancomycin resistant E. faecium isolate was detected (selective method) • 10% E. coli isolates were multi-resistant • The carrier-rate of Salmonella and Campylobacter in the normal population is lower than 1%, however several pathogenic E. coli was identified STATENS SERUM INSTITUT Comparison of Indicator E. coli from Pigs, Pork and Humans STATENS SERUM INSTITUT Trends in Ampicillin Resistance among Indicator E. coli STATENS SERUM INSTITUT Trends in Sulphomanide Resistance among Indicator E. coli STATENS SERUM INSTITUT Detection of sul1, sul2 and sul3 in sulphonamide resistant Escherichia coli isolates obtained from healthy humans, pork and pigs in Denmark (Hammerum et al. accepted for publication) STATENS SERUM INSTITUT Background • In 2003, antibiotic treatment of pigs accounted for almost 80% of the total amount of antibiotics administered to food animals in Denmark. • The combination of sulphonamide and trimethroprim was the second most used antimicrobial therapy for sows and piglets in 2003 (approx. 4 tonnes) STATENS SERUM INSTITUT • Sulphonamide or trimethroprim are used for treatment of the majority uncomplicated urinary tract infections of humans in Denmark (approx. 3 tonnes) • Potential transfer of sulphonamide resistant (sulR) Escherichia coli from animals, directly or via handling of raw meat, to humans is therefore undesirable. • SulR is often encoded by sul1 and sul2 in Enterobacteriaceae. Recently a third gene, sul3, was found to encode for sulR. STATENS SERUM INSTITUT Materials: • 998 E. coli isolates, obtained from pig faeces collected at slaughter, Danish pork collected at retail outlets and from faeces from healthy persons in Denmark • All sulphonamide resistant E. coli isolates were investigated for the presence of sul1, sul2, and sul3 genes by PCR STATENS SERUM INSTITUT Prevalence of sul1, sul2 and sul3 in 236 Sulphonamide Resistant (sulR) E. coli isolates Origin No. of isolates tested No. of isolates PCR-positive for : sul1 sul2 sul3 Number of strains with more than one sulR gene Humans 35 40% 80% 0 20% Pork 39 23% 74% 5% 5% Pigs 162 53% 50% 11% 14% STATENS SERUM INSTITUT Discussion and Conclusion: • The proportion of sulR E. coli isolates obtained from faeces of pigs increased significantly from 23% to 31% from 2002 to 2003 (DANMAP 2003). This coincided with an increased consumption of sulphonamide and trimethroprim by pigs. • Urinary tract infections are generally thought of as infections caused by bacteria from the host’s own faecal flora (Murray et al. 2004). • A recent study has demonstrated a close resemblance between certain food borne and human isolates of extra intestinal pathogenic E. coli, which suggests a possible transmission of E. coli causing urinary tract infections through food products (Johnson et al. 2005). STATENS SERUM INSTITUT Discussion and Conclusion: • The presence of sulR E. coli in faeces from pigs, in pork and in the gut flora of healthy humans is therefore of concern • The origin of the sulphonamide resistance genes found in isolates from healthy human E. coli isolates is speculative, but spread via the food chain seems very likely Statens SerumSERUM Institut INSTITUT STATENS Fluoroquinolone consumption in DK – Primary health care, hospital and veterinary use 2001 Veterinary use Primary health care Veterinary use 2002 Veterinary use Primary health care Hospital 2003 Hospital Hospital Primary health care Year Veterinary use (kg) Primary health care (kg) Hospital (kg) Total 2001 185 220 115 520 2002 97 238 143 478 2003 53 348 154 555 Source: VetStat and The Danish Medicines Agency, 2004 STATENS SERUM INSTITUT Use of fluoroquinolones in animals in Denmark 2001 and 2002 20 18 14 12 10 8 6 4 December November October August July 2002 September 2001 May April March February 0 June 2 January kg active compound 16 Source: VETSTAT 2001 & 2002 STATENS SERUM INSTITUT Companion animals Investigation of previously neglected reservoirs: • Companion animals (dogs, cats, etc.): VETSTAT data indicates large consumption of fluoroquinolones and cephalosporins in companion animals • • In 2003 danes had in total 550,000 dogs, 650,00 cats 24 milllion slaughter pigs, 130 million broiler chickens, 1.2 million cattle and dairy cows were produced during 2003 Antimicrobials Consumption in companion animals (kg) Consumption in food animals and companion animals (kg)* Cephalosporins 254 461 Fluoroquinolones 24 53 (Heuer, Jensen and Hammerum 2005) EID, vol.11, no 2.) Statens SerumSERUM Institut INSTITUT STATENS Consumption of ciprofloxacin and other fluoroquinolones in human therapy Consumption DDD/1,000 inhab.-days 0,35 0,3 0,25 Ciprofloxacin 0,2 0,15 0,1 0,05 jan -1 se 994 p-1 9 m a 94 j -1 9 jan 95 -1 se 996 p-1 9 m a 96 j -1 9 jan 97 -19 9 se p-1 8 m a 998 j -1 9 jan 99 -2 se 000 p-2 0 m a 00 j -2 0 jan 01 -20 0 se p-2 2 0 m a 02 j -2 0 jan 03 -20 04 0 Source: The Danish Medicines Agency, 2004 Andre fluorquinoloner STATENS SERUM INSTITUT Ciprofloxacin consumption in primary health care - Price versus consumption Source: Muscat M, et al. EPI-NEWS 2004, week 41. Available at: URL: http://www.ssi.dk/graphics/en/news/epinews/2004/pdf/2004_41.pdf Statens SerumSERUM Institut INSTITUT STATENS DANMAP 2003: Ciprofloxacin resistance in Escherichia coli urine isolates from primary health care and hospital Data: The average number of ciprofloxacin resistant E. coli isolates from 7 clinical microbiology laberatories (with 95 % c.i.) Hospital Primary health care 2.5 % Cipro-R E.coli Cipro-R E.coli 2.5 2.0 1.5 1.0 0.5 2.0 1.5 1.0 0.5 2002 (n=12.788) 2003 (n=13.081) Source: DANMAP report 2003 2002 (n=20.406) 2003 (n=22.933) Statens SerumSERUM Institut INSTITUT STATENS % nalidixan resistant E. coli from uncomplicated urinary tract infections Fluoroquinolone use and nalidixan-R Escherichia coli, Europe (year 2000) 30 25 20 15 10 5 0 0 1 2 3 4 Fluorquinolone use DDD/1,000 inhab.-days Source: Kahlmeter et al. 2003. JAC vol. 52, p. 1005-1010 and ESAC STATENS SERUM INSTITUT WWW.TRAINAU.dk STATENS SERUM INSTITUT What is TRAINAU? • TRAINAU is a multidisciplinary early-stage research training (EST) site on identification, characterisation and assessment of public health risks associated with non-human antimicrobial usage, i.e. antimicrobial use in animals • The project will bring together young researchers with different backgrounds (veterinary and medical microbiology, epidemiology, statistics, pharmacology, and analytical chemistry) and provide them with the scientific and technological competences necessary to obtain substantial progress in this field STATENS SERUM INSTITUT STATENS SERUM INSTITUT Seven PhD Fellowships in Denmark Open for Applications Location: Students will primarily be enrolled at the Royal Veterinary and Agricultural University, but the research activities will also be carried out at one or more of the TRAINAU institutions: The Royal Veterinary and Agricultural University, Statens Serum Institut, The Danish University of Pharmaceutical Sciences & Danish Institute for Food and Veterinary Research all situated in Copenhagen, Denmark. STATENS SERUM INSTITUT List of proposed PhD projects: P1-Transmission of antimicrobial resistant bacteria and resistance genes through the food chain P2-Transmission of antimicrobial resistant bacteria and resistance genes by contact with animals and by environmental exposure P3- In vivo and in vitro models for investigatigating the impact of different veterinary treatment strategies on development of antimicrobial resistance P4-Associations between non-human antimicrobial resistance usage and occurence of resistant bacteria in animals and food STATENS SERUM INSTITUT P5-Animal and human models for studying the consequences of antimicrobial resistance on human health P6-Mathematical models for assessing the impact of nonhuman antimicrobial resistance P7-the effect of antimicrobial drug metabolites on selection of resistant bacteria STATENS SERUM INSTITUT Is it relevant to consider animals in relation to antimicrobial resistance in humans?… Yes! • Antimicrobial resistance in bacterial populations comes from exposure to selective pressure • Substantial amounts of antimicrobials are used in animals worldwide (Therapy, Prophylaxis and Growth Promotion) creating large resevoirs of antimicrobial resistance STATENS SERUM INSTITUT Thanks to: Karin Sixhøj Pedersen, Frank Hansen, Stine Frese-Madsen, Aviaja Maya Sicka, Rikke Kubert and Inge Hansen for technical assistance Lone Jannok Porsbo, Dorthe Sandvang, Ole E. Heuer, Line Bagger-Skjøt, Christian Brandt, Lotte Jakobsen, Sigrid R. Andersen, Anne Mette Seyfarth,Eleni Galanis, Katharina E. P. Olsen, Jens S. Andersen, Vibeke F. Jensen, Jakob Neimann, Lars Bogø Jensen, Lars Hestbjerg Hansen, Dominique L. Monnet, Henrik C. Wegener and Niels Frimodt-Møller for help with data handling and scientific input STATENS SERUM INSTITUT http://www.danmap.org