Unintended consequences associated with national-level restrictions on antimicrobial use in food-producing animals
Authors: Scott A McEwen, Frederick J Angulo, Peter J Collignon, John M Conly
Journal: The Lancet Planetary Health (2018)

Among actions needed to address the antimicrobial resistance crisis are restrictions on the use of medically important antimicrobials in food-producing animals, which are often administered through national-level policy. One example is the complete restriction of antimicrobials for growth promotion, as recommended in WHO guidelines on use of medically important antimicrobials in food-producing animals.1WHOWHO guidelines on the use of medically important antimicrobials in food-producing animals.http://www.who.int/foodsafety/areas_work/antimicrobial-resistance/cia_guidelines/en/Date: Nov 7, 2017Date accessed: May 20, 2018Google Scholar The obvious intended consequence is reduced antimicrobial resistance but there could also be unintended consequences, such as harm to animal health and added cost of production. Some people in the agriculture sector fear serious consequences which deters implementation of the needed restrictions. We reviewed the published evidence on unintended consequences associated with national-level restrictions. We used keyword searches in Ovid MEDLINE and AGRICOLA databases to identify interventional or observational studies that reported national-level restriction of antimicrobial use in food animals, and compared non-antimicrobial resistance outcomes between intervention and comparator groups in food animals or in humans. Eligible antimicrobial use restrictions included mandatory or voluntary prohibition of antimicrobial use, limitations on specific drug classes, and incentives for reduced antimicrobial use. The search identified 14 articles, all from Europe (table).TableCharacteristics and findings of studies that reported on unintended consequences from national-level restrictions on use of antimicrobials in food-producing animalsCountryStudy designType of restrictionUnintended consequences evaluatedAdverse consequences of restriction*Data from some countries appear in multiple studies (eg, related to AGP termination in Denmark); findings of adverse effects are listed only for the first published study, unless additional information was provided in subsequent studies.Aarestrup et al (2010)2Aarestrup FM Jensen VF Emborg H-D Jacobsen E Wegener HC Changes in the use of antimicrobials and the effects on productivity of swine farms in Denmark.Am J Vet Res. 2010; 71: 726-733Crossref PubMed Scopus (107) Google ScholarDenmarkLongitudinal (before and after), 1993–2008AGP termination, 1999Mortality in piglets and weanling pigs, mean number of pigs produced per sow per year, average daily gain in weanling and finishing pigs, percentage of dead or condemned finishing pigs, feed unit per kg of gain in finishing pigsSmall, 1–2 year increase in mortality (approximately 0·6%) and drop in average daily gain (approximately 2·6%) in weanling pigsAarestrup (2015)3Aarestrup FM The livestock reservoir for antimicrobial resistance: a personal view on changing patterns of risks, effects of interventions and the way forward.Philos Trans R Soc Lond B Biol Sci. 2015; 370: 20140085Crossref PubMed Scopus (146) Google ScholarDenmarkLongitudinal (before and after), 1994–2013Yellow Card system of imposed measures in pig herds with highest antimicrobial consumption per pigMortality in piglets and weanling pigs; mean number of pigs produced per sow per year; average daily gain in weanling and finishing pigs, percentage of dead or condemned finishing pigsNo adverse consequences identifiedAlban et al (2013)4Alban L Dahl J Andreasen M Petersen JV Sandberg M Possible impact of the "yellow card" antimicrobial scheme on meat inspection lesions in Danish finisher pigs.Prev Vet Med. 2013; 108: 334-341Crossref PubMed Scopus (55) Google ScholarDenmarkLongitudinal (before and after), 2010–11Yellow Card system.Prevalence of nine lesions in finishing pig carcasses at slaughterIncrease in chronic peritonitis (OR 1·5), umbilical hernia (OR 1·2), and chronic enteritis (OR 1·.2) but decrease in tail bite infection (OR 0·6), chronic pericarditis (OR 0·6), and chronic pneumonia (OR 0·7)Arnold et al (2004)5Arnold S Gassner B Giger T Zwahlen R Banning antimicrobial growth promoters in feedstuffs does not result in increased therapeutic use of antibiotics in medicated feed in pig farming.Pharmacoepidemiol Drug Saf. 2004; 13: 323-331Crossref PubMed Scopus (67) Google ScholarSwitzerlandLongitudinal (before and after), 1996–2001AGP termination, 1999Use of antimicrobials in feed for treatment and disease prevention of piglets and fattening pigsNo adverse consequences identifiedde Jong et al (2013)6de Jong IC Bondt N Ge L Puister-Jansen LF van den Heuvel J Lourens A Reduction in antbiotic usage in broilers: side effects and best practices (in Dutch). April.http://edepot.wur.nl/253812Date: 2013Date accessed: May 20, 2018Google ScholarNetherlandsLongitudinal, risk factor analysis, 2011–12Mandatory antimicrobial use reduction targetsIncidence of mortality and hock burn in broilersNo adverse consequences identifiedDupont (2016)7Dupont N. Applications of VetStat data on pig antimicrobial usage: opportunities, challenges and restrictive legislation. PhD thesis, University of Copenhagen, 2016.Google ScholarDenmarkLongitudinal (before and after), 2010–11Yellow Card systemAnimal health, mortality and daily weight gain, changes in lean meat percentage, and prevalence of lesions at slaughterIncrease in mortality (0·7%) in weanling pigs, increased localised tail bites (OR 1·8), chronic peritonitis (OR 1·3), and abscesses in heads and ears (OR 1·2) but decreased pleuritis (OR 0·9), abscesses in feet and legs (OR 0·7), abscesses in front, mid, and rear sections (0·84), chronic pneumonia (OR 0·8), and infected tail bites (OR 0·4)Emborg et al (2001)8Emborg H Ersboll AK Heuer OE Wegener HC The effect of discontinuing the use of antimicrobial growth promoters on the productivity in the Danish broiler production.Prev Vet Med. 2001; 50: 53-70Crossref PubMed Scopus (68) Google ScholarDenmarkLongitudinal (before and after), 1995–99AGP termination, 1998Broilers produced (kg per square metre), feed conversion ratio, total percent dead broilersIncreased feed conversion ratio (0·016 kg/kg increase) until end of studyGrave et al (2004)9Grave K Kaldhusdal MC Kruse H Harr LMF Flatlandsmo K What has happened in Norway after the ban of avoparcin? Consumption of antimicrobials by poultry.Prev Vet Med. 2004; 62: 59-72Crossref PubMed Scopus (65) Google ScholarNorwayLongitudinal (before and after), various yearsAGP termination (avoparcin), 1995National consumption of antimicrobials for treatment and disease prevention in broilers; percentage of broiler chicken flocks treated for necrotic enteritisIncrease in use of amoxicillin (by approximately 50 kg per annum nationally), but decrease in use of penicillin (by approximately 25 kg per annum) to negligible levels; increase in percentage of broiler chicken flocks treated for necrotic enteritis of 10·1% in first year only following terminationGrave et al (2006)10Grave K Jensen VF Odensvik K Wierup M Bangen M Usage of veterinary therapeutic antimicrobials in Denmark, Norway and Sweden following termination of antimicrobial growth promoter use.Prev Vet Med. 2006; 75: 123-132Crossref PubMed Scopus (84) Google ScholarNorwayLongitudinal (before and after), 1993–2003AGP termination, 1995National consumption of antimicrobials for treatment and disease prevention (poultry and pigs)No adverse consequences identifiedLaine et al (2004)11Laine T Yliaho M Myllys V Pohjanvirta T Fossi M Anttila M The effect of antimicrobial growth promoter withdrawal on the health of weaned pigs in Finland.Prev Vet Med. 2004; 66: 163-174Crossref PubMed Scopus (26) Google ScholarFinlandLongitudinal (before and after), 1999–2000AGP termination, 1999Use of antimicrobials for treatment and disease prevention; incidence of diarrhoea; piglets weaned per sow per year, percent mortality, age at weaning (days)Increase in treatment for diarrhoea in 14% of herdsLawson et al (2008)12Lawson LG Jensen VF Otto L Lawson L Dk L The economics of use and non-use of antimicrobial growth promoters: the case of Danish broiler production.J Int Farm Manag. 2008; 4: 51-63Google ScholarDenmarkLongitudinal (before and after), 1994–2004AGP termination, 1998Effect on economic efficiency of broiler productionNo adverse consequences identifiedMevius et al (2011)13Mevius DJ Koene MGJ Wit B van Pelt W Bondt N Monitoring of antimicrobial resistance and antibiotic usage in animals in the Netherlands in 2009.http://edepot.wur.nl/165958Date: March, 2011Date accessed: May 20, 2018Google ScholarNetherlandsLongitudinal (before and after), 1999–2009AGP termination over period 1999–2006National consumption of antimicrobials for treatment and disease preventionNational consumption of antimicrobials for treatment and disease prevention (grams/kg live weight [all species]) increased by 85% 1999–2007 then decreased 15% by 2009WHO (2003)14WHOImpacts of antimicrobial growth promoter termination in Denmark. The WHO international review panel's evaluation of the termination of the use of antimicrobial growth promoters in Denmark.http://apps.who.int/iris/bitstream/10665/68357/1/WHO_CDS_CPE_ZFK_2003.1.pdfDate: 2003Date accessed: May 20, 2018Google ScholarDenmarkLongitudinal (before and after), 1999–2002AGP termination over period 1995–99National consumption of antimicrobials for treatment and disease prevention; prevalence of antimicrobial resistance in foodborne bacteria in animals, food, and humans; effects on food safety (incidence of antimicrobial residues in food or incidence of human Salmonella, Campylobacter, or Yersinia infections); effects on animal health and welfare; effects on environment (heavy metals, soil nutrients, bacteria, and antimicrobial residues); effects on animal production (total production, mortality, average daily gain, feed efficiency; cost of pig and poultry production, effects on national economyAverage increase of 46·5% (mainly in weanling pigs) in use of antimicrobials for treatment and disease prevention in 2 years following termination of AGPs in 1999 (increased use of aminoglycosides, macrolides, penicillins, tetracyclines, and sulphonamide or trimethoprim); increased tetracycline resistance (approximately 10%) in Salmonella from human infections; increased rate of antimicrobial treatment for diarrhoea in pigs by approximately 0·6 treatments per pig month at risk in weanling and grower or finishing pigs, increased necrotic enteritis diagnoses in broilers from 1–2 per 1700 flocks in the year before termination to 25 per 1700 in the year after termination; increase of 1·6 days to reach 100 kg bodyweight, 0·6% increase in mortality in weanling pigs, decrease of 2·6% in average growth rate of weanling pigs. decreased feed efficiency in poultry (−2·3%); increased cost of approximately 7·75 DKK per pig produced resulting in an increase in pig production costs of approximately 1%. Overall negative effect of termination on economy of 0·03% (363 million DKK) by 2010 (at 1995 prices) in real gross domestic product.Wierup (2001)15Wierup M The Swedish experience of the 1986 year ban of antimicrobial growth promoters, with special reference to animal health, disease prevention, productivity, and usage of antimicrobials.Microb Drug Resist. 2001; 7: 183-190Crossref PubMed Scopus (178) Google ScholarSwedenLongitudinal (before and after), 1980–99AGP termination, 1986National consumption of antimicrobials for treatment and disease prevention; preweaning and postweaning mortality, age at 25 kg and 30kg, mean number of pigs produced per sow per yearCompared with 1986 (24 903 kg active antimicrobials), total use of antimicrobials for treatment and disease prevention increased 21·2% in 1988, remained stable to 1994, and reduced by at least 17% (of 1986 amounts) between 1996 and 1999. In the first year after termination weanling pig mortality increased by approximately 1·5%, age at 25 kg increased by 5–6 days and age at 30 kg increased by 2 days.AGP=antimicrobial growth promoter. OR=odds ratio.* Data from some countries appear in multiple studies (eg, related to AGP termination in Denmark); findings of adverse effects are listed only for the first published study, unless additional information was provided in subsequent studies. Open table in a new tab AGP=antimicrobial growth promoter. OR=odds ratio. Several studies focused on bans on antimicrobial growth promoters (AGPs). AGP bans in Sweden and Denmark (but not Finland) were initially accompanied by increased diarrhoea in weanling pigs, but little or no increased disease in other species.11Laine T Yliaho M Myllys V Pohjanvirta T Fossi M Anttila M The effect of antimicrobial growth promoter withdrawal on the health of weaned pigs in Finland.Prev Vet Med. 2004; 66: 163-174Crossref PubMed Scopus (26) Google Scholar, 14WHOImpacts of antimicrobial growth promoter termination in Denmark. The WHO international review panel's evaluation of the termination of the use of antimicrobial growth promoters in Denmark.http://apps.who.int/iris/bitstream/10665/68357/1/WHO_CDS_CPE_ZFK_2003.1.pdfDate: 2003Date accessed: May 20, 2018Google Scholar, 15Wierup M The Swedish experience of the 1986 year ban of antimicrobial growth promoters, with special reference to animal health, disease prevention, productivity, and usage of antimicrobials.Microb Drug Resist. 2001; 7: 183-190Crossref PubMed Scopus (178) Google Scholar In Denmark, bans resulted in temporary increases in therapeutic use of some medically important antimicrobials leading to antimicrobial resistance problems in Salmonella spp from pigs and humans.14WHOImpacts of antimicrobial growth promoter termination in Denmark. The WHO international review panel's evaluation of the termination of the use of antimicrobial growth promoters in Denmark.http://apps.who.int/iris/bitstream/10665/68357/1/WHO_CDS_CPE_ZFK_2003.1.pdfDate: 2003Date accessed: May 20, 2018Google Scholar In both countries, these problems were addressed by improvements in animal health management and housing.14WHOImpacts of antimicrobial growth promoter termination in Denmark. The WHO international review panel's evaluation of the termination of the use of antimicrobial growth promoters in Denmark.http://apps.who.int/iris/bitstream/10665/68357/1/WHO_CDS_CPE_ZFK_2003.1.pdfDate: 2003Date accessed: May 20, 2018Google Scholar, 15Wierup M The Swedish experience of the 1986 year ban of antimicrobial growth promoters, with special reference to animal health, disease prevention, productivity, and usage of antimicrobials.Microb Drug Resist. 2001; 7: 183-190Crossref PubMed Scopus (178) Google Scholar In Norway, the ban resulted in increased use of amoxicillin for treatment of necrotic enteritis in broilers, but overall a 39% decrease in antimicrobial use for treatment or disease prevention was reported.9Grave K Kaldhusdal MC Kruse H Harr LMF Flatlandsmo K What has happened in Norway after the ban of avoparcin? Consumption of antimicrobials by poultry.Prev Vet Med. 2004; 62: 59-72Crossref PubMed Scopus (65) Google Scholar, 10Grave K Jensen VF Odensvik K Wierup M Bangen M Usage of veterinary therapeutic antimicrobials in Denmark, Norway and Sweden following termination of antimicrobial growth promoter use.Prev Vet Med. 2006; 75: 123-132Crossref PubMed Scopus (84) Google Scholar In the Netherlands, the AGP ban was initially accompanied by a compensatory increase in antimicrobial use for treatment or disease prevention; however, in Switzerland the ban did not result in increased use of feed antimicrobials for treatment or disease prevention in swine.5Arnold S Gassner B Giger T Zwahlen R Banning antimicrobial growth promoters in feedstuffs does not result in increased therapeutic use of antibiotics in medicated feed in pig farming.Pharmacoepidemiol Drug Saf. 2004; 13: 323-331Crossref PubMed Scopus (67) Google Scholar, 13Mevius DJ Koene MGJ Wit B van Pelt W Bondt N Monitoring of antimicrobial resistance and antibiotic usage in animals in the Netherlands in 2009.http://edepot.wur.nl/165958Date: March, 2011Date accessed: May 20, 2018Google Scholar The experiences of European countries that terminated AGPs suggest that other countries considering similar action should implement measures to minimise disease in vulnerable animals, especially weanling pigs. Care is needed to avoid compensatory increases in antimicrobial use for treatment or disease prevention by improving veterinary oversight, linking antimicrobial use surveillance to remedial action on excessive use, mandatory antimicrobial use reduction targets, and improvements in animal health. AGPs are ostensibly used to improve the efficiency of production. For 2 years after AGP termination in Denmark there were some production losses in weanling pigs, but over the long term, AGP termination had little discernible effect on production.2Aarestrup FM Jensen VF Emborg H-D Jacobsen E Wegener HC Changes in the use of antimicrobials and the effects on productivity of swine farms in Denmark.Am J Vet Res. 2010; 71: 726-733Crossref PubMed Scopus (107) Google Scholar, 14WHOImpacts of antimicrobial growth promoter termination in Denmark. The WHO international review panel's evaluation of the termination of the use of antimicrobial growth promoters in Denmark.http://apps.who.int/iris/bitstream/10665/68357/1/WHO_CDS_CPE_ZFK_2003.1.pdfDate: 2003Date accessed: May 20, 2018Google Scholar In broilers, production losses were offset by savings in AGP costs.8Emborg H Ersboll AK Heuer OE Wegener HC The effect of discontinuing the use of antimicrobial growth promoters on the productivity in the Danish broiler production.Prev Vet Med. 2001; 50: 53-70Crossref PubMed Scopus (68) Google Scholar Estimates of AGP effects (eg, average daily gain and feed conversion ratio) vary widely, ranging from 0% to 15% and have declined to 0–5% since the early 2000s.16Laxminarayan R Van Boeckel T Teillant A The economic costs of withdrawing antimicrobial growth promoters from the livestock sector.https://www.oecd-ilibrary.org/agriculture-and-food/the-economic-costs-of-withdrawing-anti-microbial-use-in-the-livestock-sector_5js64kst5wvl-enDate: Feb 23, 2015Date accessed: May 20, 2018Google Scholar AGPs are believed to be most beneficial when animals are raised in overcrowded and unhygienic conditions. Substantial improvements in housing, nutrition, health management, and animal genetics could explain declining efficacy of AGPs.16Laxminarayan R Van Boeckel T Teillant A The economic costs of withdrawing antimicrobial growth promoters from the livestock sector.https://www.oecd-ilibrary.org/agriculture-and-food/the-economic-costs-of-withdrawing-anti-microbial-use-in-the-livestock-sector_5js64kst5wvl-enDate: Feb 23, 2015Date accessed: May 20, 2018Google Scholar Economic effects of AGP termination in Denmark were evaluated by estimating costs of animal production, economic efficiency of broiler production, and effects on the Danish economy; the estimated effects were small (table).12Lawson LG Jensen VF Otto L Lawson L Dk L The economics of use and non-use of antimicrobial growth promoters: the case of Danish broiler production.J Int Farm Manag. 2008; 4: 51-63Google Scholar, 14WHOImpacts of antimicrobial growth promoter termination in Denmark. The WHO international review panel's evaluation of the termination of the use of antimicrobial growth promoters in Denmark.http://apps.who.int/iris/bitstream/10665/68357/1/WHO_CDS_CPE_ZFK_2003.1.pdfDate: 2003Date accessed: May 20, 2018Google Scholar Other potential adverse consequences that were assessed included effects on food safety (none identified) and environmental effects (some concerns from increased use of oral zinc oxide for prevention of pig diarrhoea).14WHOImpacts of antimicrobial growth promoter termination in Denmark. The WHO international review panel's evaluation of the termination of the use of antimicrobial growth promoters in Denmark.http://apps.who.int/iris/bitstream/10665/68357/1/WHO_CDS_CPE_ZFK_2003.1.pdfDate: 2003Date accessed: May 20, 2018Google Scholar, 15Wierup M The Swedish experience of the 1986 year ban of antimicrobial growth promoters, with special reference to animal health, disease prevention, productivity, and usage of antimicrobials.Microb Drug Resist. 2001; 7: 183-190Crossref PubMed Scopus (178) Google Scholar Unintended consequences from antimicrobial use restrictions for disease treatment or prevention have also been assessed. In 2010, Denmark introduced the Yellow Card system of restrictions on pig farmers that used twice the average quantity of antimicrobials resulting in a substantial reduction in antimicrobial use in Danish pigs with no adverse effects on mortality and production.3Aarestrup FM The livestock reservoir for antimicrobial resistance: a personal view on changing patterns of risks, effects of interventions and the way forward.Philos Trans R Soc Lond B Biol Sci. 2015; 370: 20140085Crossref PubMed Scopus (146) Google Scholar, 7Dupont N. Applications of VetStat data on pig antimicrobial usage: opportunities, challenges and restrictive legislation. PhD thesis, University of Copenhagen, 2016.Google Scholar The programme's influence on the occurrence of lesions in slaughter pigs was mixed (table).4Alban L Dahl J Andreasen M Petersen JV Sandberg M Possible impact of the "yellow card" antimicrobial scheme on meat inspection lesions in Danish finisher pigs.Prev Vet Med. 2013; 108: 334-341Crossref PubMed Scopus (55) Google Scholar In 2009, the Dutch poultry industry voluntarily discontinued use of fluoroquinolones and third generation cephalosporins, and in 2013, the swine industry voluntarily discontinued use of third generation cephalosporins. No adverse effects were reported.17European Medicines AgencyAnswers to the request for scientific advice on the impact on public health and animal health of the use of antibiotics in animals.http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/07/WC500170253.pdfDate: Dec 18, 2014Date accessed: May 20, 2018Google Scholar In 2010, the Dutch government set mandatory targets for reduction of antimicrobial use for treatment or disease prevention in food animals of 20% by 2011, 50% by 2013, and 70% by 2015. Additional restrictions included no use of new antimicrobials (eg, carbapenems) in animals, only permitting the use of fluoroquinolones and cephalosporins with evidence that other antimicrobials would be ineffective, and making colistin, β-lactams, and aminoglycosides second-choice antimicrobials.18Mevius D Heederik D Reduction of antibiotic use in animals "let's go Dutch".J für Verbraucherschutz und Leb. 2014; 9: 177-181Crossref Scopus (32) Google Scholar Non-quantitative reports of resulting disease problems in pigs have been published but there has not been sufficient time to fully assess effects of the reduction programme.17European Medicines AgencyAnswers to the request for scientific advice on the impact on public health and animal health of the use of antibiotics in animals.http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/07/WC500170253.pdfDate: Dec 18, 2014Date accessed: May 20, 2018Google Scholar No effects on mortality and morbidity in broilers were identified.6de Jong IC Bondt N Ge L Puister-Jansen LF van den Heuvel J Lourens A Reduction in antbiotic usage in broilers: side effects and best practices (in Dutch). April.http://edepot.wur.nl/253812Date: 2013Date accessed: May 20, 2018Google Scholar The lack of relevant studies from outside Europe raises questions about the global generalisability of the findings of this review, particularly for low-income countries. Clearly, more data from other parts of the world would be useful. Research investigating the effects of antimicrobial resistance interventions in agriculture and aquaculture, such as a study19Carrique-Mas JJ Rushton J Integrated interventions to tackle antimicrobial usage in animal production systems: the ViParc project in Vietnam.Front Microbiol. 2017; 8: 1062Crossref PubMed Scopus (24) Google Scholar underway in Vietnam, should be encouraged to document unintended consequences. Moreover, as global surveillance of antimicrobial resistance and antimicrobial use improves and more countries implement national-level antimicrobial stewardship initiatives in food animals, it is important to further evaluate and report unintended consequences. Overall, the available evidence indicates that unintended consequences from national-level restrictions on antimicrobial use in food animals were temporary and minor. Despite the Eurocentric nature of the data, the global implementation of appropriate restrictions at national level should not be delayed, such as those recommended in the WHO guidelines.1WHOWHO guidelines on the use of medically important antimicrobials in food-producing animals.http://www.who.int/foodsafety/areas_work/antimicrobial-resistance/cia_guidelines/en/Date: Nov 7, 2017Date accessed: May 20, 2018Google Scholar Some problems can be expected, particularly in intensive livestock farming (eg, diarrhoea in weanling pigs following AGP ban), but these effects could be mitigated by improvements to animal health management and housing. Making these improvements can be challenging, especially in low-income countries, and might require support from other countries, the UN Food and Agriculture Organization, and the World Organisation for Animal Health. Despite the data gaps, the experience from Europe indicates that restrictions on antimicrobial use in food animals, such as those recommended by WHO, can be implemented without serious harm. SAM reports contracts from Health Canada, Public Health Agency of Canada, and Ontario Ministry of Agriculture, Food and Rural Affairs. JMC reports grants from Alberta Innovates-Health Solutions and Canadian Institutes for Health Research, and consulting fees and non-financial support from Pfizer. We declare no other competing interests. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention.