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Critical appraisal of evidence that lowdose, long term (growth promotion) antimicrobial use augments public health risks from antimicrobial resistant organisms Peter Davies, Carie Alexander, Jeein Chung, Sylvia Wanzala College of Veterinary Medicine University of Minnesota Background and objectives Pressures to restrict antimicrobial use in food animals Particularly low-dose group treatments ‘low hanging fruit’ European changes Science vs. precautionary principle Danish data indicating that AGP use was Aggregate antimicrobial use in Danish swine industry Initial scope Not a systematic review Evidence cited in 4 key documents arguing for removal of AGP use in the USA PAMTA FDA guidance 209 Pew Commission report on Industrial Farm Animal Production Keep Antibiotics Working annotated bibliography Methods Compile reference list for each document FDA-209; PAMTA; PEW; KAW Screen references cited to identify relevant papers Only articles clearly unrelated to AMU or AMR eliminated Obtain original papers and compile in RefWorks database Assess relevance of retained papers Use specific appraisal tools to assess relevant papers Tools for detailed appraisal Design of tools based on Steinberg et al. (2000) and Shamliyan (2010) Check list approach Questions refined iteratively by research team Original plan to use a single too 6 screening questions for relevance Two tools developed Appraisal tool for descriptive studies Study population 7. Are inclusion/exclusion criteria for selecting subjects described? 8. Is the study population animal or human? 9. If animal, are they swine or other animals? 10. Is the age of the subjects described? 11. Is the housing system described? 12. Is the nutrition of the animals described? 13. Was the study done in an experimental or commercial/clinical setting? Treatments 14. Were multiple groups (treatments) included? Appraisal tool for descriptive studies Antimicrobial Use 17. Was antimicrobial use reported? 18. Was the antimicrobial specified? 19. Was antimicrobial use recorded, or obtained by survey questionnaire? 20. Was the antimicrobial dose reported? 21. Was the antimicrobial route recorded? 22. Was the antimicrobial duration recorded? 23. Were antimicrobial blood (or tissue/urine/other) levels measured? Antimicrobial Resistance 24. Was antimicrobial resistance reported? Appraisal tool for descriptive studies Statistical Analysis 28. 29. 30. 31. Was it conducted? Were specific statistical tests indicated? Were multivariate methods used? Were confidence intervals included? Results 32. Does the analysis directly compare antimicrobial resistance in relation to use? 33. Is there comparison of antimicrobial dose and resistance? Appraisal tool for descriptive studies Discussion 34. Were the limitations of the study discussed? 35. Was the relationship of the study population to other populations discussed? 36. Is the use of antimicrobials in food animals in relation to resistance discussed? 37. Is antimicrobial use in animals implicated in the development of resistance? 38. If so, is this with direct evidence or by inference? Appraisal process – review papers Appraisal of review studies included documentation of the number of papers cited number of citations that were original studies Examined abstracts of all citations Book chapters deemed not to be original studies and were not examined further Some references cited in reviews could not be located and were recorded as “cannot find”. Detailed appraisal Selected studies Specifically addressed AMU in food animals in relation AMR Implicated AMU in animals in AMR based on direct evidence Panel of 3 veterinarians Critically read all papers Collectively assess the design, results and Results Screening - 154 papers likely to provide some information on relationship between AMU in food animals and AMR Analytical (n = 37) Descriptive (n = 48) Reviews (n = 69) Results: screening questions for analytical studies (n = 37) Abstract present Clear Objective stated Abstract refers to AMU Abstract refers to AMR Objective refers to AMU Objective refers to AMR Abstract refers to AMU and AMR Objective refers to AMU and AMR AMU or AMR stated in abstract or objectives Yes 21 21 13 19 11 19 11 8 21 No 16 16 24 18 26 18 26 29 16 Results of analytical studies Study subjects (n = 21) 5 human subjects only 10 had animal subjects (5 in swine) 6 both human and animal subjects. 9 studies stated criteria for selecting subjects. Setting 19 in clinical/commercial settings Results of analytical studies 19 reported measurement of AMR (n = 21) 14 reported MIC method (11 with breakpoints) 4 zone diffusion methods 1 genotyping method Statistical methods 4 with no analysis or method not specified 8 studies only univariate analysis (12 used multivariate approaches) Analytical studies reporting details of AMU (n = 14) Table 2: Number of analytical studies reporting details of measuring antimicrobial u and of the antimicrobial compound, dose, route, and duration of administration AMU measured Recorded (n = 9) Survey (n = 4) Unknown (n = 1) Total (n = 14) Compound specified 9 2 1 12 Dose stated 6 0 1 7 Route stated 7 0 1 8 Duration stated 7 1 1 9 All stated 6 0 1 7 Results of analytical studies(n = 21) Compared AMU and AMR No (n = 9) Yes (n = 12) Total (n = 21) Discussed Limitations 4 5 9 Discussed Representativeness 8 8 16 Discussed AMU and AMR 8 11 19 Implicated AMU in AMR 7 10 17 12 studies for detailed review 7 of 9 studies that did not compare AMU and AMR implicated use in resistance Quality indicators of studies (n = 12) Subjects Animal (n = 7) Human (n = 3) Both(n = 2) Total (n = 12) Subjects Animal (n = 7) Both (n = 2) Human (n = 3) Total Age 5 2 1 8 Compound specified 7 2 1 10 Housing 3 0 1 4 Dose stated 5 1 0 6 Nutrition 3 0 1 4 Route stated 5 1 0 6 Control group 5 1 1 7 Duration stated 6 1 0 7 Replication 2 0 0 2 All stated 5 1 0 6 Summary 48 descriptive studies were collectively uninformative regarding association with AMR of low-dose/long term use of antimicrobials in food animals 1 (0.6%) of 154 relevant cited papers) directly compared a low and therapeutic doses of AM to food animals (poultry) on the prevalence of AMR Measurement and recording of AMU suboptimal in most studies Appraisal of review papers 37 reviews specifically on AMU or AMR All narrative reviews (29) or reports (8) no systematic review One review included search methods and one (different) review specified inclusion and exclusion criteria for studies Only 3 discussed validity in analyzing studies Specific organism-antimicrobial pairs cited in 25 review papers Enterococci Vancomycin Quinupristin/dalfopristin Salmonella Multiple drug resistance Fluoroquinolones Ceftriaxone Campylobacter Fluoroquinolones Macrolides, Tetracyclines E. coli/coliforms Nourseothricin Tetracyclines Fluoroquinolones Extended spectrum beta lactams Gentacycin, apramycin STEC Multiple drug resistance Streptococci Tylosin 20 13 7 16 10 3 3 13 12 1 11 4 3 2 1 1 1 1 Appraisal of review papers 37 sources cited 1,869 publications 1,012 (54.2%) were determined to be original studies providing original data Generally reiterated the most storied examples linking AMU in animals and AMR. Most examples related to antimicrobials used only therapeutically in the USA antimicrobials never used in the USA (avoparcin, Appraisal of review papers Individually and collectively do not identify studies contrasting impacts of low-dose, long duration AMU relative to other AMU provide evidence of any differential effects among specific modes of AMU in selecting for AMR. no evidence that measures to reduce low-dose, long term AMU that do not reduce aggregate antimicrobial use would provide benefits upon: Overall summary Enduring uncertainty over the public health consequences of AMU in animals has frustrated groups who have pursued greater regulation Vast majority of papers cited by key sources contain no primary data Shortcomings in design or reporting common Overall summary Dearth of RCT contributes to difficulty in drawing inferences about this question Available evidence inadequate for meaningful comparison of different modes of AMU in relation to emergence of AMR in pathogens or commensals in commercial swine populations The conservative position is that reducing aggregate use of antimicrobials is the most appropriate goal Removal of Growth Promoters in Denmark 1995 National ban on avoparcin Voluntary agreement to minimize the use of AGP’s 1998 National ban on virginiamycin (Jan) Voluntary agreement re. finishers (Mar) National tax on AGP’s (Sep) about $2 per pig 1999 EU ban: tylosin, bacitracin, spiramycin and virginiamycin EU ban: olaquindox and carbadox 2000 Voluntary agreement to ban AGP’s for weaners (DK) Expectations for the Restrictions Reduction of antibiotic use in food animals Minimal impact on production Reduction of antibiotic resistance Animal isolates Human isolates Reduced risk to human health Zoonotic and foodborne pathogens Response of Danish producers (2004) Increased weaning age by more than 3 days Reduced ration density (protein/energy) Practice limit feeding where possible Added ZnO and organic acids to diets Utilized more therapeutic antimicrobials Aggregate antimicrobial use in Danish swine industry Effects on weaned pig performance Percent Change Nursery Mortality v. 1998 Baseline 30% 25% 20% 15% 10% 5% 0% -5% 1998 1999 2000 2001 DANMAP 2004 Antimicrobial resistance in Salmonella DANMAP 2004 Antimicrobial resistance in Salmonella AMR in Salmonella in pigs Danmap 2004/2012 Non-susceptibility of in S. pneumoniae isolates from humans in Denmark Human MRSA cases in Denmark (DANMAP 2012) Summary of Danish experience Anticipated decrease in aggregate AMU in food animals not realized Measurable animal health impact Reduction in AMR of zoonotic and commensal isolates from pigs variable AMR in major human pathogens increased Silver lining of public health benefit hard to perceive Can we extrapolate this to the USA Differences in regulations Virtual elimination of vet dispensing (1995) Mandatory herd health consultations per year 12 farm visits per year 35 day limit in prescriptions Changes preceded AGP bans by several years To the future Growth promotant usage being phased out in USA Are we prepared? Earlier weaned pigs More disease challenge (?) – PRRS Less veterinary oversight