Peter Davies, Carie Alexander, Jeein Chung, Sylvia Wanzala

College of Veterinary MedicineUniversity of Minnesota

Critical appraisal of evidence that low-dose, long term (growth promotion) antimicrobial use augments public health risks from antimicrobial resistant organisms

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

replaced by increased therapeutic use

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

Assumption of ‘diligence’

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 Descriptive or analytical papers Reviews or reports

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?15. Was an untreated control group included?16. Was the study replicated?

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?25. Was the method of resistance testing described or referenced?26. Was the resistance description categorical, or by MIC?27. Was the origin of MIC breakpoints specified?

Appraisal tool for descriptive studies

Appraisal tool for descriptive studies

Statistical Analysis

28. Was it conducted?29. Were specific statistical tests indicated?30. Were multivariate methods used?31. 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 conclusions

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)

Yes No

Abstract present 21 16 Clear Objective stated 21 16 Abstract refers to AMU 13 24 Abstract refers to AMR 19 18 Objective refers to AMU 11 26 Objective refers to AMR 19 18 Abstract refers to AMU and AMR 11 26 Objective refers to AMU and AMR 8 29 AMU or AMR stated in abstract or objectives 21 16

Results of analytical studies (n = 21)

Study subjects 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 2 in experimental setting.

14 provided data on AMU

Results of analytical studies (n = 21)

19 reported measurement of AMR 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) 11 studies without confidence intervals

Table 2: Number of analytical studies reporting details of measuring antimicrobial use (AMU) and of the antimicrobial compound, dose, route, and duration of administration

AMU measured

Compound specified

Dose stated

Route stated

Duration stated

All stated

Recorded (n = 9) 9 6 7 7 6 Survey (n = 4) 2 0 0 1 0 Unknown (n = 1) 1 1 1 1 1 Total (n = 14) 12 7 8 9 7

Analytical studies reporting details of AMU

(n = 14)

Results of analytical studies(n = 21)

12 studies for detailed review 7 of 9 studies that did not compare AMU

and AMR implicated use in resistance

Compared AMU and AMR

Discussed Limitations

Discussed Representativeness

Discussed AMU and AMR

Implicated AMU in AMR

No (n = 9) 4 8 8 7 Yes (n = 12) 5 8 11 10 Total (n = 21) 9 16 19 17

Quality indicators of studies (n = 12)

Subjects Age Housing Nutrition Control group Replication

Animal (n = 7) 5 3 3 5 2 Human (n = 3) 2 0 0 1 0 Both(n = 2) 1 1 1 1 0 Total (n = 12) 8 4 4 7 2

Subjects Compound specified

Dose stated

Route stated

Duration stated

All stated

Animal (n = 7) 7 5 5 6 5 Both (n = 2) 2 1 1 1 1 Human (n = 3) 1 0 0 0 0

Total 10 6 6 7 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 or drawing inferences

None discussed potential limitations.

Specific organism-antimicrobial pairs cited in 25 review papers

Enterococci 20 Vancomycin 13 Quinupristin/dalfopristin 7

Salmonella 16 Multiple drug resistance 10 Fluoroquinolones 3 Ceftriaxone 3

Campylobacter 13 Fluoroquinolones 12 Macrolides, Tetracyclines 1

E. coli/coliforms 11 Nourseothricin 4 Tetracyclines 3 Fluoroquinolones 2 Extended spectrum beta lactams 1

Gentacycin, apramycin 1

STEC Multiple drug resistance 1

Streptococci Tylosin 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,

nourseothricin).

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:

prevalence of AMR organisms in food animals public health

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 Commensal organisms and animal 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

Percent Change Nursery Mortality v. 1998 Baseline

-5%

0%

5%

10%

15%

20%

25%

30%

1998 1999 2000 2001

Effects on weaned pig performance

DANMAP 2004Antimicrobial resistance in Salmonella

DANMAP 2004Antimicrobial 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