U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

WHO Guidelines on Use of Medically Important Antimicrobials in Food-Producing Animals. Geneva: World Health Organization; 2017.

Cover of WHO Guidelines on Use of Medically Important Antimicrobials in Food-Producing Animals

WHO Guidelines on Use of Medically Important Antimicrobials in Food-Producing Animals.

Show details

1.3Supplemental report to the “Restriction in the use of antibiotics in food animals and antibiotic resistance in food animals and humans” (University of Calgary, Canada)

, , , , , , , , , , and .

Author Information and Affiliations

Created: .

The full report to the World Health Organization (WHO), titled “Restriction in the use of antibiotics in food animals and antibiotic resistance in food animals and humans—a systematic review and meta-analysis” was completed in October 2016. Findings from this completed review are important in informing the development of WHO guidelines on the use and restriction of antibiotics in food animals. For further refinement in the creation of these guidelines and recommendations, the WHO Advisory Group on Integrated Surveillance of Antimicrobial Resistance (AGISAR) has requested the following supplemental work:

  1. Update of the literature search, to identify studies published since the search strategy was last run in July 2016
  2. Stratified analysis of the pooled reduction in antibiotic resistance, by the type of antibiotic use that is restricted or targeted by interventions
  3. Data extraction of the studies included in the systematic review for unintended consequences or harms from interventions that restrict antibiotic use

This report presents the results of the requested supplemental work.

I. Update of Literature Search

The search strategy described in the original systematic review was re-run in January 2017 in the following electronic databases, to capture studies published since our July 2016 search:

  • Agricola – Ebsco Platform
  • BIOSIS Previews – Web of Knowledge Platform
  • CAB Abstracts – Ebsco Platform
  • MEDLINE – Ovid Platform (Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R)
  • EMBASE – Ovid Platform
  • Global Index Medicus (http://www.globalhealthlibrary.net/): The non-MEDLINE indices included: AIM (AFRO), LILACS (AMRO/PAHO), IMEMR (EMRO), IMSEAR (SEARO), WPRIM (WPRO), WHOLIS (KMS), and SciELO.
  • ProQuest Dissertations – ProQuest Platform
  • Science Citation Index – Web of Knowledge Platform

A total of 191 citations were identified. Two authors (KT and NC) reviewed all abstracts for potential eligibility for inclusion into the systematic review. Any abstract that (a) reported on original research, (b) described an active intervention that aimed to limit antibiotic use in animals, and (c) described antibiotic resistance in animals or humans were selected for full-text review. Fifteen studies were selected for full-text review, of which four met the pre-specified criteria, as described in the original report, for inclusion into the systematic review.1–4 All four were animal studies, only one of which could be included into the main set of meta-analyses.3

We have updated the systematic review and meta-analysis to include these four studies and a revised full report, dated March 7, 2017, has been produced and provided to the WHO. The findings and conclusions in the updated report are unchanged from those in the original report.

II. Stratified Analysis by Intervention Type

To conduct stratified analysis, interventions needed to be classified based on the type of antibiotic use that was targeted. The following classification scheme was thereby created, with input and feedback from WHO AGISAR:

1.

Restriction on the use of all antibiotics

2a.

Antibiotic class-specific restriction, or restriction on the use of one or more (but not all) classes of antibiotics, for all indications of use

2b.

Antibiotic-specific restriction, or restriction on the use of one or more individual antibiotics, for all indications of use

3.

Restriction on the use of antibiotics for all non-therapeutic indications including growth promotion, prophylaxis, and metaphylaxis (Treatment of diseased animals permitted only)

4.

Restriction on the use of antibiotics for the non-therapeutic indications of growth promotion and prophylaxis (Treatment and metaphylaxis permitted)

5.

Restriction on the use of antibiotics for purposes of growth promotion only (Treatment, metaphylaxis, and prophylaxis permitted)

6.

Undetermined: Inability to classify the intervention type into one of the above categories, or where the indication for antibiotic use that is targeted by the intervention is not specified

Of particular note, every study included into the systematic review assessed an intervention that restricted the use of antibiotics. Studies that did not specify the type of antibiotic use or indication that was targeted in this restriction were classified as “Undetermined” (Category 6). This included studies, for example, that compared regions or farms using “more” versus “less” antibiotics with no indication that was specifically targeted or described, or studies that assessed the impact of reducing antibiotic use in a jurisdiction without delineating how this was achieved.

Each category in the classification scheme is mutually exclusive. If a single study included more than one intervention, then each intervention was classified separately based on the above approach. Table 1 outlines the definitions used by the classification scheme.

Table 1. Definitions for terms used in the classification scheme for interventions.

Table 1

Definitions for terms used in the classification scheme for interventions.

Figure 1 illustrates the corresponding decision rules that were followed, to apply the above classification scheme to each study.

Figure 1. Algorithm for classifying the type of antibiotic use targeted by interventions.

Figure 1

Algorithm for classifying the type of antibiotic use targeted by interventions.

A. Results – Classification of study interventions

Table 2 presents the categorization of interventions by type of antibiotic use being targeted for restriction.

Table 2. Type of antibiotic use targeted by interventions in 179 animal studies.

Table 2

Type of antibiotic use targeted by interventions in 179 animal studies.

Of the 179 animal studies included in the systematic review, 69 restricted all uses of antibiotics, 36 studies restricted use of antibiotics for all non-therapeutic purposes, while 27 restricted the use of antibiotics for growth promotion only. A total of 39 studies could not be classified based on the type of antibiotic use targeted by the intervention. An index of the 179 animal studies, their corresponding references from the original report, and their assigned classifications of interventions is presented in Supplemental Table 1 in the Appendix to this supplemental report.

Supplemental Table 1. Index of animal studies, reference numbers, and intervention types.

Supplemental Table 1

Index of animal studies, reference numbers, and intervention types.

Table 3 presents the categorization of interventions by type of antibiotic use being targeted for restriction, for human studies.

Table 3. Type of antibiotic use targeted by interventions in 21 human studies.

Table 3

Type of antibiotic use targeted by interventions in 21 human studies.

Of the 21 human studies, five restricted all uses of antibiotics, two restricted antibiotic use for all non-therapeutic indications, and seven restricted use of antibiotics for growth promotion only. Five studies could not be classified based on the type of antibiotic use targeted by the intervention. An index of the 21 human studies, their corresponding references from the original report, and their assigned classifications of interventions is presented in Supplemental Table 2 in the Appendix to this supplemental report.

Supplemental Table 2. Index of human studies, reference numbers, and intervention types.

Supplemental Table 2

Index of human studies, reference numbers, and intervention types.

B. Results – Stratified analysis

Similar to the stratified analysis conducted in the original systematic review and meta-analysis, stratified meta-analysis was performed for all studies amenable to meta-analysis, ignoring specific bacterial species, sample types, units of analysis, and antibiotic classes. Supplemental Table 1 in the Appendix to this supplemental report lists the individual animal studies amenable to stratified meta-analysis. Table 4 outlines the results from meta-analysis stratified by the type of antibiotic use targeted by interventions in animal studies.

Table 4. Stratified meta-analysis for animal studies, by intervention type.

Table 4

Stratified meta-analysis for animal studies, by intervention type.

Stratified meta-analysis must be interpreted with some caution, due to the lower numbers of studies that can be included and the overlapping confidence intervals in the pooled estimates across strata. With these caveats in mind, we would propose three high-level observations from the stratified analysis, which we summarize below, followed by further elaboration:

  1. The type of antibiotic use targeted by interventions is not specified in many of the studies identified by our search. This finding underlines the need for better characterization of interventions in future research, and perhaps even more importantly, in the development of future policy and regulations.
  2. There is some suggestion that the interventions that target only specific antibiotic classes or specific antibiotic drugs may have less effect on antibiotic resistance than do antibiotic restrictions covering all classes.
  3. Among antibiotic restriction interventions that target all classes, there does not seem to be any advantage of complete bans preventing any use relative to restrictions that still permit therapeutic and prophylactic use.

In 39 of 179 animal studies and 5 of 21 human studies, the type of antibiotic use that was targeted by interventions could not be determined. For the majority of these studies, antibiotic resistance was compared between groups having “higher” versus “lower” antibiotic use, without further delineation as to how antibiotics were being used or restricted in both groups. Though our stratified analysis suggests that lower overall antibiotic use does seem to be associated with less antibiotic resistance in this “Undetermined” group, the development of policies and regulations on antibiotic use requires more specific information on interventions, to explore whether certain interventions appear to be more or less effective than others. Therefore, future research should focus on better characterizing interventions that restrict antibiotic use.

Secondly, our stratified analysis results suggest that broad interventions that globally restrict the use of all classes of antibiotics may be more effective in reducing antibiotic resistance, compared to interventions that narrowly restrict the use of a few specific antibiotics or antibiotic classes. For example, the absolute risk differences for interventions that broadly restrict antibiotics across different classes range from −0.08 to −0.29. That is, the proportion of bacteria with antibiotic resistance is 8 to 29% lower in intervention versus comparator groups, with such broad interventions. In contrast, the absolute risk differences for interventions that restrict only a single or a few antibiotic(s) or antibiotic class(es) range between −0.02 and 0.04, with confidence intervals overlapping 0, indicating that there is no difference in antibiotic resistance in intervention versus comparator groups. Interventions that restrict specific antibiotics and antibiotic classes may therefore be less beneficial than global restrictions that are not confined to specific antibiotics and antibiotic classes.

Lastly, our results suggest that full restriction of antibiotics (where antibiotics cannot be used for any indication, including non-therapeutic and therapeutic purposes) does not appear to be superior to interventions that do allow for therapeutic use of antibiotics as well as for metaphylaxis and prophylaxis of animals. The absolute risk difference of antibiotic resistance with full antibiotic restriction was −0.18, compared to absolute risk differences between −0.08 and −0.29 for partial restrictions only. Restricted antibiotic use that permits the treatment of diseased animals and/or diseased herds does not seem to undermine efforts to reduce antibiotic resistance.

It is difficult to formulate more precise conclusions beyond the above three observations. For example, the reduction in antibiotic resistance appears to be stronger for interventions that restrict growth promotion only (RD −0.29 [95% CI −0.40, −0.19]), compared with interventions that are even more restrictive, such as those disallowing prophylaxis or metaphylaxis in addition to disallowing growth promotion (RD −0.08 [95% CI −0.11, −0.06]), or disallowing all uses of antibiotics including for therapy (RD −0.18 [95% CI −0.22, −0.14]). However, these differences in the absolute risk reductions of antibiotic resistance across interventions may be artefactual. The pooled prevalence of antibiotic resistance in comparator groups for interventions restricting use of growth promoters is 0.48 (95% 0.23, 0.73), compared to 0.13 (95% CI 0.11, 0.16) in the comparator groups for interventions that restrict all non-therapeutic uses of antibiotics. That is, the pooled “baseline” prevalence in the comparator groups is not the same across all intervention types. There is greater potential for reduction of antibiotic resistance when there is a higher baseline prevalence of resistance, such as in the case for interventions restricting the use of growth promoters. Therefore, differences in pooled effect estimates across different interventions that broadly restrict antibiotics may spurious; we cannot comment on a specific intervention being superior to others, so long as restrictions are not confined to a single class of antibiotics.

Corresponding stratified meta-analysis based on intervention type was also conducted for human studies (Table 5). Supplemental Table 2 (to be requested upon request) in the Appendix to this supplemental report lists the individual human studies amenable to stratified meta-analysis.

Table 5. Stratified meta-analysis for human studies, by intervention type.

Table 5

Stratified meta-analysis for human studies, by intervention type.

Due to the relatively small numbers of human studies and the wide and overlapping confidence intervals in subcategories, we caution against attempting to draw specific inferences regarding relative effects of the different intervention types in human studies.

III. Information on Potential Unintended Consequences of Interventions That Restrict Antibiotic Use

Data were extracted from the studies included in the systematic review, regarding potential harms stemming from interventions that restrict antibiotic use. Categories of potential harms included: 1) increased use of antibiotics (such as increased need for antibiotics for treatment purposes), 2) adverse effects on human health, 3) decrease in food and protein availability, 4) food safety, 5) adverse effects on animal health and welfare, 6) adverse effects on animal production, and 7) economic consequences.

Only 48 studies in total (all animal studies, two of which also examined antibiotic resistance in the human population) reported any data on the presence or absence of potential harms of interventions that restrict antibiotic use. Of these, 32 explicitly had at least one of the aforementioned potential harms as a primary research objective. One study examined animal production consequences as a secondary objective.8 The other 15 studies reported potential harms in the discussion section without pre-specifying these as objectives. No studies reported adverse effects on human health or on food and protein availability. Table 6 presents a summary of the extent to which information on harms is reported in the identified studies. Of note, a single study could report on more than one potential harm.

Table 6. Potential harms reported by animal and human studies.

Table 6

Potential harms reported by animal and human studies.

Table 7 summarizes the specific unintended consequences reported by individual studies.

Table 7. Specific reporting in identified studies relating to potential harms from interventions restriction antibiotic use.

Table 7

Specific reporting in identified studies relating to potential harms from interventions restriction antibiotic use.

A. Antibiotic use

Five studies reported on potential unintended consequences with regard to the total amount of antibiotics used. One study reported that when one antibiotic growth promoter was banned, there tended to be an increased use of other permitted antibiotic growth promoters until the use of these, too, was restricted.9 The other four studies reported that when antibiotic use was restricted, this resulted in increased administration of antibiotics to individual animals for therapeutic purposes, but that the total amount or volume of antibiotics used nevertheless decreased.8,10–12

B. Food safety

The most widely reported potential unintended consequence was in the domain of food safety, with 34 studies reporting on this outcome. Of these, 14 (41%) found that interventions that restricted antibiotic use resulted in increased contamination with bacteria (including Salmonella spp., Campylobacter spp., and Enterobacteriaceae) in the retail meats produced. Fifteen of 34 studies (45%) reported no difference in contamination rates between food products from intervention and comparator groups. A smaller percentage of studies (12%) demonstrated either variable results within studies or a lower level of contamination of meats in intervention versus comparator groups. The clinical and public health significance of these findings are unclear, especially as to what extent adequate preparation and cooking can mitigate the risk of bacterial contamination of raw retail meat, and whether higher bacterial contamination translates into increased clinical and zoonotic disease.

C. Animal health

Only five studies reported potential adverse effects on animal health.8,13–16 Three such studies were specific to dairy herds, showing variable results. Two of the three reported higher prevalence of intra-mammary infections when the use of antibiotics is restricted (though one study indicated that the higher prevalence was significant only at parturition but not the dry-off period),14,15 while the third study showed no difference in the prevalence of mastitis between intervention and comparator groups.16 Berge et al. reported an increase in respiratory disease but decrease of diarrhea in calves where antibiotics used for prophylaxis and growth promoters were restricted.13 Lastly, Dorado-Garcia et al. reported no difference in mortality or mean mortality age in intervention versus comparator groups.8

D. Animal production

Studies reporting on the effects of antibiotic restriction on animal production again demonstrated variable results. One study indicated that such interventions resulted in greater weight gain (from reduced diarrhea) in intervention groups,13 while two studies indicated that animal production was adversely affected by antibiotic restriction, with increased feeding time (to achieve a target weight) or increased production cycle duration in intervention groups.8,12 There may also be effects on parity and milk yield, with antibiotic restriction being associated with increased parity but lower milk yield in one study.17

E. Costs and economics

Only three studies reported potential economic consequences of antibiotic restriction interventions. One study showed that restriction in antibiotic use, in combination with restrictions in the uses of hormone implants and anti-helmintics, may increase feeding time to reach target weight in animals, leading to increases in the need for land for disposal of waste, and increases in energy consumption for animal food production.12 It is difficult to disentangle the extent to which these unintended consequences in animal production and costs are attributable to the antibiotic restrictions themselves, versus the co-interventions that were implemented in this study. Other studies show variable economic implications to treatment and veterinary costs, with one study showing an increase while another showing a decrease in such costs.8,13

In summary, proportionately few studies included in the systematic review reported on unintended consequences of interventions that restrict antibiotic use. We also note that unintended consequences of antibiotic restriction were not the focus of any study included in the systematic review. Similarly, our search strategy did not explicitly include harms or unintended consequences, and therefore the studies captured in our systematic review may not be a comprehensive reflection of the literature in this area. Given the importance of potential harms in interventions that restrict antibiotic use, a separate systematic review dedicated to this question may be needed to guide policy recommendations. This report is being provided to the WHO as a supplement to the main report, which has also been re-submitted in an updated form on the same date. Given the supplemental nature of the analysis in this report, findings do need to be reviewed in conjunction with the main report, rather than as a stand-alone report focusing on unintended consequences.

IV. Conclusion

The supplemental analysis that has been requested sheds light on various policy-relevant questions. Specifically, in the bacteria studied, broad restrictions covering all antibiotic classes appear to be more effective in reducing antibiotic resistance compared to narrow restrictions of one antibiotic class or drug. Furthermore, complete restrictions on the use of all antibiotics do not seem to be more effective than interventions that allow for appropriate therapeutic use. Regarding potential unintended consequences, there appears to be a recurring finding of somewhat increased use of therapeutic antibiotic courses in individual animals (though an overall reduction in the volume of antibiotics used) with interventions that restrict antibiotic use, and possible implications for food safety given the possible higher prevalence of bacterial contaminants in these food products. These findings are likely to be important to explore further as future guidelines and recommendations on antibiotic use are developed.

References

1.
Dorado-Garcia A, Mevius DJ, Jacobs JJH, et al. Quantitative assessment of antimicrobial resistance in livestock during the course of a nationwide antimicrobial use reduction in the Netherlands. Journal of Antimicrobial Chemotherapy. 2016;71(12):3607–3619. [PubMed: 27585970]
2.
Kassem II, Kehinde O, Kumar A, Rajashekara G. Antimicrobial-Resistant Campylobacter in Organically and Conventionally Raised Layer Chickens. Foodborne Pathog Dis. 2017;14(1):29–34. [PubMed: 27768387]
3.
Osterberg J, Wingstrand A, Jensen AN, et al. Antibiotic resistance in Escherichia coli from pigs in organic and conventional farming in four European countries. PLoS ONE. 2016;11 (6) (e0157049). [PMC free article: PMC4928804] [PubMed: 27362262]
4.
Wanninger S, Donati M, Di Francesco A, et al. Selective pressure promotes tetracycline resistance of Chlamydia suis in fattening pigs. PLoS ONE. 2016;11 (11) (e0166917). [PMC free article: PMC5125646] [PubMed: 27893834]
5.
Paulson JA, Zaoutis TE. Nontherapeutic Use of Antimicrobial Agents in Animal Agriculture: Implications for Pediatrics. Pediatrics. 2015;136(6):e1670–1677. [PubMed: 26574594]
6.
Codex Alimentarius. Code of Practice to Minimize and Contain Antimicrobial Resistance, CAC/RCP 61–2005.Food and Agriculture Organization of the United Nations/World Health Organization;2005.
7.
European Medicines Agency. Guideline for the demonstration of efficacy for veterinary medicinal products containing antimicrobial substances. London, United Kingdom 2016.
8.
Dorado-Garcia A, Graveland H, Bos ME, et al. Effects of Reducing Antimicrobial Use and Applying a Cleaning and Disinfection Program in Veal Calf Farming: Experiences from an Intervention Study to Control Livestock-Associated MRSA.[Erratum appears in PLoS One. 2015;10(9):e0139536; PMID: 26413843]. PLoS ONE. 2015;10(8):e0135826. [PMC free article: PMC4549302] [PubMed: 26305895]
9.
Aarestrup FM, Seyfarth AM, Emborg HD, Pedersen K, Hendriksen RS, Bager F. Effect of abolishment of the use of antimicrobial agents for growth promotion on occurrence of antimicrobial resistance in fecal enterococci from food animals in Denmark. Antimicrob Agents Chemother. 2001;45(7):2054–2059. [PMC free article: PMC90599] [PubMed: 11408222]
10.
Coalition for Animal Health. Political Bans on Antibiotics are Counterproductive European Test Case: Increased Animal Disease, Mixed Human Health Benefit.
11.
Jensen HH, Hayes DJ. Impact of Denmark’s ban on antimicrobials for growth promotion. Current Opinion in Microbiology. 2014;19:30–36. [PubMed: 24997397]
12.
Morley PS, Dargatz DA, Hyatt DR, et al. Effects of Restricted Antimicrobial Exposure on Antimicrobial Resistance in Fecal Escherichia coli from Feedlot Cattle. Foodborne Pathog Dis. 2011;8(1):87–98. [PubMed: 21034271]
13.
Berge ACB, Moore DA, Besser TE, Sischo WM. Targeting therapy to minimize antimicrobial use in preweaned calves: Effects on health, growth, and treatment costs. Journal of Dairy Science. 2009;92(9):4707–4714. [PubMed: 19700735]
14.
Park YK, Fox LK, Hancock DD, McMahan W, Park YH. Prevalence and antibiotic resistance of mastitis pathogens isolated from dairy herds transitioning to organic management. J vet sci. 2012;13(1):103–105. [PMC free article: PMC3317450] [PubMed: 22437543]
15.
Pol M, Ruegg PL. Relationship between antimicrobial drug usage and antimicrobial susceptibility of gram-positive mastitis pathogens. Journal of Dairy Science. 2007;90(1):262–273. [PubMed: 17183094]
16.
Roesch M, Perreten V, Doherr MG, Schaeren W, Schallibaum M, Blum JW. Comparison of antibiotic resistance of udder pathogens in dairy cows kept on organic and on conventional farms. Journal of Dairy Science. 2006;89(3):989–997. [PubMed: 16507693]
17.
Garmo RT, Waage S, Sviland S, Henriksen BI, Osteras O, Reksen O. Reproductive performance, udder health, and antibiotic resistance in mastitis bacteria isolated from Norwegian Red cows in conventional and organic farming. Acta Vet Scand. 2010;52:11. [PMC free article: PMC2829576] [PubMed: 20141638]
Copyright © World Health Organization 2017.

Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing.

Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user.

Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo).

Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “The translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”.

Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization.

Bookshelf ID: NBK487950
Contents

Views

  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this title (462K)
  • Disable Glossary Links

In this Page

Other titles in this collection

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Recent Activity

ClearTurn OffTurn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...