Prevalence of antimicrobial resistance genes and its association with restricted antimicrobial use in food-producing animals: a systematic review and meta-analysis.

BACKGROUND: There is ongoing debate regarding potential associations between restrictions of antimicrobial use and prevalence of antimicrobial resistance (AMR) in bacteria. OBJECTIVES: To summarize the effects of interventions reducing antimicrobial use in food-producing animals on the prevalence of AMR genes (ARGs) in bacteria from animals and humans. METHODS: We published a full systematic review of restrictions of antimicrobials in food-producing animals and their associations with AMR in bacteria. Herein, we focus on studies reporting on the association between restricted antimicrobial use and prevalence of ARGs. We used multilevel mixed-effects models and a semi-quantitative approach based on forest plots to summarize findings from studies. RESULTS: A positive effect of intervention [reduction in prevalence or number of ARGs in group(s) with restricted antimicrobial use] was reported from 29 studies for at least one ARG. We detected significant associations between a ban on avoparcin and diminished presence of the vanA gene in samples from animals and humans, whereas for the mecA gene, studies agreed on a positive effect of intervention in samples only from animals. Comparisons involving mcr-1, blaCTX-M, aadA2, vat(E), sul2, dfrA5, dfrA13, tet(E) and tet(P) indicated a reduced prevalence of genes in intervention groups. Conversely, no effects were detected for ß-lactamases other than blaCTX-M and the remaining tet genes. CONCLUSIONS: The available body of scientific evidence supported that restricted use of antimicrobials in food animals was associated with an either lower or equal presence of ARGs in bacteria, with effects dependent on ARG, host species and restricted drug.

Comparison of different approaches to antibiotic restriction in food-producing animals: stratified results from a systematic review and meta-analysis.

BACKGROUND: We have previously reported, in a systematic review of 181 studies, that restriction of antibiotic use in food-producing animals is associated with a reduction in antibiotic-resistant bacterial isolates. While informative, that report did not concretely specify whether different types of restriction are associated with differential effectiveness in reducing resistance. We undertook a sub-analysis of the systematic review to address this question. METHODS: We created a classification scheme of different approaches to antibiotic restriction: (1) complete restriction; (2) single antibiotic-class restriction; (3) single antibiotic restriction; (4) all non-therapeutic use restriction; (5) growth promoter and prophylaxis restriction; (6) growth promoter restriction and (7) other/undetermined. All studies in the original systematic review that were amenable to meta-analysis were included into this substudy and coded by intervention type. Meta-analyses were conducted using random effects models, stratified by intervention type. RESULTS: A total of 127 studies were included. The most frequently studied intervention type was complete restriction (n=51), followed by restriction of non-therapeutic (n=33) and growth promoter (n=19) indications. None examined growth promoter and prophylaxis restrictions together. Three and seven studies examined single antibiotic-class and single antibiotic restrictions, respectively; these two intervention types were not significantly associated with reductions in antibiotic resistance. Though complete restrictions were associated with a 15% reduction in antibiotic resistance, less prohibitive approaches also demonstrated reduction in antibiotic resistance of 9%-30%. CONCLUSION: Broad interventions that restrict global antibiotic use appear to be more effective in reducing antibiotic resistance compared with restrictions that narrowly target one specific antibiotic or antibiotic class. Importantly, interventions that allow for therapeutic antibiotic use appear similarly effective compared with those that restrict all uses of antibiotics, suggesting that complete bans are not necessary. These findings directly inform the creation of specific policies to restrict antibiotic use in food-producing animals.

Examination of unintended consequences of antibiotic use restrictions in food-producing animals: Sub-analysis of a systematic review.

Antimicrobial resistance is considered one of the greatest threats to global and public health today. The World Health Organization, the Food and Agriculture Organization, and the World Organisation for Animal Health, known as the Tripartite Collaboration, have called for urgent action. We have previously published a systematic review of 181 studies, demonstrating that interventions that restrict antibiotic use in food-producing animals are associated with a reduction in antibiotic resistant bacterial isolates in both animals and humans. What remains unknown, however, are whether (and what) unintended consequences may arise from such interventions. We therefore undertook a sub-analysis of the original review to address this research question. A total of 47 studies described potential consequences of antibiotic restrictions. There were no consistent trends to suggest clear harm. There may be increased bacterial contamination of food products, the clinical significance of which remains unclear. There is a need for rigorous evaluation of the unintended consequences of antibiotic restrictions in human health, food availability, and economics, given their possible widespread implications.

Restricting the use of antibiotics in food-producing animals and its associations with antibiotic resistance in food-producing animals and human beings: a systematic review and meta-analysis.

BACKGROUND: Antibiotic use in human medicine, veterinary medicine, and agriculture has been linked to the rise of antibiotic resistance globally. We did a systematic review and meta-analysis to summarise the effect that interventions to reduce antibiotic use in food-producing animals have on the presence of antibiotic-resistant bacteria in animals and in humans. METHODS: On July 14, 2016, we searched electronic databases (Agricola, AGRIS, BIOSIS Previews, CAB Abstracts, MEDLINE, Embase, Global Index Medicus, ProQuest Dissertations, Science Citation Index) and the grey literature. The search was updated on Jan 27, 2017. Inclusion criteria were original studies that reported on interventions to reduce antibiotic use in food-producing animals and compared presence of antibiotic-resistant bacteria between intervention and comparator groups in animals or in human beings. We extracted data from included studies and did meta-analyses using random effects models. The main outcome assessed was the risk difference in the proportion of antibiotic-resistant bacteria. FINDINGS: A total of 181 studies met inclusion criteria. Of these, 179 (99%) described antibiotic resistance outcomes in animals, and 81 (45%) of these studies were included in the meta-analysis. 21 studies described antibiotic resistance outcomes in humans, and 13 (62%) of these studies were included in the meta-analysis. The pooled absolute risk reduction of the prevalence of antibiotic resistance in animals with interventions that restricted antibiotic use commonly ranged between 10 and 15% (total range 0-39), depending on the antibiotic class, sample type, and bacteria under assessment. Similarly, in the human studies, the pooled prevalence of antibiotic resistance reported was 24% lower in the intervention groups compared with control groups, with a stronger association seen for humans with direct contact with food-producing animals. INTERPRETATION: Interventions that restrict antibiotic use in food-producing animals are associated with a reduction in the presence of antibiotic-resistant bacteria in these animals. A smaller body of evidence suggests a similar association in the studied human populations, particularly those with direct exposure to food-producing animals. The implications for the general human population are less clear, given the low number of studies. The overall findings have directly informed the development of WHO guidelines on the use of antibiotics in food-producing animals. FUNDING: World Health Organization.