The contribution of animal antibiotic use to antibiotic resistance in humans: Panel evidence from Denmark

Antibiotic use (ABU) in animals is postulated to be a major contributor to selection of antibiotic resistance (ABR) which subsequently causes infections in human populations. However, there are few quantifications of the size of this association. Denmark, as a country with high levels of pig production and good surveillance data, is an ideal case study for exploring this association. In this paper, we compile a dataset on ABU across several animal species and antibiotic classes, and data on the rate of antibiotic resistance (ABR) in humans across key pathogens, in Denmark over time (2010 - 2020). We run panel data regressions (fixed effects, random effects, first difference and pooled ordinary least squares) to test the association between the level of ABR in human infections and the level of ABU in animals. Between ABR in humans and ABU in animal species, we find a positive relationship for cattle, some evidence of a positive relationship for poultry and companion animals, and a negative relationship for fish, although the latter is likely driven by confounding factors. When lagging ABU by one year, the effect of ABU in cattle and companion animals remained similar, the effect of ABU in poultry fell in size, and ABU in fish was no longer significant, perhaps due to differences in life cycle length among animal species. Additional covariates were explored, including pet populations, agricultural production and GDP per capita (at purchasing power parity), but these results were limited by the statistical power of the dataset. Under all models, animal ABU determined only a minority of the change in human ABR levels in this context with adjusted R2 ranging from 0.19 to 0.44. This paper supports the role of animal ABU in determining human ABR levels but suggests that, despite comprising a large portion of systemwide ABU, it only explains a minority of the variation. This is likely driven in part by data limitations, and could also be due to a persistence of ABR once resistance has emerged, suggesting a significant role for socioeconomic and transmission factors in bringing ABR down to desirable levels. Highlights ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by JPIAMR (the Joint Programming Initiative on Antimicrobial Resistance), as part of the SEFASI consortium (grant no. JPIAMR2021-182 SEFASI) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used (or will use) ONLY openly available human data that were originally located at: DanMap () VETSTAT () I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at: DanMap () VETSTAT () * ABR : Antibiotic resistance ABU : Antibiotic use AMR : Antimicrobial resistance AMS : Antimicrobial stewardship AMU : Antimicrobial use DanMap : The Danish Integrated Antimicrobial Resistance Monitoring and Research Programme OLS : Ordinary least squares regression One Health : The interplay between human, animal and environmental health POLS : Pooled OLS SEFASI : Selecting Efficient Farm-Level Antimicrobial Stewardship Interventions from a One Health Perspective