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Abstract / Description of output
Background: Although antimicrobial use is a key selector for antimicrobial resistance, recent studies have suggested that the ecological context in which antimicrobials are used might provide important factors for the prediction of the emergence and spread of antimicrobial resistance. Methods: We used 1547 variables from the World Bank dataset consisting of socioeconomic, developmental, health, and nutritional indicators; data from a global sewage-based study on antimicrobial resistance (abundance of antimicrobial resistance genes [ARGs]); and data on antimicrobial usage computed from the ECDC database and the IQVIA database. We characterised and built models predicting the global resistome at an antimicrobial class level. We used a generalised linear mixed-effects model to estimate the association between antimicrobial usage and ARG abundance in the sewage samples; a multivariate random forest model to build predictive models for each antimicrobial resistance class and to select the most important variables for ARG abundance; logistic regression models to test the association between the predicted country-level antimicrobial resistance abundance and the country-level proportion of clinical resistant bacterial isolates; finite mixture models to investigate geographical heterogeneities in the abundance of ARGs; and multivariate finite mixture models with covariates to investigate the effect of heterogeneity in the association between the most important variables and the observed ARG abundance across the different country subgroups. We compared our predictions with available clinical phenotypic data from the SENTRY Antimicrobial Surveillance Program from eight antimicrobial classes and 12 genera from 56 countries. Findings: Using antimicrobial use data from between Jan 1, 2016, and Dec 31, 2019, we found that antimicrobial usage was not significantly associated with the global ARG abundance in sewage (p=0·72; incidence rate ratio 1·02 [95% CI 0·92–1·13]), whereas country-specific World Bank's variables explained a large amount of variation. The importance of the World Bank variables differed between antimicrobial classes and countries. Generally, the estimated global ARG abundance was positively associated with the prevalence of clinical phenotypic resistance, with a strong association for bacterial groups in the human gut. The associations between bacterial groups and ARG abundance were positive and significantly different from zero for the aminoglycosides (three of the four of the taxa tested), β-lactam (all the six microbial groups), fluoroquinolones (seven of nine of the microbial groups), glycopeptide (one microbial group tested), folate pathway antagonists (four of five microbial groups), and tetracycline (two of nine microbial groups). Interpretation: Metagenomic analysis of sewage is a robust approach for the surveillance of antimicrobial resistance in pathogens, especially for bacterial groups associated with the human gut. Additional studies on the associations between important socioeconomic, nutritional, and health factors and antimicrobial resistance should consider the variation in these associations between countries and antimicrobial classes. Funding: EU Horizon 2020 and Novo Nordisk Foundation.