The value of international pharmacovigilance databases to help contain antibiotic resistance from a 'one health' perspective

<p dir="ltr">Background</p><p dir="ltr">Antibiotic resistance (ABR) is a global threat to public health that requires action from a 'One health' perspective. 'One health' highlights the interlinked nature of human, animal and environmental health. ABR can occur within humans, animals and the environment and can transmit between these different areas, thus the need to incorporate 'One health' into efforts to contain ABR. However, the relative importance of different drivers within human, animal and environmental health is not known. A greater understanding of this may allow more targeted interventions across 'One health'. Furthermore, limitations within traditional, laboratory-based surveillance of ABR have led to calls to consider other data sources. One of these hypothesised sources is data from pharmacovigilance databases. Pharmacovigilance databases collect reports of suspected adverse events related to the use of medicines. Pharmacovigilance benefits from a well- established network, with a particularly large reach for human health. This thesis aimed to assess the relative associations of different aspects of 'One health' in the ABR of children from rural India. Furthermore, this thesis aimed to investigate the utility of pharmacovigilance databases as a supplementary tool to that of traditional ABR surveillance across 'One health'.</p><p dir="ltr">Methods</p><p dir="ltr">Paper I was a cohort study that used Escherichia coli isolated from the stools of 125 children (aged between one and three years old) and animals, as well as water sources within the same community. Samples were collected simultaneously across sources at seven time points over a two year period and susceptibility testing for 16 antibiotics performed. Newey-West regression models were used to study temporal associations between resistance levels in humans and that of other sources. SourceR was used for attribution modelling to estimate the proportion of ABR cases in humans which could be attributed to each of the other sources.</p><p dir="ltr">Paper II analysed potential reports of ABR in VigiBase, a global pharmacovigilance database for humans. The reports were split into 'Probable' and 'Possible' cases of ABR based on the reported adverse events in the report. All 'Probable' reports and a random selection of 599 'Possible' reports were reviewed on a case-by- case basis. The reports were reviewed for their likelihood to be a case of ABR, as well as the reporting of antimicrobial susceptibility testing, previous antibiotic use, if the cases were linked to published scientific literature and the demographics of the reported patients. Chi-square tests and logistic regression models were used to test for differences between the 'Probable' and 'Possible' reports.</p><p dir="ltr">Paper III studied the reporting of potential ABR cases in international pharmacovigilance databases across 'One health'. VigiBase and EudraVigilance Veterinary, a European-based animal health pharmacovigilance database, were used to identify cases for human, animal and environmental health. No specialist environmental health database was identified. The reports were analysed over time, by continent of the reporting country and by the type of antibiotic reported using the Anatomical Therapeutic Chemical (ATC) classification.</p><p dir="ltr">In paper IV we compared the reports of potential ABR cases in VigiBase and EudraVigilance Veterinary against the percentage of resistant tests reported to traditional ABR surveillance databases. For humans, the Global Antimicrobial Resistance and Use Surveillance System (GLASS) was used and for animals it was the European Food Safety Authority (EFSA) and European Centre for Disease Prevention and Control (ECDC) joint report on ABR. The most recent data from these ABR databases was from 2022, and the data from the pharmacovigilance databases was limited to all reports up to the end of 2022. Logistic regression models were used to compare how ABR was reported for different ATC subgroups between the different databases.</p><p dir="ltr">Results</p><p dir="ltr">Eighteen of the 69 Newey-West regression models estimating the temporal association between human ABR and that of the other sources were statistically significant. Most of these, eight, were with household drinking water. There were five, three and two statistically significant temporal relationships for wastewater, animals and source of drinking water, respectively. SourceR attribution modelling estimated that the highest proportion of attributable cases of human ABR were from household drinking water, animals and wastewater. The proportion of attributable cases of human ABR was much lower for the source of drinking water.</p><p dir="ltr">There were more 'Possible' reports of potential ABR in VigiBase (n=20,815) compared to 'Probable' (n=3,497). For both groups, most of the reports were from high-income countries. The 'Probable' reports were more likely to be cases of ABR and report antimicrobial susceptibility testing. The logistic regression models showed that the 'Probable' reports were more likely to be cases of ABR after accounting for potential confounders. However, the 'Possible' reports were more likely to be reported from non-healthcare professionals and contained valuable information regarding patients who experienced an unexpected lack of effect of antibiotic treatment.</p><p dir="ltr">In terms of total reports, there were more reports for humans (n=29,667) compared to animals (n=5,217) in international pharmacovigilance databases. There were no reports reporting both environment and ABR terms together in either VigiBase or EudraVigilance Veterinary. There were 52 reports of environment-related terms with an antibiotic. There was an increase in reports received annually over time for humans and animals, but this was less clear for environment-related reporting. There was a consistent difference, for at least one antibiotic ATC subgroup, between the antibiotics reported to pharmacovigilance databases for potential cases of ABR and the percentage of resistant tests for these antibiotic groups in specialised databases.</p><p dir="ltr">Conclusion</p><p dir="ltr">'One health' should be considered when it comes to ABR surveillance and interventions. In the rural Indian community we studied, the closest over time association was with household drinking water. Pharmacovigilance databases can be used to identify potential cases of ABR from around the globe, but the number of reports of and the scope of the database was greatest for humans followed by animals. There was an absence of a specialised database for environment-related reporting. For humans, the search of VigiBase was able to identify cases of ABR with reasonable accuracy, and this was more so for a more specific search. When compared to traditional ABR databases, there was a consistent difference between the antibiotics in the human and animal-based databases.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Mitchell J,</b> Purohit M, Jewell CP, Read JM, Marrone G, Diwan V, Stålsby Lundborg C. Trends, relationships and case attribution of antibiotic resistance between children and environmental sources in rural India. Sci Rep. 2021 Nov 19;11(1):22599. <a href="https://doi.org/10.1038/s41598-021-01174-w" rel="noreferrer" target="_blank">https://doi.org/10.1038/s41598-021-01174-w</a></p><p dir="ltr">II. <b>Mitchell J,</b> Westerberg C, Purohit M, Lundquist P, Stålsby Lundborg C. The Enhancing Role of Pharmacovigilance to Conventional Antibiotic Resistance Surveillance: Cross-sectional Identification and Analysis of Reports of Antibiotic Resistance in VigiBase. Int J Infect Dis. 2025 June 4;107947. <a href="https://doi.org/10.1016/j.ijid.2025.107947" rel="noreferrer" target="_blank">https://doi.org/10.1016/j.ijid.2025.107947</a></p><p dir="ltr">III. <b>Mitchell J,</b> Lundquist P, Westerberg C, Purohit M, Stålsby Lundborg C. A 'One Health' Analysis of Reports of Potential Antibiotic Resistance Cases in International Pharmacovigilance Databases. [Submitted]</p><p dir="ltr">IV. <b>Mitchell J,</b> Purohit M, Lundquist P, Westerberg C, Stålsby Lundborg C. A Comparison of Antibiotic Resistance Reports in Pharmacovigilance Databases to Conventional Surveillance Across 'One Health'. [Submitted]</p>