Priority Topic D - Transmission Understanding and prevention of transmission of antibiotic resistance between bacterial populations and One Health reservoirs The overarching goal of this priority topic is to investigate the dynamics of transmission and selection of AMR at the animal, human, and environmental level. Introduction Bacteria develop resistance either by gene mutation or by the acquisition of genetic components from another bacterial strain. The dynamics of AMR transmission are complex and without transmission antibiotic resistance would remain an isolated problem. However, selection and transmission lead to the amplification of resistance and have driven the development of AMR as a global health problem. Selection and transmission are two different phenomena. Selection can result from exposure to selectors (e.g. antibiotics and other biocides, disinfectants and heavy metals) which inhibit the growth of susceptible strains, thus providing an evolutionary advantage to strains able to survive antimicrobial concentrations over the epidemiological cut-off value (ECOFFs). Transmission refers to the spread of bacteria or resistance genes within and between humans, animals and the environment. Selectors have significant effects on selection, but also on transmission since transmission of resistance is far more likely to occur under pressure from a selector. However, selectors may also differentially affect bacterial species and mechanisms of resistance. The effects of selectors vary even in the different compartments of the human body, due to differences in the concentrations of drugs, competing flora, and host immune factors. For example, an antibiotic given intravenously that reaches high levels in the bloodstream, may reach only low levels in the gastrointestinal tract promoting selection of resistant bacteria. This may still have a considerable effect on the emergence and spread of antibiotic resistance as the gastrointestinal tract is the main body site where selection for resistance occurs, and in which resistance genes are exchanged between organisms resulting in new resistant clones. The gut also serves as the main reservoir for resistance from which transmission occurs due to faecal excretion of resistant bacteria. The release of these bacteria into the environment provides a range of transmission routes for the dissemination and exposure of people and animals, especially when water quality, sanitation and hygiene conditions are poor. Selection can also occur in different compartments of the environment, such as in soils, human excreta and waste, biological sewage treatment processes and natural aquatic systems, such as near shore ocean waters. Transmission is greatly influenced by behavioural, cultural and socioeconomic aspects, for example handwashing, migration, tourism, companion animals, agricultural practices (e.g. the use of antimicrobials
such as streptomycin and oxytetracyclin in crop production, and antimicrobial use in aquaculture) and trade. Transmission and selection of resistance occurs at various levels (figure 2) (page 20 SRA): Transmission of genetic resistance elements encoding antibiotic resistance within and between bacterial species. Selection of resistant strains and genetic resistance elements by use of antibiotics and other selectors. Dissemination of resistant strains between individuals, at the human population level, between hospital wards, between community and hospitals, healthcare institutions, and between healthcare settings in different countries. Transmission between human and non-human reservoirs in which resistant bacteria can replicate and vice versa. Transmission occurs in different environments such as the movement of resistant bacteria in waters (i.e. rivers, oceans, lakes) and wastewater within countries and across borders. To understand the complex biological systems that shape the spread of antibiotic resistance, multiple disciplines need to work together, according to the One Health concept, to identify and characterise the determinants that contribute to the spread of resistance in and between different reservoirs; including livestock, sick and healthy people, as well as environmental reservoirs and hotspots of resistance spread and emergence. It is of particular interest to gauge the contribution of the large veterinary and environmental reservoirs of antibiotic-resistant bacteria to resistance in humans and the role that food and water may have in transferring resistance genes and antibiotic-resistant bacteria. This is a topic of considerable debate, but few studies have been conducted to indicate causality and directionality of spread of resistance genes between human, animal and environmental reservoirs. Therapeutics acting on the genetic level may reduce the transfer of genetic material between bacterial populations resulting in new resistant strains, which occurs by transformation (the uptake of DNA fragments by bacteria), conjugation (direct transfer of DNA between two bacteria through a sex pilus), or transduction (transfer of DNA mediated by bacteriophages). Epidemiological studies on the effects of selectors on transmission are required. Interventions should be introduced to limit the spread of AMR. Potential interventions arising from these studies will be addressed in the topic Interventions. Challenges This research priority offers an opportunity to understand the complexity of how resistance is spread and aims to identify critical control points at which targeted interventions could substantially reduce the spread of resistance. For example, interventions to control the transmission of ESBL 1 have focused on hospital settings. However, recent studies have highlighted the transmission of ESBL-producing E. coli in the community, possibly by exposure to community sewage and excreta in settings with poor water, sanitation and hygiene conditions. Thus, efforts should be directed at quantifying the importance of food, faecally contaminated water and waste materials as vehicles for resistance genes and resistant bacteria. The dynamics of resistance genes in the microbiota of humans, animals and environmental sources also need to be studied. It is of crucial importance to understand how these genes can spread between the different 1 Extended Spectrum Beta Lactamases (ESBLs) are enzymes that are made by bacteria and make them resistant to almost all kinds of beta-lactam antibiotic. 2
bacteria and to determine the extent to which the mobile elements that carry resistance genes are retained in the absence of selection. Studies on these aspects of transmission of antibiotic resistance should take advantage of novel technologies and methodologies. Understanding selection and transmission of antibiotic resistance will allow for the development and use of evidence-based interventions. For example, previous investigations identified the animal use of avoparcin 1 as a growth promoter as an important selector of vancomycin-resistant enterococci (VRE) in the European community. Understanding transmission will have a profound impact on the measures that can be taken to limit the spread of resistant bacteria. A relatively understudied subject in the spread of antibiotic resistance is the assessment of the impact of international networks of healthcare in which patients are moved between healthcare providers. The assembly of a European Health Care Utilisation Atlas (European Collaboration on Healthcare Optimization) 2 may provide guidance for policy decisions and an objective assessment of the influence of the EU directive of patient rights to cross-border healthcare. It will also be possible to appraise the role of primary healthcare as gatekeepers to hospital admissions. Inherent to this analysis is the mapping of the distribution of strains and plasmids with public health importance, which will generate the contextual evidence for the association between healthcare networks and certain genomic lineages of important nosocomial pathogens. Integrating information regarding the effects of selectors on the bacterial level, with local and global surveillance data and healthcare delivery systems, will provide contextual evidence for the association between healthcare networks and bacterial evolution. Such evidence will increase the understanding of the transmission dynamics of antibiotic resistance and how this transmission can be efficiently curtailed. In addition, wastewater monitoring will give insights into AMR in humans, animals and the environment. Measuring antibiotics in wastewater will provide data on antibiotic use and contamination in underreported regions; estimating resistance genes and antibiotic resistant bacteria in wastewater will provide a noninvasive method to gain data on AMR in the general population. Minimising the spread of AMR will contribute to the control of antibiotic-resistant infections in the community, healthcare, farming and the environment. The knowledge gained will be incorporated into future clinical trials to prevent transmission of antibiotic resistance (see Interventions). Environmental studies to evaluate interventions are needed to reduce the load of AMR bacteria in water, animal waste, sewage, and industrial wastewater (see Environment). 1 Avoparcin is an antibiotic that is active against gram-positive bacteria. Chemically, it is highly similar to another antibiotic, vancomycin, which is used in the treatment of infections that are caused by Gram-positive bacteria. Because avoparcin and vancomycin are nearly identical, the use of avoparcin has led to an increase in the resistance for vancomycin in animal-related enterococci. 2 http://echo-health.eu/ 3
Research objectives and activities Unravel the complex dynamics of selection and transmission of antibiotic resistance Multidisciplinary research networks are needed to conduct collaborative and complementary studies that will unravel the complex dynamics of selection and transmission of antibiotic resistance. These studies should provide a better understanding of the mechanisms that contribute to the spread of antibiotic resistance, which provide testable hypotheses and risk assessment for interventions aimed at controlling the emergence and spread of antibiotic resistance. It should be noted that transmission routes of AMR are drug, treatment and location specific. The study of AMR transmission for antibiotics on the critical list of antibiotics for use only in humans must be conducted in human settings but should also consider complex transmission. The necessary clinical evaluation is part of the priority topic Interventions. Identify factors responsible for the persistence and spread of resistant organisms and resistance genes Factors accounting for the success of clones, organisms, and resistance patterns must be investigated to explain the epidemicity of antibiotic resistant strains. This will identify events and factors that account for the persistence and spread of resistant organisms and genetic determinants. Selection and transmission between individuals and between human and non-human sources needs to be studied. In addition, the impact of different concentrations and mixtures of antimicrobials, including the impact of different hosts and microbiomes, needs to be studied with respect to selection and transmission of AMR. Novel methodological techniques combining genomic, metagenomic techniques with machine learning, mathematical modelling, network analysis, and big data, can be used to determine the success and abundance of antibiotic resistant bacterial strains with particular public health importance through the development of risk assessment approaches that are based on the genomic repertoire of bacterial pathogens and the ecological constraints that determine their fitness in clinical, community, veterinary and environmental settings. Determine the impact on AMR of different systems of healthcare, animal production, global trade and environmental pollution and contamination Different global healthcare systems should be compared that may facilitate or inhibit the expansion of antibiotic resistance. In addition, data on the role of migration, tourism, farming and agricultural practices (including animal transport) and management of human and animal wastes on the dissemination of antibiotic resistance need to be explored. Finally, an integration of biological, environmental, epidemiological and economic data will identify the important drivers of exposure of humans to selectors and antibiotic resistance genes. This information may be translated into policy measures to control the emergence and spread of antibiotic-resistant bacteria in the participating countries. Key references Ashbolt NJ, Amézquita A, Backhaus T, et al. Human health risk assessment (HHRA) for environmental development and transfer of antibiotic resistance. Environmental Health Perspectives, 2013: 121(9), 993. Bengtsson-Palme J, Kristiansson E, Larsson D. Environmental factors influencing the development and spread of antibiotic resistance. FEMS Microbiology Reviews, 2018: 42(1), fux053. http://doi.org/10.1093/femsre/fux053 4
Chamosa LS., VE. Álvarez, M Nardelli, et al. Lateral Antimicrobial Resistance Genetic Transfer is active in the open environment. Scientific Reports, 2017: 7: 513. Davies J, Davies D, Origins and evolution of antibiotic resistance, Microbiol Mol Biol Rev. 2010 Sep;74(3):417-33. doi: 10.1128/MMBR.00016-10 Durso LM, Cook KL. One Health and Antibiotic Resistance in Agroecosystems. EcoHealth, 2018: 1-6. Gandra S, DM Barter, R Laxminarayan. Economic burden of antibiotic resistance: how much do we really know? Clinical Microbiology and Infection 2014: 20;10, 973-980 Klein EY, Van Boeckel TP, Martinez EM, et al. Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proceedings of the National Academy of Sciences, 2018: 201717295; Lanza VF, Baquero F, Martínez JL, et al. In-depth resistome analysis by targeted metagenomics. Microbiome. 2018 ;6(1):11. doi: 10.1186/s40168-017-0387-y. Li L-G, Yin X, Zhang T. Tracking antibiotic resistance gene pollution from different sources using machinelearning classification. Microbiome. 2018;6:93. doi:10.1186/s40168-018-0480-x. Martínez JL, Coque TM, Baquero F. What is a resistance gene? Ranking risk in resistomes. Nat Rev Microbiol. 2015 Feb;13(2):116-23. doi: 10.1038/nrmicro3399.3) Robinson TP., Bu DP, Carrique-Mas J, et al. Antibiotic resistance is the quintessential One Health issue. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2016: 110(7), 377 380. http://doi.org/10.1093/trstmh/trw048 5