A framework for thinking about Antimicrobial Resistance in the Environment: Source - Pathway - Receptor Framework
24 January 2020
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A framework for thinking about Antimicrobial Resistance in the Environment: Source-Pathway-Receptor Framework
This paper is the outcome of work supported and funded by Mott MacDonald Authors: Holly Small (Contaminated Land Specialist) and Lucy Bethell (Environmental Geologist) Contributors: Bryony Osbourn (Hydrogeologist), Emma Stanley, (Engineer, Water and Sanitation) Lucy Morton (Environmental Director), Claire Gordon (Clinical Microbiologist), Sarah Dobson (Technical Specialist Health), Catriona Waddington (Technical Specialist Health)
24 January 2020
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24 January 2020
Mott MacDonald | A framework for thinking about Antimicrobial Resistance in the Environment: Source – Pathway - Receptor Framework
1 Rationale Antimicrobial resistance (AMR) is when micro-organisms (e.g. bacteria, fungi, viruses) develop the ability to resist the drugs designed to combat them, causing the standard treatments to become ineffective. Potentially disease-causing organisms can enter the environment through waste (e.g. human, agricultural, healthcare), and once there have the potential to spread, and ultimately colonise or cause infections in people and animals. In particular, bacterial antimicrobial resistance (resistance in disease-causing bacteria) is universally acknowledged as an emerging major threat to global health and is the focus of this paper. Some organisms entering the environment are already resistant to important drugs. Spread of these organisms is increased by the presence of antibiotic residues in the same environment. Antibiotic compounds can enter the environment in a number of ways, for example, though pharmaceutical waste, excretion by humans and animals, or use in agriculture and fisheries. These compounds can persist in active forms lasting between a few hours and 300 days (Taso & Cho, 2016). Where concentrations of antibiotics are too low to be fatal, the presence of these compounds may also cause the emergence of resistance in previously susceptible organisms (Anderson & Hughes, 2014). As a result, antibiotic residues that remain within the environment due to extensive use of antibiotics and consistent emissions can be considered as a persistent organic contaminant (Ben, et al., 2019). Despite its evident importance, the environmental aspect of AMR is poorly understood and is seldom addressed in initiatives to reduce AMR. However, this should not preclude a proactive approach to evaluating, and where necessary mitigating against, the potential impact of interventions and environmental management strategies on the emergence and transmission of AMR. The source-pathway-receptor (SPR) framework is commonly used to understand pollutant linkage and potential risks in the environment sector. This paper uses the SPR framework as conceptualised by Ben et al. (2019) to structure our thinking about AMR and the environment; the framework also highlights the significant gaps in our empirical knowledge. The framework describes the source-pathway-receptor routes of AMR – the key point is that disrupting travel along a route at any point may prevent the consequences of that particular route. Ultimately, the impact of each route on human and animal health will vary in significance, however, in this paper we concentrate on the environmental aspects of AMR.
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Mott MacDonald | A framework for thinking about Antimicrobial Resistance in the Environment: Source – Pathway - Receptor Framework
2 The Source-Pathway-Receptor framework Elements of the framework In the context of AMR in water and the environment, the components of the source-pathwayreceptor (SPR) framework are: ● SOURCE: the source of the driving agents, namely antimicrobials and their residues, metals, biocides and antibiotic resistant genes, entering the environment. ● PATHWAY: the mechanism/route by which the driving agents from the source reaches soil, groundwater and surface water receptors, and its transportation within it to further receptors. ● RECEPTOR: the micro-organism reservoirs in water and the environment which develop or increase drug resistance before disseminating to humans. It is important to note that microorganisms can also be a “source” if they already carry resistance genes which can be transmitted to other organisms. The SPR framework is useful because a break in the source-pathway-receptor chain is a break in environmental spread which may mitigate adverse consequences (the impact on human health, animal health and ecosystems). The framework enables us to think systematically about possible interventions. The SPRs are detailed below and are illustrated in Figure 1. A simplified SPR model for AMR is given in Table 1.
Sources Human waste. Unless appropriately treated, human waste carries bacteria which may include resistant pathogens. Human waste may also contain antimicrobial compounds: up to 80% of consumed antibiotics are excreted through urine and faeces (UNEP, 2017). If this waste enters waste water treatment systems, it will either biodegrade, be absorbed to sewage sludge, or exit in sewage sludge or treated wastewater unchanged (Singer, et al., 2016). In many countries a high percentage of waste is discharged untreated directly into the environment. In Dhaka, Bangladesh, for example, 70% of waste water is untreated (UK Science and Innovation Network, 2018). Animal waste. Again, animal waste can carry resistant organisms and antimicrobials. About twothirds of all antibiotics produced each year are used in animal husbandry (Gelband, et al., 2015), and, as for humans, a significant percentage of antibiotics (30 to 90%) within animals is excreted through faeces and urine (Berensden, et al., 2015). The transmission of antibiotic resistant genes from animal to human pathogens is not well understood, but it has been demonstrated as probable (Smith, et al., 2013). The transmission of resistant organisms from animals to humans for zoonotic illnesses such as Salmonella (Michael & Schwartz, 2016) and to humans in close animal contact has been well described (e.g. livestock-associated MRSA (Monaco, et al., 2013)). Clinical waste (from the care of humans or animals) is likely to contain bacteria and antibiotic residues. If not treated properly it is a high-risk environmental contaminant. Aquaculture. Antimicrobials are used worldwide within aquaculture. It is estimated that up to 75% may be lost to the environment (UNEP, 2017).
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Mott MacDonald | A framework for thinking about Antimicrobial Resistance in the Environment: Source – Pathway - Receptor Framework
Crop pesticides. Antimicrobials are widely used as pesticides for crop disease management. The presence of these compounds in the environment has the potential to select for resistant micro-organisms (UK Science and Innovation Network, 2018). Manufacturing waste. Manufacturers of antimicrobials may release antimicrobials and their residues into the environment if there are no effective controls in place. There are no international standards for wastewater limits for antimicrobials (UK Science and Innovation Network, 2018). Similarly, high concentrations of metals can enter the environment as a result of industrial effluent (and also from agriculture and aquaculture). Metals, which may be a driving agent for AMR 1, do not biodegrade, resulting in high concentrations accumulating in aquatic sediments etc. There is little research on this area but these have the potential to drive AMR on extremely long timescales.
Pathways Municipal waste water can act as a pathway for AMR driving agents, discharging to surface watercourses, coastal waters and potentially groundwater. Manure and sewage sludge applied to land can contain bacteria and antibiotic residues that facilitate development and transmission of AMR. This can contaminate soils, groundwater, and surface waters through runoff. Aquaculture and contaminated waters. The extent and persistence of antimicrobial residues in aquaculture is currently unknown (FAO, 2016). The transport of aquaculture products within ice is also a potential pathway. Spraying of antimicrobials onto crops could potentially cause AMR, as contamination can select for resistant microorganisms. The extent of this pathway and how it interacts within the environment is not well studied. Airborne particles/bioaerosols. Airborne particles containing antimicrobial residues can potentially result from land spreading of contaminated manure or sewage sludge. Several studies have recorded antibiotics downwind of feedlots at concentrations similar to that found in rivers downstream of sewage outlets (Singer, et al., 2016).
Receptors Groundwater. Antibiotics in manure or sludge-enriched agricultural soils will enter groundwater as a result of migration due to rainfall, irrigation and other human activities. If contaminated groundwater is then used for irrigation, or makes up baseflow of rivers, streams and springs, it can also act as a pathway to surface waters.2 Surface waters include rivers, lakes, and coastal waters. Studies have found detectable levels of resistant bacteria in surface waters (UK Science and Innovation Network, 2018). Furthermore, it has been suggested that sediments within surface and coastal waters could act as reservoirs 1
Resistance mechanisms for heavy metals often double up as a resistance mechanism for pharmaceuticals by either cross-resistance (e.g. multi-drug efflux pumps) or co-resistance. Cross-resistance is when a single resistance mechanism confers resistance to an entire class of antimicrobial agents. Co-resistance occurs due to the genes providing metal-resistance and pharmaceutical-resistance being frequently located next to one another on the same plasmid, resulting in non-intentional Horizontal Gene Transfer of clinical AMR genes in response to increased heavy metal toxicity.
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Irrigation as a pathway for AMR. There are concerns that irrigation water used for crops could transfer AMR to humans via plants. Irrigation water comes from several different sources including groundwater, rivers, lakes, reservoirs, and reclaimed water, all of which are themselves potential pathways. A direct link has been found between the presence of resistant organisms on food and the quality of water used for irrigation (FAO/WHO, 2018). Irrigation water is considered to be one of the major contamination sources on fresh produce (Gekenidis, et al., 2018). The main transmission routes from irrigation water to plants is via the soil and direct contact. However, there is not extensive evidence about the transfer of AMR from crops to humans.
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Mott MacDonald | A framework for thinking about Antimicrobial Resistance in the Environment: Source – Pathway - Receptor Framework
of resistance genes and bacteria (FAO, 2016). As above, if surface water is then used for irrigation, it can also act as a pathway to groundwater and coastal waters. Food products. Evidence for AMR transmission to humans from the environment via food is limited although some links have been postulated (Day, et al., 2019). There is evidence of AMR occurrence not only in animal-derived foodstuffs but also in vegetables (Day, et al., 2019). Ecosystems (marine and terrestrial) and the flora and fauna within them are receptors, many of which are protected by environmental law. Literature reviews have documented ecologically relevant effects on a range of target organisms, such as pollution-induced autoimmunity from exposure to sub-lethal concentrations of pollutants, including antibiotics. For plants, there is evidence to suggest that seed germination, root elongation, and overall health can be sensitive to sub-inhibitory concentrations of antibiotics and metals in the soil (Pan & Chu, 2016). Exposure to sub-lethal concentrations of pollutants such as antibiotics, biocides, and metals can induce pollution-induced parasitisation, which in turn has been shown to increase susceptibility to the toxic effects of the pollutant (Khan & Thulin, 1991).
Consequences The relative importance of these sources, pathways and receptors depends on the extent to which they can lead to impact on human health, animal health and/or ecosystems. As noted in several places above, evidence about this impact is limited. Improving this evidence is a priority, but in the meantime, it is worth taking a conservative approach by exploring all means possible to break the source-pathway-receptor chain, and the costs of these various interventions. Figure 1 illustrates Sources, Pathways and Receptors and Table 1 summarises the main types of AMR sources, pathways and receptors. The impact of each route on human and animal health will vary in significance. Empirical evidence is not available for all the pathways, but we do know, for example, that water from aquaculture may contain bacteria which are already resistant and antibiotic residues, meaning there is a high theoretical risk of the surrounding water bodies containing resistant bacteria.
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Mott MacDonald | A framework for thinking about Antimicrobial Resistance in the Environment: Source – Pathway - Receptor Framework
Figure1: Source-Pathway-Receptor Model
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Mott MacDonald | A framework for thinking about Antimicrobial Resistance in the Environment: Source – Pathway - Receptor Framework
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Table 1: Simplified SPR conceptual model
Source Waste Water
Pathway •
Human waste
•
Manufacturing waste
●
Waste water effluent into surface water bodies
Receptor ●
Micro-organism populations within: ●
Receiving surface water bodies
●
Aquatic sediments
● Wetlands and flood plains: discharged watercourses flow through these environments and driving agents accumulate
Aquaculture
●
Biosolid sludge used in aquaculture and agriculture
See aquaculture and agriculture receptors below
●
Waste water effluent into surface water bodies
Micro-organism populations within:
•
Fish feed
•
Anti-fouling biocides
●
Aquatic sediments
•
Administration of clinical antimicrobials
●
Sediments surrounding water bodies and aquaculture farms
● Wetlands and flood plains: discharged watercourses flow through these environments and driving agents accumulate ●
•
Agriculture Crops
Animal husbandry
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Fertiliser consisting ● of aquaculture biosolids and ● manure
Bio-sludge/solids recycled and used as fertiliser for agriculture
See agricultural route below
Leaching from agricultural soils during rain/storm events
Micro-organism populations within:
Surface water runoff following irrigation activities
•
Pesticides and biocides
•
Animal waste
●
•
Clinical antimicrobials
Land spreading of manure, sewage sludge, and anaerobic digestate as fertiliser or soil conditioner
●
•
Bioaerosols (specifically pig and poultry)
Farmyard runoff into streams, rivers, and surrounding environment
●
Surface water bodies- particularly ponds etc.
●
Habitats surrounding fields particularly if groundwater dependent
● Aquifers below, or in close proximity to, agricultural land
Mott MacDonald | A framework for thinking about Antimicrobial Resistance in the Environment: Source – Pathway - Receptor Framework
References Anderson, D. & Hughes, D., 2014. Microbiological effects of sub-lethal levels of antibiotics. Nature Reviews Microbiology, Volume 12, pp. 465-478. Ben, Y. et al., 2019. Human health risk assessment of antibiotic resistance associated with antibiotic residues in the environment: a review. Environmental Research, pp. 483-493. Berensden, B. et al., 2015. the analysis of animal faeces as a tool to monitor antibiotic usage. Talanta, pp. 258-268. Day, M., Hopkins, K. & Wareham, D., 2019. Extended spectrum beta-lactamase-producing Escherichia coli in human-derived and food chain-derived samples from England, Wales and Scotland: and epidemiological surveillance and typing study. Lancet Infectious Disease, Volume 32, pp. 1162-1171. FAO/WHO, 2018. FAO/WHO expert meeting on foodborne antimicrobial resistance: Role of environment, crops and biocides Summary Report, s.l.: FAO/WHO. FAO, 2016. Drivers, dynamics and epidemiology of antimicrobial resistance in animal production., s.l.: Food and Agriculture Organization of the United Nations. Gekenidis, M.-T.et al., 2018. Antibiotic-resistant indicator bacteria in irrigation water: High prevalence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. PLOS|ONE. Gelband, H. et al., 2015. The State of the World's Antibiotics, Washington, DC: Centre for Disease Dynamics, Economics and Policy. Khan, R. & Thulin, J., 1991. Influence of pollution on parasites of aquatic animals. Advances in parasitology, pp. 201-238. Laxminarayan, R. et al., 2013. Antibiotic resistance- the need for global solutions. Lancet Infect Dis, p. 13(12). MacFadden, D. et al., 2018. Antibiotic resistance increases with Local temperature. Nature Climate Change, p. 510. Michael, G. & Schwartz, S., 2016. Antimicrobial resistance in zoonotic nontyphoidal Salmonella: an alarming trend?. Clin Microbiol Infect., Volume 22, pp. 968-974. Monaco, M., Pedroni, P. & Sanchini, A., 2013. Live-stock associated methicillin-resistant Staphylococcus aureus responsible for human colonisation and infection and an area of Italy with high density of pig farming. BMC Infectious Disease, Volume 13, p. 258. Pan, M. & Chu, L., 2016. Adsorption and degradation of five selected antibiotics in agricultural soil.. Science of the Total Environment, pp. 48-56. Singer, A. C., Shaw, H., Rhodes, V. & Alwyn, H., 2016. Review of Antimicrobial Resistance in the Environment and its Relevance to Environmental Regulators. Frontiers in Microbiology, p. 7:1728. Smith, T. C. et al., 2013. Methicillin-resistant Staphylococcus aureus in pigs and farm workers on conventional and antibiotic-free swine farms in the USA. PLoS ONE, p. 8:e63704. Taso, R. P. & Cho, J. Y., 2016. Veterinary antibiotics in animal waste, its distribution in soil and uptake by plants: a review.. Sci. Total Environ. , pp. 366-376.
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Mott MacDonald | A framework for thinking about Antimicrobial Resistance in the Environment: Source – Pathway - Receptor Framework
UK Science and Innovation Network, 2018. Initiatives for Addressing Antimicrobial Resistance in the Environment: Current Situation and Challenges. [Online] Available at: https://wellcome.ac.uk/sites/default/files/antimicrobial-resistance-environmentreport.pdf UNEP, 2017. Frontiers 2017 Emerging Issues of Envrionmental Concern, Nairobi : United Nations Environment Programme.
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Mott MacDonald | A framework for thinking about Antimicrobial Resistance in the Environment: Source – Pathway - Receptor Framework
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