Antimicrobial Resistance in the Environment

Antimicrobial Resistance in the Environment Key Pollutant Linkages 30 August 2019

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Antimicrobial Resistance in the Environment Key Pollutant Linkages 30 August 2019

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Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

Issue and Revision Record Revision

Date

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01

30th August 2019

H Small

L Bethell

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Description

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Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

Contents 1

2

Introduction

8

1.1 1.2

8 8

Background Objectives

Finding of Literature Review

9

2.1 2.2

Introduction Drivers 2.2.1 Antibiotics 2.2.2 Metals 2.2.3 Biocides 2.2.4 Antibiotic resistant genes 2.3 Sources 2.3.1 Human Waste 2.3.2 Animal Waste 2.3.3 Aquaculture 2.3.4 Crop pesticides 2.3.5 Antimicrobial manufacturing waste 2.4 Pathways 2.4.1 Municipal Waste water 2.4.2 Manure and sewage sludge applied to land 2.4.3 Aquaculture contaminated waters 2.4.4 Crop spraying 2.4.5 Airborne particles/ bioaerosols Receptors 2.4.6 Groundwater 2.4.7 Surface waters 2.4.8 Food Products 2.4.9 Ecosystems

9 9 9 9 10 10 10 10 10 11 11 11 11 11 11 11 11 12 12 12 12 12 12

3

Source-Pathways-Receptors

14

4

Summary of key pollutant linkages

25

5

Future work

25

6

References

26

A.

Summaries of reviewed papers

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Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

A.1

A.2 A.3 A.4 A.5

A.6 A.7 A.8 A.9

Initiatives for Addressing Antimicrobial Resistance in the Environment: Current Situation and Challenges (UK Science and Innovation Network, 2018) Frontiers 2017 Emerging Issues of Environmental Concern (UNEP, 2017) Drivers, dynamics and epidemiology of antimicrobial resistance in animal production (Food and Agriculture Organization of the United Nations, 2016) Epidemic of carbapenem-resistant Klebsiella pneumoniae in Europe is driven by nosocomial spread (David, et al., 2019) Antimicrobial resistance in the Gul Cooperation Council region: a proposed framework to assess threats, impacts and mitigation measures associated with AMR in the marine and aquatic environment (Le Quesne, et al., 2018) Review of Antimicrobial Resistance in the Environment and its Relevance to Environmental Regulators (Singer, Shaw, Rhodes, & Alwyn, 2016) Bacterial diversity and antibiotic resistance in water habitats: searching the link with the human microbiome (Vaz-Moreira, Nunes, & Manaia, 2014) The role of the natural environment in the emergence of antibiotic resistance in gram-negative bacteria (Wellington, et al., 2013) Human health risk assessment of antibiotic resistance associated with antibiotic residues in the environment: a review (Ben, et al., 2019)

28 30 31 33

34 35 38 39 40

Tables Table 1: Summary of source – pathway – receptor linkages for AMR and antibiotic residues

16

Figures Figure 1: Potential transmission pathways of AMR Figure 2: Human exposure to antibiotic resistance associated with antibiotic residues in the environment

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Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

1 Introduction The Mott MacDonald Professional Excellence and Innovation Fund has provided a grant to an initiative to work across different sections of the company on antimicrobial resistance (AMR). An early stage is to learn more about the Environmental Aspects of AMR.

1.1

Background

AMR is a recognised global threat: addressing the threat requires responses in many sectors, including water and sanitation, food production, education, social, environment, waste management, health facilities and facilities management. There is a current surge in interest in AMR: for example, the UK launched its new strategy at Davos earlier this year.

The Health Practice has been awarded funding from the MM Innovation Fund to take forward our thinking on AMR in a number of sectors beyond human health, including agriculture, water and the environment.  This work builds on International Health’s large Fleming Fund project, which works to strengthen AMR surveillance in 24 low- and middle-income countries, as well as four considerably smaller contracts about AMR. The overall purpose of this initiative is to support the growth of the business by winning new work because Mott MacDonald will be able to show that we not only understand the multisectoral nature of AMR, but that we are also actively addressing the challenge. We will achieve this by reaching out to targeted parts of the company (according to their relevance to AMR) and encouraging them to develop thought leadership activities related to AMR in their sector, which they can then discuss with clients and promote in bids. This initial mapping work represents one of those initial pieces of thought leadership.

1.2

Objectives

1. Identify the key source, pathway and receptor elements of AMR in the environment, based on a rapid literature review. Comment on the evidence about the extent of different aspects of the problem.

2. Identify projects/key staff in the environment sector who are working in areas relevant to the findings.

The focus for this study has been on AMR and antimicrobial residues. However, it is noted that other drivers, notably metals, may also be significant.

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Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

2 Finding of Literature Review 2.1

Introduction

Antimicrobial resistance (AMR) is when microbes (bacteria and fungi) develop the ability to resist the drugs that are designed to combat them, causing the standard treatments to become ineffective (UK Science and Innovation Network, 2018). Once resistant microbes are in the environment, there is potential to spread, colonise, or cause infections in people and animals. If they retain their activity in the environment, they can apply selective pressures on the microbial population and amplify resistant bacteria (UK Science and Innovation Network, 2018).

The co-location of antibiotics and antibiotic resistant genes (ARGs) in waste water treatment plants (WWTPs) can (and does) select for novel combinations of AMR that can be shared between microorganisms by horizontal gene transfer (HGT).

Recent estimates indicate that drug resistant infections are increasing, with approximately 50,000 lives lost each year to antibiotic resistant infections in Europe and the United States (O'Neill, 2019). A European wide study, of 244 hospitals, has shown that AMR bacteria are spreading in hospitals, with deaths caused by carbapenem-resistant K. pneumoniae having increased six-fold since 2007. This literature review is to determine the key drivers, sources, pathways and receptors of AMR within the environment.

2.2

Drivers

There are four main drivers of AMR: ● Antimicrobials and their residues (of which there are four subclasses: antibiotics, antifungals, antivirals and antiparasitics); ● Metals; ● Biocides (e.g. surfactants and disinfectants); and ● Antibiotic resistant genes (Singer, Shaw, Rhodes, & Alwyn, 2016) Although there are many other chemicals, natural and xenobiotic, which are also known to select for AMR, these will not be discussed here. Similarly, the antimicrobial focus will be on impacts of antibiotics.

2.2.1

Antibiotics

Antibiotics are designed to inhibit growth or destroy microorganisms. However, where concentrations are too low to be fatal, this allows for the bacteria to select for resistance (UNEP, 2017). Overuse and improper use of antimicrobials are recognised as key drivers of the emergence and spread of AMR (Food and Agriculture Organization of the United Nations, 2016). Once in the environment, antibiotics can last between a few hours and 300 days (Taso & Cho, 2016). As a result, antibiotic residues that remain within the environment as a result of extensive use of antibiotics and consistent emissions can be considered as a persistent organic contaminant (Ben, et al., 2019).

2.2.2

Metals

The presence of heavy metals has been associated with the reduction of susceptibility of bacterial populations bacteria to antimicrobials and so heavy metals are associated with the emergence and spread of AMR. (Food and Agriculture Organization of the United Nations, 2016)

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Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

2.2.3

Biocides

Biocides are commonly used in hospitals, cosmetics, household cleaning products, farmyards and for industrial purposes. These behave in a similar way to antibiotics, in that sub-lethal doses can allow microorganisms to select for antimicrobial resistant genes (Singer, Shaw, Rhodes, & Alwyn, 2016) 2.2.4

Antibiotic resistant genes

When antibiotics and antibiotic resistant genes (ARGs) are in contact, bacteria can select for novel combinations of ARG (Singer, Shaw, Rhodes, & Alwyn, 2016). These bacteria are then able to “share” combinations of AMR through a process known as horizontal gene transfer (UNEP, 2017).

2.3

Sources

There are several sources of these AMR drivers within the environment. These are namely: human and animal waste, aquaculture, crop pesticides, and antimicrobial manufacturing waste.

2.3.1

Human Waste

Human waste can carry AMR pathogens and up to 80% of consumed antibiotics are excreted through urine and faeces (UNEP, 2017). If this waste enters waste water treatment, it will have one of three fates: ○ Biodegradation; ○ Absorption to sewage sludge; or ○ Exit in the sewage sludge unchanged (Singer, Shaw, Rhodes, & Alwyn, 2016).

However, in many countries around the world, a high percentage of waste is not treated and is instead discharged directly into the environment. In Dhaka, Bangladesh, 70% of waste water is untreated (UK Science and Innovation Network, 2018). In high-income countries, untreated wastewater may still inadvertently enter the environment directly through combined sewage overflows. Further to this, wastewater treatment plants may not be sufficient where there are high levels of bacteria present, such as waste water from healthcare facilities (UK Science and Innovation Network, 2018). A European study found trace levels of antimicrobials and evidence of resistant bacteria within treated sewage sludge (Wellington, et al., 2013).

2.3.2

Animal Waste

According to The State of the World’s Antibiotics 2015, two-thirds (65,000 tonnes) of all antibiotics produced each year are used in animal husbandry (Gelband, et al., 2015). Antibiotics are increasingly being used nontherapeutically or to encourage growth (Food and Agriculture Organization of the United Nations, 2016).

Antibiotics are widely used in non-European countries without veterinary supervision due to them being readily available over the counter at a low cost (Laxminarayan, et al., 2013). The demand and use of antibiotics in animal husbandry is likely to increase in low- and middle- income countries as demand for animal protein increases.

Similar to human waste, a large percent of antibiotics within animals is excreted through faeces and urine (30 to 90% (Berensden, Wegh, Memelink, Zuidema, & Stolker, 2015).

The transmission of antibiotic resistant genes from animals to humans is not well understood. However, it has been demonstrated as probable within the literature (Smith, et al., 2013). A recent review of the academic literature that address the issue of antibiotic use in agriculture suggests that only seven studies (five percent) argued that there was no link between antibiotic consumption in animals and resistance in humans, while 100 (72%) found evidence of a link (Singer, Shaw, Rhodes, & Alwyn, 2016).

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Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

2.3.3

Aquaculture

Antimicrobials are used worldwide within aquaculture, but the quantities and types are not known (UK Science and Innovation Network, 2018). It is estimated that up to 75% of antibiotics used in aquaculture may be lost to the environment (UNEP, 2017). Nguyen Dang Giang et al (2015) estimated that approximately 5,800 tonnes of enrofloxacin, 1,800 tonnes of sulphadiazine, 12,300 tonnes of sulphamethoxazole and 6,400 tonnes of trimethoprim are discharged into the Mekong Delta every year from terrestrial livestock discharge and shrimp and fish culture systems in the region.

2.3.4

Crop pesticides

Antimicrobials are widely used as pesticides for crop disease management. These are similar to antimicrobials used in human medicine. Using these has the potential to select for resistant microbes in the environment (UK Science and Innovation Network, 2018).

2.3.5

Antimicrobial manufacturing waste

Manufacturers of antimicrobials may release antimicrobials and their residues into the environment, where there are no effective control measures in place. There are no international standards for wastewater limits for antimicrobials (UK Science and Innovation Network, 2018). The Dangerous Substances Directive 76/464/EEC lists substances that are so toxic, persistent, or bioaccumulative that efforts are required to prevent their release into the environment. However, antimicrobials are not listed here and so are not routinely tested for (Wellington, et al., 2013).

2.4

Pathways

Selected pathways through which AMR can transfer within the environment are discussed here.

2.4.1

Municipal Waste water

As discussed in 2.3.1., municipal waste water can act as a pathway for AMR and antibiotic residues. This will ultimately discharge into surface watercourses, coastal waters and potentially groundwater.

2.4.2

Manure and sewage sludge applied to land

As discussed in 2.3.1 and 2.3.2, manure and sewage sludge can contain AMR bacteria and antibiotic residues that will facilitate AMR. When applied to land this can contaminate soils, groundwater and surface waters through runoff. A recent study demonstrated that land spreading of composed sludge on a field will likely lead to the spread of antimicrobial resistance genes in the soil and wider environment (Su, et al., 2015).

2.4.3

Aquaculture contaminated waters

The unregulated use of antimicrobials in aquaculture, a fast-expanding sector in low- and middle-income countries (Food and Agriculture Organization of the United Nations, 2016), poses a serious risk of AMR developing and spreading at a local and global level. The extent and persistence of antimicrobial residues in aquaculture is currently unknown (Food and Agriculture Organization of the United Nations, 2016). It is becoming common for shrimps to be transported around the world in frozen blocks. This water may contain antimicrobial residues and AMR bacteria which can then contaminate kitchens, foods and consumers (Food and Agriculture Organization of the United Nations, 2016).

2.4.4

Crop spraying

Spraying of antimicrobials onto crops could potentially cause AMR and selection of resistant microbes. The extent of this pathway and how it interacts within the environment is not well studied.

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Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

2.4.5

Airborne particles/ bioaerosols

There is potential for airborne particles of antimicrobial residues to 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, Shaw, Rhodes, & Alwyn, 2016).

Receptors Concerns regarding AMR are in regard to human health and so, humans are the ultimate receptor. However, there are other receptors within the environment that will facilitate or encourage AMR before ultimately reaching the human receptor: 2.4.6

Groundwater

Antibiotics in manure or sludge amended agricultural soils will enter groundwater as a result of rainfall, irrigation and other human activities. Very little has been reported regarding the impact of antibiotic residues in groundwater on the generation of AMR in pathogens (Singer, Shaw, Rhodes, & Alwyn, 2016).

Groundwater may then be used for irrigiation, drinking water and act as a pathway to surface waters and coastal waters.

2.4.7

Surface waters

These 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 of resistance genes and bacteria (Food and Agriculture Organization of the United Nations, 2016). Contamination of coastal waters is particularly concerning where there are shellfish beds; these are filter feeders and so there are greater chances that these will act as reservoirs for AMR or antibiotic residues. Surface water may then be used for irrigiation, drinking water and act as a pathway to groundwater and coastal waters.

2.4.8

Food Products

Strong and direct evidence for AMR transmission via food is still limited. However, there is evidence of AMR occurrence not only in animal-derived foodstuffs but also in vegetables. This raises the issue of global trade and travel in the transboundary dissemination of resistance genes (Food and Agriculture Organization of the United Nations, 2016).

2.4.9

Ecosystems

Ecosystems (marine and terrestrial) and the flora and fauna within them are considered to be receptors and many 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. Bactericidal antibiotics can stimulate bacteria to produce reactive oxygen species (ROS), which are highly deleterious molecules that can interfere with the normal functions of oxygen-respiring organisms (Kohanski et al., 2010). ROS are mutagens, which can result in a DNA damage and repair cascade by low levels of antibiotics leading to an increase in mutation rates, which can result in the emergence of multidrug resistance (Kohanski et al., 2010).

In the case of plants, there is evidence to suggest that seed germination, root elongation and overall plant health can be sensitive to sub-inhibitory concentrations of antibiotics and metals in the soil (Pan and Chu, 2016). Exposure to sub-lethal concentrations of pollutants such as antibiotics, biocides, and metals can

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Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

induce pollution-induced parasitization, which in turn has been shown to increase susceptibility to the toxic effects of the pollutant (Khan and Thulin,1991).

Sediments, although considered an environmental reservoir for AMR, are not considered as a receptor separately for the purposes of this study.

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Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

3 Source-Pathways-Receptors Potential pathways of transmission of AMR is conceptualised in Figure 1, from (Food and Agriculture Organization of the United Nations, 2016) and adapted from (Wellington, et al., 2013).

Figure 1: Potential transmission pathways of AMR

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Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

The source pathway receptor model is conceptualised by Ben et al. (2019), as seen in Figure 2.

Figure 2: Human exposure to antibiotic resistance associated with antibiotic residues in the environment

A summary of the source, pathways and receptors in tabular format can be seen below in Table 1. The significance column represents the significance of the pathway being realised with respect to impact to human health. This is based upon the magnitude of the source, sourced from data in the literature review, and the estimated likelihood of the pathway being active. Where there is a difference between low to middle income countries and higher income countries, the one with the higher significance is presented.

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Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

Table 1: Summary of source – pathway – receptor linkages for AMR and antibiotic residues AMR/ antibiotic residue source

Environmenta l source

Pathway

Primary receptor

Human waste

Secondary receptor

Human health (via use for drinking water) Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water

Significance of result of pathway being realised on human health/ ecosystems

Comments

MM sector

AMR and antibiotic residues can pass through WwTW. The scale of antibiotic use is very country dependant. Potable water treatment does not completely remove AMR/ antibiotic residues.

Waste water treatment

AMR and antibiotic residues can pass through WwTW. The scale of antibiotic use is very country dependant and can get directly into ecosystems

Waste water treatment

AMR and antibiotic residues can pass through WwTW. The scale of antibiotic use is very country dependant. Potable water treatment does not remove AMR/ antibiotic residues.

Waste water treatment

Waste water treatment and ecology

Moderate

AMR and antibiotic residues can pass through WwTW. The scale of antibiotic use is very country dependant and can get directly into ecosystems

Low

Limited to countries using desalination, significant dilution in coastal waters likely

Waste water treatment

Moderate

Moderate

Surface waters Ecosystems

Moderate

Waste water (treated)

Human health (via use for drinking water)

Direct discharge of treated water

Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water

Moderate

Moderate

Groundwater * Ecosystems

Coastal waters **

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Human health (via use for drinking water – desalination only)

Waste water treatment

Waste water treatment

Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

AMR/ antibiotic residue source

Environmenta l source

Pathway

Primary receptor

Secondary receptor

Aquaculture and shellfish (via sorption onto sediment) (and ultimately humans via ingestion of crops)

Significance of result of pathway being realised on human health/ ecosystems

Comments

Low

Significant dilution in coastal waters likely but sorption to sediment not well understood

Ecosystems Low

Direct discharge of untreated water (eg from Combined Sewage Overflows or where sanitation systems are absent/ poor)

Waste water (untreated) or blackwater

Direct discharge of untreated water (via septic tanks/ infiltration systems or where sanitation systems are absent/ poor)

Surface waters

Groundwater

Human health (via use for drinking water) And Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water

Moderate/ high

Ecosystems

Moderate/ high

Human health (via use for drinking water) And Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water

Moderate/ high

Ecosystems

Moderate/ high

Human health (via use for drinking water – desalination only)

Direct discharge of untreated water

Greywater/ reclaimed water systems

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Low

Common in rural areas especially in low-middle income countries

Aquaculture and shellfish (via sorption onto sediment) (and ultimately humans via ingestion of crops)

Low

Ecosystems

Low

Crops

Moderate

Waste water treatment and marine ecology Waste water treatment and ecology Health, International Development Services, International Water

Health, International Development Services, International Water

Ecology Limited to countries using desalination, significant dilution in coastal waters likely

Coastal waters

Human health via ingestion Irrigation of crops

Likely significant in low- and middleincome countries where there is limited waste water treatment and poor sanitation.

MM sector

Significant dilution in coastal waters likely but sorption to sediment not well understood Plant uptake hard to quantify but high levels of greywater

Health, International Development Services, International Water Marine ecology

Health, International Development Services,

Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

AMR/ antibiotic residue source

Environmenta l source

Pathway

Primary receptor

Secondary receptor

Ecosystems

Direct discharge (eg disposal or runoff)

Surface waters

Human health (via use for drinking water) And Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water

Significance of result of pathway being realised on human health/ ecosystems

Comments

MM sector

use in the US and LTMI countries

International Water

Moderate

Ecology Water and built environment (SuDS)

Moderate

Plant uptake hard to quantify but high levels of greywater use in the US and LTMI countries Water and built environment (SuDS)

Ecosystems Moderate

Groundwater

Direct or indirect discharge (disposal or migration from irrigation)

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Disposal to landfill

Moderate

Ecosystems

Moderate

Human health (via use for drinking water – desalination only) Coastal waters

Disposal of anaerobic sludge residues (from WWTW)

Human health (via use for drinking water) And Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water

Groundwater

Low

Aquaculture and shellfish (via sorption onto sediment) (and ultimately humans via ingestion of crops)

Low

Ecosystems

Low

Human health (via use for drinking water) And Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water

Low/ Moderate

Plant uptake hard to quantify but high levels of greywater use in the US and LTMI countries

Water and built environment (SuDS)

Ecology Limited to countries using desalination, significant dilution in coastal waters likely

Water and built environment (SuDS)

Significant dilution in coastal waters likely but sorption to sediment not well understood

Marine ecology

Sludge residues may be used for agricultural uses (see Manure and sludge linkages) or disposed of to landfill if metal concentrations are too high.

Waste

Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

AMR/ antibiotic residue source

Environmenta l source

Pathway

Primary receptor

Surface waters

Land application as a fertiliser Groundwater

Animal Waste (livestock)

Manure and sludge

Secondary receptor

Significance of result of pathway being realised on human health/ ecosystems

Ecosystems

Low/ Moderate

Human health (via use for drinking water) And Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water

Moderate/ High

Ecosystems

Moderate/ High

Human health (via use for drinking water) And Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water

Moderate/ High

Ecosystems

Moderate/ High

Human health via ingestion

Crops

Runoff from manure storage/ livestock fields/ farms

Surface waters

Moderate

Human health (via use for drinking water) And Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water

Moderate

Comments

MM sector

Potentially significant although microorganism pathways from animals to humans are less well understood.

Agriculture – unclear who in MM leads this

Potable water treatment does not remove AMR/ antibiotic residues.

Scale of industrial farming increased in US and likely to increase in low to middle income countries as demand for protein increases

Agriculture – unclear who in MM leads this

Ecology

Uptake of antimicrobials by plants is not well studied or researched and so this is difficult to assess.

Agriculture – unclear who in MM leads this

Potentially significant although microorganism pathways from animals to humans are less well understood.

Agriculture – unclear who in MM leads this

Potable water treatment does not remove AMR/ antibiotic residues.

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Ecology

Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

AMR/ antibiotic residue source

Environmenta l source

Pathway

Primary receptor

Secondary receptor

Significance of result of pathway being realised on human health/ ecosystems

Ecosystems

Moderate

Human health (via use for drinking water) And Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water

Moderate

Ecosystems

Other animal byproducts (e.g. abattoir waste/ butchery waste)

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Deposition onto crops/ land

Disposal to landfill

Linkages as per land application of manure/ sludge

Groundwater (if unlined landfill)

MM sector

Considered to be a direct pathway although the uptake by ecosystem receptors is not well understood/ documented in literature.

Agriculture – unclear who in MM leads this

Potentially significant although microorganism pathways from animals to humans are less well understood.

Agriculture – unclear who in MM leads this

Potable water treatment does not remove AMR/ antibiotic residues.

Groundwater

Bioaerosols (from manure deposition)

Comments

Human health (via use for drinking water) And Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water

Ecology

Moderate

Considered to be a direct pathway although the uptake by ecosystem receptors is not well understood/ documented in literature.

Low

Likely to be lower concentrations of AMR/ microbial residues from bioaerosols

Agriculture – unclear who in MM leads this

Waste

Low/ Moderate

Less likely in countries with engineered landfills but probable where not

Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

AMR/ antibiotic residue source

Environmenta l source

Pathway

Primary receptor

Surface Waters

Direct discharge into surface waters Aquaculture

Pesticide use for aquaculture

Secondary receptor

Significance of result of pathway being realised on human health/ ecosystems

Ecosystems

Low/ Moderate

Human health (via use for drinking water) And Aquaculture food products (and ultimately humans via ingestion)

Low/ Moderate

Ecosystems

Low/ Moderate

Aquaculture food products (and ultimately humans via ingestion)

Low/ Moderate

Ecosystems

Crop Pesticides

Food produce

Direct application

Food produce

Spraying of antibiotics on crops Runoff

Surface waters

Human health (ingestion of contaminated water)

Human health (ingestion of crops)

Human health (via use for drinking water) And Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water

Agriculture – unclear who in MM leads this

Ecology Agriculture – unclear who in MM leads this Marine ecology

Low/ Moderate

Health

Low

Occurrence and likelihood unknown and not well studied or documented.

Low/ Moderate

Occurrence and likelihood unknown and not well studied or documented.

Agriculture – unclear who in MM leads this Agriculture – unclear who in MM leads this

Low/ Moderate

Potable water treatment does not remove AMR/ antibiotic residues.

Uptake of antimicrobials by plants is not well studied or researched and so this is difficult to assess.

Considered to be a direct pathway although the uptake

Ecology

Low/ Moderate

Ecosystems

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Likely less significant as contaminants will be diluted. However, quantities and use are not well documented in some countries and so difficult to assess.

MM sector

Considered to be a direct pathway although the uptake by ecosystem receptors is not well understood/ documented in literature.

Coastal waters

Contaminated water within food (ice blocks)

Comments

Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

AMR/ antibiotic residue source

Environmenta l source

Pathway

Primary receptor

Secondary receptor

Significance of result of pathway being realised on human health/ ecosystems

Comments

MM sector

by ecosystem receptors is not well understood/ documented in literature.

Human health (via use for drinking water) And Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water

Groundwater

Solid wastes

Disposal to landfill

Manufacturing Waste

Liquid effluent

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Effluent into sewerage system

Groundwater

Agriculture – unclear who in MM leads this

Low/ Moderate

Potable water treatment does not remove AMR/ antibiotic residues.

Uptake of antimicrobials by plants is not well studied or researched and so this is difficult to assess.

Ecology

Low

Considered to be a direct pathway although the uptake by ecosystem receptors is not well understood/ documented in literature. Lower impact as less groundwater dependant ecosystems.

Ecosystems

Human health (via use for drinking water) And Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water

Low/ Moderate

Ecosystems

Low/ Moderate

Linkages as for human waste but much higher doses into the system

Waste

Moderate

Less likely in countries with engineered landfills but probable where not

Higher doses may result in residual AMR/ antimicrobial residues passing

Waste water treatment

Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

AMR/ antibiotic residue source

Environmenta l source

Pathway

Primary receptor

Secondary receptor

Significance of result of pathway being realised on human health/ ecosystems

Comments

MM sector

through the treatment process Human health (via use for drinking water) And Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water

Water sector (water abstraction)

Moderate/ High

Likely significant although dilution will occur in receiving waters.

Potable water treatment does not remove AMR/ antibiotic residues.

Uptake of antimicrobials by plants is not well studied or researched and so this is difficult to assess.

Ecology

Moderate/ High

Considered to be a direct pathway although the uptake by ecosystem receptors is not well understood/ documented in literature.

Water sector (water abstraction)

Moderate/ High

Likely significant although dilution will occur in receiving waters.

Potable water treatment does not remove AMR/ antibiotic residues.

Uptake of antimicrobials by plants is not well studied or researched and so this is difficult to assess.

Considered to be a direct pathway although the uptake

Ecology

Moderate/ High

Surface Waters

Ecosystems

Direct discharge

Human health (via use for drinking water) And Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water Groundwater

Ecosystems

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AMR/ antibiotic residue source

Environmenta l source

Pathway

Primary receptor

Secondary receptor

Significance of result of pathway being realised on human health/ ecosystems

Comments

MM sector

by ecosystem receptors is not well understood/ documented in literature.

Solid waste (unused medicines)

Disposal to landfill

Disposal from hospitals ***

Liquid wastes (unused medicines)

Effluent into sewerage system

Groundwater (if unlined landfill)

Human health (via use for drinking water) And Crops/ meat (and ultimately humans via ingestion of crops) from use for irrigation/ animal drinking water

Low/ Moderate

Ecosystems

Low/ Moderate

Linkages as for human waste but much higher doses into the system

Waste

Moderate

Less likely in countries with engineered landfills but probable where not

Higher doses may result in residual AMR/ antimicrobial residues passing through the treatment process

*

Groundwater/ surface water interaction should also be considered

**

Either by direct discharge or migration through surface waters to coastal waters and potentially via groundwater

Waste water treatment

*** Hospital waste water from sanitation system is not considered separately although antibiotic use likely to be higher than in the general population

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4 Summary of key pollutant linkages Based on the assessment undertaken above, the key pollutant linkages are considered to be: Moderate – high significance • • •

Discharge of untreated waste water from human waste to groundwater/ surface water/ ecosystems Land application of animal waste to surface water/ groundwater / ecosystems Direct discharge of manufacturing waste liquid effluent to surface water/ groundwater / ecosystems

Moderate significance • • • •

Direct discharge of treated water from human waste water treatment to groundwater/ surface water/ ecosystems Irrigation/ direct discharge/ runoff from greywater/ reclaimed water systems Runoff from manure/ livestock to groundwater/ surface water / ecosystems Runoff from manure/livestock to crops

5 Future work The next stages are to identify key staff within MM within the relevant sectors and then identify clients to whom this assessment is relevant. It is likely to include water supply, wastewater treatment and waste clients.

A study on other drivers, such as metals, could be undertaken with the objective of assessing the significance of different drivers with respect to the environment.

It will be important to keep informed of further developments and research into AMR and specifically the science surrounding plant and crop uptake, health implications from chronic exposure and the relative contributions from different pathways and sources to list but a few.

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6 References Ben, Y., Fu, C., Hu, M., Liu, L., Wong, M. H., & Zheng, C. (2019). Human health risk assessment of antibiotic resistance associated with antibiotic residues in the environment: a review. Environmental Research, 483-493.

Berensden, B., Wegh, R., Memelink, J., Zuidema, T., & Stolker, L. (2015). the analysis of animal faeces as a tool to monitor antibiotic usage. Talanta, 258-268.

David, S., Reuter, S., Harris, S., Glasner, C., Feltwell, T., Argimon, S., . . . Aspbury, M. (2019).

Epidemic of carbapenem-resistant Klebsiella pneumoniae in Europe is driven by nosocomial spread. Nature Microbiology, 29:1.

Food and Agriculture Organization of the United Nations. (2016). Drivers, dynamics and epidemiology of antimicrobial resistance in animal production. .

Gelband, H., Miller-Petrie, M., Pant, S., Gandra, S., Levinson, J., Barter, D., & al., e. (2015). The State of the World's Antibiotics. Washington, DC: Centre for Disease Dynamics, Economics and Policy.

Laxminarayan, R., Duse, A., Wattal, C., Zaidi, A., Wertheim, H., Sumpradit, N., . . . Greko, C. (2013). Antibiotic resistance- the need for global solutions. Lancet Infect Dis, 13(12).

Le Quesne, W. J., Baker-Austin, C., Verner-Jeffreys, D. W., Al-Sarawi, H. A., Balkhy, H. H., & Lyons, B. P. (2018). Antimicrobial resistance in the Gulf Cooperation Council region: A proposed framework to assess threats, impacts and mitigation measures associated with AMR in the marine and aquatic environment. Envrionment International , 10031010.

O'Neill, J. (2019, August 14). Review on antibiotic resistance. Retrieved from AMR Review : https://amr-review.org/ 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, 7:1728.

Smith, T. C., Gebreyes, W. A., Abley, M. J., Harper, A. L., Forshey, B. M., & Male, M. J. (2013).

Methicillin-resistant Staphylococcus aureus in pigs and farm workers on conventional and antibiotic-free swine farms in the USA. PLoS ONE, 8:e63704.

Su, J., Wei, B., Ou-Yang, W., Huang, F., Zhao, Y., Xu, H., & Zhu, Y. (2015). Antibiotic reistome and its association with bacterial communities during sewage sludge composting.

Environ. Sci. Technol. , 7356-7363.

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. , 366-376.

UK Science and Innovation Network. (2018). Initiatives for Addressing Antimicrobial Resistance in the Environment: Current Situation and Challenges. Retrieved from Wellcome.ac.uk: https://wellcome.ac.uk/sites/default/files/antimicrobial-resistance-environment-report.pdf UNEP. (2017). Frontiers 2017 Emerging Issues of Envrionmental Concern. Nairobi : United Nations Environment Programme.

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Vaz-Moreira, I., Nunes, O. C., & Manaia, C. M. (2014). Bacterial diversity and antibiotic resistance in water habitats: searching the links with the human microbiome. Federation of European Microbiological Societies, 761-18.

Wellington, E., Boxall, A., Cross, P., Feil, E., Gaze, W., Hawkey, P., . . . Thomas, C. (2013). The role of the natural environment in the emergence of antibiotic resistance in Gramnegative bacteria. The Lancet Infectious Diseases, 155-165.

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A. Summaries of reviewed papers A.1 Initiatives for Addressing Antimicrobial Resistance in the Environment: Current Situation and Challenges (UK Science and Innovation Network, 2018) A.1.1

Human and Animal Contamination

● AMR is when microbes (i.e. bacteria and fungi) develop the ability to defeat the drugs designed to combat them- causing a threat to public health. Pathogenic antimicrobialresistant microbes can cause infections in humans that are difficult, and sometimes impossible, to treat. The report highlights data identifying the potential for the environment (waterways and soils) to be a source of pathogenic antimicrobial-resistant microbes that could affect human health. ● Contamination of the environment can occur from human and animal waste, pharmaceutical manufacturing waste, and use of antimicrobial pesticides for crops. However, the scale and risk of this is not fully understood. ● Scientific evidence shows that antimicrobials and resistance do spread in the environment and people exposed to resistance pathogens like Methicillin-resistant Staphylococcus aureus (MRSA) in environmental waters are at increased risk of infection from this exposure. ● Basic sanitation, including access to facilities for disposing of human waste safely, is critically important for preventing many diseases. ● Human waste: waste can carry antimicrobial-resistant pathogens, there is an increased risk of infections where this waste is discharged directly into the environment without treatment.

Wastewater treatment plants are essential for reducing bacteria; although this might not be sufficient where there are high levels of bacteria such as in healthcare facilities. Resistant microbes can persist and grow within healthcare plumbing systems. Studies have found detectable levels of resistant bacteria in surface waters (rivers, coastal waters). Human waste may enter the environment inadvertently through direct release into water bodies by overflow of combined sewers. In many countries around the world, a high percentage of human sewage is not treated appropriately. In Dhaka, Bangladesh, 70% is discharged directly into the environment. A European study found trace levels of antimicrobials and evidence of resistant bacteria in treated sewage sludge. ● Animal waste and agriculture: animal and human waste can be used as manure. If not treated properly, this could contain antimicrobial-resistant pathogens. Runoff from livestock could contaminate surface and groundwaters with resistant bacteria. Antimicrobials are used worldwide in aquaculture but the quantities and types used are not known. Smith et al. estimated that 1mg of antimicrobial agents was used per kg of production in Norway, yet Chile used more than 600mg per kg of salmon produced. Based on surface water samples for antimicrobial residues, it is estimated that approximately 5,800 tonnes of enrofloxacin, 1,800 tonnes of sulphadiazine, 12,300 tonnes of sulphamethoxazole and 6,400 tonnes of trimethoprim are discharged into the Mekong Delta every year from terrestrial livestock discharge and shrimp and fish culture systems in the region. Several studies have found evidence suggesting that a farm-to-environment-to-human route of transmission may occur.

However, the public health impact of AMR from agriculture exposures are not well understood. ● Once resistant microbes are in the environment, there is potential to spread, colonize, or cause infections in other people or animals. If these antimicrobials retain their activity in the

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environment, they can apply selective pressure on the microbial population and amplify resistant bacteria. ● Preventing Exposure: Treating recreational waters or segregating them from other contaminated environmental surface waters. For potable water, finishing treatment plants and maintaining water supply systems is required to enhance the probability of AMR free water. Sewage needs to be kept from fisheries and bivalve beds. Water for irrigation needs to be kept uncontaminated. However, there is a lack of available technologies for low- and middle-income countries.

A.1.2

Antimicrobial Manufacturing Waste

● Release of active pharmaceutical ingredients (APIs) into the environment may occur when antimicrobials are manufactured without effective control measures in place. The manufacturing process can result in a high amount of antimicrobials in the surrounding environment (e.g. soil, water) which may lead to selecting for antibiotic-resistant bacteria. ● Significance of how manufacturing waste might contaminate the environment is unclear. ● Manufacturers do not voluntarily disclose APIs released into the environment in their discharge water. ● There are no international standards for wastewater limits for antimicrobials. ● Localised discharges from manufacturing plans might lead to more antimicrobial contamination than the excretion of drugs that people use for therapy (human waste).

A.1.3

Antimicrobials Used as Crop Pesticides

● Antimicrobials are widely used as pesticides for crop disease management. In some cases, these antimicrobials are the same, or closely related to, antimicrobials used in human medicine. Using antimicrobials as crop pesticides has the potential to select for resistant microbes present in the environment. This is of particular concern if the microbe can cause human infection or confers transferable resistance mechanisms to antimicrobials commonly used to treat human infections. Of particular concern are cases where antibiotic use on crops increases or when the environment exposed to the pesticide is contaminated with multi-drug resistant microbes.

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A.2

Frontiers 2017 Emerging Issues of Environmental Concern (UNEP, 2017)

● It is the low concentration contamination that is of particular importance- the concentration is too low to be lethal to exposed bacteria, but sufficient to select for resistance. At low antibiotic concentration, the acquisition of resistance may be reliant more on gene transfer from another bacterium, known as horizontal gene transfer. ● Up to 75% of antibiotics used in aquaculture may be lost into the surrounding environment. ● 70% of antibiotics are used by animals. ● Major waste flows including waste water, manures and agricultural runoff contain antibiotic residues and antibiotic-resistant bacteria. ● Up to 80% of consumed antibiotics are excreted through urine and faeces. ●

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A.3 Drivers, dynamics and epidemiology of antimicrobial resistance in animal production (Food and Agriculture Organization of the United Nations, 2016) ● Overuse of antimicrobials and improper use in many parts of the world are recognized as key drivers of the emergence and spread of AMR. ● It is projected that two thirds of the future growth of antimicrobial use will be for animal production. Although antimicrobial use in animal food production has been substantially reduced in high-income countries in recent years, data available indicate that livestock antimicrobial use will continue to increase in low- and middle-income countries during the next decades due to the growing demand for animal protein. As a consequence, there is likely to be an increase in resistance to commonly used antimicrobials in these countries and regions. ● It has been observed that enterococci of animal origin can also colonize the human gut (Werner et al., 2013). ● Strong and direct evidence for AMR transmission via food is still limited. However, there is evidence of AMR occurrence not only in animal-derived foodstuffs but also in vegetables.

This raises the issue of global trade and travel in the transboundary dissemination of resistance genes. ● Antimicrobials are commonly used non-therapeutically in livestock production as a kind of “insurance” in addition to other animal disease risk management procedures. In some nonEuropean countries, antimicrobials are widely used by farmers without veterinary supervision due to their relatively low cost and ready availability for sale over the counter (Laxminarayan et al., 2013). ● Only a few countries in Europe (e.g. Netherlands, Denmark, Sweden) currently conduct integrated surveillance of antimicrobial use and AMR in humans, animals and food products of animal origin. ● Heavy metals: these may be used in agriculture as part of livestock feed supplements, and in a Chinese study were detected in manure from pig farms (Zhu et al., 2013). Heavy metals have been associated with the emergence and spread of AMR in environmental bacteria due to co-selection. The presence of heavy metals has also been associated with the reduction of susceptibility of bacterial populations and commensal bacteria to antimicrobials. ● The extent and persistence of antimicrobial residues in aquaculture production systems is currently unknown, but they are likely to be greatly diluted in the environment. ● Resistance genes and bacteria resistant to sulphonamides and trimethoprim have also been isolated from the sediment under aquaculture farms in the Baltic Sea and persisted in the environment for at least 6 years. Sediments could act as reservoirs of resistance genes and bacteria in local fish farms and in humans via food distribution. The substances used widely in aquaculture are the same as those licensed for therapy of infectious diseased in humans and livestock. ● Risk factors for the emergence of AMR in agriculture at national and international level: – Legislative framework and governance; – Financial status and stability; – Degree of international imports and exports; – Human resources: population size, education and expertise; – Culture; – Structure and organization of the various agricultural systems in use nationally. ● Aquaculture is a fast-expanding agricultural sector in many LMICs, and the unregulated use of antimicrobials in many of these countries poses serious risks of AMR developing and

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spreading at local and global level- the latter through international trade. A significant amount of water from shrimp farms is shipped along with shrimp in frozen blocks, transported from farms directly to international consumers. This water can contain antimicrobial residues and AMR bacteria. This may then come in contact with kitchen surfaces, other food stuffs, and consumers themselves, enabling the global spread of bacteria and resistance genes. â—? Both pathogenic and non-pathogenic resistant bacteria can be transmitted from livestock to humans via food consumption, or via direct contact with animals or their waste in the environment. Any mechanism that helps spread bacteria has the potential to spread resistant bacteria. Resistance may also be conferred by the exchange of genetic elements between bacteria of the same or different strains of species, and such transfer can occur in the environment where resistant bacteria have the opportunity to mix with a susceptible bacterial population, such as in the human or animal gut, in slurry spread on agricultural soil, or in aquatic environments.

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A.4 Epidemic of carbapenem-resistant Klebsiella pneumoniae in Europe is driven by nosocomial spread (David, et al., 2019) ● A European wide study (244 hospitals involved across Europe) has shown that antimicrobial resistant bacteria are spreading in hospitals. ● Klebsiella pneumoniae is resistant to drugs called carbapenems which are antibiotics used only when the infection cannot be treated by anything else. ● Deaths caused by carbapenem-resistant K.pneumoniae have increased six-fold since 2007. ● The research emphasises the importance of infection control and ongoing surveillance of antibiotic-resistant bacteria to ensure that new strains are detected early.

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A.5 Antimicrobial resistance in the Gul Cooperation Council region: a proposed framework to assess threats, impacts and mitigation measures associated with AMR in the marine and aquatic environment (Le Quesne, et al., 2018) ● The WHO considers antimicrobial resistance as one of the most pressing global issues which poses a fundamental threat to human health, development and security (WHO, 2016). ● Microbial resistance to antibiotics spans all known classes of natural and synthetic agents (D’Costa et al., 2006) and drug resistant infections are rising with recent estimates suggesting that up to 50,000 lives are lost each year to antibiotic resistant infections in Europe and the US alone (O’Neill, 2016). ● The journal suggests that genetic diversity and abundance of AMR in non-clinical settings has been underestimated and that the environment plays in integral role in enabling the development of AMR. ● Due to specific demographic and environmental factors, the Gulf Cooperation Council region may be particularly susceptible to the threat of AMR, with marine and aquatic environment potentially playing a specific role in its development and propagation. ● Demographic factors include: – Rapid population growth; – Significant international population movements; – Heavy antibiotic use; and – Insufficient antibiotic stewardship. ● Environmental factors include: – Notable outputs of untreated sewage effluent; – High ambient water temperatures; – Elevated concentrations of heavy metals; and – Poorly regulated use of antimicrobials in veterinary settings.

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A.6 Review of Antimicrobial Resistance in the Environment and its Relevance to Environmental Regulators (Singer, Shaw, Rhodes, & Alwyn, 2016) ● Low levels of antibiotics, metals, biocides can directly select (and co-select) for ARGs within the AMR pathways. ● Sub-lethal effects of antibiotics, metals and biocides on organisms, their microbiome and ecosystem services (e.g. rivers, coastal waters and sol) can impact the health, yield, and safety of economically important food products and wider biome. ● There are three well-characterised classes of resistance driving chemicals: – Antimicrobials (four subclasses: antibiotics, antifungals, antivirals, and antiparasitics); – Heavy metals; – Biocides (i.e. disinfectants and surfactants). ● However, there are many other chemicals, natural (e.g. plant derived) and xenobiotic which are also known to select for resistance. ● Drivers of resistance: antibiotics used in humans and in animals. According to The State of the World’s Antibiotics 2015, two thirds of all the antibiotics produced globally each year (65,000 of 100,000 tonnes) are used in animal husbandry. ● Pathways for antibiotics: – Municipal and industrial wastewater: Antibiotics excreted by humans will enter wastewater treatment plants with one of three fates: ○ Biodegradation; ○ Absorption to sewage sludge; or ○ Exit in the sewage sludge unchanged.

– Persistence of an antibiotic in a WWTP is a function of: ○ Influent composition; ○ Salinity; ○ Temperature; ○ Nature of WWTP (e.g. trickling bed, activated sludge, membrane bioreactor); ○ Hydraulic retention time.

– Greywater, reclaimed and black water – Veterinary and livestock: when animals consume antibiotics, as much as 30 to 90% is released into the manure and urine. Animal excreta has been shown to contaminate the environment with antibiotic resistance bacteria and antibiotics. The transmission of antibiotic resistant bacteria and genes from animals to humans has been demonstrated in the literature (Smith et al. 2013). A recent review of the academic literature that address the issue of antibiotic use in agriculture suggests that only seven studies (five percent) argued that there was no link between antibiotic consumption in animals and resistance in humans, while 100 (72%) found evidence of a link.

– Land application of manure and sludge: An estimated 37% of biosolids are land applied in Europe. ● Drivers of resistance- Biocides: Biocides are disinfectants that are commonly used in hospitals, cosmetics, household cleaning products, wipes and furniture preservatives, farmyards for purposes such as wheel and foot washes, and a range of industrial processes, including the control of fouling and scouring of pipes including oil wells. In much the same way that sub-lethal concentrations of antibiotics can select for antimicrobial resistant genes,

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sub-lethal concentrations of biocides have also been shown to select for common mutations that confer clinically relevant antibiotic resistance. ● Pathways for Biocides: Similar to antibiotics, most notably WWTPs. ● Drivers of resistance: Metals. Major urban inputs of heavy metals to WWTPs come from household effluent, drainage water, business effluent (e.g. car washes, dental uses), atmospheric deposition, and traffic related emissions. Metals such as Pb, Cu, Zn, Cd, and As have been used as animal growth promoters and nutritional supplements, pesticides, and fungicides in aquaculture and agriculture. The relationship between metal bioavailability, speciation and resistance gene selection is largely unexplored. Bacteria carrying metal resistance genes have been shown to more frequently carry ARGs as compared to those bacteria without metal resistance genes, and these genes can often be found on plasmids. ● Pathways for metals: similar to that of biocides and antimicrobials. Elevated concentrations of metals will be found in urban areas and areas that have experienced mining. ● Drivers of resistance: antibiotic resistance genes. The co-location of antibiotics and ARGs in WWTPs can (and does) select for novel combinations of AMR that can be shared between microorganisms by horizontal gene transfer (HGT). The competitive and chemically challenging environment of a sewage works offers favourable conditions for the amplification of existing resistance genes. ● WWTP Discharge: Introduction of pollutants (antibiotics, ARGs, biocides and metals) interacts with the native fauna and flora and begin to change the microbial community structure and genetic make up. These changes in the microbial community have been shown to have significant impacts on the aboveground diversity and functioning of terrestrial ecosystems. Polluting into recreational coastal and bathing waters, through combined sewer overflows, will elevate exposure to humans and by extension all wildlife that inhabits and feeds off/within the impacted waters systems. However, little is known about the chronic effects from chemical exposure or the elevated prevalence of ARGs within a food web. ● Land spreading of manure and biosolids: the dissemination of manure and biosolids onto crops and soils increases the ARG exposure risk to: – Animals (wild); – Crops; – Adjacent surface water bodies; – Groundwater; – Farm workers; – Air as dust particles from land spreading or aeolian erosion. ● A recent study demonstrated that land spreading of composted sludge on a field will likely lead to the spread of ARGs in the soil and wider environment (Su et al., 2015). Persistence in soil varies greatly in literature between a few days and 300 days. Persistence increases at low temperatures, unexposed to light, and high organic conditions. The fate will also be sensitive to pH and soil properties. ● Air transmission: several antibiotics have been recorded downwind of feedlots at concentrations similar to that found in rivers downstream of sewage outlets. ● Food plants: a significant number of papers exist in the literature demonstrating the sensitivity and uptake of antibiotics from irrigation, manure or sludge amended soils by crops into the plant biomass. The degree to which this occurs and the risk that it poses to the environment remain poorly studied. ● Aquaculture and shellfish beds: the accumulation and chronic exposure of river, estuarine and coastal environments to antibiotics, biocides and metals can persist and spread AMR

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into and from the sediment. The use and misuse of antibiotics in aquaculture has led to an increase in antibiotic resistance in fish pathogens. The implications for the spread of AMR throughout the food web from fish-eating organisms has not been well studied and is a significant knowledge gap. â—? Groundwater quality: antibiotics in manure or sludge amended agricultural soils will enter groundwater as a result of rainfall, irrigation and other human activities. Very little has been reported regarding the impact of antibiotic residues in groundwater on the generation of AMR in pathogens. â—?

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A.7 Bacterial diversity and antibiotic resistance in water habitats: searching the link with the human microbiome (Vaz-Moreira, Nunes, & Manaia, 2014) â—? Only a few bacteria found in waters were, so far, identified in the human-associated microbiome. It is still uncertain in which cases the same species and strain can live in water and colonize humans. In such case, those bacteria may be involved in the direct or indirect transfer of properties, including antibiotic resistance. â—? Water habitats host an impressive bacterial diversity. However, only a few lineages are known to harbour antibiotic resistance genes of already recognised clinical relevance.

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A.8 The role of the natural environment in the emergence of antibiotic resistance in gram-negative bacteria (Wellington, et al., 2013) ● During the past 10 years multidrug-resistant Gram-negative Enterobacteriaceae have become a substantial challenge to infection control. It has been suggested by clinicians that the effectiveness of antibiotics is in such rapid decline that, depending on the pathogen concerned, their future utility can be measured in decades or even years. ● Unless the rise in antibiotic resistance can be reversed, we can expect to see a substantial rise in incurable infection and fatality in both developed and developing regions. ● The Dangerous Substances Directive 76/464/EEC lists 129 substances that are regarded as so toxic, persistent, or bioaccumulative that efforts to control their release and prevent pollution should be given the highest priority. However, because antibiotics are not listed and are therefore not routinely tested for, their high prevalence in the environment has received little attention. Many antibiotics are not inherently biodegradable, and some synthetic antibiotics can persist in soils for long periods of time at high concentrations. Some substances (e.g. tetracyclines and fluoroquinolones) also persist in the environment for months to years. ● Wildlife as reservoirs of antibiotic resistant genes: There is good evidence that proximity to human populations, rather than direct antibiotic use on land, is sufficient to substantially affect the gut flora of local wildlife. A study comparing levels of resistance in E. coli recovered from animals with varying amounts of contact with people, from wild Atlantic salmon to dogs, support this notion. However, this is different for wild birds, where ecological factors such as migratory behaviour and high population densities increase the likelihood of the presence of clinically relevant resistance genes carried by birds even in areas of low anthropogenic effect. ● Social issues driving antibiotic resistance: Social interventions are essential to reduce antibiotic misuse within the health-care industry and the home. Campaigns aiming to raise awareness and improve antibiotic prescriptions have tended to focus on high-income countries. Various social factors can impede large-scale reductions in antibiotic prescriptions, such as an increasing capacity to afford health care, rising health care expectations, the number of vulnerable individuals who experience repeated infections, and poor professional attitudes. A rapid increase in internet access has resulted in a corresponding increase in the unregulated purchasing of antibiotics, accompanied by lowquality patient care and increased risk of environmental contaminations through unregulated disposal. Public use or misuse of antibiotics is caused by several social factors, including increased incidence of self-medication, ethnic origin, country of residence, income and education level. ● The potential threat posed by the continued evolution of ARGs seems sufficiently grave and imminent that reliance upon stakeholder behavioural change should be considered a highrisk strategy. ● The absence of full environmental fate and effect data on antibiotics inhibits an effective assessment of the potential risk through environmental pathways. ● There is now sufficient evidence to support the hypothesis that one of the most important emerging public health threats is that of large-scale dissemination of multi-resistant pathogens in the hospital environment, the community, and the wider environment. Rapid demographic, environmental, and agricultural changes are all contributing to a global antibiotic resistance crisis, which, if not stopped, will emerge as one of the major causes of death in the coming decades.

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Mott MacDonald | Antimicrobial Resistance in the Environment Key Pollutant Linkages

A.9 Human health risk assessment of antibiotic resistance associated with antibiotic residues in the environment: a review (Ben, et al., 2019) ● The extensive use of antibiotics leading to the rapid spread of antibiotic resistance poses high health risks to humans, but to date there is still lack of a quantitative model to properly assess the risks. ● Concerns over the health risk of antibiotic residues in the environment are mainly: – The potential hazard of ingested antibiotic residues in the environment altering the human microbiome and promoting emergence and selection for bacteria resistance inhabiting the human body; and – The potential hazard of creating a selection pressure on environmental microbiome and leading to reservoirs of antibiotic resistance in the environment. ● Although the half-life of most antibiotics is not long (hours to hundred days), antibiotic residues that remain in the environment can be considered as a “persistent” organic contaminant due to frequent and extensive use of antibiotics and uninterrupted emissions. ● Antibiotic resistant genes are becoming recognised as an emerging environmental pollutant. ● The paper examines and summarised the available data and information on the four core elements of antibiotic resistance associated with antibiotic residues in the environment: – Hazard identification; – Exposure assessment; – Dose-response assessment; and – Risk characterisation. ● Hazard identification: antibiotic residues in the environment could accelerate the emergency and evolution of antibiotic resistant bacteria (ARB) and antibiotic resistant genes (ARG) in the environment. The risks refer to the transmission of environmental ARB and ARGs to humans. ● Exposure assessment: exposure through surface water, wastewater, drinking water, potentially air and dust, soil, food products (meat, eggs, milk, vegetables and grains, fish and shrimp). ● Dose-response: the relationship between the antibiotic concentration and the probability of emergence of antibiotic resistance. ● Risk characterisation: how dangerous are the adverse effects of human exposure to antibiotic resistance associated with environmental antibiotic residues?

30 August 2019

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