Natural Capital in the Context of Anti-microbial Resistance

Natural Capital in the Context of Anti-microbial Resistance Is there a case for using the Natural Capital Approach in the context of AMR? 13 August 2019

Bryony Osbourn

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Is there a case for using the Natural Capital Approach in the context of AMR? 13 August 2019

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Mott MacDonald | Natural Capital in the Context of Anti-microbial Resistance Is there a case for using the Natural Capital Approach in the context of AMR?

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Mott MacDonald | Natural Capital in the Context of Anti-microbial Resistance Is there a case for using the Natural Capital Approach in the context of AMR?

Contents Executive summary

1

1

Background

2

1.1 1.2

2 2 2 2 3

2

Integrating the NCA concept within a Source-Pathway-Receptor framework 2.1

3

Scope What is antimicrobial resistance?

1.2.1 Mechanisms of resistance 1.2.2 Dissemination of AMR 1.2.3 Population scale evolution of AMR

Applying a Source-Pathway-Receptor Framework to AMR 2.1.1 Defining the ‘source contaminant’ 2.1.2 Defining the source-pathway-receptor 2.1.3 SPR Conceptual Model

Using NCA as a solution for removal of driving agents of AMR 3.1

3.2

3.3

Appropriateness of NCA to combatting clinical antimicrobials 3.1.1 Review of economic justifications 3.1.2 Review of environmental justifications 3.1.3 Interlinking with Mott MacDonald work Appropriateness of using NCA to combat metals-driven AMR 3.2.1 Role of heavy metals in generating AMR 3.2.2 Legacy of heavy metal pollution – where can NCA be used?

Precautionary considerations regarding use of NCA as an action plan for AMR 3.3.1 Natural production of antimicrobials 3.3.2 Creation of reservoirs of AMR 3.3.3 Interlinking with Mott MacDonald Work

5 5 5 5 6

8 8 8 9 9 9 9 10 12 12 13 13

4

Concluding Thoughts

15

5

References

17

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Mott MacDonald |

Executive summary Antimicrobial resistance (AMR) is a growing issue within water and the environment. Natural Capital Approaches (NCA) provide an opportunity to integrate ecosystem-oriented management with economic decision making and development in order to formulate an action plan for AMR within water catchment management. NCA may be used as a remediation strategy for the removal of driving agents (clinical antimicrobials, metals, biocides) from water and the environment. However, for this to occur, the method must be tailored to the specific driving agent intending to be removed, rather than aiming for a ‘one solution fits all’ approach.

Whilst plenty of research exists regarding the discovery of antibiotics as an emerging contaminant within water supplies, there is a significant lack of research regarding the occurrence of other clinically used antimicrobials such as antifungals or antivirals. It is a common misconception that reducing the use of clinical antimicrobials will solve AMR as it has long been known that AMR occurrence is continuing to rise exponentially within the developed world despite drastic reductions in administration of clinical antimicrobials. It is highly possible that the daughter products from biodegradation of clinically used antimicrobials continue to drive AMR, yet there is little research on the significance of what this role may be. Until further research has been completed; it is not recommended to use a NCA as an action plan for removing clinical antimicrobials from the water and environment for risk of accentuating the issue and creating a reservoir of antimicrobial daughter products of unknown effect within the environment.

As a result of both co- and cross-resistance, heavy metals are a key driving agent of AMR within the environment. High concentrations of metals enter the water environment dominantly as a result of the agricultural/aquiculture industry and industrial effluent. Metals do not biodegrade, resulting in the high concentrations accumulating within aquatic sediments etc. which continue to drive AMR on extremely long time scales. This report has concluded that, with increased awareness , NCA could be potentially effective in remediating against the concentration of heavy metals driving AMR. NCA for AMR could easily be integrated into current projects within Mott MacDonald. This report has identified that interception of pathways between agricultural runoff and surface water bodies, or between aquaculture farms and downstream water bodies, would be the most effective use of NCA for preventing the catchment-wide occurrence and circulation of AMR genes. One of the best examples of where this may be applied is within drainage ditches (both road-side and field-side).

For precautionary reasons; a more detailed assessment of the role of the natural environment in the occurrence and dissemination of AMR is crucial prior to any implementation of the NCA concept can take place.

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1 Background 1.1

Scope

The Natural Capital Approach (NCA) is a means for identifying and quantifying natural resources and associated ecosystem services that may help integrate ecosystem-orientated management and economic decision making and development.

The NCA concept is gaining considerable support globally for devising policies that reconcile environmental and economic imperatives as well as aligning policy making to sustainable development. One of the best examples of NCA being successfully used within water catchment management is the remediation of acid mine drainage and flood management through methods such as the creation of wetlands or riparian zones.

The Mott MacDonald Professional Excellence and Innovation Fund has provided a grant to an initiative to work across different sectors of the company on antimicrobial resistance (AMR), of which this report is one output. The report presents a summary of aspects of AMR in water and the environment, specifically addressing whether a natural capital management approach may be used to address the issue of AMR .

1.2

What is antimicrobial resistance?

Antimicrobials are defined as any natural or synthetic substance that kills or inhibits the growth of micro-organisms such as bacteria, fungi and algae. The minimum inhibitory concentration (MIC) is the lowest concentration of an antimicrobial required to inhibit the growth of a given strain of micro-organism. If the MIC value is greater than a defined epidemiological cut off value, then the strain is defined as being antimicrobial resistant (Burnham et al 2017).

1.2.1

Mechanisms of resistance

There are three mechanisms by which micro-organisms develop resistance to an antimicrobial agent: 1. Alteration or protection of antimicrobial target e.g. by DNA-binding proteins (e.g. quinolone resistance genes - Qnr) 2. Decreased accumulation of antimicrobial agent within the micro-organism: either by reduced penetration (e.g. gram-negative bacteria have an outer membrane preventing penetration of penicillin) or by increased efflux (excretion) of the anti-microbial agent out of the micro-organism.

3. Enzymatic modification i.e. secretion of enzymes capable of modifying or destroying the antimicrobial before it reaches its target.

Such mechanisms occur within both clinical and non-clinical environments in response to evolutionary selection pressures (Holmes et al 2015).

1.2.2

Dissemination of AMR

Horizontal gene transfer (HGT) is one of the primary methods of concern with regards to the dissemination of antimicrobial resistance within a population. HGT may occur between all unicellular organisms including viruses, bacteria, fungi etc. (Burnham et al 2017). HGT occurs via the following three mechanisms:

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● TRANSFORMATION: micro-organisms take up and incorporate free DNA from the environment and combine it with their own. ● TRANSDUCTION: viruses (bacteriophages, mycophages) mediate the transfer of DNA between micro-organisms via transduction. DNA is packaged from the donor into the virus than transferred to the next recipient of the virus. ● CONJUGATION: A sex pilus forms between two bacterial cells through which a plasmid of DNA is transferred from one micro-organism to another (Holmes et al 2015).

Another important mechanism of dissemination is the colonial expansion of strains where a point mutation occurs. Point mutations within genes may provide resistance to certain compounds, particularly when the mutation occurs on loci involved in protein biosynthesis.

Expansion of the colony containing these genes results in the development of resistant strains of micro-organisms which will rapidly out-compete susceptible strains; such as is the case with healthcare-associated MRSA clinically resistant strains. (Dean et al 2014, Chen et al 2018,).

The dissemination of AMR may occur by either of these routes, but often by a mix. For a resistant strain to maintain a competitive advantage, the selection pressure must prevail otherwise the advantage will be lost. However, due to HGT the gene in which point mutation has occurred is able to spread rapidly from one micro-organism community to another. Both mechanisms are important, and both have different implications for the control of AMR (Allison et al 2015).

1.2.3

Population scale evolution of AMR

HGT is not only responsible for the dissemination of antimicrobial genes within a population, but also allows the purpose and role of these genes to evolve. As discussed in the section above, many microbes will develop resistance as a combined consequence of point mutation and acquisition of genes by HGT which confer resistance in the recipient micro-organism.

The host organism purpose of such conferring genes often includes (Allison et al 2015): ● Genes to detoxify the original host from the antimicrobial it produces as part of its defence mechanisms. ● Genes for specific enzymes that provide resistance to anti-bacterials such as penicillin. For example, beta-lactamase aids in counteracting beta-lactams which inhibit the biosynthesis of cell walls. . ● Genes responsible for multi-element efflux pumps that allow for the trafficking of signalling molecules from the micro-organism.

The process by which specific traits/features acquire functions for which they were not originally selected for is known as ‘exaptation’; this is one of the key drivers of evolution of antimicrobial resistance within and between populations of micro-organisms (Burnham et al 2017).

Once HGT has occurred; the original use of a feature acquired, such as the efflux pump, will not be relevant due to the different biochemical and genetic context, yet will still be expressed within the new host by the processes of exaptation. A good example of this is the acquisition of multielement efflux pumps (MEP). Due to microorganisms producing different signalling systems, the MEP will no longer be relevant (or appropriate) for the trafficking of signal molecules in and out of the cell in the new host. The MEP will however, still function in trafficking toxins and antimicrobials from the micro-organisms; therefore, functioning as antimicrobial resistance without inhibiting the processes within the new host (Martinez.J, 2012).

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2 Integrating the NCA concept within a Source-Pathway-Receptor framework 2.1

Applying a Source-Pathway-Receptor Framework to AMR

Water catchment management is a growth area in the water sector through which AMR can be usefully explored. In order to standardise work on AMR, the source-pathway-receptor framework (SPR) will be applied to explore whether the NCA concept is appropriate in dealing with AMR. 2.1.1

Defining the ‘source contaminant’

In order to apply a SPR framework to AMR, we must first identify what aspect of AMR we are classifying as the ‘contaminant’ or ‘source’ for which NCA could be applied to prevent it either occurring or reaching a receptor. Through classifying the ‘contaminant’ we must also consider the appropriateness of NCA. We must ensure that by using a NCA, we are actively addressing the issue of AMR rather than simply ‘using a spider to catch a fly’ in which the chosen NCA results in a cascade effect; such as by shifting the issue of AMR in the water and environment into the ecological sector.

In order to avoid such a scenario, we must first consider the selective pressures responsible for driving the evolution and dissemination of AMR genes within populations of micro-organisms.

Various studies have concluded that the drivers of AMR may be characterised under the following three classes of antimicrobials: ● Clinical antimicrobials: anti-bacterials, antifungals, antivirals and antiparasitics ● Heavy metals ● Biocides: disinfectants, surfactants, antifouling materials It must be noted that the term ‘antimicrobials’ is often used throughout literature to describe only anti-bacterials, antifungals, antivirals and antiparasitics. However, as stated in section 1.2, the definition of antimicrobials is: any natural or synthetic substance that kills or inhibits the growth of micro-organisms. Therefore, within the context of this report, the term ‘clinical antimicrobials’ has been used to refer only to those antimicrobials which have been administered for antipathogenic purposes within clinical or veterinary environments. By contrast, the term ‘antimicrobials’ is used within this report to denote any class of antimicrobial as listed above.

In order to explore the use of NCA as an action plan for AMR, as part of water catchment management; driving agents of AMR will be considered as the ‘contaminant’ within the framework of a SPR model.

2.1.2

Defining the source-pathway-receptor

If the driving agents of AMR are to be considered the source contaminant in an S-P-R framework, then the role of micro-organisms within the SPR model must also be debated before the model may be conceptualised.

AMR genes evolve due to selective pressures within the environment; if these genes are incorporated into of a micro-organism (either within chromosomal DNA or within the cytoplasm where they may utilise protein production pathways) and expressed successfully, then that

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micro-organism will gain resistance. In this context, the micro-organism would be classified as the receptor of AMR. In evolutionary terms; if a selective pressure is removed then the evolved gene will no longer confer a selective advantage, and therefore risks being outcompeted (unless exaptation occurs). For AMR to continually and successfully disseminate throughout a population of microorganisms, the same selective pressure must exist within the reservoir in which the population is being harboured.

By this logic, AMR will be expressed as a result of contamination of the micro-organism reservoir by the ‘contaminant’ i.e. the driving agents of AMR resistance. By this argument, we may therefore classify the micro-organism reservoir as the receptor within the framework.

Thus, in the context of AMR in water and the environment, the SPR framework may be defined as: ● SOURCE: the source of the driving agents entering the water and environment ● PATHWAY: the mechanism and methods by which the driving agents enter ground and surface water and are then transported within it. ● RECEPTOR: micro-organism reservoirs (both living and non-living) within water and the environment in which both driving agents and AMR genes accumulate AMR to disseminate throughout a population.

2.1.3

SPR Conceptual Model

A simplified SPR conceptual model can be seen in Table 1.

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Table 1: simplified SPR conceptual model.

SOURCE Waste Water Treatment

PATHWAY

RECEPTOR

●

Micro-organism populations within:

Waste water effluent into surface water bodies

●

Receiving surface water bodies

●

Aquatic sediments

● Wetlands and flood plains: discharged watercourses flow through these environments and driving agents accumulate.

Aquaculture:

●

Fish Feed

●

Anti-fouling biocides

●

Administration of clinical antimicrobials

●

Biosolid sludge used in aquaculture and agriculture

See aquaculture and agricultural receptors below.

●

Waste water effluent into surface water bodies

Micro-organism populations within:

●

Agriculture

Crops

Animal husbandry

●

Fertiliser consisting of aquaculture biosolids and manure

●

Pesticides and biocides

●

Clinical antimicrobials

●

Bioaerosols (specifically pig and poultry)

Bio-sludge/solids recycled and used as fertiliser for agriculture

● Leaching from agricultural soils ●

Aquatic sediments

●

Sediments surrounding water bodies and aquaculture farms

●

Wetlands and flood plains: discharged watercourses flow through these environments and driving agents accumulate.

See agricultural route below.

Micro-organism populations within:

during rain/storm events.

●

Surface water runoff following irrigation activities

Surface water bodies – particularly ponds etc.

●

Habitats surrounding fields particularly if ground water dependent.

● Land spreading of manure, sewage sludge and anaerobic digestate as fertiliser or soil conditioner.

● Farmyard runoff into streams, rivers and surrounding environment.

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● Aquifers below, or in close proximity to, agricultural land.

Mott MacDonald | Natural Capital in the Context of Anti-microbial Resistance Is there a case for using the Natural Capital Approach in the context of AMR?

3 Using NCA as a solution for removal of driving agents of AMR As stated in section 2.1.1, the key driving agents of AMR are clinical antimicrobials, metals and biocides. Due to limited resources for conducting this review only clinical antimicrobials and metals have been examined in detail within this section of the report.

3.1 3.1.1

Appropriateness of NCA to combatting clinical antimicrobials Review of economic justifications

Clinical antimicrobials are used within the pharmacological industry, agricultural industry (animal husbandry) and within the aquaculture industry. Clinical drugs present within the water environment come predominantly from agricultural waste and effluent. Animal husbandry accounts for 60-80% of global clinical microbial use, predominantly anti-bacterial. Whilst the use of anti-bacterials as growth promoters has been banned in Europe and regions of North America, it is still used extensively throughout the developing world (Singer et al, 2016).

The degradation of antimicrobials is dependent upon the relation between their physicochemical properties and the microbial activities/aeration of the recipient soil/water in which they are released. Many studies have analysed the rate of degradation under different conditions and, whilst they do vary, the vast majority of antimicrobials have half-lives of <90 days in soils, and many of the most commonly used clinical antimicrobials have half-lives of <40 days (Albero et al 2018). Shorter half-lives are observed in aqueous environments, including soil-aqueous phases, due to reduced surface areas for adsorption, thereby increasing the availability of the antimicrobials for microbial biodegradation (Clarke and Smith , 2011).

Improved education, infection prevention and diagnostic capabilities have drastically reduced the use of clinical microbials within Europe and North America whilst improved techniques and policies have led to a drastic decline in the use (Holmes et al 2016). Despite this, there is an absence of evidence to confidently correlate the quantitative relationship between the frequency of AMR and volume of clinical microbial administration. Studies have shown that emergence of resistance under a constant selective pressure typically occurs on much shorter timescales than the decline in AMR following removal of the selection pressure. Therefore, for a significant reduction in a specific AMR, an equally significant reduction in all factors contributing to maintaining the selection pressure to which the AMR is providing the advantage must occur (Austin et al 1999). Due to the relatively insignificant effect of reduced clinical antimicrobials, many sources argue that other driving agents are responsible for the continued increase in AMR (Holmes et al 2016).

Whilst the use of clinical antimicrobials is still excessive in areas of the developing world, it may also be argued that, with improved education and awareness, the contamination of water and the environment by these compounds may be effectively reduced (Singer et al 2016). Reducing the contamination in this manner, alongside the short half-lives of the majority of clinical antimicrobials calls into question the economic justification for the use of NCA in dealing with this particular driving agent.

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3.1.2

Review of environmental justifications

The NCA concept often has the benefit of improving biodiversity. It has been shown that clinical antimicrobials, specifically anti-bacterials, have greater persistence when incorporated within the guts of small mammals and birds. Pathogenic exogenous micro-organisms (microorganisms introduced to closed biological systems, known as ‘disease-causing’) are the main target of clinical antimicrobials, such pathogens harmful to humans can often be found residing in the guts of many animals without causing harm. Returning to the metaphor of ‘using a spider to catch a fly’, there is therefore a significant risk that colonisation of areas by wildlife where NCA methods have been applied may lead to increased occurrence of exogenous microbial resistance genes (Wellington et al 2013). This becomes an even greater concern when considering bird populations; the vast distances covered both by feeding and migration patterns can result in AMR genes being distributed from one micro-organism reservoir to another very rapidly. This, in addition to the mixing of exogenous microbes in their guts, results in drastic increases in AMR as a result of HGT mechanisms (Smet et al 2010).

3.1.3

Interlinking with Mott MacDonald work

For the reasons discussed in section 3.1; at this present time there does not appear to be substantial justification for the use of NCA in the treatment of clinical antimicrobials rather than improved waste water treatment, reduced untreated waste discharges and reduced use of clinical antimicrobials. It is recommended that further research be done into the specific techniques and methods that would be incorporated into the NCA, so that the risk of unintended negative consequences may be accurately compared/mitigated against the benefit gained in using NCA over other methods.

Further research is also required into the degradation pathways of clinical antimicrobials within the environment so that a proper assessment of the daughter products and their interaction and role in generating AMR may be analysed.

3.2 3.2.1

Appropriateness of using NCA to combat metals-driven AMR Role of heavy metals in generating AMR

Heavy metals within water and soil matrices impact microbial communities and represent an important vector in the maintenance and proliferation of AMR. Heavy metals such as Zn, Cu, Mn, Ni, Cr and Fe provide essential nutrients for micro-organism growth with some resistance enzymes also requiring metal co-factors to function e.g. Metallo-beta-lactamases requires zinc for sufficient resistance activity. However, in high enough concentrations they may also act as antimicrobials, whereby the metal ions become displaced from their designated (nutrient) binding sites and instead block essential functional sites. This results in diminished enzyme functions and damage to DNA (Rodgers. K et al, 2018).

The accumulation of other heavy metals with a non-biological role such as Pb and Cd may cause oxidative stress, lipid peroxidation and mutagenesis. The toxicity of heavy metals and the misconception that clinical antimicrobials are the sole cause of AMR results in many metals, particularly Cd and Pb, being used as an alternative to clinical antimicrobials (Seiler and Berendonk, 2012). .

The toxicity of heavy metals in the environment is strongly dependent on conditions affecting the valence state, and therefore bioavailability, of metal ions. Such conditions include pH,

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concentrations of organic matter, and the redox potential of the soil, sediment or water in which they are located (Singer.A et al 2016).

To further complicate matters, a small change in conditions will result in many metals exhibiting contrary behaviours to that predicted. For example; under low-pH conditions the solubility of Pb, Cd and Zn is increased and therefore often considered effective to use within aquaculture. If, however, high contents of organic matter are present within the sediment, as if often the case in closed water systems, the sediment will act as sorption sinks for these metals. This will therefore prevent them being transported within the water column where they may be used and/or treated but instead results in the accumulation of high concentration of heavy metals within the aquatic sediment. The use of heavy metals without proper understanding of their fate within the environment has resulted in anthropogenically increased concentrations existing far above their natural environmental concentrations (Seiler and Berendonk 2012).

Due to co-selection, resistance to heavy metals often has the synergistic effect of providing resistance to other antimicrobials; particularly those of a clinical nature. The key mechanisms for metal resistance include (Rodgers. K et al, 2018): ● Sequestration of toxic metals: metal binding minimises the concentration of free toxic ions in the cytoplasm. Such binding may be via sorption, protein-metal associations, or release of organic chelators. ● Detoxification through reduction of intracellular ions: An example of this is the use of mercury reductase which reduces Hg 2+ to the less toxic Hg0, this will then diffuse out of the cell at a faster rate due to its low evaporation point. ● Extrusion of toxic ions by efflux mechanisms: cation/anion antiporters mediate resistance to metal ions by extrusion of metals from the cytoplasm through the inner and outer membrane to the surrounding environment. Such antiporters are commonly known as “multi-drug efflux pumps”.

The resistance mechanism listed above couple with clinical AMR due to either cross-resistance (e.g. multi-drug efflux pumps) or co-resistance. Co-resistance occurs due to the genes providing metal-resistance being frequently located next to clinical AMR on same plasmid, resulting in non-intentional HGT of clinical AMR genes in response to increased metal toxicity (Seiler and Berendonk, 2012).

Heavy metal toxicity is therefore considered to be the dominant driving force in the development and dissemination of AMR within water and the environment. Given that heavy metals do not degrade within the environment, not only do selective pressures derived from metals persist longer than pharmaceutical and clinical antimicrobial pressures, but due to industrial and urban pollution, the scale of the selection pressure is far more extensive than any other driving agent (Holmes et al, 2015).

3.2.2 3.2.2.1

Legacy of heavy metal pollution – where can NCA be used?

Agriculture

Due to high nutrient density; biosolids (also referred to as ‘sludge’) from waste water treatment plants, aquaculture and animal waste are recycled for use as fertiliser for the agricultural industry.

Many developed countries have existing legislation concerning the application of sludge to reduce the concentration of leached metals on the receiving soil and adjacent water body (Singer et al 2012). Whilst such legislation exists for biosolids, many countries have little

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concerning the use of manure which, in additional to the nutritional benefit, is often applied in excess to improve soil cohesion and reduce erosion (Ramos et al 2006).

It is not economically feasible to use NCA to reduce the concentration of heavy metals within biosolids and manure due the economic value derived from the high nutrient density.

Alternatively, there is justification for the use of NCA in intercepting runoff from fields, thus reducing the concentration of metals entering surface water bodies or infiltrating to the aquifer.

The role of land drains in water pollution conveyance is largely ignored within reviews of AMR, yet many studies have found extremely high concentrations of not just metals but of faecal micro-organisms within ditches following rainfall events. A similar trend of high contaminants can also be observed in roadside ditches away from agricultural land, such as within forested areas, due to the leaching of forest soils and wildlife excrement (Falbo et al 2016).

Increased manure spreading may be used during high rainfall due to the benefit of reduced soil detachment, therefore protecting the crops during the wet season. Regular spreading of manure can reduce soil detachment by up to 70% due to increased cohesion but may increase total runoff volume into drainage ditches by up to 30% during each rainfall event (Ramos et al 2006).

Due to a high organic content, a high degree of metal-sorption occurs within soil drains allowing metals to accumulate within ditches for significant periods of time. The presence of a high concentration of metals and micro-organisms within roadside ditches and land drains makes them ideal locations for HGT to occur, generating a pool of AMR genes ready to be washed into nearby water bodies or leached to shallow aquifers following storm events. The dissemination of AMR by HGT is accentuated by the fact that land drains are designed to intersect with one another, resulting in the large-scale mixing of different micro-organism reservoirs and habitats (Schipper et al, 2008).

For these reasons, drainage ditches present ideal targets where NCA may be beneficial in intercepting not only heavy metals, but also clinical antimicrobials and biocides within runoff from the surrounding environment.

Interlinking with Mott MacDonald Work: The use of NCA to remediate drainage ditches and prevent the occurrence and spread of AMR within water catchments would closely tie in with work being done using natural flood alleviation methods to combat flooding.

The potentially significant degree of crossover in this area, and that NCA methods for AMR have potential for effective integrated within NCA to combat flooding, are identified as key findings of this review and are recommended to be explored further.

3.2.2.2

Legacy of industrial pollution

Aquatic sediments are a considerable reservoir of AMR resistant micro-organisms, which are exposed to a vast range of continually changing conditions due to annual cycles in water chemistry within river systems. Naturally stressful conditions render any micro-organisms present more susceptible to stresses imposed by anthropogenic pollution (Rodgers et al, 2018).

Anthropogenic pollution in watercourses can lead to rapidly alternating conditions which may result in a switching of absorption and desorption reactions between metals and aquatic sediments. Sediments may also retain metals and nutrients through sorption on to the surface of mineral and organic particles for significant amounts of time, until destabilisation due to changes in water chemistry results in a mass release (Wellington et al, 2013).

Unlike other pollutants, metals do not degrade. Indigenous micro-organisms persist within aquatic sediments over extremely long timescales and interact with the legacy metal

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contamination, promoting HGT. This process may form layers of enhanced AMR reservoirs in the subsurface.

Additionally, micro-organism community characteristics are related to their responses to physico-chemical properties, pH, nutritional quality of the sediments and source of carbon, irrespective of the pollutant conditions. This can create extreme spatial differences of species composition and community structures, therefore, drastically enhancing the chances of coresistance due to a much more diverse range of AMR genes within the microbiome (Rodgers.K et al, 2018).

Interlinking with Mott MacDonald Work.

There is a potentially significant opportunity to target and integrate AMR with regards to industrial waste entering the water courses or remediation of polluted legacy sediments/soils.

By making AMR a key factor when assessing the suitability of projects such as discharge permit locations, planning applications, abstractions from or in proximity to watercourses or contaminated land, the dissemination of AMR could be drastically reduced.

Simple measures such as modifying common practice within preliminary risk assessments and desk studies to prevent active involvement in the spread of AMR would not only increase the awareness of staff involved, but also facilitate clients to address these issues.

The potential implication of these findings is that AMR may become a crucial factor when considering suitable remediation strategies within Mott MacDonaldâ&#x20AC;&#x2122;s contaminated land sector.

As an additional point to this, it is recommended that assessment of the positive and negative impacts of currently used remediations strategies for common industrial contamination be undertaken with a view to determining the potential role of remediation in the spread of AMR.

3.3 Precautionary considerations regarding use of NCA as an action plan for AMR 3.3.1

Natural production of antimicrobials

Many micro-organisms and organisms, including plants and animals, naturally produce antimicrobial substances; such antimicrobial substances are intended to often at concentrations too low to be effective on entire micro-organism population.

There is a significant body of evidence indicating that sub-lethal doses are significantly more likely to increase AMR due to prolonged exposure (Andersson and Hughes. 2014). Many saprophytic organisms are also known to produce a class of beta-lactam antibiotics known as carbapenems; this antibiotic is also heavily administrated within the clinical industry due to its ability to actively inhibit both aerobic and anaerobic gram positive and gram-negative organisms (Holmes et al 2016).

The use of natural capital as an action plan for AMR may naturally increase the resistance to the antimicrobial being secreted naturally, thus increasing AMR within that soil layer. Returning to the â&#x20AC;&#x2DC;using a spider to catch a flyâ&#x20AC;&#x2122; metaphor, the knock-on effect of introducing or increasing non-native antimicrobials to a system must be considered. For example; if a NCA is used in which an increase in biodiversity occurs, part of which includes an increase in saprophytic organisms, then naturally an increased resistance to carbapenems may occur within that biodome. Any wildlife, particularly birds and small mammals, interacting within this biodome will come in contact with micro-organisms in possession of the carbapenems resistant genes within

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their plasmids; through this SPR example the resistance to carbapenems will spread from one reservoir to another (Wellington et al 2013). The ecological effect of this resistance to the antibiotic producing organism must also be considered; if the produced compound no longer works then the producing organism, in this case the saprophyte, may be outcompeted by other organisms.

Symbiotic relationships may also be inadvertently impacted; Actinomycetes are a diverse family of gram-negative bacteria that have evolved to live in symbiosis with many plants, fungi, insects and sponges. Such organisms profit from the natural products produced by actinomycetes such as nutrients (e.g. nitrogen) and protection against pathogenic microbes due to the secretion of antibiotics (Van der Meij et al 2017). . Increased AMR to antibiotics such as those produced by actinomycetes, perhaps by cross- or co-resistance, could have a devastating ecological impact on the host organisms in symbiosis. Disruption to symbiotic relationships may also have impacts on crop production as reduced soil persistence of bacteria such as actinomycetes may drastically reduce the nutrient density of compounds such as nitrogen within agricultural soils (Rosenblueth et al 2018). The potential impacts that increased AMR within the environment may have on symbiotic relationships important to agriculture is something of great importance, particularly concerning what role NCA may have to play, yet this requires much more extensive research in order to be discussed further at this time.

The above is simply an example of how without proper understanding, NCA may counteract the exact thing it is being used to solve later down the line. Ecological and co-evolutionary processes occur at different spatial and time scales. Whilst single, isolated populations are typically dominated by demographic and genetic stochasticity, colonisation and extinction dynamic factors have a larger influence on metapopulations (Smith et al 2003). In order for NCA to be an effective action plan for AMR the controls on both isolated populations and metapopulations must be considered and correctly understood so as to avoid a cascade of effects at a later stage.

3.3.2

Creation of reservoirs of AMR

The risk of creating reservoirs of AMR has been discussed in detail with regards to clinical antimicrobials in section 3.1.2. In addition to what is discussed in section 3.1.2 with regards to clinical antimicrobials, consideration must be given to metals and biocides to ensure that the concentration of these driving agents is not simply reduced from the water environment by increasing/transferring them to the terrestrial environment or biosphere. Examples of ways in this may occur include: â&#x20AC;˘ â&#x20AC;˘ â&#x20AC;˘

3.3.3

Bioaccumulation of heavy metals and clinical antimicrobials in plants and animals, Alteration of the water conditions causing heavy metals to precipitate out of water courses only to accumulate in soils and leach to aquifers, The use of activated soil filters to remove biocides from infiltrating groundwater but result in concentrated layers of legacy sediments occurring within the soil zone (Bester et al 2011).

Interlinking with Mott MacDonald Work

Various sectors within Mott MacDonald could be targeted to increase awareness that the role the natural environment could have in promoting AMR. One way in which this could be done is by considering what the introduction of non-native plant species to a habitat could have on AMR, and the impact of exposing a microbial population to new and different naturally produced sub-lethal doses of antimicrobials.

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Examples of where this could be applied within current projects within Mott MacDonald include: • •

•

•

Ecology: include the broad class of antimicrobials occurring naturally within a habitat as part of ecological surveys.

Landscape Architecture: based on the ecological surveys of the area, consider the negative impact that the mixing of antimicrobials may have when choosing the plant species. Already invasive traits and characteristics must be considered when choosing non-native ornamental species. Therefore, with increased awareness, the class of antimicrobial being introduced could also be considered.

Flood management: Increased awareness of the AMR role that various natural flood management strategies may have. For example, the planting of non-native trees to form riparian zones Contaminated land: when using NCA as a remediation tactic, consider the mixing and gene pool implications that artificially creating a habitat where it would not naturally occur may have. For example, artificially created wetlands as a solution for acid mine drainage.

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4 Concluding Thoughts This literature review has shown that NCA may be used as a remediation strategy for the removal of driving agents (clinical antimicrobials, metals, biocides) from water and the environment. However, in order for this to occur, the method must be tailored to the specific driving agent intending to be removed, rather than aiming for a ‘one solution fits all’ approach.

Through applying the SPR framework to AMR several relevant pathways have been identified as opportunities for NCA to be applied in preventing AMR from spreading within the water and environment. NCA could be potentially effective in remediating against the concentration of heavy metals driving AMR. NCA for AMR could easily be integrated into current projects within Mott MacDonald. This report has identified that interception of pathways between agricultural runoff and surface water bodies, or between aquaculture farms and downstream water bodies, would be the most effective use of NCA for preventing the catchment-wide occurrence and circulation of AMR genes. One of the best examples of where this may be applied is within drainage ditches (both road-side and field-side).

Until further research has been completed; it is not recommended to use a NCA as an action plan for removing clinical antimicrobials from the water and environment for risk of accentuating the issue and creating a reservoir of antimicrobial daughter products of unknown effect within the environment. This report has also concluded that is a significant lack of research regarding the occurrence of other clinically used antimicrobials such as antifungals or antivirals.

Due to time constraints on the project, several key questions remain unanswered, some of which include: ● What is the role of the daughter products from the biodegradation of clinical antimicrobials in driving AMR? ● How does the role of NCA change when considering the controls of HGT and colonial expansion of point mutations separately within different environmental reservoirs? ● How can we tailor the NCA to the specific resistance mechanism we are trying to prevent?

For example, removing the competitive advantage that maintaining traits, such as efflux pumps provide? ● What is the impact of increased AMR on agriculturally important symbiotic relationships, such as legumes and nitrogen fixing bacteria, and what role could NCA have to play? ● What role does work completed by Mott MacDonald currently have in accentuating AMR and how could this be improved? ● Too much research focuses on AMR within bacteria, to what extent are we seeing AMR within other pathogens and do the same chemicals drive AMR in viruses, fungi etc?

Despite many unanswered questions, several key areas of Mott MacDonald have been identified in which increased awareness of AMR would be beneficial: ● Ecology and landscape architecture: What role does the natural environment play in AMR? ● Water resources and flooding: current natural flood management projects could be tailored to also address AMR, flooding is a key pathway for spreading AMR genes between water environments and soil/ecological reservoirs of micro-organisms. Drainage ditches are

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one of the main pathways for driving agents of AMR to pass from the land, particularly agriculture, to the water environment. â&#x2014;? Contaminated land: How can current remediation strategies for industrial pollutants be tailored to address AMR? What role do current remediation strategies play in spreading AMR and crating reservoirs of AMR within the environment?

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5 References Albero B, Tadeo J, Miguel E, Esther M and Rosa Ana P (2018) Persitence and availability of veterinary antibiotics in soil and soil-manure systems. SCIENCE OF THE TOTAL ENVIORNMENT 643: 1562 – 1570 Andersson DI, Hughes D (2011). Persistence of antibiotic resistance in bacterial populations.

FEMS Microbiol Rev; 35: 901–11.

Austin D, Kristinsson K and Anderson R (1999) The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance.

POPULATION BIOLOGY AND MEDICAL SCIENCES. 96: 1152 - 1156 Bester K, Banzhaf S, Burkhardt M, Janzen N, Niederstrasser B and Scheytt T (2011) Activated soil filters for removal of biocides from contaminated run-off and waste-waters.

CHEMOSPHERE. 85 (8): 1233-40.

Burnham C, Leeds J, Nordmann P, O’Grady J and Patel J (2017). Diagnosing antimicrobial resistance. NATURE REVIEWS: MICROBIOLOGY. 15: 697-703 Chen F-J, Lauderdale T-L, Lee C-H, Hsu Y-C, Huang I-W, Hsu P-C and Yang C-S (2018) Effect of a Point Mutation in mprF on Susceptibility to Daptomycin, Vancomycin, and Oxacillin in an MRSA Clinical Strain. FRONT. MICROBIOL. 9:1086.

Clarke BO and Smith SR (2011) Review of ‘emerging’ organic contaminants in biosolids and assessment of international research priorities for the agricultural use of biosolids.

ENVIRONMENT INTERNATIONAL. 37: 226-247.

Costa D, Poeta P, Saenz Y, et al (2008). Mechanisms of antibiotic resistance in Escherichia coli isolates recovered from wild animals. MICROB DRUG RESIST; 14: 71–77.

Dean M, Olsen R, Long W, Rosato A and Musser J (2014) Identification of Point Mutations in Clinical Straphyloccus aureus Strains That Produce Small-Colony Varients Auxotrophic for Menadione. INFECTION AND IMMUNITY. 82:4. 1600-1605 Falbo K, Schneider RL, Buckley DH, Walter MT, Bergholz PW and Buchanan BP (2013) Roadside ditches as conduits of faecal indicator organisms and sediment: Implications for water quality management. JOURNAL OF ENVIRONMENTAL MANAGEMENT. 128: 1050-1059.

Goulas A, Livoreil B, Grall N, Benoit P, Couderc-Obert C, Dagot C, Patureau D, Petit F, Laouenan C and Andremont A (2018) What are the effective solutions to control the dissemination of antibiotic resistance in the environment? A systematic review protocol.

ENVIRONMENTAL EVIDENCE. 7:3 Holmes, A et al (2015) Understanding the mechanisms and drivers of antimicrobial resistance.

LANCET, 2016; 387:176-87.

Manamsa K, Crane E, Stuart M, Talbot J, Lapworth D and Hart A (2016) A national-scale assessment of micro-organic contaminants in groundwater of England and Wales. SCIENCE OF THE TOTAL ENVIRONMENT. 568: 712-726

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Martinez J (2012) Natural antibiotic resistance and contamination by antibiotic resistance determinants: the two ages in the evolution of resistance to antimicrobials. FRONTIERS IN MICROBIOLOGY. Opinion Article. 3:1 Ramos MC, Quinton JN and Tyrrell SF (2006) Effects of cattle manure on erosion rates and runoff water pollution by faecal coliforms. JOURNAL OF ENVIRONMENTAL MANAGEMENT. 78: 97-101.

Rodgers K, McLellan I, Peshkur T, Williams R, Tonner R, Hursthouse A, Knapp C and Henriquez F (2018) Can the Legacy of industrial pollution influence antimicrobial resistance in estuarine sediments? ENVIRONMENTAL CHEMISTRY LETTERS. Review. 17:595 – 607.

Rosenblueth M, Oreno-orrillo E, Lopez – Lopez A, Rogel M, Reyes-hernandez B, MartinezRomero J, Reddy P and Martinez-Romero E (2018) Nitrogen Fixation in Cereals. FRONT. MICROBIOL. 9:1794.

Schipper P, Bonten L, Plette A and Moolenaar S (2008). Measures to diminish leaching of heavy metals to surface waters from agricultural soils. DESALINATION. 226: 89-96 Seiler C, Berendonk TU. Heavy metal driven co-selection of antibiotic resistance in soil and water bodies impacted by agriculture and aquaculture. FRONT. MICROBIOL 2012; 3: 399 SingerAC, Shaw H, Rhodes V and Hart A (2016) Review of Antimicrobial Resistance in the Environmetn and it’s Relevence to Environmental Regulators. FRONT. MICROBIOL. 7:1782 Smet A, Martel A, Persoons D, et al. Broad-spectrum beta-lactamases among Enterobacteriaceae of animal origin: molecular aspects, mobility and impact on public health.

FEMS Microbiol Rev 2010; 34: 295–316.

Smith DI, Ericson L and Burdon JJ (2003) Epidemiological patterns at multiple spatial scales: an 11-year study of a Triphragmium ulmariae-Filipendula ulmaria metapopulation. JOURNAL OF ECOLOgy; 91: 890–903 Van der Meij A, Worsley S, Hutchings M and van Wexel G (2017) Chemical ecology of antibiotic production by actinomycetes. FEMS MICROBIOLOGY REVIEWS. 41:3, 392 - 416 Voora VA and Venema HD (2008) The Natural Capital Approach: A Concept Paper.

International Institute for Sustainable Developent. Environment Canada – Policy Development Division, Manitoba, Canada. http://www.isd.org.

Watts J, Schreier H, Lauma L and Hale M (2017) The Rising Tide of Antimicrobial Resistance in Aquaculture: Sources, Sinks and Solutions. MARINE DRUGS. 15: 158 Wellington EMH, Boxall AB, Cross P, et al. The role of the natural environment in the emergence of antibiotic resistance in gram-negative bacteria. Lancet Infect Dis 2013; 13: 155– 65.

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Glossary Antimicrobial (agent)

Defined as a natural or synthetic substance that kills or inhibits the growth of micro-organisms such as bacteria (anti-bacterial), fungi (anti-fungal) and virus (anti-viral).

Antibiotic

An antimicrobial compound produced by an organism.

Co-resistance

Two or more genetically linked resistance genes. Genes responsible for two or more resistances can be located next to each other on one mobile genetic element therefore are likely to be subject to combined transmission by HGT.

Co-selection

The selection of multiple AMR genes when one of these genes is selected e.g. the integron is a cassette of resistance genes that are under the control of a single promotor. As a result, the genes are expressed in a coordinate manner. Since they are a form of transposon( transposable element) they can become a part of the bacterial chromosome or plasmid and can then be transmitted among different strains.

Cross-resistance

A single resistance mechanism confers resistance to an entire class of antimicrobial agents for example antibiotics and heavy metals.

Exaptation

The process by which a traits/features acquire functions for which they were not originally selected

Exogenous micro-organisms

Micro-organisms introduced to closed biological systems from the external world. Such systems can be aquatic and terrestrial systems. This class of bacteria are found in the environment but can survive in our bodies â&#x20AC;&#x201C; typically called disease causing micro-organisms.

Horizontal Gene Transfer (HGT)

The movement of genetic material between unicellular and/or multicellular organisms other than by the transmission of DNA from parent to offspring.

Integrons

Genetic elements capable of acquiring and exchanging DNA fragments named gene cassettes. Class 1 integrons are assumed to catalyse co-selection as frequently contain gene cassettes that mediate resistance to antimicrobials and are frequently found in contaminated environments.

MCC

minimum heavy metal concentration which correlates with a detection of increased resistance specified as the minimum co-selective concentration (MCC) of a metal. If the environmental metal concentrations exceed the

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corresponding MCC value then they are considered to be driving the dissemination of AMR. MIC

antimicrobial concentrations needed to inhibit microbial growth. If the MIC is greater than an epidemiological cut off value then the strain is defined as being antimicrobial resistant.

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