Balancing Water Sustainability and Public Health ... - ACS Publications

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Balancing Water Sustainability and Public Health Goals in the Face of Growing Concerns about Antibiotic Resistance Amy Pruden†,* †

Via Department of Civil and Environmental Engineering, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, United States the United States and other developed countries, our water infrastructure has reached its design lifespan, as evidenced by the American Society of Civil Engineers combined grade of “D” for the U.S. drinking water and wastewater infrastructure.5 Thus, we as a society face a key moment in history where we will either proactively take on the challenge of sustainable water infrastructure, or generally continue a much costlier reactionary approach. Clearly there is need for innovation, both technological and institutional, as recently reviewed by Kiparsky and colleagues.6 Initiatives, such as ReNUWIt, a National Science Foundation Engineering Research Center led by Stanford University and partners,7 challenge us to envision the city of the future in Global initiatives are underway to advance the sustainability of which we rethink “waste” water as a resource, consisting of a urban water infrastructure through measures such as water renewable source of water, energy, and nutrients. An integrated reuse. However, there are growing concerns that wastewater vision of water, energy, and nutrient conservation and effluents are enriched in antibiotics, antibiotic resistant bacteria, harvesting from wastewater has been proposed8 and is gaining and antibiotic resistance genes, and thus could serve as a practical acceptance, as indicated by the Water Environment contributing factor to growing rates of antibiotic resistance in Research Foundation’s recent Request for Proposals focused on human infections. Evidence for the role of the water recovery of resources from wastewater9 and other initiatives.10 environment as a source and pathway for the spread of A practice that has been in place for decades, and now in at antimicrobial resistance is examined and key knowledge gaps least 43 countries throughout the world,11,12 is the reuse of are identified with respect to implications for sustainable water advanced treated wastewater for irrigation of parks, golf systems. Efforts on the part of engineers along with investment courses, crops, and other purposes. In Singapore and Namibia, in research in epidemiology, risk assessment, water treatment this is taken a step further through “direct potable reuse” in and water delivery could advance current and future sustainable which treated wastewater is recycled as a source for drinking water strategies and help avoid unintended consequences. water. This is a vision of the future shared by many, and as INTRODUCTION rightly pointed out, “indirect” potable reuse (e.g., drinking water plant intake downstream from a wastewater plant Water is a prerequisite to life. For humans in particular, access effluent) is common-place, whether we are aware of it or not.13 to clean, safe, water is fundamental to our modern standard of On equal par with the problem of water sustainability, is the living. Accordingly, the U.S. Centers for Disease Control has problem of antibiotic resistance. Similarly, antibiotics have cited treatment and delivery of safe potable water as one of the played a fundamental role in our modern quality of life and life greatest achievements of the 20th Century.1 Basic water expectancy.14 Diseases that afflicted humanity throughout the treatment processes that we take for granted today, such as ages: tuberculosis, plague, scarlet fever, leprosy, syphilis, filtration and chlorination, have acted to eliminate once 2 gonorrhea, etc., have largely been defeated over the last century dreaded threats of waterborne disease, such as typhoid. thanks to antibiotics. Penicillin was the first antibiotic to be However, in the 21st Century, our water infrastructure faces discovered, in 1928, and by the 1930s sulfa drugs were mass a new challenge: water sustainability. produced and distributed. Other classes of drugs have been Globally, it is estimated that 2.5 billion people lack adequate developed since then, but, inevitably, microbes learn how to sanitation and 783 million people lack access to clean water.3 resist them. Without active intervention, such as careful While the problem is not yet as acute in developed countries, rationing of “last resort” drugs (e.g., vancomycin), antibiotic arid regions, such as the southwest U.S. and the Middle East, resistance has generally been observed to emerge in the clinic and highly populated urban areas, such as Singapore, are within a decade or less after deployment of a new antibiotic already facing the reality of the need for sustainable water (Table 1). An obvious and imperative battlefront is to solutions to ensure their future survival. Accordingly, continually work toward the development of new antibiotics. prominent on the National Academy of Engineering’s most Unfortunately, as highlighted recently in The New York Times,15 recent list of Grand Challenges in Engineering is “Providing 4 Access to Clean Water”. Also on the list is a closely related Published: November 26, 2013 challenge, “Restoring and Improving Urban Infrastructure”. In

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© 2013 American Chemical Society

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dx.doi.org/10.1021/es403883p | Environ. Sci. Technol. 2014, 48, 5−14

Environmental Science & Technology

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What might water sustainability and antibiotic resistance potentially have to do with each other? In plain terms, of the tons of antibiotics produced and purchased in the world per year (e.g, in the U.S. >5500 tons28,29), the vast majority are consumed and excreted, along with antibiotic resistant bacteria, into sewage or livestock manure, which eventually can enter various stages of the urban water cycle. This feature article synthesizes existing evidence for the role of the water environment as a source and pathway for the spread of antimicrobial resistance and identifies key knowledge gaps. The case is made that, while there may be apparent conflict between water sustainability and public health goals, the present moment is opportune for rethinking and rebuilding our infrastructure in a manner compatible with combatting antibiotic resistance. With appropriate investment in research, cost-effective means of limiting the spread of antibiotic resistance via the water cycle may be identified and taken into consideration when developing and implementing water treatment and infrastructure strategies. What is Antibiotic Resistance? Antibiotic resistance is the ability of bacteria to survive, and even thrive, in the presence of antibiotics. Resistance to antibiotics is encoded in segments of DNA called antibiotic resistance genes (ARGs), which enable bacteria to fight antibiotics by various mechanisms, such as modifying the cellular target, degrading or modifying the antibiotic, preventing uptake, or pumping it out of the cell (efflux).30 A major challenge is that antibiotic resistant bacteria survive and multiply better than susceptible ones in the presence of antibiotics, thus enriching populations for resistant strains during the course of antibiotic treatment. An even larger concern; however, is the tendency of ARGs to be shared among bacteria through horizontal gene transfer.31−33 Sharing of genes is facilitated through mobile genetic elements, such as plasmids, transposons, and integrons and can be driven by conjugation (i.e., bacterial mating), transduction (i.e., viral mediated), and transformation (uptake of extracellular DNA from dead cells). Thus, as recently reviewed by Dodd,34 efforts to kill resistant bacteria, such as UV or chlorine disinfection, may not be effective unless they also destroy ARGs. For these reasons, efforts to slow the spread of antibiotic resistance should ideally focus on ARGs, as well as the antibiotics that select for them. Evidence for Linkage Between Environmental and Clinical Resistance. There is growing evidence that ARGs associated with clinical infections largely originated from the environment. For example, Rhodes et al.35 noted that plasmids carrying tetracycline resistance in E. coli and Aeromonas isolated from hospital wastewater were highly similar to those in isolates from fish farms. Of concern is extensive use of antibiotics in aquaculture, including important antibiotics used in humans (e.g., quinolones), which can persist in the environment and exert selective pressure on human pathogens, which then enter the food chain.36 In the U.S. and many countries, the majority of antibiotics are administered to livestock,37 a practice that may also select resistant pathogens. Notably, recent genomic comparisons of S. aureus isolates from pigs and humans indicated that some community-acquired MRSA strains move back and forth between human and pig populations.38 Perhaps most important to recognize is that soil itself is rich in bacteria resistant to every known antibiotic, including ones only recently approved for clinical use.39 A prime example is the vanHAX cluster of ARGs that confers resistance to a last-resort antibiotic, vancomycin. vanHAX emerged in clinical strains of Enterococci and Staphylococci in the late 1980s with a specialized

Table 1. Resistance Emerges Soon after Deployment of New Antibioticsa

a

antibiotic

year of deployment

onset of resistance

sulfonamides penicillin streptomycin chloramphenicol tetracycline erythromycin vancomycin methicillin ampicillin cephalosporins

1930s 1943 1943 1947 1948 1952 1956 1960 1961 1960s

1940s 1946 1959 1959 1953 1988 1988 1961 1973 late 1960s

Sources: refs 126 and 127.

the rate of new antibiotic discovery has been drastically declining. This is because market incentives for new antibiotic development are poor; that is, people typically take antibiotics for only short time periods. Likewise, sequestering reserves of new antibiotics to prevent emergence of resistance is not a sustainable business strategy. Thus, there is legitimate and growing concern that we may again return to a preantibiotic era.16 Because of increasing rates of antibiotic resistance, it is feared that routine surgeries will become extremely dangerous, for example, it is estimated that without prophylactic use of antibiotics prior to hip replacement surgery, the chance of death due to secondary infection would be one in six.17 The dire consequences of antibiotic resistance are beginning to play out. The U.S. Center for Disease Control and Prevention, the World Health Organization, and numerous other global and national agencies have recognized antibiotic resistance as a critical challenge of our time. The global rate of antibiotic resistance among many disease-causing bacteria is continually increasing.18 One cause of great concern is resistance of Klebsiella to carbapenems, a class of last-resort antibiotics, which has risen in the U.S. from 1.6% to 10.4% from 2001 to 2011 and has spread rapidly in some hospitals.19,20 Tuberculosis is making a global comeback, and the Stop TB Partnership Global Plan estimates that between 2011 and 2015 about one million multidrug resistant TB patients will need to be identified and placed on treatment. Without early detection and proper treatment, multidrug resistant tuberculosis is very difficult and costly to treat.21,22 Methicillin-resistant Staphylococcus aureus (MRSA) is another example, and now accounts for greater than 50% of S. aureus infections,23 with over 450 000 people hospitalized for MRSA infections in the U.S. in 2009.24 Importantly, while most attention was initially focused on hospitals, it is becoming clear that a much larger scope is needed to fully encompass the sources and pathways by which antibiotic resistance spreads. For example, since the mid-1990s, MRSA has exploded in populations lacking risk factors associated with hospitals.25 A Texas study indicated a doubling in community-acquired MRSA cases among children from 2001 to 2009.26 The critical and worsening nature of the antibiotic resistance problem was recognized at the recent meeting of G8 science ministers, where it was characterized as “a major health security challenge in the 21st Century”.27 The G8 consensus statement indicated the need to combat misuse in humans, agriculture, and aquaculture and to better understand the origin, spread, evolution, and development of resistance in microorganisms. 6



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al.66 saw that even WWTP effluent treated by media filtration still resulted in elevated levels of ARGs in the Duluth Harbor of Lake Superior. In addition to aqueous effluent, WWTPs also produce biosolids, which are often applied to land as a fertilizer. However, biosolids amendment to soil has been observed to elevate tetracycline and sulfonamide ARGs in soil.67 Importantly, the mass loading of ARGs to the environment via biosolids is about 1000× higher than via aqueous WWTP effluent, suggesting that biosolids may potentially be more important as a source of resistance to the environment.68 A major research question that remains is whether direct inputs of ARGs or selective agents (e.g, antibiotics or metals) are primary drivers of elevated ARGs in impacted environments.62 ARGs are released into the environment along with coselective agents, such as antibiotics, and it is not clear to what extent antibiotics continue to exert selection pressure along transport pathways, versus simply co-occurring as a result of cotransport. Importantly, antibiotics can sometimes continue to stimulate selection and horizontal gene transfer even at very low levels.69 Recent studies, including a modeling study of the Poudre River,70 suggest that heavy metals deserve as much attention as antibiotics as selective agents.71,72 NDM-1 genes were recently detected in wastewater, impacted surface water, and chlorinated drinking water in India.73,74 NDM-1 genes have recently spread to several pathogens, rendering them virtually untreatable with existing antibiotics, and have been detected now in several countries. Thus, there is good impetus to invest in research to understand the aquatic environment as a pathway for the spread of antibiotic resistance, the mechanisms at play, and implications for resistant infections in humans. This will likely require a wide range of interdisciplinary collaboration. For example, epidemiologists and environmental engineers could work together to more precisely identify sources of antibiotic resistance and also to determine which water system designs best minimize risk of spread of ARGs, while risk assessors could help identify reasonable end points. Similarly, hydrodynamic modelers and molecular biologists could combine forces to advance understanding of gene movement in the environment and to identify critical control points. In such ways, a holistic, interdisciplinary understanding of the mechanisms and pathways by which antibiotic resistance spreads in the environment can help to support development of mitigation strategies. Implications for Sustainable Water Systems. A recent review summarizes and documents the high levels of antibiotics, antibiotic resistant bacteria, and ARGs in agricultural waste and domestic wastewater effluents,75 yet little is known about effective treatment processes for their removal. This is critical to factor in as we rethink our infrastructure in terms of water conservation and reuse of “waste” streams. Two recent reviews specifically explore implications of irrigation of agricultural lands with recycled wastewater effluent on antibiotic resistance.75,76 Few studies have directly examined ARGs in recycled water or its impacts on the environment.77−80 Negreanu and colleagues78 compared four Israeli soils irrigated with treated wastewater versus freshwater and noted no effect on levels of representative ARGs corresponding to fluoroquinolones, tetracyclines, sulfonamides, macrolides, lincosamides, or streptogramin antibiotics. However, in a bench-scale study simulating repeated irrigation of soil slurries with wastewater effluent, elevated levels of the sul2 sulfonamide resistance genes were noted in soil slurries.77 Böckelmann and colleagues80 also noted that recharge of aquifers with reclaimed water can result

resistance mechanisms likely to have been acquired from soil bacteria, such as Streptomycetes,30 making these infections extremely difficult to treat. Recent application of new metagenomic DNA sequencing technologies comparing human and soil antibiotic resistance elements have found 100% matches in some cases, further crystallizing the conclusion that clinically important ARGs emerge from environmental sources.40 Thus, greater understanding of the environmental “resistome” is an important area of future research to enable strategies to limit the spread of antibiotic resistance from the environment to the clinic.41−43 Release of residual antibiotics from wastewater treatment plants (WWTPs), livestock operations, aquaculture, and industry is of particular concern as potential sources of selection pressure that elevates levels of resistance in native bacteria.36,37,42,44 Antibiotic Resistance in Wastewater Treatment Plants (WWTPs). WWTPs are of particular concern as potential hot spots for promoting the spread of antibiotic resistance. WWTPs receive sewage containing residual antibiotics that are either excreted by patients or dumped down the drain45,46 as well as corresponding antibiotic resistant bacteria, including human pathogens.47−49 While WWTP design has been mastered for the removal of solids, organic matter, and nutrients, they have not been intentionally designed for removal of antibiotics45,50 or ARGs.51 Existing literature suggests that the high growth rates and high microbial densities that are fundamental to conventional WWTP design, along with the presence of residual antibiotics, may represent the perfect storm for promoting horizontal transfer and multiantibiotic resistance among resident bacteria.33,52,53 One study noted selective increase in antibiotic resistant Acinetobacter,54 while another observed an increase in resistance among culturable heterotrophic bacteria to nine out of eleven antibiotics investigated.55 Of particular concern may be wastewaters heavily influenced by hospital waste.56 One recent study noted elevated levels of both antibiotic resistant bacteria and sul1 and sul2 ARGs in a hospital waste stream relative to the domestic waste stream received by a WWTP and that persisted in Lake Geneva in the vicinity of the WWTP effluent discharge.55 Another noted extendedspectrum β-lactamase resistant Klebsiella in hospital waste and that the existing hospital wastewater treatment system (an upflow anaerobic sludge blanket reactor) was inadequate for removal.57 How do WWTPs and Other Human Activities Influence Levels of Resistance in the Environment? It is now clear that human activities, including WWTPs, have a strong influence on the distribution of ARGs in the aquatic environment.42,58,59 Treated wastewater effluent still can contain a variety of antibiotic resistant bacteria and ARGs, including high levels of class 1 integrons,60 which are known to facilitate horizontal gene transfer. The Cache La-Poudre River in Colorado has been extensively studied as an idealized system for tracking anthropogenic influence, given its pristine origin and relatively zonated adjacent urban and agricultural landuse.61−64 Recently, a land-use characterization and general linear regression modeling approach was used to demonstrate a strong correlation (R2 = 0.92) between levels of sul1 ARGs in river sediment and water samples and upstream capacities of WWTPs and animal feeding operations normalized for their inverse distances to river sites.62 Numerous other studies indicate that WWTPs influence ARGs in impacted environments. Auerbach et al.65 noted evidence of lakes as a recipient of tetracycline resistance genes from WWTPs, while LaPara et 7



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wastewater treatment; however, results are mixed, with one study indicating negligible removal of ARGs92 and another reporting 1−3 log removal of tetracycline and sulfonamide ARGs.59 In the broader realm of water sustainability strategies, water conservation features provide an interesting example of potential unintended consequences. Low-flow taps might save water, but also trigger increased microbial growth as a result of increased stagnation, warmer temperatures, and overall shifts in water chemistry.93 Similarly, plumbing designs intended to save water and energy, such as lower water heater settings and recirculating hot water loops, can result in temperatures more amenable to pathogen growth and even demand greater water and energy in some scenarios.94 These examples illustrate the need for public health research to accelerate its pace to keep up with advances in water sustainability technologies. Such effects of water conservation systems on pathogens and overall microbial growth suggest that studies of their impact on antimicrobial resistance are also worthy of consideration. Key Knowledge Gaps and Research Needs. One major research direction that would be of value is epidemiology. Formal epidemiological studies are typically very challenging, costly, multiyear endeavors, thus, few have been conducted to evaluate evidence of recycled water as a source of microbial illness. The most detailed assessments have been carried out in Namibia, where direct potable reuse has been in place since 1968, and no evidence of increase in diarrheal illness or death has been observed among consumers.95−97 However, no study to date has evaluated recycled water, biosolids, or other sustainable water systems specifically with respect to their contribution to antimicrobial resistant disease. This is a challenging endeavor and similar studies attempting to document effects of banning subtherapeutic agricultural antibiotic use in Europe have met with confounds, such as international travel and imported meat and produce from countries with lax antibiotic policies.98 However, new molecular epidemiological approaches enabled by next generation sequencing may provide new insight in the relative contributions of various sources to antibiotic resistant diseases in humans. A recent metagenomic study of the guts of human populations from seven different countries with various antibiotic use practices suggested highest prevalence of ARGs corresponding to antibiotics used in agriculture and that have been in use the longest.99 However, the populations selected for this study were not ideal, many had inflammatory bowel disease or were from areas with high rates of international travel, bringing the larger conclusions into question. Nevertheless, the study provides a glimpse of the power that metagenomic approaches may provide in broadly tracking relative sources of antibiotic resistance. A metagenomic approach for tracking ARGs in WWTPs has recently been demonstrated and represents a valuable technique moving forward.100 Metagenomics will also empower understanding of the interface between the human microbiome, which has been shown to carry numerous ARGs within commensal bacteria, and environmental sources of ARGs.40 Risk assessment, especially quantitative microbial risk assessment (QMRA), is also an important tool to help judge relative probabilities of contracting illness from exposure to the various sources identified.101 Granted, antibiotic resistance would require significant modification to existing risk models. Scenarios of recycled water contributing to the global pool of antibiotic resistance and resulting in resistant infections are multistep and present branched pathways. For example,

in elevated ARGs, but that ultrafiltration and reverse osmosis appeared to be effective barriers. Another important factor governing impacts of reclaimed water may be soil type, similar to how some soils appear to be more susceptible to elevated ARGs following biosolids amendment.67 In the Negreanu study,78 the complexity of soil and established resistome were hypothesized to be major factors that may buffer the effects of inputs of ARGs and selective agents; though the authors are cautiously optimistic and call for further study. Regardless, it is a certainty that pathogens, antibiotic resistant bacteria, and ARGs exist in recycled water in some form. Given that drinking water is now cited as the primary source of waterborne disease outbreak in developed countries,81 due to establishment of opportunistic pathogens in pipe and water fixture biofilms,83 it stands to reason that recycled water distribution systems are also vulnerable to colonization by pathogens. This has proven to be the case in a survey of Cryptosporidium and Giardia in U.S. recycled water distribution systems, the latter exceeded acceptable risks according to models assuming incidental ingestion.84 Of particular concern is detection of genetic markers for Legionella pneumophila, the causative agent of a severe and sometimes deadly form of pneumonia, in recycled water.77 vanA ARGs, which encode resistance to the last resort human antibiotic vancomycin, were also widely detected at the point of use in one reclaimed water system. Culturable vancomycin-resistant Enterococci were also recently found in a survey of U.S. WWTP (prechlorinated) effluents intended for reuse.85 Thus, further research is warranted considerate of exposure routes such as aerosol inhalation, skin contact, incidental ingestion on recreational fields, and of carriage of pathogens and ARGs on irrigated crops. Research aimed at better understanding changes in quality of recycled water as it travels through a distribution system would also be of value. A recent study of two recycled water distribution systems in the U.S. noted distinct water quality at the point-of-use versus the water exiting the treatment facility,77 likely due to regrowth in the pipes. Regrowth is a phenomenon commonly observed in drinking water distribution systems.82,86,87 Studies comparing the relative occurrence of ARGs in recycled versus drinking water distribution systems would be informative, given that drinking water quality is commonly used as a benchmark for recycled water quality,13,88 though typically only gross water quality parameters (e.g., TOC, E. coli) concordant with existing regulations are compared. Surveys of drinking water have detected ARGs;86,89 although reported levels appear to be lower than in recycled water.77 Effects of different disinfectant strategies are also of interest, as they may offer one approach for minimizing risk of spreading ARGs from recycled water. However, chlorine and chloramines have been associated with increased proportions of antibiotic resistant bacteria and ARGs.86,90,91 A recent metagenomic study further suggested that chlorination can act to concentrate various plasmids, insertion sequences, and integrons involved in horizontal transfer of ARGs.90 Thus, disinfection as the sole control strategy could impart a false sense of security. Irrigation with recycled water provides just one example of potential strategies to promote water sustainability. Currently there is a burst of promising technological innovation underway considerate of numerous avenues to conserve and reuse water,8 yet that clearly present knowledge gaps with respect to public health. Wetlands have been gaining attention for decentralized 8



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Figure 1. Potential for water and nutrient reclamation approaches to contribute to the spread of antibiotic resistance. Red boxes indicate key research questions that should be addressed to advance risk assessment and risk management. ARGs = antibiotic resistance genes; ARBs = antibiotic resistant bacteria; DS = distribution system.

risk management options, while incorporating information from QMRA as it becomes available. Such a precautionary approach was advocated in a recent review article mapping out potential strategies in the realms of agriculture, aquaculture, industrial wastewater treatment, domestic wastewater treatment, and policy.37 Research is needed to identify mitigation strategies that are low-cost, work with existing infrastructure or upgrade plans, and offer synergistic benefits, such as water treatment, nutrient recycling, and watershed protection (e.g., sediment and nutrient management). Disinfection is commonly considered to be a critical barrier for pathogen control in sustainable water systems, yet disinfection alone is unlikely to be able to fully address antibiotic resistance concerns. UV theoretically could be beneficial in that it damages DNA; however, studies of fieldscale facilities indicate little effect on ARGs.59,65,107 One labscale study indicated that approximately double the typical UV dose applied to WWTP effluents was required to destroy vanA, mecA, tet(A), and ampC ARGs.108 Advanced oxidation processes that combine UV with other chemicals or employ ozone to produce hydroxyl radicals and maximize breakdown of organic matter, including antibiotics and ARGs, may be more effective for WWTP effluent,34,109 especially when intended for reuse. Chlorination of wastewater effluent has been observed to diminish the culturability of MRSA47 and vancomycin-resistant Enterococci,85 though the possibility of viable but nonculturable states following disinfection shock cannot be ruled out. Chlorine also varies in efficacy for destruction of antibiotics110 and ARGs,34 and penetration of pipe biofilms can vary as a function of pipe materials, corrosion conditions, and water chemistry.111 Critical to be aware of is that no disinfection strategy can ever result in sterile water at the point-of-use. Thus it has been suggested recently in the context of potable water systems that a more realistic goal may be to establish a healthy “probiotic” microbiome that excludes pathogens,87,112 or, in this case, antibiotic resistance. This could also potentially avoid drawbacks of linkages between disinfectants and antibiotic resistance.86,90,91 Still, other work is underway focused on process aspects of WWTP operation in order to minimize effluent ARGs. Sludge digestion,113−115 especially thermophilic digestion114,115 appears to show some promise, potentially by shifting the microbial ecology of hosts. Interestingly, Rysz et al.116 recently

elevated antibiotic resistant pathogens (e.g., MRSA) may present a direct risk of exposure, while resistant nonpathogens present the risk of sharing ARGs with pathogens. Antibiotics (and metals) themselves can also contribute to risk by enriching resistant bacteria and increasing probability of horizontal gene transfer to pathogens. Further, even the naked, extracellular DNA itself can carry some risk because of the potential to be taken up by pathogens via transformation.34 Ashbolt et al.102 recently developed a comprehensive framework for a human health risk assessment tailored to environmental sources of antibiotic resistant bacteria and ARGs. They identified horizontal gene transfer rates and the role of antibiotics and metals as key unknowns worthy of further research. Concern was also expressed regarding the need to consider low probability, but high impact “one-timeevents,” such as the emergence of NDM-1.102,103 Thus, there is sufficient evidence to suspect that water reuse strategies may contribute at some level to antibiotic resistant infections in humans. The question is if the risk can be quantified and verified to be truly negligible relative to other sources. Another challenge is the rapid advancement of molecular tools for detecting and quantifying pathogens and ARGs in the environment, whereas regulations are focused mainly on fecal indicator bacteria. This is a serious problem as it is now clear that the fecal indicator paradigm is especially weak in the context of water reuse,104 yet they form the basis for existing water reuse guidelines and regulations.88 Molecular approaches are advantageous mainly because they circumvent culture-bias and provide highly sensitive, specific, and repeatable detection. In particular, new metagenomic approaches are beginning to provide broad-sweeping, high resolution information, such as has been observed in their application to biosolids, revealing a wide array of DNA from viral and bacterial pathogens that had not been detected previously.105,106 However, research is needed to better link molecular data with epidemiological outcomes in order for molecular data to be successfully incorporated into current regulatory frameworks. Including molecular data in monitoring and regulatory guidelines holds special importance for antibiotic resistance, given that it is largely driven by the spread of ARGs. Given the gravity of the antimicrobial resistance problem and that epidemiological studies and risk model development will be challenging, a rational approach may be to move ahead with 9



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guidance document for recycled water88 is an important first step, but further action is needed. Any actions that might be taken will boil down to prioritizing financial and other resources. Sustainable water systems, such as purple pipe infrastructure and advanced water treatment systems, will be a significant financial investment. To effectively prioritize, it is imperative to support research to address critical knowledge gaps regarding sustainable water systems and antibiotic resistance so that informed decisions can be made. Further, engagement in risk communication with the public as active participants is essential,120,125 especially in a matter of such fundamental importance to our modern standard of living. It may well be that we have no choice but to adopt sustainable water systems; however, such endeavors should be taken with open eyes and appropriate investment in research, policy, and engagement with the public, in order to continually assess their performance and maximize their chance of success.

conducted proof-of-concept experiments indicating that anaerobic conditions may sometimes stimulate bacteria to lose ARGs in efforts to conserve metabolism. Membranes also appear promising for removal of ARGs, and may provide better removal than would be estimated based on molecular cutoff, which could provide energy savings.117 Similarly, a membrane bioreactor applied for hot spot removal of pharmaceuticals from hospital waste showed promise.56 Low-tech approaches, such as air-drying biosolids prior to land application, may also offer benefits.118 Moving Forward. Figure 1 illustrates several aspects of water and nutrient reclamation that have the potential to contribute to the spread of antibiotic resistance and highlights key research questions. Clearly, sustainable water and antibiotic resistance represent grand challenges that must be addressed in this century. Continued investment and innovation in research, technology, and policy is greatly needed,6 particularly where the two challenges intersect. Ideally, synergies should be sought that effectively and efficiently advance both causes. The value of efforts by individual engineers to design sustainable water systems to the highest standard based on available information should also not be underestimated, much as individual doctors do their part with prudent antibiotic prescribing practices. In any case, we would be wise to also keep our eyes open to unintended consequences. History provides many examples of how innovation can have a down side. For example, the gasoline additive, methyl tert-butyl ether was heralded as the answer to the Clean Air Act Amendments of 1990, yet its high water solubility resulted in rapid contamination of groundwater supplies.119 In the case of sustainable water systems, concerns are already emerging regarding the triggering of microbial growth by water conservation features in green buildings. While it is impossible to predict all potential drawbacks, it is advisable to support research that strives to keep pace with public health concerns, especially with such high stakes problems as water sustainability and antibiotic resistance. A study of historical risk trade-offs (creating new risks, while solving existing ones) indicated that in most cases, better alternatives were known and available, but were overlooked at the time.120 The realm of nanoscience may offer a model that could be followed in addressing risks associated with new technologies. Like sustainable water systems, the nanotechnology boom offers many benefits, but also unknowns. Thus, the National Science Foundation has devoted a program area to Environmental Health & Safety of Nanomaterials and also supports the Center for Environmental Implications of Nanotechnology.121,122 Recently, the U.S. Food & Drug Administration and the U.S. Department of Agriculture have taken initiatives indicating commitment to addressing concerns about antibiotic use in agriculture,123 while the National Institutes for Occupational Safety and Health has funded a small grant related to antibiotic resistance and WWTPs.47,85 Similarly, leadership is greatly needed from the U.S. Environmental Protection Agency (EPA), as well as the National Institutes of Health, to address concerns regarding environmental sources and pathways of antibiotic resistance and to support research on risk assessment and risk management. At present, individual communities in the U.S. are stepping up to take on questions relating to antibiotic resistance and water reuse on their own,124 when clearly it is a problem of epic proportions that demands involvement at the national and even international level. Acknowledgment that antibiotic resistance is an important knowledge gap in the EPA’s recent

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AUTHOR INFORMATION

Corresponding Author

*Phone: (540) 231-3980; fax: (540) 231-7916; e-mail: [email protected]. Notes

The authors declare no competing financial interest. Biography Dr. Amy Pruden is a Professor in the Charles Edward Via, Jr. Department of Civil and Environmental Engineering at Virginia Tech. Her primary interests are focused on characterizing and managing effects of the built environment on emerging and opportunistic pathogens, particularly antibiotic resistant bacteria and their antibiotic resistance genes. Dr. Pruden serves as the Director of Strategic Planning for the Virginia Tech Institute for Critical Technology and Applied Science Water Sustainability Thrust.

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ACKNOWLEDGMENTS Dr. Pruden’s research is supported by The Alfred P. Sloan Foundation Microbiology of the Built Environment program, The National Science Foundation awards 1336650, 1402651, and 1033498, and the Virginia Tech Institute for Critical Technology and Applied Science. The perspectives presented do not represent those of the sponsors.

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REFERENCES

(1) U.S. Centers for Disease Control (CDC). A century of U.S. Water chlorination and treatment: One of the ten greatest public health achievements of the 20th century. Morb. Mortal. Wkly. Rep. 1999, 48 (29), 621−9. (2) McGuire, M. J. Eight revolutions in the history of US drinking water disinfection. J. Am. Water Works Assoc. 2006, 98 (3), 123−149. (3) United Nations (UN). World Water Day: Facts and Figures. http://www.unwater.org/water-cooperation-2013/water-cooperation/ facts-and-figures/ (accessed August 30, 2013). (4) National Academy of Engineering (NAE). Grand challenges for engineering http://www.engineeringchallenges.org/ (accessed August 31, 2013). (5) American Society of Civil Engineers (ASCE). Report card for America’s infrastructure, 2013. http://www.infrastructurereportcard. org/ (accessed on August 31, 2013). (6) Kiparsky, M.; Sedlak, D. L.; Thompson, B. H., Jr.; Truffer, B. The innovation deficit in urban water: The need for an integrated perspective on institutions, organizations, and technology. Environ. Eng. Sci. 2013, 30 (8), 395−408. (7) ReNUWit. Re-inventing the nation’s urban water infrastructure. http://urbanwatererc.org/welcome (accessed August 31, 2013).

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