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A brief multi-disciplinary review on antimicrobial resistance in medicine and its linkage to the global environmental microbiota.

Cantas, L.; Shah, Syed Q A; Cavaco, Lina; Manaia, C. M.; Walsh, F.; Popowska, M.; Garelick, H.; Bürgmann, H.; Sørum, H

Published in: Frontiers in Microbiology

Link to article, DOI: 10.3389/fmicb.2013.00096

Publication date: 2013

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Citation (APA): Cantas, L., Shah, S. Q. A., Cavaco, L., Manaia, C. M., Walsh, F., Popowska, M., ... Sørum, H. (2013). A brief multi-disciplinary review on antimicrobial resistance in medicine and its linkage to the global environmental microbiota. Frontiers in Microbiology, 4, 96. DOI: 10.3389/fmicb.2013.00096

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REVIEW ARTICLE published: 14 May 2013 doi: 10.3389/fmicb.2013.00096 A brief multi-disciplinary review on antimicrobial resistance in medicine and its linkage to the global environmental microbiota

L. Cantas 1*, Syed Q. A. Shah 1, L. M. Cavaco 2, C. M. Manaia 3, F. Wa l s h 4, M. Popowska 5, H. Garelick 6, H. Bürgmann 7 and H. Sørum 1

1 Department of Food Safety and Infection Biology, Norwegian School of Veterinary Science, Oslo, Norway 2 Research Group for Microbial Genomics and Antimicrobial Resistance, National Food Institute, Technical University of Denmark, Kgs Lyngby, Denmark 3 Centro de Biotecnologia e Química Fina, Escola Superior de Biotecnologia, Centro Regional do Porto da Universidade Católica Portuguesa, Rua Dr. António Bernardino Almeida, Porto, Portugal 4 Bacteriology, Agroscope Changins-Wädenswil, Wädenswil, Switzerland 5 Department of Applied Microbiology, Institute of Microbiology, University of Warsaw, Warsaw, Poland 6 Department of Natural Sciences, Middlesex University, London, UK 7 Department of Surface Waters - Research and Management, Eawag, Swiss Federal Institute for Aquatic Science and Technology, Kastanienbaum, Switzerland

Edited by: The discovery and introduction of antimicrobial agents to clinical medicine was Stefania Stefani, University one of the greatest medical triumphs of the 20th century that revolutionized the of Catania, Italy treatment of bacterial infections. However, the gradual emergence of populations of Reviewed by: antimicrobial-resistant pathogenic bacteria resulting from use, misuse, and abuse of Aixin Yan, The University of Hong Kong, Hong Kong antimicrobials has today become a major global health concern. Antimicrobial resistance Ingeborg M. Van Geijlswijk, (AMR) genes have been suggested to originate from environmental bacteria, as clinically Utrecht University, Netherlands relevant resistance genes have been detected on the chromosome of environmental *Correspondence: bacteria. As only a few new antimicrobials have been developed in the last decade, the L. Cantas, Department of Food further evolution of resistance poses a serious threat to public health. Urgent measures Safety and Infection Biology, Section for Microbiology, Immunology and are required not only to minimize the use of antimicrobials for prophylactic and therapeutic Parasitology, Norwegian School of purposes but also to look for alternative strategies for the control of bacterial infections. Veterinary Science, PO Box 8146 This review examines the global picture of antimicrobial resistance, factors that favor its Dep. NO-0033 Oslo, Norway. spread, strategies, and limitations for its control and the need for continuous training of e-mail: [email protected] all stake-holders i.e., medical, veterinary, public health, and other relevant professionals as well as human consumers, in the appropriate use of antimicrobial drugs.

Keywords: antimicrobial resistance, human and veterinary medicine, environment, soil, wastewater, resistance genes

BACKGROUND antimicrobials have been extremely important corner stones of Arguably one of the greatest examples of serendipity in science modern medicine since the last half of the previous century. was the discovery of natural antimicrobials between Alexander Antimicrobial drugs have saved millions of people from life- Fleming and Ernest Duchesne. Although Fleming generally holds threatening bacterial infections and eased patients’ suffering. the reputation of the discovery of penicillin in 1928, a French Today, the treatment of bacterial infections is once again becom- medical student, Ernest Duchesne (1874–1912), originally dis- ing increasingly complicated because microorganisms are devel- covered the antimicrobial properties of Penicillium earlier, in oping resistance to antimicrobial agents worldwide (Pouillard, 1896. He observed Arab stable boys that kept their saddles in 2002; Levy and Marshall, 2004; Alanis, 2005; Pallett and Hand, a dark and damp room to encourage mold to grow on them, 2010). which they said helped heal saddle sores. Curious, Duchesne A causal relationship has been demonstrated between the prepared a suspension from the mold and injected it into dis- increased use of antimicrobials in both human and veteri- eased guinea pigs along with a lethal dose of virulent typhoid nary medicine, the greater movement of people, as well as bacilli and still all animals remained healthy. His work, how- domestic and wild animals, the increased industrialization ever, was ignored because of his young age and unknown status and the increased prevalence of antimicrobial-resistant bacte- (Pouillard, 2002). In a way, with the success of the natural antibi- ria (Holmberg et al., 1987; Cheng et al., 2012). Antimicrobial otic penicillin and the synthetic antimicrobial sulfonamides in resistance (AMR) was identified in pathogenic bacteria concur- the first half of the 20th century, the modern antimicrobial rev- rently with the development of the first commercial antibiotic olution began. Since then, new natural antimicrobial compounds produced by microorganisms, penicillin (Abraham and Chain, were discovered and many semi-synthetic and synthetic antimi- 1940). Although the first concerns about drug-resistant bacteria crobial drugs were created to combat bacterial infections. Thus, appeared in hospitals, where most antimicrobials were being used

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(Levy, 1998), the importance of AMR was already recognized in different ecological locations (Figure 1), aiming to unify the many 1969 both in humans and veterinary medicine as stated in the important aspects of this problem. Finally we advocate the need Swan Report (Swann, 1969). Further research showed that the for teaching and continuous training of all stake-holders (i.e., origin and spread of AMR is, in fact, a very complex problem. medical, veterinary, public health, and other relevant profession- Hence, there cannot be a single solution for minimizing AMR; als) as well as human consumers of antimicrobial drugs, in the rather a coordinated multi-disciplinary approach will be required appropriate use of antimicrobials. toaddressthisissue(Serrano, 2005; Smith et al., 2009). We must also recognize that wherever antimicrobials are used, AMR will THE HUMAN MEDICINE AND ANTIMICROBIAL RESISTANCE inevitably follow. EMERGENCE OF ANTIMICROBIAL RESISTANCE AND ITS COST The purpose of this review is to highlight the problem of In human medicine AMR is as old as the clinical usage of antimi- resistance to antimicrobials with its consequences, including how crobial compounds. Antimicrobial-resistant pathogens have been the spread of AMR could be limited. We highlight how the observed soon after the introduction of new drugs in hos- numerous useful applications of antimicrobials led to AMR in pitals where antimicrobials are intensively used (Levy, 1998).

FIGURE 1 | Schematic representation of the complexity of the potential genetic links between the microbiotas of the various reservoirs are showed bacterial genetic web of communication between the various by arrows. Thick arrows show major selective pressures for selection of microbiotas that are impacted by the use of antibiotics in a wide antibiotic resistance genes, thin arrows show the significant directions of context. The reservoirs where antimicrobials are applied are also suggested gene flow. Future research may document unique arrows that must be as “hot spots” for horizontal gene transfer. The potentially most important integrated in the web drawn.

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Consequently, AMR in the context of human medicine has dom- of defense against the non-Enterobacteriaceae pathogens, such inated the literature for a long time (Figure 2). Over the years, as Pseudomonas aeruginosa and Acinetobacter baumannii (Brown and continuing into the present, almost every known bacterial et al., 1998). However, since the first description of the blaOXA pathogen and numerous human commensals have developed genes, there has been a worldwide increase in the dissemi- resistance to one or more antimicrobials in clinical use (Table 1). nation of new resistance determinants conferring carbapenem Extended-spectrum β-lactamases (ESBL) are the ones most often resistance. For example, the Klebsiella pneumoniae carbapene- encountered in the hospital (intensive care) setting. Methicillin- mase (KPC) type enzymes, Verona integron-encoded metallo-β- resistant Staphylococcus aureus (MRSA) and vancomycin-resistant lactamase (VIM), Imipenemase Metallo-β-lactamase (IMP) and enterococci (VRE) have also been found to have a signifi- New Delhi metallo-β-lactamase (NDM), and the OXA-48 type cant nosocomial ecology (Otter and French, 2010). In addition, of enzymes have been isolated from a number of bacterial gen- ESBL positive bacteria and MRSA infections are increasingly era irrespective of their geographical distribution (Kumarasamy detected in the community. Furthermore, the increase in flu- et al., 2010; Walsh et al., 2011). Carbapenemase resistance mech- oroquinolone resistance due to target-site mutations and the anisms are found among Escherichia coli and Klebsiella isolates in worldwide emergence of plasmid-mediated quinolone resistance hospital settings, and to a lesser extent also in the community, genes may represent a major challenge in future given the crit- thus healthy human carriers begin to be a concern (Nordmann ical importance of this antimicrobial therapy (Cattoir et al., et al., 2012). Furthermore, carbapenemase-producing organisms 2007; Strahilevitz et al., 2009). Carbapenems are the last line have also been isolated from farm animals (Fischer et al., 2012).

FIGURE 2 | The change in number of antimicrobial resistance related Hospital, (hospital∗ OR patient∗ OR clinic∗); Animal, (animal∗ OR veterinary∗ published research papers in different subdisciplines and covering OR livestock∗ OR pig∗ OR cow∗ OR chicken∗ OR poultry); Wastewater, different environments. The data for the graphs were obtained by searching (wastewate∗ OR sewage); Natural water, (wate∗ OR lake OR river OR ocean the ISI web of science for publications with titles matching the query terms OR sea); Soil, (soil∗ OR sediment∗ OR rhizosphere∗ ) (Source: http://apps. (antibioti∗ OR antimicro∗ ) AND resistan∗ AND the following specific terms: isiknowledge.com/). The search was performed on 06/03/2013.

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Table 1 | Antimicrobial resistance detection in some important pathogens soon after arrival of the “magic bullets” into the market.

Year Bacteria Drug resistance Comments References

1948 Staphylococcus aureus Penicillin In British civilian hospitals soon Barber and after the introduction of penicillin Rozwadowska-Dowzenko, 1948 1948 Mycobacterium tuberculosis Streptomycin In the community soon after the Crofton and Mitchison, 1948 clinical usage of this antimicrobial 1950’s–1960’s Escherichia coli, Shigella spp., and Multiple drugs Watanabe, 1963; Olarte, 1983; Salmonella enterica Levy, 2001 1960’s VRE- Enterococcus spp. Multiple drugs Levy and Marshall, 2004; ESBL- E. cloacae, K. pneumoniae, E. coli, Nordmann et al., 2011 MRSA, QR- Enterobacteriaceae MDR- Acinetobacter baumannii, Pseudomonas aeruginosa

VRE, Vancomycin-Resistant Enterococcus; ESBL, Extended-spectrum β-lactamase; MRSA, methicillin/oxacillin-resistant Staphylococcus aureus; QR , Quinolone resistant; MDR, Multi-drug resistant.

HUMAN MOBILITY—THE DIRECT AND INDIRECT IMPACT ON HUMAN human diseases from the mid-1940’s (Gustafson and Bowen, PATHOGENS 1997; McEwen, 2006). Even though some drugs are exclusively The increasing cross-border and cross-continental movements of designed for veterinary use, most belong to the same antimicro- people has a major impact on the spread of multi-resistant bac- bial classes as those used in human medicine with identical or very teria (Linton et al., 1972; Arya and Agarwal, 2011; Cheng et al., similar structures (Swann, 1969; Heuer et al., 2009). 2012). The emergence and global spread of the international clone Annually, large quantities of drugs are administered to ani- 1 of penicillin-resistant Streptococcus pneumoniae (Klugman, mals in the agricultural sector worldwide to secure a sufficient 2002) and the recently occurring New Delhi Metallo-β-lactamase amount of food (meat, eggs, and dairy products) to feed a rapidly (blaNDM-1) producing Enterobacteriaceae,whichinactivatesall growing world human population (Vazquez-Moreno et al., β-lactam antimicrobials, including carbapenems, are good exam- 1990; Roura et al., 1992; Rassow and Schaper, 1996). As data ples. The blaNDM-1 appears to have originated in the Indian sub- collection on antimicrobial use in animals was not harmonized continent and subsequently could be found in North America, the to provide reliable and comparable information, and following a United Kingdom, and other European countries by the movement request from the European Commission the European Medicines of people (Arya and Agarwal, 2011; Walsh et al., 2011). Agency (EMA), the European Surveillance of Antimicrobial The AMR problem remains a growing public health concern Consumption (ESVAC) programme has been created. The because infections caused by resistant bacteria are increasingly ESVAC programme is responsible for collecting, analyzing, and difficult and expensive to treat. The consequences of this problem reporting sales data from European countries and developing are: longer hospital stay, longer time off work, reduced quality of an organized approach for the collection and reporting of data life, greater likelihood of death due to inadequate or delayed treat- on antimicrobial use for animals including annual reporting ment, increases in private insurance coverage and an additional from EU member states (www.ema.europa.eu/ema/index. costs for hospitals when hospital-acquired infections occur in jsp?curl=pages/regulation/document_listing/document_listing_ addition to the increased overall healthcare expenditure (Roberts 000302.jsp). During 2007, in 10 European countries the sale of et al., 2009; Filice et al., 2010; Korczak and Schöffmann, 2010; antimicrobial drugs for therapeutic use as veterinary medicine Wilke, 2010). Thus, in order to calculate the full economic bur- varied from 18 to 188 mg/kg biomass (Grave et al., 2010). den of AMR we have to consider the burden of not having The administration of antimicrobials to food producing antimicrobial treatment options at all, which in the extreme case animals can have other purposes than treatment, such as: would probably cause a breakdown of the entire modern medi- growth promotion (although now totally banned in Europe and cal system (Alanis, 2005; Falagas and Bliziotis, 2007; Pratt, 2010). quinolones for the poultry industry are banned in the USA), pro- In short, everyone will be at risk when antimicrobials become phylaxis, and -metaphylaxis (Anthony et al., 2001; Anderson et al., ineffective and the threat is greatest for young children, the 2003; Casewell et al., 2003; Cabello, 2006). Approximately 70% of elderly, and immune-compromised individuals, such as cancer all the antimicrobials administered in animal farming are used for patients undergoing chemotherapy and organ transplant patients non-therapeutic purposes (Roe and Pillai, 2003). (Tablan et al., 2004). In the European Union (EU) the use of avoparcin was banned in 1997. Furthermore spiramycin, tylosin, and virginiamycin for THE VETERINARY MEDICINE AND AGRICULTURE SECTOR growth promotion were banned from use in 1998. All other CONSUMPTION AND REGULATION OF ANTIMICROBIAL USE IN growth promoters in the feed of food-producing animals were ANIMALS banned in the EU—countries from January 1, 2006 (http:// The antimicrobials, used in veterinary medicine were intro- europa.eu). Data from Denmark showed that animals could be duced soon after they became available for the treatment of produced at a large scale without the use of growth promoters,

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without adversely affecting the production (Aarestrup et al., 2001; underlying allergic reactions result in an increasing use of semi- Aarestrup, 2005; Hammerum et al., 2007). In the United States synthetic penicillins because of the ineffectiveness of penicillin of America, politicians are discussing the introduction of a sim- against penicillinase producing Staphylococcus pseudintermedius ilar ban on the use of antimicrobials in animal husbandry for (Yoon et al., 2010). Moreover, emerging methicillin-resistant growth promotion (http://www.govtrack.us/congress/bills/109/ Staphylococcus pseudintermedius (MRSP), methicillin-resistant s742). Despite these bans, in some parts of the world, medically Staphylococcus aureus (MRSA), and ESBL producing E. coli dis- important antibiotics are still routinely fed to livestock prophy- playing multidrug resistance has led to increased concern related lactically to increase profits and to ward-off potential bacterial to AMR in companion animal practice (Bannoehr et al., 2007; infections in the stressed and crowded livestock and aquaculture Wieler et al., 2011). Increased antimicrobial resistance devel- environments (Cabello, 2006; Smith et al., 2009; Ndi and Barton, opment and spread in companion animals due to irrational 2012). Because stress lowers the function of the immune system antimicrobial usage, especially overprescribed broad spectrum in animals, antimicrobials are seen as especially useful in intensive antimicrobials without precise diagnostics, inevitably cause (1) confinements of animals (Halverson, 2000). The non-therapeutic animal health problem (increased mortality and morbidity), (2) use of antimicrobials involves low-level exposure through feed economical problem to the owner (more visits-therapies and over long periods—an optimal way in which to enrich resistant prolonged hospitalization), (3) economical problem to the vet- bacterial populations (Sharma et al., 2008; Kohanski et al., 2010; erinarian (possible loss of customers and high costs for hospital Alexander et al., 2011; Gullberg et al., 2011). decontamination), and (4) human health problems (risks of Various monitoring programs around the world have started zoonotic transmission). Because of this threat small animal veteri- monitoring AMR and a range of research activities and inter- narians should prescribe broad spectrum antimicrobials after cul- ventions have shown that antimicrobial usage has a large effect turing and educate pet owners to handle infected-antimicrobial upon selection of AMR in animal production. A rapid and par- treated animals with precaution. allel decrease in resistant Enterococcus faecium from pig and However, emergences of resistance toward antimicrobials poultry has been reported in Denmark after the ban of growth which are critically important for human therapy are the most promoters in livestock (Aarestrup et al., 2001). The Norwegian worrisome. These include the recent emergence of ESBL pro- aquaculture industry has produced over one million tons of ducing and carbapenemase positive Enterobacteriaceae bacteria in farmed fish (http://www.ssb.no/fiskeoppdrett_en/)byusingonly animal production (Horton et al., 2011), the emergence of farm 649 kg of antimicrobials in 2011 (NORM/NORM-VET, 2011). associated MRSA ST398 (the main pig associated clone) (Cuny It is evident from the Danish integrated AMR monitoring and et al., 2010; Kluytmans, 2010; Weese, 2010) and of plasmid- research program (DANMAP) and NORM/NORM-VET Report mediated quinolone resistance in animal isolates and food prod- (NORM/NORM-VET, 2011) that reduction of antimicrobial ucts (Poirel et al., 2005; Nordmann et al., 2011). Unfortunately, usage with strict policies may still be the safest way to control the there are several examples in the literature that show that these development and spread of AMR in this sector in the future. are already widespread in Europe and other parts of the world and have a large impact on human health (Angulo et al., 2004; ANTIMICROBIAL-RESISTANT BACTERIA IN COMPANION ANIMALS Heuer et al., 2009; Forsberg et al., 2012). AND ANIMAL HUSBANDRY Aquaculture (fish, shellfish, and shrimp farming industries) The use of antimicrobials in animal husbandry has for many has developed rapidly in the last decade and has become an years actively selected for bacteria which possess genes capable important food source (FAO, 2010). Fish pathogenic bacteria of conferring AMR (Bastianello et al., 1995; Sundin et al., 1995). often produce devastating infections in fish farms where dense Consequently, this aspect has also seen much attention in the populations of fish are intensively reared. Although modern literature (Figure 2). Despite large differences in methodology, fish farming relies increasingly on vaccination and improved the results of most relevant scientific studies demonstrate that management to avoid infections (Markestad and Grave, 1997; not long after the introduction of antimicrobials in veterinary Midtlyng et al., 2011), still many bacterial infections in fish practice, resistance in pathogenic bacteria, and/or the fecal flora are regularly treated with antimicrobials in medicated feed or was observed (Caprioli et al., 2000; Jean-Louis et al., 2000). In by bath immersion. The most widely used drugs are fluoro- particular an increased emergence of pathogenic bacteria resis- quinolones, florfenicol, oxytetracyclines amoxicillin and sulfon- tant to antimicrobials has occurred in members of the genera amides (Cabello, 2006; Gräslund et al., 2003; Holmström et al., Salmonella, Campylobacter, Listeria, Staphylococcus, Enterococcus, 2003; Primavera, 2006; Soonthornchaikul and Garelick, 2009). and Escherichia coli. Some resistant strains of these genera are By now, most of the fish pathogenic bacteria from fish farms propagated primarily among animals but can subsequently infect with a history of infections have developed AMR (Colquhoun people as zoonotic agents (Levy, 1984; Corpet, 1988; Marshall et al., 2007; Lie, 2008; Sørum, 2008; Farmed Fish Health Report, et al., 1990; Giguêre et al., 2007). 2010; Shah et al., 2012a). Furthermore, in some areas of the In veterinary medicine the use of antimicrobials in compan- world, particularly in South-East Asia, integrated farming is a ion animals such as pets and horses is restricted to therapeutic common practice where organic wastes from poultry and live- purposes only. Companion animals are increasingly treated as stock are widely used in manuring the fish farms (Hoa et al., family members, in the context of applying advanced antimi- 2011; Shah et al., 2012b). It has been reported that antimicrobial crobial treatments to their infectious diseases. For instance, skin residues present in the poultry and livestock waste has pro- infections caused by staphylococci in dogs with or without vided sufficient selection pressure for the selection of AMR genes,

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increasing the complexity of transmission of bacteria, and resis- harbor-resistant bacteria (Zhang et al., 2009; Glad et al., 2010; tances between the livestock and aquatic environment (Petersen Lang et al., 2010). et al., 2002; Agersø and Petersen, 2007; Hoa et al., 2011; Shah et al., 2012b). ANTIMICROBIAL RESISTANCE IN THE ENVIRONMENT AMR has been detected in different aquatic environments MICROBIAL COMMUNITIES IN SOIL AND ANTIMICROBIAL and some resistance determinants have been found to originate RESISTANCE from aquatic bacteria. A good example is the recently emerging Research data shows that in diverse soils from various regions of plasmid-mediated quinolone resistance determinants from the the world, there is a wide dispersion of AMR. One explanation qnr family (Ash et al., 2002; Picao et al., 2008)andCTX-Mfrom for this phenomenon is the existence of antimicrobial produc- aquatic Kluyvera spp. (Decousser et al., 2001; Rodriguez et al., ing bacteria in soil. The Actinomycetes, which are common 2004; Ma et al., 2012). In addition, epidemiological and molecular soil bacteria (Streptomyces, Micromonospora, Saccharopolyspora data indicate that some fish pathogens such as Aeromonas are able genus), synthesize over half of all known most clinically rele- to transmit and share AMR determinants with bacteria isolated vant antimicrobials e.g., tetracycline, gentamicin, erythromycin, from humans such as E. coli (Rhodes et al., 2000; Sørum, 2006). streptomycin, vancomycin, and amphotericin. Bacteria of the Similarly, the fish pathogen Yersinia ruckeri have been reported to genus Bacillus also produce antibiotics, e.g., Bacillus brevis which share AMR plasmid and AMR genes with the bacterium causing producing gramicidin (Baltz, 2007). These antimicrobials now human plague (Welch et al., 2007). also reach the environment from human and animal therapeu- tics, through manure, sewage, agriculture, etc. Many retrospective ANTIMICROBIAL USE IN PLANT AGRICULTURE and prospective studies have been performed to assess the emer- Streptomycin and oxytetracycline are routinely used for the pro- gence and selection of AMR in environmental bacteria. The phylaxis of fire blight disease (causative agent Erwinia amylovora) environment is eventually the largest and most ancient reservoir in apple and pear orchards. Streptomycin use is strictly controlled of potential AMR, constituting the environmental “resistome” within the EU and is only authorized for use on a yearly basis. (Aminov and Mackie, 2007; Allen et al., 2010; D’Costa et al., However, streptomycin use in plant agriculture in the USA has 2011). Under such powerful selection pressure, it is not surpris- been replaced by oxytetracycline, due to streptomycin resistance ing that the soil resistome is so diverse (Knapp et al., 2010). development among E. amylovora in the apple orchards. Oxolinic The best example illustrating this is the tetracycline resistome. acid had been reported to be used in Israel against fire blight and Tetracyclines are an important class of antimicrobials with desir- against rice blight in Japan (Shtienberg et al., 2001). Gentamicin able broad-spectrum activity against numerous pathogens and is used in Mexico and Central America to control Fire Blight and the widespread emergence of resistance has had a massive impact various diseases of vegetable crops (Stockwell and Duffy, 2012). on these drugs (Thaker et al., 2010). Opportunistic pathogens However, the role of antimicrobial use on plants is, knowing the ubiquitous in the soil for example, Pseudomonas aeruginosa, AMR crisis in human medicine, the subject of debate (McManus Acinetobacter spp.,Burkholderiaspp., and Stenotrophomonas spp. et al., 2002). can combine intrinsic resistance to several antimicrobials with a remarkable capacity to acquire new resistance genes (Popowska DISSEMINATION OF ANTIMICROBIAL-RESISTANT BACTERIA et al., 2010). Still, little is known about the diversity, distribution, THROUGH FOOD AND FOOD PRODUCTION and origins of resistance genes, particularly among the as yet non- Resistant bacteria can be transferred from animals and plants cultivable environmental bacteria. In uncultured soil bacteria, to humans in many different ways, which can be catego- identified resistance mechanisms comprise efflux of tetracycline rized into three major modes of transmission: (1) through the and inactivation of aminoglycoside antimicrobials by phosphory- food chain to people (Roe and Pillai, 2003; Soonthornchaikul lation and acetylation (Popowska et al., 2012). In addition, bacte- and Garelick, 2009), (2) through direct or indirect contact ria resistant to macrolides including the new drug telithromycin with livestock industry or animal health workers (Levy et al., have been reported from soil (Riesenfeld et al., 2004a). In a study 1976), (3) through environments which are contaminated by (D’Costa et al., 2006), 480 strains of Streptomyces from soil with manure in agriculture (http://ec.europa.eu/environment/ were screened against 21 antimicrobials. Most strains were found integration/research/newsalert/pdf/279na4.pdf) and aquaculture to be multi-drug resistant to seven or eight antimicrobials on (Petersen et al., 2002; Shah et al., 2012b). The environment con- average, with two strains being resistant to 15 of the 21 drugs. It tains a great variety of bacteria creating an immense pool of AMR was also reported that soil is a reservoir for β-lactamases and these genes that are available for transfer to bacteria that cause human genes, if transferred to pathogens, can then impact human health disease (Riesenfeld et al., 2004b; D’Costa et al., 2006). The real- (Allen et al., 2010). It is supposed that the presence of antibiotics ization of these links sparked the recent interest in the role and in the environment has promoted the acquisition or independent dynamics of environmental AMR (Figure 2). evolution of highly specific resistance elements. These determi- In addition, other sources are available. For instance, wild nants are located mainly on mobile genetic elements such as animals may also be carriers of antimicrobial-resistant bacte- plasmids and conjugative transposons, which ensure their spread ria (Literak et al., 2011). These animals may have close contact by horizontal gene transfer. Conjugative, broad-host-range plas- to human or farming areas and/or waste and become colo- mids play a key role in this process (Martinez, 2009; Stokes nized with resistant strains (Literak et al., 2011; Nkogwe et al., and Gillings, 2011). Numerous studies have demonstrated that 2011). Interestingly, animals in remote areas have been found to the prevalence of such resistance plasmids in soil is very high

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(Götz et al., 1996). Among the plasmids conferring resistance to sewage treatment plants (Segura et al., 2009; Michael et al., 2013). antimicrobials, representatives of the incompatibility groups P, Although proportion of the antimicrobial compounds are trans- Q, N, and W have been identified. An example of this type of formed and degraded in the environment, the occurrence of mobile genetic elements may be the IncP-1 plasmids (Popowska these micropollutants is reported worldwide, with antimicrobials and Krawczyk-Balska, 2013). Results from the scientific literature of all classes being detected in wastewater habitats in concen- show that plasmids carrying resistance genes have been identi- trations ranging from ng−1 to mgL−1 (Michael et al., 2013). fied in pathogenic bacteria of the genus Escherichia, Salmonella, Simultaneously, urban sewage and wastewater contain AMR bac- Shigella, Klebsiella, Aeromonas, and Pseudomonas,thegenerathat teria and other pollutants, such as pharmaceutical and personal can be found in soil and water (Stokes and Gillings, 2011). hygiene products and heavy metals, whose effects on AMR selec- These plasmids carry determinants for resistance to at least one tion are still not very clear (Graham et al., 2011; Oberlé et al., heavy metal (Ni, Cd, Co, Cu, Hg, Pb, Zn) and antimicrobials 2012; Patra et al., 2012; Novo et al., 2013). Often, wastewater of different groups, i.e., tetracyclines, quinolones, aminoglyco- treatment is not enough to eliminate the antimicrobial residues sides, sulfonamides, β-lactams, and chemotherapeutics (Sen et al., entering the system (Michael et al., 2013). The consequence 2011; Seiler and Berendonk, 2012). Overall these data indicate is that such micropollutants, exerting selective pressures, may that soil bacteria constitute a reservoir of resistance determinants facilitate the selection of AMR bacteria or the acquisition of that can be mobilized into the microbial community including resistance genes by horizontal gene transfer (Martinez, 2009). pathogenic bacteria. Recent studies also indicate a different mech- Indeed, the relevance of wastewater habitats to the dissemina- anism of AMR in soil-derived actinomycetes, by engendering tion of AMR among human pathogens as well as commensal mutations in genes encoding the transcriptional and translational and environmental bacteria is increasingly emphasized (Baquero apparatus that lead to alterations in global metabolism. This ver- et al., 2008; Marshall and Levy, 2011; Czekalski et al., 2012; Rizzo tically selected AMR includes increased production of secondary et al., 2013). Wastewater treatment plants reduce the load of AMR metabolites (Derewacz et al., 2013). Very recently evidence for bacteria, but treated water still carries elevated levels of AMR recent exchange of AMR genes between environmental bacteria bacteria, and may select for strains with high levels of multidrug- and clinical pathogens was presented using a high-throughput resistance (Czekalski et al., 2012). Resistance gene abundance in a functional metagenomic approach (Forsberg et al., 2012). In stream system could be linked to the input of (treated) wastewater this study it was shown that multidrug-resistant soil bacteria and animal husbandry, demonstrating landscape-scale pollution contain resistance gene cassettes against five classes of antimicro- of natural aquatic systems with AMR (Pruden et al., 2012). The bials (β-lactams, aminoglycosides, amphenicols, sulfonamides, currently available literature demonstrates that most of the AMR and tetracyclines) with high nucleotide identity to genes from genetic elements found in clinical isolates are also detected in diverse human pathogens. Therefore, it is important to study this wastewater habitats, even shortly after they have been reported reservoir, which may contribute to the detection of new clini- in hospitals (Szczepanowski et al., 2009; Rizzo et al., 2013). The cally relevant AMR-mechanisms and/or the multidrug-resistant occurrence of the same AMR genetic elements in different habi- pathogens that should be avoided from entering medically impor- tats demonstrates the uniqueness of the resistome, mainly due to tant bacteria (Torres-Cortés et al., 2011). rapid dissemination processes, demonstrating the urgent needs for an integrated approach. ANTIMICROBIAL RESISTANCE IN AQUATIC ENVIRONMENTS Ubiquitous bacteria that can live in the environment and Water is one of the most important habitats for bacteria, hold- are also able to colonize humans are particularly relevant to ing complex microbial communities. Not surprisingly, water the spread of AMR in the environment and the implications also contains AMR bacteria. From natural fresh water systems to human health. Indeed, numerous studies have reported to drinking water, or from sewage to human-engineered water the occurrence of AMR in ubiquitous bacteria isolated from infrastructures, AMR, either intrinsic or acquired, have been wastewater habitats, which are also recognized as opportunistic reported in aquatic environments worldwide (e.g., Goñi-Urriza pathogens, mainly nosocomial agents. AMR bacteria of clinical et al., 2000; Volkmann et al., 2004; Schwartz et al., 2006; Ferreira relevance which may be found in the environment comprise, da Silva et al., 2007; Böckelmann et al., 2009; Vaz-Moreira et al., among others, members of the genera Acinetobacter, Enterococcus, 2011; Falcone-Dias et al., 2012). In this respect, given their Escherichia, Klebsiella, Pseudomonas,andShigella (Blanch et al., characteristics, wastewater habitats are particularly important. 2003; Reinthaler et al., 2003; Ferreira da Silva et al., 2006, 2007; Watkinson et al., 2007; Novo and Manaia, 2010; Czekalski et al., WASTEWATER HABITATS AS RESERVOIRS OF ANTIMICROBIAL 2012). In addition, non-cultivable bacteria may also be important RESISTANCE either for AMR spread or selection. Indeed, over the last years, Among the aquatic environments, wastewater habitats repre- the use of culture independent approaches brought additional sent the most important reservoir of AMR bacteria and genes. insights into the abundance and diversity of resistance genes in This type of water contains human and animal excretions with wastewaters and into the effects of antimicrobials on the bacte- abundant doses of commensal and pathogenic antimicrobial- rial communities (Volkmann et al., 2004; Czekalski et al., 2012; resistant bacteria (Yang et al., 2011; Ye and Zhang, 2011, 2013; Oberlé et al., 2012; Novo et al., 2013). In particular, several stud- Novo et al., 2013). Since antimicrobials are not fully degraded ies presented evidence that in wastewater habitats there is a high in the human and animal body, antimicrobial compounds, their potential for horizontal gene transfer, mediated by plasmids and metabolites and transformation products are abundant in urban facilitated by integrons (Tennstedt et al., 2003; Szczepanowski

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et al., 2008; Moura et al., 2010; Zhang et al., 2011). Despite the Table 2 | Degradation rates of various antimicrobials in soil. importance of wastewater as a reservoir for AMR genes, and the Class of Degradation Time References relevance of wastewater treatment to control resistance spread, antimicrobial [%] [d] to date the number of studies that have been published remains relatively low (Figure 2). Macrolides 0–50 5–30 Thiele-Bruhn, 2003* Nevertheless, over the last decades the knowledge in this Sulfonamides 0–50 22–64 Thiele-Bruhn, 2003 area has increased considerably and the importance of wastew- Fluoroquinolones 0–30 56–80 Hektoen et al., 1995; ater treatment systems for the spread of AMR is unequivocally Thiele-Bruhn, 2003 demonstrated. Therefore, it is now possible to address some spe- cific questions which we expect to be a focus of the research in Tetracycline 0–50 10–180 Björklund et al., 1991; this area in the coming years. Examples of these issues are (1) Thiele-Bruhn, 2003 the identification of the conditions that may enhance or mit- Aminoglycosides 0 30 Thiele-Bruhn, 2003 igate the occurrence of horizontal gene transfer and selection β-lactams 0–50 30 Thiele-Bruhn, 2003 of AMR (which pollutants, which concentrations, temperature, Imidasoles 50 14–75 Thiele-Bruhn, 2003 pH, hydraulic residence time of wastewater treatment, etc.); (2) the classification and quantification of risk, e.g., the likelihood Polypeptides 12–90 2–173 Thiele-Bruhn, 2003 that an AMR bacterium or gene from wastewater habitats reach ∗ humans and causes issues for human health; (3) the improvement This reference does not include the modern macrolides with very long of wastewater treatment processes in order to minimize the loads elimination half-lives. For instance, Tulathromycine has an half live (so 50% of antimicrobial-resistant bacteria and genes in the final effluent degraded, not nearly 100%) in soil of 99 days (Pfizer, personal communication (Dodd, 2012). 2013).

THE ANTIMICROBIAL RESISTANCE GENE POOL physicians in reducing antimicrobial overuse should be imple- AMR genes can be differentiated depending on the genetic event mented. Following the analysis more than 500 scientific articles, it that is required for acquiring an AMR phenotype. These include has been suggested that the elimination of non-therapeutic use of genes that are acquired by horizontal gene transfer and genes that antimicrobials in food animals, will lower the burden of AMR in are present in the bacterial genome and that can encode AMR the environment, with consequent benefits to human and animal following gene mutations or activation (Olliver et al., 2005). health (FAAIR Scientific, 2002; Swartz, 2002). AMR features evolve as a consequence of permanent exchange Better management techniques and strict legislation in the of and ever new recombinations of genes, genetic platforms, and use of antimicrobials for therapeutic use in humans and in ani- genetic vectors. Many of these genes are not primarily resistance mals will reduce the risk of development of AMR (Cunha, 2002; genes, but belong to the hidden resistome, the set of genes able to Defoirdt et al., 2011; Midtlyng et al., 2011). For example, the be converted into AMR genes (Baquero et al., 2009). As evidenced prevention of nosocomial transmission of multi-drug resistant by our discussion above, microbial organisms harboring these bacteriaispossiblewithactiveroutinesurveillanceprogramsthat genes are present naturally in all kinds of environments, but also can identify colonized patients. Numerous studies have demon- released into water and soil from organisms, including humans, strated that such a “search and containment” approach and/or where they evolve or increase in abundance under direct selection a “search and destroy” approach in which an attempt is made from exposure to antimicrobials. At the same time, antimicrobials to eliminate carriage of the organism can reduce the incidence (often at low concentrations), disinfectants, and heavy metals are of hospital-acquired infections and be cost-saving (Muto et al., disseminated into the water as well, and may act as selective fac- 2003). tors fostering the evolution of new AMR features (Cantas et al., New management techniques in the animal husbandry, such 2012a,b,c; Cantas et al., unpublished). The rate of degradation as organic farming, need to be thoroughly investigated to ensure of antimicrobials in the environment varies and is dependent on that these are viable alternatives that help to reduce the potential a range of environmental conditions, for example: temperature, for selection of AMR bacteria. Samples from organically farmed available oxygen, pH, presence of alternative sources of organic poultry showed a significantly lower level of AMR in intestinal and inorganic discharges as described in Table 2. bacteria such as E. coli and Campylobacter (Soonthornchaikul et al., 2006). However from organically farmed cattle no signifi- HOW TO SLOW DOWN THE SPREAD AND EVOLUTION OF AMR? cant differences were obtained in microbiological contamination. In this review we have emphasized that the problem of AMR E. coli and S. aureus isolates were found to have significantly lower evolution and dissemination is multifaceted and involves clinical, rates of AMR in organically raised cattle (Sato et al., 2005). More agricultural, technical, and environmental systems. Similarly studies are needed (1) to determine the reasons of antimicrobial strategies to deal with the impending AMR crisis have to take this usage in the farms by veterinarians, (2) to compare and update complexity into account. the recommended treatment protocols for veterinarians through- The overuse of antimicrobials needs to be limited or reduced out different countries, (3) to evaluate the impact of other factors in human medicine, veterinary medicine, agriculture, and aqua- other than AMR development in bacteria: e.g., immune response- culture. Ideally, the use of antimicrobials in agriculture should stress has been indicated to correlate with resistance genetic ele- be eliminated. Intensive programs to educate both patients and ment shuffling among gut microbiota in different animal models,

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such as: atlantic salmon, zebrafish, neonatal piglets, and cats or contact with the environment. Introduction of antimicrobial (Cantas et al., 2011, 2012a,b,c, 2013). Animal welfare parameters compounds into the aquatic environment via medical therapy, under intensive production such as stress should be investigated agriculture, animal husbandry and companion animals has in future studies with regards to control of resistance development resulted in selective pressures on resident environmental bacteria. in animal husbandry. Development of AMR in environmental bacteria has a great Vaccination and improved hygienic measures are among the impact and may help in explaining how human and animal important cornerstones in controlling infectious diseases and pathogens acquire resistance features. Besides the role of clinical consequently aid in reducing AMR (Potter et al., 2008). The microbiology laboratories with rapid and accurate detection of Norwegian aquaculture may serve as a good example by reduc- a diverse number of pathogens and its drug resistance profiles, tion in the use of antimicrobials from around 50 tons in the late robust routine surveillances in an epidemiological frame-work 1980’s to less than 1000 kg per annum after introduction of effec- covering the whole livestock “food chain” and the environment tive vaccines against devastating fish diseases like furunculosis and need to be taken into consideration. Due to this complexity vibriosis (Midtlyng et al., 2011; NORM/NORM-VET, 2011). the control of AMR has to include numerous actions at diverse The use of pre- and probiotics to improve the health and levels. Future research should focus on finding unknown routes performance of livestock might be a good alternative to growth of transfer of AMR between microbiotas of relevance to the promoters. This is an important biological control aiming to food chain and to all microbiotas of importance for bacterial reduce outbreaks of infectious diseases and which in turn would pathogens when they acquire antibiotic resistance genes laterally. minimize the use of antimicrobials in livestock and aquaculture Ultimately, even a successful integrative approach on all aspects, for therapeutic purposes (Verschuere et al., 2000; Callaway et al., can probably only help to slow down the spread of AMR, not 2008). prevent it. The development of new generations of antimicrobial The issue of dissemination and possible long-term enrich- should therefore receive equal attention. This is summarized ment of AMR and AMR genes in the environment (Knapp and emphasized in a 12-point action plan against the rising et al., 2008) needs to be studied further, with specific regards threats of AMR implemented by the European Commission to the actual risks associated with it. However, taking action is which includes actions in the field of human medicine, animal already possible today. For example, several treatment methods husbandry, veterinary medicine, authorization requirements for waste and wastewater disinfection and removal of microp- for commercialization of human and veterinary drugs and ollutants, including antimicrobials, are available. These include other products, on research, on scientific opinions, and under- various chemical disinfections, UV treatment, and membrane fil- taking also actions on the international level in collabora- tration. Disinfection and DNA degradation of community based tion with the WHO and Codex (http://ec.europa.eu/dgs/health_ and hospital wastewater may be effective means to reduce AMR consumer/does/communication_amr_2011_748_en.pdf, Bush release, although more research is required to fully assess the inac- et al., 2011). tivation of resistance genes (i.e., DNA released from lysed cells The problem of AMR is widespread all over the world, there- that may be available for horizontal gene transfer) by these mea- fore it is not eradicable, but can be managed. Concerted efforts sures (Dodd, 2012). The combined removal of pollutants that between medical doctors, dentists, veterinarians, scientists, fun- are potential selective agents, disinfection, and deactivation of the ders, industry, regulators, and multi-disciplinary approaches are genetic material, may be a useful strategy to reduce the pollution needed to track resistance. Furthermore, global monitoring of of environments with resistance factors. the antimicrobial drug consumption in human and veterinary medicine and AMR, is an essential part of an overall strategy CONCLUSIONS to inform, educate and get commitment of all parties, includ- Inevitably, AMR in medicine has become common place. ing farmers and patients (American Academy of Microbiology, Bacteria have evolved multiple mechanisms for the efficient 2009). All these are important measures for the efficient future evolution and spread of AMR. Meanwhile the new developments use of antimicrobials in medicine. All members of society should of quick and adequate molecular diagnostic techniques for be conscious of their role and take on responsibility for main- the identification and epidemiological surveillance of genetic taining the effectiveness of current and future antimicrobials. We determinants of AMR in different hosts and in the environment believe that future interventions can be successful in minimizing will enhance the number of control options. We have outlined this problem. above a number of potential measures that are enabled by our improved ability to track AMR. However, there seems to be a AUTHOR CONTRIBUTIONS clear need for action and policy changes. This includes drug L. Cantas defined the review theme, established the interdis- licensing, financial incentives, penalties, and ban or restriction ciplinary coordination and the collaborations, designed the on use of certain drugs. Similarly, the prescriber behavior needs manuscript, contributed to the data collection, data analysis, to be altered. Animal health and hygiene needs to be improved. and drafting and writing of the manuscript. Syed Q. A. Shah, In addition, the implementation of microbiological criteria L. M. Cavaco, C. M. Manaia, F. Walsh, M. Popowska: draft- for the detection of certain types of resistant pathogens would ing, writing, and editing the manuscript. H. Garelick and H. be important to control the trade of both food animals and Bürgmann: contributed to data analysis, drafting, and writing the food products. The problem of AMR in human medicine will manuscript. H. Sørum: contributed to manuscript design, data not be solved if nothing is done to limit the constant influx of collection, data analysis, drafting, and writing the manuscript. All resistance genes into the human microbiota via the food chain authors have contributed to, seen and approved the manuscript. www.frontiersin.org May2013|Volume4|Article96| 9 Cantas et al. The problem of antimicrobial resistance: a multi-disciplinary review

ACKNOWLEDGMENTS AND FUNDING responsible for the use which might be made of the information contained in this publication. The COST Office is not respon- sible for the external websites referred to in this publication. C. M. Manaia acknowledges National Funds from FCT— Fundação para a Ciência e a Tecnologia through projects PEst- OE/EQB/LA0016/2011 and PTDC/AAC-AMB/113840/2009. F. Walsh acknowledges funding from the Swiss Federal Office for All authors acknowledge DARE TD0803 (Detecting Agriculture, the Swiss Federal Office for the Environment and the Antimicrobial Resistance in Europe) COST Action. (http:// Swiss Expert Committee for Biosafety (SECB). Finally L. Cantas www.cost-dare.eu/). This publication is supported by COST. extend his thanks to MegaVet.no, for helpful support in reviewing Neither the COST Office nor any person acting on its behalf is the manuscript.

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