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Review

Environmental Spread of Antibiotic Resistance

by
Nicholas Skandalis
1,
Marlène Maeusli
1,2,
Dimitris Papafotis
3,
Sarah Miller
2,
Bosul Lee
2,
Ioannis Theologidis
3 and
Brian Luna
2,*
1
Department of Medicine, Keck School of Medicine at USC, Los Angeles, CA 90033, USA
2
Department of Molecular Microbiology and Immunology, Keck School of Medicine at USC, 1441 Eastlake Ave, NTT 6419, Los Angeles, CA 90033, USA
3
Department of Biology, National and Kapodistrian University of Athens, 157 72 Athens, Greece
*
Author to whom correspondence should be addressed.
Antibiotics 2021, 10(6), 640; https://doi.org/10.3390/antibiotics10060640
Submission received: 5 May 2021 / Revised: 18 May 2021 / Accepted: 24 May 2021 / Published: 27 May 2021
(This article belongs to the Section Mechanism and Evolution of Antibiotic Resistance)
Browse Figure
Versions Notes

Abstract

:
Antibiotic resistance represents a global health concern. Soil, water, livestock and plant foods are directly or indirectly exposed to antibiotics due to their agricultural use or contamination. This selective pressure has acted synergistically to bacterial competition in nature to breed antibiotic-resistant (AR) bacteria. Research over the past few decades has focused on the emergence of AR pathogens in food products that can cause disease outbreaks and the spread of antibiotic resistance genes (ARGs), but One Health approaches have lately expanded the focus to include commensal bacteria as ARG donors. Despite the attempts of national and international authorities of developed and developing countries to reduce the over-prescription of antibiotics to humans and the use of antibiotics as livestock growth promoters, the selective flow of antibiotic resistance transmission from the environment to the clinic (and vice-versa) is increasing. This review focuses on the mechanisms of ARG transmission and the hotspots of antibiotic contamination resulting in the subsequent emergence of ARGs. It follows the transmission of ARGs from farm to plant and animal food products and provides examples of the impact of ARG flow to clinical settings. Understudied and emerging antibiotic resistance selection determinants, such as heavy metal and biocide contamination, are also discussed here.

1. Introduction

Antibiotic-resistant (AR) bacteria impose a significant burden on healthcare. In 2017, the Centers for Disease Control (CDC) estimated that there were 2.8 million infections and more than 35,000 deaths in the U.S. due to infections caused by AR bacteria [1]. These estimates are nearly double the previous estimates that were published in 2013 [1,2].
It has been estimated that 20% of these infections are attributable to agricultural antibiotic usage rather than clinical treatment [3]. Foodborne antibiotic-resistant bacteria can survive the harsh conditions of the gastrointestinal tract [4]. Foodborne pathogens can cause acute illness, or they can asymptomatically persist in the gut microbiome as a reservoir for multidrug-resistant, opportunistic, extraintestinal infections [5,6,7,8].
Wastewater also contributes to AR; antibiotics persist through the wastewater treatment processes [9]. Effluents end up in receiving waters, while sludge waste is used as fertilizer [10]. All these sources of antibiotics and AR strains sink to surface waters [11,12] and agricultural soil, which readily absorbs them [13]. Crops become contaminated and serve as vehicles for the transmission of AR bacteria to the food chain [14,15], silently contributing to AR infections [16] or the global burden of illness by directly causing outbreaks of foodborne diseases [17].
The development of AR relies mainly on the prevention of access to drug targets, changes in the structure and protection of antibiotic targets, the direct modification or inactivation of antibiotics, the efflux of antibiotics, and the formation of biofilms [18]. Modifications of antibiotics include enzymatic alteration of the antibiotic by acetylation, phosphorylation and adenylation, and using enzyme like aminoglycoside modifying enzymes (AMEs) [19]. Another modification is the destruction of antibiotic molecules, which in the case of b-lactams is facilitated by b-lactamases [20]. Decreased membrane permeability is also an important mechanism of AR, mostly in Gram-negative bacteria. This is because antibiotic targets are often parts of the inner membrane and antibiotics need to go through the outer membrane first. For example, vancomycin is not effective against Gram-negative bacteria because their outer membrane is impermeable to this antibiotic [21]. Bacteria have developed complex machineries (called efflux pumps) that have the ability to extrude a number of antimicrobial compounds [22]. Another method to combat antibiotics is through interference with their target site. One mechanism of interference is target protection, which affects drugs like tetracycline [23] and fluoroquinolones [24]. Other mechanisms are based on direct modification of the target site and include mutations, enzymatic alteration (for example, methylation), replacement, or overproduction of the target [21,25,26]. Such mechanisms are facilitated by two major genetic strategies: mutational resistance and horizontal gene transfer (HGT) [21].
Another way for bacteria to survive exposure to antibiotics is tolerance. Tolerance is described as the ability to survive lethal concentrations of antimicrobial drugs [27]. Such ability is measured by the minimum duration for killing 99% of the population. Tolerance is based on evolution of mechanisms, such as dormancy [27], or persistence of a subpopulation of cells. These persister cells can survive for a much longer time than the rest of the population [28]. Contrary to dormancy, persistence evolves rapidly following frequent exposure to antibiotics in vitro [29].
This review focuses on the environmental spread of antibiotic resistance and provides insights further insights into the clinical etiology of AR infections. The selective flow of ARGs is summarized in Figure 1.

2. Antibiotics in the Environment

Natural occurrence of antibiotics. DNA recovered from 30,000 years old Beringian permafrost sediments indicate that ARGs encoding resistance to beta-lactams, tetracyclines, and glycopeptides predated their clinical use by thousands of years [30]. The coevolution of antibiotics and ARGs contributes to the difficulty of identifying effective natural products against AR bacteria [31].
Ninety percent of antibiotics used in clinics were originally identified from microorganisms [32]. For example, vancomycin, kanamycin, and erythromycin produced by Streptomyces orientalis, Streptomyces kanamyceticus, and Saccharopolyspora erythraea, respectively, were isolated from soil samples [33]. Most of the known antibiotic classes used today come from Actinomycetes and especially the genus Streptomyces. Those classes include beta-lactams, tetracyclines, macrolides, aminoglycosides, and glycopeptides [34]. It is no surprise that soil systems are abundant reservoirs of naturally occurring antibiotic compounds and anthropogenic contaminants of antibiotics, both of which select for ARGs [35,36,37,38].
Soil actinomycetes, including Streptomyces, are a common source of antibiotic compounds. However, the ocean is home to unique actinomycete genera, including Salinispora and Marinispora. Marine actinomycetes can produce secondary metabolites with antimicrobial activity [35]. For example, coastal water sampling in Southern California has led to the isolation of Marinomycin A, a natural product with antibiotic activity against methicillin-resistant Staphylococcus aureus [MRSA] and vancomycin-resistant Enterococcus faecium [VREF] [36]. Pestalone is another natural antimicrobial product against MRSA and VREF produced only in the co-culture of a marine fungus, Pesalotia sp., with an unidentified marine bacterium [39,40].
Contribution of agriculture and wastewaters in antibiotic pollution. The majority of antibacterial agents (including ionophores) purchased in the U.S. are for agricultural use (15.4 million kg, or 80% of the annual total in 2014) [3,41]. Antibiotics from a wide range of classes, including macrolides, lincosamides, sulfonamides, thiamphenicol analogs, and fluoroquinolones have been detected in agroecosystems [42]. Although antibiotics today are used at therapeutic doses to treat existing infections in livestock, they were also often administered prophylactically to prevent illness until 2017 [43]. More importantly, subtherapeutic doses were delivered to livestock over extended periods of time as feed additives to promote growth [43,44].
Another agricultural contributor to the spread of resistance, which has been overlooked, is the use of antibiotics for crop protection [45]. Plant antibiotics have historically accounted for less than 0.5% of total antibiotic use [46]. However, the recent approval for application of streptomycin and oxytetracycline to prevent the spread of citrus canker and citrus greening pandemic diseases led to an 18-fold increase of the agricultural usage of these antibiotics [47]. This regulatory change could result in an unprecedented emergence of ARGs in plant foods. In addition, the combinational use of antibiotics and biopesticides, the latterconsisting of bacterial species that have been selected based on their genetic competence to produce antibiotics [15], resist counter antibiosis [48], and colonize plant niches [49] poses another threat.
Unmetabolized antibiotics found in hospital effluents can be carried into wastewater treatment plants where the removal of antibiotics can be incomplete, ultimately feeding ARGs into the natural aqueous environment [50]. The contribution of wastewater to the spread of antibiotic resistance is supported by AR patterns in wastewater treatment plants that mirror their respective clinical prevalence [9]. Since most of these plants are not designed to completely remove contaminants, antibiotics persist through the wastewater treatment processes. Effluents end up in receiving waters (analyzed below), while sludge waste is used as fertilizer [10]. All of these sources of antibiotics and antibiotic resistance sink to surface waters where antibiotic concentrations in the micrograms per liter range have been reported [11,12]. The antibiotics with the highest concentrations detected in receiving water were trimethoprim, sulfisoxazole, ciprofloxacin, and albendazole [12].

3. Emergence of Antibiotic Resistance in the Environment

ARGs in soil. Agricultural antibiotics, manure from livestock, and hospital sewage (as well as municipal, agricultural, and aquaculture wastewater) are important sources of antibiotic residues that contaminate soil [51,52,53]. Therefore, soil bacteria act as a reservoir of ARGs [54,55]. Multiple studies have shown a substantial increase in AR nonpathogenic, environmental bacteria. More than 97% of the 123 strains tested were resistant to ciprofloxacin and almost 50% were resistant to erythromycin. Environmental strains carrying ARGs don’t have to necessarily be closely related to human pathogens. Denitrifying bacteria, classified in Brachymonas, Candidatus Competibacter, Thiobacillus and Steroidobacter genera, found in the anoxic wastewater treatment process in pig farms are also important hosts of ARGs [56]. Pseudomonas is also a dominant genus in the environment that consists of many species, such as the nonpathogens P. fluorescens and P. putida and the very important clinical pathogen P. aeruginosa, which is often associated with multidrug resistance phenotypes [57,58].
Wastewater irrigation can also affect the soil resistome. It has been shown that irrigation with untreated wastewater can increase the amount of multidrug resistant bacteria even after long periods of no irrigation [59]. Dantas et al. isolated multidrug resistant (MDR) soil bacteria that could also grow in the presence of several of the tested antibiotics, suggesting that the soil reservoir contributes to the increasing levels of MDR pathogenic bacteria [60]. This ARG reservoir may serve as a source of ARG transmission between nonpathogenic soil bacteria and human pathogens as previously described by others, but the overall dynamics of this phenomenon have not been associated with clinical practice [54,61].
ARGs in water bodies. Urban and coastal water systems can serve as gateways for the dissemination of anthropogenically associated ARGs [62,63]. Antimicrobials and the selection of ARGs occur in beef cattle storage ponds and swine treatment lagoons, [64] but also in water samples collected throughout the Pacific Ocean [37]. AR bacteria can also be transferred between locations by birds or other animal species [65,66].
Studies in the Antarctic have also provided an important model to study the dissemination of resistance genes in aqueous environments with minimal human interference [38,67,68]. Studies have found clinically relevant ARGs at sampling sites close to field research stations supporting transmission routes of human origin from wastewater plants [38,69]. Hernandez et al. reported ESBL genes blaCTX-M1 and blaCTX-M15 in seawater samples collected near Antarctic field stations [38]. Another study also reported ESBL genes (blaCTX-M2 and blaPER-2) and “plasmid-mediated AmpC beta-lactamase genes” (pAMPCDHA, pAMPCFOX) in nearby freshwater samples [67].

4. Co-Selection of ARGs Due to Other Pollutants

Major heavy metal pollutants (such as cadmium, copper, lead, chromium, arsenic, and mercury) are ubiquitous metal pollutants of soil and water due to their presence (as byproducts) in fertilizers, construction materials, and antifouling paints [70,71]. Exposure to heavy metals mainly occurs through the food chain via plant root absorption or direct ingestion via drinking of contaminated groundwater [72]. Recently, the U.S. Congress reported that baby food is tainted with dangerous levels of heavy metals [73]. Heavy metals in excess concentrations can interfere with vital cellular functions and are highly toxic to most organisms [74]. On the contrary, heavy metals are of moderate to high physiological importance for some bacterial species [75]. Bacteria have coevolved resistance mechanisms to heavy metals and antibiotics, based in extra- and intracellular sequestration, enzymatic detoxification, and metal removal [76]. Such resistance mechanisms are thought to converge [77] (based on the co-occurrence of respective resistomes in bacterial genomes [78]) and increase resistance in the absence of antibiotic treatment [79].
Other nonantibiotic antimicrobial compounds that have been observed to coselect with ARGs are biocides [79]. Common uses of biocides include: disinfectants on equipment and surfaces in facilities like farms and hospitals, antiseptics on body surfaces, decontaminants and preservatives in pharmaceuticals, and food [80]. Biocides are used in large quantities; the 2006 market in Europe was estimated at 10–11 billion euros, and it is believed that usage has only increased since then [81]. Their consumption has risen dramatically due to the Covid-19 pandemic [82]. Consequently, it is no surprise that biocides have found their way into the environment. For example, high amounts of triclosan and other biocides have been detected in rivers and wastewater treatment plant (WWTP) effluents. More specifically, 138 g/day of triclosan and 214 g/day of triclocarbon were released into the Savannah River in Georgia (U.S.) from three WWTPs [83]. In a different study conducted in eight WWTPs and the receiving aquatic environment in Thailand, they found high amounts of methylparaben up to 15.2 μg/L in the receiving Chao Phraya River, 8.47 μg/g of triclocarbon in sludge and sediment and 1.20 μg/g of triclosan in fish samples [84].
Bacteria have developed various resistance mechanisms to biocides [81,85], including target alteration [86,87], impermeability [88,89], efflux pumps [90,91], and inactivation of biocides [92,93]. Similar to heavy metal resistance, biocide resistance has the ability to coselect with antibiotics [79] and enhance antibiotic resistance [94]. For example, exposure to benzalkonium chloride increased the microbial community MICs for benzalkonium chloride, ciprofloxacin, tetracycline and penicillin G [95]. Benzalkonium chloride, as well as chlorhexidine digluconate [96], can induce the multidrug efflux pump MexCD-OprJ in Pseudomonas aeruginosa, contributing to resistance to fluoroquinolone antibiotics [97]. In a recent study, low level exposure to chlorhexidine digluconate (24.4 μg/L) and triclosan (0.1 mg/L) in E.coli have been shown to significantly increase horizontal transfer of mobile AR genetic elements by conjugation [98]. Triclosan exposure can also reduce the susceptibility to clinical antimicrobials, like ciprofloxacin and levofloxacin, in E. coli isolates from urine samples [99]. In addition, exposure of Salmonella enteritidis to chlorine increased the MIC values eight-fold for tetracycline, nalidixic acid, and chloramphenicol [100]. Information on the actual contribution of biocides to ARG emergence and transmission in the food chain remains scarce [101].

5. Transmission of ARGs across the Food Chain

ARGs in meat, poultry and fish products. It has been well established that livestock and animal products contribute to the spread of AR bacteria and genes to humans [4,8,102,103,104]. Most antibiotics purchased in the U.S. are for use in agriculture [105]. Livestock are fed these antibiotics, thereby creating a selective pressure favoring ARGs in the animal gut and feces [4,102,103]. In Belgium, about 35% of the E. coli strains isolated from live broilers were resistant to third generation cephalosporins, while over 60% of the broilers were found to be carriers of these third generation cephalosporin resistant E. coli [CREC]. AR strains can also contaminate meat industry employees. Hog slaughterhouse employees demonstrated similar numbers of Staphylococcus aureus isolates in comparison to their family and community members [106]. However, the employees’ isolates were resistant to more antibiotic types suggesting a greater selective pressure originating at the hog plant [106].
Contamination of animal products starts during slaughter and spreads throughout the food supply chain [8,104]. Even if food processing methods are applied in order to kill bacterial cells, dead cells may remain intact or be lysed and release ARGs [107]. The subsequent spread of AR bacteria and their genes can happen in the kitchen during meal preparation and by the incomplete cooking of meat surfaces prior to consumption [4,7]. Hands and cutting boards are known sources of cross contamination with ESBL-producing E. coli [108]. Furthermore, the increasing demand of minimally processed or raw fish and meat further contaminates such products with ARGs [109]. Shiga toxin-producing Escherichia coli (STEC) serotypes, including O157:H7 strains, were isolated from dairy cows, cull dairy cow feces, cider, salami, human feces, ground beef, bulk tank milk, and bovine feces in media selective for different antibiotics [110]. Extraintestinal pathogenic E. coli (ExPEC) and other antibiotic-resistant E. coli have been found in poultry, pork, and beef at grocery stores [8]. In a study performed in Austria, resistant E. coli isolates were found most often in pork (76%), followed by poultry (63%) and beef (40%) [111]. Similarly, the most predominant E. coli ARGs isolated from chicken meat were tetA (for tetracycline), aadA1 (for streptomycin), ereA (for erythromycin), aac-3-IV (for gentamicin), cmlA and catA1 (for chloramphenicol) [112].
Aquaculture is the fastest growing food production sector representing 47% of global fish production (80 million tons), equating to a $231.6 billion (USD) industry [113]. While the growth and revenue of the aquaculture industry is beneficial for feeding the world’s growing population, it is alarming that antibiotics are frequently used for prophylaxis and metaphylaxis in aquaculture without substantial regulation in the countries producing the most fish [104,114]. One such method includes the application of antibiotics with feed in open aquaculture cages. This method allows for unmetabolized antibiotics in fish excrements and unconsumed excess antibiotics to spread into surrounding water and sediment, particularly in the absence of collection systems [115]. Aquaculture waste is also used as fertilizer for land based agriculture, yet another means of spreading AR bacteria and their genes into human food sources [116]. Market finfish and shellfish can be contaminated with bacteria resistant to clinically important antibiotic classes, including tetracyclines, beta-lactams, aminoglycosides, and quinolones [117,118,119,120].
ARGs in Produce. While most scientific focus in agricultural sources of antibiotic resistance has been in livestock and meat, the role of vegetables in the spread of ARGs has been largely overlooked [121,122,123]. Likewise to the previously described AR bacteria transmitted via animal products, resistant bacteria transmitted from plants can also cause acute illness or asymptomatically colonize the gut [124]. Clinically relevant ARGs and bacteria, such as E. coli, have also been found on vegetables [7,122,123,125]. Even multidrug resistant strains of Acinetobacter baumanii, a pathogen listed under the most urgent threats by the U.S. CDC, have been reported on produce and fruit [121,122,123].
Little is still known about what plant characteristics, human behaviors, and bacterial properties drive the transmission of antibiotic resistance from produce to the mammalian gut microbiome. One possible mechanism may include persister cell populations. Persister cells of E. coli O157:H7, the causing agent of foodborne illness, increased in low humidity conditions on lettuce [126]. Salmonella persister populations in the gut have been identified as reservoirs for antibiotic resistance plasmids, and they were able to transmit these resistance genes to gut E. coli [127]. Agricultural use of antibiotics also drives selection flow of ARGs to produce. The presence of strAB genes and streptomycin-resistant genes in plant pathogens, such as Erwinia amylovora, Pseudomonas syringae, and Xanthomonas campestris, preceded the agricultural use of streptomycin. Such genes are thought to be acquired from nonpathogenic epiphytic bacteria colocated on plant hosts under natural antibiotic selection [128].
Further to previous findings, we suggest that ubiquitous bacteria harbor multiple ARGs of clinical importance. Pseudomonas corrugata, which acts as an opportunistic pathogen [129], was found to be resistant to cefepime, gentamicin, polymyxin B, and chloramphenicol (Table 1), which are currently used therapeutically for Pseudomonas aeruginosa and other human pathogenic Pseudomonads [130]. Similarly, the ubiquitous soil bacterium and opportunist plant pathogen Pectobacterium carotovorum subsp carotovorum [131] was found to be resistant to cefepime, gentamycin, and chloramphenicol (Table 1), which are clinically used against pathogenic Enterobacterales [130]. Finally, Bacillus thuringiensis sbsp. kurstaki (which is used commercially as a bioinsecticide [132]) was found to be resistant against ampicillin, penicillin, and erythromycin, which are clinically used against Bacillus pathogens other than B. anthracis [133]. Such findings are clearly suggestive of the acquisition of ARGs due to natural competition of these dominant environmental species with other plant-associated bacteria. ARGs can enter the food chain and ultimately end up in the human gut [127].
Little focus has been placed on directly modeling the mechanisms of transmission from plant foods to the gut microbiome [122,123,124,136] (Figure 1). The gut microbiome can serve as a reservoir of ARGs in asymptomatic human hosts [137]. Previous research by our group has demonstrated that lettuce can serve as a platform for the horizontal gene transfer of antibiotic resistance plasmids from nonpathogenic bacteria harboring mobile ARGs to clinically relevant, pathogenic E. coli [61]. Moreover, the challenge of mice by oral gavage of an AR E. coli clinical isolate suspended in a lettuce homogenate resulted in asymptomatic colonization of the gut and additionally allowed for the horizontal transfer of resistance to resident Klebsiella pneumoniae in the gut [61].

6. Clinical Outcomes

In the United States between 2012–2017, there was a decline in the number of cases of multidrug resistant infections of methicillin-resistant S. aureus (20.5%), vancomycin-resistant Enterococcus (39.2%), carbapenem-resistant Acinetobacter spp (32.0%), and MDR P. aeruginosa (29.7%) [138]. No trend was observed for the change of carbapenem-resistant Enterobacteriaceae during this time period. However, there was the notable exception of a 53.3% increase in ESBL-producing Enterobacteriaceae from 2012–2017 [138,139].
Predictably, the increase in the frequency of antibiotic resistance has also resulted in increased mortality. In Europe, between 2007–2015, it was found that there was an increase in the estimated number of related infections due to AR E. coli, S. aureus, P. aeruginosa, K. pneumonaie, E. faecalis, E. faecium, and S. pneumoniae from 239,238 cases to 602,609 cases [140]. A proportional relationship for the number of cases and the number of attributable deaths was observed for these pathogens, and the greatest number of cases (285,758) and deaths (8750) were observed for third-generation cephalosporin-resistant E. coli [140]. Additionally, this resulted in an increase from 11,114 to 27,249 attributable deaths over this same time period [140]. The relative increase in mortality attributed to each of the pathogens studied was variable. The greatest increase in mortality was observed for carbapenem-resistant K. pneumoniae, which was attributed to 341 and 2094 deaths in 2007 and 2015, respectively.
Hospitals are a hotspot for the emergence of AR bacteria due to the relative high density of patients with bacterial infections and the use of antibiotics and other antimicrobial disinfectants that may also inadvertently select for increased resistance. Unsurprisingly, surveillance studies often report the presence of AR bacteria on hospital surfaces and also in the water system [141,142,143]. The abundance of AR bacteria and/or resistance conferring genes within the hospital are risks for direct transmission to patients. It has been common practice for hospitals to track antibiotic resistance by isolating and characterizing individual clinical isolates. However, it has been difficult to attribute changes in antibiotic resistance patterns to specific examples of horizontal gene transfer. Most of the evidence regarding transfer of antibiotic resistance from animal foods has been based on the identification of E. coli, mostly clones and ARGs that are indistinguishable in both food and human isolates [144]. Recent advances in sequencing technology and whole genome sequencing may now provide the resolution for studying genetic relatedness, which will allow for the real-time monitoring and detection of plasmid transfer dynamics [145,146].
Significantly less data exists for characterizing the horizontal gene transfer of ARGs in a patient. Conjugative transfer of a mupirocin-resistance plasmid has been described between Staphylococcus epidermidis to methicillin-resistant Staphylococcus aureus in a nursing home resident [147]. Another study was able to show the likely plasmid transfer between E. coli and K. pneumoniae within a single patient and, additionally, that same plasmid was likely transferred to a second patient [146]. Broad-host Gram-negative plasmids have also been described to transfer the blaKPC gene that resulted in the spread of carbapenem resistance among Citrobacter freundii, Enterobacter cloacae, Klebsiella aerogenes, and Klebsiella pneumoniae in a transplant patient [148]. In addition to the more simple mechanism of the direct transfer of plasmids from one bacterium to another, plasmid dynamics can be much more complex and require genetic rearrangement involving additional plasmids, thus creating even more complexity [148,149]. Recently, mechanistic models were employed to combine date from 9000 patients and characterize the dissemination routes of a pOXA-48-like carbapenemase-encoding plasmid in a hospital setting over a 2-year period [150].

7. Conclusions

Antibiotic resistance continues to be a significant problem. While the mechanics of how genetic information can be transferred from one bacterium to another are generally understood, there remain significant knowledge gaps in how ARGs are trafficked from environmental sources to humans and animals (Figure 1). Little information is available about the inter- and intraspecies transfer of ARGs in vivo. However, recent advances in genomics tools and technologies will allow for real-time monitoring of ARG transfer dynamics. A better understanding of how ARGs are trafficked will allow for improved strategies to mitigate resistance transmission, with the ultimate goal of reducing morbidity and mortality associated with AR infections.

Author Contributions

Conceptualization, N.S. and B.L. (Brian Luna); methodology, N.S. and B.L. (Brian Luna); software, N.S.; validation, M.M. and D.P.; formal analysis, I.T.; investigation, M.M., D.P., S.M., B.L. (Bosul Lee); resources, B.L. (Brian Luna); writing—original draft preparation, N.S., M.M., D.P., S.M., B.L. (Bosul Lee); writing—review and editing, N.S., M.M., S.M., B.L. (Brian Luna); visualization, N.S.; supervision, N.S., B.L. (Brian Luna); project administration, M.M.; funding acquisition, B.L. (Brian Luna) All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Institute of Allergy and Infectious Diseases (NIAID) grant R01AI139052 to Brian Luna.

Acknowledgments

We would like to thank Brad Spellberg for useful discussions on the topic of this review.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

References

  1. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States; CDC: Atlanta, GA, USA, 2019. [Google Scholar]
  2. CDC. Antibiotic Resistance Threats in the United States, 2013; CDC: Atlanta, GA, USA, 2013. [Google Scholar]
  3. Spellberg, B.; Barlett, J.G.; Gilbert, D.N. The Future of Antibiotics and Resistance. N. Engl. J. Med. 2013. [Google Scholar] [CrossRef] [Green Version]
  4. Centers for Disease Control and Prevention. Foodborne Antibiotics: Antibiotic Resistance (AR) Solutions Initiative; CDC: Atlanta, GA, USA, 2020. [Google Scholar]
  5. Liu, C.M.; Stegger, M.; Aziz, M.; Johnson, T.J.; Waits, K.; Nordstrom, L.; Gauld, L.; Weaver, B.; Rolland, D.; Statham, S.; et al. Escherichia Coli ST131-H22 as a Foodborne Uropathogen. MBio 2018, 9. [Google Scholar] [CrossRef] [Green Version]
  6. Rangel, J.M.; Sparling, P.H.; Crowe, C.; Griffin, P.M.; Swerdlow, D.L. Epidemiology of Escherichia Coli O157:H7 Outbreaks, United States, 1982–2002. Emerg. Infect. Dis. 2005, 11, 603–609. [Google Scholar] [CrossRef] [PubMed]
  7. Davis, G.S.; Price, L.B. Recent Research Examining Links among Klebsiella Pneumoniae from Food, Food Animals, and Human Extraintestinal Infections. Curr. Environ. Health Rep. 2016, 3, 128–135. [Google Scholar] [CrossRef] [PubMed]
  8. Johnson, J.R.; Kuskowski, M.A.; Smith, K.; O’Bryan, T.T.; Tatini, S. Antimicrobial-Resistant and Extraintestinal Pathogenic Escherichia Coli in Retail Foods. J. Infect. Dis. 2005, 191, 1040–1049. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Pärnänen, K.M.M.; Narciso-da-Rocha, C.; Kneis, D.; Berendonk, T.U.; Cacace, D.; Do, T.T.; Elpers, C.; Fatta-Kassinos, D.; Henriques, I.; Jaeger, T.; et al. Antibiotic Resistance in European Wastewater Treatment Plants Mirrors the Pattern of Clinical Antibiotic Resistance Prevalence. Sci. Adv. 2019, 5, eaau9124. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Franklin, A.M.; Williams, C.F.; Watson, J.E. Assessment of Soil to Mitigate Antibiotics in the Environment Due to Release of Wastewater Treatment Plant Effluent. J. Environ. Qual. 2018, 47, 1347–1355. [Google Scholar] [CrossRef] [Green Version]
  11. Kolpin, D.W.; Furlong, E.T.; Meyer, M.T.; Thurman, E.M.; Zaugg, S.D.; Barber, L.B.; Buxton, H.T. Pharmaceuticals, Hormones, and Other Organic Wastewater Contaminants in U.S. Streams, 1999–2000: A National Reconnaissance. Environ. Sci. Technol. 2002, 36, 1202–1211. [Google Scholar] [CrossRef] [Green Version]
  12. Faleye, A.C.; Adegoke, A.A.; Ramluckan, K.; Fick, J.; Bux, F.; Stenström, T.A. Concentration and Reduction of Antibiotic Residues in Selected Wastewater Treatment Plants and Receiving Waterbodies in Durban, South Africa. Sci. Total Environ. 2019, 678, 10–20. [Google Scholar] [CrossRef] [PubMed]
  13. Tolls, J. Sorption of Veterinary Pharmaceuticals in Soils: A Review. Environ. Sci. Technol. 2001, 35, 3397–3406. [Google Scholar] [CrossRef]
  14. Solomon, E.B.; Yaron, S.; Matthews, K.R. Transmission of Escherichia Coli O157:H7 from Contaminated Manure and Irrigation Water to Lettuce Plant Tissue and Its Subsequent Internalization. Appl. Environ. Microbiol. 2002, 68, 397–400. [Google Scholar] [CrossRef] [Green Version]
  15. US Food and Drug Administration. Investigation Summary: Factors Potentially Contributing to the Contamination of Romaine Lettuce Implicated in the Fall 2018 Multi-State Outbreak of E. coli O157: H7; US Food and Drug Administration: Silver Spring, MD, USA, 2019. [Google Scholar]
  16. Wright, G.D. Antibiotic Resistance in the Environment: A Link to the Clinic? Curr. Opin. Microbiol. 2010, 13, 589–594. [Google Scholar] [CrossRef]
  17. Brandl, M.T. Fitness of Human Enteric Pathogens on Plants and Implications for Food Safety. Annu. Rev. Phytopathol. 2006, 44, 367–392. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Blair, J.M.A.; Webber, M.A.; Baylay, A.J.; Ogbolu, D.O.; Piddock, L.J.V. Molecular Mechanisms of Antibiotic Resistance. Nat. Rev. Microbiol. 2015, 13, 42–51. [Google Scholar] [CrossRef] [PubMed]
  19. Ramirez, M.S.; Tolmasky, M.E. Aminoglycoside Modifying Enzymes. Drug Resist. Updates 2010, 13, 151–171. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Tooke, C.L.; Hinchliffe, P.; Bragginton, E.C.; Colenso, C.K.; Hirvonen, V.H.A.; Takebayashi, Y.; Spencer, J. β-Lactamases and β-Lactamase Inhibitors in the 21st Century. J. Mol. Biol. 2019, 431, 3472–3500. [Google Scholar] [CrossRef] [PubMed]
  21. Munita, J.M.; Arias, C.A. Mechanisms of Antibiotic Resistance. Microbiol. Spectr. 2016, 4. [Google Scholar] [CrossRef] [Green Version]
  22. Du, D.; Wang-Kan, X.; Neuberger, A.; van Veen, H.W.; Pos, K.M.; Piddock, L.J.V.; Luisi, B.F. Multidrug Efflux Pumps: Structure, Function and Regulation. Nat. Rev. Microbiol. 2018, 16, 523–539. [Google Scholar] [CrossRef]
  23. Dönhöfer, A.; Franckenberg, S.; Wickles, S.; Berninghausen, O.; Beckmann, R.; Wilson, D.N. Structural Basis for TetM-Mediated Tetracycline Resistance. Proc. Natl. Acad. Sci. USA 2012, 109, 16900–16905. [Google Scholar] [CrossRef] [Green Version]
  24. Rodríguez-Martínez, J.M.; Cano, M.E.; Velasco, C.; Martínez-Martínez, L.; Pascual, A. Plasmid-Mediated Quinolone Resistance: An Update. J. Infect. Chemother. 2011, 17, 149–182. [Google Scholar] [CrossRef]
  25. Floss, H.G.; Yu, T.-W. Rifamycin-Mode of Action, Resistance, and Biosynthesis. Chem. Rev. 2005, 105, 621–632. [Google Scholar] [CrossRef]
  26. Roberts, M.C. Update on Macrolide-Lincosamide-Streptogramin, Ketolide, and Oxazolidinone Resistance Genes. FEMS Microbiol. Lett. 2008, 282, 147–159. [Google Scholar] [CrossRef] [Green Version]
  27. Levin-Reisman, I.; Brauner, A.; Ronin, I.; Balaban, N.Q. Epistasis between Antibiotic Tolerance, Persistence, and Resistance Mutations. Proc. Natl. Acad. Sci. USA 2019, 116, 14734–14739. [Google Scholar] [CrossRef] [Green Version]
  28. Balaban, N.Q.; Helaine, S.; Lewis, K.; Ackermann, M.; Aldridge, B.; Andersson, D.I.; Brynildsen, M.P.; Bumann, D.; Camilli, A.; Collins, J.J.; et al. Publisher Correction: Definitions and Guidelines for Research on Antibiotic Persistence. Nat. Rev. Microbiol. 2019, 17, 460. [Google Scholar] [CrossRef]
  29. Van den Bergh, B.; Michiels, J.E.; Wenseleers, T.; Windels, E.M.; Boer, P.V.; Kestemont, D.; De Meester, L.; Verstrepen, K.J.; Verstraeten, N.; Fauvart, M.; et al. Frequency of Antibiotic Application Drives Rapid Evolutionary Adaptation of Escherichia Coli Persistence. Nat. Microbiol. 2016, 1, 16020. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. D’Costa, V.M.; King, C.E.; Kalan, L.; Morar, M.; Sung, W.W.L.; Schwarz, C.; Froese, D.; Zazula, G.; Calmels, F.; Debruyne, R.; et al. Antibiotic Resistance Is Ancient. Nature 2011, 477, 457–461. [Google Scholar] [CrossRef] [PubMed]
  31. Wright, G.D.; Poinar, H. Antibiotic Resistance Is Ancient: Implications for Drug Discovery. Trends Microbiol. 2012, 20, 157–159. [Google Scholar] [CrossRef]
  32. Clardy, J.; Fischbach, M.A.; Currie, C.R. The Natural History of Antibiotics. Curr. Biol. 2009, 19, R437–R441. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Nasfi, Z.; Busch, H.; Kehraus, S.; Linares-Otoya, L.; König, G.M.; Schäberle, T.F.; Bachoual, R. Soil Bacteria Isolated From Tunisian Arid Areas Show Promising Antimicrobial Activities Against Gram-Negatives. Front. Microbiol. 2018, 9, 2742. [Google Scholar] [CrossRef] [Green Version]
  34. Mast, Y.; Stegmann, E. Actinomycetes: The Antibiotics Producers. Antibiotics 2019, 8, 105. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Fenical, W.; Jensen, P.R. Developing a New Resource for Drug Discovery: Marine Actinomycete Bacteria. Nat. Chem. Biol. 2006, 2, 666–673. [Google Scholar] [CrossRef]
  36. Kwon, H.C.; Kauffman, C.A.; Jensen, P.R.; Fenical, W. Marinomycins A-D, Antitumor-Antibiotics of a New Structure Class from a Marine Actinomycete of the Recently Discovered Genus “Marinispora”. J. Am. Chem. Soc. 2006, 128, 1622–1632. [Google Scholar] [CrossRef] [PubMed]
  37. Hatosy, S.M.; Martiny, A.C. The Ocean as a Global Reservoir of Antibiotic Resistance Genes. Appl. Environ. Microbiol. 2015, 81, 7593–7599. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Hernández, J.; Stedt, J.; Bonnedahl, J.; Molin, Y.; Drobni, M.; Calisto-Ulloa, N.; Gomez-Fuentes, C.; Astorga-España, M.S.; González-Acuña, D.; Waldenström, J.; et al. Human-Associated Extended-Spectrum β-Lactamase in the Antarctic. Appl. Environ. Microbiol. 2012, 78, 2056–2058. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Villa, F.A.; Gerwick, L. Marine Natural Product Drug Discovery: Leads for Treatment of Inflammation, Cancer, Infections, and Neurological Disorders. Immunopharmacol. Immunotoxicol. 2010, 32, 228–237. [Google Scholar] [CrossRef] [PubMed]
  40. Cueto, M.; Jensen, P.R.; Kauffman, C.; Fenical, W.; Lobkovsky, E.; Clardy, J. Pestalone, a New Antibiotic Produced by a Marine Fungus in Response to Bacterial Challenge. J. Nat. Prod. 2001, 64, 1444–1446. [Google Scholar] [CrossRef]
  41. FDA. Antimicrobials Sold or Distributed for Use in Food-Producing Animals; Food and Drug Administration: Silver Spring, MD, USA, 2016. [Google Scholar]
  42. Williams-Nguyen, J.; Sallach, J.B.; Bartelt-Hunt, S.; Boxall, A.B.; Durso, L.M.; McLain, J.E.; Singer, R.S.; Snow, D.D.; Zilles, J.L. Antibiotics and Antibiotic Resistance in Agroecosystems: State of the Science. J. Environ. Qual. 2016, 45, 394–406. [Google Scholar] [CrossRef] [PubMed]
  43. O’neill, C.B.Y.J. The Review on Antimicrobial Resistance. Available online: https://www.wipo.int/edocs/mdocs/mdocs/en/wipo_who_wto_ip_ge_16/wipo_who_wto_ip_ge_16_www_356156.pdf (accessed on 2 February 2020).
  44. Andersson, D.I.; Hughes, D. Microbiological Effects of Sublethal Levels of Antibiotics. Nat. Rev. Microbiol. 2014, 12, 465–478. [Google Scholar] [CrossRef]
  45. Kaur, S. Molecular Approaches towards Development of Novel Bacillus Thuringiensis Biopesticides. World J. Microbiol. Biotechnol. 2000, 16, 781–793. [Google Scholar] [CrossRef]
  46. Fillinger, U.; Lindsay, S.W. Suppression of Exposure to Malaria Vectors by an Order of Magnitude Using Microbial Larvicides in Rural Kenya. Trop. Med. Int. Health 2006, 11, 1629–1642. [Google Scholar] [CrossRef]
  47. Boyce, R.; Lenhart, A.; Kroeger, A.; Velayudhan, R.; Roberts, B.; Horstick, O. Bacillus Thuringiensis Israelensis (Bti) for the Control of Dengue Vectors: Systematic Literature Review. Trop. Med. Int. Health 2013, 18, 564–577. [Google Scholar] [CrossRef] [PubMed]
  48. Chen, X.-H.; Koumoutsi, A.; Scholz, R.; Borriss, R. More than Anticipated—Production of Antibiotics and Other Secondary Metabolites by Bacillus Amyloliquefaciens FZB42. J. Mol. Microbiol. Biotechnol. 2009, 16, 14–24. [Google Scholar] [CrossRef] [PubMed]
  49. Dimopoulou, A.; Theologidis, I.; Liebmann, B.; Kalantidis, K.; Vassilakos, N.; Skandalis, N. Bacillus Amyloliquefaciens MBI600 Differentially Induces Tomato Defense Signaling Pathways Depending on Plant Part and Dose of Application. Sci. Rep. 2019, 9, 1–2. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  50. Publications Office of the European Union. State of the Art on the Contribution of Water to Antimicrobial Resistance; Publications Office of the European Union: Luxembourg, 2018; ISBN 9789279984785. [Google Scholar]
  51. D’Costa, V.M.; McGrann, K.M.; Hughes, D.W.; Wright, G.D. Sampling the Antibiotic Resistome. Science 2006, 311, 374–377. [Google Scholar] [CrossRef] [Green Version]
  52. Marshall, B.M.; Levy, S.B. Food Animals and Antimicrobials: Impacts on Human Health. Clin. Microbiol. Rev. 2011, 24, 718–733. [Google Scholar] [CrossRef] [Green Version]
  53. Manyi-Loh, C.; Mamphweli, S.; Meyer, E.; Okoh, A. Antibiotic Use in Agriculture and Its Consequential Resistance in Environmental Sources: Potential Public Health Implications. Molecules 2018, 23, 795. [Google Scholar] [CrossRef] [Green Version]
  54. Forsberg, K.J.; Reyes, A.; Wang, B.; Selleck, E.M.; Sommer, M.O.A.; Dantas, G. The Shared Antibiotic Resistome of Soil Bacteria and Human Pathogens. Science 2012, 337, 1107–1111. [Google Scholar] [CrossRef] [Green Version]
  55. Crits-Christoph, A.; Diamond, S.; Butterfield, C.N.; Thomas, B.C.; Banfield, J.F. Novel Soil Bacteria Possess Diverse Genes for Secondary Metabolite Biosynthesis. Nature 2018, 558, 440–444. [Google Scholar] [CrossRef] [PubMed]
  56. Yang, Y.; Wu, R.; Hu, J.; Xing, S.; Huang, C.; Mi, J.; Liao, X. Dominant Denitrifying Bacteria Are Important Hosts of Antibiotic Resistance Genes in Pig Farm Anoxic-Oxic Wastewater Treatment Processes. Environ. Int. 2020, 143, 105897. [Google Scholar] [CrossRef]
  57. Luczkiewicz, A.; Kotlarska, E.; Artichowicz, W.; Tarasewicz, K.; Fudala-Ksiazek, S. Antimicrobial Resistance of Pseudomonas Spp. Isolated from Wastewater and Wastewater-Impacted Marine Coastal Zone. Environ. Sci. Pollut. Res. Int. 2015, 22, 19823–19834. [Google Scholar] [CrossRef] [Green Version]
  58. Molecular Characterization of Clinical and Environmental Pseudomonas Aeruginosa Isolated in a Burn Center. Saudi J. Biol. Sci. 2019, 26, 1731–1736. [CrossRef] [PubMed]
  59. Monitoring of Indicator and Multidrug Resistant Bacteria in Agricultural Soils under Different Irrigation Patterns. Agric. Water Manag. 2017, 184, 19–27. [CrossRef]
  60. Dantas, G.; Sommer, M.O.A.; Oluwasegun, R.D.; Church, G.M. Bacteria Subsisting on Antibiotics. Science 2008, 320, 100–103. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  61. Maeusli, M.; Lee, B.; Miller, S.; Reyna, Z.; Lu, P.; Yan, J.; Ulhaq, A.; Skandalis, N.; Spellberg, B.; Luna, B. Horizontal Gene Transfer of Antibiotic Resistance from Acinetobacter Baylyi to Escherichia Coli on Lettuce and Subsequent Antibiotic Resistance Transmission to the Gut Microbiome. mSphere 2020, 5. [Google Scholar] [CrossRef]
  62. Port, J.A.; Wallace, J.C.; Griffith, W.C.; Faustman, E.M. Metagenomic Profiling of Microbial Composition and Antibiotic Resistance Determinants in Puget Sound. PLoS ONE 2012, 7, e48000. [Google Scholar]
  63. Felis, E.; Kalka, J.; Sochacki, A.; Kowalska, K.; Bajkacz, S.; Harnisz, M.; Korzeniewska, E. Antimicrobial Pharmaceuticals in the Aquatic Environment—Occurrence and Environmental Implications. Eur. J. Pharmacol. 2020, 866, 172813. [Google Scholar] [CrossRef]
  64. Zhang, Y.; Zhang, C.; Parker, D.B.; Snow, D.D.; Zhou, Z.; Li, X. Occurrence of Antimicrobials and Antimicrobial Resistance Genes in Beef Cattle Storage Ponds and Swine Treatment Lagoons. Sci. Total Environ. 2013, 463–464, 631–638. [Google Scholar] [CrossRef] [Green Version]
  65. Martiny, A.C.; Martiny, J.B.H.; Weihe, C.; Field, A.; Ellis, J.C. Functional Metagenomics Reveals Previously Unrecognized Diversity of Antibiotic Resistance Genes in Gulls. Front. Microbiol. 2011, 2, 238. [Google Scholar] [CrossRef] [Green Version]
  66. Foti, M.; Giacopello, C.; Bottari, T.; Fisichella, V.; Rinaldo, D.; Mammina, C. Antibiotic Resistance of Gram Negatives Isolates from Loggerhead Sea Turtles (Caretta Caretta) in the Central Mediterranean Sea. Mar. Pollut. Bull. 2009, 58, 1363–1366. [Google Scholar] [CrossRef]
  67. Jara, D.; Bello-Toledo, H.; Domínguez, M.; Cigarroa, C.; Fernández, P.; Vergara, L.; Quezada-Aguiluz, M.; Opazo-Capurro, A.; Lima, C.A.; González-Rocha, G. Antibiotic Resistance in Bacterial Isolates from Freshwater Samples in Fildes Peninsula, King George Island, Antarctica. Sci. Rep. 2020, 10, 3145. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Rabbia, V.; Bello-Toledo, H.; Jiménez, S.; Quezada, M.; Domínguez, M.; Vergara, L.; Gómez-Fuentes, C.; Calisto-Ulloa, N.; González-Acuña, D.; López, J.; et al. Antibiotic Resistance in Escherichia Coli Strains Isolated from Antarctic Bird Feces, Water from inside a Wastewater Treatment Plant, and Seawater Samples Collected in the Antarctic Treaty Area. Polar Sci. 2016, 10, 123–131. [Google Scholar] [CrossRef]
  69. Miller, R.V.; Gammon, K.; Day, M.J. Antibiotic Resistance among Bacteria Isolated from Seawater and Penguin Fecal Samples Collected near Palmer Station, Antarctica. Can. J. Microbiol. 2009, 55, 37–45. [Google Scholar] [CrossRef]
  70. Dafforn, K.A.; Lewis, J.A.; Johnston, E.L. Antifouling Strategies: History and Regulation, Ecological Impacts and Mitigation. Mar. Pollut. Bull. 2011, 62, 453–465. [Google Scholar] [CrossRef]
  71. Li, Z.; Ma, Z.; van der Kuijp, T.J.; Yuan, Z.; Huang, L. A Review of Soil Heavy Metal Pollution from Mines in China: Pollution and Health Risk Assessment. Sci. Total Environ. 2014, 468, 843–853. [Google Scholar] [CrossRef]
  72. Chowdhury, S.; Mazumder, M.A.J.; Al-Attas, O.; Husain, T. Heavy Metals in Drinking Water: Occurrences, Implications, and Future Needs in Developing Countries. Sci. Total Environ. 2016, 569–570, 476–488. [Google Scholar] [CrossRef]
  73. Subcommittee on Economic and Consumer Policy, Committee on Oversight and Reform. Baby Foods Are Tainted with Dangerous Levels of Arsenic, Lead, Cadmium, and Mercury; U.S. House of Representatives: Washington, DC, USA, 2021. [Google Scholar]
  74. Tchounwou, P.B.; Yedjou, C.G.; Patlolla, A.K.; Sutton, D.J. Heavy Metal Toxicity and the Environment. Exp. Suppl. 2012, 101, 133–164. [Google Scholar]
  75. Nies, D.H. Microbial Heavy-Metal Resistance. Appl. Microbiol. Biotechnol. 1999, 51, 730–750. [Google Scholar] [CrossRef]
  76. Seiler, C.; Berendonk, T.U. Heavy Metal Driven Co-Selection of Antibiotic Resistance in Soil and Water Bodies Impacted by Agriculture and Aquaculture. Front. Microbiol. 2012, 3. [Google Scholar] [CrossRef] [Green Version]
  77. Li, L.G.; Xia, Y.; Zhang, T. Co-Occurrence of Antibiotic and Metal Resistance Genes Revealed in Complete Genome Collection. ISME J. 2017, 11, 651–662. [Google Scholar] [CrossRef]
  78. Pal, C.; Bengtsson-Palme, J.; Rensing, C.; Kristiansson, E.; Larsson, D.G.J. BacMet: Antibacterial Biocide and Metal Resistance Genes Database. Nucleic Acids Res. 2014, 42, 737–743. [Google Scholar] [CrossRef] [Green Version]
  79. Wales, A.D.; Davies, R.H. Co-Selection of Resistance to Antibiotics, Biocides and Heavy Metals, and Its Relevance to Foodborne Pathogens. Antibiotics 2015, 4, 567–604. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Scientific Committee on Emerging and Newly Identified Health Risks Assessment of the Antibiotic Resistance Effects of Biocides. Available online: https://ec.europa.eu/health/ph_risk/committees/04_scenihr/docs/scenihr_o_021.pdf (accessed on 20 March 2021).
  81. Maillard, J.-Y. Resistance of Bacteria to Biocides. Microbiol. Spectr. 2018, 6. [Google Scholar] [CrossRef]
  82. Paul, D.; Mondal, S.K.; Mandal, S.M. Biologia Futura: Use of Biocides during COVID-19-Global Reshuffling of the Microbiota. Biol. Futur. 2021. [Google Scholar] [CrossRef]
  83. Kumar, K.S.; Priya, S.M.; Peck, A.M.; Sajwan, K.S. Mass Loadings of Triclosan and Triclocarbon from Four Wastewater Treatment Plants to Three Rivers and Landfill in Savannah, Georgia, USA. Arch. Environ. Contam. Toxicol. 2010, 58, 275–285. [Google Scholar] [CrossRef]
  84. Juksu, K.; Zhao, J.-L.; Liu, Y.-S.; Yao, L.; Sarin, C.; Sreesai, S.; Klomjek, P.; Jiang, Y.-X.; Ying, G.-G. Occurrence, Fate and Risk Assessment of Biocides in Wastewater Treatment Plants and Aquatic Environments in Thailand. Sci. Total Environ. 2019, 690, 1110–1119. [Google Scholar] [CrossRef]
  85. Gnanadhas, D.P.; Marathe, S.A.; Chakravortty, D. Biocides--Resistance, Cross-Resistance Mechanisms and Assessment. Expert Opin. Investig. Drugs 2013, 22, 191–206. [Google Scholar] [CrossRef]
  86. McMurry, L.M.; McDermott, P.F.; Levy, S.B. Genetic Evidence That InhA of Mycobacterium Smegmatis Is a Target for Triclosan. Antimicrob. Agents Chemother. 1999, 43, 711–713. [Google Scholar] [CrossRef] [Green Version]
  87. Heath, R.J.; Li, J.; Roland, G.E.; Rock, C.O. Inhibition of the Staphylococcus Aureus NADPH-Dependent Enoyl-Acyl Carrier Protein Reductase by Triclosan and Hexachlorophene. J. Biol. Chem. 2000, 275, 4654–4659. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Tattawasart, U.; Maillard, J.Y.; Furr, J.R.; Russell, A.D. Development of Resistance to Chlorhexidine Diacetate and Cetylpyridinium Chloride in Pseudomonas Stutzeri and Changes in Antibiotic Susceptibility. J. Hosp. Infect. 1999, 42, 219–229. [Google Scholar] [CrossRef]
  89. Winder, C.L.; Al-Adham, I.S.; Abdel Malek, S.M.; Buultjens, T.E.; Horrocks, A.J.; Collier, P.J. Outer Membrane Protein Shifts in Biocide-Resistant Pseudomonas Aeruginosa PAO1. J. Appl. Microbiol. 2000, 89, 289–295. [Google Scholar] [CrossRef]
  90. Rouch, D.A.; Cram, D.S.; DiBerardino, D.; Littlejohn, T.G.; Skurray, R.A. Efflux-Mediated Antiseptic Resistance Gene qacA from Staphylococcus Aureus: Common Ancestry with Tetracycline- and Sugar-Transport Proteins. Mol. Microbiol. 1990, 4, 2051–2062. [Google Scholar] [CrossRef]
  91. Heir, E.; Sundheim, G.; Holck, A.L. The Staphylococcus qacH Gene Product: A New Member of the SMR Family Encoding Multidrug Resistance. FEMS Microbiol. Lett. 1998, 163, 49–56. [Google Scholar] [CrossRef] [Green Version]
  92. Nishihara, T.; Okamoto, T.; Nishiyama, N. Biodegradation of Didecyldimethylammonium Chloride by Pseudomonas Fluorescens TN4 Isolated from Activated Sludge. J. Appl. Microbiol. 2000, 88, 641–647. [Google Scholar] [CrossRef]
  93. Meade, M.J.; Waddell, R.L.; Callahan, T.M. Soil Bacteria Pseudomonas Putida and Alcaligenes Xylosoxidans Subsp. Denitrificans Inactivate Triclosan in Liquid and Solid Substrates. FEMS Microbiol. Lett. 2001, 204, 45–48. [Google Scholar] [CrossRef] [Green Version]
  94. Kampf, G. Biocidal Agents Used for Disinfection Can Enhance Antibiotic Resistance in Gram-Negative Species. Antibiotics 2018, 7, 110. [Google Scholar] [CrossRef] [Green Version]
  95. Tandukar, M.; Oh, S.; Tezel, U.; Konstantinidis, K.T.; Pavlostathis, S.G. Long-Term Exposure to Benzalkonium Chloride Disinfectants Results in Change of Microbial Community Structure and Increased Antimicrobial Resistance. Environ. Sci. Technol. 2013, 47, 9730–9738. [Google Scholar] [CrossRef]
  96. Morita, Y.; Murata, T.; Mima, T.; Shiota, S.; Kuroda, T.; Mizushima, T.; Gotoh, N.; Nishino, T.; Tsuchiya, T. Induction of mexCD-oprJ Operon for a Multidrug Efflux Pump by Disinfectants in Wild-Type Pseudomonas Aeruginosa PAO1. J. Antimicrob. Chemother. 2003, 51, 991–994. [Google Scholar] [CrossRef] [Green Version]
  97. Shigemura, K.; Osawa, K.; Kato, A.; Tokimatsu, I.; Arakawa, S.; Shirakawa, T.; Fujisawa, M. Association of Overexpression of Efflux Pump Genes with Antibiotic Resistance in Pseudomonas Aeruginosa Strains Clinically Isolated from Urinary Tract Infection Patients. J. Antibiot. 2015, 68, 568–572. [Google Scholar] [CrossRef]
  98. Jutkina, J.; Marathe, N.P.; Flach, C.-F.; Larsson, D.G.J. Antibiotics and Common Antibacterial Biocides Stimulate Horizontal Transfer of Resistance at Low Concentrations. Sci. Total Environ. 2018, 616, 172–178. [Google Scholar] [CrossRef]
  99. Zeng, W.; Xu, W.; Xu, Y.; Liao, W.; Zhao, Y.; Zheng, X.; Xu, C.; Zhou, T.; Cao, J. The Prevalence and Mechanism of Triclosan Resistance in Escherichia Coli Isolated from Urine Samples in Wenzhou, China. Antimicrob. Resist. Infect. Control. 2020, 9, 1–10. [Google Scholar] [CrossRef]
  100. Potenski, C.J.; Gandhi, M.; Matthews, K.R. Exposure of Salmonella Enteritidis to Chlorine or Food Preservatives Increases Susceptibility to Antibiotics. FEMS Microbiol. Lett. 2003, 220, 181–186. [Google Scholar] [CrossRef] [Green Version]
  101. Hardy, K.; Sunnucks, K.; Gil, H.; Shabir, S.; Trampari, E.; Hawkey, P.; Webber, M. Increased Usage of Antiseptics Is Associated with Reduced Susceptibility in Clinical Isolates of Staphylococcus Aureus. MBio 2018, 9. [Google Scholar] [CrossRef] [Green Version]
  102. Centers for Disease Control and Prevention. Antibiotic Resistance from the Farm to the Table. Available online: https://www.cdc.gov/foodsafety/pdfs/ar-infographic-508c.pdf (accessed on 24 August 2017).
  103. Spellberg, B.; Hansen, G.R.; Kar, A.; Cordova, C.D.; Price, L.B.; Johnson, J.R. Antibiotic Resistance in Humans and Animals. NAM Perspect. 2016. Discussion paper 6. [Google Scholar] [CrossRef] [Green Version]
  104. Nadimpalli, M.; Delarocque-Astagneau, E.; Love, D.C.; Price, L.B.; Huynh, B.-T.; Collard, J.-M.; Lay, K.S.; Borand, L.; Ndir, A.; Walsh, T.R.; et al. Combating Global Antibiotic Resistance: Emerging One Health Concerns in Lower- and Middle-Income Countries. Clin. Infect. Dis. 2018, 66, 963–969. [Google Scholar] [CrossRef]
  105. Food and Drug Administration. Food and Drug Administration 2018 Summary Report on Antimicrobials Sold or Distributed for Use in Food-Producing Animals; Food and Drug Administration: Silver Spring, MD, USA, 2018. [Google Scholar]
  106. Neyra, R.C.; Frisancho, J.A.; Rinsky, J.L.; Resnick, C.; Carroll, K.C.; Rule, A.M.; Ross, T.; You, Y.; Price, L.B.; Silbergeld, E.K. Multidrug-Resistant and Methicillin-Resistant Staphylococcus Aureus (MRSA) in Hog Slaughter and Processing Plant Workers and Their Community in North Carolina (USA). Environ. Health Perspect. 2014, 122, 471–477. [Google Scholar] [CrossRef] [Green Version]
  107. Verraes, C.; Van Boxstael, S.; Van Meervenne, E.; Van Coillie, E.; Butaye, P.; Catry, B.; de Schaetzen, M.-A.; Van Huffel, X.; Imberechts, H.; Dierick, K.; et al. Antimicrobial Resistance in the Food Chain: A Review. Int. J. Environ. Res. Public Health 2013, 10, 2643–2669. [Google Scholar] [CrossRef] [Green Version]
  108. Tschudin-Sutter, S.; Frei, R.; Stephan, R.; Hächler, H.; Nogarth, D.; Widmer, A.F. Extended-Spectrum β-Lactamase (ESBL)-Producing Enterobacteriaceae: A Threat from the Kitchen. Infect. Control. Hosp. Epidemiol. 2014, 35, 581–584. [Google Scholar] [CrossRef] [Green Version]
  109. McMahon, M.A.S.; Xu, J.; Moore, J.E.; Blair, I.S.; McDowell, D.A. Environmental Stress and Antibiotic Resistance in Food-Related Pathogens. Appl. Environ. Microbiol. 2007, 73, 211–217. [Google Scholar] [CrossRef] [Green Version]
  110. Srinivasan, V.; Nguyen, L.T.; Headrick, S.I.; Murinda, S.E.; Oliver, S.P. Antimicrobial Resistance Patterns of Shiga Toxin-Producing Escherichia Coli O157:H7 and O157:H7- from Different Origins. Microb. Drug Resist. 2007, 13, 44–51. [Google Scholar] [CrossRef]
  111. Mayrhofer, S.; Paulsen, P.; Smulders, F.J.M.; Hilbert, F. Antimicrobial Resistance in Commensal Escherichia Coli Isolated from Muscle Foods as Related to the Veterinary Use of Antimicrobial Agents in Food-Producing Animals in Austria. Microb. Drug Resist. 2006, 12, 278–283. [Google Scholar] [CrossRef]
  112. Rahman, M.M.; Husna, A.; Elshabrawy, H.A.; Alam, J.; Runa, N.Y.; Badruzzaman, A.T.M.; Banu, N.A.; Al Mamun, M.; Paul, B.; Das, S.; et al. Isolation and Molecular Characterization of Multidrug-Resistant Escherichia Coli from Chicken Meat. Sci. Rep. 2020, 10, 21999. [Google Scholar] [CrossRef]
  113. Food and Agriculture Organization of the United Nations. 2018 The State of World Fisheries and Aquaculture: Meeting the Sustainable Development Goals; FAO: Rome, Italy, 2018; ISBN 9789251305621. [Google Scholar]
  114. Lewis, G.; Wang, B.; Shafiei Jahani, P.; Hurrell, B.P.; Banie, H.; Aleman Muench, G.R.; Maazi, H.; Helou, D.G.; Howard, E.; Galle-Treger, L.; et al. Dietary Fiber-Induced Microbial Short Chain Fatty Acids Suppress ILC2-Dependent Airway Inflammation. Front. Immunol. 2019, 10, 2051. [Google Scholar] [CrossRef] [Green Version]
  115. Cabello, F.C.; Godfrey, H.P.; Buschmann, A.H.; Dölz, H.J. Aquaculture as yet Another Environmental Gateway to the Development and Globalisation of Antimicrobial Resistance. Lancet Infect. Dis. 2016, 16, e127–e133. [Google Scholar] [CrossRef]
  116. Watts, J.E.M.; Schreier, H.J.; Lanska, L.; Hale, M.S. The Rising Tide of Antimicrobial Resistance in Aquaculture: Sources, Sinks and Solutions. Mar. Drugs 2017, 15, 158. [Google Scholar] [CrossRef] [Green Version]
  117. Ryu, S.-H.; Park, S.-G.; Choi, S.-M.; Hwang, Y.-O.; Ham, H.-J.; Kim, S.-U.; Lee, Y.-K.; Kim, M.-S.; Park, G.-Y.; Kim, K.-S.; et al. Antimicrobial Resistance and Resistance Genes in Escherichia Coli Strains Isolated from Commercial Fish and Seafood. Int. J. Food Microbiol. 2012, 152, 14–18. [Google Scholar] [CrossRef]
  118. Furushita, M.; Shiba, T.; Maeda, T.; Yahata, M.; Kaneoka, A.; Takahashi, Y.; Torii, K.; Hasegawa, T.; Ohta, M. Similarity of Tetracycline Resistance Genes Isolated from Fish Farm Bacteria to Those from Clinical Isolates. Appl. Environ. Microbiol. 2003, 69, 5336–5342. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  119. He, Y.; Jin, L.; Sun, F.; Hu, Q.; Chen, L. Antibiotic and Heavy-Metal Resistance of Vibrio Parahaemolyticus Isolated from Fresh Shrimps in Shanghai Fish Markets, China. Environ. Sci. Pollut. Res. Int. 2016, 23, 15033–15040. [Google Scholar] [CrossRef] [Green Version]
  120. Santos, L.; Ramos, F. Antimicrobial Resistance in Aquaculture: Current Knowledge and Alternatives to Tackle the Problem. Int. J. Antimicrob. Agents 2018, 52, 135–143. [Google Scholar] [CrossRef]
  121. Centers for Disease Control and Prevention. Antibiotic/Antimicrobial Resistance (AR/AMR). Available online: https://www.cdc.gov/drugresistance/about.html (accessed on 11 November 2020).
  122. Carvalheira, A.; Silva, J.; Teixeira, P. Lettuce and Fruits as a Source of Multidrug Resistant Acinetobacter spp. Food Microbiol. 2017, 64, 119–125. [Google Scholar] [CrossRef]
  123. Bezanson, G.S.; MacInnis, R.; Potter, G.; Hughes, T. Presence and Potential for Horizontal Transfer of Antibiotic Resistance in Oxidase-Positive Bacteria Populating Raw Salad Vegetables. Int. J. Food Microbiol. 2008, 127, 37–42. [Google Scholar] [CrossRef]
  124. Hölzel, C.S.; Tetens, J.L.; Schwaiger, K. Unraveling the Role of Vegetables in Spreading Antimicrobial-Resistant Bacteria: A Need for Quantitative Risk Assessment. Foodborne Pathog. Dis. 2018, 15, 671–688. [Google Scholar] [CrossRef]
  125. O’Flaherty, E.; Solimini, A.G.; Pantanella, F.; De Giusti, M.; Cummins, E. Human Exposure to Antibiotic Resistant-Escherichia Coli through Irrigated Lettuce. Environ. Int. 2019, 122, 270–280. [Google Scholar] [CrossRef]
  126. Munther, D.S.; Carter, M.Q.; Aldric, C.V.; Ivanek, R.; Brandl, M.T. Formation of Escherichia Coli O157:H7 Persister Cells in the Lettuce Phyllosphere and Application of Differential Equation Models To Predict Their Prevalence on Lettuce Plants in the Field. Appl. Environ. Microbiol. 2020, 86. [Google Scholar] [CrossRef]
  127. Bakkeren, E.; Huisman, J.S.; Fattinger, S.A.; Hausmann, A.; Furter, M.; Egli, A.; Slack, E.; Sellin, M.E.; Bonhoeffer, S.; Regoes, R.R.; et al. Salmonella Persisters Promote the Spread of Antibiotic Resistance Plasmids in the Gut. Nature 2019, 573, 270–280. [Google Scholar] [CrossRef]
  128. Sundin, G.W.; Wang, N. Antibiotic Resistance in Plant-Pathogenic Bacteria. Annu. Rev. Phytopathol. 2018, 56, 161–180. [Google Scholar] [CrossRef]
  129. Catara, V. Pseudomonas Corrugata: Plant Pathogen and/or Biological Resource? Mol. Plant. Pathol. 2007, 8, 233–244. [Google Scholar] [CrossRef]
  130. National Committee for Clinical Laboratory Standards, USA. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Third Informational Supplement; CLSI: Annapolis Junction, MD, USA, 2013. [Google Scholar]
  131. Pérombelon, M.C.M. Potato Diseases Caused by Soft Rot Erwinias: An Overview of Pathogenesis. Plant. Pathol. 2002, 51, 1–12. [Google Scholar] [CrossRef]
  132. Schnepf, E.; Crickmore, N.; Van Rie, J.; Lereclus, D.; Baum, J.; Feitelson, J.; Zeigler, D.R.; Dean, D.H. Bacillus Thuringiensis and Its Pesticidal Crystal Proteins. Microbiol. Mol. Biol. Rev. 1998, 62, 775–806. [Google Scholar] [CrossRef] [Green Version]
  133. National Committee for Clinical Laboratory Standards, USA. Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria. Available online: https://clsi.org/standards/products/microbiology/documents/m45/ (accessed on 2 September 2020).
  134. Varympopi, A.; Dimopoulou, A.; Theologidis, I.; Karamanidou, T.; Kaldeli Kerou, A.; Vlachou, A.; Karfaridis, D.; Papafotis, D.; Hatzinikolaou, D.G.; Tsouknidas, A.; et al. Bactericides Based on Copper Nanoparticles Restrain Growth of Important Plant Pathogens. Pathogens 2020, 9, 1024. [Google Scholar] [CrossRef]
  135. Skandalis, N.; Dimopoulou, A.; Georgopoulou, A.; Gallios, N.; Papadopoulos, D.; Tsipas, D.; Theologidis, I.; Michailidis, N.; Chatzinikolaidou, M. The Effect of Silver Nanoparticles Size, Produced Using Plant Extract from Arbutus Unedo, on Their Antibacterial Efficacy. Nanomaterials 2017, 7, 178. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Huijbers, P.M.C.; Blaak, H.; de Jong, M.C.M.; Graat, E.A.M.; Vandenbroucke-Grauls, C.M.J.E.; de Roda Husman, A.M. Role of the Environment in the Transmission of Antimicrobial Resistance to Humans: A Review. Environ. Sci. Technol. 2015, 49, 11993–12004. [Google Scholar] [CrossRef]
  137. Gurnee, E.A.; Ndao, I.M.; Johnson, J.R.; Johnston, B.D.; Gonzalez, M.D.; Burnham, C.-A.D.; Hall-Moore, C.M.; McGhee, J.E.; Mellmann, A.; Warner, B.B.; et al. Gut Colonization of Healthy Children and Their Mothers With Pathogenic Ciprofloxacin-Resistant Escherichia coli. J. Infect. Dis. 2015, 212, 1862–1868. [Google Scholar] [CrossRef] [Green Version]
  138. Jernigan, J.A.; Hatfield, K.M.; Wolford, H.; Nelson, R.E.; Olubajo, B.; Reddy, S.C.; McCarthy, N.; Paul, P.; McDonald, L.C.; Kallen, A.; et al. Multidrug-Resistant Bacterial Infections in U.S. Hospitalized Patients, 2012–2017. N. Engl. J. Med. 2020, 382, 1309–1319. [Google Scholar] [CrossRef] [PubMed]
  139. Stadler, T.; Meinel, D.; Aguilar-Bultet, L.; Huisman, J.S.; Schindler, R.; Egli, A.; Seth-Smith, H.M.B.; Eichenberger, L.; Brodmann, P.; Hübner, P.; et al. Transmission of ESBL-Producing Enterobacteriaceae and Their Mobile Genetic Elements-Identification of Sources by Whole Genome Sequencing: Study Protocol for an Observational Study in Switzerland. BMJ Open 2018, 8, e021823. [Google Scholar] [CrossRef] [PubMed]
  140. Cassini, A.; Högberg, L.D.; Plachouras, D.; Quattrocchi, A.; Hoxha, A.; Simonsen, G.S.; Colomb-Cotinat, M.; Kretzschmar, M.E.; Devleesschauwer, B.; Cecchini, M.; et al. Attributable Deaths and Disability-Adjusted Life-Years Caused by Infections with Antibiotic-Resistant Bacteria in the EU and the European Economic Area in 2015: A Population-Level Modelling Analysis. Lancet Infect. Dis. 2018. [Google Scholar] [CrossRef] [Green Version]
  141. Weingarten, R.A.; Johnson, R.C.; Conlan, S.; Ramsburg, A.M.; Dekker, J.P.; Lau, A.F.; Khil, P.; Odom, R.T.; Deming, C.; Park, M.; et al. Genomic Analysis of Hospital Plumbing Reveals Diverse Reservoir of Bacterial Plasmids Conferring Carbapenem Resistance. MBio 2018, 9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  142. D’Souza, A.W.; Potter, R.F.; Wallace, M.; Shupe, A.; Patel, S.; Sun, X.; Gul, D.; Kwon, J.H.; Andleeb, S.; Burnham, C.-A.D.; et al. Spatiotemporal Dynamics of Multidrug Resistant Bacteria on Intensive Care Unit Surfaces. Nat. Commun. 2019, 10, 4569. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Hu, H.; Johani, K.; Gosbell, I.B.; Jacombs, A.S.W.; Almatroudi, A.; Whiteley, G.S.; Deva, A.K.; Jensen, S.; Vickery, K. Intensive Care Unit Environmental Surfaces Are Contaminated by Multidrug-Resistant Bacteria in Biofilms: Combined Results of Conventional Culture, Pyrosequencing, Scanning Electron Microscopy, and Confocal Laser Microscopy. J. Hosp. Infect. 2015, 91, 35–44. [Google Scholar] [CrossRef]
  144. Muloi, D.; Ward, M.J.; Pedersen, A.B.; Fèvre, E.M.; Woolhouse, M.E.J.; van Bunnik, B.A.D. Are Food Animals Responsible for Transfer of Antimicrobial-Resistant Escherichia Coli or Their Resistance Determinants to Human Populations? A Systematic Review. Foodborne Pathog. Dis. 2018, 15, 467–474. [Google Scholar] [CrossRef] [Green Version]
  145. Peter, S.; Bosio, M.; Gross, C.; Bezdan, D.; Gutierrez, J.; Oberhettinger, P.; Liese, J.; Vogel, W.; Dörfel, D.; Berger, L.; et al. Tracking of Antibiotic Resistance Transfer and Rapid Plasmid Evolution in a Hospital Setting by Nanopore Sequencing. mSphere 2020, 5. [Google Scholar] [CrossRef]
  146. Evans, D.R.; Griffith, M.P.; Sundermann, A.J.; Shutt, K.A.; Saul, M.I.; Mustapha, M.M.; Marsh, J.W.; Cooper, V.S.; Harrison, L.H.; Van Tyne, D. Systematic Detection of Horizontal Gene Transfer across Genera among Multidrug-Resistant Bacteria in a Single Hospital. eLife 2020, 9, e53886. [Google Scholar] [CrossRef] [PubMed]
  147. Hurdle, J.G.; O’Neill, A.J.; Mody, L.; Chopra, I.; Bradley, S.F. In Vivo Transfer of High-Level Mupirocin Resistance from Staphylococcus Epidermidis to Methicillin-Resistant Staphylococcus Aureus Associated with Failure of Mupirocin Prophylaxis. J. Antimicrob. Chemother. 2005, 56, 1166–1168. [Google Scholar] [CrossRef] [Green Version]
  148. Conlan, S.; Lau, A.F.; Deming, C.; Spalding, C.D.; Lee-Lin, S.; Thomas, P.J.; Park, M.; Dekker, J.P.; Frank, K.M.; Palmore, T.N.; et al. Plasmid Dissemination and Selection of a Multidrug-Resistant Klebsiella Pneumoniae Strain during Transplant-Associated Antibiotic Therapy. MBio 2019, 10. [Google Scholar] [CrossRef] [Green Version]
  149. Conlan, S.; Park, M.; Deming, C.; Thomas, P.J.; Young, A.C.; Coleman, H.; Sison, C.; Weingarten, R.A.; Lau, A.F.; NISC Comparative Sequencing Program. Plasmid Dynamics in KPC-Positive Klebsiella Pneumoniae during Long-Term Patient Colonization. MBio 2016, 7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  150. León-Sampedro, R.; DelaFuente, J.; Díaz-Agero, C.; Crellen, T.; Musicha, P.; Rodríguez-Beltrán, J.; de la Vega, C.; Hernández-García, M.; López-Fresneña, N.; R-GNOSIS WP5 Study Group. Pervasive Transmission of a Carbapenem Resistance Plasmid in the Gut Microbiota of Hospitalized Patients. Nat. Microbiol. 2021, 6, 606–616. [Google Scholar] [CrossRef] [PubMed]
Antibiotics 10 00640 g001 550
Figure 1. The selective flow of ARGs from the environment to clinic. Clinical, agricultural, and natural antibiotics as well as biocides and heavy metals select for ARGs and contaminate plant, animal, and fish products. Contaminated foods end up into the gastrointestinal tract of humans, where antibiotic resistance emerges from antibiotic presence or is transferred from ARGs to gut microbiota. The endpoints of this antibiotic resistance transmission are human pathogens, which develop AR infections. Created with BioRender.com, accessed on 21 January 2020.
Figure 1. The selective flow of ARGs from the environment to clinic. Clinical, agricultural, and natural antibiotics as well as biocides and heavy metals select for ARGs and contaminate plant, animal, and fish products. Contaminated foods end up into the gastrointestinal tract of humans, where antibiotic resistance emerges from antibiotic presence or is transferred from ARGs to gut microbiota. The endpoints of this antibiotic resistance transmission are human pathogens, which develop AR infections. Created with BioRender.com, accessed on 21 January 2020.
Antibiotics 10 00640 g001
Table
Table 1. Susceptibility testing of the plant-pathogenic bacterium Pseudomonas corrugata. Methods were used as previously described [134,135]. Interpretive criteria (S: susceptible, I: intermediate, and R: resistant) are based on the Clinical and Laboratory Standards Institute breakpoints. Pseudomonas corrugata strain 870 BPIC (Benaki Phytopathological Institute Collection) breakpoints correspond to (a) “other non-Enterobacterales including Pseudomonas spp. but excluding P. aeruginosa” breakpoints [130] (R1, I1, S1 in red); (b) “Pseudomonas. aeruginosa breakpoints [130] (R2, I2, and S2 in blue). Pectobacterium carotovorum subsp carotovorum isolate 3412/17 BPIC breakpoints correspond to “Enterobacterales breakpoints” [130] (R1, I1, and S1 in black). Bacillus thuringiensis sbsp. kurstaki strain ABTS-351 (ATCC-SD-1275) breakpoints correspond to “Bacillus spp. and related genera (not B. anthracis)” breakpoints [135]. AMP: ampicillin, PEN: penicillin, FEP: cefepime, VAN: vancomycin, FOF: fosfomycin, ERY: erythromycin, CLI: clindamycin, GEN: gentamicin, MEM: meropenem, TET: tetracycline, PMB: polymyxin B, CHL: chloramphenicol, CIP: ciprofloxacin, RIF: rifampicin, LCM: lincomycin.
Table 1. Susceptibility testing of the plant-pathogenic bacterium Pseudomonas corrugata. Methods were used as previously described [134,135]. Interpretive criteria (S: susceptible, I: intermediate, and R: resistant) are based on the Clinical and Laboratory Standards Institute breakpoints. Pseudomonas corrugata strain 870 BPIC (Benaki Phytopathological Institute Collection) breakpoints correspond to (a) “other non-Enterobacterales including Pseudomonas spp. but excluding P. aeruginosa” breakpoints [130] (R1, I1, S1 in red); (b) “Pseudomonas. aeruginosa breakpoints [130] (R2, I2, and S2 in blue). Pectobacterium carotovorum subsp carotovorum isolate 3412/17 BPIC breakpoints correspond to “Enterobacterales breakpoints” [130] (R1, I1, and S1 in black). Bacillus thuringiensis sbsp. kurstaki strain ABTS-351 (ATCC-SD-1275) breakpoints correspond to “Bacillus spp. and related genera (not B. anthracis)” breakpoints [135]. AMP: ampicillin, PEN: penicillin, FEP: cefepime, VAN: vancomycin, FOF: fosfomycin, ERY: erythromycin, CLI: clindamycin, GEN: gentamicin, MEM: meropenem, TET: tetracycline, PMB: polymyxin B, CHL: chloramphenicol, CIP: ciprofloxacin, RIF: rifampicin, LCM: lincomycin.
Pseudomonas corrugata
AntibioticAMPPENFEPVANFOFERYCLIGENMEMTETPMBCHLCIPRIFLCM
MIC (mg/L)>32>6432>64256>64>81681>1632<0.532>32
Breakpoint R1 ≥ 32 ≤ R2 R1 ≥ 32 ≤ R2I1 = 8 ≤ R2S1 ≤ 4R2 ≥ 4R1 ≥ 32S1 > 0.5 = S2
Pectobacterium carotovorum sbsp. carotovorum
AntibioticAMPPENFEPVANFOFERYCLIGENMEMTETPMBCHLCIPRIFLCM
MIC (mg/L)>32>648>3212832>832<11<1128<0.54>32
BreakpointR ≥ 32 R ≥ 16 R ≥ 256 R ≥ 16R ≥ 4R ≥ 16R ≥ 4R ≥ 32R ≥ 1
Bacillus thuringiensis sbsp. kurstaki
AntibioticAMPPENFEPVANFOFERYCLIGENMEMTETPMBCHLCIPRIFLCM
MIC (mg/L)3216>64<464>81<2<1<2>16<4<0.5<0.516
BreakpointR ≥ 0.5R ≥ 0.25 S ≤ 4 R ≥ 8R ≥ 4R ≥ 16R ≥ 16R ≥ 16 R ≥ 32R ≥ 4R ≥ 4
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Skandalis, N.; Maeusli, M.; Papafotis, D.; Miller, S.; Lee, B.; Theologidis, I.; Luna, B. Environmental Spread of Antibiotic Resistance. Antibiotics 2021, 10, 640. https://doi.org/10.3390/antibiotics10060640

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Skandalis N, Maeusli M, Papafotis D, Miller S, Lee B, Theologidis I, Luna B. Environmental Spread of Antibiotic Resistance. Antibiotics. 2021; 10(6):640. https://doi.org/10.3390/antibiotics10060640

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Skandalis, Nicholas, Marlène Maeusli, Dimitris Papafotis, Sarah Miller, Bosul Lee, Ioannis Theologidis, and Brian Luna. 2021. "Environmental Spread of Antibiotic Resistance" Antibiotics 10, no. 6: 640. https://doi.org/10.3390/antibiotics10060640

APA Style

Skandalis, N., Maeusli, M., Papafotis, D., Miller, S., Lee, B., Theologidis, I., & Luna, B. (2021). Environmental Spread of Antibiotic Resistance. Antibiotics, 10(6), 640. https://doi.org/10.3390/antibiotics10060640

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