Abstract
The control of infectious diseases has always been a top medical priority. For years during the so-called antibiotic era, we enjoyed prolonged life expectancy and the benefits of superior pathogen control. The devastating failure of the medical system, agriculture and pharmaceutical companies and the general population to appreciate and safeguard these benefits is now leading us into a grim post-antibiotic era. Antimicrobial resistance (AMR) refers to microorganisms becoming resistant to antibiotics that were designed and expected to kill them. Prior to the COVID-19 pandemic, AMR was recognised by the World Health Organization as the central priority area with growing public awareness of the threat AMR now presents. The Review on Antimicrobial Resistance, a project commissioned by the UK government, predicted that the death toll of AMR could be one person every 3 seconds, amounting to 10 million deaths per year by 2050. This review aims to raise awareness of the evergrowing extensiveness of antimicrobial resistance and identify major sources of this adversity, focusing on agriculture’s role in this problem and its solutions.
Keypoints
• Widespread development of antibiotic resistance is a major global health risk.
• Antibiotic resistance is abundant in agricultural produce, soil, food, water, air and probiotics.
• New approaches are being developed to control and reduce antimicrobial resistance.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
The UK review of antimicrobial resistance (AMR) presented now outdated 2014 data on AMR consequences for human life. They estimated that 700,000 people die every year from AMR. This prediction was recently updated with the data from 2019 presenting that the deaths of 4.95 million people were related to drug-resistant bacterial infections and 1.27 million deaths were directly attributable to AMR (Antimicrobial Resistance 2022; Lancet 2022); data was based on 471 million individual records. The estimated death rate was highest in Africa and lowest in Australasia.
In India, a country with high antibiotic use and high AMR, approximately 60,000 newborn babies die each year from antibiotic-resistant neonatal infections (Chaurasia et al. 2019; Laxminarayan et al. 2013). The profile of the most devastating pathogens involved in neonatal sepsis in South Asia points to the dominance of Gram-negative infections; Klebsiella sp., Escherichia coli and Acinetobacter sp. leading the list, with Staphylococcus aureus as the most lethal Gram-positive (Chaurasia et al. 2019). With soaring and out of control global expansion of AMR, it is not surprising that most of these pathogens are multidrug resistant (MDR) and that the victims are very young children and elderly, hinting at the dire predictions that AMR could return the world to middle ages, where high childbirth and neonatal mortality could become a reality again.
The AMR problem is more prominent in low and middle-income countries but by no means restricted to them. There were more than two million AMR infections in the USA in 2016, costing the USA health system 20 billion USD (O’Neill 2016). The UK AMR committee recommended a strong response to AMR (Fig. 1); however, other than agriculture, which was required in many countries to respond to AMR threat and remove antibiotics from production altogether, other directives are lagging far behind on implementation. Some of these directives are very basic, like growing public awareness, improving diagnostics and hygiene worldwide, or continuing to work on antibiotic alternatives, these are suggestions that do not seem like an impossible or unrealistic task, and they are slowly moving forward. Other more complex and funding/investment dependent recommendations like the global coalition, increased funding for research on controlling AMR, better AMR diagnostics and speeding up the development of new antibiotics and vaccines are not progressing as expected, and the lack of progress suggests that these directives were not taken seriously enough. Getting all countries in the world to unite and work together on one task, even if it is survival related, is a mission impossible in a divided world, and pharmaceutical companies are no longer seeing the development of new antibiotics as financially viable.
Many governments have antimicrobial stewardship plans, with some countries moving from words to hard-hitting actions, for example, the ban on nontherapeutic antibiotic use in livestock (Levy 2014) that started in Scandinavia and spread to other countries of the European Union. India, one of the countries in the world known for very high antibiotic use, came up with India’s National Action Plan (NAP) (2017) with objectives comparable to those of O’Neill (2016), and the improvements are already visible (Ranjalkar and Chandy 2019). Although low and middle-income countries are also taking individual approaches to AMR control, there is no global coordination, and as our review will show below, AMR knows no geographic boundaries, and colossal efforts by some countries are undermined by the mild response of others.
Progress in developing diagnostic tools is very slow, and rapid molecular genomics methods are not optimised and developed for mass distribution. Microbial culture followed by susceptibility testing seems to be a widely used solution, and the time delay in identifying the correct treatment can mean the difference between life and death. Global surveillance of AMR is manifested by a range of publications cataloguing AMR genes in different clinical pathogens using hospital samples and data on AMR presence in all aspects of the environment.
The majority of work on alternatives to antibiotics came from the livestock industry (pig, chicken and cattle) because the ban on antibiotic use for growth-promoting purposes resulted in an increase in disease outbreaks since the antibiotics also kept pathogens in check while improving growth performance measures. This dire need induced the industry to invest in research on alternatives to antibiotics, and the market is now flooding with antimicrobial products that have no overlap with antibiotics. Among the most successful and widely used are phytogens, plant antimicrobial products whose antibacterial properties can successfully provide growth-promoting and pathogen controlling effects (Abdelli et al. 2021; Shehata et al. 2022).
In addition to searching for natural alternatives to antibiotics that would not result in AMR cross-resistance, the industry introduced significant changes toward improving animal health, welfare and on-farm biosecurity. On the other hand, the customer-driven shift toward free and open-range production systems aimed at improving animal welfare is backfiring via increased disease outbreaks caused by direct contact of animals with wildlife, insects, soil bacteria, rodents, wild birds, predators and other animals (Phung et al. 2019). The industry also offers a range of new products capable of disturbing biofilms in sheds and equipment or controlling pathogen growth in the litter. However, although it is reasonable to expect that these products would assist in the control of AMR, evidence of this is expected to develop in the future.
Developing new antibiotics seems to be slowly moving from the long break in the 1990s that, not surprisingly, coincides with the beginning of the rise of AMR. Despite having a few new antibiotics in the clinical trial stage, and although they are efficient against some of the major MDR pathogens, they are not based on a novel mode of action and the AMR against them is likely to develop fast (Bettiol and Harbarth 2015). Developing new classes of antibiotics with a novel mode of action would be the only longer-term solution with likely more use time before the AMR genes appear; however, this is now considered a low or no return investment due to the high risk and cost of product development. With antibiotics being steadily turned ineffective by MDR bacteria, the alternative of focusing on the immune response using vaccines and therapeutic monoclonal antibodies is starting to look more attractive.
Major contributors to AMR rise
Despite some effort from developed countries to monitor and reduce AMR, the lack of global effort and international coordination is concerning. The current situation could be defined as the saturation of the human environment, including water, soil, food and air, with high levels of AMR. Major contributors include human and hospital waste and agriculture.
Human and hospital waste
The sewage microbial community comprises mainly human intestinal bacteria and some bacteria that grow on the sewage equipment and system. Antibiotics are developed to be resilient to metabolic degradation and active during biological transit time. It is estimated that 50–80% of antibiotics is excreted in urine and 4–30% in faecal material (Riaz et al. 2020). This indicates that all unmetabolised antibiotics used by the human population, at home and in hospitals, end up in the sewage system. The sewage is saturated with antimicrobial-resistant bacteria (ARB) and their antimicrobial-resistant genes (ARGs). The troubling issue is the abundance of mobile genetic elements (MGEs), such as plasmids, which serve as vectors transferring ARGs between bacterial strains in the sewage environment. Sewage is the breeding ground for new ARBs via ARG transfer.
Unfortunately, wastewater treatment plants (WWTPs) were not designed to remove or reduce AMR contamination (Hiller et al. 2019). On the contrary, some MDR species of Escherichia, Shigella and Klebsiella increase two-fold from raw to treated water. Similarly, total MDR Enterobacteriaceae surged from 5.5 to 14.1% in the treated wastewater. Species like methicillin-resistant Staphylococcus aureus (MRSA) are abundant in raw and treated sewage (Krzemiński et al. 2020). Hospitals often have their own waste treatment facility. However, that is reserved for medical waste rather than the general waste from toilets, kitchens and laundry. There is a whole new level of AMR enrichment in a hospital environment. Here, it is important to note that all hospital waste eventually ends up in sewage and WWTP.
AMR from the agriculture
Agriculture is commonly acknowledged as one of the principal contributors to AMR pollution. With Denmark and other countries of the European Union banning the use of antibiotics in livestock (Levy 2014), the stunned livestock industry finally recognised the urgent need for antibiotic alternatives. Continual use of antibiotics in animal feed controls pathogens and improves performance, but it also alters microbial community depending on the product used (Crisol-Martinez et al. 2017). This can be detrimental in poultry since the industrialised hatching practices involve separating eggs from the mother hen, disinfecting them and hatching in clean and bacteria-deprived environment, resulting in unnatural microbial communities that can only further suffer from continual supplementation of antibiotics in the feed (Stanley et al. 2013). The industry invested in alternative and natural antimicrobial products capable of controlling pathogens, such as biochar (Willson et al. 2019), zeolite (Prasai et al. 2017) or plant-derived complex phytogenic products (Bajagai et al. 2020; Flees et al. 2021; Greene et al. 2021; Wang et al. 2021). Recently, using a mixed phytogenic alternative product, RNAseq analysis showed that herb-based antibiotic alternative triggers ileum gene expression response significantly matching the response to doxycycline and geldanamycin (Bajagai et al. 2022), indicating a broad spectrum of the antibiotic alternative products. The main products of the livestock industry, such as meat, milk or eggs, are meant for human consumption; however, byproducts such as manure play a significant role in other areas of agriculture.
Three major manure types are used in agriculture: bovine, pig and poultry. Although animal manures enrich the soil with essential and rare plant nutrients, they also contain biological impurities that include bacteria, fungi, helminths, parasites and other intestinal and environmental biological contaminants. Antibiotic use in agriculture is a major issue in developing countries (Hosain et al. 2021). Residual concentration of antibiotics in manure may not be very high and is reported commonly as ~ 1–10 mg/kg (Krzemiński et al. 2020); it was estimated that in the last 50 years, more than 1 MT of antibiotics entered the soil via manure (Allen et al. 2010).
The animal manure contains both urinary and faecal excrements, and both are used to excrete unmetabolised antibiotics. In addition to adding antibiotics to the soil via manure, we also add ARB and ARGs. The survival time of pathogens in the soil is up to 10 years, and on plant surfaces, up to 1 year (Krzemiński et al. 2020). Defra project by UK Centre for Ecology & Hydrology (Nicholson et al. 2016) estimated that approximately 96 million tonnes of farm manure are used annually in the UK. With this volume of manure applied worldwide, antibiotic accumulation in the soil is inevitable.
Although manure is a major source of antibiotics, ARG and ARB in the soil, in the USA and many other countries, all manure is considered as an organic product and it can be used on crops grown organically, thus introducing residual excreted antibiotics into organic plants and allowing AMB to colonise plants and ARGs exchange with native farm soil microbiota. As a result, many organic plants carry an abundance of AMR (Roberts 2019). Manure and faecal effluent processing are highly variable, not only on the global scale but also from one farm to another in the same country. Ultimately, all of these biological contaminants end up in food and waterways (Fig. 2).
There is another dimension of the presence of AMR in pig and chicken sheds — farm employees’ welfare and safety. A good example is the UK use of vancomycin-similar drug avoparcin in poultry which resulted in the development of vancomycin-resistant Enterococcus faecium (VRE) in chicken. VRE was then found in processed meat and farmers and abattoir staff slaughtering the VRE + animals, some of whom had to be hospitalised with the VRE infection (Cetinkaya et al. 2000; van den Bogaard et al. 2002). Additionally, van den Bogaard et al. (2002) reported that AMR for nearly all antibiotics was higher in broiler farmers than in egg farmers and slaughterhouse workers. This is in agreement with the higher use of antibiotics in broilers. Moreover, it was reported by multiple investigators that in cattle and swine, faecal AMR decreases as food animals age, but this was not observed in poultry with short production life (Gaire et al. 2020).
Despite much attention to livestock and manure, one of the biggest AMR offenders is aquaculture (Krzemiński et al. 2020). Aquaculture is the fastest-growing food-producing area in the world and is considered by many the future of the food industry. Integrated aquaculture that involves feeding fish livestock manure is a traditional practice of the smaller Asian farms. Tetracyclines were extensively used in aquaculture, and aquaculture is mainly blamed for the broad tet-genes’ distribution in the world. In 2017, 59 tetracycline resistance genes were identified even in the world’s most pristine remote environments like Antarctica and the Arctic (Roberts 2019). It was estimated that 70% of an enormous amount of antibiotics administered in aquaculture end up in waterways. In addition to using and releasing massive amounts of antibiotics into waterways, the aquaculture AMR bio-waste contaminates adjacent soils and waterways’ sediments where it is actively concentrated.
With the rise in seafood consumption, seafood-borne bacterial diseases are becoming more severe health hazards worldwide, and due to antibiotic use in production, it resulted in numerous AMR pathogens outbreaks in the USA (Elbashir et al. 2018). However, there is a considerable discrepancy in antibiotic usage in different countries. For example, antibiotics are used in a wide range — from 1 g/t in Norway to 700 g/t in Vietnam (Defoirdt et al. 2011). Strict government-controlled surveying and transparent antibiotic use reporting in Scandinavian countries, with high use of alternatives to antibiotic use, can be credited for this outstanding practice in Norway (Defoirdt et al. 2011; Krzemiński et al. 2020; Narbonne et al. 2021). Asian countries yield two-thirds of global food fish production, yet concerning levels of resistance to clinically critical antibiotics and high levels of foodborne zoonotic pathogens are evident (Schar et al. 2021), and it resulted in accumulated resistance along with Asia’s major river systems, especially in China and India (Schar et al. 2021). Furthermore, AMR, ARB and ARGs are regularly present in drinking water (Roberts 2019).
AMR in the soil
Soil represents one of the richest microbiota systems, abundant with bacterial and fungal communities, and it is the origin of many clinical antibiotics (Afzaal et al. 2020). Similar to waterways, the soil acts as a major sink that accepts the AMR from major contaminants like hospital waste, wastewater treatment, aquaculture and manure. Although some antibiotics can chemically bond with the soil and persist, soil factors such as soil texture and AMR gene stability play a role in AMR persistence in the soil (Macedo et al. 2020). In addition to antibiotics, many metals in the soil that generate toxic metal resistant bacteria and toxic metal resistant genes show potent cross- and co-resistance to antibiotics and can result in AMR gene emergence without any exposure to antibiotics (Yazdankhah et al. 2018). This is further complicated with both manure and inorganic fertilisers.
AMR in the food
AMR pathogens in human food present a major risk to public health. Food is contaminated by the presence of antibiotics and ARB on food due to the use of antibiotics in production and cross-contamination processing (Verraes et al. 2013). This is of special concern with seafood (Elbashir et al. 2018). ARB and ARG have been identified in tap water and feed, including milk, eggs, meat and vegetables, all of them as processed and unprocessed foods (Roberts 2019); thus, the food chain is one of the principal means of AMR transmission. Although often present in a very low amount on meat, ARBs can often amplify to high numbers due to poor meat handling, storage and hygiene practices (Plaza-Rodriguez et al. 2021).
While ARB and AMR in the meat are a consequence of the contamination in slaughterhouses and processing, vegetables are known to actively uptake antibiotics and AMR genes from the soil or irrigation water (Azanu et al. 2016), especially if the manure is used for fertilising (Tasho and Cho 2016). Wang et al. (2015) and many others reviewed in Tasho and Cho (2016) identified highly abundant ARGs on vegetables growing on soil with more than 3 years of manure usage.
Although very little attention is given to wild animals, the levels of AMR infiltration into their habitat through water, soil, and plants suggest that they could not remain unaffected. Even in wild animals that have minimal contact with humans and live in generally considered pristine environments, ARB, like highly multiresistant MRSA, were detected in dear, boar, wolfs, foxes, pigeons, pheasants and birds of prey (reviewed in Silva et al. 2020).
Fruit and vegetables are declared safe for human use if they have antibiotic residue under the selected maximum threshold. Similarly, fish and seafood heavily treated with antibiotics can be used after being housed in antibiotic-free water for some time, referred to as the withdrawal period (Bhattacharjee 2016). Unfortunately, the antibiotic residue is a much smaller problem than ARB and ARGs in food. Additionally, washing fruit and vegetables in drinking tap water will not help since many researchers detected AMR in tap water (Roberts 2019).
On the other hand, no food is ever sterile, and there are three major types of microbial contamination: resident food microbiota, pathogens and spoilage bacteria. Throughout history, people relied on residential food bacteria to start the process of natural fermentation. Whole grains carry a range of probiotic lactic acid bacteria (Carrizo et al. 2016; Wu et al. 2018) with a range of Lactobacillus Pediococcus, Leuconostoc and Enterococcus species capable of performing sourdough fermentation. Bacterial and fungal endophytes are known as plant probiotics and are extensively documented in grains (Ahlawat et al. 2021; Makar et al. 2021) and legumes (Ruiz Mostacero et al. 2021). Recently microbiota of poultry feed raw ingredients such as meat and bone meal, wheat, corn, canola, barley, soybean, millrun, sorghum, poultry oil, oats, limestone and bloodmeal was described using the 16S methodology (Haberecht et al. 2020).
Likewise, animals’ microbiota is not limited to the intestinal community, and the use of advanced sequencing methodologies challenged the concept of sterile organs, demonstrating that stressful events can trigger massive leaky gut events capable of colonising and infecting the host’s organs (Amar et al. 2011; Stanley et al. 2016). Proteobacteria and Firmicutes are the main members of human blood microbiota, with Proteobacteria present in the blood of more than 80% of healthy human subjects (Paisse et al. 2016). The involvement of tissue bacteria has been investigated in the onset of diseases such as diabetes (Amar et al. 2011) and stroke (Stanley et al. 2016). Furthermore, food processing often adds pathogenic and food spoilage microorganisms and their growth is highly dependent on the storage and packaging conditions and meat residential microbiota structure (Patarata et al. 2020). Despite relatively recent knowledge on natural food microbiota, the bulk of research in this area is focused on foodborne pathogens, ARGs and AMR, without acknowledging the contribution of natural and beneficial microbiota in food products towards AMR load. It is well established that AMR is not exclusive to pathogens but that even probiotic species carry and disseminate AMR (Baumgardner et al. 2021). This could be highly overestimating the role and danger of AMR in the feed, and the actual risk of AMR in food should be further investigated, taking into account the origin of the AMR detected.
AMR in the air
Although it may seem implausible, AMR and ARGs have been isolated from the air, especially in highly industrialised countries. Li and colleagues (2018) conducted a well-known study investigating air samples from 19 major cities worldwide and screening 30 ARGs. The ARGs were detected to vary by nearly 100-fold in different cities. The highest number of ARGs was detected in Bejing, and San Francisco had the highest ARG abundance. Antibiotic resistance genes conferring resistance to clinically critical antibiotics such as vancomycin were detected in air samples (Li et al. 2018), indicating that urban air represents a health risk associated with continual exposure to airborne ARGs. Li and colleagues (2018) also analysed bacterial communities in the air, their networks and contributions to ARGs. They found 50 genera in the urban air, including Corynebacterium, Escherichia/Shigella, Streptococcus and other potentially pathogenic genera.
The airborne AMR emission of 8 AMR-related genes from 163 layer farms near Beijing was quantified in Gao et al. (2022). The authors developed the atmospheric transport model with a gene degradation module for the assessment of the spatial and temporal distribution of poultry AMR while evaluating their regional exposure and sedimentation. Their findings demonstrate the deposition of AMR in residents’ upper respiratory tract, highlighting that the air is a much more hazardous AMR dissemination pathway than previously thought. The study by Xin et al. (2022) confirms the importance of the air as a dissemination pathway. They investigated pathways of 30 ARGs, four MGEs and four human pathogens from four animal species across 20 farms. Apart from the high concentration of these resistance markers in the air near the farms, they reported high inhaling exposure of farm workers. Unlike AMR in soil, the AMR in air and water are highly mobile, and diffusion, floods and rain play a role in spreading AMR, ARB and ARGs to the remote and “untouched” ecosystems.
AMR in probiotics
Although often ignored, it is well established that most probiotics carry AMR and ARGs. This is well investigated and comprehensively reviewed (Gueimonde et al. 2013; Li et al. 2020). The probiotics carry ARGs because a complete AMR profile was initially not required for their registration. Authors universally agree that ARGs on mobile genetic elements, such as plasmids, constitute a significant problem because of the transfer of resistance to other potentially pathogenic species (Baumgardner et al. 2021; Zheng et al. 2017). Liu et al. (2009) confirmed the presence of antibiotic resistance, including clinically critical, in commercial probiotics, identifying vancomycin, rifampicin, streptomycin, bacitracin and erythromycin ARGs (Liu et al. 2009), and suggested new regulations to a re-evaluation of probiotic safety (Liu et al. 2009).
Probiotics are continually added into the intestinal community due to regular use in humans and continuous supplementation in livestock and poultry (Zheng et al. 2017), and the AMR accumulation effects are not yet investigated. Baumgardner and colleagues (2021) performed a comprehensive study to determine if transferable ARGs are present in 47 commercially available veterinary probiotics, including products marketed for cattle, dogs, camelids, cats, goats and horses. Ninety-seven percent of the 47 probiotics contained at least one mobile AMR gene, and 82% contained two or more. This study is highly relevant to poultry and other livestock, and it confirms the risk for transmission of these mobile AMR genes into the meat products, manure and environment.
Considering the scale of production and administration of probiotics, they also strongly contribute to AMR enrichment in manure and from manure to the soil, water and the environment. In a survey of fermented food starter cultures from 90 different sources in Switzerland, Kastner et al. (2006) confirmed AMR in the most common starter culture species. A recent study by Montassier et al. (2021) published in Nature Microbiology brings this story to another level. An administration of antibiotics increased the lower GI tract resistome. However, the addition of probiotics further exacerbated AMR and ARGs expansion in the gut mucosa by promoting the bloom of strains carrying vancomycin resistance genes different to the resistance genes carried by the probiotic strains. This can open an interesting new area of research on identifying supplements that expand or reduce resistome in human and animal intestines. This is a very tricky research area as it depends on contradicting questions — was AMR increased or reduced simply because the product affects specific taxa carrying that particular AMR gene, and would the AMR gene be reduced if another, product-unaffected taxa carried it? This means that precise in vitro experiments performed in continuous culture could be useful to establish mechanisms and causality before it was confirmed in vivo in complex and uncontrolled intestinal microbiota. Additionally, the faecal transplant can assist in reducing ARGs in the gut (Montassier et al. 2021). This could be quite variable depending on the donor AMR profile. The cycle of AMR spread on a global scale is presented in Fig. 2.
Future directions
The estimated death toll from rising AMR is millions per year (O’Neill 2016), and medical practitioners are constantly reporting new all-resistant strains of pathogens while the AMR related annual mortality is on the steep rise (Antimicrobial Resistance 2022). There are numerous suggestions to improve monitoring, surveillance and diagnostics; however, efforts to reduce AMR load in the environment are urgently needed. In addition to alternative antimicrobial products and improved animal welfare and biosecurity combined with the strict control of antibiotic administration and other measures prosed by O’Neill and collaborators (O’Neill 2016), one of the emerging methods is bioremediation using living organisms that can remove or reduce ARG load in treated samples.
Bacteria and other microorganisms such as protozoa and yeast are the most promising and widely used for AMR and antibiotic bioremediation. However, this is based on complex microbial interactions and is not yet fully understood or optimised. To assist bioremediation, microorganisms must be able to survive and thrive under extreme conditions (e.g. oxidative pressure, nutrient depletion, osmotic stress) (reviewed in Apreja et al. 2021). It was reported that a combination of bacteria and microalgae could efficiently remove a range of antibiotics from the sludge, where the symbiotic interactions between bacteria and microalgae played a major role in the kinetics of antibiotic removal (da Silva Rodrigues et al. 2021). Although this area of research is relatively new, modern methodologies such as shotgun sequencing of antibiotic-resistant isolates revealed new enzymes capable of bioremediation (dos Santos et al. 2015). They opened an opportunity for the rapid development of bacterial libraries capable of removing antibiotics from the environment. Bacillus species, alone or in combination with other microorganisms, are among the most promising candidates (Al-Gheethi et al. 2019).
Phytoremediation is the removal of antibiotics using algae. Cyanobacteria are among the most interesting: they use light as an energy source and CO2 as a carbon source, also helping in carbon sequestration during the bioremediation process. Additionally, they are hardy, capable of growing under extreme conditions and capable of fixing up atmospheric nitrogen. Successful examples of algal bioremediation of antibiotics are well presented and reviewed in the literature (Grimes et al. 2019; Xiao et al. 2021; Zhou et al. 2021). It is, however, important to monitor the production of algal toxins before selecting the algae of choice for bioremediation.
Mycoremediation and phytoremediation are up-and-coming remediation techniques using fungi and plants to remove antibiotics from the environment. We previously discussed how plants accumulate antibiotics from the soil; although this is an issue for vegetable and other edible plant production, it is excellent in bioremediation.
One of the superior technologies capable of removing antibiotics, AMR and ARGs, is aerobic and anaerobic digestion using carefully selected microbial inoculums and optimised digestion conditions (reviewed in Waseem et al. 2020). The major advantages of using digesters are the reduction of greenhouse gas emissions and the production of renewable energy. If properly optimised, they can remove AMR and ARGs by degrading the DNA. This suggests the treatment of manure with digesters which can often be coupled with pelletising machines resulting in safe manure for the environment and farmers (Waseem et al. 2020).
Concluding remarks
There is no doubt that AMR is one of the major global health issues. AMR is a natural phenomenon that existed for as long as microorganisms. The preservation of intestinal content in naturally and deliberately mummified human remains confirmed the presence of resistance genes to most known antibiotics, including those most recently discovered (reviewed in Santiago-Rodriguez et al. 2017). This notion that AMR was always there became an excuse for many to ignore the current global AMR pollution putting aside the fact that never in history have we had millions of tonnes of antibiotics and AMR pumped into the environment. Positive actions by the agriculture industry in removing antibiotics from the feed and field and replacing them with natural antimicrobial alternatives, improving the health and welfare of the animals and upgrading production systems towards better pathogen and AMR control, combined with continually reducing antibiotic administration to humans, animals and plants are promising trends. Actions taken by several European governments to provide transparency on the use of antibiotics that allows the consumer to select more sustainable product are exceptional. However, these actions are strongly variable on the global scale, and ignoring the AMR issue in any part of the world may impact the global dissemination of AMR.
References
Abdelli N, Sola-Oriol D, Perez JF (2021) Phytogenic feed additives in poultry: achievements, prospective and challenges. Animals 11(12). https://doi.org/10.3390/ani11123471
Afzaal M, Mirza SA, Arooj T, Almas M, Ahmed S (2020) Antimicrobial and antibiotic resistance genes in the environment. In: Hashmi MZ (ed) Antimicrobial resistance genes. Springer
Ahlawat OP, Yadav D, Kashyap PL, Khippal A, Singh G (2021) Wheat endophytes and their potential role in managing abiotic stress under changing climate. J Appl Microbiol. https://doi.org/10.1111/jam.15375
Al-Gheethi A, Noman E, Radin Mohamed RMS, Ismail N, Bin Abdullah AH, Mohd Kassim AH (2019) Optimizing of pharmaceutical active compounds biodegradability in secondary effluents by beta-lactamase from Bacillus subtilis using central composite design. J Hazard Mater 365:883–894. https://doi.org/10.1016/j.jhazmat.2018.11.068
Allen HK, Donato J, Wang HH, Cloud-Hansen KA, Davies J, Handelsman J (2010) Call of the wild: antibiotic resistance genes in natural environments. Nat Rev Microbiol 8(4):251–259. https://doi.org/10.1038/nrmicro2312
Amar J, Serino M, Lange C, Chabo C, Iacovoni J, Mondot S, Lepage P, Klopp C, Mariette J, Bouchez O, Perez L, Courtney M, Marre M, Klopp P, Lantieri O, Dore J, Charles M, Balkau B, Burcelin R, Group DESIRS (2011) Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept. Diabetologia 54(12):3055–61. https://doi.org/10.1007/s00125-011-2329-8
Antimicrobial Resistance C (2022) Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 399(10325):629–655. https://doi.org/10.1016/S0140-6736(21)02724-0
Apreja M, Sharma A, Balda S, Kataria K, Capalash N, Sharma P (2021) Antibiotic residues in environment: antimicrobial resistance development, ecological risks, and bioremediation. Environ Sci Pollut Res Int. https://doi.org/10.1007/s11356-021-17374-w
Azanu D, Mortey C, Darko G, Weisser JJ, Styrishave B, Abaidoo RC (2016) Uptake of antibiotics from irrigation water by plants. Chemosphere 157:107–114. https://doi.org/10.1016/j.chemosphere.2016.05.035
Bajagai YS, Alsemgeest J, Moore RJ, Van TTH, Stanley D (2020) Phytogenic products, used as alternatives to antibiotic growth promoters, modify the intestinal microbiota derived from a range of production systems: an in vitro model. Appl Microbiol Biotechnol 104(24):10631–10640. https://doi.org/10.1007/s00253-020-10998-x
Bajagai YS, Petranyi F, Horyanto D, Batacan R Jr, Lobo E, Ren X, Whitton MM, Yu SJ, Kayal A, Stanley D (2022) Ileum transcriptional response to prolonged supplementation with phytogenic product containing menthol, carvacrol and carvone. Heliyon 8(3):e09131. https://doi.org/10.1016/j.heliyon.2022.e09131
Baumgardner RM, Berreta A, Kopper JJ (2021) Evaluation of commercial probiotics for antimicrobial resistance genes. Can Vet J 62(4):379–383
Bettiol E, Harbarth S (2015) Development of new antibiotics: taking off finally? Swiss Med Wkly 145:w14167. https://doi.org/10.4414/smw.2015.14167
Bhattacharjee MK (2016) Development of resistance to antibiotics. In: Bhattacharjee MK (ed) Chemistry of antibiotics and related drugs. Springer
Carrizo SL, Montes de Oca CE, Laino JE, Suarez NE, Vignolo G, LeBlanc JG, Rollan G (2016) Ancestral Andean grain quinoa as source of lactic acid bacteria capable to degrade phytate and produce B-group vitamins. Food Res Int 89(Pt 1):488–494. https://doi.org/10.1016/j.foodres.2016.08.013
Cetinkaya Y, Falk P, Mayhall CG (2000) Vancomycin-resistant enterococci. Clin Microbiol Rev 13(4):686–707. https://doi.org/10.1128/CMR.13.4.686
Chaurasia S, Sivanandan S, Agarwal R, Ellis S, Sharland M, Sankar MJ (2019) Neonatal sepsis in South Asia: huge burden and spiralling antimicrobial resistance. BMJ 364:k5314. https://doi.org/10.1136/bmj.k5314
Crisol-Martinez E, Stanley D, Geier MS, Hughes RJ, Moore RJ (2017) Understanding the mechanisms of zinc bacitracin and avilamycin on animal production: linking gut microbiota and growth performance in chickens. Appl Microbiol Biotechnol 101(11):4547–4559. https://doi.org/10.1007/s00253-017-8193-9
da Silva Rodrigues DA, da Cunha C, do Espirito Santo DR, de Barros ALC, Pereira AR, de Queiroz Silva S, da Fonseca Santiago A, de Cassia Franco Afonso RJ (2021) Removal of cephalexin and erythromycin antibiotics, and their resistance genes, by microalgae-bacteria consortium from wastewater treatment plant secondary effluents. Environ Sci Pollut Res Int 28(47):67822–67832. https://doi.org/10.1007/s11356-021-15351-x
Defoirdt T, Sorgeloos P, Bossier P (2011) Alternatives to antibiotics for the control of bacterial disease in aquaculture. Curr Opin Microbiol 14(3):251–258. https://doi.org/10.1016/j.mib.2011.03.004
dos Santos DF, Istvan P, Noronha EF, Quirino BF, Kruger RH (2015) New dioxygenase from metagenomic library from Brazilian soil: insights into antibiotic resistance and bioremediation. Biotechnol Lett 37(9):1809–1817. https://doi.org/10.1007/s10529-015-1861-x
Elbashir S, Parveen S, Schwarz J, Rippen T, Jahncke M, DePaola A (2018) Seafood pathogens and information on antimicrobial resistance: a review. Food Microbiol 70:85–93. https://doi.org/10.1016/j.fm.2017.09.011
Flees JJ, Ganguly B, Dridi S (2021) Phytogenic feed additives improve broiler feed efficiency via modulation of intermediary lipid and protein metabolism-related signaling pathways. Poult Sci 100(3):100963. https://doi.org/10.1016/j.psj.2020.12.060
Gaire TN, Scott HM, Sellers L, Nagaraja TG, Volkova VV (2020) Age dependence of antimicrobial resistance among fecal bacteria in animals: a scoping review. Front Vet Sci 7:622495. https://doi.org/10.3389/fvets.2020.622495
Gao M, Zhang X, Yue Y, Qiu T, Wang J, Wang X (2022) Air path of antimicrobial resistance related genes from layer farms: emission inventory, atmospheric transport, and human exposure. J Hazard Mater 430:128417. https://doi.org/10.1016/j.jhazmat.2022.128417
Greene ES, Emami NK, Dridi S (2021) Research note: phytobiotics modulate the expression profile of circulating inflammasome and cyto(chemo)kine in whole blood of broilers exposed to cyclic heat stress. Poult Sci 100(3):100801. https://doi.org/10.1016/j.psj.2020.10.055
Grimes KL, Dunphy LJ, Loudermilk EM, Melara AJ, Kolling GL, Papin JA, Colosi LM (2019) Evaluating the efficacy of an algae-based treatment to mitigate elicitation of antibiotic resistance. Chemosphere 237:124421. https://doi.org/10.1016/j.chemosphere.2019.124421
Gueimonde M, Sanchez B, GdLR-G C, Margolles A (2013) Antibiotic resistance in probiotic bacteria. Front Microbiol 4:202. https://doi.org/10.3389/fmicb.2013.00202
Haberecht S, Bajagai YS, Moore RJ, Van TTH, Stanley D (2020) Poultry feeds carry diverse microbial communities that influence chicken intestinal microbiota colonisation and maturation. AMB Express 10(1):143. https://doi.org/10.1186/s13568-020-01077-5
Hiller CX, Hubner U, Fajnorova S, Schwartz T, Drewes JE (2019) Antibiotic microbial resistance (AMR) removal efficiencies by conventional and advanced wastewater treatment processes: a review. Sci Total Environ 685:596–608. https://doi.org/10.1016/j.scitotenv.2019.05.315
Hosain MZ, Kabir SML, Kamal MM (2021) Antimicrobial uses for livestock production in developing countries. Vet World 14(1):210–221. https://doi.org/10.14202/vetworld.2021.210-221
Kastner S, Perreten V, Bleuler H, Hugenschmidt G, Lacroix C, Meile L (2006) Antibiotic susceptibility patterns and resistance genes of starter cultures and probiotic bacteria used in food. Syst Appl Microbiol 29(2):145–155. https://doi.org/10.1016/j.syapm.2005.07.009
Krzemiński P, Markiewicz M, Popowska P (2020) Entry routes of antibiotics and antimicrobial resistance in the environment. In: Hashmi MZ (ed) Antibiotics and antimicrobial resistance genes. Springer, pp 415–434. https://doi.org/10.1007/978-3-030-40422-2_19
Lancet T (2022) Antimicrobial resistance: time to repurpose the Global Fund. Lancet 399(10322):335. https://doi.org/10.1016/S0140-6736(22)00091-5
Laxminarayan R, Duse A, Wattal C, Zaidi AK, Wertheim HF, Sumpradit N, Vlieghe E, Hara GL, Gould IM, Goossens H, Greko C, So AD, Bigdeli M, Tomson G, Woodhouse W, Ombaka E, Peralta AQ, Qamar FN, Mir F, Kariuki S, Bhutta ZA, Coates A, Bergstrom R, Wright GD, Brown ED, Cars O (2013) Antibiotic resistance-the need for global solutions. Lancet Infect Dis 13(12):1057–1098. https://doi.org/10.1016/S1473-3099(13)70318-9
Levy S (2014) Reduced antibiotic use in livestock: how Denmark tackled resistance. Environmental Health Perspectives 122(6) https://doi.org/10.1289/ehp.122-A16
Li J, Cao J, Zhu YG, Chen QL, Shen F, Wu Y, Xu S, Fan H, Da G, Huang RJ, Wang J, de Jesus AL, Morawska L, Chan CK, Peccia J, Yao M (2018) Global survey of antibiotic resistance genes in air. Environ Sci Technol 52(19):10975–10984. https://doi.org/10.1021/acs.est.8b02204
Li T, Teng D, Mao R, Hao Y, Wang X, Wang J (2020) A critical review of antibiotic resistance in probiotic bacteria. Food Res Int 136:109571. https://doi.org/10.1016/j.foodres.2020.109571
Liu C, Zhang ZY, Dong K, Yuan JP, Guo XK (2009) Antibiotic resistance of probiotic strains of lactic acid bacteria isolated from marketed foods and drugs. BES 22(5):401–412. https://doi.org/10.1016/S0895-3988(10)60018-9
Macedo G, Hernandez-Leal L, van der Maas P, Heederik D, Mevius D, Schmitt H (2020) The impact of manure and soil texture on antimicrobial resistance gene levels in farmlands and adjacent ditches. Sci Total Env 737:139563. https://doi.org/10.1016/j.scitotenv.2020.139563
Makar O, Kuzniar A, Patsula O, Kavulych Y, Kozlovskyy V, Wolinska A, Skorzynska-Polit E, Vatamaniuk O, Terek O, Romanyuk N (2021) Bacterial endophytes of spring wheat grains and the potential to acquire Fe, Cu, and Zn under their low soil bioavailability. Biology (Basel) 10(5). https://doi.org/10.3390/biology10050409
Montassier E, Valdes-Mas R, Batard E, Zmora N, Dori-Bachash M, Suez J, Elinav E (2021) Probiotics impact the antibiotic resistance gene reservoir along the human GI tract in a person-specific and antibiotic-dependent manner. Nat Microbiol 6(8):1043–1054. https://doi.org/10.1038/s41564-021-00920-0
Narbonne JA, Radke BR, Price D, Hanington PC, Babujee A, Otto SJG (2021) Antimicrobial use surveillance indicators for finfish aquaculture production: a review. Front Vet Sci 8:595152. https://doi.org/10.3389/fvets.2021.595152
Nicholson F, Chambers B, Lord E, Bessey R, Misselbrook T (2016) Estimates of manure volumes by livestock type and land use for England and Wales. NERC Environmental Information Data Centre. In: Hydrology UCfE (ed). https://doi.org/10.5285/517717f7-d044-42cf-a332-a257e0e80b5c
O’Neill J (2016) The review on antimicrobial resistance. Tackling drug-resistant infections globally: final report and recommendations. https://amr-review.org/
Paisse S, Valle C, Servant F, Courtney M, Burcelin R, Amar J, Lelouvier B (2016) Comprehensive description of blood microbiome from healthy donors assessed by 16S targeted metagenomic sequencing. Transfusion 56(5):1138–1147. https://doi.org/10.1111/trf.13477
Patarata L, Novais M, Fraqueza MJ, Silva JA (2020) Influence of meat spoilage microbiota initial load on the growth and survival of three pathogens on a naturally fermented sausage. Foods 9(5). 10.3390/foods9050676
Phung C, Vezina B, Anwar A, Wilson T, Scott PC, Moore RJ, Van TTH (2019) Campylobacter hepaticus, the cause of spotty liver disease in chickens: transmission and routes of infection. Front Vet Sci 6:505. https://doi.org/10.3389/fvets.2019.00505
Plaza-Rodriguez C, Mesa-Varona O, Alt K, Grobbel M, Tenhagen BA, Kaesbohrer A (2021) Comparative analysis of consumer exposure to resistant bacteria through chicken meat consumption in Germany. Microorganisms 9(5). https://doi.org/10.3390/microorganisms9051045
Prasai TP, Walsh KB, Bhattarai SP, Midmore DJ, Van TT, Moore RJ, Stanley D (2017) Zeolite food supplementation reduces abundance of enterobacteria. Microbiol Res 195:24–30. https://doi.org/10.1016/j.micres.2016.11.006
Ranjalkar J, Chandy SJ (2019) India’s national action plan for antimicrobial resistance - an overview of the context, status, and way ahead. J Family Med Prim Care 8(6):1828–1834. https://doi.org/10.4103/jfmpc.jfmpc_275_19
Riaz L, Yang Q, Sikandar A, Safeer R, Anjum M, Mahmood T, Rehman MSU, Rashid A, Youan W (2020) Antibiotics use in hospitals and their presence in the associated waste. In: Hashmi MZ (ed) Antibiotics and antimicrobial resistance genes. Springer, pp 27–50. https://doi.org/10.1007/978-3-030-40422-2_2
Roberts MC (2019) Antibiotics and resistance in the environment. In: Fong IW, Shlaes D, Drlica K (eds) Antimicrobial resistance in the 21st century, pp 383–408. https://doi.org/10.1007/978-3-319-78538-7_12
Ruiz Mostacero N, Castelli MV, Barolo MI, Amigot SL, Fulgueira CL, Lopez SN (2021) Fungal endophytes in Peperomia obtusifolia and their potential as inhibitors of chickpea fungal pathogens. World J Microbiol Biotechnol 37(1):14. https://doi.org/10.1007/s11274-020-02954-8
Santiago-Rodriguez TM, Fornaciari G, Luciani S, Toranzos GA, Marota I, Giuffra V, Cano RJ (2017) Gut microbiome and putative resistome of Inca and Italian nobility mummies. Genes (Basel) 8(11). https://doi.org/10.3390/genes8110310
Schar D, Zhao C, Wang Y, Larsson DGJ, Gilbert M, Van Boeckel TP (2021) Twenty-year trends in antimicrobial resistance from aquaculture and fisheries in Asia. Nat Commun 12(1):5384. https://doi.org/10.1038/s41467-021-25655-8
Shehata AA, Yalcin S, Latorre JD, Basiouni S, Attia YA, Abd El-Wahab A, Visscher C, El-Seedi HR, Huber C, Hafez HM, Eisenreich W, Tellez-Isaias G (2022) Probiotics, prebiotics, and phytogenic substances for optimizing gut health in poultry. Microorganisms 10(2). https://doi.org/10.3390/microorganisms10020395
Silva V, Correia S, Pereira JE, Igrejas G, Poeta P (2020) Surveillance and environmental risk assessment of antibiotics and amr/args related with MRSA: one health perspective. Springer, pp 271–296. https://doi.org/10.1007/978-3-030-40422-2_13
Stanley D, Geier MS, Hughes RJ, Denman SE, Moore RJ (2013) Highly variable microbiota development in the chicken gastrointestinal tract. PLoS One 8(12):e84290. https://doi.org/10.1371/journal.pone.0084290
Stanley D, Mason LJ, Mackin KE, Srikhanta YN, Lyras D, Prakash MD, Nurgali K, Venegas A, Hill MD, Moore RJ, Wong CH (2016) Translocation and dissemination of commensal bacteria in post-stroke infection. Nat Med 22(11):1277–1284. https://doi.org/10.1038/nm.4194
Tasho RP, Cho JY (2016) Veterinary antibiotics in animal waste, its distribution in soil and uptake by plants: a review. Sci Total Environ 563–564:366–376. https://doi.org/10.1016/j.scitotenv.2016.04.140
van den Bogaard AE, Willems R, London N, Top J, Stobberingh EE (2002) Antibiotic resistance of faecal enterococci in poultry, poultry farmers and poultry slaughterers. J Antimicrob Chemother 49(3):497–505. https://doi.org/10.1093/jac/49.3.497
Verraes C, Van Boxstael S, Van Meervenne E, Van Coillie E, Butaye P, Catry B, de Schaetzen MA, Van Huffel X, Imberechts H, Dierick K, Daube G, Saegerman C, De Block J, Dewulf J, Herman L (2013) Antimicrobial resistance in the food chain: a review. IJERPH 10(7):2643–2669. https://doi.org/10.3390/ijerph10072643
Wang X, Ryu D, Houtkooper RH, Auwerx J (2015) Antibiotic use and abuse: a threat to mitochondria and chloroplasts with impact on research, health, and environment. BioEssays 37(10):1045–1053. https://doi.org/10.1002/bies.201500071
Wang J, Su S, Pender C, Murugesan R, Syed B, Kim WK (2021) Effect of a phytogenic feed additive on growth performance, nutrient digestion, and immune response in broiler-fed diets with two different levels of crude protein. Animals 11(3). https://doi.org/10.3390/ani11030775
Waseem H, Jameel S, Ali J, Jamal A, Ali MI (2020) Recent advances in treatment technologies for antibiotics and antimicrobial resistance genes. In: Hashmi MZ (ed) Antibiotics and antimicrobial resistance genes, pp 395–414. https://doi.org/10.1007/978-3-030-40422-2_18
Willson NL, Van TTH, Bhattarai SP, Courtice JM, McIntyre JR, Prasai TP, Moore RJ, Walsh K, Stanley D (2019) Feed supplementation with biochar may reduce poultry pathogens, including Campylobacter hepaticus, the causative agent of spotty liver disease. PLoS One 14(4):e0214471. https://doi.org/10.1371/journal.pone.0214471
Wu H, Rui X, Li W, Xiao Y, Zhou J, Dong M (2018) Whole-grain oats (Avena sativa L.) as a carrier of lactic acid bacteria and a supplement rich in angiotensin I-converting enzyme inhibitory peptides through solid-state fermentation. Food Funct 9(4):2270–2281. https://doi.org/10.1039/C7FO01578J
Xiao G, Chen J, Show PL, Yang Q, Ke J, Zhao Q, Guo R, Liu Y (2021) Evaluating the application of antibiotic treatment using algae-algae/activated sludge system. Chemosphere 282:130966. https://doi.org/10.1016/j.chemosphere.2021.130966
Xin H, Gao M, Wang X, Qiu T, Guo Y, Zhang L (2022) Animal farms are hot spots for airborne antimicrobial resistance. Sci Total Environ 851(Pt 1):158050. https://doi.org/10.1016/j.scitotenv.2022.158050
Yazdankhah S, Skjerve E, Wasteson Y (2018) Antimicrobial resistance due to the content of potentially toxic metals in soil and fertilizing products. Microb Ecol Health Dis 29(1):1548248. https://doi.org/10.1080/16512235.2018.1548248
Zheng M, Zhang R, Tian X, Zhou X, Pan X, Wong A (2017) assessing the risk of probiotic dietary supplements in the context of antibiotic resistance. Front Microbiol 8:908. https://doi.org/10.3389/fmicb.2017.00908
Zhou H, Cui J, Li X, Wangjin Y, Pang L, Li M, Chen X (2021) Antibiotic fate in an artificial-constructed urban river planted with the algae Microcystis aeruginosa and emergent hydrophyte. Water Environ Res.:e1670. https://doi.org/10.1002/wer.1670
Acknowledgements
Shorter form of this review was published as a conference proceeding at The Australian Poultry Science Symposium (APSS 2022), and it is adapted for publication in AMAB with the permission of the conference proceedings editor. APSS is the leading international conference in avian science.
Funding
Open Access funding enabled and organized by CAUL and its Member Institutions
Author information
Authors and Affiliations
Contributions
DS wrote the first draft of the manuscript; RB and YB edited and improved the manuscript. All the authors edited and approved the final version of the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Stanley, D., Batacan, R. & Bajagai, Y.S. Rapid growth of antimicrobial resistance: the role of agriculture in the problem and the solutions. Appl Microbiol Biotechnol 106, 6953–6962 (2022). https://doi.org/10.1007/s00253-022-12193-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00253-022-12193-6