Open access peer-reviewed chapter
Abstract
The spread of antimicrobial resistance (AMR) in the environment is an alarming issue for the world as the extensive use of antimicrobials in different sectors including healthcare facilities, food and pharmaceutical industries, agriculture, and animal farming has resulted in the enrichment of antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) in different environmental compartments such as surface water, wastewater, soil, and drinking water. Not only single-drug-resistant but multidrug-resistant (MDR) organisms are increasing at an alarming rate. Treatment technologies used in wastewater treatment plants (WWTP) are mostly focused on the removal of physical and chemical contaminants and less focused on the removal of biological contaminants like antimicrobial-resistant genes, which pose serious threats for both humans and the environment. Antimicrobial stewardship (AMS) programs have been started in different countries of the world to overcome the problem of antimicrobial resistance and minimize the impacts on the environment. This program is based on collective efforts from clinicians, technicians, physicians, scientists, leaders, and the public and their active participation in the possible eradication of antimicrobial resistance from the world.
Keywords
- multidrug-resistant bacteria
- wastewater treatment plant
- chlorine
- horizontal gene transfer
- antimicrobial stewardship
1. Introduction
With the production of antibiotics in the twentieth century, the world is facing the dilemma of AMR, which decreases the efficiency of antimicrobial compounds for the treatment of infectious diseases. Antimicrobial resistance (AMR) has been recognized as a global threat and the endless emergence of multi-drug resistant strains of bacteria like New Delhi Metallo-β-lactamase-1 (NDM-1) containing
Antimicrobial resistance is not only developed in organisms when they are exposed to antimicrobial agents in the natural environment but also without any contact with antibiotics in the form of intrinsic resistance. Furthermore, not only the higher concentrations of antibiotics but also minimum inhibitory concentration (MIC) could enrich the antibiotic-resistant bacteria and their genes in the environment [4]. The high level of ARB and ARGs is due to anthropogenic activities and needs immediate attention as the use of antibiotics is continuously increasing, and the development of the next genera of antibiotics is limited.
2. Wastewater and antimicrobial resistance
Wastewater is one of the major sources of ARB and ARGs in the environment. The higher concentrations of antibiotics in wastewater cause the enrichment and propagation of resistance among other bacteria and also transfer resistance to another environment [5]. The discharge of untreated wastewater has resulted in the enrichment and prevalence of ARGs in the water environment and the wastewater treatment plants (WWTP) act as a major reservoir of ARB and ARGs as activated sludge and treated effluent contain ARB and ARGs in abundance [6]. Activated sludge faces a lot of stress and induces the AMR through the co-selection process in the wastewater environment [7].
Wastewater contains a variety of pollutants and diverse microbial communities and provides a favorable environment for the proliferation of ARGs among bacteria. The major sources of antimicrobial resistance are humans and animals. Discharges from clinical and industrial sources also contribute to the ARB and ARGs. These pollutants move with the water cycle and reach other water environments [5]. Natural water bodies now have higher concentrations of antimicrobial compounds in water and their sediments. Treatment technologies used in WWTP are not focused on the removal of ARB and ARGs, and they remain active in effluent. During wastewater treatment, primary, secondary, and tertiary treatments have been used to remove most of the pollutants, and disinfection is also applied at the last stages of the treatment. Biological treatments including aerobic and anaerobic bioreactors and constructed wetlands are used to remove resistant bacteria. The concentrations of commonly used antibiotics are much higher in wastewater and surface water indicating the possible transfer of these resistances to other environments as well as due to the use of polluted water or untreated or partially treated wastewater in agriculture and for plantation in many countries.
3. Drinking water and antimicrobial resistance
Physical, chemical, and biological environmental factors affect the occurrence and enrichment of ARB and ARGs in drinking water including the disinfectants such as chlorine and pipe materials of the distribution system [8]. Wastewater is considered a hotspot for the ARB and ARGs due to the presence of human excreta and chemicals that contribute to the emergence of resistance in the bacterial population, although drinking water can also harbor the same [9] despite having different physico-chemical and biological characteristics. Drinking water supply systems contain pathogens and resistant bacteria that can transfer genes to other populations. The water distribution system is considered a complex system, and it is difficult to inactivate and treat the resistant bacteria as complete information about the behavior of these bacteria is not well known. Disinfectants used for the treatment of pathogenic microorganisms can result in the proliferation of ARB and their genes in the water distribution system and drinking water.
Chlorine is a cheap and effective disinfectant for the elimination of harmful microorganisms, especially pathogens from drinking water [10]. It is used as residual disinfection, and it reacts with the organic matter in water and produces undesirable disinfectant by-products (DBPs). Several DBPs can be found in the treated drinking water at much higher concentrations; trihalomethane (THM), haloacetic acid HAA, dichloroacetic acid (DCAA), trichloroacetic acid (TCAA), dibromochloromethane (DBCM), trichloromethane (TCM), tribromomethane (TBM), bromodichloromethane (BDCM). Their concentration in drinking water depends on the chlorine dose, temperature, and pH of the water. They can cause several health effects; adverse birth outcome, growth reduction in infants, mutagenesis, bladder and colon cancer (carcinogenic), and neurotoxicity but the extent of adverse effects depends on the concentration of the DBP and the exposure duration, which in some cases exceeded up to 40 years [11, 12].
The response of antimicrobial compounds such as chlorine and monochloramine in the main distribution system and the premise plumbing system could be different: They disappear more quickly from the premise plumbing than the main system. As a reactive chemical and strong oxidizing agent, chlorine can react with plumbing materials such as copper [13, 14]. The concentration decreases and this sub-lethal concentration can cause the selection and enrichment of ARB. The minimum selective concentration of disinfectants exerts selective pressure on the resistant population to survive and proliferate in the distribution system thus enriching the ARB and ARGs [8].
Opportunistic pathogens are an emerging water-borne issue. They are not contaminants. They are a normal habitant of drinking water, but they can cause life-threatening human diseases with an economic loss of one billion dollars annually. Their common characteristics help them to proliferate in the drinking water distribution and plumbing systems. They are oligotrophic and can grow at low organic carbon. They are persistent in drinking water, have thermal tolerance, and can grow in amoebae and stagnant water [15].
Common sources of waterborne diseases from opportunistic pathogens are
A consistent habitant of the drinking water plumbing system is
Opportunistic pathogens found in premise plumbing systems share some common features and have a selective advantage over other competitors. Their resistance to disinfectants and phagocytosis, the ability of biofilm formation and regrowth, and tolerance of low oxygen concentrations allow their enrichment in drinking water distribution systems posing a health hazard for the population. Slow growth also facilitates their survival as they skip during disinfection, and their death rate is also diminished due to the growth rate. As normal inhabitants of drinking water, their concentration does not decrease when they move from the source as compared to contaminants [20, 25].
Bacteria added to the water from the environment cause water contamination.
One recommended method to kill these pathogens is to increase the concentration of disinfectants, but it proves to be ineffective as resistance has been developed against the higher doses of the disinfectants. The same results were observed with disinfection substitution. Turbidity reduction can also reduce the number of these bacteria such as
4. Agriculture, soil, and animal farming
In soil, antibiotics are absorbed on the organic residues and also undergo transformation and biodegradation thus increasing their persistence in the soil environment. Their strong binding with soil organic components resulted in stable residues that persist in the agro-environment for a longer period. They can make enzymatic changes in local microorganisms and alter their metabolic activities for different nutrient resources such as carbon. Additionally, they manipulate microbial biomass and relative abundances of different microbial species [26].
Landfilling sites that receive municipal solid waste as disposed material contain large amounts of pharmaceutical and personal care products; these are the key anthropogenic sources of antibiotics in soil [27]. The leachate from the landfilling sites serves as the hotspots for the dissemination and enrichment of ARB and ARGs. An important source of the development of ARB is the agroecosystem, which has a direct effect on human leaching from agricultural soil resulting in the contamination of surface water [28]. In agriculture, feces-contaminated manure is used, which can be a source of resistant development in soil bacteria as repeated exposure to sub-inhibitory concentrations of antibiotics provokes resistance in them [29].
Different factors might be involved in the overall occurrence of antimicrobial resistance in the agro-environment. The physicochemical properties of the antibiotic residues, soil characteristics, and climate factors such as rainfall, temperature, and humidity all could contribute to the persistence of antibiotic resistance in the soil environment [30]. Microbial colonization is very diversified in soil, which serves as a reservoir of resistance genes. A complete insight into the gene transfer mechanism is required to understand the mechanism [31]. Horizontal gene transfer (HGT) and co-selection are the two major methods of antimicrobial-resistant gene transfer in soil environments [32, 33]. Horizontal gene transfer is carried out by three methods in a bacterial cell, which are transduction, conjugation, and transformation. Transduction is the transfer of genetic material through a virus, conjugation is the direct transfer of genetic material from one bacterium to another, and in transformation bacteria directly take up foreign or exogenous genetic material from the environment without any direct contact with other bacteria (Figure 1).
Figure 1.
Horizontal gene transfer in bacterial cells. a. transduction, b. conjugation, c. transformation.
Antibiotics have been used extensively in different industries causing environmental contamination and the development of resistant organisms with human health impacts, such as increased use of antibiotics in animal farming could result in the selection of organisms with resistance to human-used antibiotics [29]. The European Union banned the use of growth-promoting antibiotics in the veterinary industry in 2006 [34]. Antibiotic use in animal husbandry has not only a higher potential for water pollution but also more ecotoxicological risks [29].
5. Antibiotic stewardship
To combat the complicated AMR, the widely used method is antimicrobial stewardship (AMS), which emphasizes minimized and controlled use of antibiotics in different fields and prevents the exposure of pathogens in the natural environment. Antibiotic stewardship is responsible and careful management of antibiotic use [35]. It is also mandatory to avoid the over-prescription of antibiotics by healthcare professionals as they are the major driving force for the misuse of antibiotics. Antibiotic stewardship programs educate them about the overuse of antibiotics and their impact on human beings in the natural environment. The incidences of overtreatment with multiple antibiotics must be minimized in healthcare [36] as this practice evolved AMR into harmless bacteria. Antibiotic stewardship programs also focus on the reduced cost of treatment and minimize the economic impact of AMR. A situational analysis is performed before starting AMR stewardship, and it consists of strengths, weaknesses, opportunities, and threats (SWOT) of any facility [37]. It identifies the possible barriers to the implementation of the AMS program and facilitators who can contribute to the process of AMS.
Broad-spectrum antibiotics are used in healthcare for the treatment of infectious diseases but to defeat the AMR, narrow-spectrum antibiotics becomes the choice along with the use of combinatorial drug therapy as no single antibiotic is found to be effective for the treatment of all infectious diseases [38]. Combination drug therapy has more efficiency than single antibiotics against bacterial infections as they are based on synergism and antagonism [39]. Contrary to this, narrow-spectrum antimicrobials can put immense selective pressure on bacteria and can cause serious complications. Similarly, combinatorial drug therapy is expensive because two or more antibiotics are used in treatment although it is one of the most reliable and effective methods for the treatment of infectious diseases. This strategy is more effective for gram-negative bacteria than for gram-positive bacteria.
Several programs have been started by governments and agencies in developed countries for the eradication of AMR such as the National Antimicrobial Resistance Monitoring System for Enteric Bacteria (NARMS) by the Centers for Disease Control and Prevention (CDC) in the USA, which was established in 1996 and provides information about the emerging bacterial resistance. Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS) started in 2002 and collects information about the current trends in antimicrobial use and AMR in enteric bacteria to prolong the effectiveness of antimicrobial drugs in humans and livestock. The Danish Integrated Antimicrobial Resistance Monitoring and Research Programme (DANMAP) in Denmark, working since 1995, reviews the use of antibiotics in different sectors, the occurrence of antimicrobial resistance, the relationship between the use of antibiotics and the development of resistance, and the route of transmission to minimize the spread of AMR [1].
Although the use of some antibiotics has decreased in the world, on the other hand, the use of other antibiotics has increased. This resulted in a decrease in resistance to one class of antibiotics but an increase in resistance to another class of antibiotics. There is no alternative drug for some antibiotics as pathogens have developed resistance against many broad-spectrum antibiotics. Many recently developed antimicrobial resistance genes have been identified such as Mobile Colistin Resistant Genes (MCR) for Colistin, which are isolated from multiple environmental sources including sea, rivers, and sewage wastewater [40].
Regular monitoring of the use of antibiotics in different sectors and their discharge into the natural environment must be effectively examined to prevent the spread of AMR in these environments. A hundred percent effectiveness of any program can be achieved by proper implementation of rules, regulations, public laws, and policies, especially those related to public health and the environment. Uninterrupted data inspection is needed for the use of antibiotics, development of resistance, resistant patterns of antibiotics, resistance to other drugs, and outbreak of bacterial diseases. National and international coordination with proper guidance for health organizations is necessary for antimicrobial stewardship as it becomes a challenge for developing countries that lack infrastructure and good governance. Developed countries ensure the antimicrobial stewardship implementation program to eradicate AMR.
Another issue facing the world regarding the eradication of AMR in the environment is the lack of discovery for advanced antibiotics as a drastic decline has been observed since 2000. The development of antibiotics is a time-consuming process that involves research, clinical trials, approvals, and production costs; hence pharmaceutical industries are not taking much interest in research and development for brand-new drugs. Bacteria have shown AMR against most of the antibiotics used in the world, and highly potent antibiotics are urgently needed to reduce the outbreaks of diseases [39]. Innovation is another factor for the development of effective antibiotics as most industries are using already well-established compounds. Only one or two potentially active compounds against gram-negative bacteria are expected in the next decade, although a lot of research is going on for this, but the success rate is low. Extensive investment should be made by the industries to solve the issue. Governments must declare it as a priority and provide the funding and human resources for AMR stewardship in their countries.
Increased use of antibiotics is prevalent not only in humans but also in animals for livestock management and food production, which resulted in the fixation of AMR in bacteria. These bacteria can transfer resistant genes from animal to human by direct or indirect contact. Direct contact involves the interaction with animals and their biological fluids such as blood, urine, milk, and saliva whereas indirect contact may involve the use of contaminated food such as dairy products, eggs, and meat. Thus, zoonotic animals are also a reservoir of AMR just like humans including adults, children, and infants. An important factor that contributes to the increased use of antibiotics is the over-the-counter availability of antibiotics in many countries. Co-selection of resistant genes is another important factor contributing to the spread of AMR in bacteria as it causes resistance to many antibiotics simultaneously, which belong to different classes of antibiotics [41].
Public awareness about any problem plays a vital role in the management and control of that problem. There is a lack of public awareness among people and even among practitioners and doctors who intentionally or forcefully over-prescribe antibiotics for treatment on the demands of pharmaceutical companies. Clinicians use higher doses of antibiotics than required and also prescribe them for a longer period than necessary [2]. Optimum use of antimicrobial compounds could also help to reduce the development of AMR. It is essential to start public awareness about AMR on a wider scale if we want to prevent it further. Similarly, public participation is a key factor in such stewardship programs as the active contribution of the general population makes the program successful.
Healthcare workers and policymakers must be encouraged to adapt best practices to combat AMR. Effective communication and training must be provided to the people working in the healthcare system so that they can educate others. Extensive research is needed to understand the mechanisms of development of AMR in the natural environment. Personal sanitation and hygiene should also be encouraged for infection prevention.
All forms of life from the smallest to largest organisms have defense mechanisms in the form of antimicrobial peptides, which have broad-spectrum activity against prokaryotic and eukaryotic microorganisms [39]. Due to their characteristics, they can be a useful alternative to currently used antibiotics [42]. An emerging method to control AMR is the use of bacteriophages (BP) for phage therapy [38, 43]. It uses natural or bioengineered phages for the lysis of disease-causing bacteria (Figure 2). It has many advantages over other methods such as lack of cross-resistance for other antibiotics, strain-specific, and effectiveness against a wide range of bacteria. They can be used individually or in combination with other antibiotics [43]. Small particles that are favorable to use against AMR are nanoparticles (NPs) as they are target-specific and stabilize the drugs inside the body [38]. They can help in horizontal gene transfer, and their use can cause the emergence of resistance in other bacteria in the environment [44].
Figure 2.
Phage therapy as an alternative to antibiotics for the treatment of bacterial infections.
The bioactive phytochemicals in plants that belong to different chemical classes can also be used against AMR as they have bactericidal properties and can reverse AMR [45]. They have synergistic effects with other antibiotics and can serve as promising solutions for AMR. Biosurfactants have anti-adhesive properties. They inhibit bacterial colonization and have shown effectiveness against multidrug-resistant
Figure 3.
Quorum sensing inhibition mechanisms includes inhibition of synthesis of signal molecules (1), inhibition of transport of signal molecules (2), their degradation (3), and receptor inhibition of signal molecules through competitive inhibition.
Antimicrobial stewardship programs are based on three pillars, which include the strengthening of the health system by an integrated approach, patient safety, and infection prevention and control. It applies to human, animal, food, agriculture, and pharmaceutical sectors. Proper technology and data must be available to cope with AMR. State-of-the-art laboratories with advanced equipment and other facilities must be present for the on-time diagnosis and treatment of infectious diseases [38]. Furthermore, patients’ records must be maintained who have been treated for multidrug-resistant infections or using antibiotics for a longer period [39]. AMR eradication from the natural environment is a slow and steady process and cannot be achieved overnight.
Leadership commitment plays a vital role in the success of any program and antibiotic stewardship also needs this commitment from leadership, healthcare workers, and physicians. Production and distribution records of antibiotics must be maintained by the government and healthcare facilities. Similarly, regulations and responsibilities should be documented to avoid the overuse of antibiotics in the healthcare system [39]. There must be accountability and proper distribution of responsibilities to achieve the target. A multidisciplinary team is needed, which may consist of physicians, microbiologists, nurses, lab technicians, pharmacists, and experts in infection management [42, 48] with a fast-track approach of rapid diagnosis, testing, and reporting of results [49].
AMR is a global concern and needs novel, innovative, and permanent solutions as the burden of the AMR economy is huge and needs to be solved immediately. Both developed and underdeveloped countries must work together to overcome the obstacles. The development of potent novel antimicrobial compounds and monitoring of antibiotic abuse are mandatory to win the fight against AMR [38, 42].
6. Conclusion
As the antibiotic use increased in the world, the issue of their dispersion also increased in the environment resulting in the need for new and broad-spectrum antimicrobial compounds. The world has been trying to overcome the threat since the beginning of the development of resistance in bacteria against powerful antimicrobials, but the issue is not solved fully as it is present in almost all environments, and removal is not possible. The antimicrobial stewardship program has been designed keeping in mind the uncontrolled dispersion of resistance in the environmental compartments. Therapeutic strategies are highly anticipated with modern technology to eradicate multi-drug resistance from the environment and reduce the cost of treatment for the general public. Additionally, a comprehensive understanding of the advantages and disadvantages of the dispersion and enrichment of the ARB and ARGs in the environment and the use of modern and easily accessible technologies could broaden our horizon to get rid of the global threat permanently for all stakeholders.
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