Antibiotics induced antibacterial resistance

Antibiotics induced antibacterial resistance

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Pathmalal M. Manage and Gayani Yasodara Liyanage Centre for Water Quality and Algae Research, Department of Zoology, University of Sri Jayewardenepura, Nugegoda, Sri Lanka

18.1

Introduction

Antibiotics have always been considered one of the wonder discoveries of the 20th century. Their role has expanded from treating serious infections to preventing infections in surgical patients, protecting cancer patients, people with compromised immune system, promoting growth, and preventing disease in livestock and other food animals (Baquero et al., 2008). The rapid emergence of resistant bacteria is occurring worldwide and endangering the efficacy of antibiotics. Overuse and misuse of antibiotics in clinical context are widely regarded as major pathways to enter antibiotic residues to hospital effluent and promoting antibiotic resistance (Canto and Baquero, 2008). Other nonclinical large-scale uses of antibiotics in aquaculture, livestock, and poultry farms have highly contributed to antibiotic contaminations and development of pathogenic bacterial resistance (Kaur et al., 2011). Bacteria resist against the effects of antibiotics by four main strategies with thousands of variations (Mccoy et al., 2011). Major categories of antibiotic resistance have been identified as natural (intrinsic) resistance, acquired resistance, cross resistance, and multidrug resistance following five mechanisms of destructive enzymes, modifying antibacterial targets, efflux, reducing permeability, and creating alternative metabolic pathways (Mccoy et al., 2011; Manage, 2018). When a bacteria cell divides, the chromosome of the bacterium is passed into its daughter cells, which is called vertical chromosome transfer; and apart from this, genetic information can also be passed between bacteria through fecal matter, wind, water, etc., which is known as horizontal gene transfer (HGT) (Huddleston, 2014). HGT promotes antibiotic resistance and their spread-up in the environment (Kummerer, 2001). Thus improper disposal and misuse of antibiotics, in human therapy (Huddleston, 2014), farm animal husbandry, and aquaculture (Ritter et al., 2008) may influence on the development of multidrug-resistant bacteria in the environment (Huddleston, 2014). Multidrug resistance occurs by the accumulation of resistance plasmids (Kummerer, 2001), transposons of genes (Cabello, 2006), or by the action of multidrug efflux pumps (Mccoy et al., 2011). Those antibioticresistant bacteria may act as reservoir of antibiotic resistance genes (ARGs) for other bacteria, which might be conserved within bacterial population even without related antibiotics or antibiotic exposure (D’Costa et al., 2011). In future, Pharmaceuticals and Personal Care Products: Waste Management and Treatment Technology. DOI: https://doi.org/10.1016/B978-0-12-816189-0.00018-4 © 2019 Elsevier Inc. All rights reserved.

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antibacterial resistance will be resulted in failure of bacterial response to standard treatment (Sturini et al., 2012), leading to prolonged illness (Kummerer, 2001), higher expenditures for healthcare (Kaur et al., 2011), an immense risk of death, and production losses at agricultural farms (Sturini et al., 2012).

18.2

Sources and contamination status of antibiotics

18.2.1 Human therapy The total antibiotic consumption increased by more than 40% (approximately 50 70 billion Standard Units) in between 2000 and 2010 (WHO, 2010). In most of the countries in the world, about 20% of antibiotics are used in hospitals and other health-care facilities, while 80% are used in the community, either prescribed by health-care providers or purchased directly by consumers or caregivers without prescriptions (Kotwani and Holloway, 2011). It was estimated that worldwide annual consumption of antibiotics by humans was about 100,000 200,000 t, and per capita values vary from country to country (Kummerer, 2001). The total human consumption of antibiotics in Asian countries (China, India) increased by nearly 30% compared to European countries, such as the United States and the United Kingdom from 2010 to 2014 (Van Boeckel et al., 2014; WHO, 2015) (Fig. 18.1). Antibiotic prescription rates and intake without + 4.2 14 2010

+ 3.8 12

Standard units (billion)

2014 10 –0.3 8

+ 1.4 + 3.4

6

+ 1.8 + 1.2

4

–1.2 + 0.2

2

+ 0.1

1

0 China

India Pakistan Brazil France Germany Russia

South Africa

UK

USA Australia

Country

Figure 18.1 Total antibiotic consumption of selected countries in the world for human therapy.

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prescription also vary noticeably from country to country (Molstad et al., 2002). Doses of antibiotics used for different diseases are also varying between different countries but mostly practice as defined daily dose as recommended by the World Health Organization (WHO) guidelines (WHO, 2015). Antibiotics in penicillin and cephalosporin groups accounted for nearly 60% of total consumption in 2010 and increased by 41% from 2010 to 2016 (WHO, 2015). Among the oldest antibiotics available in the market, penicillin and cephalosporin are still the most common antibiotics and used as a primary treatment for the majority of common infectious diseases around the world (Van Boeckel et al., 2014). After administration to the human body, some antibiotics are excreted as it is or as other forms of metabolites into the environment in different ways (Ritter et al., 2008). Residual amounts can contaminate sediments, surface, and groundwater as well (Giorgia et al., 2004). Thus the removal of antibiotic from environment is critically needed; however, physical and chemical methods for the removal of antibiotics are not accessible in all parts of the world due to high operational cost, while bioremediation technology has been suggested as an economically viable, cost-effective green technology to remove antibiotics from the environment.

18.3

Antibiotics in agriculture (aquaculture, animal farms, veterinary clinics)

Global population is expected to reach 9 billion by 2050, and the world foodproducing sector needs to secure food and nutrition for the growing population through increased production and reduced waste (FAO, 2014). Globally, fish protein represents around 16.6% of animal protein supply and fulfills 6.5% of requirements of protein for humans (FAO, 2014). During the last 20 years, it has shown a fourfold growth in industrial aquaculture worldwide (Naylor and Burke, 2005), and it is expected to rise at a faster rate in future due to the depletion of fisheries and globalization of sources of food supply. Nearly two thirds of the seafood that is ingested will be farm raised in 2030 (Cabello, 2006; Naylor and Burke, 2005). On the other hand, antibiotics are used to treat infectious diseases in animals for as long as they have been widely available (FAO, 2010). It has been estimated that large amounts of antibiotics are used in poultry, swine, and cattle farms to prevent diseases (Park et al., 2012), and as growth promoters, than used by the entire human population (FAO, 2014). In Europe, only 14 medicinal products are authorized and approved for aquaculture, including nine human antibiotic products [amoxicillin (AMX), ampicillin (AMP), florfenicol, chloramphenicol, oxolinic acid, oxytetracycline (OTC), erythromycin, streptomycin, and sulfadiazine] (EAHC, 2013) (Table 18.1). Only fluoroquinolones (FQ) and tetracyclines (TET), in addition to being employed in human therapy (Cabello, 2006; Martinez et al., 2009; Naviner et al., 2011), are also widely used and are effective veterinary antibiotics to prevent

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Table 18.1 Selected antibiotics used at fish farm and their importance in human medicine Antibiotic

Classification

Mechanism of action

Importance in human medicine

Amoxicillin

β-lactam

Critically important

Ampicillin

β-lactam

Chloramphenicol

Amfenicol

Florfenicol

Amfenicol

Erythromycin

Macrolide

Streptomycin

Aminoglycoside

Oxolinic acid

Quinolone

Oxytetracycline

Tetracycline

Sulfadiazine

Sulfonamide

Inhibition of cell wall synthesis Inhibition of cell wall synthesis Inhibition of protein synthesis Inhibition of protein synthesis Inhibition of protein synthesis Inhibition of protein synthesis Inhibition of DNA synthesis Inhibition of protein synthesis Inhibition of protein synthesis

Critically important Important Important Critically important Critically important Critically important Critically important Important

and treat fish diseases (FAO, 2010). The top three classes by global sales for animal use in 2009 were macrolide ($600 million), penicillin ($600 million), and tetracycline ($500 million), and those antibiotics are categorized as critically important for human medicine (WHO, 2011). In Portugal the total consumption of FQ was 22.42 t with 9.02 t for veterinary medicine in 2011. The higher consumption data regarding this group is mainly due to ciprofloxacin (CIP) (10.94 t, human medicine) and enrofloxacin (8.39 t, veterinary medicine) (Pereira et al., 2015). Antibiotic release into the environment creates serious ecological impacts as 90% of these antibiotics are excreted unchanged (Sapkota et al., 2008; Davies and Davies., 2010). These residues may contaminate surface waters, groundwaters, sediments, and biota (Kummerer, 2010; Redshaw et al., 2013). The frequent use of antibiotics results in their “pseudo-durability,” and their ubiquitous occurrence in the aqueous environment may exert selective pressure for resistant bacteria in aquaculture animals and the environment (Fig. 18.2) (IGEM, 2015; Kim et al., 2004). According to the United Nations Food and Agriculture Organization, meat consumption will increase by 73% and dairy consumption by 58% in all over the world in the next 35 years from 2011 (FAO, 2011). Thus demand for meat and other animal products is predicted to more than double in the next 35 years. Accordingly, increase usages of antibiotics are expected globally.

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Figure 18.2 Contribution of different sources for antibiotic contamination in aquatic environment in Asian countries.

18.4

Metabolism of antibiotic compounds

The metabolic rate of antibiotics depends on their chemical properties (Kummerer, 2010), functional groups (Redshaw et al., 2013), and the reactive atoms in the structures (Redshaw et al., 2013). Garcı´a-G et al. (2008) reported the specific identification of metabolites of sulfonamides including 5-hydroxyl sulfadiazine, 4-hydroxysulfadiazine, 5-hydroxysulfadiazine glucuronide, and seven other forms. Sulfonamides are metabolized similarly in animals as in humans; however, animals used for livestock also include other forms, such as the N4-acetyl-conjugates, deaminated metabolites, and N4 glucose conjugates (Richardson and Ternes, 2014). All the metabolites include amine group which act as an active group of sulfonamides. Other antibiotics, such as cyclosporine, are metabolized in a similar manner, resulting in conjugation to water-soluble molecules (Campo et al., 2009). Nitrofurans is another group of antibiotics commonly used in agricultural and veterinary medicine and represent structures that are composed of oxazolidine groups coupled with furan group through a methylenamine bridge (Richardson and Ternes, 2014). Studies from Leitner et al. (2008) show that the nitrofuran structure is attacked by the cytochrome system and hydrolyzed into single ringed moieties, where the oxazolidin rings remain largely conserved after detoxification as well (Leitner et al., 2008; Cooper et al., 2005). This process implies that the nitrofuran compound generate metastable metabolites in the urine of animals, fish, and humans which are less water soluble than conjugated variants (Richardson and Ternes, 2014). It has been recorded that cephalosporin antibiotics do not readily metabolize, and animal studies have revealed that rats, mice, and dogs excrete the antibiotic wholly unmodified through the renal urinary tract (Sullivan et al., 2001).

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The studies on surface water samples showed several compounds of antibiotics; sulfadimethoxine, sulfathiazole, sulfamethazine, and sulfamethoxazole (SMX) are present at ng/mL concentrations (Dı´az-Cruz et al., 2008). Similar findings have also been reported by Chang et al. (2008), where 16 sulfonamide types were found in lakes and ponds in Japan at the concentrations of up to 8.9 ng/L (Chang et al., 2008). Metabolites of antibiotics are therefore apparent sources of pollution in the environment, with a focus on the water phase and groundwater reserves (Van Boeckel et al., 2014). The accumulation of antibiotics and their metabolites in animal and humans represent the toxicological threat with increasing poor regulated use of antibiotics in the western world (Manzetti and Stenersen, 2010). Thus renewing and developing better decontamination approaches for wastewater is critical, as clinical and aquaculture wastewater are frequently released to the environment without any treatment, especially for antibiotics, even in industrialized nations (Manzetti and Stenersen, 2010).

18.5

Major pathways of environmental contamination of antibiotics

During the recent years, antibiotics have been categorized as high-risk pollutants in the environment because of their toxic effects on bacteria and algae even at very low concentrations and also due to their toxic capacity to create resistant among natural bacteria populations (Watkinson et al., 2009). Antibiotic resistance bacteria (ARB) and ARGs have been recorded in different environments, including natural rivers, hospital effluents, sewage treatment plants and lakes (Richardson and Ternes, 2014). Thus much more attention has been drawn about the antibiotic contamination in environment (Xu et al., 2015; Canto and Baquero, 2008). Asian countries such as China, India, and Pakistan identified hospitals, animal husbandry, agriculture, and pharmaceutical manufacturers as major sources which caused for antibiotic pollution in environment (IGEM, 2015) (Fig. 18.2). Antibiotics can be more or less extensively metabolized by human, animals and finally reach the environment (Ritter et al., 2008; Costanzo et al., 2005). The important point to highlight is that the nonmetabolized fractions of antibiotic are excreted with an antibacterial activity of the compound (Ritter et al., 2008) and may partially be eliminated during the treatment processes and released to the aquatic and soil compartment of the environment. Residual amounts can contaminate sediments, surface, and groundwater as well (Giorgia et al., 2004). Ahmad et al. (2012) detected AMX in different types of wastewaters in Lahore, India and recorded high concentration of AMX in hospital effluent (7.31 39.13 ng/ mL), municipal wastewater (0.54 1.29 ng/mL), and in River Ravi (0.14 0.37 ng/ mL). Diwan et al. (2010) monitored hospital wastewater in India and reported high concentration of CIP (218 236 g/L), SMX (4.6 g/L), oxytetracyclin (3.2 g/L), and trimethoprim (2.2 g/L) in hospital wastewater as well. Rehman et al. (2015) have also observed that OTC, trimethoprim, and sulfonamides were at higher

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concentrations (.25 μg/L) in hospital effluents in Korea. Rodriguez-Mozaz et al. (2015) detected FQ at the highest concentration, especially in hospital effluent samples in Girona, Spain. In fact, CIP and ofloxacin were present in hospital effluents, ranging from 13.78 μg/L for CIP and 14.38 μg/L for ofloxacin. Environmental contamination status of four important antibiotic classes, sulfonamides, penicillin, tetracycline, and macrolides, which are commonly used in human and veterinary medicine in Sri Lanka were studied by Liyanage et al. (2015). According to the study, high environmental contamination of AMP (water; 546,000 ng/L, sediments; 4000 ng/L), AMX (water; 704,000 ng/L, sediments; 10,000 ng/L), and SMX (water; 34,000 ng/L, sediments; 2000 ng/L) was detected in hospital effluents. Globally, different environmental exposure pathways have been identified for the antibiotic contaminations in the environment (Watkinson et al., 2009; Liyanage and Manage, 2014). The heavy use of antibiotics in farm animals, plant protection, veterinary, and aquaculture in unregulated manner have been identified as major causes for the increase of antibiotic contamination in the environment (Hernandez et al., 2004) (Fig. 18.3). Brown et al. (2006) reported concentrations of OTC (0.001 0.008 μg/mL), TET (0.001 0.005 μg/mL), AMX (not detected), and AMP (not detected) in livestock effluents in New Mexico. Liyanage and Manage (2016a) recorded OTC concentration in aquaculture farms in Sri Lanka ranging from 0.008 to 0.234 μg/mL, whereas TET concentration was from 0.001 to 0.112 μg/mL. According to Liyanage and Manage (2017a), antibiotic concentrations in effluent water of livestock farms in

Antibiotics Veterinary medicine

Livestock feed

Injection/ Excretion

Injection/Excretion Manure

Human infections

Unused

Topical application

Municipal/Septic tanks

Land application of solid

Runoff

Surface/Groundwater contamination

Drinking water contamination

Figure 18.3 Possible routes of antibiotics into water.

Location

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Puthukudirippu (Pt) Ambakandawila 3 (Am 3) Ambakandawila 2 (Am 2) Ambakandawila 1 (Am 1) Kahandamodara (Ka) Orna fish farm–Colombo (Or) Rambodagalle (Rm) Ampara (AM) Batticalo 01 (Bt 1) Jaffna 02 (Jf 2) Jaffna 01 (Jf 1) Udappuwa (Ud) Muthupanthiya (Mt) Ginigathhena (Gi) Lunugamwehera (Lu) Ranna (Ra) Dambulla (Da)

OTC TET AMP AMX SMX SDI ERM

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

Antibiotic concentration (µ µg/mL)

Figure 18.4 Antibiotic contaminations in aquaculture effluent water in Sri Lanka. OTC, Oxytetracycline; TET, tetracycline; AMP, ampicillin; AMX, amoxicillin; SMX, sulfamethoxazole; SDI, sulfadiazine; ERM, erythromycin.

Sri Lanka was ranged between 0.001 and 0.004 μg/mL for OTC, 0.001 and 0.005 μg/mL for TET, and 0.001 and 0.003 μg/mL for AMX (Fig. 18.4). Based upon the WHO estimates, considerable differences were recorded in antibiotic usage among different animal species (swine vs poultry) (Hernandez et al., 2004). Therefore the types of antibiotic compounds that are likely to be found in effluent water of livestock farms will strongly depend upon the types of livestock operations within the environment. In 2010 China has estimated that the consumption of antibiotics in their livestock is the maximum, followed by the United States, Brazil, Germany, and India (Hernandez et al., 2004). Consumption of antibiotics in Brazil, Russia, India, China, and South Africa (the BRICS) is expected to double by 2030 as their population increases by 13% (Van Boeckel et al., 2014). Liyanage and Manage (2017a) recorded that approximately 45% from the TET, 35% from the OTC, and 20% of AMX contributed to environment pollution through the effluent water, and more or less similar results were presented by Hsieh et al. (2011). The high detection frequency and concentration of tetracycline are likely due to the large amount of OTC and TET usage in livestock and poultry as feed additives and therapeutic drugs for diseases in farm sites (Van Boeckel et al., 2014). Therefore results of the study by Liyanage and Manage (2017a) are comparable to the findings of Brown et al. (2006), who reported concentrations of OTC (0.001 0.008 μg/mL), TET (0.001 0.005 μg/mL), AMX (not detected), and AMP (not detected) in livestock effluents in New Mexico. The widespread and often inappropriate administration of antibiotics in aquaculture, livestock, and hospitals has been shown in the development of antibioticresistant bacteria and is generally accepted to be a primary pathway for their

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proliferation in the environment (Tello et al., 2012). There is a further concern that antibiotic-resistant bacteria might develop from long-term environmental exposure to low concentrations of antibiotic (ng/L μg/L) (Tello et al., 2012). As a result of the continuous exposure to antibiotic residues in the environment, multidrugresistant pathogens can make drugs ineffective and pose a serious risk to the global pharmaceutical and health-care industry (Pruden et al., 2013). Furthermore, wastewater effluent from hospitals and intensive farming facilities can also be considered the major sources of adding pathogenic, antibiotic-resistant organisms, and antibiotic resistance genes into the environment (Zhang and Li, 2011). Antibiotics used in aquaculture, animal husbandry, horticulture, beekeeping, antifouling paints, and laboratories are the major pathways carrying out genetic manipulation and the evolutionary pressure for the development of antibiotic resistance (Rodriguez-Mozaz et al., 2015).

18.6

Development of antibiotic resistance

Antibiotic resistance is a serious and growing problem in modern medicine, and it is emerging as a major public health threat. Antibiotic resistance is a kind of drug resistance where a microorganism is capable to survive the exposure to an antibiotic (Frieden, 2013). The control of infectious diseases has become critical considering the rising number of microorganisms that are resistant to antibiotics (Canto and Baquero, 2008). The widespread use of antibiotics cause creating selection pressure on environmental microorganisms and contribute to the development of antibiotic resistance in within microorganism community (Muhlemann, 2002). The most recent worldwide estimates of global antibiotic resistance, published by the WHO in 2015, has listed Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, and Staphylococcus aureus as the four agents of greatest concern, associated with both hospital and community-acquired infections. High rates of resistance to first and second-line drugs are already increasing reliance on lastresort drugs has been identified (WHO, 2015). While antibiotics are still effective at treating many bacterial infections, some strains have been found extremely difficult to treat (Appelbaum, 2012). Each year in the United States alone, at least 2 million people acquire serious infections with bacteria that are resistant to one or more antibiotics, and at least 23,000 people die annually as a direct result of the antibiotic-resistant infections (CDC, 2013). Wright (2010) recorded bacteria such as Mycobacterium tuberculosis, and multidrugresistant Acinetobacter baumannii, Neisseria gonorrhea, Pseudomonas aeruginosa, and Enterobacteriaceae can be carrying extended spectrum β-lactamases (ESBLs) which confers resistance to penicillin and cephalosporin. A study conducted by the European Union has been estimated that antibiotic-resistant bacteria are responsible for over 25,000 deaths every year (Aronsson et al., 2009).

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18.7

Pharmaceuticals and Personal Care Products: Waste Management and Treatment Technology

Mechanisms of antibiotic resistance

Bacteria evolved with the origin of the earth, and it can be an inherent trait that renders it natural resistance, or it may be acquired by means of mutation in its own DNA or acquisition of resistance-conferring DNA from another source (Levin and Rozen, 2006; Manage, 2018). The intrinsic resistance of a bacterial species to a particular antibiotic is shown by changing structural or functional characteristics of the antibiotic (Aminov and Mackie, 2007). In addition to intrinsic resistance, bacteria can acquire or develop resistance to antibiotics (Jain et al., 2003). This can be mediated by several mechanisms such as the changes that occur in the receptor that are connected to the drug, enzymatic inactivation of antibiotics, reduction of the inner and outer membrane permeability, flush out of the drug, and using an alternative metabolic pathway (Blair et al., 2014; Manage, 2018) (Fig. 18.5).

18.8

The changes that occur in the receptor that are connected to the drug

Connections of the antibiotic target areas are different, and it can be a different enzyme or ribosome. Resistance associated with the alterations in the ribosomal target is the most frequently observed in macrolide antibiotics. Moreover, this is common for developed resistance to β-lactams, quinolones, and tetracycline as well (Paterson and Bonomo, 2005; Bush et al., 2011).

Figure 18.5 Antibiotic resistance mechanisms (1—alteration of target site; 2—enzyme inactivation; 3—reduction of inner and outer membrane permeability; 4—efflux pump; 5—using an alternative metabolic pathway).

Antibiotics induced antibacterial resistance

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439

Enzymatic inactivation of antibiotics

Most of the Gram-positive and Gram-negative bacteria synthesize enzymes that degrade antibiotics. As an example, β-lactamases inactivate antibiotics in penicillin group (Paterson and Bonomo, 2005). Other modifying enzymes such as acetylase, fosforiaz, and adenilaz are involved inactivating different types of antibiotics, including aminoglycosides, chloramphenicol, and erythromycin (Paterson and Bonomo, 2005; Bush et al., 2011).

18.10

Reduction of the inner and outer membrane permeability

This resistance results in a decrease in drug uptake into the cell or quickly ejected from the active resistance of the pump systems. Reduction in permeability of the outer membrane may play an important role in resistance to quinolones and aminoglycosides (Blair et al., 2014).

18.11

Flush out of the drug (active pump system)

The production of complex bacterial machineries capable to extrude a toxic compound out of the cell can also result in antimicrobial resistance (Bush et al., 2011). Many classes of efflux pumps have been characterized in both Gram-negative and Gram-positive pathogens. This mechanism of resistance affects a wide range of antimicrobial classes, including protein synthesis inhibitors, FQ, β-lactams, carbapenems, and polymyxins (Poole, 2005).

18.12

Using an alternative metabolic pathway

Unlike some of the changes in the target bacteria, this type of resistance develops a new pathway for drug susceptibility eliminates from the cell. This type of resistance is seen among the sulfonamide and trimethoprim. Bacteria can gain property of getting ready folate from the environment instead of synthesizing folate (Jacoby, 2009).

18.13

Transfer of resistance genes

When a bacterial cell divides, the chromosome of the bacterium is passed on to its daughter cells. But apart from this vertical transfer, genetic information can also take place through the processes known as HGT. The three main processes of HGT

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are transformation, transduction, and conjugation (Huddleston, 2014). The nature of the genetic elements transferred is an important aspect of HGT. While chromosomally located genes certainly can be transferred in HGT, particularly by transformation, transduction, and conjugation (Huddleston, 2014).

18.14

Multidrug resistance in bacteria

Inappropriate use of antibiotics for different diseases results in the selection of pathogenic bacteria resistance to multiple drugs (D’Costa et al., 2011). This means that a particular antibiotic is no longer able to kill or control the bacteria. Multiple resistances in bacteria can occur by one or two mechanisms. If the bacteria strains resistant to three or more classes of drugs, it is considered multidrug resistant (D’Costa et al., 2011). Although urgently needed, information regarding the extent of multidrug resistance and common combinations of resistance mechanisms is rarely available on a larger scale, especially in Gram-negative organisms. In general, meticillin/oxacillin resistance in S. aureus, the production of ESBLs, and carbapenemase production in Gram-negative bacteria are simple markers for the multidrug resistance. Liyanage and Manage (2017b) has recorded multidrug resistance against E. coli, Staphylococcus sp., Acinetobacter sp., Klebsiella sp., P. aeruginosa, Haemophilus sp., and Aeromonas hydrophila strains particularly associated with gastrointestinal illnesses and many other human infections, and Ochoa-Repa´raz et al. (2009) recorded E. coli as multidrug-resistant bacteria which is a common causative agent for childhood diarrhea. Further, it has been reported that multidrug resistance in Klebsiella and Proteus spp. were medically important among the causative agents of urinary tract infections (Moges et al., 2014). Multiple antibiotic resistances are known to arise due to acquisition of resistance genes through genetic exchange, mutation, and physiological mechanisms such as possession of specific proteins and efflux pumps (Davies and Davies, 2010). Thus significant rise in drug-resistant bacterial contamination exhibited by Gram-negative and positive bacteria, including pollution indicator organisms, is a risk to public health, particularly due to the emergence of resistance within microbial diversity (Davies and Davies, 2010). Further, it is a known fact that ARB tend to adopt various resistance mechanisms to survive in the unfavorable environmental conditions.

18.15

Risk of antibiotic resistance for human and animal health

Antibacterial agents may disturb the microflora of human/animal intestinal tract and increase risk for certain infections. When people are taking an antibiotic for any reason, it increases the risk for infections due to particular pathogens become resistant to that antibiotic (Pham et al., 2015). In addition the increased frequency

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of treatment failure and increased severity of infection as a result of antibiotic resistance may lead to have prolonged duration of illness, increased frequency of bloodstream infections, and increased hospitalization (Giorgia et al., 2004). According to D’Costa et al. (2011), resistance among common pathogens causing community and hospital-associated infections has increased significantly worldwide, though regional patterns of resistance vary. It has been recorded that resistance to lastresort antibiotics has led to an epidemic of hard-to-treat infections, such as methicillin-resistant S. aureus, ESBL-producing Enterobacteriaceae, carbapenemresistant Enterobacteriaceae, vancomycin-resistant enterococci, and gonorrhea (Pham et al., 2015). These infections have the potential to spread quickly through international trade and travel (Kim et al., 2012). K. pneumoniae is the most commonly reported Gram-negative pathogen in Asia and Africa, making up nearly half of all Gram-negative infections in neonates (Pham et al., 2015). In Asia, median resistance of K. pneumoniae to AMP was 94%, and to cephalosporins, 84%, while it was 100% and 50%, respectively, in Africa (Moges et al., 2014). Multidrug resistance appeared as 30% of strains in Asia and 75% of strains in Africa (Giorgia et al., 2004). Moreover, several lines of evidence connect antibiotic use in livestock with effects in humans such as (1) direct animal-to-human transmission of resistance; (2) animal food-to-human transmission of resistance; (3) food-borne outbreaks of infection; and parallel trends in antibiotic use in animals and related antibiotic resistance in humans were recorded (Naylor and Burke, 2005). Antibacterial resistant nontyphi Salmonella serotypes and Campylobacter increased morbidity or mortality has been demonstrated (Kim et al., 2012). It is reasonable to assume that the same phenomenon that has been demonstrated for Salmonella and Campylobacter species can occur with other drug-resistant human pathogens, for which resistance may originate in aquaculture. In addition, ARGs and ARB in farm wastewater may lead to problems in the efficiency of antibiotics which are used to treat fish diseases and eventually to production losses at the fish farms (Naylor and Burke, 2005). Thus more comprehensive data collection, systematic examination, and dissemination of existing data are needed to complete the global picture of antibiotic resistance.

18.16

Bioremediation of antibiotic as a green solution

Elimination of antibiotics is the result of its fate and degradation pathways which ultimately depends on its physicochemical properties. In a wastewater treatment plant, antibiotics undergo mechanical, chemical, and biological processes (HallingSørensen et al., 1998; Manage, 2018). Removal efficiencies of conventional sewage treatment are found to be varying substantially, and they are not designed to deal with emerging pollutants such as antibiotics. However, membrane bioreactor systems were reported to be slightly more efficient than conventional activated sludge treatment systems (Watkinson et al., 2009), and the fate of ß-lactams, sulfonamides,

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trimethoprim, macrolides, FQ, TC, and nitroimidazoles has been studied in biological treatment, activated carbon adsorption treatment, and advanced oxidation processes (Rizzo et al., 2013). However, the real applicability of such techniques is expensive and inaccessible in most part of the world, especially in the developing countries due to high operational cost. Thus bioremediation is economically viable, cost-effective green technologies which produce nonharmful compounds such as carbon dioxide, water nitrogen, and organic matter during the microbial degradation processes (Sturini et al., 2012; Liyanage and Manage, 2016b). Transformation of organic compounds can be intracellular or extracellular of microbes; it is the major pathway of the degradation by enzymatic transformation under aerobic and anaerobic conditions by bacteria, algae, or fungi have been recorded (Campo et al., 2009). However, the biodegradation of antibiotics under aerobic conditions assisted by bacteria is found to be rare (Halling-Sørensen et al., 1998). Alexy (2009) assessed the biodegradability in the closed bottle test according to the test guidelines of the Organization for Economic Cooperation and Development (OECD) “301 D” for 18 antibiotics. Out of these, only a few were slightly degraded in 28 days. It was recorded that benzylpenicillin sodium salt degraded by 27%, AMX by 5%, nystatin and trimethoprim by 4%, and the rest was reported to be ,4% (Alexy, 2009). Kummerer (2010) reported no reduction for CIP, and ofloxacin showed only 5% reduction in the OECD 301 D test even after 40 days. Gartiser et al. (2009) also studied the inherent biodegradability of 17 antibiotics in a combined test, the ZahnWellens test, and CO2-evolution test (OECD 301 B and OECD 302 B). Maki et al. (2006) has isolated Flavobacterium strains responsible for the degradation of a group of antibiotics, including OTC and AMP. Liyanage and Manage (2018) reported complete degradation of CIP by Lactobacillus gasseri at the end of 14 days of incubation with an average degradation rate of 0.182 6 0.15 μg/day. Further, Liyanage and Manage (2018) recorded the degradation rates of CIP by Enterobacter sp. (0.75 6 0.03 day21) and Bacillus sp. (0.41 6 0.02 day21) at 8 and 6 days, respectively (Liyanage and Manage, 2018). Thus bioremediation is an economically viable, cost-effective green technology which may lead to degradation of antibiotics by converting into simple, nontoxic compounds such as carbon dioxide, water nitrogen, and organic materials during the process of microbial degradation (Sturini et al., 2012).

18.17

Future challenges in aquaculture, livestock, and human health due to antibacterial resistance

WHO (2014) estimated that by 2050, antimicrobial resistance will be responsible for 4.7 million deaths in the Asia region. The most effective risk management option is to prevent and control the development and spread of antibacterial resistance and reducing the need of antibacterial treatments (Moges et al., 2014). Globalization increases the vulnerability of countries to imported diseases, and infectious diseases travel faster and farther than ever before. The rate of

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development of antimicrobial resistance (AMR) is accelerated by the use and misuse of antimicrobials in health and aquaculture sector. Thus the factors responsible for future challenges due to antibacterial resistance include over-the-counter availability of antibiotics without regulation, the use of drugs of low potency and effectiveness as a result of poor manufacture or counterfeiting, and the availability of drugs from roadside stalls and hawkers who have little or no knowledge of dosage regimens, indications, or contraindications. Thus containment of AMR requires a range of strategies to be adopted. Resistance to antimicrobial therapies reduces the effectiveness of the drugs, leading to increased morbidity, mortality, and health-care expenditure (Liyanage and Manage, 2017b). Because globalization increases the vulnerability of any country to diseases occurring in other countries, resistance presents a major threat to global public health, and no country acting on its own can adequately protect the health of its population against the drug (Sturini et al., 2012). Therefore international collective action is essential. Nevertheless, responsibility for health remains predominantly national. Consumers of aquaculture products may be exposed to resistant bacteria via contact with or consumption of animal products—a far-reaching and more complex route of transmission (Ritter et al., 2008). There is undeniable evidence that foods from many different animal sources and in all stages of processing contain abundant quantities of resistant bacteria and their resistance genes (Giorgia et al., 2004). The rise of antibiotic-resistant bacteria among farm animals and consumption of meat and fish products has been well documented demonstrating whether such reservoirs of resistance pose a risk to humans has been more challenging as a consequence of the complex transmission routes between farms and consumers and the frequent transfer of resistance genes among host bacteria (Cabello, 2006). Some of the ARGs identified in food bacteria have also been identified in humans, providing indirect evidence for transfer by food handling and/or consumption (Naviner et al., 2011). Sullivan et al. (2001) confirmed the risk of consuming meat products colonized with resistant bacteria, and Campo et al. (2009) showed that glycopeptideresistant Enterococcus faecium of animal origin ingested via chicken or pork lasted in human stool for up to 14 days after ingestion. Thus a national-level regulatory framework is needed for registration, approval, and control of the use of antibacterial agents. In May 2015 the World Health Assembly endorsed the Global Action Plan on Antimicrobial Resistance, which calls on all countries to adopt national strategies within 2 years (WHO, 2015). Prevention in reaching of ARGs to people is vital. Thus the best way to achieve this is through improved sanitation, which is a continuing global challenge. Several other approaches can reduce antibiotic contamination from agriculture: managing nutrients, controlling runoff, composting manure, and upgrading infrastructure (Pruden et al., 2013). Managing hotspots by containing industrial and hospital wastes before they reach water sources is also to be addressed. Overall, strengthening control through risk assessment, surveillance, and interventions can reduce the amount of antibiotics entering the environment (Berendonk et al., 2015) in order to safeguard people.

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