Development of antimicrobial resistance: future challenges

Development of antimicrobial resistance: future challenges

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Delfina C. Domı´nguez1,2 and Samantha M. Meza-Rodriguez2 1 Clinical Laboratory Science Program, The University of Texas at El Paso, El Paso, TX, United States, 2Department of Public Health Sciences, The University of Texas at El Paso, El Paso, TX, United States

16.1

Introduction

Throughout history, mankind has continuously battled a wide variety of infectious diseases [plague, influenza, malaria, tuberculosis (TB), and more recently, human immunodeficiency virus] that have caused significant mortality and morbidity (Gould, 2016; Tenover, 2006). The discovery of antibiotics has been one of the most significant medical advances of the 20th century, saving and improving the lives of millions of people (CDC, 2013). Antibiotic therapy transformed medicine and has become indispensable for many clinical interventions such as surgeries, organ transplants, and management of immunocompromised patients (Davies and Davies, 2010). Unfortunately, bacteria developed resistance soon after antibacterial drugs are introduced. As the administration of antimicrobials increased, the level of complexity of antimicrobial resistance (AMR) mechanisms developed by bacteria increased (Ventola, 2015). The emergence of resistant and multidrug-resistant (MDR) organisms has become a global health concern affecting the diagnosis, treatment, and prevention of infections (WHO, 2018). The US Centers for Disease Control and Prevention estimates that about 2 million patients each year develop antibiotic-resistant infections, and at least 23,000 people die of those infections (CDC, 2013). Moreover, predictions by the year 2050 estimate that 300 million deaths will occur, with a loss of $100 trillion to the global economy (Munita and Arias, 2016; O’Neill, 2016; Piddock, 2016). Concurrent with the increasing rates of resistance to conventional antibiotics is the deceleration in the development of new antimicrobials by the pharmaceutical industry (Fischbach and Walsh, 2009), which has worsened the situation leaving medical professionals with no alternatives to treat patients battling lifethreatening infections. The problem of AMR is very complex. The inappropriate and excessive use of antibiotics in hospitals and outpatient settings is believed to be the major facilitators of the growing resistance trend (Canton et al., 2013; Fleming-Dutra et al., 2016). However, besides the medical field, numerous human activities have contributed to the spread of AMR within the community and the environment (Bengtsson-Palme et al., 2018; Davies and Davies, 2010; Yang et al., 2018). Antibiotics are commonly Pharmaceuticals and Personal Care Products: Waste Management and Treatment Technology. DOI: https://doi.org/10.1016/B978-0-12-816189-0.00016-0 © 2019 Elsevier Inc. All rights reserved.

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used in animals for prophylaxis and/or growth enhancers (Doyle et al., 2006; Landers et al., 2012), in agriculture and aquaculture (Allen et al., 2010), and recent research has highlighted wastewater treatment plants, soil and water environments as reservoirs and sources of antibiotic resistance (Moura et al., 2010; Pruden et al., 2013; Santos and Ramos, 2018). The present chapter will provide a general overview of AMR including a brief history of antibiotics, main mechanisms of resistance, MDR organisms called “superbugs,” the spread of resistant genes in humans and nature, and antibiotics in the environment. New therapeutic approaches and alternatives to antibiotics will also be briefly reviewed.

16.2

History of antibiotics

The use of antibiotics dates back to ancient times. Millenary cultures such as the Chinese, Egyptians, and the Greeks utilized traditional remedies with antimicrobial effects for the management of infections (Aminov, 2010; Gould, 2016; Sengupta et al., 2013). There is evidence that bone sections dating back to 350 550 AD (Bassett et al., 1980; Nelson et al., 2010) and skeletons dating from the Roman period contained traces of tetracycline (Cook et al., 1989). By the 15th (1654) century, van Leeuwenhoek was the first to describe microorganisms by using powerful lenses he created. He called the little creatures “animalcules.” However, it was not until the late 17th century (1800s) when Robert Koch and Louis Pasteur associated bacteria with disease (Gould, 2016). In 1899, Emmerich and Lo¨w prepared the first antimicrobial compound that was used in hospitals as an antibiotic. The compound was prepared from the extracts of Pseudomonas aeruginosa and was called pyocyanase (Emmerich and Lo¨w, 1899). The compound showed activity against various bacterial pathogens, but the treatments were abandoned due to toxicity and the lack of reproducibility (Aminov, 2010). The modern antibiotic era (20th century) began with Paul Ehrlich and Alexander Fleming. Ehrlich was looking for a compound that would kill microorganisms in a single dose. He coined the terms “magic bullet” and “chemotherapy” to describe what he wanted to achieve (Williams, 2009). With the aim to treat syphilis, which was a devastating disease at that time, Ehrlich began the synthesis of organoarsenic compounds. In 1907 the chemist Alfred Bertheim synthesized the so-called 606 compound, arsphenamine, which was later tested successfully against syphilisinfected rabbits by the bacteriologist Sahachiro Hata, a member of Ehrlich’s team (Aminov, 2010; Ehrlich and Hata, 1910; Williams, 2009). Arsphenamine was the first successful antibiotic treatment against syphilis in humans. Despite its side effects the drug was marketed under the trade name Salvarsan in 1910. Ehrlich continued improving Salvarsan developing a less toxic and more soluble compound called neosalvarsan. Arsenicals remained the mainstay of treatment for syphilis until penicillin was introduced (Mahoney et al., 1943; Williams, 2009).

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By the end of 1920s the Friedrich Bayer Company, inspired by Ehrlich’s methods, started extensive research developing synthetic chemicals to treat bacterial infections. In 1932 a new compound that showed activity against highly virulent streptococcal strains, coded KI-695, was synthesized. The drug was named Prontosil and was used to treat puerperal infections resulting in positive outcomes (Bentley, 2009; Domagk, 1935). In 1928, while studying staphylococci variants, Fleming discovered penicillin. He found a petri dish of staphylococci, which contained a fungus contaminant, and noticed that close to the fungus there was extensive bacterial growth inhibition (Bentley, 2009; Fleming, 1929). He named the antibiotic Penicillin. However, it was Chain, Florey, and coworkers who discovered the remarkable in vivo activity of the antibiotic (Chain et al., 2005). Penicillin began being used in clinical setting in 1940 (Saga and Yamaguchi, 2009). The X-ray structure of penicillin was determined in 1949 (Hodgkin, 1949), and the total synthesis in 1959 (Sheehan and Henerylogan, 1959). The discovery of the first antimicrobials, Salvarsan, Prontosil, and Penicillin, has been a revolutionary event setting the path for future drug discovery. During subsequent decades new classes of antibiotics were discovered and introduced, with continuous improvement, broadening the spectrum and effectiveness of antibiotics.

16.3

Development of antibiotic resistance

Antibiotics are chemical substances produced by microorganisms that may inhibit growth (bacteriostatic) or kill (bactericidal) bacteria (Mascaretti, 2003). Antibiotic resistance occurs when bacteria are able to grow/survive in the presence of an antibiotic. Bacteria that resist the effects of an antibiotic have a better chance of persisting in the body, increasing the risk of spreading to other patients. Antibiotic resistance can be intrinsic or acquired. Intrinsic resistance occurs when bacteria are innately resistant to a class of antibiotics (Martinez, 2009; Tenover, 2006). Acquired resistance occurs when bacteria become less susceptible to antibiotics they were once readily susceptible to. This differs from intrinsic resistance in that the genes or mutations that confer resistance were not originally present in the bacteria (Davies and Davies, 2010). Antibiotic resistance is a natural phenomenon that occurs as a result of evolutionary natural selection. However, the abuse and misuse of antibiotics is considered to be one of the driving forces for AMR (CDC, 2013; WHO, 2018). It is estimated that at least 30% of antibiotics prescribed in outpatient settings are unnecessary. In the United States 50% of all outpatient antibiotic use is categorized as inappropriate (CDC, 2011; Pichichero, 2002; Shapiro et al., 2014). Most of these antibiotics are often taken for respiratory infections where antibiotics are not needed such as colds, sore throats, or bronchitis caused by viruses (Fleming-Dutra et al., 2016). Because children and older adults use antibiotics the most, antibiotic resistance is a serious concern regarding these populations (CDC, 2018).

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Figure 16.1 Timeline of key events in the development of antimicrobial resistance. The figure illustrates the dates antibiotics were discovered by year (top) and the year that the antibiotic was reported to be resistant (bottom).

Besides healthcare, antibiotics are abused and misused in agriculture and aquaculture. Antibiotics are given to animals to promote growth and for the prevention of infections (Landers et al., 2012; Roca et al., 2015). Antibiotics used in animals allow for the development of resistant bacteria, which can be shed through feces or their skin. These resistant bacteria can migrate around the farm, in slaughter houses, and during meat processing and can eventually enter into the environment (Landers et al., 2012; Marshall and Levy, 2011; CDC, 2017). Other important factors contributing to the dissemination of AMR are human activities such as waste disposal, industrial effluents, and wastewater treatment plants, which are considered reservoirs for the resistant genes and bacteria (Davies and Davies, 2010; Wright, 2010). Fig. 16.1 shows the timeline of when antibiotics were introduced and the year resistance to antibiotics arose.

16.4

Mechanisms of resistance

Bacteria have developed several ways to block the effects of antibiotics. There are four main mechanisms by which bacteria resist antibiotic effects (Fig. 16.2) (Nordmann et al., 2012). (1) Inactivation of the antibiotic by enzyme production. A common modification of the antibiotic is through the action of enzymes produced by bacteria, which break specific sites of the antibiotic molecule rendering it ineffective, as in the case of β-lactamases and extended-spectrum β-lactamases (ESBL) enzymes (Munita and Arias, 2016). ESBLs are a group of β-lactamases that are a serious health concern and a common cause of hospital-acquired infections ranging from uncomplicated urinary tract infections to life-threatening conditions such as sepsis (Canton and Coque, 2006; Rawat and Nair, 2010). (2) Changes in membrane permeability (prevention of antibiotic to reach its target). This may occur through downregulation of the expression of porins. An example would be how strains of P. aeruginosa are resistant to imipenem by lacking the porin OprD, which is required for the entry of the antibiotic (Cloete, 2003; Fernandez and Hancock, 2012).

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Figure 16.2 Mechanisms of antimicrobial resistance. (1) Inactivation of the antibiotic by enzyme production, (2) prevention of antibiotic to reach its target, (3) extrusion of toxic compounds (efflux pump), and (4) target site modification. Source: Reproduced with permission from Nordmann, P., Dortet, L., Poirel, L., 2012. Carbapenem resistance in Enterobacteriaceae: here is the storm! Trends Mol. Med. 18(5), 263 272.

(3) Extrusion of toxic compounds (efflux pumps). This mechanism prevents the antibiotic to reach intracellular concentration levels that will harm the cell. Efflux pumps have the capacity to pump out a wide variety of toxic substances. Therefore these pumps have been called multidrug efflux pumps. These pumps are proteins that contribute significantly to multidrug resistance and are present in various bacteria. Tetracycline and fluoroquinolone resistance is an example of efflux-mediated resistance (Giedraitiene et al., 2011; Munita and Arias, 2016). (4) Target site modification. In this mechanism, bacteria change the structure of the target or decrease the affinity of the antibiotic to bind the target, thus preventing attachment or binding. Altered penicillin-binding proteins (PBPs) in Staphylococcus aureus are an example. Since the protein binding site is modified, the β-lactam antibiotic cannot bind to the altered PBP, and the bacteria continue to replicate even at high concentrations of the antibiotic (Lim and Strynadka, 2002). An additional less common mechanism of resistance is changing the metabolic pathway (e.g., trimethoprim/sulfonamides) of folic acid. A list of the most commonly used antibiotics and their mechanism of action are shown in Table 16.1.

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Table 16.1 Antibiotics and mechanisms of resistance Antibiotic class

Antibiotics

Antibiotic mode of action

Antibiotic resistance mechanism

Aminoglycosides

Amikacin Gentamicin Kanamycin Streptomycin Tobramycin

Inhibition of protein synthesis (translation)

Beta-lactams

Penicillin Cephalosporins Carbapenems Monobactams Ciprofloxacin Ofloxacin Levofloxacin Sparfloxacin Trimethoprim Sulfonamides Vancomycin Teicoplanin

Inhibition of peptidoglycan synthesis

Modifying enzymes (phosphorylation, acetylation, nucleotidylation) Altered ribosomal target Reduced uptake (efflux) Altered target (PBP2a) Hydrolysis (beta-lactamase) Reduced permeability (efflux) Acetylation Efflux Altered DNA gyrase

Macrolides

Erythromycin Clarithromycin Azithromycin

Inhibition of protein synthesis (translation)

Rifamycins

Rifampin

Tetracyclines

Tetracycline Doxycycline Minocycline Tigecycline

Inhibition of RNA synthesis (transcription) Inhibition of protein synthesis (translation)

Fluoroquinolones

Folate inhibitors Glycopeptides

16.5

Inhibition of DNA replication Inhibition of folic acid synthesis Inhibition of peptidoglycan synthesis

Efflux Novel target enzymes Altered drug target (reprogramming peptidoglycan biosynthesis) Modifying enzymes (glycosylation, phosphorylation) Efflux Altered ribosomal target Hydrolysis Altered RNA polymerase ADP-ribosylation Efflux Altered ribosomal target Efflux Monooxygenation

Spread of antimicrobial resistance

16.5.1 Conjugation, transformation, and transduction AMR spreads through the transfer of genetic material. The transfer can be “vertical” when new progeny receives antibiotic-resistant genes or “horizontal” when bacteria (and viruses) share and exchange the fragments of genetic material with each other (Deng et al., 2015; Balcazar, 2014; Martinez, 2009). Horizontal gene transfer (HGT) was discovered about 70 years ago with the introduction of

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experimental microbial genetics (Arber, 2014). HGT occurs through three main mechanisms: (1) conjugation, (2) transformation, and (3) transduction (Fig. 16.3). Conjugation is a multistep process that requires tight cell contact between the donor and the recipient cell. In this type of genetic transfer a fertility factor F is present in the donor cell, which is an autonomous DNA molecule. Conjugation is considered the most common mechanism responsible for antimicrobial resistant gene transfer (Arber, 2014; von Wintersdorff et al., 2016). Transformation involves the uptake of naked DNA, which is released into the environment as a result of cell lysis and incorporation into the host cell either by integration into the genome or by recircularization of the DNA molecule (plasmids) (Tenover, 2006; Thomas and Nielsen, 2005; von Wintersdorff et al., 2016). Transduction is mediated by the infection of

Figure 16.3 Spread of resistance mechanisms. (A) Conjugation, the transfer of genes from one bacterial cell to another requires cell-to-cell contact, (B) transformation, transfer of genetic material via free DNA, (C) transfer of host genes from one cell to another by a virus, (D) Gene transfer agents like bacteriophages, which are released upon cell lysis. Source: Courtesy of von Wintersdorff, C.J., Penders, J., Van niekerk, J.M., Mills, N.D., Majumder, S., Van alphen, L.B., et al., 2016. Dissemination of antimicrobial resistance in microbial ecosystems through horizontal gene transfer. Front. Microbiol. 7, 173.

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bacteria by viruses, called bacteriophages, and the incorporation of any portion of the viral genome into the host cell or by transferring specific genes to the recipient cell (Balcazar, 2014). The mobilization of antibiotic-resistant genes by bacteriophages has been documented in various bacterial species and in different environments, including: hospitals, clinics, food production, river samples sewage plants, and soil (Colavecchio et al., 2017). However, the role of bacteriophages in the transfer of antimicrobial resistant genes is still controversial (Allen et al., 2010; Enault et al., 2017; Yosef et al., 2015).

16.5.2 Mobile genetic elements Mobile genetic elements (MGE) play a crucial role in the development and persistence of AMR. One major challenge is to understand this diverse collection of mobile elements, which are dependent on natural selection. Further complexity arises by the fact that these elements may be mosaics, made up of different genes and subelements, which allows a wide variety of interactions with other genetic elements promoting their adaptability and survival (Norman et al., 2009). Examples of MGE include plasmids, integrons, transposons (Tn), insertion sequences (IS), and genomic islands, which can mobilize resistant genes in different bacterial species, animal hosts, and the environment (Stokes and Gillings, 2011). Plasmids are small circular DNA molecules within a bacterial cell that replicates independently of the host chromosome. Plasmids differ from the bacterial chromosome in that they don’t carry essential genes, but genes that may benefit the host cell (Madigan et al., 2012). Plasmids may become essential for survival to the host cell such as in the case of AMR. Plasmids are transferred cell to cell by conjugation and transformation. The global dissemination of resistant genes is mainly due to plasmids conferring resistance to critically important drugs such as β-lactams, carbapenems, and colistin (Buckner et al., 2018). Plasmids also carry resistance genes to disinfectants and biocides promoting the development of multidrug-resistant organisms (Ignak et al., 2017; Santos and Ramos, 2018). Integrons are genetic elements that are capable of capturing and rearranging exogenous DNA and incorporating it into a single unit. In general the structure of these elements is defined by the presence of an integrase gene (intI) and a recombination site (attI) (Cambray et al., 2010; Martinez, 2009). The mobility of integrons is considered a major concern since these are associated with plasmids and Tn, playing a key role in dissemination and spread of AMR (Deng et al., 2015). Besides clinical settings, integrons have been recovered from many environmental sources, including water treatment plants, rivers, treated water, and marine outfalls (Barrantes and Achi, 2016; Kotlarska et al., 2015). Transposable elements (TE) are the segments of DNA that can move from one site on a DNA molecule to another site. TE are inserted into DNA; they are not found as separate DNA molecules, and they cannot replicate by themselves but are replicated when the host DNA molecule into which they are inserted is replicated. Host molecules for TE include chromosomes, plasmids, viral genomes, and other DNA molecules. Bacteria have two major types of TE, IS and Tn. Each type of TE

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Figure 16.4 Diagram of an insertion sequence and a transposon. (A) IS 2 is 1375 bp with inverted repeats 41 bp at the ends, (B) Tn 5 contains the insertion sequences IS 50 at the ends, and it is 5.7 kbp. The genes kan, str, and bleo confer resistance to kanamycin, streptomycin, and bleomycin. bp, Base pairs; IS 2, insertion sequence 2; Tn 5, transposon 5.

has two essential components: two regions at the end of the DNA sequence and a gene that encodes a transposase (an enzyme that binds to the end of the Tn and allows transfer). IS are short DNA segments [600 700 base pairs (bp)], whereas Tn are larger (.2000 bp) (Madigan et al., 2012). Fig. 16.4 shows a map of IS 2 and Tn 5. HGT is one of the key mechanisms that mediate the acquisition of virulence and AMR. For example, the increased spread of carbapenemase-producing P. aeruginosa, which is a current worldwide threat, is due to MGE (Botelho et al., 2018). The evolution and the emergence of new epidemic clones of methicillin-resistant S. aureus (MRSA) are also due to MGE (Jamrozy et al., 2017). In addition to the clinical setting, reports indicate that MGE play an important role in AMR in aquaculture and in the environment (Chenia and Jacobs, 2017).

16.6

Superbugs

The term “superbugs” refers to bacterial strains that have the ability to cause high mortality and morbidity due to development of multiple resistant mechanisms. The therapeutic approaches to treat and manage infections caused by these organisms are limited. Usually patients require long hospitalization, and reinfection often occurs (CDC, 2013; Davies and Davies, 2010). In 2013 the Centers for Disease Control and Prevention published a list of resistant microorganisms that represent a threat to the United States. These organisms were classified as urgent, serious, and concerning threats. The urgent and serious classifications require constant monitoring and prevention measures to limit transmission, whereas the threats in the concerning classification require less scrutiny. The 18 drug-resistant organisms that pose health threat are shown in Table 16.2. Carbapenem-resistant Enterobacteriaceae (CRE) is a continuing public-health concern of global dimensions (Meletis, 2016). The spread of these bacteria is rapid, and the treatment failure is high. Almost half of the patients who acquire a CRE blood infection die (CDC, 2013). Some of the most common enteric bacteria that

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Table 16.2 CDC’s top 18 drug-resistant threats in the United Statesa Urgent threats

Serious threats

Concerning threats

a

Have the potential to become widespread and are highconsequence resistant threats, requiring urgent public health attention. Although not classified as urgent, serious threats require public health monitoring and prevention practices. These threats are classified a serious due to low or declining domestic incidence and availability of therapeutic agents.

Classified as a low-resistant threat with multiple therapeutic options available.

Clostridium difficile (CDIFF) Carbapenem-resistant Enterobacteriaceae Neisseria gonorrhoeae Multidrug-resistant (MDR) Acinetobacter Drug-resistant Campylobacter Fluconazole-resistant Candida Extended spectrum Enterobacteriaceae Vancomycin-resistant Enterococcus MDR Pseudomonas aeruginosa Drug-resistant nontyphoidal Salmonella Drug-resistant Salmonella serotype Typhi Drug-resistant Shigella Methicillin-resistant Staphylococcus aureus Drug-resistant Streptococcus pneumonia Drug-resistant Tuberculosis Vancomycin-resistant S. aureus Erythromycin-resistant Group A Streptococcus Clindamycin-resistant Group B Streptococcus

Centers for Disease Control and Prevention https://www.cdc.gov/drugresistance/biggest_threats.html.

are CRE include Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Enterobacter species. Additional pathogens that can cause serious infections caused by multiresistant Enterobacteriaceae members are Salmonella, Serratia, Proteus mirabilis, and Citrobacter. Hospital-acquired infections of great concern caused by other commonly encountered superbugs are P. aeruginosa and Acinetobacter baumannii. P. aeruginosa is a common hospital-associated threat. This organism is intrinsically resistant but has also developed mechanisms that allow it to resist immune defenses and persist in the human body. Cystic fibrosis patients are greatly affected by this opportunistic pathogen (Bhagirath et al., 2016; Silva Filho et al., 2013). A. baumannii, also primarily hospital associated, is one of the most clinical significant MDR pathogens

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as its resistance to antibiotics has risen dramatically (Cerezales et al., 2018; Liu et al., 2018; Yuan et al., 2018). The rapid AMR of A. baumannii may be attributed to the pathogen’s ability to survive in diverse environmental conditions and its biodegradation capabilities (Davies and Davies, 2010). Both P. aeruginosa and A. baumannii cause a wide variety of infections including urinary, respiratory, wound, and septicemia, especially in debilitated patients and patients with weak immune system (Cerezales et al., 2018). A well-known superbug is methicillin-resistant S. aureus commonly known as MRSA. S. aureus is a versatile pathogen that is resistant to multiple antibiotics through different mechanisms. MRSA may cause a wide variety infections ranging from a mild skin infection to sepsis (CDC, 2013). Studies showed that MRSA may be carried in the anterior nares in 1.3% 2% of the population (Davis et al., 2004). MRSA infections are commonly healthcare associated but can also be acquired in the community. However, community-associated strains are genetically different and have a distinct clinical presentation compared to healthcare-associated MRSA (Hsiao et al., 2015). Clostridium difficile is the most common intestinal healthcare-associated infection in US hospitals, and it is a common cause of death among Americans 65 years and older (CDC, 2015). The infection is caused by the prolonged intake of antibiotics, which disrupt the intestinal flora allowing proliferation of the toxin-producing bacteria (Sun and Hirota, 2015). C. difficile is resistant to multiple antibiotics, which are usually given in hospital settings to treat infections. Since C. difficile is a spore-forming bacterium, once antibiotic treatment is stopped, spores surviving therapy may germinate causing the relapse of C. difficile infection (CDI). A major concern during the last few years is that new C. difficile strains have developed resistance to vancomycin and metronidazole, two antibiotics that remain the mainstay treatment for CDI resulting in very limited therapeutic options (Peng et al., 2017). Although CDI is typically a healthcare-associated infection, it has also been reported in the community. Sources for CDI in the community could be discharged patients that continue to shed spores after therapy, contaminated food, water, and animals (Gupta and Khanna, 2014). As AMR continues to escalate, communityacquired CDI surveillance needs to be improved and antimicrobial stewardship programs implemented. These efforts will help to prevent community-associated CDI. Mycobacterium tuberculosis is the classical human pathogen that has evolved with mankind and, to this day, remains a major global health problem. It is estimated that in 2016, 600,000 people developed MDR-TB, and 240,000 people died (WHO, 2017). The treatment regime for TB has been the use of antibiotic cocktails (combination of three antibiotics), which were effective until new MDR strains (resistant to isoniazid and rifampicin) and extensive drug-resistant (XDR) strains (resistance to any fluoroquinolone, and at least one of the injectable drugs in addition to MDR) emerged. The continued spread of resistant bacterial strains is an urgent and difficult challenge. Treatment is complicated and costly, and inappropriate management may have a fatal outcome. To date, XDR-TB cases continue to increase worldwide (Ei et al., 2018; Forson et al., 2018). Proper treatment, prevention, management, and control of MDR-TB prevent the emergence of XDR-TB and additional resistant strains (WHO, 2017).

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Antimicrobial resistance in the environment

AMR was traditionally confined within the clinical setting. However, investigations show that bacteria found in natural environments, even in apparently antibiotic-free environments, possess an enormous diversity of antibiotic resistance genes (ARG) (Aminov, 2010). Studies showed that AMR is ancient and has existed for millions of years. ARG have been recovered from inhospitable environments such as permafrost and prehistoric caves (Bhullar et al., 2012; D’Costa et al., 2011). Samples of DNA collected from 30,000-year-old permafrost sediments revealed genes encoding for β-lactams, glycopeptides, and tetracycle. Furthermore, the vancomycin-resistant element VanA found in these samples was highly similar to modern variants of VanA gene (D’Costa et al., 2011). Bacterial strains collected from a cave that has been isolated for millions of years were shown to be MDR and contain novel antibiotic-inactivating enzymes, which may have clinical implications (Bhullar et al., 2012). Why can so many resistant genes be found in natural environments? Bacteria in the environment interact with a wide variety of toxicants, chemicals, and byproducts from other organisms such as fungi, plants, and animals; therefore many of these genes arise from these interactions. Many of the resistant genes are involved in nutrition, metabolism, detoxification of noxious substances, and catabolic processes (Baquero et al., 2013). Moreover, many soil bacteria utilize antibiotics (produced by other bacteria) as carbon source leading to higher levels of resistance (Martinez, 2009; Wright, 2010; Dantas et al., 2008). The potential transfer of these genes to pathogens is a concern. There is indeed evidence that ARG have originated from environmental bacteria. Environmental bacteria that appear to be reservoirs of various resistant genes found in pathogens include Kluyvera as source of ESBLs genes, Shewanella algae and Vibrio species as reservoir for plasmid-encoding quinolone resistance qnrA, and waterborne Shewanella species as origin of carbapenem-hydrolyzing β-lactamases (von Wintersdorff et al., 2016). Other bacteria that grow in the environment and are opportunistic pathogens, such as Stenotrophomonas maltophilia and Pseudomonas putida, may contribute to the spread of antimicrobial elements as they may be recipients of human-associated bacteria and then taken them back to the environment (Bengtsson-Palme et al., 2017). During the past few years, evidence continues to accumulate indicating that environmental bacteria are the potential reservoir of ARG and that resistant genes in pathogens have an environmental origin. Furthermore, the environment has been recognized as the reservoir and responsible for the dissemination of ARG (Bengtsson-Palme et al., 2017; Bengtsson-Palme et al., 2014; Martinez, 2009). The role of environmental bacteria as potential sources for ARG is rather recently a focus of research. One of the major goals of studying AMR in the environment is to obtain knowledge of the health risks and to develop interventions to prevent or delay transfer of resistant elements to pathogens from environmental bacteria (Wright, 2010).

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Transfer of environmental bacteria to the human microbiome may occur by different ways including interaction with wild animals, ingestion of meat from wild animals, ingestion of raw food, or drinking contaminated water (Bengtsson-Palme et al., 2017; Wright, 2010; Baquero et al., 2008). In addition, environmental factors that facilitate the spread of resistant bacteria are physical forces such as watershed and wind, water treatment plants, sewage, water bodies (rivers, lakes), and marine environments (Korzeniewska and Harnisz, 2013; Pal et al., 2016; Yang et al., 2018). Furthermore, the presence of biocides, preservatives, and metals in the environment as a result of human practices contributes to the horizontal transfer of mobile ARG. Exposure to subinhibitory levels of disinfectants promotes expression of efflux pumps allowing the organisms to survive and evolve new genes or generate new variants (Pal et al., 2016; Romero et al., 2017; Zhang et al., 2017). Evidence of the environment functioning as a reservoir of resistant microorganisms and its contributions to the dissemination of ARG is clear (Ashbolt et al., 2013; Bengtsson-Palme et al., 2014; Finley et al., 2013). However, the factors that contribute to the transfer (other than agricultural, water treatment, etc.) of ARG in pathogens and the understanding of the evolutionary and ecological processes leading to ARG are still lacking. Quantitative studies for the measurements of HGT, investigation of dissemination barriers, and assessment of the extent of selection for resistance in the environment have to be developed.

16.8

New therapeutic approaches

For more than 70 years, antibiotics have saved countless lives worldwide. However, due to the increase and persistence of AMR and the decline in the development of antibiotics by the pharmaceutical industry, the search for alternative and novel strategies to combat resistant bacteria is receiving special attention. In 2010 the Infectious Diseases Society of America proposed an initiative for developing 10 new antimicrobial agents by 2020 (Gilbert et al., 2010). In 2014 the Centers for Disease and Prevention recommended that all acute care hospitals implement an Antibiotic Stewardship Program (ASP). There is evidence that these ASPs can optimize infection treatments, reduce antibiotic side effects, help clinicians to improve patient care, reduce treatment failures, and increase frequency of correct prescribing for both prophylaxis and therapy. In addition, ASPs can result in significant drug cost savings (CDC, 2014). In 2015, President Obama proposed an action plan to combat AMR bacteria with a budget of $1.2 billion (The White House, Office of the Press Secretary, 2015). The Wellcome Trust in England commissioned 24 scientists, from academia and industry, to review and identify alternative approaches to the use of antibiotics. A potential portfolio of alternative approaches was developed by these scientists (Czaplewski et al., 2016). Alternative approaches that promise to be successful include bacteriophage lysins (Fischetti, 2018; Larpin et al., 2018; Yang et al., 2014), antibodies against virulence factors (Hauser et al., 2016; Skinner et al., 2014; Lachmann, 2012),

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inhibitors of signal transduction (Tiwari et al., 2017; Hauser et al., 2016), immune stimulation (Gjini and Brito, 2016), antibiofilm peptides (Chung and Khanum, 2017; Wang et al., 2017; Pletzer and Hancock, 2016), modulation of the microbiota, and vaccines (Czaplewski et al., 2016; Hauser et al., 2016). Additional alternative approaches are antiresistance nucleic acids, liposome-based toxin inhibitors, antibiotic degrading enzymes, hemoperfusion devices (Kang et al., 2014; McCrea et al., 2014; Opal, 2016), and metal chelation (Czaplewski et al., 2016; Opal, 2016; Rizzotto, 2012). A summary of the nonantibiotic therapeutic strategies to treat bacterial infection is listed in Table 16.3. Some of the alternative approaches are briefly described below.

16.9

Phage lysins

Lysins are enzymes produced by bacterial viruses (also called bacteriophages) that destroy the bacterial cell wall of Gram-positive bacteria. Phage therapy to treat bacterial infections is not new. It was introduced since the early 1920s and has been commonly used in Eastern Europe (Opal, 2016). Successful elimination and prevention of bacterial infection by a phage lysin was shown in 2001 by Nelson et al. (Fenton et al., 2010). In contrast to antibiotics, lysins are specific to certain bacterial strains and do not destroy normal flora. Lysins showed a high degree of cell lysis strongly reducing the number of bacteria present after the addition of the enzyme (Rios et al., 2016). Lysins that were used successfully against different bacteria include those for Streptococci (Lysins Cpl-1, Pal, and PlyGBS), Staphylococcus, including MRSA and vancomycin-resistant S. aureus (LysH5, M, MV-L, MR11, and CF 301), Bacillus anthracis, a bioterroristic agent (PlyG and PlyH), and C. difficile (CD27L) (Fenton et al., 2010; Fischetti, 2018; Rios et al., 2016). Lysins can be produced as recombinant proteins in E. coli, which make them very attractive for clinical treatment of MDR bacteria. Several lysins (N-Rephasin, P128, and Art-175) are in various stages of clinical trials. CF301 is currently the first lysin in phase 2 clinical trials for the treatment of hospitalized patients with endocarditis or bacteremia (Fischetti, 2018; Sharma and Paul, 2017). Lysins can be administered topically or can be administered intravenously for systemic infections (Opal, 2016). Some of the advantages of lysins over antibiotics are as follows: (1) phage lysins are highly specific and therefore do not affect normal flora; (2) low concentrations of lysins are effective after seconds of delivery significantly reducing the number of bacteria; (3) studies show good synergistic activity with antibiotics; (4) bacterial resistance to these enzymes has not been reported to date; (5) since phages are very abundant, the variety of lysins is considerably high; (6) lysins are thermostable; and (7) engineered lysins can be improved to enhance killing and improve solubility. Disadvantages/Limitations associated with these enzymes include the following: (1) stimulate the immune response and antibody production, which may degrade the lysin; (2) the majority of lysins are more active against Gram-positive bacteria; and

Table 16.3 Alternative approaches for antimicrobial therapy Alternative agent

Mechanism

Benefits

Disadvantages

Reference

Bacteriophage lysins

Enzymes produced by bacteriophages to destroy the cell wall of target bacteria. Exhibit direct antibacterial action against Gram-positive bacteria and can target specific strains without harming normal flora Can bind to and inactivate the bacteria, its virulence factors, or the toxins it produces. Are effective against Gram-positive and Gram-negative bacteria

Low concentrations are highly effective, good synergistic activity with antibiotics, no bacterial resistance to date, thermostable, can be improved through engineering

Can activate an immune response, more effective against Gram-positive bacteria, low spectrum of action

Fenton et al. (2010), Rios et al. (2016), and Fischetti (2018)

Considered low risk, safe, and has a high degree for technical feasibility

Synthesis and purification is expensive, limited to systemic delivery, may lose effectiveness over time due to changes in antigen

Molecules that can block the production or expression of genes responsible for increasing the virulence or key functions of a pathogen Repurposing the use of certain drugs and microbiota to enhance the expression of immune peptides and to stimulate the immune system

Target the TCS system which is vital for bacteria virulence and survival

The specific targets for TCS are not well defined

Czaplewski et al. (2016), Hauser et al. (2016), and Sparrow et al. (2017) Hauser et al. (2016) and Opal (2016)

Minimal toxicity, adjunct therapy for both Gram-positive and Gram-negative infections

Not as effective against established infections

Antibodies

Signal transduction inhibitors

Immune stimulation

Czaplewski et al. (2016) and Hauser et al. (2016) (Continued)

Table 16.3 (Continued) Alternative agent

Mechanism

Benefits

Disadvantages

Reference

Antimicrobial peptides

Cause cell membrane destruction via pore formation and causes the cell to lyse

Liposomebased toxin inhibitors

Liposomes can bind to toxins secreted by pathogens, thus inhibiting the toxin from binding to its receptor and damaging the host cell

Very low amounts have demonstrated antimicrobial activity, have synergistic activity with antibiotics Efficient delivery of pore-forming toxins and protection of host cell membranes from injury

Czaplewski et al. (2016) and Rios et al. (2016) Opal (2016)

Hemoperfusion devices

A device used to pump or filter blood outside of the body to remove a toxin

Quickly reduce the bacterial concentration

Susceptible to proteases, activity can be influenced by pH changes, and the production and purification cost is high Liposomes may be recognized, neutralized, or eliminated by the immune system. Permeability and retention effect need to be exploited further Studies in vivo need to be done

Metal chelation

A method of preventing the pathogen from successfully using metal elements to carry out virulence or pathogenicity processes

Chelating agents selectively disrupt essential metal metabolism inhibiting enzymes and disturbing homeostasis

TCS, Two-component system.

Chelation therapy may produce side effects. Toxicity has to be evaluated and careful design of formulations

McCrea et al. (2014), Opal (2016), and Kang et al. (2014) Czaplewski et al. (2016), Rizzotto (2012), and Santos and Ramos (2018)

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(3) in comparison to antibiotics, lysins have a narrow spectrum of action and may need to be combined to achieve bacterial killing in polymicrobial infections (Fenton et al., 2010; Rios et al., 2016; Yang et al., 2014). Considering both the benefits and disadvantages of lysins, lysins represent a powerful approach to fight AMR.

16.10

Signaling inhibitors

Bacteria have developed different mechanisms to communicate to each other sending and capturing signals in different environmental conditions. These bacterial systems (signal transduction pathways) comprise a variety of regulatory proteins that bind to metabolites or ions affecting gene regulation. An example of these systems are the two-component systems (TCSs), which may respond to specific signals such as pH, oxygen content, nutrient levels, quorum-sensing proteins, and antibiotics (Tiwari et al., 2017). Systems like this, which regulate virulence gene expression in pathogens, are very attractive for therapeutic intervention. Many antimicrobial determinants such as biofilm formation, efflux of antibiotics, changes in cell wall synthesis and metabolism are regulated by TCS (Bem et al., 2015; Poole, 2012). The high degree of conservation in the structure of these systems suggests that a single inhibitor can target multiple TCS. To date, more than 100 TCS inhibitors have been described, and most of these are for Gram-positive bacteria (Bem et al., 2015). Inhibitors to the synthesis of quorum-sensing signaling molecules or to the interaction of these molecules with their receptors have been developed. A synthetic analogue to Furanone C-30 reduced P. aeruginosa lung infection in mice, and LED209 reduced expression of virulence factors in enterohemorrhagic E. coli, Salmonella enterica, and Francisella tularensis (Hauser et al., 2016). TCSs are promising antimicrobial drug targets because of their important role in bacterial virulence and survival. However, more research is needed to define the structure of TCS targets and understand the mechanisms of action of the inhibitors.

16.11

Antimicrobial peptides

Antimicrobial peptides (AMPs), also called host-defense peptides, consist of 10 50 amino acids that possess a positive charge and hydrophilic and hydrophobic domains, which allow to bind and disrupt the membranes of microbes. AMPs are molecules of the immune system that have a broad antimicrobial spectrum. AMPs have synergistic activity with antibiotics (Chung and Khanum, 2017). Several AMPs demonstrate therapeutic antimicrobial activity in very low amounts (micrograms and nanograms). The mechanism of action of these peptides, in general, is cell membrane disruption via pore formation and subsequent cell lysis (Rios et al., 2016). AMPs show antiinflammatory activity and inhibit biofilm formation. Antibiofilm peptides differ from AMPs in structure and activity. Antibiofilm peptides have been found to kill multiple species of bacteria in biofilms, including both Gram-positive and Gramnegative bacteria (Pletzer and Hancock, 2016). The synthetic AMP LL-37 inhibits the

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production of biofilm by S. aureus at 3 μg/mL, and the IDR-1018 showed very broad-spectrum activity against P. aeruginosa, E. coli, A. baumannii, MRSA, and K. pneumoniae (Chung and Khanum, 2017; Pletzer and Hancock, 2016). Novel peptides have also been developed for applications in different areas of dentistry (Wang et al., 2017). Some disadvantages of these peptides include the following: are susceptible to proteases, activity may be influenced by pH changes, and the cost for production and purification is high and may induce sensitivity and allergy. To solve some of the disadvantages associated to AMP, chemical modifications have been proposed to protect from the action of proteases, encapsulation in liposomes, and synthesis via genetic engineering (Rios et al., 2016).

16.12

Antibodies to treat infections

Antibacterial antibody treatment is not yet a reality. There are many monoclonal antibodies (mAbs) that are under development for various infectious diseases, and most mAbs recently discovered are under clinical trials. There are three mAbs that have been licensed: palivizumab for the prevention of respiratory syncytial virus in highrisk infants and raxibacumab and obiltoxaximab (GlaxoSmithKline) for prophylaxis and treatment of inhalational anthrax. Some of the mAbs in active clinical trials include CDA1/CDB1 for C. difficile, anti-Pseudomonas IgY, KB001, and panobacumab; Shiga mAbs for Shiga toxin-producing E. coli; and pagibaximab for S. aureus (Hauser et al., 2016; Rios et al., 2016; Skinner et al., 2014; Sparrow et al., 2017). The advantages of antibody therapy are the high specificity, highly effective and safe. Challenges that have to be overcome include synthesis, and purification processes are expensive; the delivery is only systemically and may lose effectiveness over time due to changes in the antigens of bacteria (Rios et al., 2016).

16.13

Conclusions

AMR continues to be a serious global health crisis. Despite several programs created to control the misuse and abuse of antibiotics worldwide, data shows that antibiotic consumption continues to increase (65% from 2000 to 2015) (Klein et al., 2018). What is of most concern is the worldwide increased use of last-resort antibiotics such as carbapenems, oxazolidinones, and polymyxins. While the studies of antibiotic consumption in humans have been done, estimates of the antibiotic usage in agriculture and aquaculture worldwide are unknown. Predictions about AMR for the next decade are dire if the same trend continues. The need for global surveillance is critical in order to enhance policy making and antibiotic reduction. It is of primary importance to protect the antibiotics that we still have, support new international research efforts to develop nonantibiotic approaches and novel therapies against bacterial pathogens.

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Glossary Acquired resistance Immune response elicited by a specific stimulus from a foreign molecule that causes antigen recognition by B, TH, or TC cells and results in the proliferation and differentiation of the stimulated cells into effector cells and memory cells; an immunity resulting from a previous encounter of the host and an antigenic stimuli. Antibiotic Substance used to prevent or treat infection caused by bacteria and other pathogenic microorganisms. Bactericidal Antimicrobial that kills a microorganism. Bacteriophages A virus that infects prokaryotic cells. Bacteriostatic Antimicrobial that inhibits bacterial growth but does not kill the bacteria. Biofilm A group of microorganisms that adhere to each other, frequently embedded within a self-produced extracellular matrix. B-lactamases Enzymes produced by bacteria that destroy the activity of β-lactam agents by hydrolyzing the β-lactam ring portion of the β-lactam molecule; many types of β-lactamase affect specific β-lactam agents. Conjugation Transfer of genetic material between bacteria through cell-to-cell contact. Efflux pumps Proteins located in the bacterial cell membrane, which transport molecules out of the cell. Enterobacteriaceae Large family of Gram-negative bacteria, many are harmless and part of the intestinal flora. Others may be pathogenic such as Salmonella, Shigella, Yersinia, and certain strains of E. coli. Extended-spectrum beta-lactamase (ESBL) Beta-lactamase produced by E. coli, Klebsiella spp., Proteus mirabilis, and other Enterobacteriaceae that hydrolyze and inactivate penicillins, cephalosporins, and aztreonam. Fertility factor Allows genes to be transferred from one bacterium carrying the factor to another bacterium lacking the factor by conjugation, also called F sex factor. Genomic Islands Portion of the genome that has evidence of horizontal transfer. These islands can code for different functions such as virulence, pathogenesis and helps the organism in adaptation. Horizontal gene transfer The transfer of genetic information between unrelated organisms. Immunocompromised Term used to describe an individual with deficient function of the immune system. Insertion sequence (IS) The simplest type of transposable element, which carries only genes involved in transportation. Integrase The enzyme that inserts cassettes into an integron. Integron Mobile DNA element that can capture and carry genes, especially those that carry antibiotic resistance. Intrinsic resistance Type of antimicrobial resistance; an inherent genotypic characteristic disseminated horizontally to progeny. Mechanisms that mediate intrinsic resistance to antibiotics include cell wall impermeability, efflux, biofilm formation, and expression of genes mediating inactivating enzymes. Lysins Antibodies that induce lysis. Lysis Loss of cellular integrity with the release of cytoplasmic contents. Multidrug efflux Mechanism responsible for moving multiple antibiotics out of the cell. Multidrug-resistant bacteria Bacteria that have developed resistance to more than two antibiotics.

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Penicillin-binding proteins (PBPs) Transpeptidase enzymes important in bacterial cell wall formation. These proteins have various affinities to the β-lactamase, including oxacillin, methicillin, nafcillin, cloxacillin, and dicloxacillin. Plasmid An extrachromosomal genetic element that is not essential for growth and has no extracellular form. Porins Protein channels in the outer membrane of Gram-negative bacteria through which small-to-medium-sized molecules can flow. Prophylaxis Action taken to prevent disease. Quorum sensing The monitoring of the environment for other bacteria, resulting in the coordination of gene expression. Recombinant protein A protein that is produced as a result of genetic engineering. Recombination site Sites in the bacterial genome where DNA exchange takes place. Sepsis A life-threatening condition that arises when the body’s response to infection causes injury to its own tissues and organs. Spore Unit of asexual reproduction that appears as a highly retractile body in the cell. Spores are visualized microscopically as unstained areas in a cell using traditional bacterial stain (Gram) or specific spore stain. Transduction The transfer of bacterial genes by a bacteriophage (bacterial virus) from one cell to another. Transformation Uptake and incorporation of naked DNA into a bacterial cell. Transposase An enzyme that catalyzes the insertion of DNA segments into other DNA molecules. Transposon A type of transposable element that carries other genes in addition to those involved in transposition; often these genes confer selectable phenotypes such as antibiotic resistance. Vertical gene transfer DNA inherited from parental organism.

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