Workshop Overview

ANTIBIOTIC RESISTANCE: IMPLICATIONS FOR GLOBAL HEALTH AND NOVEL INTERVENTION STRATEGIES

Infectious diseases remain among the leading causes of morbidity and mortality on our planet. The development of resistance in microbes—bacterial, viral, or parasites—to therapeutics is neither surprising nor new. However, the scope and scale of this phenomenon is an ever-increasing multinational public health crisis as drug resistance accumulates and accelerates over space and time. Today some strains of bacteria and viruses are resistant to all but a single drug, and some may soon have no effective treatments left in the “medicine chest.” The disease burden from multidrug-resistant strains of organisms causing AIDS, tuberculosis, gonorrhea, malaria, influenza, pneumonia, and diarrhea is being felt in both the developed and the developing worlds alike.

The accelerating growth and global expansion of antimicrobial1 resistance (hereinafter referred to as AMR) is a demonstration of evolution in “real time” in response to the chemical warfare waged against microbes through the therapeutic and non-therapeutic uses of antimicrobial agents. After several decades in which it appeared that human ingenuity had outwitted the pathogens, multidrug-resistant “superbugs” have become a global challenge, aided and abetted by the use, misuse, and overuse of once highly effective anti-infective drugs. In the words of the

1

In this document, “antimicrobial” is used inclusively to refer to any agent (including an antibiotic) used to kill or inhibit the growth of microorganisms (bacteria, viruses, fungi, or parasites). This term applies whether the agent is intended for human, veterinary, or agricultural applications.



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Workshop Overview ANTIBIOTIC RESISTANCE: IMPLICATIONS FOR GLOBAL HEALTH AND NOVEL INTERVENTION STRATEGIES Infectious diseases remain among the leading causes of morbidity and mor- tality on our planet. The development of resistance in microbes—bacterial, viral, or parasites—to therapeutics is neither surprising nor new. However, the scope and scale of this phenomenon is an ever-increasing multinational public health crisis as drug resistance accumulates and accelerates over space and time. Today some strains of bacteria and viruses are resistant to all but a single drug, and some may soon have no effective treatments left in the “medicine chest.” The disease burden from multidrug-resistant strains of organisms causing AIDS, tuberculosis, gonorrhea, malaria, influenza, pneumonia, and diarrhea is being felt in both the developed and the developing worlds alike. The accelerating growth and global expansion of antimicrobial1 resistance (hereinafter referred to as AMR) is a demonstration of evolution in “real time” in response to the chemical warfare waged against microbes through the therapeutic and non-therapeutic uses of antimicrobial agents. After several decades in which it appeared that human ingenuity had outwitted the pathogens, multidrug-resistant “superbugs” have become a global challenge, aided and abetted by the use, mis - use, and overuse of once highly effective anti-infective drugs. In the words of the 1 In this document, “antimicrobial” is used inclusively to refer to any agent (including an antibiotic) used to kill or inhibit the growth of microorganisms (bacteria, viruses, fungi, or parasites). This term applies whether the agent is intended for human, veterinary, or agricultural applications. 

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 ANTIBIOTIC RESISTANCE late Joshua Lederberg, humans and microbes continue to be locked in a contest between “our wits and their genes” (Lederberg, 2000). It should be noted at the outset of this document that the meaning of the phrase “antimicrobial resistance” is wholly context-dependent. Most commonly, it refers to infectious microbes that have acquired the ability to survive exposures to clinically relevant concentrations of drugs that would kill otherwise sensitive organisms of the same strain. The phrase is also used to describe any pathogen that is less susceptible than its counterparts to a specific antimicrobial compound (or combination thereof). Resistance manifests as a gradient based on genotypic and phenotypic variation within natural microbial populations, and even microbes with low levels of resistance may play a role in propagating resistance within the microbial community as a whole (American Academy of Microbiology, 2009). Pathogens resistant to multiple antibacterial agents, while initially associ - ated with the clinical treatment of infectious diseases in humans and animals, are increasingly found outside the healthcare setting. Therapeutic options for these so-called community-acquired pathogens, such as methicillin-resistant Staphylo- coccus aureus (MRSA) are extremely limited, as are prospects for the develop- ment of the next generation of antimicrobial drugs. On April 6 and 7, 2010, the Institute of Medicine’s (IOM’s) Forum on Microbial Threats convened a public workshop in Washington, DC, to consider the nature and sources of AMR, its implications for global health, and strategies to mitigate the current and future impacts of AMR. Through invited presenta - tions and discussions, participants explored the evolutionary, genetic, and eco - logical origins of AMR and its effects on human and animal health worldwide. Participants also discussed host and environmental factors associated with the expansion of AMR, strategies for extending the useful life of antimicrobials, alternative approaches for treating infections, incentives and disincentives for prudent antimicrobial use, and prospects for the discovery and development of ”next generation” antimicrobial therapeutics. While it was the “intent” of the workshop planners and organizers to cover the phenomenon of AMR broadly, workshop presentations and discussions focused almost exclusively on bacterial resistance to antibacterial drugs. Organization of the Workshop Summary This workshop summary was prepared by the rapporteurs for the Forum’s members and includes a collection of individually authored papers and commen - tary. Sections of the workshop summary not specifically attributed to an individ - ual reflect the views of the rapporteurs and not those of the Forum on Microbial Threats, its sponsors, or the IOM. The contents of the unattributed sections are based on the presentations and discussions at the workshop. The workshop summary is organized into sections as a topic-by-topic description of the presentations and discussions that took place at the workshop.

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 WORKSHOP OVERVIEW Its purpose is to present lessons from relevant experience, to delineate a range of pivotal issues and their respective problems, and to offer potential responses as discussed and described by the workshop participants. Manuscripts and reprinted articles submitted by some but not all of the workshop’s participants may be found, in alphabetical order, in Appendix A. Although this workshop summary provides a description of the individual presentations, it also reflects an important aspect of the Forum’s philosophy. The workshop functions as a dialogue among representatives from different sectors and allows them to present their beliefs about which areas may merit further attention. These proceedings only summarize the statements of participants in the workshop. They are not intended to be an exhaustive exploration of the subject matter or represent the findings, conclusions, or recommendations of a consensus committee process. Antimicrobial Drug Resistance in Context The History of Medicine: • 2000 B.C.—Here, eat this root. • 1000 A.D.—That root is heathen. Here, say this prayer. • 1850 A.D.—That prayer is superstition. Here, drink this potion. • 1920 A.D.—That potion is snake oil. Here, swallow this pill. • 1945 A.D.—That pill is ineffective. Here, take this penicillin. • 1955 A.D.—Oops . . . bugs mutated. Here, take this tetracycline. • 1960–1999 A.D.—39 more “oops.”. . . Here, take this more powerful antibiotic. • 2000 A.D.—The bugs have won! Here, eat this root. —Anonymous, as cited by the World Health Organization (WHO, 2000a) An Inevitable History The use of antimicrobial drugs, no matter how well controlled, “inevitably leads to the selection of drug-resistant pathogens,” according to workshop speaker Julian Davies, of the University of British Columbia (Davies, 2009). (Dr. Davies’ contribution to the workshop summary report can be found in Appendix A, pages 149-160.) As may be seen in the following illustration (Figure WO-1), there is no man-made defense that cannot be outmaneuvered by microbial evolution and adaptation. As speaker Gerard Wright of McMaster University observed, “there is no such thing as an irresistible antibiotic.” (Dr. Wright’s contribution to the workshop summary report can be found in Appendix A, pages 401-419.) This characteristic of antimicrobial drugs has been well-known since the dawn of the antibiotic era over seven decades ago, and all too often has been either

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 ANTIBIOTIC RESISTANCE FIGURE WO-1 The relationship between antibiotic resistance development in Shigella dysenteriae isolates in Japan and the introduction of antimicrobial therapy between 1950 and 1965. In 1955, the first case of plasmid determined resistance was characterized. MDR = multidrug resistance. Transferable, multi-antibiotic, resistance was discovered five years later in 1960. SOURCES: Davies (2007, 2009). Reprinted by permission from Macmillan Publishers Ltd.: EMBO Reports Davies, Copyright 2007. underestimated or ignored. Hailed as a miracle drug when it was first introduced in 1943, penicillin was eagerly purchased by consumers who initially obtained it without a prescription following the conclusion of World War II (Stolberg, 1998). In a 1945 interview with the New York Times, penicillin’s discoverer Alexander Fleming anticipated the development of drug-resistant bacterial strains. Indeed, penicillin-resistant strains were first isolated from patients in significant numbers a year later, in 1946. Over the next several decades, researchers discovered and developed a range of antimicrobial agents and classes of compounds with antimicrobial properties, as illustrated in Figure WO-2. Like penicillin, some antimicrobial drugs were directly derived from soil microbes; others were synthesized or modified versions of naturally occurring antimicrobial products (Salmond and Welch, 2008). Begin- ning in the early 1950s, antimicrobials were also widely adopted for non-human applications, most importantly as livestock feed additives (Davies, 2009). Despite the warnings of Fleming and others to the contrary, in 1967, the Sur- geon General of the United States, Dr. William H. Stewart, claimed that infectious diseases had been conquered through the development and use of antibiotics and vaccines and that therefore it was time to shift the U.S. government’s attention and resources to the “War on Cancer” (Stewart, 1967; Stolberg, 1998).

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 WORKSHOP OVERVIEW FIGURE WO-2 Major classes of antimicrobials and the year of their discovery. SOURCE: Davies (2009), IOM (2009b). The “Antibiotic Era” has been marked by a series of epidemics of resistant organisms (see Box WO-4 [which appears on pages 58-63]), including • penicillin-resistant Staphylococcus aureus, • methicillin-resistant Staphylococcus aureus (MRSA), • vancomycin-intermediate Staphylococcus aureus (VISA), • multi-drug-resistant (MDR) Vibrio cholerae, • multidrug-resistant (MDR) and extensively drug-resistant (XDR) Myco- bacterium tuberculosis (hereinafter MDR- and XDR-TB), • CTX-M2 resistant Escherichia coli and Klebsiella pneumoniae, • Clostridium difficile, and many others. Reports of new outbreaks of these so-called “superbugs” in the popular press are becoming increasingly commonplace events (Davies, 2009). Numerous studies, reports, and review articles—several of which are cited 2 Cefotaximases are β-lactamase enzymes named for their greater activity against ce - fotaxime than other oxyimino-beta-lactam substrates (e.g., ceftazidime, ceftriaxone, ce - fepime). Rather than arising by mutation, cefotaximases represent examples of plasmid acquisition of β-lactamase genes normally found on the chromosome of Kluyvera species, a group of rarely pathogenic commensal organisms.

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 ANTIBIOTIC RESISTANCE throughout this workshop overview—have addressed the phenomenon of AMR from a variety of perspectives. The Forum on Microbial Threats was created in 1996 to provide an ongoing opportunity to explore and discuss a variety of emerging and reemerging infectious disease challenges including the rise of AMR and related issues that were highlighted in the 1992 IOM report, Emerging Infec- tions: Microbial Threats to Health in the United States (IOM, 1992), and further elaborated upon a decade later in the IOM report Microbial Threats to Health: Emergence, Detection, and Response (IOM, 2003). Many Forum workshops have also drawn attention to the significant contribution of AMR to the emergence of infectious diseases as a global public health challenge and have explored the proliferation and distribution of resistant microbes, hosts, vectors, and genes through migration, travel, conflict, trade, and tourism (IOM, 2006, 2008a, 2009a, 2009b, 2010). The Tragedy of the Commons The phenomenon of AMR is ultimately both a global public health and environmental catastrophe, a “classic” example of the “tragedy of the commons” illustrated more than 40 years ago in a seminal article by the late ecologist Garrett Hardin (1968). Hardin’s “tragedy of the commons” has proven to be a useful metaphor for understanding how we have come to be at the brink of numerous environmental catastrophes—whether land use, global climate change, access to and availability of uncontaminated and abundant fresh water resources, or antimicrobial resistance. Simply stated, we face a serious dilemma—an instance where individual rational behavior, acting without restraint to maximize personal short-term gain—can cause long-range harm to the environment, others and ultimately to oneself. Many of the planet’s natural resources are treated as a “commons,” wherein individuals have the right to freely consume its resources and return their wastes to the collective environment. The “logic of the commons” ultimately results in its collapse with the concomitant demise of those who depend upon the com - mons for survival (Diamond, 2005). Like climate change (IOM, 2008a) and the global water crisis (IOM, 2009a), the emergence of drug-resistant microbes was catalyzed by rational behavior: humans acting without restraint to maximize personal short-term gain. According to Baquero and Campos (2003), “antibiotics have been considered to be an inexhaustible common, both for prescribers and the general public,” and the resulting over-consumption has produced a “net increase in antibiotic resistance and a likely reduction in the therapeutic efficacy of the drugs.” If one person’s misuse of a drug speeds up the evolution of resistant strains, while simul- taneously decreasing his or her chance of being cured, then antimicrobial efficacy can be viewed as a scarce commodity in need of responsible management, on a par with energy, safe food, clean water, and climate stability. As Walker and

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 WORKSHOP OVERVIEW coauthors (2009) observed, these and other resources in crisis comprise a nexus of “serious, intertwined global-scale challenges spawned by the accelerating scale of human activity.” Addressing such challenges and their interactive effects, they contend, demands “cooperation in situations where individuals and nations will collectively gain if all cooperate, but each faces the temptation to take a free ride on the cooperation of others.” Parallels with Pesticides The rise of AMR closely parallels that of pesticide resistance, as observed by keynote speaker David Pimentel of Cornell University (National Research Council, 2000; Pimentel et al., 1992). (Dr. Pimentel’s contribution to the work - shop summary report can be found in Appendix A, pages 294-300.) According to Pimentel, about 550 species of insects and mites are known to be resistant to insecticides, as are 330 species of plant pathogens (fungi, bacteria, and viruses) and 220 weed species in the United States today. Pesticide-resistant organisms represent a serious global problem for agriculture, he observed, with an estimated annual direct cost in the United States alone of $1.5 billion. Pimentel went on to describe the pesticide “treadmill,” wherein the acqui - sition of resistance by “pest” organisms through repeated exposures to these toxic chemical compounds forces farmers to use ever-increasing amounts of a given pesticide—or combination of pesticides—to achieve the same level of pest control—until the next generation of effective pesticides becomes available to eradicate the resistant agricultural pests (National Research Council, 2000; Pimentel et al., 1992). This pesticide treadmill is doomed to repeat until either the pest meets a resistance-proof pesticide or the supply of effective new pesticides is exhausted. Dichlorodiphenyltrichloroethane (DDT) was such a pesticide, Pimentel said, and like penicillin, its introduction after the end of World War II dramatically improved peoples’ lives. Originally used for malaria control, DDT was initially applied only to the insides of houses and huts for vector control, exposing about one mosquito in a million to the pesticide, he explained. Resistance to DDT did not appear until it came into widespread, uncontrolled, agricultural uses, thereby vastly increasing the numbers and types of insects directly or indirectly exposed to the insecticide. As Anopheles mosquito populations became increasingly resis- tant to DDT, he continued, malaria rates—which greatly declined following DDT’s introduction in the 1940s—began to rise. While the use of pesticides appear to improve U.S. crop yields by some $40 billion per year, Pimentel observed, these gains must be weighed against the direct and indirect harmful effects associated with pesticide use and abuse to pub- lic and environmental health, which he valued at a minimum of $12 billion per year. He noted, moreover, that despite the application of some 6 billion pounds

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 ANTIBIOTIC RESISTANCE of pesticides worldwide,3 at a cost of approximately $40 billion, pests continue to consume nearly half of the food produced annually. Microbial Evolution and the Origins of Resistance While it is self-evident that the use of antimicrobial drugs has imposed selec- tive pressures on the emergence of resistant microbes, to attribute the development of resistance entirely to imprudent antimicrobial use is, in the words of Spellberg and coauthors, “a fallacy that reflects an alarming lack of respect for the incredible power of microbes” (Spellberg et al., 2008a). In addition to the range of anthropo- genic factors that encourage the development of antimicrobial resistance, workshop participants also reflected on the natural systems into which synthetic and mass- produced antibiotics were introduced in the post-World War II era. Antibiotics in Nature Humans did not invent antibiotics; we merely observed—often by accident— that bacteria and other microorganisms produced biological compounds capa - ble of killing or suppressing the growth and reproduction of other bacteria (Martinez, 2009). There are a variety of explanations for why microoganisms make antibiotics. A conventional ecological and evolutionary view holds that they enable organisms to kill—or suppress the growth of—competitors and to defend ecological niches (Salmond and Welch, 2008). It is also possible that these products serve other functions, such as signaling or nutrient sequestration (Martinez, 2009). Some enzymes in the antibiotic biosynthetic pathways appear to have evolved millions to billions of years ago, which suggests that antibiotic-resistance genes and their cognate proteins are also ancient. For example, the bacterial meta- bolic pathways that produce both β-lactam antibiotics and the enzyme that foils them, β-lactamase, are thought to be more than 10 million years old (Spellberg et al., 2008a). Synthetic antibiotics (most of which are based on naturally-occurring bacterial products) target a variety of bacterial systems, as illustrated in Figure WO-3, including those involved with cell wall synthesis, membrane integrity, transcription, and translation (Salmond and Welch, 2008; Walsh, 2003). In his workshop presentation, Davies placed antibiotics within the general class of biologically active small molecules, which he referred to as the “par- vome.” He observed that members of this “universe of bioactive natural products” share several common attributes, including Or slightly less than a pound of pesticide for every man, woman, and child on the 3 planet each year.

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 WORKSHOP OVERVIEW • ancient evolutionary origins, including structural components found in meteorites and “primordial soup” reactions; • vast structural diversity; • functions that involve many aspects of microbial physiology, behavior, and morphology, including interactions between cells; • mechanisms of action involving molecular or macromolecular ligands that subsequently modulate transcription; and • presence in all living organisms (best characterized in bacteria, fungi, and plants). The subset of molecules in the parvome that we have harnessed as antibiot - ics did not evolve to serve that function, Davies continued. “I believe . . . that in nature antibiotics are not antibiotics and in nature resistance genes are not resistance genes,” he stated. Davies noted that antibiotic molecules have been found to promote a great variety of other activities, including recombination, horizontal gene transfer, mutation, metabolism, gene regulation, and signaling, all of which are mediated through cell receptors. Indeed, he added, most of the negative side-effects of anti- biotic drugs stem from their interactions with a variety of human cell receptors. Erythromycin and other macrolide drugs, for example, cause stomach upset due to their ability to bind strongly to a receptor for motilin, a peptide that stimulates smooth muscle contraction in the gut. Additional workshop presentations describ- ing the ability of antibiotic compounds to function as mutagens and hormones are discussed in the following section of this overview. Antibiotics “have amazing effects on bacterial cell physiology,” Davies con - cluded (Davies et al., 2006). If we knew more about the functions of antibiotic compounds (and resistance genes) in their native environments, he said, “we might get some better ideas on how to control antibiotic resistance and also how to use antibiotics properly.” In particular, Davies suggested studying how small molecules with antibiotic properties influence interactions between and among soil bacteria and single cells. The Nature of AMR Soil microbes that produce antibiotics also have mechanisms of resistance, as speaker Gerard Wright, of McMaster University, pointed out. If they did not, he said, “they would produce their antibiotic once and immediately commit suicide.” The variety of mechanisms that microbes use to protect themselves includes altered membrane permeability or binding sites, efflux pumps that export incom - ing antibiotics, and antibiotic-degrading enzymes, as illustrated in Figure WO-4 (Arias and Murray, 2009; Davies 2009; Salmond and Welch, 2008). Some soil bacteria not only resist clinical antibiotics but can actually subsist on them as a carbon source (Dantas et al., 2008).

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0 ANTIBIOTIC RESISTANCE FIGURE WO-3 Principal targets for antibiotic action: a–f depict metabolic pathways in FIGURE WO-3.eps the cell that have been, or are proposed to be, targets for antibiotic action. a | Cell wall biosynthesis: the intracellular steps of murein (peptidoglycan) biosynthesis are catalysed bitmap, landscape by the enzymes MurA–F and MurG (steps 1–4). Peptidoglycan is a polymer of two hexoses (filled hexagons)—N-acetylglucosamine (GlcNac) and N-acetyl-muramic acid (MurNAc). Peptidoglycan units are transferred to a carrier lipid—bactoprenol-phosphate (orange circles)—which transports precursor molecules across the cell membrane, gen - erating Lipids I and II. Sugars and phosphates are added by transglycosylation and pyrophosphorylation (steps 5 and 6), and finally, a peptide bond between the peptide chains is formed (step 7). Antibiotics that inhibit cell-wall synthesis are indicated. b | Protein biosynthesis: bacterial ribosomes comprise two subunits (30S and 50S) of rRNA and protein. Structural studies have identified the sites at which antibiotics bind (Carter et al., 2000; Hansen et al., 2002; Pioletti et al., 2001; Schlunzen et al., 2001). c | DNA and RNA replication: rifampin binds to RNA polymerase and prevents attachment of the polymerase to DNA, thereby inhibiting transcription. Ciprofloxacin and novobiocin bind to DNA gyrase, thereby preventing the introduction of supercoils in DNA. d | Folate metabolism: folate is necessary for the synthesis of thymine, which, in turn, is an essential component of DNA. The figure shows antibiotics that block steps in folate metabolism and therefore block the synthesis of thymine. e | Cell-surface decoration: during cell-wall synthesis in Gram-positive bacteria, surface proteins are cleaved by sortases—enzymes that are anchored in the membrane by an amino-terminal membrane-

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 WORKSHOP OVERVIEW spanning sequence. Sortases covalently attach the amino-terminal cleavage fragment of the surface protein to the peptidoglycan (PG) layer of the cell wall (Pallen et al., 2001). f | Isoprenoid biosynthesis: the enzymes of the non-classical isoprenoid pathway in bacteria are not present in higher organisms (Rohdich et al., 2001), and should therefore be good antibacterial targets. dTMP, thymidylate; dUMP, deoxyuridine monophosphate; DXR, 1-deoxy-D-xylulose 5-phosphate (DX) reductoisomerase; DXS, DX synthase; GcpE, 1-hydroxy-2-methyl-2-(E)-butenyl- 4-diphosphate synthase; GTP, guanosine tri - phosphate; LytB, Isoprenoid H protein; YchB, 4-diphospho-2 C-2-methyl-D-erythritol kinase; YgbB, 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase; YgbP, 4-diphos - phocytidyl-2C-methylerythritol synthase. SOURCE: Walsh (2003). Reprinted by permission from Macmillan Publishers Ltd.: Na- ture Reviews Microbiology Walsh, Copyright 2003. A wealth of antimicrobial-resistant soil bacteria and genes discovered in pristine environments would suggest that a variety of antimicrobial resistance mechanisms exist in nature (Allen et al., 2010; Davies, 2009). Wright described a group of 480 isolates of soil bacteria from the group actinomycetes that his group collected in diverse environments throughout Canada; their drug resistance profiles are presented in Figure WO-5 (D’Costa et al., 2006). Every isolate proved to be resistant to multiple antibiotic drugs. Wright also reported similar levels of resistance to clinical antibiotics in bac - terial samples collected from a Kentucky cave system that has been sealed from the external environment for about 2 million years (Gerard Wright, McMaster University, personal communication, April 6, 2010). Antibiotic-resistance genes isolated from soil bacteria and those isolated from clinical pathogens share similar structures and functions, Wright noted. He presented a particularly impressive example of this resemblance that occurred among approximately 1 percent of the previously described actinomycete isolates (D’Costa et al., 2006). These microbes were found to possess a suite of genes conferring resistance to vancomycin, once considered an “irresistible” antibiotic because it targets a cell wall polymer rather than an easily mutated protein or nucleic acid. However, not only have clinical cases of resistance to vancomycin been reported, but these findings suggest that the five-gene cluster found to con - fer resistance in clinical isolates of vancomycin-resistant enterococci (VRE) has existed for thousands of years among bacteria that have never been exposed to vancomycin, as may be seen in Figure WO-6. AMR is also widespread among commensal organisms, Wright said, referring to a recent study that employed complementary strategies to look for antibiotic-resistance genes and antibiotic-resistant culturable organisms in the microbial flora of healthy humans (Sommer et al., 2009). These investigators

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