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Workshop Overview
Pages 1-74

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From page 1...
... 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.
From page 2...
... . 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.
From page 3...
... 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.)
From page 4...
... 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.
From page 5...
... , • vancomycin-intermediate Staphylococcus aureus (VISA) , • multi-drug-resistant (MDR)
From page 6...
... . 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)
From page 7...
... (Dr. Pimentel's contribution to the work shop summary report can be found in Appendix A, pages 294-300.)
From page 8...
... . In addition to the range of anthropogenic factors that encourage the development of antimicrobial resistance, workshop participants also reflected on the natural systems into which synthetic and massproduced antibiotics were introduced in the post-World War II era.
From page 9...
... . If we knew more about the functions of antibiotic compounds (and resistance genes)
From page 10...
... 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)
From page 11...
... 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)
From page 12...
... In Panel A, resistance to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus is caused by the production of a β-lactamase enzyme (penicillinase) and a low-affinity penicillinbinding protein (PBP)
From page 13...
...  WORKSHOP OVERVIEW FIGURE WO-5 Survey of 480 soil actinomycetes and their level of resistance to each antibiotic of interest. SOURCE: Adapted from D'Costa et al.
From page 14...
... . The vast majority of antimicrobial resistance genes reside on mobile genetic elements such as insertion sequences, 4 integrons,5 transposons,6 and plasmids,7 according to workshop speaker Henry "Chip" Chambers of the University of California, San Francisco.
From page 15...
... "Antibiotic resistance is absolutely everywhere." This observation raises important questions as to how resistance genes move from the environment into the clinic, and whether barriers to horizontal gene transfer exist or could be created to slow the development of resistance to antimicrobial drugs. To facilitate such research, Wright and colleagues in the United Kingdom are developing a Comprehensive Antibiotic Resistance Database to enable investigators to scan genomes and link resistance gene sequences to molecular, clinical, and surveillance data (McArthur et al., 2010)
From page 16...
... As speaker Patrice Courvalin of the Institut Pasteur pointed out, bacteria can mini mize the often considerable energy cost of maintaining AMR in one of two ways: by having resistance genes on mobile genetic elements (since their acquisition can be transient and antibiotic resistance is useful only transiently) and by having antibiotic-inducible resistance mechanisms.
From page 17...
... . "This is really scary to think about," Chambers observed, "because now we're not talking just about antibiotics selecting for drug resistance; we're talking about antibiotics generating drug resistance and selecting for drug resistance -- an amplification, if you will." Sublethal antibiotic exposures have also been demonstrated to increase the horizontal transmission of mobile genetic elements among bacteria via the SOS response, Courvalin and Collins noted (Maiques et al., 2006; Ubeda et al., 2005)
From page 18...
... In some organisms, low levels of bactericidal antibiotics have been shown to induce competence for transformation,12 leading to increased transfer and distribution of antibiotic resistance genes. The bacterial agent of pneumonia, Streptococcus pneumoniae, which lacks an SOS response, readily integrates genes from other organisms into its chromosome when exposed to sublethal concentrations of bactericidal antibiotics (Prudhomme et al., 2006)
From page 19...
... Thus, the critical unit of AMR transmission is the resistance-associated gene or gene cassette, and the "vector" could be viewed alternatively as the microbial genome in which the gene or cassette is found, or the microbial community in which the resistant microbe resides, or the host or broader ecosystem that carries the community. Hospital-Acquired Infections Resistance poses a growing threat to the treatment and control of infectious diseases, including those that have long been endemic in human populations
From page 20...
... . Yet AMR in developing countries undoubtedly adds to the already heavy burden of infectious diseases experienced in these countries (Okeke et al., 2005)
From page 21...
... (Dr. Weinstein's contribution to the workshop summary report can be found in Appendix A, pages 379-400.)
From page 22...
... bacteria: nomogram for in-hospital costs. This nomogram can be used to calculate yearly in-hospital costs attributable to infections due to multidrug-resistant bacteria with various values for the total number of infections, the average extra length of hospital stay per infection, and the average cost per hospital day.FIGURE WO-10.eps bitmaps with some vector type & masks SOURCE: ECDC and EMEA (2009)
From page 23...
... In addition to the previously described health and economic costs associated with resistance in hospital-acquired infections, Rice noted that AMR negatively affects the ability of hospital physicians to care for patients in the following ways: • AMR has rendered formerly beneficial therapies, such as prophylactic antibiotic treatment to reduce neutropenia14 in oncology patients, useless. • Regional variations in AMR among various pathogens complicate the interpretation of treatment guidelines for infectious diseases.
From page 24...
... 16 Between 40 and 80 percent of the antimicrobial agents used in the United States each year are used in food animals; many are identical or very similar to drugs used in humans. These nontherapeutic uses contribute to resistance and create health dangers for humans (Shea, 2003)
From page 25...
... 1. Most foodborne diseases are zoonoses (infectious diseases that can be transmitted from vertebrate animals to humans)
From page 26...
... No public health reporting system exists in the United States to track the use of antimicrobial drugs in livestock production operations (Shea, 2003)
From page 27...
... AGP = antimicrobial growth promoters. SOURCE: Adadpted from Aarestrup et al.
From page 28...
... The extent of this harm remains to be determined, however, along with other potential outcomes of the Danish experiment, such as whether this attempt to reduce the non-therapeutic use of antimicrobials in food animals has resulted in fewer resistant bacterial infections in humans. Antimicrobial Treatment of Crop Plants Fungi and viruses pose a greater threat to most crop plants than bacteria (Vidaver, 2002)
From page 29...
... . Figure WO-12 depicts a network of genetic "reactors" -- including the microbiota of individual animals, as well as larger ecosystems such as farms, aquaculture facilities, and hospitals -- that amplify and distribute antimicrobial resistance genes.
From page 30...
... . Travel is increasingly rapid, more socially widespread, and more ubiquitous, connecting once-remote areas (which serve as both "sources" and "sinks" for emerging infectious diseases)
From page 31...
... Laxminarayan added, however, that it is equally difficult to calculate the direct health and economic benefits of antimicrobial drugs. If penicillin had never been introduced, he mused, might improvements in infection control eventually have reduced infectious disease mortality to current levels?
From page 32...
... Their publication, along with many other analyses of AMR (American Academy of Microbiology, 2009; Center for Global Development, 2010; Interagency Task Force on Antimicrobial Resistance, 2001; OTA, 1979; Spellberg et al., 2008a; Tenover and Hughes, 1996; WHO, 2001a) , recommends preserving the effec tiveness of existing antimicrobials as long as possible while encouraging the development of new classes of antimicrobials and alternative therapeutic strategies to address infectious diseases.
From page 33...
... Prudent use Antimicrobial stewardship -- using these drugs to maximize their efficiency while limiting opportunities for resistance to develop -- is the best short-term approach to mitigating the impact of AMR, Rice asserted. He went on to suggest that efforts to support the prudent use of antimicrobials had been hampered by the lack of data regarding the effectiveness of specific measures, coupled with the general perception by physicians that antibiotics represent, at worst, a "therapeutically neutral" treatment choice for infectious disease.
From page 34...
... (Dr. Tenover's contribution to the workshop summary report can be found in Appendix A, pages 365-379.)
From page 35...
... Davies noted that daptomycin, an antibiotic used exclusively in humans, has been in use for about a decade without the development of trans ferable drug resistance, despite the known existence of resistance genes. Developing Novel Antimicrobials Novel antimicrobial drugs are needed for a number of reasons, including treating chronic infections.
From page 36...
... FIGURE WO-13.eps SOURCE: Reprinted from Clinical Infectious Diseases, Spellberg et al.
From page 37...
... (Dr. Lewis' contribution to the workshop summary report can be found in Appendix A, pages 233-256.)
From page 38...
... For this reason, the FDA has come to insist that comparator drugs used in noninferiority trials be previously shown to be superior in efficacy to placebo. This policy has far-reaching implications for the approval of novel antimicrobial drugs, according to Spellberg.
From page 39...
... . Lewis observed that, when sublethal antibiotic exposures trigger the SOS response, it can lead to the creation of persisters that are multidrug tolerant.
From page 40...
... (Dr. Fischbach's contribution to the workshop summary report can be found in Appendix A, pages 160-174.)
From page 41...
... scaffold has been for the treatment of bacterial infections," he said. This approach to new drug discovery could also serve as a basis for generations of improved derivatives.
From page 42...
... The quinolone scaffold WO-15.eps FIGURE is synthetic, whereas the other scaffolds are natural products. SOURCE: Reprinted from Fischbach and Walsh (2009)
From page 43...
... He advised researchers to look for large, diverse, chemical libraries to screen for antibi otic activity, such as those libraries developed by pharmaceutical companies to address a range of therapeutic areas. Novel natural products The "low-hanging fruit" of natural antibiotics may already have been harvested, Fischbach acknowledged.
From page 44...
...  FIGURE WO-16 Surmounting resistance with scaffold alterations. Two ways of overcoming resistance are shown, using tetracycline (center)
From page 45...
... FIGURE WO-17 Mining genes for drugs.  SOURCE: Reprinted from Walsh and Fischbach (2009)
From page 46...
... (Dr. Levy's contribution to the workshop summary report can be found in Appendix A, pages 222-232.)
From page 47...
... Casadevall's contribution to the workshop summary report can be found in Appendix A, pages 75-82.) The legacy of cheap, effective, well-tolerated, broad-spectrum antimicrobials is not limited to AMR, he said, but also includes damage to indigenous microbial communities, such as the human intestinal microbiota, and the phenomenon of superinfection (a secondary infection that occurs during treatment for infection by a different pathogen)
From page 48...
... . The downside to both vaccines and immunotherapy is the cost compared to antimicrobial drugs.
From page 49...
... In her presentation, which outlined efforts by the Pew Charitable Trusts to support stewardship and development of antimicrobial drugs, Hearne asserted that policy makers should view antimicrobials much as they view energy: a limited, valuable resource to be conserved, and for which new sources need to be identified and exploited. She outlined four basic steps that she felt were needed in order to achieve the interrelated goals of antimicrobial stewardship and development -- strategies that were discussed throughout the workshop -- and that have long been advocated to address the threat of AMR: • limit the use of antimicrobials, • discourage their misuse, • reduce infection through disease prevention measures, and • create incentives for improved treatment and innovation.
From page 50...
... What, they asked, can be done to convince people -- indeed, societies -- to change these behaviors? Addressing this challenge is central to the mission of APUA "to control infectious diseases worldwide through appropriate access to, and use of, antimicrobials and the containment of antimicrobial resistance," according to Levy.
From page 51...
... Opportunities for National Legislation and Regulatory Policies Hearne identified three legislative proposals -- two of which have been introduced to the Congress of the United States (see Box WO-3) and a third more comprehensive synthesis of these and other policy elements -- that collectively would advance the twin goals of antibiotic stewardship and development: • The Strategies to Address Antimicrobial Resistance (STAAR)
From page 52...
... On May 13, 2009, U.S. Representative Jim Matheson introduced the Strategies to Address Antimicrobial Resistance (STAAR)
From page 53...
... To that end, Hearne said she was heartened by the growing interest among policy makers to address antimicrobial resistance and by the number of supporters in both the House and Senate for PAMTA. Returning to the workshop discussion on the interpretation of the results of the Danish ban on the use of growth-promoting antimicrobials in food animals, she said that a similar "dissection of data" should be taking place on this issue at the U.S.
From page 54...
... Bringing new drugs to market Spellberg stated that a statutory change might be needed in order for the FDA to establish an approval process for antimicro bial drugs based on noninferiority studies with clinical endpoints. He and Levy, among others, observed that such a change is justified given the uniqueness of antimicrobials as a class of drugs, on the basis of the following factors: • Antimicrobial use by individuals, through the subsequent shedding of both active and resistant bacteria, affects every community from the immediate family to the local environment to the global ecosystem.
From page 55...
... When public health standards underlie regulatory decision making, reform can be achieved more efficiently through administrative channels than through legislation, Levi asserted. Based on his lengthy prior experience with regulatory reform to address HIV/AIDS, he assured advocates of antimicrobial stewardship and development that, armed with scientific evidence and "good, compelling, very emotional cases," it is possible to reach the regulators and achieve more flexibility in the drug approval process.
From page 56...
... Needed data would include not only the incidence and prevalence of resistant infections, but also accurate measurements of the full spectrum of resistance mechanisms contributing to the ongoing burden of infectious disease and their far-reaching medical and socioeconomic effects (American Academy of Microbiology, 2009)
From page 57...
... Less people affected, less effect on the environment, less effect on the innocent bystanders: the other bacteria that are sharing that environment." WORKSHOP OVERVIEW REFERENCES Aarestrup, F
From page 58...
... . FIGURE WO-4-1 Methicillin-resistant Staphylococcus aureus.
From page 59...
... . FIGURE WO-4-2 Vancomycin-resistant Staphylococcus aureus.
From page 60...
... . There are also extensively drug-resistant strains of TB, which defy second-line therapies, and newly emerged TB strains (Loddenkemper and Hauer, 2010)
From page 61...
... As with VRSA, VRE infections can be treated with a very few recently introduced antibiotics, and even for those, resistant cases have already been reported. VRE have caused hospital outbreaks worldwide, and the vancomycin-resistance gene (vanA)
From page 62...
... . Resistance to almost all clinically used antibiotics has occurred among strains of Escherichia coli, its relative Klebsiella pneumoniae (Figure WO-4-7)
From page 63...
... In much of the world, gonococci are resistant to penicillin, tetracycline, spectinomycin, and ciprofloxacin. Currently, the CDC sexually transmitted disease treatment guidelines recommend that cephalosporin antibiotics be used to treat all gonococcal infections in the United States (CDC, 2009; WHO, 2001b)
From page 64...
... An update from the Infectious Diseases Society of America. Clinical Infectious Diseases 48(1)
From page 65...
... Clinical Infectious Diseases 42(Suppl 2)
From page 66...
... Clinical Infectious Diseases 40(4)
From page 67...
... Clinical Infectious Diseases 49(8)
From page 68...
... Clinical Infectious Diseases 45(Suppl.
From page 69...
... Clinical Infectious Diseases 34(Suppl.
From page 70...
... Clinical Infectious Diseases 49(8)
From page 71...
... 2008a. The epidemic of antibiotic resistant infections: A call to action for the medical community from the Infectious Diseases Society of America.
From page 72...
... Clinical Infectious Diseases 34(Suppl 3)
From page 73...
... Emerging Infectious Diseases 11(6)


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