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Testimony

Statement by
Anthony S. Fauci   M.D.
Director
National Institute of Allergy and Infectious Diseases
National Institutes of Health
U.S. Department of Health and Human Services

on
The Role of NIH Research in Addressing Antimicrobial Resistance 

before
Committee on Energy and Commerce
Subcommittee on Health
United States House of Representatives


Wednesday April 28, 2010

Mr. Chairman and members of the Committee, thank you for the opportunity to discuss the serious public health challenge posed by antimicrobial resistance and the research being conducted and supported by the National Institutes of Health (NIH), an agency within the Department of Health and Human Services (HHS), to address this challenge.  I am the Director of the National Institute of Allergy and Infectious Diseases (NIAID), the lead component of NIH for research relating to infectious diseases including research on antimicrobial resistance.

NIAID plays a critical role in the federal government’s comprehensive efforts to combat the problem of antimicrobial resistance.  NIAID oversees a major effort built upon a foundation of basic research to understand the biology of microbial pathogens, the interactions between these pathogens and their human hosts, and the biological mechanisms by which pathogens develop resistance to antimicrobial drugs.  In addition, NIAID is committed to basic and translational research to identify new antimicrobial targets and to translate this information into the development of therapeutics; to advance the development of new and improved diagnostic tools for infections; and to create safe and effective vaccines to control infectious diseases and thereby limit the need for antimicrobial drugs.   Finally, NIAID is conducting studies to inform the rational use of existing antimicrobial drugs or alternative therapies to help limit the development of antimicrobial resistance.

OVERVIEW
Microbes are living organisms that multiply frequently and spread rapidly, efficiently increasing their numbers.  Microbes include bacteria (e.g., Staphylococcus aureus), viruses (e.g., influenza and HIV), fungi (e.g., Candida albicans, which causes some yeast infections), and parasites (e.g., Plasmodium falciparum, which causes malaria).  Some microbes are pathogenic; that is, they cause disease in their hosts. Others exist in the host without causing harm and may, in fact, be beneficial.

In 1928, while working with Staphylococcus bacteria, Scottish scientist Alexander Fleming noticed a “halo” of inhibited bacterial growth surrounding a type of mold growing by accident on a laboratory plate. The substance secreted by the mold, which Fleming called penicillin, later became one of the world’s first antibiotic drugs.  Though not widely prescribed until the 1940s, antibiotics and other antimicrobial drugs (a general term given to medicines that kill or slow the growth of a microbe) have saved countless lives and blunted serious complications of many diseases and infections.  The success of antimicrobials against disease-causing microbes is among modern medicine's great achievements.

Yet, for all of the success that antimicrobial drugs brought to the fight against infectious diseases, microbes continuously are developing ways to circumvent these powerful medical tools.  Antimicrobial resistance refers to the ability of a microbe to grow in the presence of an antimicrobial drug that would normally kill it or limit its growth.  The practical consequence of antimicrobial resistance is that the effectiveness of existing antimicrobial drugs is declining and that strains of pathogens that defy treatment with commonly available therapeutics are emerging.  The emergence and increasing prevalence of these drug-resistant strains has become a global public health issue.

To illustrate this point, consider that in the United States in 2005, CDC estimated that 94,360 individuals developed an invasive methicillin-resistant Staphylococcus aureus (MRSA) infection—most acquired in healthcare settings—and 18,650 patients died.1  In recent years, there has been a markedly increased rate of infections caused by community-acquired MRSA (CA-MRSA).2  The majority of CA-MRSA infections are skin and soft-tissue infections; however, CA-MRSA increasingly has been associated with severe invasive disease.3  Acinetobacter infections are a significant concern among wounded soldiers returning from the Middle East.  Among these soldiers, CDC reports that 35% of Acinetobacter isolates are susceptible to only one commonly used antimicrobial drug; 4% of isolates are resistant to all commonly used drugs.4  Moreover, antimicrobial resistance is not solely a domestic health issue.  The emergence of chloroquine-resistant malaria has contributed to the resurgence of malaria throughout the world, and resistance to second-line artemisinin-based therapies also has begun to emerge.  Further, the World Health Organization (WHO) estimates that 3.6% of all tuberculosis (TB) cases are multidrug-resistant (MDR) TB, or resistant to at least two first-line TB drugs; 440,000 new MDR-TB cases arose in 2008.5  In some regions of Eastern Europe and Asia, the incidence is far worse; for example, in Baku, Azerbaijan, nearly a quarter of all new TB cases (22.3%) were reported as MDR-TB.6  An estimated 5.4% of MDR-TB cases are extensively drug-resistant (XDR), or resistant to second-line TB drugs.7  Viruses also develop resistance.  Antiretroviral therapy (ART) has revolutionized the treatment of people with HIV infection, but as ART becomes accessible to more people around the world, concerns about the widespread emergence of drug-resistant HIV increase.  Finally, while the pandemic 2009 H1N1 influenza strain is usually sensitive to the antiviral drug oseltamivir, strains of the virus resistant to oseltamivir have emerged sporadically around the world.  Resistance developed to other classes of influenza drugs as well.  For example, NIAID scientists recently identified a case of 2009 H1N1 influenza that rapidly developed resistance to the experimental antiviral drug peramivir.8  To deal with this increasing threat, we need a better understanding of how drug resistance arises and how it can be prevented and managed.

Antimicrobial resistance occurs universally in microorganisms as a natural and unavoidable manifestation of their ability to evolve and adapt to their environment.  Microbes acquire the ability to resist antimicrobial drugs by undergoing genetic changes—either by mutation or gene transfer within or between species—that allow microbes to defend themselves against the onslaught of antimicrobial drugs.  For example, these genetic changes may alter bacterial cell membranes so that drugs cannot enter the cells, modify the microbial proteins with which the drugs normally interfere, or enhance the microbe’s ability to degrade or pump antimicrobial drugs out of the cell.  The use of antimicrobial drugs can exert a selective pressure on a population of resistant and susceptible microbes, allowing resistant microbes to multiply and emerge unharmed as the predominant strains in a population. 

While even the appropriate use of antimicrobial drugs creates a selective pressure for resistant organisms, there are additional societal factors that act to accelerate the emergence of antimicrobial resistance.  For example, physicians may inappropriately prescribe antibacterial drugs to patients with viral infections because the patients expect—or demand—such treatment.  Also, physicians must often use incomplete or imperfect information to diagnose an infection and thus prescribe an antimicrobial “just in case” an infection is present or prescribe a broad-spectrum antimicrobial for a known infection when a specific antibiotic may have been sufficient.  Once patients have antimicrobial drugs in hand, they may take the drugs incorrectly or fail to complete a treatment course such as by stopping the drugs once symptoms have been relieved.  These situations contribute to selective pressure and accelerate the development of antimicrobial resistance.  In hospital settings, critically ill patients often are given antimicrobial drugs because these individuals are more susceptible to infections.  However, the use of antimicrobials in these patients can exacerbate the problem by selecting for antimicrobial-resistant pathogens.  The extensive use of antimicrobials and close contact among sick patients in hospitals or other health care facilities creates a fertile environment for the spread of antimicrobial-resistant microbes.  Lastly, the practice of adding antibiotics to agricultural feed is thought to promote drug resistance.  More than half of the antibiotics produced in the United States are used for agricultural purposes; however, there is much debate about whether drug-resistant microbes in animals pose a significant human health burden.

Success against the emergence of antimicrobial resistance will require a multifaceted approach that includes increased surveillance, more judicious use of antimicrobial drugs, and increased research on the biology of the microbes, mechanisms of resistance, host responses, vaccines, diagnostics, and therapeutics.  Antimicrobial resistance is a long-standing research focus of NIAID, and the Institute has engaged in important partnership efforts to further basic and applied research and support public health efforts to manage antimicrobial resistance, including participation in the federal government’s Interagency Task Force on Antimicrobial Resistance.  NIH, through NIAID, co-chairs this task force, which is implementing an action plan to address the consequences of antimicrobial resistance, including rising health care costs and increasing morbidity and mortality from certain infections.9 The task force comprises representatives from NIH, the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Agency for Healthcare Research and Quality, the Department of Agriculture, the Department of Defense, the Department of Veterans Affairs, the Environmental Protection Agency, the Centers for Medicare and Medicaid Services, and the Health Resources and Services Administration.  NIAID also participates in the Transatlantic Task Force on Antimicrobial Resistance (TATFAR), established in 2009 by presidential declaration.  The main goals of TATFAR are to enhance communication and cooperation in antimicrobial stewardship, to promote prevention and control of antimicrobial resistance, and to enrich the antimicrobial drug development pipeline through research and regulatory strategies.  The U.S. representatives are HHS, CDC, FDA, and NIH.

NIAID RESEARCH
The problem of antimicrobial resistance requires a multi-pronged research strategy.  NIAID supports and conducts research on many aspects of antimicrobial resistance, including basic research on how microbes develop resistance, as well as clinical trials that translate research from laboratory findings into potential treatments.  NIAID works in concert with other federal agencies and partners with industry and nonprofit organizations to develop comprehensive programs aimed at controlling antimicrobial resistance. 

Basic Research
NIAID supports basic research on pathogens, host-pathogen interactions, mechanisms of drug resistance, and identification of new antimicrobial targets and therapeutics.  NIAID-supported researchers are studying how microbes cause disease, including how they colonize and invade the host, the toxins they produce, and how they avoid or overcome an attack by the host’s immune defenses, as well as the mechanisms used by microbes to block antimicrobial drugs.   For example, NIAID scientists have shown that genetic factors that enhance the ability of Staphylococcus to cause disease and those that enable drug resistance both can be transferred from one strain to another in a single event.10  This suggests that, in some cases, Staphylococcus strains that acquire genes for antimicrobial resistance may simultaneously acquire the ability to cause more severe disease. 

Knowledge of the nucleic acid sequences of a microbe’s genes can bolster our understanding of antimicrobial resistance, reveal vulnerable areas in a microbe’s genome that could be potential drug targets, and aid in the development of better diagnostic tests.  By isolating the same species of microbe from different geographic locations or from different human populations and comparing their genetic characteristics, it is sometimes possible to identify when and where drug resistance first emerged in these species and what mechanisms of resistance these microbes are using.  NIAID supports such efforts to understand microbial genomes through its biological resource centers and genomic sequencing services.  Biological resource centers offer the research community a centralized and reliable source of a wide range of strains of microbes and reagents.  Since 2000, NIAID has supported a resource center for Staphylococcus aureus that has been particularly useful for studies of antimicrobial resistance.  The Institute’s extensive genomics program has sequenced more than 750 bacterial pathogens that infect humans (including multiple strains of some pathogens); nearly all key drug-resistant species have been sequenced.  Examples include bacteria that cause XDR-TB; several species of Staphylococcus; and several species of Streptococcus, including one that causes so-called “flesh-eating” disease.  These resources not only serve basic microbial research but also facilitate the translation of basic findings into products with clinical applications.

NIAID-supported basic research not only helps elucidate the mechanisms of antimicrobial resistance but also facilitates the identification of potential targets for new antimicrobial drugs.  Some of these targets have been licensed for further development.  For example, resistance to the antimicrobial drug tetracycline is mediated by a protein “pump” that eliminates tetracycline from the bacterial cell.  Through basic research, NIAID-supported scientists determined the crystal structure of this protein pump and identified the bacterial genes that encode for these proteins.11  This knowledge has enabled private-sector partners to develop new drug candidates that block this pump.
  
Translational and Applied Research

Building on this foundation of basic research, NIAID supports research to advance the development of new and improved therapeutics, diagnostic tools, and safe and effective vaccines to control infectious diseases and limit the use of antimicrobial drugs.  Before discussing NIAID’s activities in this area, however, it is important to understand the current landscape of the pharmaceutical and biotechnology industries and the challenges that we face in developing new antimicrobial drugs and other products for clinical use.

In recent years, the number of large pharmaceutical companies that are involved in antimicrobial drug development has dwindled.  Drug development is an expensive process, costing hundreds of millions of dollars to bring a product from concept to market.  When it is evident that a given pharmaceutical product has a potential to make a profit, the large pharmaceutical companies are willing to engage in the economically risky research and development process and feed the “pipeline” of drugs.  However, companies generally will not embark on this development effort if there is no guarantee of a return on investment.  This frequently is the case with antimicrobial drugs.  Large companies may be unwilling to invest scarce resources to develop a drug that may be used in a relatively small number of patients for short (10-day to two-week) treatment courses.  Yet, we desperately need to develop new classes of antimicrobial drugs to ensure that we have viable treatment options for newly emerging resistant strains.
 
NIAID has engaged smaller companies and academic investigators who are working to identify new leads for vaccines, therapeutics, and diagnostics.  Yet this community, by and large, lacks the resources to move a candidate antimicrobial drug all the way from preclinical testing through advanced development.  NIAID continues to provide a comprehensive set of services for researchers to facilitate the efficient progression of a basic research concept to product development, including preclinical resources that are capable of reducing the risk to drug development entities at each key point in the drug development process.  These preclinical services include quality-controlled research reagents, animal models and clinical specimens to accelerate the rate of discovery.  

In addition to these research resources, NIAID supports a broad portfolio of research to develop new antimicrobial drugs.  These projects span the research and development spectrum from target identification through preclinical development and evaluation.  For example, the Institute supports the discovery of new drugs for such novel targets as those involved in quorum sensing, a biological process that allows bacteria to group together into complex, difficult-to-treat communities called biofilms.  NIAID-supported academic and small business researchers are also engaged in the development of new broad-spectrum antibiotics targeting both well-characterized and novel bacterial pathways.  In addition, NIAID-supported researchers are actively pursuing alternative treatment approaches, such as therapeutic monoclonal antibodies, for many drug-resistant pathogens of concern, including Staphylococcus aureus.

NIAID also is supporting the development of rapid diagnostic methods to identify infectious microbes and the drugs that may be active against these microbes.  These new and improved tools will facilitate targeted treatment with specific antimicrobial drugs and reduction in the use of broad-spectrum antibiotics, and also reduce the inappropriate use of antibiotics for viral infections.  For example, researchers are working to speed the development of techniques to rapidly detect the microbes most often responsible for life-threatening sepsis and community-acquired pneumonia.  Also, a promising new TB diagnostic test developed with NIAID support is being evaluated in advanced-stage clinical studies.  In addition, a new program will assist in developing rapid diagnostics for a number of healthcare-associated bacterial infections that are showing signs of increased drug resistance, including Clostridium difficile, Pseudomonas, Acinetobacter, Enterobacter, and Klebsiella.

Effective vaccines against drug-resistant microbes would also reduce the occurrence of antimicrobial resistance and alleviate the need for new antimicrobials.  For example, vaccines against Streptococcus pneumoniae have reduced the rate of invasive pneumococcal disease among vaccinated children under the age of five by 94% in the United States.12  A similarly effective vaccine against staphylococcal infections would reduce the need for new antimicrobial drugs.  Several groups of NIAID-supported researchers have been developing and assessing candidate Staphylococcus vaccines, including those targeted at surface proteins and surface polysaccharides.  Several of these candidate vaccines have been shown to be protective against staphylococcal infection in animal models.13  Academic and government researchers have become partners in this endeavor, and NIAID will continue to encourage and support their efforts.

Another important area of translational research for NIAID is the evaluation of effective treatment strategies for endemic and emerging infectious diseases using existing drugs.  Such treatment strategies are needed to limit the development of antimicrobial resistance.  Well-designed and executed clinical trials that address standard-of-care antimicrobial treatment versus shorter durations of therapy or no antimicrobial therapy at all are crucial to the rational use of antimicrobials.  Because pharmaceutical companies have little incentive to conduct clinical trials using generic drugs, NIAID plays a key role in ensuring that the value of each potentially active drug is fully realized by organizing and supporting such studies.  If generic antimicrobial drugs can be effective front-line agents, newer antimicrobials can be held in reserve for more serious drug-resistant infections.

In an example of such an effort, NIAID in 2008 launched a new initiative, Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance, to target disease areas in which there is a risk of developing antimicrobial resistance.  This solicited research program supports the design and conduct of clinical protocols that test the safety and effectiveness of different therapeutic approaches and regimens.  The ultimate goal of the studies is to provide data for the most prudent use of existing antibiotics in order to reduce the probability of the emergence of drug resistance by minimizing unnecessary drug exposure.  NIAID plans to support additional clinical trials of strategies aimed at reducing antimicrobial resistance in a similar initiative in FY 2011.  NIAID also continues to support two contracts under the Clinical Trials for Community-Acquired Methicillin-Resistant Staphylococcus aureus (CA-MRSA) initiative.  These contracts support clinical trials to determine the optimal treatment of uncomplicated cases of skin and soft tissue infections caused by CA-MRSA using existing off-patent antibiotics. 

CONCLUSION
Antimicrobial resistance is a perpetual challenge in our attempts to maintain the upper hand in the perpetual battle between microbes and the human species.  NIAID is addressing the problem of antimicrobial resistance by offering tools and resources to the scientific community to facilitate the highest-quality research and provide a flexible infrastructure to respond to emerging needs; supporting basic and translational research likely to lead to clinical applications that will reduce the prevalence of antimicrobial resistance; encouraging development of broad-based vaccines and therapeutics that are effective against multiple pathogens; and supporting the development of diagnostic tools that will enable clinicians to make informed treatment choices.  The efforts of NIAID and our partners from the public health, research, medical, and pharmaceutical communities are critical to addressing this daunting challenge.


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2 Klevens, 1763.

3 Klevens, 1769.

4Acinetobacter baumannii Infections Among Patients at Military Medical Facilities Treating Injured U.S. Service Members, 2002—2004. MMWR. 2004;53(45):1063-1066.

5 World Health Organization.  Multidrug and extensively drug-resistant TB (M/XDR-TB): 2010 Global Report on Surveillance and Response.  2010:1.  Available at http://www.who.int/tb/features_archive/world_tb_day_2010/en/index.html.

6 WHO, 7.

7 WHO, 2.

8 Memoli et al.  Rapid Selection of Oseltamivir‐ and Peramivir‐Resistant Pandemic H1N1 Virus during Therapy in 2 Immunocompromised Hosts.  Clinical Infectious Diseases 2010;50:1252–1255.

9 US Interagency Task Force on Antimicrobial Resistance.  A Public Health Action Plan to Combat Antimicrobial Resistance. 2001. Available at http://www.cdc.gov/drugresistance/actionplan/html/index.htm.

10 S Queck et al. Mobile genetic element-encoded cytolysin connects virulence to methicillin resistance in MRSA. PLoS Pathogens. 2009;5(7)e1000533:1-12.

11 Levy SB. Active efflux, a common mechanism for biocide and antibiotic resistance. J Appl Microbiol 2002; 92(Suppl):65S–71S.

12 US Department of Health and Human Services. The Jordan Report: Accelerated Development of Vaccines. 2007:109.  Available at http://www.niaid.nih.gov/about/organization/dmid/Documents/jordan2007.pdf.

13 McKenney, D. et al., Broadly Protective Vaccine for Staphylococcus aureus Based on an in Vivo-Expressed Antigen. Science. 1999 May 28;284(5419):1523-7; and Stranger-Jones, YK et al., Vaccine assembly from surface proteins of Staphylococcus aureus. PNAS. 2006 Nov 7;103(45):16942-7.

Last revised: June 18, 2013