ANTIMICROBIAL RESISTANCE: THE NIH RESPONSE TO A GROWING PROBLEM
Statement of
Anthony S. Fauci, M.D., Director
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Before the Senate Committee on Health, Education, Labor, and Pensions Subcommittee on Public Health and Safety
February 25, 1999
Accompanying Posters
Senator Frist and members of the Subcommittee, I am pleased to appear before you today to discuss the role of the National Institutes of Health (NIH) in combating the problem of antimicrobial resistance, and the recent progress and initiatives in addressing this enormous problem.
As you are aware, many diseases are increasingly difficult to treat because of the emergence of drug-resistant organisms, including HIV and other viruses; bacteria such as staphylococci, enterococci, and E. coli which cause serious infections in hospitalized patients; bacteria that cause respiratory diseases such as pneumonia and tuberculosis; food-borne pathogens such as Salmonella and Campylobacter; sexually transmitted organisms such as Neisseria gonorrhoeae; Candida and other fungi; and parasites such as Plasmodium falciparum, the cause of malaria. According to the Institute of Medicine (IOM), the total cost of treating antimicrobial-resistant infections may be as high as $5 billion annually in the United States.
Because of antimicrobial resistance, some infections have become untreatable in certain circumstances. Patients in our best hospitals have died with strains of the tuberculosis (TB) bacterium resistant to the entire armamentarium of anti-TB drugs. Some strains of Pseudomonas aeruginosa, a bacterium that causes septicemia and pneumonia in cystic fibrosis and immunocompromised patients, are becoming difficult to treat with currently available antimicrobial agents. Enterococcal infections are increasingly resistant to vancomycin, a drug which is often a physician's "ace-in-the-hole" when treating bacterial infections that do not respond to other drugs. In the past two years, strains of Staphylococcus aureus with reduced susceptibility to vancomycin have emerged, threatening to return us to the pre-antimicrobial era, when S. aureus infections were untreatable and frequently resulted in the death of previously healthy children and adults in the prime of life.
Treating antimicrobial-resistant infections often requires the use of more expensive or more toxic drugs and can result in longer hospital stays. For example, many isolates of Streptococcus pneumoniae, a leading cause of earaches, pneumonia, and meningitis, are resistant not only to penicillin but to the second and third-line antimicrobials as well. Alternatives are expensive and in some cases not licensed for children, making the management of this common infection increasingly difficult.
The emergence of antimicrobial resistance is not a new phenomenon, nor an unexpected one. In fact, resistance pre-dates the discovery of antibiotics and is an inevitable result of the rapid replication and evolution of microbes. A single random gene mutation can have a large impact on an organism's disease-causing properties. A mutation that helps a microbe survive in the presence of an antimicrobial agent will quickly become predominant throughout the microbial population. Microbes also commonly acquire genes, including those encoding for resistance, by direct transfer from members of their own species or from unrelated microbes. Once established in a microbial population, resistance is virtually impossible to eradicate.
The innate adaptability of microbes is accelerated by the selective pressure of widespread and often inappropriate use of antimicrobial agents. The Centers for Disease Control and Prevention (CDC) has estimated that one-half of the more than 100 million courses of antibiotics prescribed annually by U.S. office-based physicians are unnecessary — that is, they are prescribed for colds and other viral infections which they do not affect. Hospitals provide a fertile environment for drug-resistant pathogens. Patients at increased risk for development of infections (surgical, trauma, chemotherapy and transplant), a high density of very sick people and extensive use of antimicrobials are circumstances associated with resistance.
It is underappreciated that all major groups of microorganisms — viruses, fungi, and parasites as well as bacteria — become resistant to antimicrobials. For example, strains of HIV resistant to multiple antiretroviral drugs are now commonplace, and can be transmitted from an infected individual to an uninfected one. Although treatments that combine new drugs called protease inhibitors with other anti-HIV medications often effectively suppress HIV production in infected individuals, studies suggest that many treatment failures occur due to the development of resistance by the virus. Fungal pathogens account for a growing proportion of nosocomial infections, and clinicians are concerned that the increasing use of antifungal drugs will lead to drug-resistant fungi. Recent studies have documented resistance of Candida species to fluconazole, a drug used widely to treat patients with systemic fungal diseases. Parasitic diseases such as malaria are also becoming more difficult to treat. Resistance to chloroquine, a drug once widely used and highly effective for preventing and treating malaria, has emerged in most parts of the world, and resistance to other antimalarial drugs also is widespread and growing. The impact of chloroquine resistance is profound, especially in resource-poor settings. For example, in Nigeria it costs 75 cents to treat a chloroquine-sensitive case of malaria, but $25 to treat a resistant infection.
A broad consensus has emerged that decreasing the incidence of infections resistant to antimicrobials will require the cooperation of many individuals and organizations worldwide, including health care providers; patients and their families; local, state and territorial health departments; U.S. federal agencies (e.g. CDC, NIH, Food and Drug Administration); professional and non-profit organizations; the World Health Organization and its member states; industry; and academia. In the past few years, most if not all of these groups have been represented in major meetings and reports on antimicrobial resistance, including one from the Institute of Medicine's Forum on Emerging Infections. The Forum was created in response to a request by CDC and NIH, and has conducted a series of workshops, including one concerning antimicrobial resistance in July, 1997.
The IOM and other organizations have emphasized the need for improved systems for monitoring outbreaks of drug-resistant infections and a more judicious use of antimicrobial drugs, in both human medicine and agriculture. They also underscore the critical role that basic and applied research plays in combating the problem of antibiotic resistance. It is in this latter capacity that NIH is predominantly involved.
NIH funds a diverse portfolio of grants and contracts to study antimicrobial resistance in major viral, bacterial, fungal, and parasitic pathogens. The National Institute of Allergy and Infectious Disease (NIAID) has a lead role in many of these activities, but numerous other Institutes and Centers at NIH also support and participate in research related to antibiotic resistance.
NIH-funded projects include basic research into the disease-causing mechanisms of pathogens, host-pathogen interactions, and the molecular mechanisms responsible for drug resistance, as well as applied research to develop and evaluate new or improved products for disease diagnosis, intervention, and prevention. Numerous genome projects seek to identify new gene targets for the development of drugs and vaccines. Other NIH sponsored activities with relevance to antimicrobial resistance include physician and researcher training and education. In addition, NIH supports a number of clinical trials networks with the capacity to assess new antimicrobials and vaccines with relevance to drug-resistant infections. Among these are the AIDS Clinical Trials Groups, the Mycoses Study Group, the Collaborative Antiviral Study Group, and Vaccine and Treatment Evaluation Units.
Basic research funded by NIH has yielded extraordinary results. For example, NIAID intramural scientists recently illuminated one way in which the anti-TB drug isoniazid blocks the TB bacterium, information which previously had eluded researchers. They found that isoniazid disables a protein of the bacterium involved in cell wall synthesis called KasA, and also found mutations in the KasA gene that contribute to isoniazid resistance. With the knowledge that KasA is important to mycobacterial growth, it may be possible to develop other drugs that specifically target this molecule. The finding also opens the door to the development of new tests to detect isoniazid resistance, and assays to quickly screen new anti-TB drugs for their ability to target KasA.
Research into the molecular basis of drug resistance in parasites has led to the development of molecular tools to identify drug-resistant parasites; the identification of the genetic basis of resistance and resulting biochemical alterations in several parasite species; the identification of methods to reverse resistance; and the synthesis of drugs that are effective against drug-resistant strains of malaria. In an important technical achievement, NIAID-supported researchers recently determined the complete genetic sequence of chromosome 2 of Plasmodium falciparum, the parasite that causes the most severe form of malaria. This new information promises to help identify virulence factors and proteins involved in the parasite's lifecycle that may eventually serve as targets for the development of drugs and vaccines. Other researchers have determined the complete genomic sequence of two strains of M. tuberculosis, which promises to facilitate identification of new targets for TB vaccine development, and provide insights relevant to drug design and a better understanding of TB pathogenesis.
Indeed, the remarkably rapid and accurate methods now available for sequencing the genomes of disease-causing microbes promises to revolutionize the study of microbial pathogenesis and drug resistance. In addition to M. tuberculosis and P. falciparum, NIH supports the genetic sequencing of many other pathogens with high levels of drug resistance, including HIV, Enterococcus faecalis, S. pneumoniae, Neisseria gonorrhoeae, Salmonella typhimurium, Streptococcus pyogenes, Candida albicans, and, as noted below, both drug-resistant and drug-susceptible strains of S. aureus.
Over the past two fiscal years, NIH and NIAID have been adding funds for antimicrobial resistance research. With this increased support, NIH has been able to accelerate research in this area. Among many initiatives undertaken in consultation with the research community, NIH developed a plan for S. aureus that may serve as a model for addressing drug resistance. This strategy includes the funding of grants to sequence the genomes of two strains of the pathogen (one resistant to methicillin and one susceptible), a workshop to facilitate the use of emerging data from the genome projects, and a Request for Proposals (RFP) entitled "Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA)." An award for the network will be made in the next few months; we anticipate that this project will give basic and clinical investigators a common reference for discussing the organisms and access to the same research strains. Another outgrowth of this effort and NIAID grant support is the recent discovery of a potential novel therapeutic target to block the disease-causing mechanisms of S. aureus.
These new projects build on significant initiatives in each of the previous two years. In 1996, NIH encouraged the scientific community with a Program Announcement to submit grant applications to support basic and applied research on emerging infectious diseases, including fungal diseases and those due to bacteria that are resistant to antibiotics. In 1997, NIAID released a Program Announcement to encourage basic research on the molecular biology and genetics of resistance among bacteria and fungi, development of new tests for detecting resistance, identification of new classes of antimicrobial agents, and evaluation of alternative treatments of drug-resistant infections.
Vaccine research is a key to preventing infections caused by drug-resistant organisms. The NIH vaccine research portfolio includes projects to develop and test new and improved candidate vaccines against many infectious organisms with high levels of resistance. A notable success story was the development of vaccines against Haemophilus influenzae type b (Hib), a bacterium which can lead to life-threatening meningitis, pneumonia and other complications, especially in young children. In the 1970s and 1980s, widespread H. influenzae resistance to penicillin-like drugs began to appear, making patient care increasingly difficult. Working with partners in industry and academia, NIH-supported researchers developed a Hib vaccine that protected children older than two years; this vaccine reached the market in 1985. Subsequently, researchers developed conjugated vaccines to protect children under two years of age from Hib; previous versions of the Hib vaccine were not immunogenic in young infants. The success of Hib conjugate vaccines has been extraordinary: more than 35 countries have followed the lead of the United States and adopted these vaccines into their immunization programs, cutting the incidence of invasive Hib disease to negligible levels wherever the vaccine has been used. In the United States only 258 cases of invasive Hib disease among children younger than 5 years were reported in 1997, a 97 percent reduction from 1987.
Many in the public health community are optimistic that the Hib vaccine success story can be repeated with a new conjugated vaccine against another important respiratory pathogen widely resistant to antimicrobials, i.e. Streptococcus pneumoniae. More than one-third of S. pneumoniae isolates have intermediate or high-level resistance to penicillin. The burden of this pathogen is enormous; S. pneumoniae is the leading cause of morbidity and mortality in infants and young children worldwide, resulting in 1.2 million child deaths each year. In this country, pneumococcal disease is responsible for 40,000 deaths, 500,000 cases of pneumonia, and 7 million cases of otitis media.
The current pneumococcal vaccine is not immunogenic in young children and only moderately efficacious in the elderly, another group at risk of severe pneumococcal disease. New conjugated pneumococcal vaccines, developed with the help of NIAID funding and tested in the Institute's Vaccine and Treatment Evaluation Units, promise to be significantly more effective. For example, a recent report from a three-year study of more than 38,000 infants in California found that a 7-valent conjugated pneumococcal vaccine was 100 percent efficacious in preventing meningitis and bacteremia in young infants. NIH-supported vaccine development is underway for other resistance problems such as malaria, gonorrhea, and TB.
The recent IOM report on antimicrobial resistance asserts: "What is needed now is sustained, sufficient support — for basic pioneering research, for the clinical research required to move truly new products from the laboratory to the pharmacy, and for the infrastructure underpinning both." With our current and planned initiatives, NIH is well-positioned to play a pivotal role in combating the many drug-resistant pathogens that threaten human health.
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