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STATEMENT FOR
THE RECORD
NATIONAL INSTITUTES OF
HEALTHSUBCOMMITTEE ON LABOR,
HEALTH AND HUMAN SERVICES,
EDUCATION, AND RELATED AGENCIES
COMMITTEE
ON APPROPRIATIONS
HEARING ON ANTIMICROBIAL
RESISTANCE
SEPTEMBER 20, 2000
Role of NIH in Meeting the Public Health
Needs in Antimicrobial Resistance
NIH has a lead role in coordinating the
participating agencies’ research efforts to address antimicrobial
resistance, and the National Institute of Allergy and Infectious
Diseases (NIAID) is the lead Institute at NIH for antimicrobial
resistance. Antimicrobial resistance is not one problem, but
a whole array of problems spanning microbiology. Basic and
clinical research provides the fundamental knowledge necessary
to develop appropriate responses to antimicrobial resistance.
The broad scope of the U.S. research community as assessed
by the NIH and other relevant agencies has a major contribution
to make in meeting the diverse challenges such as: new diagnostic
tests; new antimicrobial agents (including novel therapeutics);
and vaccines and other prevention methods.
NIH Congressional Testimony and Briefings
on Antimicrobial Resistance
On February 25, 1999, Dr. Anthony Fauci,
Director, NIAID, testified before the Senate Committee on
Health, Education, Labor, and Pensions Subcommittee on Public
Health and Safety (see ATTACHMENT I), summarizing the
Institute’s research activities related to antimicrobial resistance
(www.niaid.nih.gov/director/congress/1999/0225.htm ).
Many of the activities referenced in this testimony have expanded
during the past year; for example, additional genomes have
been sequenced. The NIAID website provides updated information
on many of these items (see ATTACHMENT II, the NIAID
website – main link: www.niaid.nih.gov ;
specific microbiology and infectious diseases information
link: www.niaid.nih.gov/research/dmid.htm ).
In addition, on June 29, 2000, a briefing
for staff to Senator Thad Cochran (R-MS), a member of the
Labor/HHS Appropriations Subcommittee, was held to discuss
the draft "Public Health Action Plan to Combat Antimicrobial
Resistance." Presentations were made by the respective
HHS Co-Chairs on the Interagency Task Force on Antimicrobial
Resistances: Dr. Dennis M. Dixon, NIH/NIAID; Dr. David Bell,
CDC/NCID/OD (Office of the Director, National Center for Infectious
Diseases); and Dr. Jesse Goodman, FDA/CBER (Center for Biologics
Evaluation and Research, Food and Drug Administration). Also
on this same date, a similar briefing was held for House staff
that was sponsored by Representative Louise Slaughter (D-NY).
NIAID program officers also have participated
in two antimicrobial resistance briefings over the past two
years for staff to Senators Edward Kennedy (D-MA) and William
Frist (R-TN).
NIH’s Role in the Interagency Task
Force on Antimicrobial Resistance
The Interagency Task Force on Antimicrobial
Resistance, co-chaired by CDC, FDA and NIH and also including
HCFA, HRSA, AHRQ, EPA, DoD, USDA, and VA, was initiated by
the agencies following the February 1999 congressional hearing
on antimicrobial resistance to link the relevant agencies
to coordinate the public health response. The initial public
activities of this task force were announced in the June 28,
1999, Federal Register in conjunction with a July 1999 meeting
organized by the Task Force to involve the scientific and
public communities in the development of a Public Health
Action Plan to Combat Antimicrobial Resistance. A draft
of the plan was posted on the Internet, public comment was
received, and the comments are being addressed.
NIH’s Role and Ongoing Responsibilities
in the Public Health Action Plan to Combat Antimicrobial
Resistance
Summary of Plan
The plan addresses four key issues: surveillance,
prevention and control, research, and product development.
NIH took the lead in identifying research areas of need for
incorporation into the plan.
Three key challenges facing the public
health are central to the mission of the NIH: developing better
means of diagnosis, prevention, and treatment of disease.
Meeting these challenges has three general requirements: identifying
and addressing gaps in the understanding of microbiological
processes (basic research); drawing upon and focusing a robust
research infrastructure; and establishing a critical pathway
for movement of research findings to useful products.
Top Research Priority Action Items
The research chapter of the Action Plan
identifies the responsible agencies and some targeted actions.
Representative priority actions (NIH is active in each) include
the following:
- Basic Research: Genomics. Determining
the genetic complete genetic code of the individual microbes
and deciphering the function of the genes gets at the
central operations of the organisms. The NIH will continue
to play a leadership role in pathogen genome sequencing
and genomics, and in collaborating and coordinating with
other agencies and groups to make this vital information
publicly available to guide efforts for the three primary
challenges: better diagnosis, better treatment, and better
prevention of the infections. We have completed numerous
microbial genome projects and have launched new systems
for managing genome sequencing and genome information.
The NIAID has demonstrated the ability to devise and implement
a priority setting process that includes community involvement
to address the complex issues. For genomics, these include
the selection of organisms; the public availability of
data, and meeting the public health need. This is a cross
cutting activity, of interest to many agencies. The USDA
has embarked upon a similar priority setting process for
agriculturally important organisms.
- Clinical Research: Clinical trials
of antimicrobial resistance issues that are difficult
to resolve in the industrial sector.
- Novel therapies in need of a proof
of principle.
- Existing antimicrobials used in
novel ways
- Combinations of antimicrobials
NIAID has had good success with
trial groups for viruses (Collaborative Antiviral Study
Group), and for fungi (Mycoses Study Group). These examples
include partnering with industry. There is no strictly
analogous multi-center antibacterial study group with
a focus on antimicrobial resistance that is currently
in existence. The Task Force and the developing Action
Plan already have contributed to shaping one new activity
that NIAID is currently soliciting with existing resources.
ATTACHMENT
I
Dr. Anthony
S. Fauci’s February 25, 1999 Testimony Before the Senate
Committee on Education, Labor, and Pensions
Subcommittee
on Public Health and Safety
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 combatting
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 combatting 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 combatting the many drug-resistant
pathogens that threaten human health.
ATTACHMENT II (www.niaid.nih.gov)
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