[Senate Hearing 106-859]
[From the U.S. Government Publishing Office]
S. Hrg. 106-859
ANTIMICROBIAL RESISTANCE
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HEARING
before a
SUBCOMMITTEE OF THE
COMMITTEE ON APPROPRIATIONS UNITED STATES SENATE
ONE HUNDRED SIXTH CONGRESS
SECOND SESSION
__________
SPECIAL HEARING
__________
Printed for the use of the Committee on Appropriations
Available via the World Wide Web: http://www.access.gpo.gov/congress/
senate
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COMMITTEE ON APPROPRIATIONS
TED STEVENS, Alaska, Chairman
THAD COCHRAN, Mississippi ROBERT C. BYRD, West Virginia
ARLEN SPECTER, Pennsylvania DANIEL K. INOUYE, Hawaii
PETE V. DOMENICI, New Mexico ERNEST F. HOLLINGS, South Carolina
CHRISTOPHER S. BOND, Missouri PATRICK J. LEAHY, Vermont
SLADE GORTON, Washington FRANK R. LAUTENBERG, New Jersey
MITCH McCONNELL, Kentucky TOM HARKIN, Iowa
CONRAD BURNS, Montana BARBARA A. MIKULSKI, Maryland
RICHARD C. SHELBY, Alabama HARRY REID, Nevada
JUDD GREGG, New Hampshire HERB KOHL, Wisconsin
ROBERT F. BENNETT, Utah PATTY MURRAY, Washington
BEN NIGHTHORSE CAMPBELL, Colorado BYRON L. DORGAN, North Dakota
LARRY CRAIG, Idaho DIANNE FEINSTEIN, California
KAY BAILEY HUTCHISON, Texas RICHARD J. DURBIN, Illinois
JON KYL, Arizona
Steven J. Cortese, Staff Director
Lisa Sutherland, Deputy Staff Director
James H. English, Minority Staff Director
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Subcommittee on Departments of Labor, Health and Human Services, and
Education, and Related Agencies
ARLEN SPECTER, Pennsylvania, Chairman
THAD COCHRAN, Mississippi TOM HARKIN, Iowa
SLADE GORTON, Washington ERNEST F. HOLLINGS, South Carolina
JUDD GREGG, New Hampshire DANIEL K. INOUYE, Hawaii
LARRY CRAIG, Idaho HARRY REID, Nevada
KAY BAILEY HUTCHISON, Texas HERB KOHL, Wisconsin
TED STEVENS, Alaska PATTY MURRAY, Washington
JON KYL, Arizona DIANNE FEINSTEIN, California
ROBERT C. BYRD, West Virginia
(Ex officio)
Professional Staff
Bettilou Taylor
Mary Dietrich
Jim Sourwine
Ellen Murray (Minority)
Administrative Support
Kevin Johnson
Carole Geagley (Minority)
C O N T E N T S
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Page
Opening statement of Senator Thad Cochran........................ 1
Statement of Jeffrey P. Koplan, M.D., Director, Centers for
Disease Control and Prevention, Department of Health and Human
Services....................................................... 2
Prepared statement........................................... 5
Statement of Jane E. Henney, M.D., Commissioner, Food and Drug
Administration, Department of Health and Human Services........ 10
Prepared statement........................................... 14
Prepared statement of the National Institutes of Health.......... 22
Statement of F.E. ``Ed'' Thompson, M.D., State health officer,
State of Mississippi........................................... 54
Prepared statement........................................... 56
Statement of Martin Rosenberg, Ph.D., senior vice president and
director of anti-infectives, Smithkline Beecham Pharmaceuticals 58
Prepared statement........................................... 61
Statement of Merle A. Sande, M.D., professor and chairman,
Department of Medicine, Clarence M. and Ruth N. Birrer
Presidential Endowed Chair in Internal Medicine, University of
Utah School of Medicine........................................ 61
Statement of Alice M. Clark, Ph.D., director, National Center for
the Development of Natural Products, University of Mississippi. 65
Prepared statement........................................... 68
Statement of Mark L. Nelson, Ph.D., senior director of chemistry,
Paratek Pharmaceuticals, Inc................................... 70
Prepared statement........................................... 72
ANTIMICROBIAL RESISTANCE
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WEDNESDAY, SEPTEMBER 20, 2000
U.S. Senate,
Subcommittee on Labor, Health and Human
Services, and Education, and Related Agencies,
Committee on Appropriations,
Washington, DC.
The subcommittee met at 9:30 a.m., in room SD-124, Dirksen
Senate Office Building, Hon. Thad Cochran presiding.
Present: Senator Cochran.
OPENING STATEMENT OF SENATOR THAD COCHRAN
Senator Cochran. The subcommittee will please come to
order.
This morning we are conducting a hearing on the subject of
antimicrobial resistance, a growing national health threat.
When penicillin was launched in the early forties, it was
touted as a miracle drug capable of countering everything from
the common cold to pneumonia and even staph infection.
This antibiotic and others developed since then have
enabled us to have a more healthy, productive, and longer
living population. These and other antimicrobials have proven
to be enormously successful.
But these miracle drugs are producing fewer miracles these
days. What we considered easily treatable diseases are now
becoming increasingly deadly. As our once invincible
pharmaceuticals have begun to lose their ability to kill
diseases caused by microbes--to kill disease-causing microbes.
Our extensive use of antimicrobial drugs as well as the
remarkable ability of microbes to mutate and develop resistance
threatens to return us to the situation we had in the early
1900's, where common infections were often lethal.
Antimicrobial resistance is a threat to the health and
safety of countries worldwide, including the United States. All
human kind is at risk.
The most susceptible to the threat are the most vulnerable,
those who are sick in hospitals and the young in daycare
centers. But drug-resistant infections are now occurring in all
urban and rural settings and among all populations.
And these are not new unknown microbes. They are such well-
known illnesses as tuberculosis, malaria and gonorrhea and such
common ailments as sore throats and ear infections.
The threat is real and growing at a time when our society
cannot afford the social or financial cost of a drug-resistant
outbreak of infectious diseases.
This problem is very serious and I hope we can address it
with the urgency that it requires.
At this hearing, I hope we can get suggestions from the
experts about how the Federal and State governments, the
private sector and academia can work together to deal with the
threat.
The Senate has already recognized the problem when it
approved an amendment to a Labor HHS appropriations bill this
year, which provides funds for pilot projects in antimicrobial
resistance surveillance and research.
Another bill that is pending is the--in the legislative
committee is S. 2731, the Public Health Threats and Emergencies
Act. It also provides new authorization for Federal programs to
address antimicrobial resistance surveillance, education and
research.
These are good first steps. But they are only the beginning
of a full-scale attack we need to solve this serious problem.
A public health action plan to combat antimicrobial
resistance has been developed by an interagency task force led
by the Centers for Disease Control, the Food and Drug
Administration, and the National Institutes of Health. This
plan will provide a blueprint for the next decade's fight
against resistance. The action plan confirms that we must
immediately begin to work on a variety of fronts through a
comprehensive and concentrated public, private partnership.
I expect our panelists will testify today that this
initiative must include surveillance, prevention, and education
as well as research into resistance mechanisms and the
development of new and more effective antimicrobial drugs.
We will begin today's hearing with a panel including Dr.
Jeffrey Koplan, from the Centers for Disease Control and
Prevention; and Dr. Jane Henney, who is Commissioner of the
Food and Drug Administration.
Then we will hear from our second panel that will include
Dr. Ed Thompson, State Health Director for the State of
Mississippi; Dr. Alice Clark, Director of the National Center
for the Development of Natural Products; Dr. Merle Sande,
Professor and Chairman of the Department of Medicine at the
University of Utah School of Medicine; Dr. Martin Rosenberg,
Senior Vice President and Director of Anti-Infectives at
SmithKline Beecham Pharmaceuticals; and Dr. Mark Nelson, Senior
Director of Chemistry at Paratek Pharmaceuticals.
Our witnesses have submitted statements to the committee,
which will be made a part of the record in full, and the
National Institutes of Health has also submitted a statement,
which will be made a part of the record.
STATEMENT OF JEFFREY P. KOPLAN, M.D., DIRECTOR, CENTERS
FOR DISEASE CONTROL AND PREVENTION,
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Senator Cochran. Let us begin with Dr. Koplan of the
Centers for Disease Control. You may proceed.
Dr. Koplan. Thank you, Senator Cochran. Good morning. And
thank you for your invitation to testify on the national and
global problem of antimicrobial resistance and CDC's response
to it.
Incredible changes in infectious diseases have occurred
within our own life span. Many of the diseases that threatened
our parents are distant history for our children.
In 1942, a 33-year-old woman was hospitalized for a month
in Connecticut with a life-threatening streptococcal infection.
She was delirious. Her temperature reached almost 107 degrees.
Her doctors gave her an experimental drug called penicillin
at Grace New Haven Hospital. Her condition began to improve
overnight. She was the first woman American civilian that was
saved by penicillin. And she died just this past year at the
age of 90.
The typical population of hospital medical wards was very
different in the Thirties than it is today. Today wards are
filled with patients who have cancer, heart disease, diabetes,
complications of high-blood pressure.
In contrast, the wards then were populated by patients with
pneumonia, sepsis, typhoid fever, diphtheria and rheumatic
fever. There were few effective therapies for most of these
conditions. And within a few years, many of these infections
became memories of the pre-antimicrobial era.
Unfortunately, the emergence of drug resistance threatens
to reverse the progress prompted by the discovery of penicillin
and the other miracle antimicrobials that have been developed.
Even with these drugs, infectious diseases remain a leading
cause of death worldwide and in the United States.
Antimicrobial resistance contributes to this burden as it
affects virtually all of the pathogens we have previously
considered to be easily treatable.
Here in the 21st century, drug options to treat common
infections are becoming increasingly limited and reliance on
more expensive options contribute to escalating health-care
costs.
Drug resistance is a target plan--is a target area in CDC's
plan, ``Preventing Emerging Infectious Disease: A Strategy for
the 21st Century.'' Public health priorities in the plan are
organized under four broad goals, each of which can be applied
to antimicrobial resistance: one, surveillance and response;
two, applied research; three, infrastructure and training; and
four, prevention and control.
Surveillance data help clinicians know which antimicrobials
to prescribe, help researchers focus their efforts and help
public health officials mount prevention campaigns.
For many infections, resistance rates vary widely. For
example, 15 percent of Streptococcus pneumoniae strains in
parts of Maryland are resistant to penicillin, whereas in 5
Tennessee counties, 38 percent are resistant. In Connecticut,
the frequency of resistance varies from zero to nearly 40
percent among hospitals. These data highlight the need for such
information at all levels--local, State and Federal--in order
to guide clinical decisions and target interventions.
With our partners, CDC conducts limited surveillance to
monitor resistance for several important pathogens. For
example, surveillance for resistance among invasive
pneumococcal infections is conducted through nine State health
departments involved in CDC's Emerging Infections Program.
Other projects monitor drug-resistance in Helicobacter
pylori, typhoid fever, HIV, and malaria, but only in a handful
of sites. With our colleagues in--at the FDA, we monitor food-
borne pathogens for antibiotic resistance.
None of these systems is operational in all States, in all
hospitals, or covers all organisms for which resistance is a
problem. Coordinated national antimicrobial resistance
surveillance is needed.
Applied research needs include developing new drugs and
vaccines, identifying molecular mechanisms of drug resistance
and risk factors associated with its spread, developing
improved diagnostic tests and assessing the role of new
vaccines and orphan drugs in preventing and controlling the
spread of resistant infections.
For example, CDC has entered into a promising research
collaboration with a consortium formed by the University of
Mississippi, Tulane University, and Xavier University in New
Orleans to develop and test new antimalarial drugs.
CDC's ongoing effort to rebuild the U.S. public health
infrastructure, to address infectious diseases, is critical in
improving the capacity of health departments, health-care
delivery organizations, and clinical and public health
laboratories to detect and report drug-resistant infections and
to implement prevention and control strategies.
Antimicrobial resistance is constantly changing, requiring
that laboratory testing methods be kept up to date. For
example, a 1998 survey of laboratories found that only 18
percent were actively using appropriate methods to detect
emerging resistance in Staphylococcus aureus; only 32 percent
were using appropriate methods to find resistance in organisms
that typically cause infections in ICU's.
We need to ensure that whenever a doctor sends a specimen
to a laboratory, the correct test will be done to detect drug-
resistant infections and that the test result will be
interpreted correctly and reported. State public health labs
will play leading roles in this effort.
CDC's Epidemiology and Laboratory Capacity agreements with
State health departments in 43 States and localities provide a
mechanism to do this.
Perhaps the most daunting challenge is to develop a
coordinated program to prevent the spread of antimicrobial
resistance by translating information into public health
prevention and control measures. We can all relate to the
parent of a sick child who wants his or her child to feel
better.
For too long, this has often meant requesting an antibiotic
from the child's doctor. We now know that antibiotics are not
effective for many conditions for which they have been
prescribed.
CDC has conducted focus groups with parents and physicians
to better understand the factors behind inappropriate
antibiotic use. For example, parents told us that they need an
antibiotic in order for their children to return to daycare.
Physicians told us that they do not typically have enough time
to educate a patient about the problem of antimicrobial
resistance and the reasons why antibiotics do not work for
viral infections. This reinforced our belief that we must move
forward on a nationwide public information campaign.
In cooperation with professional societies, CDC has
developed educational materials for physicians and parents,
including a prescription pad for physicians to provide patients
written instructions for treating symptoms of viral illnesses,
for which antibiotics would be inappropriate.
Preliminary data suggests that these approaches are
effective. For example, in certain rural Alaskan villages, an
education intervention for the public and health-care providers
successfully reduced antibiotics prescribing by 31 percent.
These data hold promise that we can make a difference.
Combating antimicrobial resistance will require Federal
leadership and collaboration among public and private sector
partners. Beginning in June 1999, CDC, FDA and NIH joined with
seven other Federal agencies to form the Interagency Task Force
that you mentioned earlier. It provides a blueprint for
specific coordinated Federal actions to address this emerging
threat.
CDC's primary role in implementing the plan is in the areas
of surveillance and prevention and control, addressing the
needs I have detailed already.
PREPARED STATEMENT
In conclusion, recent increases in antimicrobial resistance
are cause for serious concern but not pessimism. The rapid
spread of resistance demands an immediate and aggressive
response. By forming effective partnerships, we can prolong the
effectiveness of currently available antimicrobial drugs;
accelerate the development of new tools and reduce the threat
of antimicrobial resistance for patients today and in future
generations. Thank you very much.
Senator Cochran. Thank you, Dr. Koplan, for your
interesting and provocative statement.
[The statement follows:]
PREPARED STATEMENT OF HON. JEFFREY P. KOPLAN
I am Dr. Jeffrey P. Koplan, Director, Centers for Disease Control
and Prevention (CDC). Thank you, Mr. Chairman and members of the
Subcommittee, for your invitation to testify today on the emerging
national and global problem of antimicrobial resistance and the
response by CDC.
ANTIMICROBIAL RESISTANCE AS A PUBLIC HEALTH ISSUE
In March 1942, a 33-year-old woman was hospitalized for a month
with a life-threatening streptococcal infection at a New Haven,
Connecticut, hospital. She was delirious, and her temperature reached
almost 107 deg.F. Treatments with sulfa drugs, blood transfusions, and
surgery had no effect. As a last resort, her doctors injected her with
a tiny amount of an obscure experimental drug called penicillin. Her
hospital chart, now at the Smithsonian Institution, indicates a sharp
overnight drop in temperature; by the next day she was no longer
delirious. That woman was the first U.S. civilian whose life was saved
by penicillin, and she died last year at the age of 90.
The typical medical ward of a large city hospital was very
different in the 1930s than it is today. Today's wards are filled with
patients with cancer, heart disease, or the complications of diabetes
or high blood pressure. In contrast, the wards of the pre-antimicrobial
era were populated by patients with pneumonia, meningitis, sepsis,
typhoid fever, diphtheria, syphilis, tuberculosis, and rheumatic fever.
There were few effective therapies for most of these conditions. Many
of the patients were young, and most would die of the disease or its
complications. But within a few years, many of these bacterial
infections, and particularly their complications, rapidly faded to
become memories of the pre-antimicrobial era.
Unfortunately, the emergence of drug resistance threatens to
reverse the progress prompted by the discovery of penicillin and other
miracle drugs that have been developed over the last 50 years. Even
with these miracle drugs, infectious diseases are a leading cause of
death worldwide and the third leading overall cause of death in the
United States. Antimicrobial resistance contributes to the burden of
infectious diseases domestically and globally including bacterial,
fungal, parasitic and viral diseases. Antimicrobial resistance already
affects virtually all of the pathogens we have previously considered to
be easily treatable. Here in the 21st century, drug options for the
treatment of common infections are becoming increasingly limited, and
reliance on more expensive options contributes to escalating health
care costs. A 1995 Office of Technology Assessment report estimated
that the emergence of antimicrobial resistance among six common
bacteria in hospitals adds approximately $661 million per year in
hospital charges, and this estimate does not include indirect costs.
Many other scientific, policy, and government organizations have called
attention to this issue, including, in the United States, the American
Society for Microbiology, the Infectious Diseases Society of America,
the Institute of Medicine, and the General Accounting Office.
International organizations that have expressed concern about this
issue include the World Health Organization, the European Union, the
United Kingdom House of Lords, and Health Canada.
Antimicrobial resistance is a complex and multifaceted public
health issue. The use of antimicrobials in agriculture can lead to the
development of resistant strains of pathogens that can spread to humans
through the food supply or through contact with infected animals.
International travel and trade increases the likelihood that drug-
resistant pathogens from distant corners of the world can appear in the
United States. For example, malaria is frequently brought into our
country by U.S. travelers, and is being transmitted domestically at an
increasing rate. Because drug-resistant strains of malaria now
predominate across the globe, they present a growing problem here. This
complexity highlights the importance of a coordinated, overarching
multidisciplinary public health approach that involves physicians,
epidemiologists, laboratory and behavioral scientists, veterinarians,
and health educators. We are all striving to make antimicrobial
resistance a manageable problem that does not compromise the
availability of safe and effective drugs to treat infectious diseases.
Drug resistance is one of the target areas in CDC's plan,
``Preventing Emerging Infectious Diseases: A Strategy for the 21st
Century.'' Public health priorities in the plan are organized under
four broad, interdependent goals, each of which can be applied to
antimicrobial resistance: improving surveillance and response capacity,
addressing applied research priorities, repairing the Nation's public
health infrastructure and training programs, and strengthening
prevention and control programs. Copies of CDC's plan have been
provided to the Subcommittee.
SURVEILLANCE AND RESPONSE
Public health surveillance is the ongoing, systematic collection,
analysis, interpretation, and dissemination of health data that results
in public health action. These data are used to detect outbreaks,
characterize disease transmission patterns, evaluate prevention and
control programs, and project future health care needs. In the case of
drug resistance, surveillance data available in a timely manner at
national, state, and local levels are needed to help clinicians know
which antimicrobials to prescribe, help researchers focus their efforts
to develop new drugs and vaccines, and help mount campaigns to improve
antimicrobial use and infection control practices.
With the exception of drug-resistant tuberculosis, which is
reportable in all 50 states, many states do not require reporting of
other drug-resistant infections. In those states where drug-resistant
infections are reportable, the extent and type of reporting varies. To
obtain more systematic information, CDC, in collaboration with state
and local health departments and other partners, conducts limited
surveillance in some areas to monitor resistance for several important
pathogens. For example, surveillance for resistance among invasive
pneumococcal infections is conducted through the nine state health
departments involved in CDC's Emerging Infections Program cooperative
agreements. Surveillance is also conducted in 300 hospitals for
healthcare-acquired infections, in 15 states in collaboration with the
Food and Drug Administration (FDA) and the Department of Agriculture
for foodborne infections, and in 25 clinics for gonoccocal infections.
Other projects monitor drug resistance in Helicobacter pylori, typhoid
fever, HIV, and malaria, but only in a handful of sites. In many
communities, the rates of drug resistance for common, serious
infections are based on limited and potentially unreliable data or are
simply unknown. Existing systems are not well-coordinated.
For many infections, resistance rates vary widely among communities
and among hospitals within communities. As one example, data show that
the penicillin resistance of Streptococcus pneumoniae can vary
considerably by location: 15 percent of strains in parts of Maryland
are resistant to penicillin, whereas in five Tennessee counties, 38
percent are resistant. In Connecticut the frequency of resistance
varies from zero to 39 percent among hospitals. These data highlight
the need for such information at all levels--local, state, and
federal--in order to guide clinical decisions and target interventions.
None of these surveillance systems is operational in all 50 states,
in all hospitals, or covers all organisms for which antimicrobial
resistance is a problem. Coordinated national antimicrobial resistance
surveillance is needed to monitor antimicrobial resistance in
microorganisms that pose a threat to public health. Core capacities at
state and local levels need to be defined. A system to monitor patterns
of antimicrobial drug use needs to be developed and implemented. This
information is essential to interpret trends and variations in rates of
antimicrobial resistance, improve our understanding of the relationship
between drug use and resistance, and help identify interventions to
prevent and control antimicrobial resistance.
APPLIED RESEARCH
Applied research needs include developing new drugs and vaccines;
identifying molecular mechanisms of drug resistance and risk factors
associated with its development and spread; developing new and improved
rapid diagnostic laboratory tests; and, in collaboration with other
agencies and private industry, assessing the role of new vaccines and
orphan drugs in preventing and controlling the spread of resistant
infections. These and related research needs will require collaboration
with other agencies and private industry.
CDC has entered into a promising research collaboration with a
consortium formed by the University of Mississippi, Tulane University,
and Xavier University in New Orleans to develop and test new
antimalarial drugs. This work builds on the complementary strengths of
the universities. It focuses on the use of computer-assisted drug
design and natural products in the development and testing of promising
new medicines.
We also need to develop, implement, and evaluate preventive
interventions, including infection control strategies, such as those in
hospitals, day care centers, long-term care and home health care
settings; improve drug-prescribing practices of health care providers;
and the use of vaccines to prevent drug-resistant infections. For
example, a new conjugate vaccine for children against Streptococcus
pneumoniae, the leading cause of pneumonia, meningitis, and ear
infections, was licensed for use in February 2000. CDC is evaluating
the impact of introduction of this vaccine on drug-resistant
pneumococcal infections in children. Research is also necessary to
evaluate the impact of drug resistance, including clinical outcomes and
economic costs of treating resistant infections. Without these kinds of
studies, it is extremely difficult to develop and recommend prevention
and control measures to institutions and communities.
INFRASTRUCTURE AND TRAINING
CDC's ongoing effort to rebuild the U.S. public health
infrastructure to address infectious diseases is critical in improving
the capacity of health departments, health care delivery organizations,
and clinical and public health laboratories to detect and report drug-
resistant infections and to implement prevention and control
strategies. Part of this effort includes enhancing capacity to respond
to outbreaks and training public health professionals to be able to
respond to emerging threats now and in the future. Antimicrobial
resistance is a constantly changing challenge requiring that laboratory
testing methods be kept up-to-date. For example, a 1998 survey was
conducted among laboratories that routinely collaborate with CDC. Only
18 percent were actively using appropriate methods to detect emerging
resistance in Staphylococcus aureus, and only 32 percent were using
appropriate methods to find resistance in organisms that typically
cause infections in intensive care units. Thus for two important groups
of hospital- acquired infections, less than one-third of laboratories
were performing proficiently.
We need to ensure that laboratories remain up-to-date with training
and that whenever a doctor sends a specimen for culture to a
laboratory, the correct test will be done to detect drug resistant
infections, the test result will be interpreted correctly and reported
to the doctor in a way that helps to select the appropriate drugs, and,
if appropriate, reported to a surveillance system. CDC's Epidemiology
and Laboratory Capacity agreements to health departments in 43 states
and localities currently help support these types of efforts. In
addition, the Emerging Infectious Diseases Laboratory Fellowship
Program is a partnership between CDC and the Association of Public
Health Laboratories designed to prepare laboratory scientists for
careers in public health.
PREVENTION AND CONTROL
Perhaps the most daunting challenge is to develop a coordinated
program to prevent the spread of antimicrobial resistance by
translating information gleaned from surveillance and research into
practical public health prevention and control measures. We can all
relate to the parent awake at night with a sick child. All that person
wants is for his or her child to feel better. For too long, that has
often meant requesting an antibiotic from the child's doctor. Although
antibiotics work for bacterial infections, we now know that they are
not effective for many conditions for which they have been prescribed
including fluid accumulation in the middle ear, colds, and bronchitis.
CDC has conducted focus groups with parents and physicians to
better understand the factors behind inappropriate antibiotic use. We
learned many things from these conversations. For example, parents told
us they need an antibiotic in order for their children to return to
daycare. This led us to develop a daycare letter that parents can use
to get around this ill-conceived policy. Physicians told us that they
do not typically have enough time to educate a patient about the
problem of antimicrobial resistance and the reasons why antibiotics do
not work for viral infections. This reinforced our belief that we must
move forward on a nationwide public information campaign.
A key component of CDC's plan to address antimicrobial resistance
is promoting appropriate antimicrobial drug use. CDC is developing a
national campaign to improve physician prescribing practices and to
educate parents and patients about the proper use of antibiotics. By
promoting better communication between the public and the medical
community, we are attempting to change the entire culture around which
antibiotics are prescribed. We are working towards a day when a patient
or parent sees his or her health care provider and rather than
requesting an antibiotic, asks for the best treatment available. Where
antibiotic use is appropriate, CDC promotes methods to increase
adherence to and completion of treatment. For instance, CDC uses
directly observed therapy, short-course (DOTS), to ensure patient
compliance with tuberculosis treatment. Use of DOTS has increased the
proportion of patients completing therapy, lowering the incidence of
multidrug-resistant tuberculosis. CDC and FDA have also worked with the
American Veterinary Medical Association in its activities to develop
prudent-use guidelines for therapeutic veterinary uses of
antimicrobials, and CDC strongly supports the new framework articulated
by FDA to consider the impact on human drug resistance as part of the
approval process for antimicrobials used in food animal production.
In cooperation with professional societies, CDC has developed
educational materials for physicians and parents, including a
``prescription pad'' for physicians to provide patients written
instructions for treating symptoms of viral illnesses, for which
antibiotics would be inappropriate. In collaboration with AAP and the
American Society for Microbiology, CDC has also developed a brochure
for parents, ``Your Child and Antibiotics,'' explaining why antibiotics
should not be given for most colds, coughs, sore throats, and runny
noses. These materials have been distributed widely and are available
on the CDC website. Interventions using these materials and behavioral
strategies, such as physician-peer discussions, have proved successful
in several locations, including managed care settings in Boston and
Seattle, rural communities in northern Wisconsin, Alaska Native
villages, and on a county-wide basis in Knoxville, Tennessee.
Preliminary data suggest that these approaches are effective. For
example, in certain rural Alaskan villages, an education intervention
for the public and health care providers successfully reduced
antibiotic prescribing by 31 percent. No change was seen in communities
not receiving the intervention. Although work is ongoing to measure the
impact of reduced antibiotic prescriptions on drug-resistance in the
community, these data hold promise that we do have the ability to make
a difference.
Appropriate drug-use policies should be implemented through a
public health education campaign that promotes appropriate
antimicrobial drug use as a national health priority. Improved
diagnostic practices should be promoted, including the use of rapid
diagnostic methods to guide drug prescribing. Reduced infection
transmission should be addressed through campaigns that promote
vaccination and hygienic practices such as hand washing and safe food
handling. Infection control in health care settings should be enhanced
by developing new interventions based on rapid diagnosis, improved
understanding of the factors that promote cross-infection, and modified
medical devices or procedures that reduce the risk of infection.
Comprehensive, multi-faceted programs involving a wide variety of
non-federal partners and the public are required to prevent and control
antimicrobial resistance. We need to support demonstration projects
that use multiple interventions to prevent and control antimicrobial
resistance. We need to encourage the incorporation of effective
programs into routine practice by implementing model programs in
federal health-care systems and promoting the inclusion of
antimicrobial resistance prevention and control activities as part of
quality assurance and accreditation standards for health care delivery
nationwide.
EXAMPLES OF SUCCESSES IN PREVENTING ANTIMICROBIAL RESISTANCE
Although there has been much discussion of how the problem of
antimicrobial resistance is increasing, it is also important to note
some successes that provide models for future programs. Public health
officials in Iowa, in partnership with physicians and health
departments in Nebraska and South Dakota, the Indian Health Service,
and CDC, recently succeeded in halting an increase in acquisition of
vancomycin-resistant enterococci (VRE) among hospitalized patients and
residents of long-term care facilities in the tri-state Siouxland
region surrounding Sioux City, Iowa.
VRE is a highly resistant organism that is transmitted in health-
care settings. Some patients carry the organism without experiencing
symptoms, but others develop infections that may be life-threatening.
After a rapid increase in VRE was reported in early 1997, a task force
was formed by the Siouxland district health department, consisting of
local physicians, infection control practitioners, and public health
officials.
The VRE task force formulated several interventions, including
performing screening cultures on admitted patients, implementing strict
infection control policies based on CDC guidelines, and educating
health care workers about the epidemiology of VRE and prudent use of
antibiotics, especially vancomycin. This strategy was effective. Over a
two year period, the overall prevalence of VRE at all the healthcare
facilities decreased from 2.5 to 0.5 percent. There was an elimination
of VRE from all the hospitals and a significant reduction in VRE at the
long-term care facilities. The key to success was the partnership
between public health and clinical medicine so that when surveillance
data indicated an emerging problem, science-based prevention and
control measures could be implemented rapidly to prevent the spread of
a serious drug-resistant infection in this community.
Other countries are grappling with problems of drug resistance as
well, and we can learn important lessons from their experiences. In the
early 1990s, Finland noted a dramatic increase in resistance of Group A
streptococci to the antimicrobial drug erythromycin. Use of
erythromycin had tripled and drug-resistance rates correlated with the
level of use in local areas. A program of public and physician
awareness combined with changes in recommendations for prescribing
resulted in reduced erythromycin prescribing for minor outpatient
infections and a steady decrease in erythromycin resistance rates among
Group A streptococci. It was uncertain if this success could be
replicated in a country like the United States with a more
heterogeneous population and health care system, but preliminary
findings from intervention studies sponsored by CDC and others are
encouraging.
Another success relies on modern information technology, which can
facilitate rapid collection, analysis, and feedback of information to
clinicians. A pioneering program of computer-assisted decision support
developed at LDS Hospital in Salt Lake City offers antibiotic
recommendations to clinicians based upon computerized assessment of the
patient's medical record and surveillance data on drug resistance in
the health care system. This program was developed with input from
local physicians, who view it as a valuable resource. The program is
associated with decreased inappropriate antibiotic use, reduced
frequency of adverse drug reactions, reduced patient care costs, and a
stable rate of drug resistance.
COLLABORATION TO ADDRESS ANTIMICROBIAL RESISTANCE
Combating antimicrobial resistance will require federal leadership
and close collaboration among public and private sector partners.
Federal agencies need to work together with partners in clinical
medicine, laboratory and behavioral science, state and local public
health agencies, industry, and the public. International cooperation is
also critical. Together, we need to develop public health goals and
objectives, along with time frames for implementation.
Beginning in June 1999, CDC, FDA, and the National Institutes of
Health joined with seven other federal agencies and departments to form
an Interagency Task Force on Antimicrobial Resistance to develop ``A
Public Health Action Plan to Combat Antimicrobial Resistance.'' In
addition to the three lead agencies, the Task Force includes members
from the Department of Agriculture, the Department of Defense, the
Department of Veterans Affairs, the Environmental Protection Agency,
and other agencies of the Department of Health and Human Services,
including the Agency for Healthcare Research and Quality, the Health
Care Financing Administration, and the Health Resources and Services
Administration. The Action Plan provides a blueprint for specific,
coordinated federal actions to address the emerging threat of
antimicrobial resistance. It reflects a broad-based consensus of
federal agencies, which was reached with input from consultants from
state and local health agencies, universities, professional societies,
pharmaceutical companies, health care delivery organizations,
agricultural producers, consumer groups, and other members of the
public. Implementation of this plan will require close collaboration
with all of these partners, which is a major goal of the process. This
summer, the draft of the Action Plan was provided for public comment.
The Interagency Task Force has recently completed reviewing comments
received through this process and is now modifying the Action Plan for
final publication. This draft plan identifies 11 top priority action
items, and overall it has 87 specific action items addressing the
important areas of surveillance, prevention and control, research and
product development.
The Action Plan includes a summary and a list of issues, goals, and
action items and specifies ``coordinator'' and ``collaborator''
agencies or departments, and timelines for each. CDC's primary role is
in the areas of surveillance and prevention and control, addressing the
needs I have detailed already in this testimony. The Interagency Task
Force will facilitate coordination among agencies and monitor
implementation of the Action Plan. The Task Force plans to produce
periodic reports detailing how the plan is being implemented, solicit
comments from the public, and update the Plan as new information and
issues arise. Copies of this draft plan have been distributed to the
Subcommittee members. This document is Part I of the Action Plan,
focusing on domestic issues. Since resistance transcends national
borders and requires a global approach to its prevention and control,
Part II of the plan, to be developed subsequently, will identify
actions that address international issues.
CONCLUSIONS
In conclusion, recent increases in antimicrobial resistance are
cause for serious concern but not pessimism. The rapid spread of
resistance demands an immediate and aggressive response domestically
and globally. Preliminary data suggest that antibiotic prescribing
practices can be improved. By forming effective partnerships involving
clinicians, researchers, public health officials, and patients, we can
prolong the effectiveness of currently available antimicrobial drugs;
accelerate the development of needed new tools, including rapid
diagnostic tests, new antimicrobial agents, and new or improved
vaccines; and reduce the threat of antimicrobial resistance for
patients today and in future generations.
Thank you very much for your attention. I will be happy to answer
any questions you may have.
STATEMENT OF JANE E. HENNEY, M.D., COMMISSIONER, FOOD
AND DRUG ADMINISTRATION, DEPARTMENT OF
HEALTH AND HUMAN SERVICES
Senator Cochran. Dr. Henney is Director of the Food and
Drug Administration.
We welcome you to the hearing. You may proceed.
Dr. Henney. Mr. Chairman, I am Jane Henney, Commissioner of
Food and Drugs.
I am extremely pleased to be here this morning to talk
about antimicrobial resistance and FDA's important role in
addressing this growing public health problem. I appreciate
your including my full written testimony for the record.
As you and Dr. Koplan have already so clearly articulated,
antibiotic resistance is well-recognized as a major threat to
the health of the U.S. citizens and people around the world.
Although, we have been using antibiotics for more than 50
years, the extent of resistance is much greater than ever
before. FDA's goal is to be sure that practitioners have a
continuous supply of safe and effective antimicrobials
available to protect the health of humans and animals, and
reliable laboratory test products to direct appropriate
antibiotics use.
Antibiotics are different from most other drugs approved by
FDA, because their effectiveness is so fragile. Another unique
characteristic is that these drugs effect not only the patient
who receives them, but also their personal contacts, the
environment, and the health of the community.
We need to protect the effectiveness of this special class
of drug products by using them in a thoughtful way that is
based on the best available science.
As with most issues that involve fragile resources, this
one has global ramifications. In some countries, antibiotics
are available without prescription, and may be impure or sub-
potent and many patients cannot afford adequate courses of
treatment.
With frequent and wide-ranging air travel and extensive
immigration we are able to pass our pathogens to one another
with frightening speed.
That means that in order for us to succeed in our efforts
to use antibiotics wisely, similar steps must be taken by
nations around the world.
In late 1998, an FDA Task Force on Antimicrobial Resistance
was established to develop a clear consensus regarding what,
given limited resources, should be the key priorities of the
agency.
The FDA Task Force Report, completed in draft in October
1999, focuses on four key areas where FDA should and is able to
play an important role in achieving specific and practical
outcomes. And they are: one, effectively responding to current
public health threats; second, facilitating product
development; three, facilitating safe and effective use of
antimicrobials; and, four, coordinating the FDA's scientific
response to antimicrobial resistance.
Details on each of these areas are included in my written
statement, but I would like to focus on two of them--product
development and education.
There will continue to be a critical need for innovative
product development to meet the threat posed by antimicrobial
organisms. Desired products include not only new antibiotics
but also vaccines to prevent infections and reduce antibiotics
use, and improved, more rapid diagnostics to identify pathogens
and drug resistance. At each step of the product development
process, there is room for improvement and innovations.
We have increased our internal efforts to facilitate
development of drugs, vaccines, and medical devices. And these
measures include, one, granting a priority review to
applications for new antibiotics, which ensures that these
applications are acted on in 6 months or less.
Two, working early on with sponsors of critical products
and overall product development, clinical trial design and
other issues that may arise so that the process can be as
effective and efficient as possible.
Three, using different regulatory approaches to provide
more rapid development, early consultation and early access,
the Subpart E designation, and accelerated approval utilizing a
surrogate endpoint, Subpart H, are the tools that are being
considered.
Two of the most recent approvals for products to treat
highly resistant organisms, Synercid and Zyvox, were developed
and reviewed using these approaches. Prior to the approval of
these products, patients who were infected with vancomycin-
resistant enterococci had no other available therapies. Many of
these patients are the most vulnerable and these products are
truly life-saving for these patients.
We are also actively encouraging the development of new
vaccines to help reduce the need for antibiotics. Earlier this
year, FDA approved the first vaccine to prevent invasive
pneumococcal disease in infants and children, Prevnar. Through
the provisions provided in the FDA Modernization Act, Prevnar
was granted fast track designation and assigned priority review
status.
We are also looking at pneumococcal vaccines for the
prevention of otitis media and pneumonia, which are often due
to pneumocci. The potential contribution of these pneumococcal
vaccines in helping to reduce these diseases could further
reduce the use of antimicrobials.
Vaccines are also under development that would indirectly
affect antimicrobial use. For example, ear infections and
respiratory diseases are often treated with antibiotics, but
most often caused by viral infections, such as parainfluenza
and RSV.
Development of vaccines to prevent these viral infections
would also be an important mechanism impacting on unneeded and
non-beneficial antibiotics use.
We also want to facilitate the development of new
diagnostic tests that can rapidly determine and certainly
indicate whether an infection is truly bacterial. The test
would also be expected to identify an appropriate antibiotic
for treatment.
And finally, in our initiatives geared to new product
development, we are committed to developing strategies to
overcome economic disincentives for new antimicrobial product
development and at the same time balance the need for more
restricted appropriate use.
Education is another key component of the FDA's plan.
Physicians tell us, as you have also heard from Dr. Koplan,
that patients often pressure them to prescribe antibiotics.
They may have limited time to explain the rationale for not
using an antibiotic, or for using an alternative treatment.
Some may not have access to rapid diagnostics or to antibiotic
sensitivity testing.
It may be far too tempting to simply prescribe an
antibiotic. Since this is often a shot in the dark, because the
bacteria have not been identified and susceptibility testing
not done, the physician is further tempted to prescribe a new
and powerful blockbuster antibiotic that may have the greatest
chance of working.
Such antibiotics are often not warranted as many community
acquired infections are viral and do not respond to antibiotics
or are caused by bacteria still sensitive to older alternative
drugs.
And once an antibiotic is prescribed a lack of patient
understanding and therefore compliance may also contribute to
resistance. Patients, either by omission or commission, often
do not take the antibiotic according to directions and
frequently fail to take the entire course of antibiotics.
Instead, they stop taking it when they feel better and then
save the rest for the next time or share the leftover drugs
with a sick friend. The result, inadequate treatment courses,
also is a recipe for inducing resistance.
The FDA pledges to work with industry and public health
officials using a variety of means to provide better and more
consistent information to consumers and health professionals
about the judicious use of antibiotics.
We believe it is particularly important to include
additional information in the labeling of prescription
antibiotics. Yesterday, FDA proposed a regulation that will
require statements on prescription antibiotic drug labeling
that discusses the appropriate use of antibiotics and how to
reduce the development of drug-resistant microorganisms.
The proposal is intended to encourage physicians to
prescribe systemic antibacterials more judiciously, and only
when clinically necessary, and to encourage physicians to
counsel their patients about the proper use of such drugs and
the importance of taking them as directed.
The recently approved antimicrobial, Zyvox, reflects some
of this language in its package labeling. We believe that this
type of information on product labeling will influence
prescribing behavior.
The Zyvox labeling is a step in the right direction and we
applaud Pharmacia and Upjohn for working with the agency to
develop this message.
Let me briefly address our efforts in the area of
antimicrobial use in food-producing animals, an area of
controversy that has spanned nearly 30 years. Antibiotics have
for decades played a key role in ensuring the health of food
animals.
Producers have used some of these same products as growth
promoters. Such uses have benefits and contribute to the
general availability of safe food products at reasonable
prices.
At the same time, the potential risks posed by
antimicrobial resistance have become of increasing concern.
Although it is not the focus of this hearing, I have
provided a summary of the agency's activities in the area of
animal drugs and animal health in my written testimony.
I would also note that earlier this week, the Department
and the USDA submitted our joint report to Congress on
antibiotic resistance in livestock. As you know, this report
was requested in fiscal year 2000's appropriations. And the
report explains the strategy and includes a timetable and
budget for tackling the problem of antimicrobial use and the
emergence of antimicrobial resistance.
We recognize at FDA that managing antimicrobial resistance
requires coordinated actions and partnerships with many other
entities, both within and outside the Federal government.
We are pleased to co-chair with CDC and NIH the Interagency
Task Force on Antimicrobial Resistance that has already been
mentioned.
I believe that the plan that has been developed reflects a
very broad-based consensus of these Federal agencies and others
on actions to combat antimicrobial resistance and a very clear
blueprint for our Federal actions.
The draft part I of the action plan really focused on
domestic issues and was published this past June. It proposes
many activities, which FDA will address either as the
coordinator or as a partner with other agencies.
Part II of the plan, which will be developed subsequently
will follow the development of WHO's approach and identify U.S.
agency actions that can more specifically help address
international issues.
Mr. Chairman, I would be remiss if I did not take this
opportunity to thank you for approving the FDA's antimicrobial
resistance increase requested in the fiscal year 2001 Senate
Appropriations bill. Both the Senate and the House bills as
passed include full funding of FDA's request for antimicrobial
resources.
As you know it builds upon 3 years of intense work and
cooperation among several key agencies and several State and
local health agencies.
We believe that your funding of our Food Safety Initiative
has served a key role in establishing a coordinated approach to
food safety and antimicrobial resistance. We expect funding for
antimicrobial resistance to be a continuing priority of ours.
Let me once again underscore that to adequately address
this public health issue, it will take responsible action by
more than just the Federal agencies. It is going to take the
energy and determination on the part of the medical and
veterinary professions, the pharmaceutical and animal health
industries and those who grow and care for food-producing
animals.
PREPARED STATEMENT
Our highest priority should be to ensure that we have safe
and effective antimicrobials to protect human and animal health
today and into the future. We are committed to doing our part
to ensure that this happens.
And I would be happy to answer any of the questions you may
have.
Senator Cochran. Thank you very much, Dr. Henney, for your
interesting and complete informative statement. We appreciate
it very much.
[The statement follows:]
PREPARED STATEMENT OF JANE E. HENNEY
INTRODUCTION
Mr. Chairman and members of the Committee, I am Dr. Jane E. Henney,
Commissioner of Food and Drugs, Food and Drug Administration (FDA or
Agency). I am pleased to be here this morning to talk about issues
related to antimicrobial resistance and FDA's important role in
addressing this growing public health problem. While I understand the
focus of this hearing is human drugs, my testimony also will include
issues related to animal drugs and animal health.
Antibiotic resistance is well recognized as a major threat to the
health of U.S. citizens and people around the world. Although we have
been using antibiotics for more than 50 years, the extent of resistance
is much greater than ever before. Antimicrobial resistance is a natural
biological phenomenon that is the result of the rapid replication and
evolution of microbes. When a microbial population is exposed to an
antibiotic, the more susceptible organisms will succumb, leaving behind
only the resistant organisms. Through this selective process, resistant
organisms become more 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,
sometimes, from unrelated microbes. However, the likelihood of microbes
developing resistance becomes magnified by widespread and often
inappropriate antimicrobial use.
In addressing the antimicrobial resistance problem, FDA's goal is
to be sure that practitioners have a continuous supply of safe and
effective antimicrobials available to protect the health of both humans
and animals, as well as reliable laboratory test products to rapidly
direct appropriate antibiotic use.
Antibiotics are different from most of the other drugs approved by
FDA, because their effectiveness is so fragile. Another unique
characteristic is that these drugs affect not only the patient who
receives them but also their personal contacts, the environment and the
health of the community. We need to protect the effectiveness of this
special class of drug products by using them in a thoughtful way that
is based on the best available science. If these drugs are overused, or
misused, their effectiveness will not be there when patients need them.
We already have some infectious diseases where there are either no or
few satisfactory therapeutic options because of antibiotic resistance.
We should look at our array of antibiotics as a valuable resource
that deserves careful protection. And, as with most issues that involve
fragile resources, this one has global ramifications. With frequent and
wide-ranging air travel and extensive immigration, we are able to pass
our pathogens to one another with frightening speed. That means that in
order for us to succeed in our effort to use antibiotics wisely,
similar steps must be taken by nations around the world. In some
countries, antibiotics are available without prescription and may be
impure or subpotent, and many patients cannot afford adequate courses
of treatment. Not surprisingly, rates of resistance, particularly to
common community acquired and food borne pathogens, are often even
higher than in the United States (U.S.). This causes suffering and
further demands on already overstretched resources abroad and poses
risks to the U.S. through transport of resistant pathogens to our
citizens. An example of this type of trans-national threat has been the
spread of multi-drug resistant tuberculosis.
FDA TASK FORCE ON ANTIMICROBIAL RESISTANCE
As you know, FDA has key roles in helping facilitate the
development of drugs, vaccines, devices and diagnostics as well as
ensuring their safe and effective use. In addition, FDA has an
important role in informing the public and health professionals of
antibiotic resistance and principals of appropriate use through
educational outreach, by assuring useful and accurate product labeling,
and appropriate marketing. Traditionally, FDA has been active in
addressing the resistance problem. However, to further stimulate and
coordinate FDA's actions to combat antimicrobial resistance, in late
1998, an internal ``FDA Task Force on Antimicrobial Resistance'' (Task
Force) was established to develop a clear consensus regarding what,
given limited resources, should be the key priorities of the Agency.
While FDA saw the need to better coordinate and focus antimicrobial
resistance activities within the Agency, it also recognizes that
managing antimicrobial resistance requires coordinated actions and
partnerships with many other entities, both within and outside the
Federal government. FDA is privileged to co-chair with the Centers for
Disease Control and Prevention (CDC) and the National Institutes of
Health (NIH) an Interagency Task Force on Antimicrobial Resistance that
was formed in 1999 to develop a Public Health Action Plan to Combat
Antimicrobial Resistance. The Public Health Action Plan will be briefly
discussed later in my testimony.
The internal FDA Task Force Report, completed in draft in October
1999, focuses on issues and areas where FDA should and is able to play
an important role in achieving specific and practical outcomes.
Recommendations are in four key areas:
1. Promptly and effectively responding to current threats from drug
resistance;
2. Facilitating and encouraging development and appropriate use of
products which help address the issue;
3. Facilitating the safe and effective use and thus prolonging the
life of products by helping improve the quantity and quality of
information available to consumers and health professionals regarding
antibiotics resistance and principles of appropriate usage; and,
4. Maximizing and coordinating FDA's scientific research to address
needs in antimicrobial resistance.
Let me discuss each of these four key areas for addressing the
problem of antimicrobial resistance.
1. Effectively Responding to Current Public Health Threats
Therapeutic options for resistant infections have become
increasingly limited and, therefore, important to protect and preserve
for these critical uses. In particular, there are agents, including
among them both those recently or previously approved and those as yet
unlicensed, which are either the only or among the very few available
treatments for life threatening resistant infections. This concept of
critical ``Category I Drugs'' is also embodied in the proposed Center
for Veterinary Medicine (CVM) Framework. The proposed Framework
document, which I will discuss later, outlines the categorization of
drugs by their importance to human medicine as well as a risk-based
Framework for their use in food animals.
How antibiotics are used could, as it has in the past, be regarded
as primarily an issue of ``medical practice.'' However, it is widely
acknowledged that the rapidity of development of resistance to an agent
is increased with the magnitude of antibiotic use. Thus, use of these
precious drugs of last resort for infections easily treated by other
medicines is highly likely to ultimately compromise their efficacy, and
hence, their safety in treatment of serious infections. FDA plans to
partner with and obtain input from others, including other Federal
agencies, professional groups and the pharmaceutical industry, in order
to assure that important antibiotics are used as wisely as possible.
The development of appropriate public health strategies for
managing antimicrobial resistance will require more than sporadic and
ad hoc data on the occurrence of resistance. A comprehensive system of
antimicrobial resistance surveillance is needed to provide a measure of
the resistance patterns, an early warning system for emerging problems,
and a baseline to target and evaluate prevention control measures. In
addition to establishing baselines and showing trends, early warning of
an emerging problem may alert clinicians to a possible problem and have
an immediate impact on prescribing decisions and outcome for the
patient. There is also a need to improve the understanding of the
relationship between drug use and resistance in order to use drugs
wisely. This need is pressing with regard to both human and food animal
antibiotic use. Again, FDA has important partnerships with CDC and U.S.
Department of Agriculture (USDA) addressing surveillance and we are
committed to continuing these efforts and broadening our efforts as we
consider use issues.
2. Facilitating Product Development
There is and will be a critical need for innovative product
development to meet the threat posed by antimicrobial organisms.
Desired products include not only new antibiotics, but also vaccines to
prevent infections and reduce antibiotic use. We also need improved,
more rapid, diagnostics to identify pathogens and drug resistance. At
each step of the product development process, there is room for
improvement and innovation.
As we address this matter we also need to acknowledge that each new
antimicrobial agent represents a major investment by a pharmaceutical
company, which must shepherd the product through pre-clinical studies
and clinical testing. As is stated in a recent World Health
Organization (WHO) report, few breakthroughs in the discovery of
antimicrobials have been accidental discoveries, stumbled upon by
chance. Instead, they are the result of dedicated scientific effort and
vast amounts of money, time, and human labor. This is also true of the
development of novel new treatments and of vaccines.
FDA and its partners will continue to consult with representatives
of the pharmaceutical industry and other expert parties, such as FDA's
Advisory Committee on Anti-Infective Drugs, on strategies to promote
the development of new antimicrobial drugs, vaccines, and diagnostic
tests. We need to collectively address overcoming economic
disincentives to new antimicrobial product development and renewed
efforts to promote and expect appropriate use of these important
products.
Some examples of what we are doing to facilitate product
development for drugs, vaccines, and medical devices follow.
DRUGS
During July 1998, FDA's Center for Drug Evaluation and Research
(CDER) sponsored a public meeting with industry, academia and other
public health agencies to receive input on the topic of antibiotic
resistance. This meeting was followed in October 1998, by an Advisory
Committee meeting to discuss the issues raised at the July meeting, and
included: ways to help speed product development, including approaches
to improve clinical trials for studying drugs targeted at resistant
organisms; programs that may provide incentives for drug development,
such as Orphan Drug designation; and approaches to promote the
appropriate use of antibiotics.
As I stated previously, to provide therapeutic options for the
treatment of infections due to resistant organisms, critical
antibiotics need to be brought to market as expeditiously as possible.
The Agency is granting these applications a priority review, which
ensures that these applications are acted on in six months or less.
Shortening the development time of these products is also important in
bringing these products to market as soon as possible. In this regard,
the Agency has worked with sponsors of these products though early
discussions on overall product development, clinical trial design, and
other issues that may arise so that the process can be as efficient as
possible and provide the data that would be necessary to determine the
safety and effectiveness of the product. In addition, the use of
regulatory approaches to provide more rapid development, such as early
consultation and early access (Subpart E designation), and accelerated
approval utilizing a surrogate endpoint (Subpart H), has also been
discussed.
Two of the most recent approvals for products to treat highly
resistant organisms--Synercid and Zyvox--were
developed and reviewed using these approaches. Prior to the approval of
these products, patients who were infected with vancomycin-resistant
enterococci had no other available therapies. Many of these patients
are immunocompromised or have serious underlying illness requiring care
in an intensive care unit and are therefore the most vulnerable. These
products are truly ``live saving'' for these patients.
The development of innovative new products to treat infections due
to resistant organisms, especially those for which there are few
treatment options, such as multiple resistant gram negative or gram
positive organisms, is critically important. CDER has taken the
initiative in developing policies regarding the development and the
appropriate use of drugs of last resort. This will include developing
recommendations that focus the development of these products on the
area of need, guidance on the design of clinical trials for these
products, the application of regulatory approaches, such as accelerated
approval, and the development of policies that will promote the
appropriate use of these products. There are a number of issues that
will require further refinement and resolution. At present, antibiotics
are usually developed for a number of indications (diseases) caused by
a variety of organisms, including organisms resistant to other
antibiotics. This provides a potentially large market for the sponsor
to recoup their research and development costs. This is not a good
approach if one wishes to preserve antibiotics that treat resistant
organisms. However, the numbers of patients infected with resistant
organisms may be sufficiently limited to discourage drug development
only for this population. Strategies to overcome these potential
economic disincentives to development and to appropriate use will also
be considered. The application of existing programs, such as Orphan
Drug designation, has been discussed as one potential approach at
public meetings in July and October, 1998.
VACCINES
The Agency also is encouraging the development of new vaccines to
help reduce the need for antibiotics and, thus, slow the spread of
resistance. Pointing to the global importance of vaccines, the WHO
refers to prevention through vaccination as the ultimate weapon against
infection and drug resistance.
An important vaccine for the prevention of meningitis (a severe
infection of the lining of the brain or spinal cord) occurred earlier
in the decade. Before the approval of the first Haemophilus influenzae
type b (Hib) vaccine in 1990 for infants, Hib was the leading cause of
bacterial meningitis and was becoming increasingly antibiotic
resistant. Today, invasive Hib infection has been virtually eliminated
from the U.S. by effective vaccines, reducing not only harm to children
but also antibiotic use.
Earlier this year, FDA approved the first vaccine to prevent
invasive pneumococcal diseases in infants and children, Prevnar. This
vaccine prevents invasive diseases caused by the organism Streptococcus
pneumoniae, including bacteremia (an infection of the bloodstream) and
meningitis, a severe infection of the lining of the brain or spinal
cord. Streptococcus pneumoniae remains as one of the leading causes of
bacterial meningitis, and we are hopeful that vaccines like Prevnar
will greatly reduce this threat.
This new vaccine is great news for parents and their children
because now, we have a highly effective way to prevent pneumococcal
infection, now the major cause of meningitis and serious blood
infections in the most susceptible children--those under two years of
age.
In addition, pneumococcal vaccines are being studied for the
prevention of otitis media and pneumonia, which are often due to
pneumocci. The potential contribution of pneumococcal vaccines in
helping to reduce these diseases could further reduce the use of
antimicrobials. Numerous other promising vaccine candidates to protect
against organisms for which antimicrobials are typically administered
are in various stages of clinical development.
In addition to vaccines that directly impact on pathogens with
recognized high rates of resistance, vaccines are also under
development that would indirectly affect antimicrobial use. For
example, ear infections and respiratory diseases are often treated with
antibiotics, but most are caused by viral infections, such as
parainfluenza and respiratory syncytial virus . Therefore, development
of vaccines to prevent these viral infections would also be an
important mechanism impacting on unneeded and nonbeneficial antibiotic
use.
FDA's Center for Biologics Evaluation and Research (CBER)
recognizes the importance of expediting clinical development of these
products and their public health benefit. CBER has worked with
academia, manufacturers, and other government agencies to address the
development of new vaccines and therapies as alternative approaches to
reduce antimicrobial use. For example, CBER has participated in several
workshops addressing key issues related to the development of
combination vaccines against multiple childhood diseases. In addition,
CBER has expedited the clinical development and approval of these
products. For example, through the provisions provided by FDAMA,
Prevnar was granted fast track designation and assigned priority review
status.
DEVICES
Another product line that we want to facilitate that will have a
significant impact on the appropriate use of antimicrobials is the
development of new diagnostic tests that can rapidly determine and
certainly indicate whether an infection is bacterial. The test would
also then be expected to identify an appropriate antibiotic for
treatment. Diagnostic tests that are reliable and whose results are
more quickly available have great potential for reducing prescription
of antibiotics when they are not necessary and over prescribing a more
powerful antibiotic than is clinically necessary. Conversely, rapid
identification of resistant infections can lead to earlier use of
effective treatments and better outcomes for patients. FDA's Center for
Devices and Radiological Health (CDRH) reviews these types of products
premarket, assuring that expected performance is reliable for use in
patient management and gathering data for surveillance.
3. Facilitating Safe and Effective Use of Antimicrobials
As I stated, antimicrobial resistance is an inevitable consequence
of the selective pressure of widespread and often inappropriate
antimicrobial use. We all--physicians, patients, pharmaceutical
companies, public health professionals, and government agencies--must
concede the fact that individually and collectively we are a part of
the problem, and acknowledge that it will take all of our efforts to
arrive at the solution.
The medical profession plays an important role in this issue.
Physicians tell us that patients often pressure them to prescribe
antibiotics. They may have limited time to explain the rationale for
not using an antibiotic, or for using an alternative treatment. They
may not have access to rapid diagnostic tests or to antibiotic
sensitivity testing. In addition, there may be financial disincentives
to perform these tests. It can be far too tempting to simply prescribe
an antibiotic. Since this is often a shot in the dark, because the
bacteria have not been identified and susceptibility testing not done,
the physician is further tempted to prescribe the latest powerful
blockbuster antibiotic. Such antibiotics are often not warranted, as
many community acquired infections are viral and do not respond to
antibiotics or are caused by bacteria still sensitive to older
alternative drugs. A colleague of mine told an interesting story. She
was waiting in line at the pharmacy in a hospital in the Washington
area. This was just outside the outpatient surgery area. She was the
fifth person in line. Now this was shortly after a particular
fluoroquinolone was approved. I will not mention the name of the
product. The point is that, believe it or not, every single person in
the line in front of her was given this new fluoroquinolone. And so was
she. It was the blockbuster antibiotic of the day. One might conclude
that it was being pushed a little too hard and perhaps used when it was
not necessary.
Once an antibiotic is prescribed a lack of patient understanding
and, therefore, compliance may also contribute to resistance. Patients,
either by omission or commission, often do not take the antibiotic
according to directions, and frequently fail to take the entire course
of antibiotics. Instead, they stop taking it when they feel better, and
then save the rest for the next time or share the leftover drug with a
sick friend. The result, inadequate treatment courses, also is a recipe
for inducing resistance.
It is not easy to accurately establish the extent of overuse or
inappropriate use of antibiotics by the medical profession or patients,
but several studies have given estimates that present a picture of
substantial overuse of these products. Office-based physicians in the
U.S. write more than 100 million antibiotic prescriptions each year.
According to CDC, perhaps as many as half of those prescriptions--a
total of 50 million--may be unnecessary. They are prescribed for
patients who have the common cold and other viral infections, including
influenza. I would like to recognize here the encouraging report last
week from CDC that showed that the rate of prescriptions written for
children with respiratory illnesses declined between 1989-1990 and
1997-1998. Hopefully, this study is an indication that antibiotics are
being used more wisely.
A third component that contributes to antibiotic resistance is the
marketing practices of pharmaceutical companies. The messages conveyed
are naturally geared to persuading health professionals to buy and use
their products. With well over 80,000 detail people and active direct
to consumer advertising campaigns, there are effective means to get any
marketing message out. An article in USA Today commented that,
``Physicians must be honest with themselves and with their patients.
Decisions on which prescriptions to write must be made in accordance
with the best scientific evidence, not on the best marketing
campaign.''
However, we have also been remiss at the Federal, State, and Local
levels in not aggressively getting out the message about the importance
of appropriate antibiotic use and the need to protect these resources.
We need to educate physicians and the public about the resistance
problem and encourage more judicious use of antimicrobial drugs. We
pledge to do our share with both industry and other public health
officials, to provide better and more consistent information to
consumers and health care professionals. We believe it is particularly
important to include additional information in the labeling of
prescription antibiotics.
Yesterday, FDA proposed a regulation that will require statements
on prescription antibiotic drug labeling that discuss the appropriate
use of antibiotics and how to reduce the development of drug-resistant
microorganisms. The proposal is intended to encourage physicians to
prescribe systemic antibacterials more judiciously and only when
clinically necessary. The proposal also is intended to encourage
physicians to counsel their patients about the proper use of such drugs
and the importance of taking them as directed.
Specifically, the proposed rule would require that:
--``. . . at the beginning of the label, under the product name, the
labeling must state that inappropriate use may increase the
prevalence of drug resistant microorganisms and may decrease
the effectiveness of the drug product and related antimicrobial
agents, and that the drug product should be used only to treat
infections that are proven or strongly suspected to be caused
by susceptible microorganisms;
--``the `Clinical Pharmacology' section state that appropriate use of
the drug product includes, where applicable, identification of
the causative microorganism and determination of its
susceptibility profile;
--``the `Indications and Usage' section state that local epidemiology
and susceptibility patterns of the listed microorganisms should
direct initial selection of the drug product for the treatment
of the listed indications and that because of changing
susceptibility patterns, definitive therapy should be guided by
the results of susceptibility testing of the isolated
pathogens;
--``the `Precautions' subsection entitled `General' state that
inappropriate use may increase the prevalence of drug resistant
microorganisms and may decrease the future effectiveness of the
drug product and related antimicrobial agents. This subsection
would also include a statement that the drug product should
only be used to treat infections that are proven or strongly
suspected to be caused by susceptible microorganisms; and,
--``the `Precautions' subsection entitled `Information for Patients'
state that patients should be counseled that the drug product
should be used only to treat bacterial infections and that it
does not treat viral infections. The subsection would also
advise physicians to counsel patients that the medication
should be taken exactly as directed.''
The recently approved antimicrobial, Zyvox (linezolid),
has some of this language in its package labeling. Under Indications
and Usage, the labeling states, ``Due to concerns about inappropriate
use of antibiotics leading to an increase in resistant organisms,
prescribers should carefully consider alternatives before initiating
treatment with Zyvox in the outpatient setting.''
It goes on to say, ``Appropriate specimens for bacteriological
examination should be obtained in order to isolate and identify the
causative organisms and to determine their susceptibility to linezolid
[Zyvox]. Therapy may be instituted empirically while awaiting
the results of these tests. Once these results become available,
antimicrobial therapy should be adjusted accordingly.'' The Agency also
has issued a request to the sponsor of another drug of last resort
asking that they include a statement in the package insert regarding
the appropriate use of their product. Discussions with the firm are
ongoing.
We believe that having more of this type of information on product
labeling will influence prescribing behavior, and that the
Zyvox labeling is a step in the right direction and we
applaud Pharmacia and Upjohn for working with the Agency to develop
this message.
4. Coordinating FDA's Scientific Response to Antimicrobial Resistance
Lastly, research is an important FDA activity in supporting and
filling gaps in the science base of the Agency. Basic and applied
research provide the foundation for combating the problem of
antimicrobial resistance. Research is essential to support the
development of new antimicrobial drugs, vaccines, and diagnostic tests
and the development of innovative uses of products. Research also plays
an essential role in supporting the science base for regulatory
structures and decisions.
Although NIH is the lead government agency focusing on research
associated with antimicrobial resistance, FDA research supports
strategic goals, such as the development of knowledge bases, and
method, agent, or concept driven research. FDA has important scientific
resources invested in antimicrobial research and related areas and FDA
scientists have made important contributions to the field. The spectrum
of such research ranges from the basic, such as mechanisms of
resistance induction and transfer related to food animal use of
antimicrobials, to the applied, such as improved detection of resistant
pathogens in regulated food products.
CVM'S FRAMEWORK DOCUMENT
Let me next briefly address our effort in the area of antimicrobial
use in food-producing animals--an area of controversy that has spanned
the past 30 years. Antibiotics have, for decades, played a key role in
ensuring the health of food animals. And, as you know, producers have
used some of these same products as growth promoters. Such uses
contribute to the general availability of safe food products at
reasonable prices. At the same time, the potential risks posed by
antimicrobial resistance have become of increasing concern.
In response, FDA developed in 1999 a discussion document entitled
``A Proposed Framework for Evaluating and Assuring the Human Safety of
the Microbial Effects of Antimicrobial New Animal Drugs Intended for
Use in Food-Producing Animals.''
The proposed Framework describes the Agency's best thinking on how
to evaluate the microbial safety of antimicrobials for use in food
animals. The concepts described in the Framework could be used to
assess not only new antibiotics, but also previously approved
antibiotics. The Agency will take appropriate procedural steps to
develop and implement any policies resulting from the concepts.
We believe that the proposed Framework presents a sound science and
risk-based approach to the antimicrobial resistance issue, and
consistent with guidance issued in December 1999, we are asking
companies to assess the microbial safety of all new antimicrobials to
be used in food animals.
Depending on the results of this assessment, the drug sponsor may
need to conduct pre-approval studies to assess the rate and extent of
resistance development in pathogens or commensals of human health
concern. We will be issuing a guidance document in the near future to
more specifically outline how such studies can be conducted. In
addition, we will hold a scientific workshop in January 2001, to
outline our approach and seek public input on the establishment of
resistance and monitoring thresholds. I would also like to note that
the veterinary medical profession and specialty practice organizations
of veterinary practitioners are developing judicious use guidelines as
well.
As the mechanism for regulating these drugs, the proposed Framework
discusses three categories of antimicrobial drugs. The categories would
be based on the drug's unique or relative importance to human medicine.
The chain of events that leads to the transfer of antimicrobial
resistance from animals to humans is complex. It includes the ability
of the drug to induce resistance in bacteria, and the likelihood that
use of the drug in food-producing animals will promote resistance. It
also includes the likelihood that any resistant bacteria in or on the
animal will then be transferred to humans. The final link in this chain
of events is the likelihood that such transfer will result in loss of
efficacy of human antimicrobial therapies.
The proposed Framework also includes a characterization of the
likelihood of human exposure to resistant, foodborne pathogens as HIGH,
MEDIUM or LOW. To do this, the drug's attributes--for example, its
mechanism and rate of resistance induction, and its induction of cross-
resistance to other related or unrelated drugs--would be considered.
The proposed Framework also includes an evaluation of how the product
is used, and other relevant factors such as animal and manure
management practices, environmental contamination, and food processing.
The extent of data required before and after approval of a new
antimicrobial drug would depend upon a consideration of the drugs
importance to human medicine, the potential for human exposure, and
other factors as they may be deemed relevant.
The need for FDA to have additional and more detailed animal drug
distribution information is also discussed in the proposed Framework.
This information would be most useful if it could be reported by state,
species, dosage form, season of use, and an estimate of the
antimicrobial activity units sold. Implementation of the concepts
articulated in the Framework document would be presented to the public
through guidance or notice and comment rulemaking, as appropriate.
NATIONAL ANTIMICROBIAL RESISTANCE MONITORING SYSTEM:
ENTERIC BACTERIA
To make this Framework operational we will depend upon an effective
resistance surveillance system and scientifically sound risk
assessments. We can now obtain valuable resistance data through the
National Antimicrobial Resistance Monitoring System: Enteric Bacteria
(NARMS). FDA proposed NARMS in 1995 in response to growing concern
about the emergence of untreatable antimicrobial resistance. NARMS was
developed in 1996 as a collaborative surveillance effort by FDA's CVM,
CDC, and the USDA. This system allows us to prospectively monitor
changes in the antimicrobial susceptibility of selected zoonotic,
enteric pathogens and commensals.
Currently, NARMS monitors the susceptibility of Salmonella and E.
coli to 17 antimicrobial drugs, including ciprofloxacin, ceftriaxone,
ceftiofur, tetracycline, and others. NARMS also monitors susceptibility
of Campylobacter isolates to eight antimicrobial drugs-among them--
azithromycin, ciprofloxacin, clindamycin, erythromycin, and
tetracyline.
Seventeen State and Local Health departments submit human clinical
isolates of non-typhoid Salmonella and E. coli. Eight State health
departments submit human clinical Campylobacter isolates. And four
States submit Campylobacter isolates from retail poultry. In 1998,
NARMS was expanded to include sentinal sites at veterinary diagnostic
laboratories.
USDA conducts animal isolate testing which is done at their
Agricultural Research Service Russell Research Center. And CDC conducts
testing on human isolates at their National Center for Infectious
Diseases Foodborne Disease Laboratory.
NARMS is proving to be a valuable source of resistance data, and is
helping us characterize the scope of the resistance issue, and monitor
changes. NARMS serves as a model surveillance system for other nations
establishing their own surveillance systems.
RISK ASSESSMENT
Last December, FDA released a draft quantitative risk assessment
that modeled the human health impact of fluoroquinolone-resistant
Campylobacter infections associated with the consumption of chicken. We
used data from NARMS, CDC's case control studies, FoodNet, and other
sources, for the risk assessment. We'll finalize the results of the
risk assessment by early this fall, but the preliminary results did
indicate that there is an impact on human health from fluoroquinolone-
resistant Campylobacter associated with chicken consumption.
And we have initiated a second risk assessment. We are currently
conducting a feasibility study to determine whether sufficient data can
be obtained to complete a quantitative risk assessment. This one will
assess the plausibility of a link between the use of virginiamycin in
animals and quinupristin/dalfopristin resistance in humans as well as
the human health impact attributable to use of virginiamycin in food-
producing animals. This risk assessment will also evaluate risk
management options to address the human health impact if it is deemed
unacceptable. Ultimately, we want to ensure that significant human
antimicrobial therapies are not compromised or lost due to
antimicrobial use in animals. At the same time, we want to provide for
the use of safe and effective antimicrobials in food animals.
The other major issue related to the use of antimicrobials in food-
producing animals is their use for growth promotion in livestock. The
Framework approach could also be applied to these products and we will
focus our efforts on evaluating those uses that pose the greatest risk
to public health. As in all of our decision-making, the best available
science will be used to ground and guide our actions.
Antimicrobial Resistance and the Budget
Mr. Chairman, I would be remiss if I did not take this opportunity
to thank you for approving FDA's antimicrobial resistance increase
request in the fiscal year 2001 Senate Appropriations bill. Both the
Senate and the House bills as passed include full funding of FDA's
request for antimicrobial resources. The fiscal year 2001 request
builds upon three years of intense work and cooperation among several
key agencies, FDA, CDC, NIH, USDA and several State and Local Health
agencies. FDA believes Congressional funding of the Food Safety
Initiative has served a key role in establishing a coordinated approach
to food safety and antimicrobial resistance. We expect funding for
antimicrobial resistance to be a continuing priority.
INTERAGENCY TASK FORCE ON ANTIMICROBIAL RESISTANCE
As I mentioned above, FDA recognizes that managing antimicrobial
resistance requires coordinated actions and partnerships with many
other entities, both within and outside the Federal government. FDA co-
chairs with CDC and NIH an Interagency Task Force on Antimicrobial
Resistance that was formed in 1999 to develop a Public Health Action
Plan to Combat Antimicrobial Resistance.
The Public Health Action Plan reflects a broad-based consensus of
Federal agencies on actions to combat antimicrobial resistance and
provides a blueprint for specific, coordinated Federal actions. A draft
Part I of the Action Plan focusing on domestic issues was published in
late June of this year. Part I includes many proposed activities which
FDA will address either as a coordinator or as a partner with other
agencies, including priority items to foster product development, to
educate professionals and the public, and to develop and implement the
concepts outlined in the CVM Framework. Part II of the plan, to be
developed subsequently, will follow development of WHO's approach and
identify U.S. agency actions that can more specifically help address
international issues. Development and implementation of the Public
Health Action Plan also has included and will continue to include the
participation and efforts of the Agency for Healthcare Research and
Quality, USDA, the Department of Defense, the Department of Veteran
Affairs, the Environmental Protection Agency, the Health Care Financing
Administration, and the Health Resources and Services Administration.
These partners are critical given the complex nature of resistance and
the need to address the issue in an inclusive and coordinated manner,
with consideration of such diverse areas as health care systems, the
environment, and agriculture.
CONCLUSION
Let me once again underscore that to adequately address this public
health issue, it will take responsible action by more than just Federal
agencies. It is going to take energy and determination on the part of
the medical and veterinary professions, the pharmaceutical and animal
health industries, and those who grow and care for food-producing
animals.
Our highest priority should be to ensure that we have safe and
effective antimicrobials to protect human and animal health today and
in the future. FDA is committed to doing our part to ensure that this
happens. We feel that the internal FDA Task Force Plan and the
Interagency Public Health Action Plan are important blueprints to move
us forward in a coordinated and effective way.
I would be happy to answer any questions you may have.
______
PREPARED STATEMENT OF THE NATIONAL INSTITUTES OF HEALTH
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 (http://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:
http://www.niaid.nih.gov/; specific microbiology and infectious
diseases information link: http://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:
1. 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.
2. 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.
______
A PUBLIC HEALTH ACTION PLAN TO COMBAT ANTIMICROBIAL RESISTANCE
[June 2000 Draft]
EXECUTIVE SUMMARY
This Public Health Action Plan to Combat Antimicrobial Resistance
(Action Plan) was developed by an interagency Task Force on
Antimicrobial Resistance that was created in 1999. The Task Force is
co-chaired by the Centers for Disease Control and Prevention, the Food
and Drug Administration, and the National Institutes of Health, and
also includes 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 Health Care
Financing Administration, and the Health Resources and Services
Administration.
The Action Plan reflects a broad-based consensus of federal
agencies on actions needed to address antimicrobial resistance (AR),
which was reached based on input from consultants from state and local
health agencies, universities, professional societies, pharmaceutical
companies, health care delivery organizations, agricultural producers,
consumer groups, and other members of the public. While some actions
are already underway, complete implementation of this plan will require
close collaboration with all of these partners, a major goal of the
process. The plan will be implemented incrementally, dependent on the
availability of resources.
The Action Plan provides a blueprint for specific, coordinated
federal actions to address the emerging threat of antimicrobial
resistance. This document is Part I of the Action Plan, focusing on
domestic issues. Since AR transcends national borders and requires a
global approach to its prevention and control, Part II of the plan, to
be developed subsequently, will identify actions that more specifically
address international issues. The Action Plan, Part I (Domestic
Issues), includes four focus areas: Surveillance, Prevention and
Control, Research, and Product Development. A summary of the Priority
Goals and Action Items in each Focus Area follows below. A complete
list is found in pages 12-38.
Surveillance
Unless AR problems are detected as they emerge--and actions are
taken quickly to contain them--the world may soon be faced with
previously treatable diseases which have again become untreatable, as
in the pre-antibiotic era. Priority Goals and Action Items in this
focus area address ways to:
--Develop and implement a coordinated national plan for AR
surveillance
--Ensure the availability of reliable drug susceptibility data for
surveillance
--Monitor patterns of antimicrobial drug use
--Monitor AR in agricultural settings to protect the public's health
by ensuring a safe food supply as well as animal and plant
health
A coordinated national AR surveillance plan for monitoring AR in
microorganisms that pose a threat to public health will be developed
and implemented. The plan will specify activities to be conducted at
national, state, and local levels, define the roles of participants,
promote the use of standardized methods, and provide for timely
dissemination of data to interested parties, e.g., public health
officials, clinicians, and researchers. Needed core capacities at state
and local levels will be defined and supported. When possible, the plan
will coordinate, integrate, and build upon existing disease
surveillance infrastructure. All surveillance activities will be
conducted with respect for patient and institutional confidentiality.
The availability of reliable drug susceptibility data is essential
for AR surveillance. The accuracy of AR detection and reporting will be
improved through training and proficiency testing programs for
diagnostic laboratories and by promoting and further refining
standardized methods for detecting drug resistance in important
pathogens, including bacteria, parasites, fungi, and viruses. Public
and private sector partners will address barriers to AR testing and
reporting, e.g., barriers due to changes in healthcare delivery.
A plan to monitor patterns of antimicrobial drug use will be
developed and implemented as an important component of the national AR
surveillance plan. This information is essential to interpret trends
and variations in rates of AR, improve our understanding of the
relationship between drug use and resistance, and help identify
interventions to prevent and control AR.
Improved surveillance for AR in agricultural settings will allow
early detection of resistance trends in pathogens that pose a risk to
animal and plant health, as well as in bacteria that enter the food
supply. Agricultural surveillance data will also help improve
understanding of the relationship between antimicrobial drug and
pesticide use and the emergence of drug resistance.
Prevention and Control
The prevention and control of drug-resistant infections requires
measures to promote the prudent use of antimicrobial drugs and prevent
the transmission of infections (whether drug-resistant or not).
Priority Goals and Action Items in this focus area address ways to:
--Extend the useful life of antimicrobial drugs through prudent use
policies that discourage overuse and misuse
--Improve diagnostic testing practices
--Prevent infection transmission through improved infection control
methods and use of vaccines
--Prevent and control emerging AR problems in agriculture
--Ensure that comprehensive programs to prevent and control AR
involve a wide variety of non-federal partners and the public
and become a part of routine practice nationwide
Prudent drug-use policies will be implemented through a public
health education campaign that promotes prudent antimicrobial drug use
as a national health priority. Other actions in support of prudent drug
use will include reducing inappropriate prescribing through development
of guidelines, computer-assisted decision support, consideration of
regulatory changes, and other interventions that promote education and
behavior change among clinicians, and informing consumers about the
uses and limitations of antimicrobial drugs.
Improved diagnostic practices will be promoted, including the use
of rapid diagnostic methods to guide drug prescribing, the appropriate
use of clinical laboratories, and appropriate testing methods by those
laboratories. Improved diagnostic practices will be promoted through
guidelines, training, and regulatory and reimbursement policies.
Reduced infection transmission will be addressed through public
health campaigns that promote vaccination and hygienic practices such
as hand hygiene and safe food handling. Infection control in health
care settings will be enhanced by developing new interventions based on
rapid diagnosis, improved understanding of the factors that promote
cross-infection, and modified medical devices or procedures that reduce
the risk of infection.
The prevention and control of AR in agriculture requires (1)
improved understanding of the risks and benefits of antimicrobial use
and ways to prevent the emergence and spread of resistance; (2)
development and implementation of principles for prudent antimicrobial
drug use in the production of food animals and plants; (3) improved
animal husbandry and food-production practices to reduce the spread of
infection; and (4) a regulatory framework to address to need for
antimicrobial drug use in agriculture while ensuring that such use does
not pose a risk to human health.
Comprehensive, multi-faceted programs involving a wide variety of
non-federal partners and the public are required to prevent and control
AR. The AR Task Force agencies will ensure ongoing input and review and
collaboration with non-federal partners. The appropriate agencies will
support demonstration projects that use multiple interventions to
prevent and control AR (e.g., through surveillance, judicious drug use,
optimized diagnostic testing, immunization practice, and infection
control). The Task Force agencies will encourage the incorporation of
effective programs into routine practice by implementing model programs
in federal health-care systems and promoting the inclusion of AR
prevention and control activities as part of quality assurance and
accreditation standards for health care delivery nationwide.
Research
Understanding of the fundamental processes involved in
antimicrobial resistance within microbes and the resulting impact on
humans, animals, and the environment forms an important basis for
influencing and changing these very processes and outcomes. Basic and
clinical research provides the fundamental knowledge necessary to
develop appropriate responses to antimicrobial resistance emerging and
spreading in hospitals, communities, farms, and the food supply.
Priority Goals and Action Items in this focus area address ways to:
--Increase understanding of microbial physiology, ecology, genetics
and mechanisms of resistance
--Augment the existing research infrastructure to support a critical
mass of researchers in AR and related fields
--Translate research findings into clinically useful products, such
as novel approaches to detecting, preventing, and treating
antimicrobial resistant infections
Needs in the field of AR research will be identified and addressed
through a government-wide external program review. Additional research
is needed, for example, on the epidemiology of resistance genes; on
mechanisms of AR emergence, acquisition, spread, and persistence; and
on the effects of antibiotics used as agricultural growth promotants on
microbes that live in animals, humans, plants, soil and water. Further
study is also required to determine whether variations in drug use
regimens may stimulate or reduce AR emergence and spread. Improved
understanding of the causes of AR emergence will lead to the
development of tools for reducing microbial resistance, as well as for
predicting where AR problems are likely to arise.
A comprehensive research infrastructure will help ensure a critical
mass of AR researchers who will interact, exchange information, and
stimulate new discoveries. This will be achieved through the
appropriate mechanisms and scientific conferences that promote research
on AR. The AR Task Force agencies will work with the academic and
industrial research communities to attract AR researchers, prioritize
needs, identify key opportunities, and optimize the utilization of
resources to address AR problems.
The translation of research findings into innovative clinical
products to treat, prevent, or diagnose drug-resistant infections is an
area in which the government can play an important role, focusing on
gaps not filled by the pharmaceutical industry or by other non-
governmental groups. Special efforts will be placed on the
identification, development and testing of rapid, inexpensive, point-
of-care diagnostic methods to facilitate judicious use of
antimicrobials. The AR Task Force agencies will also encourage basic
research and clinical testing of diagnostic methods, novel treatment
approaches, new vaccines and other prevention approaches for resistant
infections.
Product Development
As antimicrobial drugs lose their effectiveness, new products must
be developed to prevent, rapidly diagnose, and treat infections. The
Priority Goals and Action Items in this focus area address ways to:
--Ensure that researchers and drug manufacturers are informed of
current and projected gaps in the arsenal of antimicrobial
drugs, vaccines, and diagnostics, and of potential markets for
these products (designated here as ``AR products'')
--Stimulate the development of priority AR products for which market
incentives are inadequate, while fostering their appropriate
use
--Optimize the development and use of veterinary drugs and related
agricultural products that reduce the transfer of resistance to
pathogens that can infect humans
Current and projected gaps in the arsenal of AR products and
potential markets for these products will be reported to researchers
and drug manufacturers through an interagency working group convened to
identify and publicize priority public health needs.
The development of urgently needed AR products will be stimulated
from drug discovery through licensing. The regulatory process for AR
products will continue to be streamlined, and incentives that promote
the production and appropriate use of priority AR products will be
evaluated in pilot programs that monitor costs and assess the return on
the public investment.
The production of veterinary AR products that reduce the risk of
development and transfer of resistance to drugs used in human clinical
medicine will be expedited through a streamlined regulatory and
approval process. As with drugs for the treatment of human infections,
pilot programs will be initiated to evaluate incentives to encourage
the development and appropriate use of priority products that meet
critical animal and plant health needs.
Private and public partners will also evaluate ways to improve or
reduce the agricultural use of particular antimicrobial drugs, as well
as ways to prevent infection, such as the use of veterinary vaccines,
changes in animal husbandry, and the use of competitive exclusion
products (i.e., treatments that affect the intestinal flora of food
animals).
top priority action items to combat antimicrobial resistance
(All 11 items have top priority, regardless of their order in the list)
Surveillance
With partners, design and implement a national AR surveillance plan
that defines national, regional, state, and local surveillance
activities; the roles of clinical, reference, public health, and
veterinary laboratories; and is consistent with local and national
surveillance methodology and infrastructure that currently exist or are
being developed. (Action Item #2)
Develop and implement procedures for monitoring patterns of
antimicrobial drug use in human medicine, in agriculture, and in
consumer products. (Action Item #5)
Prevention and Control
Develop and implement a public health education campaign to promote
judicious antimicrobial use as a national health priority. (Action Item
#27)
In collaboration with professional societies and other
stakeholders, develop, disseminate, and evaluate clinical guidelines
that address judicious antimicrobial use. (Action Item #29)
In consultation with stakeholders, refine and implement the
proposed FDA framework for approving new antimicrobial drugs for use in
food-animal production and, when appropriate, for re-evaluating
currently approved veterinary antimicrobial drugs. (Action Item #61)
Support demonstration projects to evaluate comprehensive strategies
that use multiple interventions to promote judicious drug use and
reduce infection rates, in order to assess how interventions found
effective in research studies can be applied effectively on a routine
basis and on a large scale and how this application can be done most
cost-effectively. (Action Item #66)
Research
Provide to the research community genomics and other powerful
technologies to identify targets in critical areas for the development
of new rapid diagnostics methodologies, novel therapeutics, and
interventions to prevent the emergence and spread of resistant
pathogens. (Action Item #73)
Develop a human clinical trials network, involving medical research
and health-care institutions, to coordinate and conduct clinical trials
addressing AR issues that are difficult to resolve in industry-
sponsored studies (e.g., novel therapies, new treatment regimens, and
other products and practices). (Action Item #78)
Identify, develop, test, and evaluate the impact of new rapid
diagnostic methods (e.g., tests for resistance genes including
nonculture specimens, point of care diagnostics for patients with
respiratory infections and syndromes, and diagnostics for drug
resistance in microbial pathogens). (Action Item #79)
Product Development
Create an Interagency AR Product Development Working Group to
identify and publicize priority public health needs for new AR products
(e.g., innovative drugs, targeted spectrum antibiotics, point-of-care
diagnostics, vaccines, anti-infective medical devices, and biologics).
(Action Item #82)
In consultation with stakeholders, economic consultants, and the AR
Product Development Working Group, identify ways (e.g. financial and/or
other incentives or investments) to promote the development and/or
judicious use of priority AR products for which market incentives are
inadequate. (Action Item #83)
INTRODUCTION AND OVERVIEW
Background
In the 1940s, the widespread availability of penicillin and the
subsequent discovery of streptomycin led to a dramatic reduction in
illness and death from infectious diseases. However, bacteria and other
disease-causing organisms--viruses, fungi, and parasites--have a
remarkable ability to mutate and acquire resistant genes from other
organisms and thereby develop resistance to antimicrobial drugs. When
an antimicrobial drug is used, the selective pressure exerted by the
drug favors the growth of organisms with mutations that allow them to
resist the drug's action. The extensive use of antimicrobial drugs has
resulted in the emergence of drug resistance that threatens to reverse
the miracles of the last half century.
Drug-resistant pathogens are a growing menace to all people,
regardless of age, gender, or socioeconomic background. They endanger
people in affluent, industrial societies like the United States, as
well as in less developed nations. Examples of clinically important
microbes that are rapidly developing resistance to available
antimicrobials include bacteria that cause pneumonia, ear infections,
and meningitis (e.g., Streptococcus pneumoniae [1]), skin, bone, lung,
and bloodstream infections (e.g., Staphylococcus aureus [2] [3]),
urinary tract infections (e.g., Escherichia coli [4]), foodborne
infections (e.g., Salmonella [5]), and infections transmitted in health
care settings (e.g., enterococci [6] and Klebsiella [7]).
For example, up to 30 percent of S. pneumoniae found in some areas
of the United States are no longer susceptible to penicillin, and
multi-drug resistance is common. Approximately 11 percent of S.
pneumoniae are resistant to ``third generation'' cephalosporin
antibiotics, and resistance to the newest fluoroquinolone
antimicrobials has already been reported. [8] Nearly all strains of
Staphylococcus aureus in the United States are resistant to penicillin,
and many are resistant to newer methicillin-related drugs.\2\ Until
1997, vancomycin was the only uniformly effective treatment for S.
aureus infections. Since 1997, however, strains of S. aureus with
decreased susceptibility to vancomycin have been reported. [9] [10]
Many other pathogens--including the bacteria that cause
tuberculosis [11] and gonorrhea, [12] the virus that causes AIDS, [13]
the fungi that cause yeast infections, [14] and the parasites that
cause malaria [15]--are also becoming resistant to standard therapies.
If we do not act to address the problem of AR, we may loose quick and
reliable treatment of infections that have been a manageable problem in
the United States since the 1940s. Drug choices for the treatment of
common infections will become increasingly limited and expensive--and,
in some cases, nonexistent.
Who is at risk?
While anyone may acquire a drug-resistant infection, certain people
are at increased risk, including patients in hospitals and children in
daycare centers. Drug-resistant infections may be acquired in health
care settings (e.g., staphylococcal infections in intensive care
units), in the community (e.g. pneumococci acquired from a classmate)
and through the food supply (e.g., salmonella acquired from meat or
eggs), both domestically and overseas. However, resistant microbes are
increasingly appearing in new settings. Methicillin-resistant S.
aureus, which for 30 years with few exceptions was a problem only in
hospitals, is now occurring in the community.[3] [16]
Financial costs.--The costs of treating AR infections place a
significant burden on society--a burden that is likely to grow larger
as the number of cases of drug-resistant illness increase. Individuals
infected with drug resistant organisms are more likely to require
hospitalization, to remain in the hospital for a longer time, and to
have a poor prognosis. For example, it has been estimated that the in-
hospital cost of hospital-acquired infections caused by just six common
kinds of resistant bacteria are at least $1.3 billion per year, in 1992
dollars.[17] This estimate does not include the costs of infections
caused by other pathogens, the costs of lost workdays, post-hospital
care, or resistant infections in the outpatient or extended care
facility settings.
SOLUTIONS: WHAT SHOULD BE DONE? AR will always be with us. The
challenge before us is to transform this increasingly urgent threat
into a manageable problem. Over the past ten years, the Institute of
Medicine, [18] the American Society for Microbiology, [19] other panels
of distinguished experts, the Congressional Office of Technology
Assessment, [17] and the General Accounting Office [20] [21] have
provided recommendations and options for government action to address
the dangers posed by AR. The experts agree that we need to improve
surveillance for emerging AR problems, to prolong the useful life of
antimicrobial drugs, to develop new drugs, and to utilize other
measures, e.g., improved vaccines, diagnostics, and infection control
measures to prevent and control AR.
Despite the urgency of the problem, the achievement of these goals
has not been simple or straightforward, and accomplishments to date
have been insufficient. Monitoring, preventing, and controlling AR
requires sustained effort, commitment, and collaboration among many
groups in the public and private sectors, and involvement of the
general public. It also requires support and leadership from the
Federal Government and a willingness to address complex and sometimes
controversial scientific, medical, and economic issues.
A PUBLIC HEALTH ACTION PLAN TO COMBAT ANTIMICROBIAL RESISTANCE
This ``Public Health Action Plan to Combat Antimicrobial
Resistance'' provides a blueprint for specific, coordinated federal
actions to address this emerging threat. The Plan builds upon reports
prepared by expert panels in recent years. This document is Part I of
the Plan, focusing on domestic issues. Since AR transcends national
borders and requires a global approach to its prevention and control,
Part II of the plan, to be developed subsequently, will identify
actions that more specifically address international issues. A National
Action Plan to Combat Multi-drug Resistant Tuberculosis has been
published previously. [22]
Partnerships and Implementation
This plan was developed by an Interagency Task Force on
Antimicrobial Resistance that was created in 1999. The Task Force is
co-chaired by the Centers for Disease Control and Prevention (CDC), the
Food and Drug Administration (FDA), and the National Institutes of
Health (NIH), and also includes the Agency for Healthcare Research and
Quality (AHRQ), the Department of Agriculture (USDA), the Department of
Defense (DOD), the Department of Veterans Affairs (DVA), the
Environmental Protection Agency (EPA), the Health Care Financing
Administration (HCFA), and the Health Resources and Services
Administration (HRSA).
The Plan reflects a broadly-based consensus of federal agencies on
actions to combat AR. The Plan is based in part on input from a public
meeting held in Atlanta, Georgia, in July 1999. [23] Present at the
meeting were consultants from a wide variety of groups, including state
and local health agencies, universities, professional societies,
pharmaceutical and biotechnology companies, health care delivery
organizations, agricultural producers, consumer groups, and the public.
Implementation of this plan will require collaboration with all of
these partners. The plan will be implemented incrementally, as
resources and, where needed, new appropriations, become available. The
agencies recognize that a number of the items may require either new
statutory authority or the adoptions of changes in regulatory
requirements. The extent to which such measures may be needed to
implement a given action item will be considered by the coordinators
and collaborators assigned to each item.
The Plan includes a summary and a list of issues, goals, and action
items addressing surveillance, prevention and control, research, and
product development. Except where specified, these issues, goals, and
action items apply to human AR issues and not to non-human (e.g.,
agricultural) issues. Agricultural issues refer to the production of
animals and plants, as well as fish and other species (aquaculture).
For each action item, ``coordinator'' and ``collaborator'' agencies/
departments are specified. Contingent on available resources, the
coordinators will assume the primary responsibility of carrying out the
specified action items and the collaborators will assist and/or carry
out part of the specified action. The Interagency Task Force will
monitor and, if necessary, update the Plan, during the coming years.
THE FOCUS AREAS
I. Surveillance
INTRODUCTION
Surveillance of AR is critical to provide early warning of emerging
problems, monitor changing patterns of resistance, and target and
evaluate prevention and control measures.\1\ Timely surveillance
information is also necessary to assist researchers in developing new
drugs and for good patient care. For example, clinicians should be
informed of drug resistance problems in their communities that may
influence their prescribing decisions and help them avoid treatment
failures. In addition, monitoring patterns of antimicrobial drug use is
needed to interpret trends and variations in rates of AR, improve
understanding of the relationship between drug use and resistance, and
help identify preventive interventions.
---------------------------------------------------------------------------
\1\ Public health surveillance is the ongoing, systematic
collection, analysis, and interpretation of data for use in the
planning, implementation, and evaluation of public health practice.
desirable qualities of any system include simplicity, flexibility,
acceptability, sensitivity, and representativeness. a surveillance
system also includes the timely dissemination of these data to persons
who can undertake effective prevention and control activities,
including clinicians, researchers, laboratorians and public health
personnel. MMWR, guidelines of evaluating surveillance systems, May 6,
1988/37(s5); 118.
---------------------------------------------------------------------------
At present, the United States lacks a coordinated national plan for
AR surveillance. Creating a national plan requires collaboration with
partners in the public and private sectors. Improved AR surveillance
depends upon enhanced epidemiologic and laboratory capabilities at
local, state, and national levels, use of standardized and reliable
laboratory testing methods, and enhanced use of informatics.
A. Issue.--The United States lacks a coordinated national plan for
surveillance of:
--AR emergence in organism-drug combinations of public health
importance
--Antimicrobial drug use in human and non-human settings
1. Goal.--Collaborate with appropriate partners to develop procedures
and methods for nationwide surveillance of AR emergence in
organism-drug combinations of public health importance
a. Action Items
(1) Determine which organisms and susceptibility to specific
antimicrobial drugs should be under surveillance and create a mechanism
for periodic updating of this list.
Coordinators: CDC, FDA, USDA, EPA
Timeline: Initiated
(2) TOP PRIORITY ACTION ITEM.--Identify the components of a
national AR surveillance plan and the roles of partners in its design
and implementation.
--Determine which surveillance activities should be conducted
routinely at national, regional, state, or local levels and
which may require specialized projects.
Cordinators: CDC, FDA, USDA
--Define the roles of clinical, reference, public health, and
veterinary laboratories at federal, state, and local levels in
AR surveillance.
Coordinator: CDC; Collaborators: DOD, DVA, FDA, USDA, HCFA
--Improve coordination of AR surveillance systems at CDC, FDA, and
USDA (e.g., identify components for integration).
Coordinators: CDC, FDA, USDA
--Ensure that the national AR surveillance plan is consistent with
local and national surveillance methodology and infrastructure
that currently exist or are being developed.
Coordinators: CDC, USDA, FDA
Timeline: For entire action item 2, begin within one to two
years
(3) Develop standards and methodologies.
--Develop standards and methodologies for monitoring drug-resistant
infections in humans and animals, as well as for monitoring
drug-resistant microbes in food products and environmental
samples.
Coordinators: CDC, UDSA, FDA, EPA
--Develop standardized laboratory methodologies and data elements
that allow susceptibility test results and AR surveillance data
to be compared across geographic jurisdictions.
Coordinators: CDC, UDSA, FDA, EPA
--Similarity, use standardized definitions and methodology (Related
Action Item: Surveillance #5) to create an electronic
surveillance system that health care institutions can use to
compare AR data from other local facilities.
Coordinator: CDC; Collaborators: HCFA, DVA, DOD, HRSA
--Develop standards for reporting quantitative resistance data (e.g.,
MICs or zone diameters) in ways that will detect decreased
susceptibility. This is necessary because numerical AR test
results reported non-quantitatively (e.g., as susceptible,
intermediate, or resistant) as"susceptible'' may mask an
emerging AR problem (i.e, microbes with a small decrease in
susceptibility may still be classified as susceptible).
Coordinators: CDC, USDA, FDA
--Assess how current policies on maintaining the confidentiality of
medical and veterinary data collected for other purposes relate
to procedures for gathering data on antimicrobial resistance.
If necessary, develop a comprehensive national confidentiality
policy on human and agricultural AR surveillance that includes
both patient and institutional confidentiality, is consistent
with confidentiality policies applied to other forms of
surveillance and research data, and that recognizes the
differences in human and animal agriculture surveillance
programs.
Coordinator: CDC; Collaborators: DVA, HCFA, DOD, FDA, USDA
Timeline: For entire action item 3, initiated
(4) Address additional surveillance issues unique to AR.
--Conduct post-marketing surveillance for the development of
resistance to critical antimicrobial drugs. Surveillance should
be linked to information on drug use, and criteria should be
developed to allow a prompt response to a finding of increased
resistance related to a specific pattern of use (e.g. consumer
and professional alerts, enhanced education, labeling changes,
or restrictions on use).
Coordinators: FDA, CDC, USDA
--Facilitate the collection on AR surveillance data on pathogens for
which cultures are not routinely obtained, either because the
infections are empirically treated without laboratory diagnosis
or because they are diagnosed with non-culture tests.
Coordinator: CDC
Timeline: For entire action item 4, begin within one to two
years
2. Goal.--Collaborate with appropriate partners to develop procedures
and methods for nationwide surveillance of antimicrobial drug
use in human and non-human settings
a. Action Item
(5) TOP PRIORITY ACTION ITEM.--Develop and implement procedures for
monitoring antimicrobial drug use in human medicine, in agriculture,
and in consumer products.
--Incorporate appropriate confidentiality protections in these
procedures
--Link human drug-use data to clinical information (e.g., diagnosis,
severity of illness, and outcome)
--Link agricultural drug-use data to species and usage patterns.
--Assess geographic variations in drug use
Coordinators: CDC, FDA, USDA; Collaborators: EPA, DVA, DOD
Timeline: For entire action item 5, begin within one to two
years
(6) Identify and evaluate methods for collecting (e.g., optimal
sampling methods) and disseminating the surveillance data on
antimicrobial drug use:
--Identify inexpensive sources of drug use data (e.g., the National
Ambulatory Medical Care Survey [NAMCS], the National Hospital
Ambulatory Medical Care Survey [NHAMCS], and databases in some
health care delivery systems and pharmacies) and evaluate their
usefulness for surveillance purposes
Coordinators: CDC, FDA
--Consider ways that results of periodic drug use surveys could be
made available to food animal producers and veterinarians to
encourage participation in data collection
Coordinators: CDC, FDA, USDA
Timeline: For entire action item 6, begin within one to two
years
(7) Work with accrediting agencies to address antimicrobial drug-
use monitoring as part of quality assurance in health care delivery
systems. (Related Action Item: Prevention and Control #67)
Coordinators: CDC, HCFA
Timeline: Begin within one to two years
(8) Convene a working group to assess the possible need for
additional federal regulations to facilitate and protect
confidentiality in antimicrobial drug use monitoring programs.
Coordinators: CDC, USDA, FDA
Timeline: Begin within one to two years
B. Issue.--Implementation of the national plan for AR surveillance will
require:
--Reliable drug susceptibility data
--Adequate capacity and resources at state and local health and
agricultural agencies
--An accessible, centralized source of AR data
1. Goal.--Promote the consistent and appropriate use of reliable
laboratory tests for antimicrobial drug susceptibility
a. Action Items
(9) Ensure that clinical laboratories that provide data for AR
surveillance purposes have clinical access to and routinely participate
in pertinent training and applicable proficiency testing programs with
good performance and indicate AR testing methodologies in their
surveillance reports (e.g., specific automated methods or manual
techniques).
Coordinator: CDC; Collaborator: HCFA
Timeline: Initiated
(10) Evaluate the performance of licensed, automated AR testing
devices in context of changing resistance patterns and update their
labeling where appropriate (e.g., changes in quantitative resistance
that may make a test result invalid).
Coordinators: FDA, CDC
Timeline: Begin within one to two years
(11) Work with the National Committee for Clinical Laboratory
Standards (NCCLS) further to refine antifungal susceptibility testing
methods for yeasts and molds.
Coordinators: CDC, USDA, HCFA
Timeline: Initiated
(12) Develop and promote standardized clinical, epidemiologic, and
laboratory methods for documenting drug resistance among parasites
(e.g., lice, Trichomonas, Giardia).
Coordinators: CDC, NIH
Timeline: Begin within three to five years
(13) Identify ways to overcome economic, legal, and other barriers
to appropriate AR testing and to the reporting of results (e.g.,
reimbursement policies, managed-care practices, cost considerations,
empiric treatment recommendations, etc.). (Related Action Item:
Prevention and Control #37)
Coordinators: HCFA, HRSA, CDC, AHRQ
Timeline: Begin within one to two years
(14) Identify a legal mechanism for manufacturers to provide
otherwise unavailable drugs to government reference laboratories for
the sole purpose of antimicrobial drug susceptibility testing (as part
of surveillance) with the understanding that these drugs will not be
used for drug discovery purposes.
Coordinator: CDC
Timeline: Begin within one to two years
2. Goal.--Ensure that state and local health and agricultural agencies
have the capacity to conduct surveillance of drug-resistant
organisms of public health importance
a. Action Items
(15) With state health and agriculture departments and other
stakeholders, define needed core capacity (the minimum needed in human,
laboratory, and electronic resources) at the state and local level to
ensure that basic AR surveillance is conducted in these jurisdictions.
As part of this effort, ensure that state public health and veterinary
diagnostic laboratories maintain the capacity to test the drug-
susceptibility patterns of resistant organisms of public health
importance, especially for drug-microorganism combinations for which
testing methods are not routinely available at hospital and commercial
laboratories.
Coordinators: CDC, USDA, FDA
Timeline: Begin within one to two years
(16) Provide resources to assist in meeting state and local core
capacity needs for AR surveillance. Strive to prove consistent funding
from year to year to state and local public health and veterinary
diagnostic laboratories that meet quality assurance standards.
Coordinators: CDC, USDA, FDA
Timeline: Initiated
3. Goal.--Disseminate surveillance data in a timely manner to public
health officials, clinicians, and others who may make decisions
based on an analysis of the data
a. Action Items
(17) Provide an accessible, centralized source of AR data from
major surveillance systems involving animal and human populations. In
consultation with stakeholders, determine how to report AR data in a
way that is useful to interested parties (e.g., clinicians, public
health officials, veterinarians, and researchers). Include sufficient
detail in surveillance reports to permit local analysis and comparison
with trends in drug use and medical and agricultural practices.
Coordinators: CDC, USDA, FDA, HCFA
Timeline: Begin within one to two years
(18) Provide health-care system administrators and other decision
makers with data on the impact of drug-resistant organisms (e.g.,
outcome, treatment costs) and on effective prevention and control
measures.
Coordinators: CDC, AHRQ
Timeline: Begin within one to two years
C. Issue.--Monitoring AR in agricultural settings is essential to
ensure animal and plant health and a safe food supply
1. Goal.--Monitor AR in animal and plant pathogens and in bacteria that
can be transmitted to humans through the food supply
a. Action Items
(19) Expand and enhance coordination of surveillance for drug-
resistance in enteric bacteria in sick and healthy humans, and sick and
healthy animals on farms, at slaughter, and at retail. This effort may
include:
--Expanding the National Antimicrobial Resistance Monitoring System:
Enteric Bacteria (NARMS:EB)
--Comparing AR data on pathogenic and non-pathogenic organisms
detected on farms (in sick and healthy animals), at slaughter,
and in commercial food products
--Utilizing these data to monitor the transmission of resistant
infections and assess the effectiveness of prevention measures
Coordinators: CDC, FDA, USDA
Timeline: Initiated
(20) Evaluate the usefulness of monitoring sentinel human
populations (e.g., farm, abattoir, fruit and vegetable, and food
processing plant workers) and persons in the general community for
infection or colonization with resistant enteric bacteria.
Coordinators: CDC, USDA, FDA
Timeline: Begin within three to five years
(21) Conduct pilot studies to assess the extent and impact of
environmental contamination by antimicrobial drug residues and drug-
resistant organisms that enter the soil or water from human and animal
waste. If appreciable contamination is detected, conduct routine or
sentinel surveillance in waste, in surface and ground water, and in
soil from agricultural areas in which waste is used for fertilizer.
(Related Action Item: Prevention and Control #58)
Coordinators: EPA, CDC, USDA
Timeline: Begin within three to five years
(22) Gather information on the relationship between antimicrobial
pesticide and herbicide use and the emergence of drug-resistance, by
monitoring:
--The prevalence and incidence of drug-resistant organisms in
agricultural areas where antimicrobial pesticides are and are
not used
--The prevalence of colonization or infection with resistant bacteria
in human or animal populations who live or work near orchards
or who consume fruit products sprayed (or treated) with
antimicrobial pesticides (Related Action Item: Prevention and
Control #64)
Coordinators: EPA, CDC, USDA
Timeline: Begin within three to five years
II. Prevention and Control
INTRODUCTION
Prevention and control of drug-resistant infections requires
measures to promote the prudent use of antimicrobial drugs (i.e.,
maximizing their therapeutic effect while minimizing the potential for
development of resistance). Prudent antimicrobial drug use can be
facilitated by promoting appropriate prescribing by clinicians,
informing consumers about the uses and limitations of antimicrobial
drugs, and improving diagnostic techniques. Measures to prevent
transmission of infection, whether drug-resistant or not, are also
important in controlling AR. These include the appropriate use of
vaccines and infection control, sanitation, and hygiene measures.
Efforts to control drug-resistant infections must become part of
everyday practice in health-care settings across the nation, as well as
in other settings (e.g., agriculture) in which antimicrobial drugs are
used. Partners in many sectors of society, as well as the general
public, will need to be involved in this effort.
A. Issue.--Overuse and misuse of antimicrobial drugs can hasten the
development of resistance and shorten the drug's useful
life.
1. Goal.--Identify methods for promoting judicious antimicrobial use
a. Action Items
(23) Identify factors that promote or impede judicious drug use in
hospitals, extended care facilities, and outpatient settings, working
in collaboration with health policy researchers and organizations that
can help implement AR prevention and control strategies.
Coordinator: CDC; Collaborators: FDA, AHRQ, DVA, DOD
Timeline: Initiated
(24) Develop judicious drug use policies and evaluate the
effectiveness (including cost-effectiveness) of implementing these
policies in hospitals and other health-care delivery settings. Identify
ways to increase adherence to judicious use policies proven to be
effective.
Coordinator: CDC; Collaborators: AHRQ, FDA, DVA, DOD, HCFA
Timeline: Initiated
(25) Evaluate the relationship between prescribing behavior and
specific antimicrobial drug marketing and promotional practices. Assess
the public health effects of these practices.
Coordinators: CDC, FDA
Timeline: Begin within three to five years
(26) Help individual hospitals and health care systems analyze how
the availability of AR data and computer-assisted decision support
systems influences prescriber behavior, health outcomes, and costs.
This may include the provision of computer software and the
establishment of projects that involve the Medicare Peer Review
Organizations (PROs).
Coordinator: CDC; Collaborators: HCFA, DVA, DOD
Timeline: Begin within three to five years
2. Goal.--Promote judicious antimicrobial use through educational and
behavioral interventions found to be effective
a. Action Item
(27) TOP PRIORITY ACTION ITEM.--Develop and implement a public
health education strategy to promote judicious antimicrobial use as a
national health priority. The strategy should involve patients,
clinicians, educators, industry, and policy makers. Elements of this
campaign may include:
--Culturally appropriate educational and behavioral interventions
implemented through community-based programs that target
--Patients and selected populations and communities, such as
daycare centers and schools
--Prescribing clinicians
--Health care delivery-systems
--A clearinghouse for educational materials (e.g., booklets and CD-
ROM presentations) on judicious drug use and AR prevention
--A periodically updated priority list of drug-resistant
microorganisms in humans and animals
--A glossary disseminated through CDC Website that defines technical
words commonly used in discussions of AR issues
Coordinator: CDC; Collaborators: USDA, FDA, HCFA
Timeline: Begin within one to two years
(28) Work with pharmaceutical manufacturers to implement programs
directed at clinicians and the public that promote judicious
antimicrobial drug use for priority drug-pathogen combinations.
Consider providing incentives to participating companies. (Related
Action Item: Product Development #83)
Collaborator: CDC; Collaborators: USDA, FDA, HCFA
Timeline: Begin within one to two years
3. Goal.--Promote judicious antimicrobial use through guidelines,
regulatory changes, and public policy actions
a. Action Items
(29) TOP PRIORITY ACTION ITEM.--In collaboration with professional
societies and other stakeholders, develop, disseminate, and evaluate
clinical guidelines that address:
--Judicious antimicrobial use
--Self-care and symptomatic treatment for common viral infections
--Advice to patients on how to help prevent the emergence of AR
infections through appropriate use of antimicrobial drugs
Coordinators: CDC, FDA; Collaborator: NIH
Timeline: Initiated
(30) Explore ways to integrate judicious use information into
antimicrobial package inserts and promotional materials, to provide
such information to patients with each prescription, and to provide
clear guidance to industry to ensure that promotion of antimicrobials
directed towards consumers does not encourage inappropriate or unneeded
use.
Coordinator: FDA; Collaborator: CDC
Timeline: Begin within one to two years
(31) Articulate factors that support the current approach of
requiring prescription-only dispensing for all systemic (i.e., non-
topical) antimicrobial drugs used in clinical medicine.
Coordinator: FDA; Collaborator: CDC
Timeline: Begin within three to five years
(32) Periodically review and update antimicrobial drug
susceptibility information included in drug labeling, in coordination
with the National Committee for Clinical Laboratory Standards (NCCLS).
Coordinator: FDA; Collaborator: CDC
Timeline: Begin within one to two years
(33) Convene an advisory panel or other expert group to consider
the management of drugs of last resort for the treatment of resistant
infections. Issues for discussion might include:
--Promoting early and wide adoption of prudent use guidelines
--Establishing intensive surveillance of drugs of last resort, with
mechanisms for triggering changes in product labeling and use
when increased resistance is detected
--Labeling drugs of last resort with the recommendation that they be
preferentially used for the treatment of conditions associated
with organisms that are resistant to other drugs
Coordinator: FDA; Collaborator: CDC
Timeline: Begin within one to two years
(34) Convene a working group to examine the impact of federal
reimbursement policies for home parenteral antimicrobial treatment on
judicious antimicrobial use. Where needed, the working group will make
recommendations for modifying these policies.
Coordinator: HCFA; Collaborators: CDC, HRSA
Timeline: Begin within one to two years
(35) Develop and submit measures for appropriate antimicrobial use
to the National Committee for Quality Assurance for inclusion in Health
Plan Employer Data and Information Set (HEDIS), which provides
comparative data on managed care organizations.
Coordinator: CDC; Collaborator: HCFA
Timeline: Initiated
B. Issue.--Improve diagnostic practices can enhance antimicrobial use
and patient care.
1. Goal.--Identify and promote the widespread use of diagnostic testing
and reporting strategies that effectively facilitate judicious
use of antimicrobial drugs in routine practice
a. Action Items
(36) Evaluate the potential impact of improved diagnostic tests,
including rapid point-of-care tests on antimicrobial drug use and
patient care, and assess their financial implications. Take into
account tests that distinguish between bacterial and viral infections;
tests that identify resistant pathogens; and tests that distinguish
common clinical syndromes such as bacterial sinusitis and acute
bacterial otitis media from illnesses with similar manifestations for
which antimicrobials are not beneficial. (Related Action Item: Research
#79)
Coordinator: CDC; Collaborators: DVA, DOD
Timeline: Begin within one to two years
(37) Identify economic and other barriers in the health care system
(e.g., reimbursement policies by third-party payers, managed care
practices, cost considerations, empiric treatment recommendations,
etc.) to diagnostic testing that promotes appropriate use of
antimicrobials. Develop recommendations that remove disincentives or
promote incentives to such testing.
Coordinator: HCFA; Collaborators: CDC, HRSA
Timeline: Begin within three to five years
(38) In collaboration with professional societies, industry, and
other stakeholders, develop guidelines for use by clinicians and
clinical microbiology laboratories that address:
--Appropriate specimen collection
--Performance, interpretation, and reporting of antimicrobial
(including antifungal) susceptibility tests performed on
clinical specimens
--Use of in-office (point-of-care) tests for infection, including AR
infections
Coordinator: CDC; Collaborator: FDA
Timeline: Begin within three to five years
(39) In collaboration with professional societies, industry, and
other stakeholders, develop guidelines for use by health-care-delivery
organizations that address the use of clinical microbiology
laboratories. The guidelines will:
--Promote access to clinical microbiology services by clinicians
--Promote access to appropriate on-site microbiology services in
acute care facilities
--Allow physicians to submit specimens to clinical laboratories other
than those designated by their health care delivery
organization or the patient's insurance company, with
appropriate justifications
Coordinator: CDC; Collaborator: HCFA for bullet 2.
Timeline: Begin within three to five years
(40) Promote the increased performance of direct examination of
microbiological specimens (e.g., by Gram stain or other rapid method),
in circumstances where appropriate clinically relevant and reliable
information can be garnered, as a readily available point-of-care
diagnostic test. This will require working within the framework of the
Clinical Laboratory Improvement Amendment (CLIA) regulations and
involving medical education and health care delivery organizations.
Coordinator: CDC; Collaborator: HCFA
Timeline: Begin within one to two years
C. Issue.--Preventing infection transmission through improved infection
control and use of vaccines can help prevent the spread of
antimicrobial resistance.
1. Goal.--Identify ways to reduce disease transmission in health-care
settings and in the community
a. Action Items
(41) Identify factors that promote transmission of drug-resistant
pathogens in health-care facilities, in extended care facilities, and
in community settings such as daycare centers. These may include
characteristics of the facilities and of the populations that they
serve.
Coordinator: CDC; Collaborators: DVA, DOD
Timeline: Initiated
(42) Evaluate the effectiveness (including cost-effectiveness) of
current and novel infection-control strategies used in hospitals and
other health-care delivery settings.
Coordinator: CDC; Collaborators: DOD, DVA
Timeline: Initiated
(43) Identify ways to increase adherence to infection-control
practices proven to be effective in previous studies.
Coordinator: CDC; Collaborators: DOD, DVA
Timeline: Initiated
(44) Evaluate the cost-effectiveness and impact on patient care and
drug resistance of medical devices that incorporate anti-infective
compounds to prevent infection (e.g., anti-infective urinary catheters
and prosthetic heart valves). Where appropriate, encourage the clinical
use of these devices. (Related Action Item: Product Development #85)
Coordinator: CDC; Collaborators: AHRQ, DOD, DVA, FDA, HRSA,
HCFA
Timeline: Begin within three to five years
(45) Encourage the development of clinical alternatives to those
invasive medical procedures and devices that increase the risk of
infection in hospitals and other health care setting, e.g.,
substitution of transcutaneous monitoring of blood oxygen levels of
indwelling catheters.
Coordinator: CDC; Collaborators: FDA, DVA
Timeline: Begin within three to five years
(46) Evaluate the benefits and risks of incorporating
antimicrobial, disinfectants, or antiseptic chemicals into consumer
products (e.g., soap, toys, kitchen utensils, clothes, paints,
plastics, and film preservatives). Consider whether they:
--Have any efficacy in reducing infection
--May play a role in promoting drug resistance
Coordinators: CDC, EPA; Collaborator: FDA
Timeline: Begin within three to five years
2. Goal.--Promote infection control through behavioral and educational
interventions
a. Action Items
(47) Conduct a public health campaign to promote hand hygiene and
other hygienic practices that prevent the transmission of infectious
organisms, in collaboration with professional societies and
stakeholders. This campaign may be coordinated with the public health
education strategy to promote judicious antimicrobial use described in
Action Item #27: Prevention and Control. Components will include:
--Evaluating the curricula of school hygiene courses
--Funding school-based and other programs that promote hand hygiene
and other behaviors that prevent infection
--Building on previous campaigns (e.g., ASM's Operation Clean Hands)
Coordinator: CDC
Timeline: Begin within one to two years
(48) Support ongoing public health education campaigns on food-
safety such as FDA and USDA's Fight BAC program, [24] whose aim is to
educate food producers, suppliers, retailers, and consumers about food
safety practices that reduce foodborne infections (including AR
infections) [25]
Coordinators: USDA, CDC, FDA
Timeline: Initiated
(49) Educate the public about the merits and safety of irradiation
as one tool to reduce bacterial contamination of food.
Coordinator: CDC
Timeline: Begin within one to two years
3. Goal.--Optimize the use of vaccines to prevent drug-resistant
infections and reduce antibiotic use
a. Action Items
(50) Support community-based programs that promote and facilitate
availability of recommended vaccinations for adults and children.
Coordinator: CDC
Timeline: Initiated
(51) Identify vaccines useful in reducing drug-resistant infections
and evaluate novel methods for improving coverage with these vaccines.
For example:
--Evaluate the risks and benefits of allowing certain vaccines for
adults (e.g., for pneumococci and influenza virus) to be
dispensed by pharmacists without prescription
--Review and evaluate methods to promote administration of
pneumococcal vaccines (e.g., offering vaccination when patients
are discharged from the hospital), and encourage the use of
methods found to be effective
Coordinator: CDC; Collaborators: DVA, FDA, HCFA
Timeline: Begin within three to five years
D. Issue.--Prevention and control of drug resistance in agriculture is
important to promote animal and plant health, as well as to
prevent AR transmission to humans through the food supply
or through contact with infected animals.
1. Goal.--Improve understanding of the risks and benefits of
antimicrobial use, and ways to prevent the emergence and spread
of drug resistance, in agricultural settings
a. Action Items
(52) Evaluate the nature and magnitude of the impact of using
various antimicrobial drugs as growth promotants in different species,
using current animal husbandry practices. Use this information to
assist in risk-benefit assessments of such use.
Coordinator: USDA; Collaborators: CDC, FDA
Timeline: Begin within one to two years
(53) Conduct additional research to further define the effects of
using various veterinary drugs on the emergence of resistant bacteria
that infect or colonize food animals of different species, using
various animal husbandry practices. Identify risk factors and
preventive measures. Assess the associated risk of:
--Transmission of AR infections to humans
--Clinical disease in humans
--Transfer of resistance factors from animal flora to human flora
Coordinators: CDC, USDA, FDA
Timeline: Initiated
(54) Conduct epidemiologic and laboratory studies to assess the
risk of development and transfer of resistance related to the use of
antimicrobial drugs in food and non-food plants, and identify risk
factors and potential preventive measures.
Coordinator: USDA; Collaborators: CDC, FDA, EPA
Timeline: Initiated
(55) Develop rapid tests for inspecting fresh commodities like
fruit for evidence of contamination with bacteria that are resistant to
antibiotics.
Coordinator: USDA; Collaborators: EPA, FDA, CDC
Timeline: Begin within one to two years
(56) Evaluate the effect of current food processing and
distribution methods on the emergence and spread of drug-resistant
organisms.
Coordinator: USDA; Collaborators: CDC, FDA
Timeline: Begin within one to two years
(57) Identify and evaluate new food pasteurization strategies.
Coordinator: USDA; Collaborators: FDA, CDC
Timeline: Begin within three to five years
(58) Assess the risk of AR emergence and spread due to
environmental contamination by antimicrobial drugs or by resistant
bacteria in animal and human waste. Collect information on whether
environmental contamination by antimicrobial drugs can lead to the
development of resistance in bacteria that live in the soil or in
water. (Related Action Item: Surveillance #21)
Coordinators: USDA, CDC, EPA, FDA
Timeline: Initiated
(59) Assess the impact of antimicrobial use in companion animals
(pets) on colonization and infection with drug-resistant organisms in
the animals and their human household contacts.
Coordinator: CDC
Timeline: Begin within three to five years
2. Goal.--Promote judicious antimicrobial use in agricultural settings
a. Action Items
(60) Work with veterinary and agricultural communities to help
educate users of veterinary and agricultural antimicrobial about AR
issues, and promote the implementation and evaluation of guidelines
that address:
--Judicious antimicrobial use in agricultural settings
--Performance and interpretation of antimicrobial susceptibility
tests performed on specimens from different species of animals
--Point-of-care tests for infection, including AR infections
Coordinators: USDA, CDC, FDA; Collaborator: EPA
Timeline: Initiated
(61) TOP PRIORITY ACTION ITEM.--In consultation with stakeholders,
refine and implement the proposed FDA framework [26] for approving new
antimicrobial drugs for use in food-animal production and, when
appropriate, for re-evaluating currently approved veterinary
antimicrobial drugs.
Coordinator: FDA
Timeline: Initiated
(62) Strongly encourage involvement of veterinarians in decisions
regarding the use of systemic antimicrobial drugs in animals,
regardless of the distribution system through which the drug is
obtained (e.g., regardless of whether a prescription is required to
obtain the drug).
Coordinators: FDA, USDA
Timeline: Initiated
(63) Evaluate the potential impact of making all systemic
veterinary antimicrobial drugs available by prescription only.
Coordinators: FDA, USDA
Timeline: Begin within three to five years
(64) Convene an expert group to consider how to incorporate AR
issues into regulations governing the use of pesticides. Invite
external experts, stakeholders, and the public to provide input.
Coordinator: EPA
Timeline: Begin within one or two years
E. Issue.--Efforts to prevent and control AR emergence and spread must
be comprehensive and multi-faceted, and involve a wide
variety of non federal partners and the public, and become
a part of routine practice nationwide.
1. Goal.--Ensure input from non-federal experts on federal efforts to
combat antimicrobial resistance
a. Action Items
(65) Establish an ongoing mechanism to obtain periodic input from
external experts on AR issues. This will include ensuring input from
stakeholders (e.g., state and local health agencies, the private
sector, and the public) in developing and reviewing federal efforts to
address antimicrobial resistance.
Coordinators: CDC, FDA, NIH; Collaborators: USDA, EPA, DOD,
DVA, AHRQ, HRSA, HCFA
Timeline: Begin within three to five years
2. Goal.--Develop and evaluate comprehensive demonstration programs to
prevent and control AR
a. Action Items
(66) TOP PRIORITY ACTION ITEM.--Support demonstration projects to
evaluate comprehensive programs that use multiple interventions to
promote judicious drug use and reduce infection rates. These projects
will:
--Assess how interventions found effective in research studies can be
applied effectively on a routine basis and on a large scale and
how this application can be done most cost-effectively
--Evaluate the use of these programs in health care systems (federal
and non-federal), in the community, and in agricultural
settings
--Involve partnerships with local and state agencies, health care
systems, professional societies, community organizations,
schools, private industry, and the public
Coordinator: CDC; Collaborators: FDA, DVA, DOD, HRSA, HCFA,
USDA
Timeline: Initiated
3. Goal.--Incorporate effective AR prevention strategies and programs
into routine clinical practice
a. Action Items
(67) Utilize federal health care systems (e.g., DOD, VAH, etc.) as
model systems for AR surveillance and prevention and control activities
involving judicious drug use, optimized diagnostic testing, infection
control, and vaccination practice.
Coordinator: CDC; Collaborators: DVA, DOD, HCFA, HRSA
Timeline: Begin within three to five years
(68) For all health care systems for which federal funds are
provided, identify and promote strategies to establish AR prevention
and control activities as part of quality monitoring programs.
Coordinator: CDC; Collaborators: DVA, DOD, HCFA, HRSA
Timeline: Initiated
(69) Encourage nationally recognized accrediting agencies such as
the National Committee for Quality Assurance (NCQA) and the Joint
Commission on Accreditation of Healthcare Organizations (JCAHO), to
include accreditation standards that promote efforts to prevent and
control AR, including judicious antimicrobial use, infection control,
vaccine use, and diagnostic testing. These standards may draw on the
findings of existing data and demonstration programs and AHRQ Evidence-
Based Practice Centers.
Coordinator: CDC; Collaborators: HCFA, AHRQ
Timeline: Begin within one to two years
III. Research
INTRODUCTION
Antimicrobial resistance is among the most challenging problems in
microbiology, clinical medicine, and public health. Antimicrobial
resistance is not one problem, but an overarching term for a whole
array of problems. Microbiology, the study of microorganisms, tells us
that the processes by which drug resistance occur, are essentially
those of evolution. To evolve is to change, and this change is
inevitable. Basic and clinical research provides the fundamental
knowledge necessary to develop appropriate responses to antimicrobial
resistance emerging and spreading in hospitals, communities, farms, and
the food supply. Major scientific accomplishments throughout the years
have contributed much to the understanding of the fundamental
biological processes of AR within microbes and the resulting impact on
human, animals, and the environment and provides us the opportunity to
influence these very processes and outcomes.
The broad scope of the U.S. research community has a major
contribution to make in meeting the challenge of AR in order to reach
the goals the AR Task Force has set forth. The research and development
of diagnostic tests, new antimicrobial agents, novel therapeutic
products, and vaccines and other preventive approaches in response to
AR is a multi-step process that begins with basic research discoveries
and ends with the availability and use of a new product or
implementation of a process. Along this pathway three areas need to be
addressed: the identification of gaps and needs in the molecular and
cellular understanding of resistance, the infrastructure to support a
robust research community, and finally a pathway for movement of
research findings into the development of new products.
Through efforts of the Interagency Task Force, important research
questions about microbial physiology, ecology, genetics and mechanisms
of resistance have been identified. Existing gaps in knowledge and
understanding should be addressed to augment the federal and private
sector response to the overall problem. Efforts are underway to build
and enhance the field of AR research, through increased focus,
recognition, and collaboration. The aim is to develop a research
infrastructure to support a critical mass of AR researchers who will
interact, exchange information, and stimulate new discoveries. In order
to move novel ideas arising at the research bench to useful products or
approaches, support of the underlying infrastructure to study and test
products and a mechanism to transition to industrial partners is
necessary.
This effort will involve federal agencies that conduct, support and
promote basic and clinical research in academia and industry and will
involve prioritizing needs, identifying key opportunities, recruiting
new investigators to the field, and making responsible use of resources
to address AR problems.
A. Issue.--Specific scientific gaps remain in the understanding of
microbial physiology, ecology, genetics and mechanisms or
resistance.
1. Goal.--Address existing research needs and identify new ones
a. Action Items
(70) Additional research is needed to enhance the understanding and
assess the impact of:
--Mechanisms of AR emergence, acquisition, spread, persistence, and
decline, with special regard to multi-drug resistant organisms
--Emergence and transfer of resistance genes among microorganisms in
vivo, including epidemiologic factors
--Effects of preventive, therapeutic, and growth promoting agents on
the micro biota of animals, plants, soil, and aquatic
environments
--Host factors and immune modulators (e.g., cytosine) in clinical
resistance to treatments for opportunistic infections
--Variations in antimicrobial use patterns that may affect the
emergence and spread of resistance and the outcome of
treatment, including:
--Differences in duration and dosage in the administration of
antimicrobial agents
--Prophylactic use of antimicrobial (including antibacterial and
antifungal) agents
--Drug combinations used to treat resistant organisms
--The rotation (cycling) of antimicrobial drugs to prevent the
emergence of resistance
--The determinants of colonization and infection with drug-
resistant pathogens
Coordinator: NIH; Collaborators: CDC, FDA, DVA, USDA, EPA, DOD
Timeline: Initiated
(71) Conduct further government-wide, in-depth, assessment of the
scope and composition of AR research to identify research
opportunities.
Coordinators: NIH, CDC, FDA, USDA; Collaborators: DOD, DVA,
AHRQ, EPA, HCF
Timeline: Initiated
B. Issue.--The existing research infrastructure needs to ensure a
critical mass of researchers in AR and related fields.
1. Goal.--Augment the scientific research infrastructure
a. Action Items
(72) Work with the appropriate peer review structures to ensure
that the requisite expertise is applied to the review process to
facilitate funding of quality AR research.
Coordinators: NIH, DVA, FDA
Timeline: Begin in one to two years
(73) TOP PRIORITY ACTION ITEM.--Provide to the research community
genomics and other powerful technologies to identify targets in
critical areas for the development of new rapid diagnostics
methodologies, novel therapeutics, and interventions to prevent the
emergence and spread of resistant pathogens. Examples include tools
such as microbial genome sequences, information on comparative
genomics, DNA chip technology, and informatics.
Coordinator: NIH; Collaborators: DOD, USDA, FDA
Timeline: Initiated
(74) Encourage sharing of AR data between industry and the research
community.
Coordinator: NIH; Collaborators: DOD, USDA, FDA
Timeline: Begin in three to five years
2. Goal.--Develop a critical mass of researchers in AR
a. Action Items
(75) Bring new researchers into the field, by utilizing appropriate
strategies such as training and research opportunities.
Coordinator: NIH; Collaborators: CDC, FDA, USDA, DOD, DVA
Timeline: Initiated
(76) Organize conferences that address research issues relating to
AR.
Coordinator: NIH; Collaborators: CDC, USDA, FDA, DVA, DOD, AHRQ
Timeline: Initiated
C. Issue.--Special efforts are needed to translate research findings
into medically useful products for human and veterinary
use, such as novel antimicrobial therapeutics, diagnostic
tests, vaccines and other tools for preventing AR emergence
and spread.
1. Goal.--Address the governmental role in translating novel ideas into
new clinically relevant products, focusing on gaps not filled
by pharmaceutical industry and other non-government groups
a. Action Items
(77) Explore the need to encourage preclinical studies on the
toxicology, pharmacokinetics, and pharmacodynamics of novel therapeutic
agents for the treatment of multi-drug-resistant pathogens and
facilitate the transition of potential products from preclinical to
clinical studies leading to development by industry of novel
therapeutic agents.
Coordinator: NIH; Collaborators: DOD, DVA, FDA, USDA
Timeline: Begin within one to two years
(78) TOP PRIORITY ACTION ITEM.--Develop a human clinical trials
network, involving medical research centers and health-care
institutions, to coordinate and conduct clinical trials addressing AR
issues that are difficult to resolve in industry-sponsored studies,
including:
--Novel therapies
--Existing antimicrobials administered in treatment regimens and
combinations that may not be included in approved indications
and dosing schedules
--Other products and practices relevant to the control and treatment
of antimicrobial-resistant pathogens including devices,
diagnostics, disinfectants, etc.
Coordinator: NIH; Collaborators: CDC, DVA, DOD, FDA
Timeline: Begin within one to two years
2. Goal.--Develop rapid, inexpensive, point-of-care diagnostic methods
to facilitate judicious use of antimicrobials
a. Action Items
(79) TOP PRIORITY ACTION ITEM.--Identify, develop, test, and
evaluate the impact of new rapid diagnostic methods. Such methods
should include:
--Tests for resistance genes that are associated with drug resistance
including non-culture specimens
--Rapid point-of-contact diagnostics for patients with viral
respiratory infections and clinical syndromes such as otitis
media, sinusitis, and pneumonia
--Rapid methods for detecting drug resistance among fungi, parasites,
and mycobacteria
Coordinators: NIH, FDA; Collaborators: DOD, USDA, CDC, AHRQ,
DVA
Timeline: Initiated
3. Goal.--Develop new products and strategies to prevent and treat
colonization and infection with resistant organisms in
patients, prevent transmission of resistant infections in the
community, and prevent AR emergence
a. Action Items
(80) Encourage basic research in support of the development and
appropriate use of vaccines. Vaccines are needed to:
--Prevent prevalent viral infections that predispose to bacterial
infection or are mistaken for bacterial infections and are
inappropriately treated with antibacterial agents (e.g.,
influenza virus)
--Prevent colonization, infection, and transmission of resistant
organisms such as enterococci and staphylococci
--Prevent common bacterial infections (S. pneumoniae, nontypable
Haemophilus influenzae) to reduce antibacterial use
Coordinators: NIH, FDA; Collaborators: CDC, DOD, DVA, USDA
Timeline: Initiated
(81) Encourage basic research in support of novel approaches to
preventing or treating infections with resistant organisms. Novel
approaches may include:
--Bacteriophage therapy
--Active (vaccine) and passive (antibody, hyperimmune globulin)
immunization
--Host-derived antimicrobial agents
--Non-antibiotic antimicrobials with broad or nonspecific anti-
infective activities (e.g., defending and non-specific
immunostimulants)
--Microbial ecology
Coordinator: NIH; Collaborators: DOD, DVA, FDA, USDA, CDC
Timeline: Initiated
IV. Product Development
INTRODUCTION
New products are not being developed rapidly enough to address
increasing microbial resistance. Needed products include not only new
classes of antimicrobials able to kill otherwise resistant organisms,
but also vaccines and anti-infective devices with the potential to
prevent infections as well as improved diagnostic tools to aid in
appropriate use of therapeutics. With respect to antimicrobial drugs,
each new agent represents a major investment by a pharmaceutical
company, which must shepherd the product through pre-clinical studies
and clinical testing, followed by large and expensive clinical trials.
Pharmaceutical companies may be reluctant to invest extensive resources
in the development of drugs, such as those antimicrobials targeted to
resistant organisms, which are often given for short time periods to
small numbers of patients. Manufacturers are similarly concerned that
judicious use policies may limit sales and profits. On the other hand,
when a drug is used widely, allowing recovery of costs and
profitability, resistance may develop more rapidly and shorten the
useful life of the drug.
Due to these economic realities--as well as to scientific
limitations and a lag in the perception of a need for new agents--very
few novel antimicrobial drugs have reached the market for several
years. A major aim of this interagency effort is to work with the
private sector to explore and test innovative ways to address these
issues. Approaches to be considered include providing incentives (and
overcoming disincentives) to promote and assist the development of
important products to address AR.
Product development is also a very important issue for veterinary
medicine and agriculture. U.S. agencies and private sector partners
must intensify efforts to encourage the development and use of
veterinary drugs and agricultural practices that are unlikely to
stimulate resistance to important human drugs or spread resistant
pathogens to humans. Again, increased attention also needs to be turned
to strategies to prevent infections of animals (e.g., vaccines, changes
in husbandry) and to the improved use of existing and new products.
A. Issue.--Researchers and drug manufacturers need to be better
informed of current and projected gaps in the arsenal of
antimicrobial drugs, vaccines, diagnostics, and of
potential markets for these products.
1. Goal.--Provide a systematic assessment of the current status and
projected future needs for AR products
a. Action Items
(82) TOP PRIORITY ACTION ITEM.--Create an Interagency AR Product
Development Working Group to identify and publicize priority public
health needs for new AR products (e.g., innovative drugs, targeted
spectrum antibiotics, point-of-care diagnostics, vaccines, anti-
infective medical devices, and biologics). The Working Group will:
--Obtain input from stakeholders, including pharmaceutical companies,
physicians, epidemiologists, and microbiologists, on which
products are needed
--Include experts in the non-medical disciplines (e.g., engineering
and remote sensing, etc.)
--Model future resistance trends, product needs, and potential
markets, taking into account AR surveillance data and numbers
of patients at high risk of developing drug resistant
infections (e.g., increases in immunocompromised patients)
--Evaluate current market incentives for the development of priority
AR products (Related Action Item: Product Development #83)
--Reassess AR product priorities on a regular basis
Coordinators: FDA, USDA, CDC; Collaborators: NIH, AHRQ
Timeline: Begin within one to two years
B. Issue.--Existing market incentives and regulatory processes may be
insufficient to stimulate the development of certain
priority AR products while fostering their appropriate use.
1. Goal.--Investigate and act upon potential approaches for stimulating
and speeding the entire AR product development process, from
drug discovery through licensing
a. Action Items
(83) TOP PRIORITY ACTION ITEM.--In consultation with stakeholders,
economic consultants, and the AR Product Development Working Group
(Related Action Item: Product Development #82), identify ways (e.g.
financial and/or other incentives or investments) to promote the
development and/or judicious use of priority AR products for which
market incentives are inadequate.
--All such proposals will require careful economic modeling and
analysis. New approaches should be used on a trial basis, for
limited time periods, and the costs and benefits of incentives
used in these pilot programs should be monitored to assess the
return on the public investment.
Coordinators: FDA, CDC; Collaborators: USDA, AHRQ
Timeline: Begin within three to five years
(84) In consultation with academia and industry, consider whether
government has a constructive role to play in discovery of drugs and
other products targeted to address areas where market incentives are
limited and unmet needs exist (e.g., novel antimicrobial drugs targeted
to specific resistant organisms). (Related Action Items: Research Issue
B)
--Such a role could utilize intramural, extramural or partnership
type mechanisms. Products developed under such mechanisms could
be licensed commercially either with or without specific
stipulations regarding use.
Coordinator: NIH; Collaborators: USDA, FDA, CDC
Timeline: Begin within three to five years
(85) Continue ongoing approaches that streamline the regulatory
process, including clinical trials, to help bring AR products
(including drugs, vaccines, diagnostics and devices) to market as
efficiently and rapidly as possible, while still assuring their safety
and efficacy.
--This might involve use of an expedited process in which certain
drugs are considered for approval after the completion of Phase
2 clinical trials, in accordance with Subpart E of the
Investigational New Drug (IND) regulations. It might also
involve defining new surrogate endpoints that indicate a
meaningful response benefit over existing treatments for
particular infections (e.g., CD4 counts as surrogate markers in
the treatment of HIV/AIDS), in accordance with Subpart H of New
Drug Application (NDA) regulations.
--In the case of approvals for anti-infective medical devices, AR
concerns will be addressed during the pre-and post-licensing
review, to ensure that these products reduce infection without
engendering significant resistance.
Coordinator: FDA; Collaborator: USDA
Timeline: Initiated
C. Issue.--The development and use of antimicrobial drugs and related
products in agriculture should be optimized to reduce the
transfer of resistance to pathogens that can infect humans.
1. Goal.--Promote the development and use of new and existing AR
products that reduce the risk of the development and transfer
of antimicrobial resistance to humans, as well as new
approaches to reducing agricultural use of antimicrobial drugs
a. Action Items
(86) In consultation with stakeholders and expert consultants,
identify ways to promote the development of new and alternative
veterinary treatments and the improved use of existing therapies that
are unlikely to stimulate resistance to drugs in clinical medicine.
This action will include consideration of the incentives and approaches
listed in Action Item #31 (Prevention and Control), and the
implementation of pilot programs to stimulate the development of
priority products that meet critical animal health needs.
--Approaches for evaluation should include ways to improve and/or
reduce the use of specific antimicrobial drugs, as well as ways
to prevent infection, such as vaccines, changes in animal
husbandry, and the use of competitive exclusion products (e.g.,
treatments that affect the intestinal flora of food animals).
Coordinators: FDA, USDA, NIH, CDC, EPA
Timeline: Begin within three to five years
(87) Streamline the regulatory and approval process for veterinary
and agricultural antimicrobial drugs and related products that are
unlikely to result in transfer of antimicrobial resistance to humans.
Coordinators: FDA, EPA, USDA
Timeline: Begin within three to five years
ENDNOTES
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resistant Salmonella enterica serotype typhimurium DT104 infections in
the United States. N Engl J Med. 1998;338:1333-8.
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it happen in the United States? Infect Control Hosp Epidemiol
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[7] Wiener J, Quinn JP, Bradford PA, et al. Multiple antibiotic-
resistant Klebsiella and Escherichia coli in nursing homes. JAMA
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[8] CDC. Active Bacterial Core Surveillance, unpublished data 1999.
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136.
[10] Smith TL, Pearson ML, Wilcox KR, et al. Emergence of
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[11] Pablos-Mendez A, Raviglione MC, Laszlo A, et al. Global
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Med 1998;338:1641-9.
[12] Fox KK, Knapp JS, Holmes KK, et al. Antimicrobial resistance
in Neisseria gonorrhoeae in the United States, 1998-1994: the emergence
of decreased susceptibility to the fluoroquinolones. J Infect Dis
1997;175:1396-403.
[13] Wainberg MA, Friedland G. Public health implications of
antiretroviral therapy and HIV drug resistance. JAMA 1998;279:1977-83.
[14] Rex JH, Rinaldi MG, Pfaller MA. Resistance of Candida species
to fluconazole. Antimicrob Agents Chemotherapy 1995;39:1-8.
[15] White NJ. Drug resistance in malaria. Br Med Bull 1998;54:703-
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[16] Adcock PM, Pastor P, Medley F, et al. Methicillin-resistant
Staphylococcus aureus in two child care centers. J Infect Dis
1998;178:577-80.
[17] U.S. Congress, Office of Technology Assessment, Impacts of
Antibiotic-Resistant Bacteria, OTA-H-629, Washington, DC: U.S.
Government Printing Office, September 1995.
[18] National Academy of Sciences, Institute of Medicine. Forum on
Emerging Infections, Antimicrobial Resistance: Issues and Options
[Workshop Report], Washington, DC, 1998.
[19] American Society for Microbiology. Report of the ASM Task
Force on Antibiotic Resistance, Washington, DC, 1995.
[20] General Accounting Office, Antimicrobial Resistance: Data to
assess public health threat from resistant bacteria are limited, GAO/
HEHS/NSIAD/RCED-99-132, Washington, DC, April 1999.
[21] General Accounting Office, Food Safety: The agricultural use
of antibiotics and its implications for human health, [GAO/RCED-99-74],
Washington, DC, April 1999.
[22] CDC. A nation plan to combat multi-drug resistant
tuberculosis. MMWR 1992;41(RR-11).
[23] HHS. Development of a public Health Action Plan to Combat
Antimicrobial Resistance. Federal Register 1999;64:34558.
[24] American Society for Microbiology. Partnership for Food Safety
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[25] Department of Agriculture. U.S. Government Food Safety for
Farm to Table: A National Food-Safety Initiative, A Report to the
President, Washington, DC, May 1997.
[26] Food and Drug Administration. A Proposed Framework for
Evaluating and Assuring the Human Safety of the Microbial Effects of
Antimicrobial New Animal Drugs Intended for Use in Food-producing
Animals, Washington, DC, February 1999.
Senator Cochran. Dr. Koplan, sometimes health scares are
sensationalized. Some people may tend to overstate concerns to
get the attention of the public and--for no real private or
selfish reason. I think in the use of some words for example,
we tend to have our attention riveted to a health problem like
the word ``outbreak.''
I remember when I first heard about an outbreak when I got
to Congress, I thought, ``My goodness, that has to be millions
of people involved in this outbreak.'' But I found out there
were only a few.
An outbreak is a word of art and does not really describe
the total numbers of people who are involved in a disease
problem or threat to human health.
But is this a problem that you would consider to be
overstated or exaggerated or is this the real thing? The words
that are being used today seem to have an alarmist tone to
them, but is that justified? Do we have a serious situation
here that requires the immediate and urgent action of these
Federal agencies, and State governments, and other health
professionals and researchers?
Dr. Koplan. It is the real thing. And I think your words
are well chosen. It requires immediate and urgent action.
It is--these are diseases that we are all prey to at some
time or other, our children, our parents, our neighbors--
infectious diseases that--organisms that cause infectious
diseases are all around us and they are not going away.
And this pattern of resistance has been both a repeated one
and one that is getting worse for a number of organisms. And
these are the organisms that if we are hospitalized or we get
sick, a wide range of illnesses can befall us.
And we want antibiotics that work when we or our friends or
relatives get sick. And we are in a situation where the
armamentarium that we can bring to bear on it is severely
compromised and will continue to be unless we take aggressive,
intensive and immediate steps to address it.
Senator Cochran. I know you have mentioned that penicillin
was discovered--what, 50 years ago, more or less----
Dr. Koplan. Yes.
Senator Cochran [continuing]. And we are just now hearing
more and more about the resistance problem. Is this a problem
that has been growing in seriousness for a good while now or is
it--why has it just seemed to have come on us all of a sudden
and affects a lot more than just penicillin?
Dr. Koplan. Well, I think to some extent, we probably have
been complacent at certain times, thinking we had a pretty good
set of antibiotics to use and that the infectious disease era
was behind us.
And our complacency has caught up with us, that we always
need new agents, antimicrobial agents, but we also need to
prolong the use, as Dr. Henney said, of the ones we have got.
And the life span of some of these antimicrobials has decreased
over ones that we have used for longer period of time.
The organisms are in competition with us and they may not
be able to do some of the things we do, but they can do other
things much better, and one of them is adapt to the environment
they are in and produce resistance to the antibiotics that we
provide.
So it is not a--it has been a problem since the day Sir
Alexander Florey discovered penicillin. The next day the bugs
were getting together to figure out how they could combat it.
But it has become an increasing problem with more complicated
organisms, complicated medical procedures and an environment in
which these antimicrobials have not been used as responsibly as
they might.
Senator Cochran. Now, Dr. Henney, you mentioned the action
you took just yesterday to require physicians to give
information to patients and to include the warnings in effect
about taking antibiotics as directed and only when necessary.
Why has this been so late in coming since the problem has
been emerging over time now? And it seems that the medical
community ought to have been notified by Federal agencies of
this kind of thing long before now.
Dr. Henney. Well, Mr. Chairman, I think that there has
always been information on the label that clearly articulates
what a product's indications or contra-indications might be. I
think what we are trying to do with this proposed rule is to
underscore those kind of messages, particularly in the
antibiotic area, where judicious use is so important, and
reminding physicians every time they use one of these
antibiotics how important these products are and that
resistance could occur.
So in nearly every section, now, in the label, we will
underscore information to the physician. Right at the start of
the product label, there will be statements to this effect in
the clinical pharmacology section. Again, the underscoring is
to identify and determine susceptibility to the different
antibiotics prior to treating or as soon as possible.
Underscoring in the indications and usage sections; in the
precaution sections, all throughout the label, this message is
that these products must be used quite judiciously if they are
going to be effective for the patient that is in front of you,
but also for all of the other patients that you might treat
into the future for whom you have a responsibility to use these
products wisely.
Senator Cochran. There has been a tremendous increase in
product advertising by pharmaceutical companies, drugs by name,
trade names, battling for the attention of the consuming
public--what impact, if any, has that had?
I will ask Dr. Henney and Dr. Koplan both this question.
Can it have a positive influence, or has it had a negative
influence? Is it part of the problem in this area?
Dr. Henney. Well, we have really seen an increase of direct
consumer advertising in the past 3 years. And I think there was
actually even an article in the New York Times on this matter
this morning about how direct consumer advertising may be
influencing what patients might know about products and what
the practices of industry are in terms of using this vehicle to
market their products.
I think that we see two things when the advertising is full
and complete, when there is a balanced approach to providing
both benefits and risk. It makes consumers more aware of
products, but it also sometimes serves as a reminder that they
are supposed to be taking a drug that they may have put to the
side. There are some real positives to this.
On the other hand, we hear a lot of expression both from
the medical community and somewhat from the lay public that
they feel bombarded with these advertisements in terms of
sorting out what it all means.
We have actually taken several actions against companies
where we have found the advertising to be out of bounds in
terms of expressing more of the benefits and a limited amount
of the risks that might be involved with products that are
advertised.
It is our intention to look specifically at the direct to
consumer advertising issue as it relates to antimicrobials
because of our commitment to this whole issue of resistance.
And that will be undertaken in our center on drugs.
Senator Cochran. Dr. Koplan, what is your reaction to that
question and that problem?
Dr. Koplan. This is an area of Dr. Henney's expertise in
particular. But I would say that the message we are trying to
get out, and sometimes it may be in conflict with this direct
marketing, is to consumers that antibiotics are not always in
their best interest and that there are a large number of
infectious diseases they may have and which antibiotics are
either of no benefit or potentially harmful to them and that
they need to consider that when they are meeting with their
doctor.
And we have programs in partnership with the American
Academy of Pediatrics and American Academy of Family Physicians
to encourage placement of information in doctors' waiting rooms
and in other settings for consumers to begin to get a better
appreciation that antibiotics are great when needed, but they
are not always needed.
If I could correct a previous statement I made?
Senator Cochran. Yes.
Dr. Koplan. I do not want to leave an inaccuracy in the
record, but it was Professor Fleming that invented penicillin.
I do not want to be historically incorrect here. Thanks.
Senator Cochran. You mentioned--both of you mentioned the
action plan that involves your agencies and also the NIH, is
there a request pending or will--would it be submitted to the
appropriations committee for additional funding to carry out
that plan? What in your judgment would be the proper level of
funding for Federal agency action in this area?
Dr. Henney. Mr. Chairman, with respect to the public health
service plan that has been developed, I think that what the
agencies went through was really outlining these specific
actions that we need to take.
We will now go back and look at those plans and develop a
budget and make sure that that is reflected in future budget
requests. But it was really the intention, in terms of the
first effort of this plan, to look at the domestic side of this
issue and what should be done.
I think the next step would also be to look internationally
at what we would need to do, but I am sure that we will all be
coming forward, the many agencies that are involved here, to
tell you what it will take to accomplish this on the part of
the Federal agencies involved.
Senator Cochran. Among the specific actions in the plan,
are there any areas that have greater priority than any others,
or is that something that you are going to come up with later
in--in your request for funding?
Dr. Henney. Well, there was great intention as the
different agencies crafted this plan to make sure that they
gave emphasis to those things where they thought that they
could make the greatest impact and difference. So of the 87
action items that are listed in that plan, I believe 11 are
listed as the top priority.
Senator Cochran. OK. Dr. Koplan, what is, in your view, a
program, an example of a program that you have already
implemented that has worked in this area? So are there any
lessons that have been learned from previous initiatives that
have been implemented by the Centers for Disease Control?
Dr. Koplan. Thank you. There are some model programs that
show great promise. One specific example is in the State of
Iowa where officials along with colleagues in Nebraska and
South Dakota, the Indian Health Service and CDC recognized a
marked increase in vancomycin-resistant enterococci, a bacteria
that can wreak havoc in a number of bodily systems and can be
quite fatal, particularly amongst hospitalized patients and
residents of long-term care facilities. Through this
educational program and careful surveillance they sought to
reduce the amount of this infection.
Over the course of a couple of years, they were able to see
a fairly rapid improvement and a decrease in the rates of
resistance within an area right around Sioux City, Iowa, but
covering three States.
This gives us optimism that even with tools we have in hand
now, we can turn around some of these patterns and trends of
resistance.
Senator Cochran. We also have what is called an Emerging
Infections Plan. How does the action plan relate to CDC's
Emerging Infections Plan?
Dr. Koplan. I think they dovetail very nicely. The plan for
antibiotic resistance provides more specific steps that need to
be taken in this area and is really the next step for us of how
we then move ahead.
The Emerging Infections Plan is a 5-year plan of which
about 40 percent of the action items in that are underway. And
we hope to add another 40 percent in the next year.
Senator Cochran. Dr. Henney, what is the most immediate
area where the Food and Drug Administration and the
pharmaceutical industry can work together to address the
problem of resistance?
Dr. Henney. Well, I would say in two or three areas, Mr.
Chairman.
Clearly, in the whole area of product development and
whether that is an antimicrobial, whether that is a vaccine or
whether it is a diagnostic tool. I think the early consultation
with the agency about plans underway so that we can facilitate
and make efficient our review of a new application certainly is
one area where we need to work effectively with industry and
are doing so.
I think second is clearly the implementation of this in
terms of labeling. And I think, third, we need to sit down both
with industry and others and look at the balance that we need
in terms of recognizing how much of an industrial investment it
takes to develop a new product that we might then limit in
terms of our recommendation for use.
So we do need to have discussions as to incentive programs
that might be developed to recognize that. That may require
legislation and, if so, we will be back to you to discuss that.
I think we clearly have incentive programs in other areas,
orphan drugs, pediatrics and the like, and what we will be
discussing internally and certainly with industry and others
is, ``Do we have an appropriate tool now that could be applied
that could be effective in this area in this balancing act, or
do we need another?'' And if so, I think we need to come back
to you if we need that kind of different or a more unusual kind
of approach.
Senator Cochran. Let me thank you both again for being here
today to discuss this important issue. We appreciate the time
you have spent in preparing for the hearing and the quality of
the statements you have made this morning.
It gives us a big challenge, I think, to work with you in a
supportive way to try to make sure that the funds are there as
you need them to deal with this very serious problem, not just
a United States problem, but as you both pointed out a
worldwide problem that needs our immediate and best efforts.
Thank you very much.
Dr. Koplan. Thank you.
Dr. Henney. Thank you.
STATEMENT OF F.E. ``ED'' THOMPSON, M.D., STATE HEALTH
OFFICER, STATE OF MISSISSIPPI
Senator Cochran. Our next panel of witnesses I have already
identified. I hope you will all come forward and take places at
the witness table.
Dr. Ed Thompson, who is the State Health Officer at the
Mississippi Department of Health; Dr. Martin Rosenberg, who is
Senior Vice President and Director of Anti-Infectives with
SmithKline Beecham Pharmaceuticals; Dr. Merle Sande, Professor
and Chairman of the Department of Medicine at the University of
Utah School of Medicine; Dr. Alice M. Clark, who is Director of
the National Center for the Development of Natural Products at
the University of Mississippi; and Dr. Mark L. Nelson, who is
Senior Director of Chemistry at Paratek Pharmaceuticals in
Boston, Massachusetts.
Thank you very much for being here and for helping us with
this hearing. We have copies of your statements, which will be
printed in the record in their entirety and we invite you to
proceed to discuss your thoughts about this subject in a
summary fashion and in whatever way you think would be helpful
to our committee.
Let us start with Dr. Thompson. Welcome. You may proceed.
Dr. Thompson. Thank you, Senator. Mr. Chairman, members of
the staff, I am Dr. Ed Thompson, State Health Officer of
Mississippi. I am representing ASTHO, the Association of State
and Territorial Health Officials.
From your statement, Senator, earlier and from those of the
previous witnesses and from seeing who is in this room, I
realize today that I am doing what we in Mississippi call
preaching to the choir. But I will try to bring the perspective
of State health departments on this important issue of
antimicrobial resistance.
We are greatly concerned about the specter of increasing
antimicrobial resistance. Our parents were the last generation
to grow up in the pre-antibiotic era.
Now, largely due to our own profligate misuse of these
wonder drugs, we face the real probability that our children
may live in a post-antibiotic era, in which infectious diseases
once again cannot be cured.
This is a textbook of pediatric medicine. It belonged to my
grandfather. He, like me, was a physician, but he practiced
before antibiotics were available.
If you read the treatments in this 1914 medical book, you
realize how helpless doctors once were against infectious
diseases. There was little they had to offer their patients but
to--to wait, to hope and too often to watch them die.
As a physician, I never want to go back to the helplessness
that underlies so much of this and other medical books of that
era.
Even rural States are well aware of the threat of
antimicrobial resistance. In 1976, multi-drug resistant
tuberculosis was diagnosed in an 18-year-old high school
student in Alcorn County, in rural north Mississippi.
Testing of his immediate contacts revealed an infection
rate of 50 to 80 percent. Subsequent testing of his entire
school found an infection rate of 21 percent.
Within a year, two of his classmates had developed multi-
drug resistant active tuberculosis. In all, between 1965 and
1977, 23 cases of drug-resistant TB were identified in the
county.
The outbreak demonstrated for the first time that multi-
drug-resistant tuberculosis could be transmitted from one
person to another. The outbreak was identified and investigated
by the State Department of Health with assistance from the
Centers for Disease Control.
It illustrates clearly the integral role that State public
health agencies play in addressing any emerging public health
threat.
Despite the important contributions of Federal agencies,
the initial detection, response and much of the control effort
will depend on State and local public health departments.
Recently, a survey of Mississippi clinical laboratories
found 40 percent or more of Staphylococcus aureus isolates to
have some level of penicillin resistance.
We also found that many labs in the State were not
performing resistance testing adequate to detect such
pathogens. As noted in the 1999 GAO report on Emerging
Infectious Diseases, this is the case in many States.
State health departments have a crucial role in two major
components of a national response to the threat of emerging
antimicrobial resistance. The detection of resistant organisms
and the prevention of their emergence.
State health departments will play a pivotal role in
detecting the development of resistant organisms. State laws
and regulations requiring the reporting of disease are the
basis of all disease surveillance. These laws and regulations
can be modified by States to require reporting of resistant
organisms.
Nebraska is one good example of States in which this is
already taking place. And at least 26 States have requirements
for the reporting of one or more forms of antimicrobial
resistance.
State public health laboratories are indispensable in
detecting antimicrobial resistance. Our public health
laboratories must maintain and expand their capacity to test
for drug resistance in organisms of public health importance,
especially those not addressed by routine hospital and
commercial laboratory work.
Preventing the emergence of new resistant organisms will
require changing patterns of antibiotic use by health-care
providers and the public. And the center of this effort will be
education of both providers and patients.
Most State and local health departments have relationships
and communication channels with their medical communities that
afford an excellent venue for ongoing provider education. While
national level action, as described previously, will be
necessary, State-based efforts will be the key to success.
Maryland's ``Use Antibiotics Wisely'' campaign in the
Baltimore area is an excellent example of this kind of effort.
To fulfill our responsibility in detecting and preventing
the emergence of drug-resistant microorganisms, States will
need help. Extending surveillance to include antimicrobial
resistance will require increased epidemiology staffing and
laboratory capacity in the States.
States cannot bear the cost of this alone. Funding from the
Federal level is needed as well. ASTHO commends this committee
for beginning to consider that need.
ASTHO particularly supports two significant national
efforts to address antimicrobial resistance. The first of these
is the Public Health Service's draft, ``Public Health Action
Plan to Combat Antimicrobial Resistance.''
This plan is a sound approach, providing a framework for
addressing all aspects of the issue, its implementation--and
funding--should be a national public health priority.
The second is legislation introduced by Senators Frist and
Kennedy. Their bill, S. 2731, includes Federal actions to
address antimicrobial resistance, as well as other urgent
public health threats.
Importantly, it also authorizes funding to respond to these
threats. Its provisions can contribute to restoring some of the
public health infrastructure described by the Institute of
Medicine as in disarray over a decade ago and still not
repaired.
PREPARED STATEMENT
Again, ASTHO commends this committee for moving to address
this important public health issue. And for myself, speaking as
a doctor and for other doctors like me, I ask you, Senator,
please do not send us back to the bed sides of our patients
with nothing more to offer than our grandfathers had.
Senator Cochran. Thank you, Dr. Thompson, for your
excellent statement. The illustration that you provide us is
very impressive. We do not want to go back to that earlier
generation.
[The statement follows:]
PREPARED STATEMENT OF ED THOMPSON
Mr. Chairman, and members of the committee, I am Dr. Ed Thompson,
State Health Officer of Mississippi, and past president and current
member of the Executive Committee of ASTHO, the Association of State
and Territorial Health Officials. I will speak today to the role of
states in addressing the challenge of antimicrobial resistance.
ASTHO, and the state health officials who make it up, are gravely
concerned about the specter of increasing antimicrobial resistance.
While advances in basic sanitation and the advent and use of effective
vaccines against a number disease agents are the backbone of most of
our progress in combating infectious disease, the development of
effective antibiotic agents made possible the control of such diseases
as TB and Syphilis, and rendered such former scourges as pneumonia and
wound infection treatable instead of fatal. Our parents were the last
generation to grow up in the pre-antibiotic era. Now, largely due to
our own profligate use of these ``wonder drugs,'' we face the real
possibility that our children may live in a `` post-antibiotic'' era,
in which infectious diseases can no longer be cured.
The book on the table in front of me is a textbook of pediatric
medicine. It belonged to my grandfather. Like me, he was a physician,
but he practiced before antibiotics were available. As you read the
``treatments'' described in this 1904 medical book, you realize how
nearly helpless doctors were when their patients became ill with
infectious diseases. The only thing they could really do was wait,
hope, and too often, watch them die. As a physician, I never want to go
back to the helplessness that underlies so much of this and other
medical books of that era.
STATE PERSPECTIVES
Even rural states are well aware of the threat of antimicrobial
resistance.
In 1976, Tuberculosis was diagnosed in an 18 year-old high school
student in rural north Mississippi. TB bacilli isolated from the
student were resistant to multiple antimicrobial agents. The student's
father had been diagnosed with multi-drug resistant TB 12 years
earlier, and had stabilized after erratic treatment. His mother had
died of TB 10 years previously; her organisms were not tested for
antimicrobial sensitivity. The father's drugresistant TB was found to
have re-activated.
Testing of the student's close contacts on the football and
baseball teams and in his classes found an infection rate of 50-80
percent. Subsequent testing of the entire school revealed a 21 percent
infection rate. Within a year, two of his fellow students developed
multidrug resistant TB. In all, from 1965 to 1977, 23 cases of drug-
resistant TB were identified in the county. Prior to this occurrence,
many experts believed that drug-resistant TB could not be transmitted.
This outbreak demonstrated for the first time that multidrug-resistant
TB could be spread from one person to another. The outbreak was
identified and investigated by the Mississippi State Department of
Health, with assistance from the Centers for Disease Control. It
clearly illustrates the integral and vital role of state and local
public health departments in dealing with any emerging public health
threat. Despite the critical and valuable activities of Federal
agencies, detection and first response, as well as much of the control
effort, will necessarily depend on state and local health departments.
The threat is not only real, it is imminent. A 1995-1996 survey of
Mississippi clinical laboratories found 40 percent or more of
Staphylococcus aureus isolates from six major hospitals covering all
parts of the state to have intermediate to high level of penicillin
resistance. We also found small but disturbing numbers of isolates of
vancomycin-resistant enterococci throughout the state. We also found
that many labs in the state were not performing antibiotic sensitivity
testing adequate to detect such pathogens. As noted in the 1999 GAO
report on Emerging Infectious Disease, this is the case in many states.
States have direct experience with another aspect of emerging
antimicrobial resistance: its cost. In 1990, Mississippi's public
health clinics treated roughly 14,000 cases of Gonorrhea. The drugs
used were oral ampicillin and probenicid. The cost of treatment was $1
per patient, resulting in a total expenditure of $14,000 annually. By
1991, due to the emergence of increasing penicillin resistance in our
gonococcal isolates, we began using ciprofloxacin as our standard
therapy. At a cost of $2 per patient, it cost us a total of $24,000 to
treat that year's 12,000 gonorrhea cases.
Even more dramatic is the effect of drug resistance on the cost of
TB therapy. In 1983 a Mississippi patient with multidrug resistant TB
had to be transported to National Jewish Hospital in Denver, at that
time the only institution in the country able to treat his disease. The
total cost of his treatment, at state expense, was $286,000, over a
quarter of our total inpatient TB budget for that year.
STATE FUNCTIONS AND CAPACITIES
Two major components of a national response to the threat of
emerging antimicrobial resistance in which states have a crucial role
are the detection of resistant organisms and the prevention of their
emergence.
In detecting the development of resistant organism, the traditional
role of state health departments in disease surveillance positions us
perfectly to play a pivotal role. State laws and regulations requiring
the reporting of disease are the basis of all such surveillance. These
laws can be modified as necessary to require reporting of resistant
organisms. Nebraska is but one example of states in which this is
already taking place. At least 26 states have requirements for the
reporting of one or more forms of antimicrobial resistance to the state
health department. The relationships developed by state health
departments with physicians, infection control practitioners,
laboratories, and hospitals in their states around general disease
surveillance will facilitate expansion of surveillance for resistant
organisms.
A key element in state-based national surveillance for
antimicrobial resistance is coordination and standardization of
reporting requirements. This responsibility falls to CDC and ASTHO's
affiliate organization, The Council of State and Territorial
Epidemiologists (CSTE).
State public health laboratories are an indispensable component of
a national approach to detecting antimicrobial resistance. Already a
source of reference laboratory services in our states, our public
health laboratories must maintain and expand their capacity to test for
drug resistance in organisms of public health importance. This is
particularly important for organism or drugs not routinely addressed by
hospital and commercial laboratories. Here, a key participant in all
planning is another ASTHO affiliate organization, the Association of
Public Health Laboratories (APHL).
Preventing the emergence of new resistant organisms will depend
heavily on changing patterns of antibiotic use by health care providers
and the public. The center of this effort will be education, of both
providers and patients.
Changes in antibiotic prescribing patterns can never be expected to
occur unless public expectations about antibiotics are changed. Efforts
must focus on educating the public about what antibiotics cannot treat,
to reduce demand for antibiotic prescriptions for viral or other non-
bacterial illnesses. Equally important, they must stress the proper use
of antibiotics by patients when they are properly prescribed: take the
whole bottle, don't ``share'' with family and friends, and don't self
treat.
State and local health departments can help in these educational
efforts, and can initiate many of their own. A coordinated national
educational campaign, however, is even more critical.
It is in the area of provider education that state health
departments can be the most important contributors. Most state and
local health departments have relationships and communication channels
with their medical communities that can afford the best venue for
ongoing provider education. In Mississippi, although most physicians
subscribe to a number of different publications, the only one that
uniformly goes to every physician licensed to practice in the state is
the monthly ``Mississippi Morbidity Report,'' a newsletter published by
the State Department of Health and well suited to disseminating
information about antimicrobial resistance and its prevention. Most
state health agencies have similar publications. Other key state-level
players are state medical associations, medical specialty societies,
and pharmacists' associations. While national level efforts will also
be necessary, these state-based efforts will be the key to success.
Maryland's ``Use Antibiotics Wisely'' program in the Baltimore area is
an excellent example of this kind of effort.
FUTURE NEEDS--THE NEXT STEPS
Despite the vital role states play in detecting and preventing the
emergence of drug resistant microorganisms, and our willingness to
fulfill that responsibility, we will need help. Extending surveillance
to include antimicrobial resistance is clearly within the power and
ability of states to accomplish, but it will require both increased
epidemiology staffing and laboratory capacity in the states. States
cannot bear the cost of this alone. Funding from the federal level is
needed as well. ASTHO commends this committee for beginning to consider
that need.
ASTHO particularly supports two significant national efforts to
address antimicrobial resistance as a public health threat. The first
of these is the CDC's draft ``Public Health Action Plan to Combat
Antimicrobial Resistance.'' This plan is a sound approach, providing a
framework for addressing of the issue. It incorporates the role of
State Health Departments as I have described them above. Its
implementation--and funding should be a national public health
priority.
The second is the legislation placed before the Senate by Senators
Frist and Kennedy. Their bill, S. 2731, includes federal actions to
address antimicrobial resistance as well as other urgent public health
threats. Importantly, it also authorizes funding to respond to those
threats. Its provisions contribute to restoring some of the public
health infrastructure described by the Institute of Medicine as ``in
disarray'' over a decade ago and still not repaired.
Again, ASTHO commends this committee for moving to address this
critical issue. And for myself, speaking as a doctor, and for other
doctors like me, I ask you, please: don't send us back to the bedsides
of our patients with no more to offer than our grandfathers had.
STATEMENT OF MARTIN ROSENBERG, Ph.D., SENIOR VICE
PRESIDENT AND DIRECTOR OF ANTI-INFECTIVES,
SMITHKLINE BEECHAM PHARMACEUTICALS
Senator Cochran. Dr. Martin Rosenberg is the senior vice
president and director of SmithKline Beecham Pharmaceuticals.
Dr. Rosenberg.
Dr. Rosenberg. Yes.
Senator Cochran. You may proceed.
Dr. Rosenberg. Thank you very much for the invitation to
come and present some information on this very important
subject.
What I would like to concentrate on, in fact, is the
industry response to this issue and, again, perhaps to go back
a little bit in time to be able to understand today's response
in relationship to what the industry has done previously.
As you indicated before, antibiotic resistance and the
discovery of antibiotics have almost come hand in hand from the
time when penicillin was first discovered 50 years ago. In that
first 25 years, the industry, of course, continued to identify
new compounds and a limited spectrum of compounds that were in
fact, the compounds that have been used for the last 50 years
to defend us against these micro-organisms.
In the second 25 years of that 50-year period, the industry
has been focused on derivatizing these same compounds, making
derivatives of these compounds, chemical derivatives such that
we now have these semi-synthetic antibiotics, which, in fact,
still work against the same targets in the micro-organisms but,
of course, what has been achieved is incremental increases in
potency and effectiveness, and therefore the industry as it
developed these limited set of materials that have basically
satisfied the unmet medical needs that we had during the
Seventies and Eighties of being able to defend us against
micro-organisms, basically felt that the job had been done.
And what had happened during the Eighties is that industry
began to turn much of its science to other unmet medical needs.
And what we saw certainly in the period of the Eighties was
industry start to move its research efforts to some of the--the
other diseases that were, of course, important as antibiotic--
as antibiotics were solving the unmet medical needs at that
time.
I think the awakening really came in the early Nineties.
And it really happened--you asked the question before as to
kind of how these--how these microbes all of a sudden appeared
or was it there all the time, well the resistance was there at
low levels all the time.
But it was really in the Nineties that we really began to
see maybe because of our surveillance methods became better,
but also because the bugs themselves had found solutions over
time, which they had cemented into themselves in such a way
that it was beginning to be very difficult to go back to non-
resistant types of pathogens.
Once these bugs can adapt, these incredible abilities to
avoid the limited set of compounds we had--and remember our
compounds were always derivatives of derivatives of the same
materials, and therefore the mechanisms that they achieved were
simply constantly catching up with our ability to destroy these
by the advancements we made.
And in that awakening in the early Nineties, I think the
industry all of a sudden began to realize that the products
that had been developed over the last 30 or 40 years were not
sufficient to deal with what could be the problem as it
continued to fester.
What happened at that time was very interesting. There was
quite a different spectrum of activities in the different
industrial components. Some industries continued to downplay
antimicrobials and kept their efforts in other areas of unmet
medical need, not thinking that the commercial success of these
compounds would allow them good return on investment.
Other companies, many of them still retain a watching brief
in this area. And a few companies have, in fact, seen that the
problem may be getting out of hand enough to start to reinvest
in this area.
Now, the problem with the reinvestment is that we had
basically run out of ways to discover antibiotics. The way we
discovered antibiotics originally was, of course, we grew
bacteria on plates, on petri dishes, and we screened for things
that killed them. And that gave us the limited number of
compounds that we have today to use against these bugs.
What happened in the Nineties, though, was, in fact, a
breakthrough in science, and as usual along with new scientific
technology comes this idea, often in industry and academia to
spur new avenues of discovery in this area.
And, of course, what we have all heard, we probably have
heard this term ``genomics'' in the--and the information
content that one can now obtain from any living organism.
We have heard just recently, of course, about the first
mapping of the human genome, but, of course, the same
technology has been applied over the last few years to many of
the pathogen genomes.
And from this information, from this new genomic
information coupled with new chemical technologies, what we now
have for the first time probably in decades are new discovery
strategies to identify new and novel antibiotic materials that
work through novel mechanisms of action, in other words work on
systems in the bacteria that were unknown prior to, in fact,
the advent of this information.
And it is now that information, which will form the basis
of some of the new strategies to develop new antimicrobial
agents for the 21st Century.
However there is a problem here. And that problem really
extends from the fact that the investments for industry to do
this are tremendous, huge investments. The lead time--you asked
again about that concern of is this problem now or is it soon
to be in the future?
You have to remember that the lead times to do discovery
and to commercialize are often a decade of time goes by before
you actually get these products to market. And the risks are
incredibly high.
And because of that and because of the competition, because
of genomic information also leading to new breakthroughs in
cancer, and Alzheimer's disease, and all of the other diseases
that the pharmaceutical industry can invest in, this area of
antimicrobials has to compete with those areas and therefore it
has to compete on the commercial basis as to what the industry
is willing to invest.
And therefore one of the key requirements will be, of
course, that there is a commercially supportive environment
that has to be created to be able to take this new information
and allow the industry to continue that investment to produce a
new wave of antibiotics in the future.
PREPARED STATEMENT
And, of course, as I think Dr. Henney said, that will
require very interesting collaborations with government and it
will probably require appropriate incentives for people to be
able to make these investments at a time when the commercial
interests in this is a difficult sale within the pharmaceutical
industry.
Senator Cochran. Very interesting statement. We appreciate
so much your being a part of this panel and giving us this
perspective.
[The statement follows:]
PREPARED STATEMENT OF MARTIN ROSENBERG
The occurrence of microbial resistance is predictable, inevitable
and can only worsen in the absence of the discovery of new mechanism of
action antibiotics.
Bacteria are relentless and highly efficient at evolving and
adapting. For each human generation, bacteria undergo 100,000
generations--more than all mankind has undergone. Bacteria can pass
resistance to their progeny, as well as to their neighbors, even other
species of bacteria. Bacteria utilize a variety of ingenious mechanisms
to defeat antibiotics including: modifying the antibiotic to
inactivity, pumping them out of the bug, becoming inpenetrable to the
drug and by altering or adding gene information such that the target of
the antibiotic is ignored.
Antibiotics were first discovered only 50 years ago; however, there
has only been one new class of antibiotic developed in the past 25
years. Why has this happened?
The current arsenal of drugs satisfied the medical need until
recently. Industry shifted resources to other areas of higher unmet
medical need. Basic research funding also shifted to human biology due
to new advances in molecular approaches. Moreover, there were no new
strategies for discovering antibiotics--efforts remained focused on
derivative improvements of current medicines. The shift in scientific
emphasis have led to a shortage of scientific expertise in certain
areas of microbial research.
But all the news isn't bad. The technical advances of the 1990s, in
particular genomics, are revolutionizing our ability to study the very
genes that define a living organism. Genomics provides access to the
entire genetic dictionary of any biological species--both man and
microbe.
For the first time, genomics is unveiling many new potential
targets for antibiotic discovery. Our current antibiotics work against
only a handful of bacterial targets; fewer than 15. Genomics gives us
access to scores of potential new targets for drug discovery. This
information also enables us to create tests for rapid diagnosis and
improve our surveillance methods for resistant organisms. Thus, our
current technology advances will help us achieve the rationalization of
antibiotic prescribing practices--that is prescribing the appropriate
antibiotic at the right dose and duration for the infection and thereby
reduce empirical prescribing. Most importantly, these new technologies
provide for the first time in decades, new strategies for discovering
novel antibiotics.
However, it must be recognized that application of this research to
antibiotic drug discovery and development requires a large investment
of resources, long lead times and carries high risks. It is imperative
that these research efforts progress in a commercially supportive
environment. Investments required to commercialize new antibiotics will
only be sustained if regulatory and market forces allow sufficient
returns to be achieved relative to other areas of medical need. It is
imperative that government and industry work together to identify ways
to promote the development and appropriate use of priority anti-
infective products for which market incentives are inadequate.
To accomplish this requires effort and resources on the part of
governments, academia and industry alike. Significantly reducing the
severe medical consequences resulting from the growth of microbial
resistance can only be accomplished effectively through collaboration.
STATEMENT OF MERLE A. SANDE, M.D., PROFESSOR AND
CHAIRMAN, DEPARTMENT OF MEDICINE, CLARENCE
M. AND RUTH N. BIRRER PRESIDENTIAL ENDOWED
CHAIR IN INTERNAL MEDICINE, UNIVERSITY OF
UTAH SCHOOL OF MEDICINE
Senator Cochran. Dr. Merle Sande is Professor and Chairman
of the Department of Medicine at the University of Utah School
of Medicine.
We will hear from you next, Dr. Sande.
Dr. Sande. Thank you, Senator. My name is Merle Sande and I
guess I am the token clinician on the council.
I have been a primary physician in infectious diseases for
the last 35 years. And I will try to give you my perspective on
this problem.
In thinking about what happened, I really do not know how
we got into this mess. You know, 50 years ago, we were told by
astute microbiologists and infectious disease clinicians that
this would happen. They knew then that if we misused and abused
antibiotics, their life expectancy would be limited.
And in those days when a physician treated an infection, he
made a diagnosis. He isolated the organism and he treated very
specifically and very effectively.
These antibiotics were treated like gold and something
happened over the last 30 or 40 years that I really do not
understand. Somehow, it has become standard of care to treat
runny noses and fevers and coughs with antibiotics.
Now, I will bet you if I took a survey in this room today
and asked you all if you developed acute bronchitis with a
chronic or acute productive cough and green sputum and you went
to your physician, what would you expect? And I will bet you
that two-thirds of you would say, ``I want an antibiotic.''
And the facts are they do not work for bronchitis. They
have no effect for bronchitis. They do not work at all. But,
yet, we have that expectation.
And that today is our dilemma. And what they do do when you
treat bronchitis is they create a perfect environment for the
development of resistant strains.
So we have seen that--you have all heard this morning that
this problem is out of control. Antibiotic use is out of
control and the emergence of drug resistance is out of control.
Now, as Marty Rosenberg has said, I think that in the
past--and I think your question, Senator, was very astute, why
did we not act--we react before?
Well, you know, the drug companies always pulled us out.
They always found a new drug--a new drug for a new resistant
bug. And I think what--from the discussion that Dr. Rosenberg
has given, that I do not think we can expect the drug companies
to do that in the future.
I think we have to do it ourselves. Now, I think it is
important to remember that every time we use an antibiotic, we
create an environment for these resistant drugs to develop.
But there is one other point that has not come out yet this
morning and that is if you are on an antibiotic, you present a
very fertile home for an already drug-resistant bug that is
circulating in our environment.
Now, you asked a question about the pneumococcals. How--why
did it take so long? It turns out the pneumococcals took about
30 years to really express high-level penicillin resistance. It
took about six to eight mutations, but over this time there now
are about 12 clones. We call them the international clones of
high-level penicillin resistance.
And they spread in our noses and in our throats on 747's
throughout the world. Now, we were very interested in this
problem and we felt, well, that must mean that the--that the
airport hubs in the big cities would be the place where you
would find the antibiotic resistance.
So we actually went to southern Utah to some very small,
isolated farming communities to see if those ugly bugs had, in
fact, found these isolated farming communities. And sure enough
they were there.
Thirty percent of all the pneumococci in those highly
isolated communities were now resistant to penicillin and other
antibiotics and these were these international clones.
So the environment in those small communities that were
predisposed to this colonization was, in fact, as you would
expect, high-level antibiotic abuse.
Now, I think as a clinician we have a real problem. And I
am scared. There are infections out there that I can no longer
treat with antibiotics.
Dr. Henney mentioned the new recent advances in the
treatment of what we call VRE, which is vancomycin-resistant
enerococci. These drugs are fine but they do not kill the bug.
So if we have infections like on heart valves, with
endocarditis by these organisms, we cannot cure them. We have
got to cut the valve out in--in order to cure the infection.
We have had to change how we approach acute bacterial
meningitis. We now use two drugs rather than one. And we are
very concerned that next year we will not have any drugs to use
to treat bacterial meningitis.
I personally have seen failures in acute otitis media. I
have seen failures in pneumonia with drugs that from the
beginning of time--my time, have worked to treat these
infections and they no longer work.
So I think your--your comment this morning was very astute.
Are we overplaying this problem? I do not think we are
overplaying this problem at all.
I think this is an extremely serious problem. And I am
scared.
Now, on the good side of this, what is very interesting is
that once you take the pressure off, once you reduce the
antibiotic arena, these bugs will tend to dry up. They will
tend to disappear.
There is no selective advantage for this bacteria to have
resistant genes if they do not need them. So if, in fact, we
are able to reduce antibiotic use and abuse, change our
orientation towards the use of these drugs, I am fairly
convinced that we can markedly prolong the life of these drugs.
Now, how do we do this, and how do we approach this? This
is a real challenge. There is something about changing
physician behavior that has eluded scientists from the
beginning of time.
It seems like once we learn something it is very hard for
us to unlearn it and change our behavior. But there have been,
I think, some really interesting observations. And it seems
that it is possible.
There is a wonderful study done in Denver by Ralph Gonzalez
who is a professor at the University of Colorado. He used the
Kaiser system, 350,000 patients to study ways to influence
antibiotic use for the treatment of bronchitis.
So first of all he tried educating the physicians and the
health-care providers. It made no difference at all.
But then he used--CDC devised and designed information
packets. And these are very creative. And, in fact, they will
say--if I can sort of take some liberty here--that antibiotics
can be bad for your health.
And, in fact, if you go to a doctor and insist on an
antibiotic for an indication that is not there, in fact, it
will do harm because it will set you up and your children up
for colonization of resistant bugs. And then if they get
infected with those resistant bugs, they are going to be harder
to treat.
Now, approaching the families of this large cluster of
patients plus the physicians, they were able to reduce
antibiotic use by 40 percent. So it is possible, but I think
the key here is to educate the population, educate the
patients, educate the families that antibiotic use is, in fact,
bad for your health.
And I would like to see a much more aggressive national
agenda to achieve this. I would try to use the experience with
the anti-tobacco campaigns, because I think this is as serious.
And I would hit the families. And I would hit the schools.
And I would let the CDC lead this charge. I think that is a
very, very critically important initiative.
Now, I would also encourage the expansion of the current
surveillance and intervention methods used by the CDC. Dr.
Koplan gave you one example of VRE in Iowa and how effective
that has been.
But actually the CDC has been very effective in pilot
projects particularly through their hospital infections branch
and by using surveillance, giving feedback on the surveillance
and then supporting the professionals that are in place with
facts that they have been able to change behavior in hospitals
and reduce blood-stream infections by 40 percent.
And in some recent studies in ICU's, intensive care units,
they have actually, by controlling the use of antibiotics, been
able to reduce the drug-resistant bacterial infections by a
significant amount.
So I would like to see the CDC projects that have been
worked now go national. Let us put them into all the hospitals.
And I think this is one to--one way to control in-hospital
infections and the emergence of resistance.
Now, let me go back to the drug companies, because I think
this is a very complicated interaction, but I think we need the
drug companies on our side. I think that the public health
message that reducing antibiotic use for indications that are
not there is good. And I think that the drug companies in the
long term will do better profit-wise if they preserve their
drugs for a longer period of time.
Now, maybe we need to give them some relief on patent
times, extend the patent times. But to answer your question
specifically about patient directed advertising for
antibiotics, I think it stinks. I think it is a terrible thing.
It is totally going in the wrong direction. So what you are
doing with this is you are encouraging antibiotic use, when, in
fact, we need to be discouraging antibiotic use.
But I think a partnership between government, academia and
the--and the drug industry could work in the right direction if
handled in the right way, and I think that is a very important
thing to go after.
Now, one of my, I guess, pet peeves in terms of this area
is our new medical system of HMO's in which the orientation is
rapid fast delivery of medical care, get the patient in, get
the patient out, do not spend a lot of money on them, but keep
them happy.
Now, when you think about this, what this tends to create
is an adversarial relationship with those of us who are trying
to control antibiotic use. It is much easier if you see
somebody with a cold--and by the way 53 percent of the time
that a patient in this country goes to see a doctor for a cold,
they come out with an antibiotic. And it does no good at all.
But it is easier. It is faster. You do not use diagnostic
tests, just give them an antibiotic. And that is the most cost-
effective way to deliver medical care.
But it is just dead flat wrong. And that is why we got in
this trouble. So now I do not know how to do this but I think
there needs to be incentives for HMO's to play the game
correctly.
I think there need to be incentives whether it is through
JCHO or tax breaks or whatever it is for these HMO's to do
surveillance in their own organizations and reward the
physician for going along with the CDC-approved protocols that
use judicious antibiotics.
I think anything else is going to--is going to not work. So
I think this is another very important area.
And so finally I think that our future in medical care is
going to be focused on the use of computers. There are some
wonderful examples where clinical decision support systems have
worked to limit antibiotic use, reduce errors, and decrease
costs.
And one of the best is actually in Salt Lake City at the
LDS Hospital, where they have reduced antibiotic use by 40
percent; and costs and errors by about 50 percent over the last
12 years.
So I think supporting the development of these tools to
help young clinicians--now, I am afraid that some of us are too
old to respond well to computers, but I think the young
physicians will use these computer tools and help guide the use
of antibiotics in--in this arena.
So, Senator, I am delighted to be here today. I feel
passionately about this, because as a clinician I find myself
very concerned that tomorrow I will not have the tools of my
trade. I will not be able to treat these severe infections that
I have been treating for the last 35 years. And I really worry
about my grandkids. So thank you very much.
Senator Cochran. Thank you, Dr. Sande, for your very
helpful and informative, provocative, interesting presentation
to our committee this morning. We appreciate your being here
and we think it has been a valuable contribution.
STATEMENT OF ALICE M. CLARK, Ph.D., DIRECTOR, NATIONAL
CENTER FOR THE DEVELOPMENT OF NATURAL
PRODUCTS, UNIVERSITY OF MISSISSIPPI
Senator Cochran. Dr. Alice Clark is Director of the
National Center for the Development of Natural Products at the
University of Mississippi.
Dr. Clark, we welcome you and encourage you to present your
suggestions for dealing with this. You may have to emphasize
research coming from where you do.
Dr. Clark. Thank you. I will. Thank you.
Good morning, Senator Cochran. Thank you for the invitation
to be here and to provide input on this important topic.
I am, as the Senator noted, Alice Clark, director of the
Natural Products Center at the University of Mississippi. I am
also Professor of Pharmacognosy in the School of Pharmacy
there.
I will focus my comments today primarily on the role of
academic research in addressing the issue of antimicrobial
resistance. And I hope to leave you with three major messages:
the need for urgent attention to the problem; the need for
basic and applied research to discover and develop new drugs to
treat resistant pathogens; and the role of natural products in
this discovery process.
Antimicrobial resistance is an urgent and massive threat to
the health of our citizens. It transcends cultural, economic,
ethnic and geographic boundaries. It can and will affect anyone
anywhere as we have heard.
We have also heard that we are rapidly approaching a time
when infections that were once considered ordinary may become
life-threatening because we have no effective therapies for
them.
We have heard reference to the development of resistance to
vancomycin by enerococcus. This is a potentially deadly
combination that raises a fearful question that most people
neither want to ask nor hear, ``Now, what?''
Many of the pathogens that concern us are presently
fortunately familiar primarily to the health-care
professionals. We must do whatever is necessary to prevent
terms like VRE and MRSA and VISA--when we are not talking about
the credit card--from becoming so common in our community that
they become household names.
Although we have contributed to the problem, we are not
entirely to blame for it. It is important to remember that
antimicrobial resistance is also due to evolutionary adaptation
by the pathogens, which means that it will likely always exist
as it always has existed even in the earliest days of the
antibiotic era.
This means that we have to work hard to stay one step ahead
of the pathogens. We are now beginning to understand not only
the enormous magnitude of the problem, but also importantly
what causes resistance at both the molecular and systemic
levels, how and where it occurs. This understanding can empower
us to do something about the problem.
As a pharmacy educator, teaching antibiotics to senior
pharmacy students for 20 years, I have seen the effects of
antimicrobial resistance over this time. Unfortunately, I have
also known someone whose life was cut short by one of these
insidious pathogens that was no longer affected by drugs that
we once considered miracle cures.
And this, in spite of the fact, that dozens of new
antimicrobial drugs were introduced into the market over the
past few decades.
Unfortunately, though, the problem is that less than a
handful of these could be considered totally new classes of
antimicrobials acting by novel mechanisms. And even more
unfortunate and something that should serve as a call to arms
for all of us is that resistance is now being reported to many
of those few antibiotics that just a few short years ago were
considered breakthroughs for their time.
If we are talking about this in the classroom, then this
means it is happening in our communities, in our schools, and
in our daycares, in our nursing homes and in our hospitals. We
must act now to shift the balance of power back in our favor.
Research is needed to find solutions and keep pace with the
microorganisms, who clearly consider this a battle for life and
death, and we should as well. We simply must find ways to
restock our chemotherapeutic arsenal.
Academic researchers clearly have a role in this effort.
The frontiers of knowledge are pushed forward everyday by
academic researchers throughout this country.
The information that is generated in academic labs will be
a major factor in our overall success in turning the tide of
antimicrobial resistance. Information regarding everything from
understanding the magnitude of the problem, to understanding
how it is that microorganisms evade the action of antimicrobial
drugs, to identifying new compounds to serve as leads for drug
development.
Presently what is often referred to as the pipeline of new
drugs in this category is woefully inadequate. And so the
question specifically is how and where will the next new leads
be discovered.
The category of antimicrobial drugs is dominated by the
antibiotics, which is a term that is unfortunately often
misused. Antibiotics are by definition derived from natural
products.
In fact, most of our current antibiotics had their original
derivation from agents discovered from microorganisms that
occur commonly in our environment but principally through a
process that could best be described as random screening.
With today's technologies and information that search can
take place at a scale and with a focus never dreamed of by our
scientific forefathers. Nevertheless drug discovery and
development by its very nature remains a lengthy, iterative,
and expensive process built largely on two fundamental
questions: where do we search and how do we go about it?
In one approach, we learn all we can about the pathogen and
then find or design something that interferes with a critical
process in that organism. Certainly, the advances in genomics
that were referred to earlier have made this approach more
feasible and productive than could have been dreamed possible
even 5 years ago.
But we can also take what exists in the world, the
chemistry of nature and identify those substances that control
the pathogen and then study how they work. This approach has
yielded important successes, obviously in the antibiotics, but
also in other therapeutic categories, such as the anticancer
drugs taxol and campthothecin. There is every reason to believe
that similar successes will result from a systematic effort to
identify new natural products that are effective against drug-
resistant microbes.
But we must broaden the search beyond the commonly
occurring microorganisms of the environment, to include plants,
marine life and microorganisms from unusual environments. We
have not begun to tap the full potential of nature, which is a
vast and virtually unlimited source of novel chemical
structures with interesting biological effects.
What will be required to accomplish this? As in any
endeavor that threatens the security and well being of our
citizens, substantial resources must be directed to the effort
immediately.
We must improve the use of existing agents and we must
discover new agents. We must also accept the reality that
virtually any antimicrobial drug may have only a limited finite
life span of medical utility. Therefore, research and education
in anti-infective drug discovery and development are badly
needed.
Different strategies must be employed and all of these will
be important. There will be no single answer, no magic bullet.
We would no more rely on a single strategy to achieve a
military victory than we should to achieve important victories
against public health enemies.
The time is now to invest in people, facilities, equipment
and collaborative multi-disciplinary partnerships between
academia, government and the private sector. An investment now
will pay off in the future.
Who is to say that a substantial investment 20 years ago to
mount an aggressive, concerted effort to address this problem
might not have changed the balance of power, and we might be
today talking instead about the remarkable successes that can
be achieved through a concerted effort.
PREPARED STATEMENT
I urge each of us to do what we can so that 20 years from
now that is the story that can be told. Thank you.
Senator Cochran. Thank you, Dr. Clark. A very interesting
challenge that you put before us, and observations from your
experiences and knowledge and expertise are deeply appreciated
and helpful to the committee.
[The statement follows:]
PREPARED STATEMENT OF ALICE M. CLARK
Good morning Senator Cochran, committee members. Thank you for the
invitation to be here and to provide input on this important topic.
I am Alice Clark, Director of the National Center for Natural
Products Research and Professor of Pharmacognosy in the School of
Pharmacy at The University of Mississippi.
I will focus my comments today primarily on the role of academic
research in addressing the problem of antimicrobial resistance, and
hope to leave you with three messages: the need for urgent attention to
this problem, the need for basic and applied research to discover and
develop new drugs that will be effective against resistant pathogens,
and the role of natural products as potential leads for drug discovery.
As you have already heard from this distinguished panel,
antimicrobial resistance is an urgent, massive threat to the health of
our citizens, and transcends cultural, economic, ethnic and geographic
boundaries--it can and will affect anyone, anywhere.
You have also heard that we are rapidly approaching a time when
infections that were once considered ordinary may become life-
threatening because there may be no effective therapies for them.
We have helped to create this problem through our own behavior: a
combination of the overuse and misuse of antibiotics by the public and
healthcare providers, a diminished emphasis on research aimed at
understanding, preventing and controlling resistance and a diminished
emphasis on the education and training of researchers and healthcare
professionals who will be prepared to address this problem, now and in
the future.
The rapid development of resistance to vancomycin by Enterococcus
is a deadly combination of the most commonly acquired hospital
infection with the last resort drug--raising the fearful question no
one wants to ask or hear--Now what? Many of the pathogens that concern
us are, presently, familiar only to the healthcare professional. We
must do whatever is necessary to prevent terms like VRE, VISA, and MRSA
from becoming so common in the community that they become household
names. But, resistant Pnemococcus jumped from virtually nonexistent in
the early 80s to as high as 30 percent or more in some parts of the
country today.
Although it has been noted that we have contributed to this
problem, we are not entirely to blame. It is important to remember that
antimicrobial resistance is also due to evolutionary adaptation by
pathogens, which means that there will likely always be the development
of resistance, as there always has been. It was known even in the
earliest days of the antibiotic era that some strains of bacteria
developed resistance. This, in turn, means that we must work hard to
stay one step ahead of the pathogens, and this can only be achieved by
concerted efforts to keep track and predict trends in antimicrobial
resistance and, through basic and applied research, to develop
strategies to preempt or answer these threats.
Now, thanks in large part to the efforts of those conducting
surveillance and monitoring work, we are beginning to understand not
only the enormous magnitude of the problem, but, importantly, what
causes resistance at both the molecular and systemic levels. This
understanding is the first step in identifying workable solutions--
understanding can empower us to do something about the problem.
However, understanding, in and of itself, is not enough. We must apply
that understanding to developing ways to prevent and control
antimicrobial resistance.
As a pharmacy educator, teaching antibiotics to senior Pharmacy
students for 20 years, I have seen the effects of antimicrobial
resistance development over this time. Unfortunately, I have also, as
some of you may have, known of someone whose life was cut short by one
of these insidious pathogens that is no longer affected by the drugs we
once considered miracle cures--this, in spite of the fact that dozens
of new antimicrobials were introduced for clinical use over the past 20
years. In many cases, the principal distinguishing characteristic of a
newly introduced antimicrobial was that it was effective against a
specific resistant pathogen or overcame a specific type of resistance.
Yet, unfortunately, less than a handful of these could be
considered totally new classes of antimicrobials, acting by novel
mechanisms. Even more unfortunate, and something that should serve as a
clear and loud call to arms for all of us, is that resistance has been
reported to many of those few antimicrobials that were once considered
breakthroughs.
If we are talking about this in the classroom, then it is happening
in our communities, hospitals, daycares, and schools. We must act now
to change the course of this battle and shifting the balance of power
once again in our favor.
Research is needed to find solutions and keep pace with the
microorganisms, who are clearly in a battle for life or death--as we
should be. We simply must find ways to restock our chemotherapeutic
arsenal--ideally with multiple weapons that target different molecular
sites in the pathogens.
I believe there is a role for academic researchers in this war--the
frontiers of knowledge are pushed forward every day by academic
researchers throughout this country. The information that is generated
in academic laboratories will be a major contribution to our overall
success in turning the tide of antimicrobial resistance--everything
from understanding the magnitude of the problem to understanding the
specific mechanisms by which pathogens evade the action of
antimicrobial drugs to identifying new leads for drug development.
Presently, what is often referred to as the pipeline of new drugs
is woefully inadequate. Specifically, where and how will new leads that
can become the next antimicrobial drugs agents be discovered? The
category of antimicrobial drugs is dominated by the antibiotics, a term
which, unfortunately is often misused, even by professionals.
Antibiotics are, by definition, derived from natural products. Most of
the current antibiotics were originally derived from microorganisms
that occur commonly in the environment, principally through a process
that could best be described as random screening.
With today's technologies and information, the search can take
place at a scale and with a focus never dreamed of by our scientific
forefathers. Nevertheless, drug discovery and development, by its very
nature, remains a lengthy, iterative, and expensive process built
largely on two fundamental questions: where do we search and how do we
go about it?
In one approach we learn all we can about the pathogen, and then
find or design something that interferes with a critical process.
Certainly, the advancements in genomics make this approach more
feasible and productive than was possible even five years ago. The
discovery of new, selective molecular targets in resistant pathogens
will no doubt lead to advances in the discovery and design on new,
effective antimicrobial drugs.
We can also take what exists in the world, the chemistry of nature,
and identify those substances that control the pathogen, and then study
how they do this--this approach has yielded important successes in
other therapeutic categories, such as the anticancer drugs taxol and
camptothecin, and there is every reason to believe that similar
successes will result from a systematic effort to identify new natural
products effective against drug resistant microbes.
But, we must broaden our search to include other organisms,
especially plants, marine life, and microorganisms from unusual
environments. We've not begun to tap the full potential of nature,
which is a vast and virtually unlimited source of novel chemical
structures with a variety of biological effects.
It is estimated that there are more than a quarter million species
of terrestrial plants on our planet, yet less than 10 percent of these
have been investigated in any way, and certainly not for the presence
of novel natural products that may become new antibiotic leads. No
doubt, similar statistics could be quoted for other natural sources
such as marine life and unusual microbes.
What will be required to accomplish this?
As in any endeavor that threatens the security and well-being of
our citizens, substantial resources in the form of coordinated effort,
creative energy, synergy of effort, information, and funds must be
combined and immediately directed to address this threat.
We must improve the use of existing agents and we must discover new
agents. We must also accept the reality that virtually any antibiotic
may have only a finite lifespan of medical utility. The ``antibiotic
gap'' in new drugs must be filled through basic and applied
multidisciplinary research by creative, well-trained scientists from
all sectors. Research and education in anti-infective drug discovery
and development are badly needed.
Different strategies must be employed, and all will be important;
we would no more rely on a single strategy to achieve a military
victory than we should to achieve important victories against public
health enemies. There will be no single answer, no single strategy, no
single hero, no magic bullet; true success will only be achieved
through combined efforts.
The time is now to invest in people, facilities, and equipment, in
collaborative multidisciplinary strategies that maximize our
information and resources, and in creating and sustaining both physical
and intellectual enviromnents that foster partnerships between
academia, government, and the private sector to develop innovative
solutions.
Investment now will pay off in the future.
Who is to say that a substantial investment 20 years ago to mount
an aggressive, concerted multidisciplinary effort would not have
changed the balance of power and we might be talking today, instead, of
the remarkable successes that can be achieved through a rational,
planned, and concerted effort. I encourage each of us to do what we can
so that 20 years from now, that is the story that can be told.
STATEMENT OF MARK L. NELSON, Ph.D., SENIOR DIRECTOR OF
CHEMISTRY, PARATEK PHARMACEUTICALS, INC.
Senator Cochran. Dr. Mark Nelson is Senior Director of
Chemistry for Paratek Pharmaceuticals in Boston.
Welcome, Dr. Nelson.
Dr. Nelson. Good morning, Senator Cochran.
Senator Cochran. You may proceed.
Dr. Nelson. I am Dr. Mark Nelson, senior director of
chemistry for Paratek Pharmaceuticals. And we are a startup
company that grew out of research that I conducted with Dr.
Stuart Levy while at Tufts University School of Medicine in
Boston.
Dr. Levy is a world-recognized authority in the area of
antibiotic resistance, and was one of the first scientists in
the United States to sound the alarm about the threat of the
antibiotic resistance crisis.
Paratek, as a small company, is an emerging company
dedicated to the discovery of new antibiotics against these
resistant bacteria. I would like to speak to you today about
the uncertain future of antibiotics against infections common
today in the clinics and hospitals and to also explain to you
why antibiotics are a natural resource that must be studied,
researched and developed.
The development of new antibiotics is extremely important
to our national health while also being strategically important
to our national defense.
I would also like to describe some of the difficulties of
developing new antibiotics and steps that could be taken to
ensure a potent arsenal of antibiotics for the future.
Bacteria have been winning the war against antibiotics for
some time now, but the issue really became public in 1994 when
Newsweek had as its cover story, ``Antibiotics, the End of
Miracle Drugs,'' and they also said, ``Warning, no longer
effective against killer bugs.''
It was sometime later, though, that the scientific
community declared the antibiotic resistance problem the New
Apocalypse.
Both addressed the issues of antibiotics resistance
correctly and told the story of the emergence of these
superbugs, antibiotic-resistant bacteria.
In our country, we are seeing infections that are resistant
to all known antibiotics and are causing alarm within both the
scientific and public domains.
In the hospitals, ``superbugs,'' such as vancomycin-
resistant enerococci, are increasing in frequency and severity,
where if the patient develops these infections and vancomycin
does not work, the patient may die.
Other infections such as MRSA, which is an acronym for
resistant infection of a Staph, increases the costs of a
hospital stay dramatically, where the patient is kept in
isolation-type condition and expensive precautions must be
taken to stop the spread of this infection.
Earlier, I mentioned that antibiotics are a natural
resource, and once they become ineffective against an
infection, they are functionally useless. Because of this, we
must preserve and protect antibiotics as we would any natural
resource before these become an extinct species.
I also stated that antibiotics are of strategic importance
to our country, not only due to their economic benefit in human
health, but because of their use in national defense.
Biological weapons that may be antibiotic resistant is a very
real threat.
It has even been proposed that these weapons, such as
anthrax and other plagues, could be antibiotic resistant, so
that efforts to thwart a biological attack will be useless.
Developing an appropriate arsenal of antibiotics against
such an attack and preserving their use is of the utmost
importance as a counteractive measure.
Now, in the public eye, antibiotic resistance must be
addressed quickly with directives and solid objectives that
will preserve and increase the number of antibiotics that we
have to treat bacterial infections.
There also must be new research initiatives and funding
opportunities to study the antibiotic resistance phenomenon and
even more importantly to discover new antibiotics. Increasing
funding and research initiatives for both academia and
pharmaceutical development will help in the fight against
bacterial resistance, as the risks and difficulties of
developing antibiotics today are many.
The time it takes to discover a new antibiotic is ever
increasing, leaving still the time to develop, approve and
finally deliver a life-saving drug to the public.
And there is the role of education. Increasing funding to
institutions such as the NIH and the NSF, funding basic
research in the areas of the biological and chemical sciences
will also help in the fight against drug-resistant bacteria.
Even though the driving force of antibiotic development
today rests primarily with the private sector, technological
change and the production of new antibiotics will always start
with the efforts and dedication of scientists. And education
and training of scientists to study antibiotic resistance and
to produce new antibiotics will be key.
Legislation may also help in the discovery and production
of new antibiotics. Such measures, such as giving older
antibiotics extra legal and patent protection could also
increase our antibiotic arsenal.
Other mechanisms targeting increased collaboration between
pharmaceutical companies may also work to produce antibiotics
against superbugs. By fostering collaborations in industry, for
example, the Multilateral Initiative on Malaria, companies can
create partnerships to speed up the drug discovery and
development process and fight this and other microbial
diseases.
And the list of possible answers to the antibiotic--
antibiotic resistance question goes on.
I would like to conclude by sharing some history with you,
illustrating the importance of developing new antibiotics. In
1941, the U.S. Department of Agriculture was approached by
researchers from the United Kingdom, anxious for assisting and
helping them produce a substance that they found could fight
bacterial diseases for the first time. This antibiotic could
not easily be mass-produced to fight infections.
Our Government met their challenge and helped them to
produce their drug in large enough quantities just in time to
help cure the battlefield infections that were rampant in World
War II. That drug was penicillin.
PREPARED STATEMENT
It was the proactive role of our Government and its
involvement that eventually made antibiotics the life-saving
drugs that they are today. And now with the antibiotic-
resistance crisis at hand, the role of the government to
protect and aid in the development of new antibiotics is even
more crucial to the health, prosperity and security of our
nation.
Thank you and I welcome any questions you may have.
Senator Cochran. Thank you very much, Dr. Nelson, for your
contribution to our hearing and the insight that you have
provided to us.
[The statement follows:]
PREPARED STATEMENT OF MARK L. NELSON
Good morning Mr. Chairman and Committee members: I am Dr. Mark L.
Nelson, Senior Director of Chemistry for Paratek Pharmaceuticals, a
start-up biotechnology company that grew out of research that I
conducted with Dr. Stuart Levy while at Tufts University School of
Medicine in Boston. Dr. Levy is a world-recognized authority in the
area of antibiotic resistance, and one of the first scientists in the
United States to sound the alarm about the threat of the antibiotic
resistance crisis. Paratek is an emerging company dedicated to the
discovery of new antibiotics against antibiotic resistant bacteria.
I would like to speak to you today about the uncertain future of
antibiotics against infections common today in the clinics and
hospitals, and to also explain to you why antibiotics are a natural
resource that must be studied and developed. The development of new
antibiotics is extremely important to our national health while also
being strategically important to our National Defense. I would also
like to describe some of the difficulties of developing new
antibiotics, and steps that could be taken to insure a potent arsenal
of antibiotic agents for the future.
Bacteria have been winning the war against antibiotics for some
time now, but the issue really became a public one in 1994, when
Newsweek (March 28, 1994) had as its cover story the title
``Antibiotics--The End of Miracle Drugs'' and ``Warning: No longer
effective against killer bugs''. It was later that the scientific
community declared the antibiotic resistance problem ``The New
Apocalypse''. Both addressed the issues of antibiotic resistance
correctly and told the story of the emergence of ``superbugs''--
antibiotic resistant bacteria.
In our country, we are seeing infections that are resistant to all
known antibiotics, and are causing alarm within both the scientific and
public domains. In the hospitals, ``superbugs'' such as vancomycin
resistant Enteroccoci, are increasing in frequency and severity, where
if the patient develops these infections and vancomycin does not work
as the antibiotic of last resort, the patient may die. Other resistant
infections such as MRSA--an acronym for a resistant infection from a
common Staph bacterium, increases the costs of a hospital stay
dramatically, where the patient is kept in isolation and expensive
precautions must be taken to stop the spread of this infection.
Earlier, I mentioned that antibiotics are a natural resource. Once
they become ineffective against an infection, they are useless. Because
of this, we must preserve and protect antibiotics as we would any
natural resource, before antibiotics become an extinct species.
I also stated that antibiotics are of strategic importance to our
country, not only due to their economic benefit in human health, but
because of their use in National Defense. The use of biological weapons
that may use antibiotic resistant bacteria is a very real threat. It is
even been proposed that biological weapons such as anthrax and other
plagues (Yersinia pestis) could be antibiotic resistant, so that
efforts to thwart a biological attack will be useless. Developing an
appropriate arsenal of antibiotics against such an attack and
preserving their use is of the utmost importance as counteractive
measures.
Now in the public eye, antibiotic resistance must be addressed
quickly with directives and solid objectives that will preserve and
increase the number of antibiotics that we have to treat bacterial
infections. There also must be new research initiatives and funding
opportunities to study the antibiotic resistance phenomenon, and even
more important, to discover new antibiotics.
Increasing funding and research initiatives for both academia and
pharmaceutical development will help in the fight against bacterial
resistance, as the risks and difficulties of developing antibiotics
today are many. The time it takes to discover a new antibiotic is ever-
increasing, leaving still the time to develop, approve, and finally
deliver a life-saving drug to the public.
And there is the role of education. Increasing funding to
institutions such as the NIH and NSF, funding basic research in the
areas of the molecular and chemical sciences, will also help in the
fight against drug resistant bacteria. Even though the driving force of
antibiotic development today rests primarily with the private sector,
technological change and production of new antibiotics will always
start with the efforts and dedication of scientists. And education and
training of scientists to study antibiotic resistance and produce new
antibiotics will be key.
Legislation may also help in the discovery and production of new
antibiotics. Such measures, such as giving older antibiotics extra
legal and patent protection, could also increase our antibiotic
arsenal.
Other mechanisms targeting increased collaborations between
pharmaceutical companies may also work to produce antibiotics against
``superbugs''. By fostering collaborations in industry, for example,
the Multilateral Initiative on Malaria, companies can create
partnerships to speed up the drug discovery and development process,
and fight this and other microbial diseases.
And the list of possible answers to the antibiotic resistance
question and finding new antibiotic goes on.
I'd like to conclude by sharing some history with you, illustrating
the importance of developing antibiotics. In 1941, the U.S. Department
of Agriculture was approached by researchers from the United Kingdom,
anxious for assistance in helping them produce a substance they found
could fight bacterial diseases for the first time. This antibiotic
could not easily be mass produced to fight infections. Our government
met their challenge and helped them to produce their drug in large
enough quantities just in time to help cure the battlefield infections
rampant in VMI. That drug was penicillin. It was the proactive role of
our government and its involvement that eventually made antibiotics the
life-saving drugs they are today.
Now with the antibiotic resistance crisis at hand, the role of the
government to protect and aid in the development of new antibiotics is
even more crucial to the health, prosperity and security of our nation.
Thank you, and I welcome any questions you may have.
Senator Cochran. You mentioned in your written statement
the New Apocalypse. If we fail to act on this issue and this
challenge, what would you describe as the worst case scenario?
Dr. Nelson. The worst case scenario for the New Apocalypse.
Well, the New Apocalypse was described by the scientific
community and what could possibly happen if we do not have
antibiotics to fight a common drug-resistant infection that
could occur, such as a Staphoreus infection that was resistant
to such a drug like vancomycin.
Well, I would have to say it would be pandemonium. There
would be large loss of life. There would be flooding of
hospitals and it would be a crucial time in the health history
of the United States.
Senator Cochran. Is it your view that companies like yours
have a role to play, a special role maybe in the development of
new antibiotics?
Dr. Nelson. It is. Our company started out of academia. And
what has happened--in the early years it was very difficult to
develop and do research in this area.
Now, as the antibiotic resistance movement is growing and
people are understanding it, there is more opportunity for
smaller research labs to become active and to produce hopefully
new antibiotics.
Senator Cochran. I want to ask both you and Dr. Rosenberg
this question, some--it follows on the questions I have asked
earlier witnesses about what the government can do, what the
Federal Government particularly can do in terms of funding and
legislation? What incentives, in your view, should the Federal
Government provide firms in the pharmaceutical business to
develop new antibiotic treatments?
Dr. Rosenberg. I will start.
Senator Cochran. OK. Dr. Rosenberg.
Dr. Rosenberg. Yes. Well, there are a number of certain
things that can be done that have already been discussed and
that is basic research funding. And that is to be able to make
sure that our academic partners, our Government partners are
funded to be able to achieve the basic research ideas that
eventually find them their ways into the pharmaceutical sector.
The problem in the pharmaceutical sector comes from, in
fact, the enormous costs and lead times to develop these as
commercial products. And in the end, there has to be seen some
kind of return on investment for this industry for us to be
able to make that investment, particularly today when the
number of other therapeutic modalities that we suffer from and
the other diseases and unmet medical conditions attract those
investments.
And, of course, no matter how big a company you are, you
only have so much money to invest. And therefore you--those
investments are tracked by the level of unmet medical need and
the desire to return to our investors some kind of a return on
investment for what they have put in.
So then it comes down to: What are the kinds of incentives
that you have talked about? Some have been mentioned. There
could be effects on patents. One could think about extending
patents of antibiotics, new antibiotics, but one could also
think of having the industry create antibiotics that may never
make money themselves but incentivize them by, for example,
extending patents on other drugs they may produce.
And therefore the industry would certainly welcome the
ability to get its return on investment through some other
unmet medical need mechanism, through some other solution it
was providing and still be able to work on products that may
never unto themselves produce any revenues for the company. I
think those are all kinds of possibilities.
Senator Cochran. Yes.
Dr. Nelson.
Dr. Nelson. Patent protection increases would definitely
help to foster further development. Other areas would be, as
Dr. Rosenberg had mentioned, is education, developing programs
that, again, as I mentioned earlier, fostering relationships
between companies and even to change how legislature perceives
these collaborations.
In some cases, antitrust laws keep drug companies from
collaborating because of perceived monopoly of that market. And
that is actually one area that people have looked at to help
foster these relationships is to change or reexamine some of
those issues.
Senator Cochran. Let me ask Dr. Rosenberg this as well,
what can you do to more completely implement the guidelines for
using treatments for ear infections, sinusitis and the like?
Dr. Rosenberg. Well, I think what you would want to do is
address that question to probably Dr. Merle Sande, the
physician at the end, given that he is the one who has to
actually implement such guidelines.
Senator Cochran. Yes. Yes.
Dr. Rosenberg. I think he would be a better person to ask
that question.
Senator Cochran. OK. Dr. Sande.
Dr. Sande. Well, I actually think, Dr. Rosenberg, that you
can help.
I think that--well, let me back up. Guidelines are nice,
but when it comes down to a--guidelines are based upon public
health needs and also trying to take into account the patient/
physician relationship. But we have been taught in medical
school and throughout our training that our primary
responsibility is to our patient, not to the public health. And
I think that is a big mistake in our medical education and I
think it needs to change.
But when it comes down to sitting down with your patient
who says, ``Doc, I have got bronchitis, and I really want an
antibiotic.'' And you sit there and talk to that patient, you
know the guidelines are not going to support that.
But on the other hand, you have developed a relationship
with this patient that is sacred. So you take the easy way out.
You write a prescription for an antibiotic.
So I think you need to think of the incentives to the
physician to change that behavior. No. 1 I mentioned the study
in Colorado where the patient comes in and says, ``Doc, I love
you dearly. You have been giving me antibiotics for years, but
I just found out they were not doing me any good.'' Now, that
would help the physician a lot to go by the guidelines.
But the other way to approach it is to approach it from the
incentive way and that is why I mention the HMO's and how they
reward the physician. If the physician was rewarded in terms of
financial incentives or others, because he went along with the
guidelines, then he might question whether he should respond to
the patient's desire or not.
It is a complicated issue. But going back to the drug
companies, I think they can help sell guidelines by actually
utilizing their vast advertising potential to sell the public
health aspect of their drugs, how to use them correctly for the
benefit of all mankind, not just for the quick buck that may
occur this year and disappear next year.
Senator Cochran. What about the advertising problem? Is it
appropriate in your view? I will ask Dr. Rosenberg and Dr.
Nelson--to advertise and promote the use of antibiotics, should
we stop that right now, just like we stopped the advertising of
smoking, or cigarettes or tobacco products?
Dr. Rosenberg. I think the advertising issue is a complex
one and I think Dr. Henney really described it as the best.
People today want information. Now, whether that
information is about how they want to cure a variety of
diseases, they will want to get that information. The Internet
has proven that, and television advertising certainly has
proven that.
And therefore the complexity comes as to how you provide
information appropriately so that people are aware of new
discoveries and things that they might want to know about
versus what harm it does by giving them information that they
have to then act on.
Now, the advantage that we have always seen to this was
that standing between any information you give them and the
ability for them to get access to any of the drugs that are
advertised is a physician, supposedly a competent person who is
supposed to give them the proper advice. And they cannot get a
hold of that material until that physician scripts it on a
piece of paper. And therefore----
Senator Cochran. So we do not have on the counter, or off-
the-shelf purchases of antibiotics. That is not permitted? You
have to have a prescription right now to----
Dr. Rosenberg. You have to have a prescription for almost
all oral antibiotics in this country.
Senator Cochran. Almost all?
Dr. Rosenberg. Yes----
Senator Cochran. So there are some----
Dr. Rosenberg [continuing]. Other than the stuff that you
put on your cuts and the triple antibiotic creams that you put
on your cuts.
Senator Cochran. Right.
Dr. Rosenberg. Every other antibiotic has to be obtained
through seeing a physician and getting a script for it.
Senator Cochran. All right.
Dr. Rosenberg. Right.
Senator Cochran. OK. I did not give you a chance to answer
that.
Dr. Nelson. Well, I think Dr. Rosenberg hit on all the
points.
Senator Cochran. Gave a good answer, OK.
Dr. Nelson. Correct.
Senator Cochran. Well, should there be funding from the
Federal Government to help promote the guidelines to combat
antibiotic resistance? Is there any need for any special
funding programs that embody and endorse the use of guidelines?
What do you think?
Dr. Rosenberg. I think the guidelines are an important
start and one of the things that I think we have to recognize,
again, is that we are still dealing with empiric treatments;
and that is that the physician, particularly the general
practitioner, maybe not the infectious disease specialist, but
the general practitioner is still dealing with having to make
decisions without having all the tools available to them to
make that decision.
And therefore the guidelines provide some capability, some
context for them to make that correct decision. I think of
particular interest in the guidelines and in the thoughts that
have gone now into what antibiotics to use has been the fact
that the--it seems to be both laboratory data and now clinical
data seems to be indicating that the best way to treat these
infections so that they do not become resistant is, of course,
to use the most potent and best antibiotics.
We used to have a controversy in this area. It used to be
save the best to last. And that was use the older ones, save
the best to last.
Well, it turns out it is the older ones that often drive
resistance. And if there is a wonderful recent publication by
the World Health Organization, and if I could just quote you,
in fact, coming from their publication--it is called,
``Overcoming Antimicrobial Resistance,'' the WHO states the
most effective strategy against antimicrobial resistance is to
get the job done right the first time, to unequivocally destroy
the microbe,'' meaning dead microbes do not mutate. And
therefore that is how to best defeat resistance is to use your
best antibiotic up front--that kills bugs.
Senator Cochran. What characteristics of anti-infectives
fight antibiotic resistance?
Dr. Rosenberg, yes, sir.
Dr. Rosenberg. Yes. Well, there are a number of them.
Probably the best for antibiotics, of course, would be to have
new mechanism of action antibiotics, because they circumvent
the--all of the resistant mechanisms that have come forward in
using the older antibiotics that we have.
So I think it was mentioned several times that the classes
of antibiotics we have are still very few. You can count them
on just about two hands.
And because of that, if we can get outside of that scope
and be able to create antibiotics that see new targets, that
will be one of the greatest ways to circumvent the resistance
problems that we are now facing, our older antibiotics.
Senator Cochran. Dr. Clark, you noted that we should expand
our search for new antibiotic leads to sources that have not
been investigated such as plants, natural products. Could you
comment on the likelihood that new antibiotics may be found
from plants and other sources?
Dr. Clark. Yes, sir. I think as has been noted, the
majority of the antibiotics that we have on the market have
been found from a relatively small number and source of
microorganisms that occur, for example, in the soil.
We have just plants, as an example, there are over a
quarter million species of plants on this planet and less than
ten percent of them have been investigated in any way for any
of their chemistry and the biology of that--those chemicals.
And so certainly the odds would be in our favor that a
systematic evaluation of plants would generate new structures
with biological activities against these resistant pathogens.
Senator Cochran. Could you explain how you would envision a
collaborative, multi-disciplinary partnership between academia,
government and the private sector working?
Dr. Clark. Well, actually we have a very nice model for
that in the National Center for Natural Products Research,
where we have a partnership with a USDA agricultural research
service unit aimed at discovering new agricultural chemicals
and new pharmaceuticals from plants. And this is defined
through a memorandum of understanding and through partnerships
with the private sector to advance those discoveries once they
are made.
Senator Cochran. Coming from a pharmacy school as you have,
as a teacher there, you have been involved in educating
pharmacists. Can you comment on the role the pharmacist can
have in preventing and controlling the development of
antimicrobial resistance?
Dr. Clark. Gladly. I think this is interesting that in much
of the discussion we have had today about educating the
consumer and educating the physician, the pharmacist's role has
not been highlighted. And the practice of pharmacy today is
founded in pharmaceutical care, which is--has as its central
tenet, counseling patients regarding the proper use of
medication and working with other health-care professions
regarding the proper selection and use of medications; and
antimicrobials are certainly no--no exception there.
As one of the most accessible health-care professionals to
the general public, I think the pharmacists are in a unique
position to provide a real input and make a difference in this
issue, and it would educate both the consumer, the patient, and
the other health-care professionals.
Senator Cochran. I think you and Dr. Sande both mentioned
that over the past 20 years there have been dozens of new
antimicrobials, but that very few were really new or novel.
What does this mean in terms of emphasis and the importance of
our understanding that at this hearing?
Dr. Clark. I will take----
Senator Cochran. I will ask you, and then Dr. Sande to
comment on it, too.
Dr. Clark. I think that as Dr. Rosenberg pointed out, our
search for new antimicrobial agents really has to be broadened
and encompass the information available to us now so that we
can identify new mechanisms.
Having multiple classes of agents that affect multiple
targets, give us multiple weapons in this battle.
Senator Cochran. Now, Dr. Sande, you mentioned derivatives.
Most of the new drugs were derivatives of older drugs, is that
right? And is that----
Dr. Sande. That is right. And I think what has happened is
that the easy targets have been exploited.
Bacteria have just a certain number of ways that you can
attack them by. And the ones that are easy to screen, and these
multiple screening that the pharmaceutical companies tend to
do, have I think exploited the easy targets. So it makes sense
then that by slight modification of old drugs, maybe you can
develop a drug that will fight a resistant enzyme or will fight
a way that the bacteria has mutated around the effect.
But you just manipulate the molecule. I think what Dr.
Rosenberg said is absolutely crucial. The future is going to be
dependent upon finding new targets. And now with this whole new
field of bacterial genomics that should become possible.
But it is going to be slow and it is going to be expensive.
And that is what makes me the most concerned is that the
pharmaceutical companies are going to look at the bill for this
and they are going to say, ``Hey, I have got other areas that I
can make more money in. That by getting deep into this area,
which is a real craps shoot and a fishing expedition.''
So I think that is where the government can help. I think
by some of the techniques we have talked about they can
encourage this long-term investment by the pharmaceutical--if
it does not happen, no matter how much we control antibiotics,
I think eventually these bugs are going to get resistant to the
current groups of drugs that we have.
We are going to need new drugs.
Senator Cochran. Dr. Thompson, should there be a national
reporting requirement for antimicrobial resistance. You talked
about your effort to identify and screen in one county in
Mississippi for tuberculosis that was resistant. Should there
be a reporting requirement? Should you have had to report that
to a national center?
Dr. Thompson. Well, the short answer, Senator, is no. But
there should be national surveillance of antibiotic resistance.
One part of surveillance is the required reporting of
diseases. And this takes place both practically and
constitutionally at the State level.
It is to State health departments that there should be
required reporting of appropriate level of antibiotic
resistance as there is now for a variety of infections without
regard to their antibiotic sensitivity.
We have no national reporting requirements for any disease,
nor--and speaking now for ASTHO--should we ever have. This
should always remain coordinated by the CDC and an affiliate of
ASTHO, the Council of State and Territorial Epidemiologists.
We should have a national list of diseases that should be
made reportable by the States, but to make the final decision
that it is a reportable condition by law, this is a State
decision. And we are firmly committed to this being the best
way to do it. And it works very, very well for the dozens of
diseases that are now reportable.
The same model can work well with antibiotic resistant
organisms.
Senator Cochran. Do you have any difficulty with hospitals
and physicians who refuse to report or just are negligent about
reporting these? How do you overcome that challenge?
Dr. Thompson. Well, with--one of the biggest problems you
have with hospitals and physicians--and I am sure that my
clinical colleagues have seen this as well--it is the kind of
``I thought it was your uncle'' problem.
A man is talking to his wife and he says, ``Listen, your
uncle has been here for 2 weeks. He is eating us out of house
and home. I am tired of it. He has got to go home.''
And she says, ``My uncle? I thought he was your uncle.''
And that is the sort of thing you often see in a large
academic institution, a variety of people each thinking the
other has reported the condition appropriately, all failed to
do so. And coordinating that, making sure that there is someone
who is responsible for that; and here the infection control
practitioner in the hospital, typically a nurse, is the key to
this sort of thing.
That is, again, the sort of thing that State health
departments can work very effectively in. By developing
relationships with the societies of infection control
practitioners in their local jurisdictions, they can develop a
communication channel that an infection control practitioner
knows that it is to be reported. She takes--or he--takes the
responsibility for making sure that it gets reported.
Senator Cochran. Can your laboratory process the specimens
and handle the additional reporting requirements? And if this
is a problem, how do we address it and does the Federal
Government have a role in that?
Dr. Thompson. Well, yes, Senator, you do. We--we said in,
in fact, the GAO report in 1999 commented on the fact that--
that most States do not require reporting of very many
antimicrobial resistant organisms, and in particular they do
not require the submission of specimens from clinical
laboratories to the State department of health laboratory for
further testing and for testing for specialized patterns of
resistance.
The reason we do not is two-fold. One, we have only come to
realize in relatively recent years that there is a need to do
that. But even more importantly, even once we know it must be
done, we cannot process the specimens without additional staff,
without some additional laboratory space, without some
expansion, some additional technology, some increase in the
amount of existing technology we have got.
And until we are able to actually carry out the laboratory
work that would be required in processing those specimens, we
cannot require the submission of those specimens to us. So we
need more resources, some of which must come from the States
themselves.
We cannot look to the Federal Government for the entire
cost of this. But at the same time, we do need Federal support
for this in much the same way that you have provided fairly
recently support for increased State capacity in the area of
bio-terrorism response, most recently in the area of arboviral
surveillance, with regard to West Nile surveillance.
The Federal funds that you have provided to the States have
been--have enabled us to expand what we were already doing to
cover new pathogens without supplanting what we were already
doing. We simply supplement that and make our efforts greater.
A similar effort in terms of Federal funding is going to be
needed for antimicrobial resistance at the State health
department level.
Senator Cochran. Thank you very much. This has been an--an
excellent panel in a cross-disciplinary approach to informing
and educating the--the Senate on how we can better respond to
this very important challenge that we face.
And I think the description of it by the first panel, our
CDC director and the commissioner of the Food and Drug
Administration set the tone for the importance of it and the
seriousness of it, the comprehensive plan that has been put
forward by those two agencies and NIH.
And now with the pharmacy, educators, the companies, the
clinicians represented and the State health organizations from
around the country represented, I think we have a much better
understanding of things that we can do and that we should try
to do quickly to help deal with this problem.
And so your participation has been very helpful and very
important to us. And we thank you all very much.
CONCLUSION OF HEARING
Thank you all very much for being here. That concludes our
hearing. The subcommittee will stand in recess subject to the
call of the Chair.
[Whereupon, at 11:28 a.m., Wednesday, September 20, the
hearing was concluded, and the subcommittee was recessed, to
reconvene subject to the call of the Chair.]