```

[Senate Hearing 106-859]
[From the U.S. Government Publishing Office]

                                                        S. Hrg. 106-859

                        ANTIMICROBIAL RESISTANCE

=======================================================================

                                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

                               __________

                    U.S. GOVERNMENT PRINTING OFFICE
67-868                     WASHINGTON : 2001

_______________________________________________________________________
            For sale by the U.S. Government Printing Office
Superintendent of Documents, Congressional Sales Office, Washington, DC 
                                 20402

                      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
                                 ------                                

 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

                              ----------                              
                                                                   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

                              ----------                              

                     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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to fluconazole. Antimicrob Agents Chemotherapy 1995;39:1-8.
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Staphylococcus aureus in two child care centers. J Infect Dis 
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Antibiotic-Resistant Bacteria, OTA-H-629, Washington, DC: U.S. 
Government Printing Office, September 1995.
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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.]

                                   
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