```

[Senate Hearing 110-989]
[From the U.S. Government Publishing Office]

                                                        S. Hrg. 110-989

   EMERGENCE OF THE SUPERBUG: ANTIMICROBIAL RESISTANCE IN THE UNITED 
                                 STATES

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

                                HEARING

                                 OF THE

                    COMMITTEE ON HEALTH, EDUCATION,
                          LABOR, AND PENSIONS

                          UNITED STATES SENATE

                       ONE HUNDRED TENTH CONGRESS

                             SECOND SESSION

                                   ON

    EXAMINING THE PUBLIC HEALTH IMPACTS OF ANTIMICROBIAL RESISTANT 
    BACTERIAL INFECTIONS IN THE UNITED STATES, FOCUSING ON CURRENT 
   ANTIMICROBIALS AND CONTINUED DEVELOPMENT OF NEW SOLUTIONS FOR THE 
             FUTURE PROTECTION AGAINST INFECTIOUS DISEASES

                               __________

                             JUNE 24, 2008

                               __________

 Printed for the use of the Committee on Health, Education, Labor, and 
                                Pensions

  Available via the World Wide Web: http://www.gpoaccess.gov/congress/
                                 senate

                  U.S. GOVERNMENT PRINTING OFFICE
43-267 PDF                WASHINGTON : 2010
-----------------------------------------------------------------------
For sale by the Superintendent of Documents, U.S. Government Printing 
Office Internet: bookstore.gpo.gov Phone: toll free (866) 512-1800; DC 
area (202) 512-1800 Fax: (202) 512-2104  Mail: Stop IDCC, Washington, DC 
20402-0001

          COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS

               EDWARD M. KENNEDY, Massachusetts, Chairman
CHRISTOPHER J. DODD, Connecticut     MICHAEL B. ENZI, Wyoming
TOM HARKIN, Iowa                     JUDD GREGG, New Hampshire
BARBARA A. MIKULSKI, Maryland        LAMAR ALEXANDER, Tennessee
JEFF BINGAMAN, New Mexico            RICHARD BURR, North Carolina
PATTY MURRAY, Washington             JOHNNY ISAKSON, Georgia
JACK REED, Rhode Island              LISA MURKOWSKI, Alaska
HILLARY RODHAM CLINTON, New York     ORRIN G. HATCH, Utah
BARACK OBAMA, Illinois               PAT ROBERTS, Kansas
BERNARD SANDERS (I), Vermont         WAYNE ALLARD, Colorado
SHERROD BROWN, Ohio                  TOM COBURN, M.D., Oklahoma
           J. Michael Myers, Staff Director and Chief Counsel
        Ilyse Schuman, Minority Staff Director and Chief Counsel

                                  (ii)

                            C O N T E N T S

                              ----------                              

                               STATEMENTS

                         TUESDAY, JUNE 24, 2008

                                                                   Page
Brown, Hon. Sherrod, a U.S. Senator from the State of Ohio, 
  opening statement..............................................     1
Tenover, Fred C., Ph.D., Director of the Office of Antimicrobial 
  Resistance, Centers for Disease Control and Prevention, 
  Atlanta, GA....................................................     3
    Prepared statement...........................................     5
 Hatch, Hon. Orrin G., a U.S. Senator from the State of Utah, 
  statement......................................................    11
Tollefson, RADM Linda R., D.V.M., M.P.H., Assistant Commissioner 
  for Science....................................................    12
    Prepared statement...........................................    14
Noble, Brandon, Former NFL Player and MRSA Survivor, Chester 
  Springs, PA....................................................    27
    Prepared statement...........................................    29
Brennan, Patrick J., M.D., President, The Society for Healthcare 
  Epidemiology of America, Philadelphia, PA......................    30
    Prepared statement...........................................    32
Graham, Jay P., Ph.D., MBA, Consultant, The Pew Commission on 
  Industrial Farm Animal Production, Baltimore, MD...............    36
    Prepared statement...........................................    37
Vogel, Lyle P., D.V.M., M.P.H., DACVPM, Assistant Executive Vice 
  President, American Veterinary Medical Association, Schaumburg, 
  IL.............................................................    41
    Prepared statement...........................................    42
Eisenstein, Barry I., M.D., Senior Vice President of Scientific 
  Affairs, Cubist Pharmaceuticals, Inc., Lexington, MA...........    49
    Prepared statement...........................................    51

                          ADDITIONAL MATERIAL

Statements, articles, publications, letters, etc.:
    Durbin, Hon. Richard J., a U.S. Senator from the State of 
      Illinois...................................................    66
    Response by Fred C. Tenover, Ph.D. to questions of:
        Senator Kennedy..........................................    67
        Senator Enzi.............................................    69
        Senator Brown............................................    70
        Senator Burr.............................................    72
    Response by the Department of Health and Human Services, Food 
      and Drug Administration, to questions of:
        Senator Kennedy..........................................    74
        Senator Brown............................................    77
        Senator Burr.............................................    80
    Response by Patrick J. Brennan, M.D. to questions of:
        Senator Kennedy..........................................    81
        Senator Brown............................................    82
        Senator Burr.............................................    82
    Response by Jay P. Graham, Ph.D., MBA to questions of:
        Senator Kennedy..........................................    98
        Senator Burr.............................................    99

                                 (iii)
  
    Response by Lyle P. Vogel, D.V.M., M.P.H., DACVPM to 
      questions of:
        Senator Kennedy..........................................   102
        Senator Brown............................................   105
        Senator Burr.............................................   107
    Response by Barry I. Eisenstein, M.D. to questions of:
        Senator Kennedy..........................................   110
        Senator Brown............................................   111
        Senator Burr.............................................   111
        Senator Hatch............................................   112

  

 
   EMERGENCE OF THE SUPERBUG: ANTIMICROBIAL RESISTANCE IN THE UNITED 
                                 STATES

                              ----------                              

                         TUESDAY, JUNE 24, 2008

                                       U.S. Senate,
       Committee on Health, Education, Labor, and Pensions,
                                                    Washington, DC.
    The committee met, pursuant to notice, at 10:33 a.m. in 
Room SD-430, Dirksen Senate Office Building, Hon. Sherrod 
Brown, presiding.
    Present: Senator Brown, Sanders, Burr, and Hatch.

                   Opening Statement of Senator Brown

    Senator Brown. The Senate Health, Education, Labor, and 
Pensions Committee will come to order. Thank you. Thank the 
witnesses for joining us. Thanks all of you in the audience for 
joining us for this important hearing today.
    I would notify people that there will be a vote on the 
Senate floor at 11 o'clock. So we will temporarily recess the 
committee and come back as soon as I can go vote and return.
    I'd like to thank our witnesses on both panels for being 
here today. Thank you very much. We welcome your insight as the 
committee examines the phenomenon that clearly has not received 
the public attention that it deserves.
    Over the last year we've seen news reports about outbreaks 
around the country of dangerous infections for which there are 
increasingly fewer treatment options. One of the most common is 
a strain of staph infection that's resistant to penicillin and 
other related antibiotics commonly referred to by the acronym 
as you know, MRSA. While MRSA was previously thought to occur 
only in hospital settings, that's bad enough. Americans have 
begun to contract it in the community, at schools and through 
sporting events primarily.
    Last year the Journal of the American Medical Association 
reported that MRSA infections occur in approximately 94,000 
people each year and are associated with approximately 19,000 
deaths. That supercedes deaths from AIDS, a scourge that has 
taken hard thinking in legislation to help treat. MRSA is a 
wake up call. It signals the need, the urgent need to confront 
antimicrobial resistance.
    Antimicrobial resistance can occur whenever antibiotics are 
not used appropriately, when doctors over prescribe, when 
patients don't understand the importance of taking their full 
course of therapy, when animals are fed antibiotics to maintain 
health rather than to restore it and when in various ways 
antimicrobials find their way into the environment. All of this 
takes its toll. In recent years infections that used to be 
easily treated with antimicrobials are now drug resistant 
leading to much more serious, sometimes life threatening 
infections.
    We will hear testimony today from Brandon Noble who will 
share how his MRSA infection has had such a profound effect on 
his life. Thank you Brandon, again, for being here.
    Unfortunately MRSA is just one of the drug resistant 
infections setting the clock back on modern medicine. When our 
soldiers come home from Iraq and Afghanistan they may face yet 
another deadly threat, drug resistance strains of 
acinetobacter. There are numerous drug resistant organisms, 
some of which could be avoided with better infection control 
practices on the part of medical personnel and hospitals and 
even simple hand washing as CDC repeatedly suggests us to do.
    Our witness, Dr. Brennan, will elaborate on the issue of 
hospital-based infection control. It's clear we also need new 
antimicrobial agents which simultaneously move medical science 
forward. And make up for the ground lost to drug resistance.
    But, there are barriers to creating new antibiotics. One of 
these barriers simply is profitability. Except in a rare case, 
the antibiotics are short-term treatments which means they 
don't bring in as much revenue as those for chronic problems. 
We'll still hear from Dr. Eisenstein and Dr. Tollefson about 
some of the challenges we face in antibiotic development.
    We'll also hear from Dr. Tenover of the CDC, who will 
describe efforts there to track and combat antimicrobial 
resistance. Doctors Graham and Vogel will speak about the use 
of antimicrobials in animal feed, an issue that I worked on in 
the House almost a decade ago. Chairman Kennedy has been 
instrumental in raising the profile of this important issue.
    In my State of Ohio there were 12 outbreaks of MRSA last 
year. Ohioans contracted MRSA in health care settings, in the 
workplace, on sports team, in correctional facilities. I would 
like to relate the story of Dr. Froncie Gutman of Chagrin 
Falls, chairman of ophthalmology for 22 years at the Cleveland 
Clinic.
    In April of last year, Dr. Gutman came down with pneumonia. 
By the time he went to the hospital he was semi-conscious. He 
was given an antibiotic common in the treatment of bacterial 
pneumonia.
    After a week he wasn't getting better. His blood pressure 
dropped. He was going into septic shock and his kidneys were 
shutting down. The doctors were not able to identify the 
organism that was causing the infection.
    He was taken to surgery where a portion of his lung was 
removed. They were able then to identify the organism which was 
MRSA. Dr. Gutman was in a coma for more than a week. He 
fortunately regained consciousness. With the help of a newer 
antibiotic called Zyvox, Dr. Gutman is recovered.
    The message Dr. Gutman asked us to convey about his 
experience is this, no matter the quality of care he received 
at the Cleveland Clinic, Dr. Gutman would not be alive today 
without Zyvox. Now he's concerned about what will happen when 
these organisms adapt to Zyvox. The same story.
    Antimicrobial resistance is a powerful counter force 
undermining our Nation's progress against infectious disease. 
We shouldn't underestimate it. We obviously can't ignore it.
    My friend, Senator Hatch, and I introduced the strategies 
to address Antimicrobial Resistance Act to reinvigorate efforts 
to combat antimicrobial resistance, efforts that accelerated in 
the 1990s and then stalled. Our bill would launch a coordinated 
effort to prevent outbreaks of MRSA and other dangerous drug 
resistant infections. It would jump start research on 
superbugs. It would explore strategies to ensure a more robust 
pipeline, if you will, for new antibiotic drugs.
    I thank Senator Hatch for his leadership on this issue and 
for introducing the bill with me. I look forward to hearing 
from our witnesses whose testimony will no doubt underscore the 
importance of moving quickly and decisively against this major 
public health threat.
    The first panel is Dr. Fred Tenover and Linda Tollefson. 
Dr. Tenover is the Director of the Office of Antimicrobial 
Resistance at the CDC. He is also Director of the World Health 
Organization's collaborating Center for Global Monitoring of 
Antimicrobial Resistance and an adjunct professor of public 
health at Emory University, my mother's alma mater. He serves 
on the editorial boards of antimicrobial agents and 
chemotherapy antimicrobial drug resistance. He has been author 
or co-author of over 290 journal articles and 31 book chapters. 
Thank you for joining us, Dr. Tenover.
    Linda Tollefson before her appointment as Assistant 
Commissioner for Science at the FDA, Admiral Tollefson served 
as Deputy Director of the Center for Veterinary Medicine. She 
also directs FDA's Offices of Women's Health and Orphan 
Products Development. She's received many public health service 
awards and honors including her notorious service, the 
outstanding service, the commendation medals for his leadership 
in the Commission Corps.
    Thank you both for testifying and especially thank you for 
your public service to our government and to our country. Dr. 
Tenover, if you would begin. Thank you.

     STATEMENT OF FRED C. TENOVER, PH.D., DIRECTOR OF THE 
OFFICE OF ANTIMICROBIAL RESISTANCE, CENTERS FOR DISEASE CONTROL 
                  AND PREVENTION, ATLANTA, GA

    Mr. Tenover. Thank you and good morning, Chairman Brown. I 
am Dr. Fred Tenover. It is my pleasure to be here today in my 
capacity as the Director of the Office of Antimicrobial 
Resistance at the Centers for Disease Control and Prevention to 
discuss with you our growing concerns about the problem of 
antimicrobial resistance.
    CDC appreciates this opportunity to share information with 
you. While antimicrobial resistance is not a new issue for the 
CDC, the fact that so many different types of microorganisms 
are becoming resistant to antibiotics is of major importance. 
Increasing rates of resistance among bacteria, fungi, viruses 
and even parasites are clearly limiting our options for 
treating individual patients and are causing the medical 
community to change many long established treatment regiments 
to more complex antimicrobial agents or combinations of agents 
instead of a single drug.
    A small but growing subset of bacterial strains that cause 
health care associated infections like the acinetobacter and 
pseudomona species have become resistant to all available 
antimicrobial agents. Other infections such as those caused by 
the bacterial species Clostridium difficile often cause 
debilitating diarrhea or even more severe disease in patients 
that have received antibiotics for other infections. This shows 
us that taking an antibiotic, even when needed, can be risky. 
CDC's key responsibilities regarding antimicrobial resistance 
are to define the scope and magnitude of the problem to try and 
prevent infections so microorganisms cannot develop resistance, 
to promote appropriate use of antibiotics and to control the 
spread of resistant organisms when they do develop.
    The public health response to the problem of antimicrobial 
resistance is best viewed as a continuing series of successes 
and setbacks. For example in 2000, a new conjugate vaccine 
became available for children that prevented infections caused 
by strains of streptococcus pneumoniae, otherwise known as 
pneumococcus. The vaccine's targets included the most common 
multi-drug resistant strains of pneumococci.
    Since the vaccine was introduced as part of routine 
childhood immunization, penicillin resistant pneumococcal 
infections declined by 35 percent. It is estimated that 170,000 
severe pneumococcal infections and 10,000 deaths have been 
prevented by vaccine use. Yet even a CDC surveillance system 
was recording these record declines in pneumococcal infections, 
it also noted the rise of infections caused by a new multi-drug 
resistant strain of pneumococcus called serotype 19A, a strain 
type that was not covered by the current vaccine. Thus a new 
vaccine is under development.
    In a similar fashion the rates of infections among 
hospitalized patients in the United States caused by 
Methicillin Resistant Staphylococcus Aureus or MRSA has been a 
concern for well over a decade. However, new data from 
hospitals participating in the National Health Care Safety 
Network has shown a significant drop over the last 5 years in 
the incidents of both MRSA and methicillin susceptible staph 
aureus blood infections in patients within dwelling central 
lines.
    While the incidence of MRSA and MSSA blood stream 
infections has decreased substantially, MRSA infections are 
rising dramatically in the community. The number of MRSA-
related skin and soft tissue infections resulting in 
hospitalization doubled between 2000 and 2005. Thus our MRSA 
successes in hospitals have to be balanced with new challenges 
of controlling MRSA in the community.
    One of the most common communicable infections in the 
United States is gonorrhea. CDC's efforts to control the spread 
of gonorrhea suffered a major setback in 2007 when we had to 
withdraw the recommendation to use fluoroquinolones antibiotics 
as primary treatment for gonorrhea infections due to a rapid 
rise in fluoroquinolone resistant strains. This loss of the 
easy to administer and effective therapy leaves us only with 
cephalosporin type drugs to treat gonococcal infections. When 
cephalosporin resistance emerges, the treatment and control of 
gonorrhea will become much more difficult.
    CDC's successful collaborations with several Federal 
partners on antimicrobial resistance issues have illustrated 
the benefits of coordinating activities with other Federal 
agencies. This has led to expanded activities of the 
Interagency Task Force on Antimicrobial Resistance, 
specifically to facilitate communication on resistance issues 
among Federal partners. The Task Force which consists of 10 
Federal agencies recently held a consultants meeting to obtain 
input on revising the Public Health Action Plan to combat 
antimicrobial resistance. Based on comments from the 
consultants the Federal agencies are revising the Action Plan 
and refocusing it.
    In summary antimicrobial agents are used in humans, 
animals, fish, vegetables and fruit, decorative plants and even 
in marine paint. The pressure for resistant microorganisms to 
develop and spread is high and continues to grow. Yet our 
supply of new antimicrobial agents is dwindling.
    While we cannot totally stop the development and spread of 
resistant microorganisms, we can minimize their impact by using 
antibiotics we have wisely and minimizing the spread of 
resistant organisms when they develop. In doing so we can 
preserve our ability to treat life threatening infections while 
we continue to develop and implement new measures to prevent 
and control them. Thank you for this opportunity to testify. I 
will be happy to address your questions.
    [The prepared statement of Mr. Tenover follows:]
              Prepared Statement of Fred C. Tenover, Ph.D.
                              introduction
    Good morning Chairman Brown, Ranking Member Enzi, and other 
distinguished members of the committee. I am Dr. Fred Tenover, and it 
is my pleasure to be here today in my capacity as Director of the 
Office of Antimicrobial Resistance at the Centers for Disease Control 
and Prevention (CDC). While I have certain managerial responsibilities 
at CDC, I continue to work as an active microbiologist and have 
authored or co-authored over 290 journal articles and 31 book chapters 
in the field of clinical medicine and microbiology. I also serve as 
Director of the World Health Organization's Collaborating Centre for 
Global Monitoring of Antimicrobial Resistance and am an Adjunct 
Professor in the Division of Epidemiology at Emory University's Rollins 
School of Public Health. CDC appreciates the opportunity to address 
this timely issue and I look forward to discussing with you our growing 
concerns about the problem of Antimicrobial Resistance
    Antimicrobial resistance will always be with us, it is not a new 
issue; but we need to continue to find manageable solutions. Resistant 
microorganisms have been reported for over 60 years; however, it is the 
increasing magnitude of the problem and the fact that so many different 
types of microorganisms are becoming resistant to antimicrobials, a 
general term for drugs, chemicals, or other substances that either kill 
or slow the growth of microbes, that is of major concern to us. 
Although most bacterial, fungal, viral, and parasitic pathogens remain 
susceptible to a least some antimicrobial agents, the increasing rates 
of resistance are requiring more complex options for treating 
individual patients and are causing the medical community to change 
long-established treatment regimens for many infectious illnesses to 
different antibiotics that may be more expensive, or combinations of 
antibiotics instead of a single drug. When a patient with a resistant 
organism is treated with an ineffective antibiotic, the organism will 
continue to infect the patient and could potentially spread to other 
patients, further extending the resistance problem. However, with 
surveillance, reduced antibiotic usage, vaccination of persons at high 
risk, and product development antimicrobial resistance is manageable.
    To provide a sense of the problem, unpublished data from CDC's 
National Nosocomial Infection Surveillance System indicate that >90 
percent of strains of Staphylococcus aureus, a bacterial species that 
causes a spectrum of illnesses from minor skin infections to serious 
life-threatening diseases, are no longer treatable with penicillin, 
while one third of Streptococcus pneumoniae isolates, a common cause of 
ear infections, pneumonia, and meningitis, are also no longer treatable 
with penicillin. Many such penicillin resistant strains are, in fact, 
multiply resistant to other commonly used drugs like ceftriaxone, 
erythromycin, and trimethoprim-sulfamethoxazole. In addition, strains 
of Salmonella Newport, which cause infections in food animals, such as 
dairy cows, have been shown to be resistant to as many as seven 
antibiotics. CDC data further show that a small but growing subset of 
the gram-negative bacterial strains that cause healthcare-associated 
infections, like Acinetobacter baumannii and Pseudomonas aeruginosa, 
have become resistant to all available antimicrobial agents. And 
worldwide, tuberculosis due to strains resistant to the two most 
commonly used anti-tuberculosis agents, isoniazid and rifampin, was 
recently estimated to affect approximately half a million persons 
annually.
                    antimicrobial use and resistance
    Simply put, antibiotics are the most important tool we have to 
control many life threatening infectious diseases, yet increasing 
levels of antibiotic resistance are compromising the effectiveness of 
these drugs. Bacteria, in particular, have developed multiple ways of 
becoming resistant to antibiotics. The more often bacteria are exposed 
to antibiotics, the more chances they have to ``learn'' to survive 
through one of these mechanisms. Many people may not know the extent to 
which antimicrobial agents are used. Antimicrobial agents also are 
widely used in animals (as prevention measures and for growth 
promotion), fish, vegetables and fruit (to prevent outbreaks of 
bacterial disease in orchards), decorative plants, and even in marine 
paint (to inhibit growth of sea life on ships). It is imperative that 
we assess the use of all antimicrobial agents carefully and use them 
only when necessary, to avoid promoting the development of resistance 
among bacteria and other microorganisms. Unnecessary use of antibiotics 
reduces the effectiveness of the drugs we have at a time when there are 
relatively few new antimicrobial agents in development.
                 cdc's antimicrobial resistance program
    CDC's key responsibilities regarding antimicrobial resistance are:

     to define the scope and magnitude of the problem,
     to define the risk factors that lead to the development 
and spread of resistant microorganisms,
     to develop evidence-based guidelines and design and 
implement programs that minimize the development and spread of 
resistant infections in humans and animals,
     to respond to outbreaks of resistant microorganisms, and
     to conduct research on the prevention and control of 
resistant organisms in a variety of settings.

    In addition to the responsibilities listed above, CDC laboratories 
are responsible for:

     tracking the spread of resistant microorganisms both 
nationally and globally,
     providing national reference laboratory services to 
confirm unusual antimicrobial resistance patterns, and
     working with professional societies to standardize methods 
for testing antimicrobial resistance among a variety of microorganisms 
including fungi, viruses, and parasites.
      defining the scope and magnitude of antimicrobial resistance
    CDC uses several types of surveillance systems (including data from 
laboratories, hospital information systems, and microbiologic 
examination of retail meats), to monitor the development and spread of 
resistant microorganisms and the infections that they cause. The 
organism groups under surveillance include many bacterial species 
(including Mycobacterium tuberculosis), fungi, viruses, and several 
parasites, such as malaria. Examples of surveillance systems at CDC 
include the Active Bacterial Core Surveillance (ABCs) system conducted 
through CDC's Emerging Infections Program (a network of sites that work 
together to conduct population-based surveillance and research 
projects), the Gonococcal Isolate Surveillance Program (GISP), and the 
National Healthcare Safety Network (NHSN). To conduct surveillance for 
resistant microorganisms and infections, CDC collaborates with many 
partners, including healthcare facilities; State public health 
departments; other Federal agencies, including the Food and Drug 
Administration (FDA) and the U.S. Department of Agriculture (USDA); and 
international organizations, such as the World Health Organization. 
Recently CDC also developed a training tool for laboratorians to 
enhance their understanding and improve their proficiency in performing 
antimicrobial susceptibility testing (M.A.S.T.E.R.). Accurate 
antimicrobial susceptibility test results not only help physicians 
choose the best therapy for their patients, but guide infection control 
efforts to the most serious infections.
    Surveillance data are used not only to monitor resistance rates 
among microorganisms, but to indicate the effectiveness of prevention 
programs, to set national benchmarks for infection control efforts, to 
monitor the effectiveness of treatment guidelines, and to inform timely 
changes regarding treatment recommendations. In addition, surveillance 
data collected through the ABCs system provide a source of national, 
population-based estimates of the antimicrobial resistance disease 
burden of multiple bacterial species, while NHSN serves both as a 
system for tracking healthcare-associated infections and as a sentinel 
warning system for unusual resistant organisms, such as vancomycin-
resistant strains of Staphylococcus aureus.
    Data from CDC's surveillance systems have often identified the 
emergence of new resistant microorganisms, such as the recent 
recognition by the ABCs system of the first ciprofloxacin-resistant 
strains of Neisseria meningitidis in the upper Midwestern United States 
reported this year, or the recognition of first strains of vancomycin-
resistant enterococci in U.S. hospitals, reported by the National 
Nosocomial Infection Surveillance system, the predecessor to NHSN, a 
decade ago. Such reports have prompted outbreak investigations from 
which CDC has garnered a wealth of information on the development and 
spread of resistant organisms.
          promoting appropriate and optimal antimicrobial use
    Multiple efforts are underway at CDC to promote appropriate 
antimicrobial use to preserve the effectiveness of the antibiotics we 
have for the longest period of time. CDC's ``Get Smart: Use Antibiotics 
Wisely'' campaign has been very successful in delivering educational 
messages on appropriate antibiotic use to physicians and the general 
public. Since its inception in 2003, this program has delivered its 
message of the importance of prudent antibiotic use through State 
health department initiatives, physician's offices, on television, over 
the radio, and in print media. Since the late 1990s, there has been a 
25 percent reduction in antibiotic prescriptions generated during 
outpatient visits for presumed viral infections, for which antibiotics 
are ineffective, which was a key target of the campaign. Additional 
educational efforts include developing curricula on prudent antibiotic 
use for medical schools and primary care residency programs. These 
programs are designed to raise the awareness of key healthcare 
providers to the downsides of unnecessary antibiotic use. The ``Get 
Smart'' program has expanded to include ``Get Smart on the Farm'' to 
focus on use of antimicrobial agents in animals, and has partnered with 
another CDC program, the ``Campaign to Prevent Antimicrobial 
Resistance,'' which focuses on educating healthcare-based physicians 
about antimicrobial resistance issues, in an attempt to further 
decrease unnecessary antibiotic use.
    CDC has long worked to promote the appropriate treatment of 
tuberculosis, both here and abroad, in order to minimize the 
development and spread of resistant TB. CDC provides financial and 
technical assistance to all 50 States and 10 large cities to reduce the 
spread of TB and ensure curative treatment for those with TB. Important 
to this effort is ensuring that patients are treated with drugs that 
will work against the strain that they have contracted. In 2006, over 
92 percent of all patients with an initial positive TB culture in the 
United States were tested for TB drug susceptibility. CDC also supports 
TB laboratories and funds regional training and medical consultation 
centers for healthcare workers to ensure appropriate treatment and 
diagnosis.
    In addition to these programmatic educational efforts, CDC sponsors 
the TB Trials Consortium (TBTC), which conducts clinical trials of TB 
medications on four different continents to optimize the effectiveness 
of current tuberculosis treatment regimens and identify new TB drugs 
that could be used to treat drug-resistant strains. The TBTC includes 
members from TB control programs, academic medical institutions, and 
CDC, as well as international partners from the commercial sector, the 
not-for-profit private sector, and the public sector, all of whom are 
essential for this work. The Global Alliance for TB Drug Development is 
a public/private partnership with whom CDC works to stimulate new drug 
development for treating tuberculosis. Over 30 organizations, including 
the Bill & Melinda Gates Foundation, National Institute of Allergy and 
Infectious Diseases at the National Institutes of Health, the 
Rockefeller Foundation, the U.S. Agency for International Development, 
the World Bank, and WHO, are stakeholders along with CDC in this 
innovative partnership. The major goals are to shorten the treatment of 
TB, minimize the impact of drug-resistant TB, and facilitate TB control 
in the poorest countries in the world.
      successes and setbacks in prevention and control activities
Multiply Resistant Pneumococcal Infections
    The fight against antimicrobial resistance can best be viewed as a 
continual series of successes and setbacks. For example, pneumococcal 
infections resistant to penicillin and multiple other antibiotics 
became common during the 1990's. But in 2000, a new vaccine called 
Prevnar became available for children in the United States and CDC 
began tracking the vaccine's impact on resistant pneumococcal 
infections. Since the vaccine was introduced into the routine childhood 
immunization program in the United States, penicillin-resistant 
pneumococcal infections declined by 35 percent. Not only has the 
vaccine been shown to prevent antibiotic-resistant infections, it has 
been shown to reduce the need for prescribing antibiotics for children 
with pneumococcal infection in the first place. CDC data also show that 
adults are getting fewer resistant pneumococcal infections because the 
vaccine is preventing spread of pneumococci from infected children to 
adult populations. Since 2001, it is estimated from CDC data that 
170,000 severe pneumococcal infections and 10,000 deaths have been 
prevented by vaccine use. According to data published in the Archives 
of Pediatric Adolescent Medicine, the vaccine is highly cost-effective, 
saving an estimated $310 million in direct medical costs each year.
    Yet, even as infections caused by the most common multi-drug 
resistant strains of pneumococci were declining in frequency, the CDC 
began noting, through its Active Bacterial Core Surveillance System, a 
gradual increase in infections caused by a new multi-drug resistant 
strain of pneumococcus called serotype 19A. This strain is not covered 
by the current vaccine. While the amount of serotype 19A invasive 
pneumococcal disease is small compared with the very large amount of 
disease averted by introduction of the vaccine, it still emphasizes the 
continuing struggle public health faces against microorganisms that are 
uniquely capable of adapting and surviving even our newest prevention 
measures. Fortunately, CDC's ongoing surveillance through the ABCs 
system detected this trend and indicated the need to develop a new 
vaccine that will confer protection against serotype 19A strains. A new 
vaccine containing 19A strain is already in clinical trials.
                            mrsa infections
    In a similar fashion, Staphylococcus aureus is a bacterial species 
that is commonly carried on the skin or in the nasal passages of 25 
percent to 30 percent of healthy people in the United States. This 
organism, however, can and does cause a lot of skin infections, 
although most of these infections are minor. More importantly, S. 
aureus can cause life-threatening diseases including bloodstream 
infections, endocarditis (infection of the heart valves), toxic shock 
syndrome, and pneumonia, particularly among hospitalized patients. 
Methicillin-resistant strains of S. aureus (also called MRSA) first 
emerged in Europe in 1961 but by the 1980s were causing infections in 
patients in many U.S. hospitals. The continued increase in the rates of 
MRSA infections in U.S. hospitals has been a topic of considerable 
concern for over a decade and has resulted in a series of local, 
regional, and national interventions to halt its spread. For example, 
CDC in collaboration with the Veterans Affairs Pittsburgh Healthcare 
System achieved a 50 percent reduction in the rate of MRSA infections 
after it implemented a series of infection control procedures based on 
CDC guidelines designed to decrease the transmission of MRSA in 
hospitals. The measures included strict attention to hand hygiene, 
enhanced surveillance for infections, effective use of isolation rooms, 
and behavior modification techniques to emphasize the importance of the 
new procedures. These interventions are being implemented in VA medical 
centers nationwide and in multiple other healthcare systems. In 
addition, CDC is working with the Agency for Healthcare Research and 
Quality (AHRQ) to improve MRSA prevention in the healthcare facilities.
    New national data from CDC's National Healthcare Safety Network 
(NHSN), a surveillance tool for hospitals and State health departments 
that measures healthcare associated infections (HAIs), show that there 
has been a significant drop in the incidence of both MRSA and 
methicillin-susceptible S. aureus (MSSA) central line-associated 
bloodstream infections among intensive care unit patients in U.S. 
hospitals over the last 5 years. The incidence of MRSA bloodstream 
infections per 1,000 central line days (i.e., a measurement of 
infection burden derived from the number of patients who have a central 
line, or catheter, whether infected or not) decreased by 49.6 percent, 
while the incidence of central line-associated MSSA infections 
decreased even more substantially, by 70.1 percent. Data on invasive 
MRSA infections from the Active Bacterial Core Surveillance system for 
2005-2006 also show a decrease in hospital-onset and healthcare-
associated MRSA infections, confirming this downward trend. Thus, it 
appears that these practical efforts to reduce the transmission of MRSA 
in hospitals are working thereby, further reducing the need for 
antibiotic usage.
    Yet, even as we document success in controlling MRSA in hospitals, 
CDC, through the ABCs system and other public health agencies around 
the world, have noted an increase in MRSA infections in community 
settings. While most of these are skin infections, severe and often 
fatal cases of necrotizing pneumonia continue to be reported among 
otherwise healthy people in the community with no links to the 
healthcare system. Based on national hospital discharge data analyzed 
by CDC, the number of S. aureus-related skin and soft tissue infections 
resulting in hospitalization doubled from 2000 through 2005; most, if 
not all, of this increase is likely due to community strains of MRSA. 
Thus, our MRSA successes in hospitals have to be balanced with the new 
challenges of controlling MRSA in community settings and CDC will 
continue to look for practical efforts to reduce these infections in 
community settings as have been done in hospitals.
Fluoroquinolone-resistant Neisseria gonorrhoeae
    While CDC's efforts to control the spread of pneumococci in the 
community and MRSA in hospitals show success, CDC's efforts to maintain 
cost-effective strategies for preventing the spread of gonorrhea in the 
United States had a setback in 2007. In 2007, the level of 
fluoroquinolone (a family of drugs that includes the well-known 
Ciprofloxacin) resistance among surveillance isolates submitted to 
CDC's Gonococcal Isolate Surveillance Program (GISP) exceeded the 5 
percent level, which has been used as the threshold for changing 
nationally recommended treatment. In response, CDC was compelled to 
announce the withdrawal of fluoroquinolone antibiotics as a primary 
treatment of gonorrhea infections, due to the rapid rise of 
fluoroquinolone resistance among strains of Neisseria gonorrhoeae. The 
loss of fluoroquinolones will likely have a significant impact on the 
treatment of gonorrhea in the United States as we are now left with 
only one class of recommended antibiotics, the cephalo-
sporins, to treat gonococcal infections. When cephalosporin resistance 
emerges, the treatment and control of gonorrhea will become extremely 
difficult. Currently, there is no recommended treatment available for 
infected patients who have severe allergies to cephalosporins, and 
treatment in these patients requires the use of therapies that have 
greater side effects and for which resistance has already begun to 
develop.
    Although the detection of the increase in gonococcal resistance to 
fluoroquinolones was timely, it highlights another challenge in CDC's 
effort to prevent and control this infectious disease, which is the 
critical need to identify the emergence of cephalosporin resistance in 
a timely fashion both nationally and locally. When cephalosporin 
resistant gonococci emerge, preventing their spread will be 
challenging--but even more so without expansion of existing capacity, 
since emergence may occur in populations not covered by the current 
surveillance system, allowing the gonococci to spread before effective 
control measures can be put in place.
Clostridium Difficile Infections
    Another example of the fact that taking antibiotics is not without 
risk is the rapid increase in the United States since 2000 of the 
number of Clostridium difficile infections primarily in hospitalized 
patients. C. difficile disease can range from mild to debilitating 
diarrhea, to more severe life-threatening infections. The development 
of C. difficile infections among patients treated with antibiotics has 
long been considered an unintended consequence of antibiotic use. 
Recognized in the 1970s as a cause of ``antibiotic associated 
diarrhea,'' in the 1980s and 1990s this anaerobic bacterial species 
caused increasing numbers of outbreaks of diarrheal disease in 
hospitals and long-term care facilities.
    Recently, however, CDC and others have recognized the emergence of 
C. difficile disease, including more life-threatening forms of disease, 
among otherwise healthy patients in the community. A number of the 
community patients had not taken antibiotics prior to their illness. 
Based on data from Ohio, estimates suggest that currently there may be 
as many as 500,000 cases of C. difficile infection occurring annually 
in the United States, contributing to between 15,000 and 30,000 deaths. 
Some antibiotic-resistant strains of C. difficile, including those 
resistant to macrolides and fluoroquinolones, are emerging. These 
strains appear to be more virulent due to increased toxin production 
and the presence of a novel virulence factor called the binary toxin. 
Surveillance data from other public health agencies around the world 
show such strains are spreading globally. While this antimicrobial 
resistance doesn't directly affect therapy for the C. difficile 
infection, since such infections are treated with other drugs, the 
resistance may allow C. difficile to spread more readily among patients 
who have received either a macrolide or fluoroquinolone antibiotic. 
This broadens even further the number of people at risk for acquiring 
disease. CDC will begin to collect data from healthcare institutions 
using NHSN to track C. difficile infections.
    Some challenges to future surveillance activities include limited 
public health infrastructure for detecting resistance and the heavy 
reliance on hospital microbiology laboratories around the United States 
to provide the antibiotic resistance data. While hospital microbiology 
laboratories recognize the importance of tracking antimicrobial 
resistance patterns nationwide, many of these laboratories cite 
increasing pressures from their institutions to discontinue these 
services due to limited resources and competing priorities.
                     working with federal partners
    CDC's successful collaborations with several Federal partners on 
antimicrobial resistance issues have illustrated the benefits of 
coordinating activities with other Federal agencies. For example, CDC 
worked closely with the Food and Drug Administration, which works with 
manufacturers to implement recalls of contaminated products, such as in 
the recent outbreak of contaminated mouthwashes containing resistant 
Burkholderia species in multiple States. In addition, monitoring the 
development and spread of antimicrobial resistance among foodborne 
bacterial pathogens like Salmonella, Shigella, and Campylobacter, such 
as is done through the National Antimicrobial Resistance Monitoring 
System, requires the cooperation of three Federal agencies (CDC, FDA, 
and USDA) to screen isolates from humans, animals, and the food supply. 
Another example is the current AHRQ-CDC partnership to fund a 
community-wide MRSA initiative to assess the role of and strategies to 
reduce inter-facility MRSA transmission. The necessity of Federal 
agencies working together highlights the need for the Interagency Task 
Force on Antimicrobial Resistance, specifically to facilitate 
communication among Federal partners on the issue of antimicrobial 
resistance.
         the interagency task force on antimicrobial resistance
    The Interagency Task Force on Antimicrobial Resistance consists of 
10 Federal agencies (Agency for Healthcare Research and Quality, 
Centers for Disease Control and Prevention, Centers for Medicare and 
Medicaid Services, Department of Agriculture, Department of Defense, 
Department of Veterans Affairs, Environmental Protection Agency, Food 
and Drug Administration, Health Resources and Services Administration, 
and the National Institutes of Health) and is co-chaired by CDC, FDA, 
and NIH. Recently, the Task Force held a consultants meeting to obtain 
input and recommendations for revising and updating ``A Public Health 
Action Plan to Combat Antimicrobial Resistance, which was first 
released in 2001.'' In addition to over 50 consultants from the United 
States, 9 international consultants from Canada, Denmark, France, 
Germany, The Netherlands, and the United Kingdom participated in the 
meeting. The consultants included experts from human and veterinary 
medicine, the pharmaceutical and diagnostics industries, animal 
husbandry industry, clinical microbiology, epidemiology, infectious 
disease and infection control specialists, and State and local public 
health departments. Representatives of most of the Federal agencies 
also participated. The open meeting also was attended by members of the 
public, including representatives of a variety of professional 
societies, advocacy groups, and concerned citizens. The discussions 
centered on four topic areas: surveillance; prevention and control; 
research; and product development. The consultants focused on issues 
that they felt were critical to address over the next 3-5 years.
    Based on comments from the consultants and the Federal agencies, 
the revised draft Action Plan has been reformatted around five focus 
areas:

     reducing inappropriate antimicrobial use,
     reducing the spread of antimicrobial resistant 
microorganisms in institutions, communities, and agriculture,
     enhancing laboratory capacity to detect resistant 
microorganisms,
     encouraging the development of new anti-infective 
products, vaccines, and adjunct therapies, and
     supporting basic research on antimicrobial resistance.

    The Task Force plans on submitting the revised Action Plan for 
public comment this fall.
                                summary
    In summary, given the growing worldwide usage of antimicrobial 
agents (including antibacterials, antifungals, antivirals, and 
antiparasitic agents), the pressure for resistant microorganisms to 
develop and spread remains high. CDC's strengths in surveillance, 
research, prevention and control, and education have proven to be 
critical assets in fighting resistance and have been rewarded with some 
remarkable successes in controlling the spread of resistant infections. 
Yet, CDC has also seen its share of setbacks, due to the ability of 
microorganisms to adapt to our prevention measures. We are hopeful that 
we can retain the vital core needed to continue to monitor the most 
important resistant organisms, while we develop and implement new 
measures to prevent and control resistant infections.
    Thank you again for the opportunity to testify today. I am happy to 
answer any questions you may have.

    Senator Brown. Thank you, Dr. Tenover. Before Admiral 
Tollefson speaks, Senator Hatch would like to make some 
comments. The co-sponsor of our legislation too.

                       Statement of Senator Hatch

    Senator Hatch. Well thank you. Thank you, Mr. Chairman. We 
welcome all of the witnesses here today.
    For more than 60 years since their discovery, antibiotics 
have saved millions of lives and helped patients cope with 
suffering related to infection. But as we've seen, our country 
continues to face a growing number of troubling questions about 
whether we are prepared to address the increasing problem of 
drug-resistant bacterial infections. Data from the Centers for 
Disease Control and Prevention (CDC), indicate resistant 
strains of infections have spread rapidly.
    These infections can strike anyone, and antibiotic 
resistance is an elevated problem for those with comprised 
immune systems; for example, individuals with HIV and patients 
in intensive or critical care units. Treatment options are few 
while this alarming trend continues to worsen.
    Antibiotic resistant organisms have been in existence for 
about 60 years, too. This is not a new issue. The issue is that 
national surveillance data and studies show antibiotic 
resistant bacteria have multiplied and spread at disquieting 
rates in recent years.
    Infections that were once easily cured with antibiotics are 
now becoming difficult and in some cases impossible to treat. 
This is happening not just in hospitals, but also community 
settings and homes. We have heard the news reports of MRSA, 
outbreaks within schools in New York, Kentucky and Virginia.
    Resistant infections also strain public health systems by 
leading to higher health care costs because they require more 
expensive treatment and care. According to estimates from the 
Institutes of Medicine and the former Congressional Office of 
Technology Assessment, the economic burden placed on our 
national health care system as a result of resistant bacteria 
totals billions of dollars annually.
    These are reasons why Senator Brown and I introduced S. 
2313, the STAAR Act. We recognize that antibiotic resistance is 
a complex problem and our bill is not the sole answer to that 
problem.
    Our bill focuses on providing adequate infrastructure 
within the government to collect the data, coordinate the 
research and conduct the surveillance necessary to stop drug 
resistant infections in their tracks.
    The STAAR Act lays out the framework by which we can begin 
to take action against this serious public health threat. At a 
minimum, we need better testing, hospital controls, medications 
and funding to support these efforts, particularly the works of 
the Centers for Disease Control and Prevention.
    I am interested to hear the Agency's testimony and thank 
its representatives for being here.
    I would like to conclude with three thoughts on incentives 
to encourage the development of new classes of antibiotics.
    First, this committee worked hard last year to include 
provisions in the Food and Drug Administration Amendments Act 
of 2007 to encourage the development of new antibiotics. This 
law included language to strengthen the Office of Orphan Drugs 
and its FDA grant program and our hope was to have this 
language apply to antibiotics as well. Unfortunately that does 
not appear to be the case, so any assistance the FDA can give 
Congress in this area would be greatly appreciated by the 
committee.
    Second, I believe it's important for the FDA to issue 
guidance regarding the development of antibiotics. It is my 
hope that the guidance will lower the costs of development and 
speed up the approval process so patients will have access to 
new antibiotics to treat drug resistant infections.
    Finally, I believe that Congress should consider adding 
additional incentives for new antibiotics that treat life 
threatening conditions. Currently, these types of drugs are 
held in reserve and not used until there is a drug-resistant 
outbreak. I believe that if these drugs are held in reserve and 
not used, at minimum, their developers should be rewarded and 
the exclusivity should be extended to them for the period in 
which the use is significantly limited.
    I am pleased to have all of our witnesses here today who 
took time out of their busy schedules to be with us today. 
Thank you and I look forward to hearing from you all.
    Senator Brown. Thank you. Thank you, Senator Hatch. Thank 
you also for being here, Senator Burr. Thank you for your 
leadership, Senator Hatch.
    Senator Hatch. I want to thank you for your leadership. I 
think without it we wouldn't be here.
    Senator Brown. Thanks. Admiral Tollefson, I need to let 
people know the vote has been moved to 11:15. We will probably 
get through this first panel. We'll do our best. Admiral 
Tollefson, thank you for being here.

STATEMENT OF RADM LINDA R. TOLLEFSON, D.V.M., M.P.H., ASSISTANT 
    COMMISSIONER FOR SCIENCE, FOOD AND DRUG ADMINISTRATION, 
                         ROCKVILLE, MD

    Admiral Tollefson. Thank you. Good morning, Senators. I am 
Rear Admiral Linda Tollefson, Assistant Commissioner for 
Science at the Food and Drug Administration and the FDA Co-
chair of the Federal Agency Task Force on Antimicrobial 
Resistance. Thank you for the opportunity to discuss FDA's role 
with regard to antimicrobial resistance.
    Successful management of current antimicrobials and the 
continued development of new ones is absolutely vital to 
protecting human and animal health against infectious microbial 
pathogens. Approximately 2 million people acquire bacterial 
infections in U.S. hospitals every year. Ninety thousand die as 
a result. About 70 percent of those infections are resistant to 
at least one antibiotic.
    Resistant pathogens lead to higher health care costs as 
Senator Hatch mentioned, because they often require more 
expensive drugs and extended hospital stays. The problem is not 
limited to hospitals. As we've heard community acquired 
infections are also frequently resistant to multiple 
antibiotics, such as community acquired Methicillin-resistant 
Staphylococcus aureus, common respiratory pathogens including 
streptococcus pneumoniae and gram negative bacilli which can 
infect humans through food.
    Antimicrobial agents have been used in human and veterinary 
medicine for more than 50 years with tremendous benefits to 
both human and animal health. However, after several decades of 
successful antibacterial use we have seen and continue to see 
the emergence of multi-resistant bacterial pathogens which are 
less responsive to therapy. Antimicrobial resistant bacterial 
populations emerge because of the combined impact of the 
various uses of antimicrobial drugs including their use in 
humans and animals.
    As I mentioned, FDA co-chairs, along with CDC and NIH, the 
U.S. Interagency Task Force on Antimicrobial Resistance and in 
2001 we published the Public Health Action Plan to combat 
antimicrobial resistance. This provides a blueprint for 
specific, coordinated Federal actions to address the emerging 
threat of 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 medical societies, pharmaceutical companies, 
health care delivery organizations, agricultural producers, 
consumer groups and other members of the public.
    The Action Plan has four major components: surveillance, 
prevention and control, research, and product development. FDA 
has the lead on the product development focus area. As 
antimicrobial drugs lose their effectiveness, new products must 
be developed to prevent, rapidly diagnose and treat infections.
    Our Center for Drug Evaluation and Research has launched 
several initiatives to address resistance including drug 
labeling regulations, emphasizing the prudent use of 
antimicrobials and has been revising its guidances to industry 
on the development of drugs for the treatment of bacterial 
infections.
    For example, in January of this year, FDA co-sponsored a 
workshop at the Infectious Diseases Society of America on the 
topic of clinical trial designs for community-acquired 
pneumonia. The workshop provided the platform for the 
discussion of issues in trial designs. The Agency followed that 
with the meeting of the Advisory Committee, April 2008, to get 
additional advice. We are now actively engaged in writing a 
draft guidance document that will provide the Agency's thinking 
on informative trial designs for this disease.
    Our Center for Biologics Evaluation and Research has a 
robust research program to investigate vaccine development 
because measures, any measures which reduce the need for 
antibiotic use also serve to reduce the emergence of antibiotic 
resistant microorganisms. Prevention of infections through the 
use of vaccines has effectively eliminated or markedly 
decreased the problem of resistance in organisms such as 
haemophilus influenzae, type B and as Dr. Tenover mentioned, 
the streptococcus pneumoniae. Vaccines also contribute to the 
control of resistance by decreasing the use of the antibiotics.
    In addition, development of increasingly sensitive 
diagnostic assays for the detection of resistance allows for 
more rational and more targeted antibiotic use. Our Center for 
Devices and Radiological Health has led several efforts to 
clarify the regulatory requirements to clear such devices. For 
example, they recently assisted device manufacturers by quickly 
clearing an alternative method for detecting vancomycin 
resistance in Staphylococcus aureus through use of our 
expedited review process.
    Finally our Center for Veterinary Medicine is addressing 
potential human health risks associated with the use of 
antimicrobial drugs in food producing animals.
    In summary FDA in alignment with the Federal Interagency 
Task Force on the Antimicrobial Resistance has been working for 
several years to develop and implement programs to combat or 
mitigate antimicrobial resistance in all relevant sectors, 
humans, animals and the environment. Antimicrobial resistance 
is a very important public health issue that can only be 
addressed by collaborative efforts of the relevant Federal 
agencies, State health departments and the private sector.
    Thank you for the opportunity to discuss FDA's role. I 
would be happy to answer any questions.
    [The prepared statement of Rear Admiral Tollefson follows:]
       Prepared Statement of RADM Linda Tollefson, D.V.M., M.P.H.
                              introduction
    Mr. Chairman and members of the committee, I am Rear Admiral Linda 
Tollefson, Assistant Commissioner for Science at the Food and Drug 
Administration (FDA or the Agency), which is a part of the Department 
of Health and Human Services (HHS), and the FDA co-chair of the 
Interagency Task Force on Antimicrobial Resistance. Thank you for the 
opportunity to discuss FDA's role with regard to antimicrobial 
resistance.
    Successful management of current antimicrobials, and the continued 
development of new ones, is vital to protecting human and animal health 
against infectious microbial pathogens. Approximately 2 million people 
acquire bacterial infections in U.S. hospitals each year, and 90,000 
die as a result. About 70 percent of those infections are resistant to 
at least one drug. The trends toward increasing numbers of infection 
and increasing drug resistance show no sign of abating. Resistant 
pathogens lead to higher health care costs because they often require 
more expensive drugs and extended hospital stays. Resistant infections 
impact clinicians practicing in every field of medicine. The problem is 
not limited to hospitals. Community-
acquired infections are also frequently resistant to multiple 
antibiotics, such as community-acquired methicillin-resistant 
Staphylococcus aureus (CA-MRSA), common respiratory pathogens including 
Streptococcus pneumoniae, and gram-negative bacilli, which can infect 
humans through food.
    In my testimony, I will provide background information on 
antimicrobial resistance, discuss FDA's involvement with the 
Interagency Task Force on Antimicrobial Resistance, and describe FDA's 
actions to combat resistance and promote product development.
                               background
    Antimicrobial drugs are used to treat infections caused by 
microorganisms. This statement focuses mainly on the development of 
resistance in bacterial organisms to antibacterial drugs; however, it 
should be noted that resistance is also a problem in other 
microorganisms, including viruses, tuberculosis, parasites (such as 
malaria), and fungi.
    Another term commonly used to describe an antibacterial drug is 
``antibiotic.'' The term refers to a natural compound produced by a 
fungus or another microorganism that kills bacteria that cause disease 
in humans or animals. Some antibacterial drugs may be synthetic 
compounds (not produced by microorganisms), and thus do not meet the 
technical definition of antibiotic but are referred to as antibiotics 
in common usage.
    Many factors contribute to the spread of antimicrobial resistance. 
In some cases, doctors prescribe antibiotics too frequently or 
inappropriately. Sometimes patients do not complete the prescribed 
course of an antibiotic, making it more likely that surviving microbes 
will develop resistance. In addition, antibiotics used to prevent 
infections in livestock may contribute to the emergence of resistant 
germs that can infect people. Through international trade and travel, 
resistant microbes can spread quickly worldwide.
    Antibiotics have had an enormous beneficial effect. Many infections 
that were fatal, or left individuals with severe disabilities, are now 
treatable or preventable. Antibiotic resistance is the ability of 
bacteria or other microbes to resist the effects of an antibacterial 
drug. Antibiotic resistance occurs when bacteria change in some way 
that reduces or eliminates the effectiveness of drugs, chemicals, or 
other agents designed to cure or prevent infections. The bacteria 
survive and continue to multiply causing more harm. Antibiotic 
resistance is expected. Bacteria, also referred to as microbes, are 
adept at surviving and adapting to their environments. Therefore, 
regulation of antibacterial drugs is essential to delay the development 
of resistance. Misuse and overuse of these drugs contribute to an even 
more rapid development of resistance.
    Antimicrobial agents have been used in human and veterinary 
medicine for more than 50 years, with tremendous benefits to both human 
and animal health. However, after several decades of successful 
antibacterial use, we have seen and continue to see the emergence of 
multi-resistant bacterial pathogens, which are less responsive to 
therapy. Antimicrobial resistant bacterial populations emerge because 
of the combined impact of the various uses of antimicrobial drugs, 
including their use in humans and animals. However, all of these 
pathways are not clearly defined or understood.
    New classes or modifications of older classes of antimicrobials 
over the past six decades have been matched slowly but surely by the 
systematic development of new bacterial resistance mechanisms. As of 
today, antimicrobial resistance mechanisms have been reported for all 
known antibacterial drugs that are currently available for clinical use 
in human and veterinary medicine. In some cases, strains have been 
isolated that are resistant to multiple antibacterial agents.
        u.s. interagency task force on antimicrobial resistance
    FDA co-chairs, along with the Centers for Disease Control and 
Prevention (CDC) and the National Institutes of Health (NIH), the U.S. 
Interagency Task Force on Antimicrobial Resistance (Task Force), which 
was created in 1999.
    The Task Force also includes the Agency for Healthcare Research and 
Quality (AHRQ), Centers for Medicare and Medicaid Services (CMS), the 
Health Resources and Services Administration (HRSA), the Department of 
Agriculture (USDA), the Department of Defense, the Department of 
Veterans Affairs, and the Environmental Protection Agency. In 2001, the 
U.S. Agency for International Development joined the Task Force to help 
address global antimicrobial resistance issues.
Public Health Action Plan to Combat Antimicrobial Resistance
    In 2001, the Task Force published the ``Public Health Action Plan 
to Combat Antimicrobial Resistance'' (Public Health Action Plan or the 
Action Plan). 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, healthcare delivery organizations, 
agricultural producers, consumer groups, and other members of the 
public.
    The Action Plan has four major components: surveillance, prevention 
and control, research, and product development. Highlights of the 
Action Plan include:

    Surveillance. Information and statistics about the emergence and 
spread of resistant microbes and the use of antimicrobial drugs can 
help experts interpret trends and identify strategies to prevent or 
control antimicrobial resistance. CDC is working with State health 
departments and other Task Force members to design and implement a 
strategy to coordinate national, regional, State, and local 
surveillance efforts. In addition, FDA, CDC, and USDA developed and 
expanded systems to monitor patterns of antimicrobial resistance among 
foodborne bacteria in human medicine, in agriculture, and in retail 
meat.
    Prevention and Control. Research shows that controlling the use of 
antibiotics can help reduce the incidence of antimicrobial resistance. 
In 2003, FDA partnered with CDC's launch of its Get Smart: Know When 
Antibiotics Work campaign. The goal of the campaign is, and has been, 
to educate consumers and healthcare professionals on the appropriate 
use of antibiotics. In partnership with doctors and other medical 
professionals, CDC has developed clinical guidelines for health 
professionals on how best to use antimicrobials, and supports pilot 
projects to identify effective strategies to promote appropriate 
antimicrobial drug use. FDA has promulgated regulations for labeling 
antibiotics regarding their appropriate use for infections caused by 
bacteria. FDA's Center for Veterinary Medicine (CVM) has developed, in 
conjunction with stakeholders in-depth antimicrobial prudent use 
principles for beef, dairy, swine, poultry, and more recently, aquatic 
veterinarians. In 2003, FDA published Guidance for Industry #152 
(``Evaluating the Safety of Antimicrobial New Animal Drugs with Regard 
to their Microbiological Effects on Bacteria of Human Health 
Concern''). Guidance #152 outlines a recommended approach for 
conducting a qualitative risk assessment to evaluate the likelihood 
that an antimicrobial drug used to treat a food-producing animal may 
cause an antimicrobial resistance problem in humans. The risk 
assessment approach recommended in the guidance considers a broad set 
of information, including the importance of the drug in question to 
human medicine. This information is collectively considered in 
determining whether the proposed antimicrobial product will pose a risk 
to public health.
    Measures that reduce the need for antibiotic use also serve to 
reduce the emergence of antibiotic-resistant microorganisms. Prevention 
of infections through the use of vaccines has effectively eliminated or 
markedly decreased the problem of resistance in organisms such as 
Haemophilus influenzae type b (virtually eliminated in the United 
States while still a problem in other parts of the world) and 
Streptococcus pneumoniae, also known as pneumococcus. Published 
research has confirmed that the latter pneumococcal vaccine has lowered 
common infections that are often treated with antibiotics. Vaccines 
also contribute to the control of resistance by preventing or 
decreasing the use of antibiotics. For example, vaccines against 
respiratory viruses, such as influenza, by preventing respiratory 
illnesses, decrease infections which often lead to unnecessary 
antibiotic use and also prevent complicating, sometimes serious 
secondary infections caused by bacteria such as staphylococcus or 
pneumococcus. In addition, development of increasingly sensitive 
diagnostic assays for detection of resistance allows for rational 
targeted antibiotic use.
    Research. The Action Plan promotes expanding existing research in 
antimicrobial resistance and related fields in an effort to improve 
treatments and outcomes. NIH is leading a team of agencies to provide 
the research community with new information and technologies, including 
genetic blueprints for various microbes, to identify targets for 
desperately needed new diagnostics, treatments, and vaccines to combat 
the emergence and spread of resistant microbes. NIH supports clinical 
studies to test new antimicrobials and novel approaches to treating and 
preventing infections caused by resistant pathogens. NIH also continues 
to support and evaluate the development of new rapid diagnostic methods 
related to antimicrobial resistance, in conjunction with FDA's Center 
for Devices and Radiological Health (CDRH). In addition, AHRQ funds 
various studies on the use of antimicrobial drugs and antimicrobial 
resistance, including ongoing research on reducing unnecessary 
prescribing of antibiotics to children. FDA's Center for Biologics 
Evaluation and Research (CBER) conducts research that facilitates 
vaccine development for diseases in which resistance is an issue, such 
as malaria, staphylococcus (MRSA), and enteric diseases.
    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 
the product development focus area address ways to:

     Ensure researchers and drug developers are informed of 
current and projected gaps in the arsenal of antimicrobial drugs, 
vaccines, and diagnostics, and of potential markets for these products;
     Stimulate development of priority antimicrobial 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; and
     Facilitate development of effective prophylactic vaccines: 
in particular, focusing on vaccines against microbes that are known to 
develop antibiotic resistance (e.g., MRSA), thereby reducing the need 
for antibiotics and the occurrence of antibiotic resistant strains.

    On December 12 and 13, 2007, the Task Force held a meeting in 
Atlanta, GA, to obtain input from outside consultants for revising and 
updating the Action Plan. The consultants, including a diverse group of 
experts from the United States and six other countries, reviewed the 
2001 Action Plan in detail and participated in discussions on updating 
the Action Plan for the next 5 years.
            fda accomplishments on antimicrobial resistance
    Since 1996, FDA has actively addressed the issue of antimicrobial 
resistance. As an Agency composed of several product centers, FDA has 
addressed antimicrobial resistance through a variety of initiatives, 
primarily through four key areas:

     Surveillance: Monitoring and surveillance of antimicrobial 
resistance and then promptly and effectively responding to current 
threats from drug resistance.
     Product Development: Facilitating and encouraging 
development and appropriate use of products to help address the issue 
including new drugs, vaccines, and improved, more timely tests for 
infectious diseases.
     Education: Facilitating the safe and effective use of 
antibiotics and thus prolonging the life of products by helping improve 
the quantity and quality of information available to consumers and 
health professionals regarding antibiotic resistance and principles of 
appropriate usage. In addition, FDA has an important role in informing 
the public and healthcare professionals both through educational 
outreach and by assuring useful and accurate product labeling and 
appropriate marketing.
     Research: Maximizing and coordinating FDA's scientific 
research to address needs in antimicrobial resistance.

    Specific activities by the various Centers within FDA include the 
following:
Center for Drug Evaluation and Research (CDER)
    CDER has launched several initiatives to address antimicrobial 
resistance. Through CDER's initiatives, FDA has issued drug labeling 
regulations, emphasizing the prudent use of antibiotics. The 
regulations encourage healthcare professionals to prescribe antibiotics 
only when clinically necessary, and to counsel patients about the 
proper use of such drugs and the importance of taking them as directed.
    We are living in challenging times for antibacterial drug 
development. Over the last several years, CDER has been evaluating the 
design of clinical trials that are used to study the safety and 
efficacy of drugs for the treatment of a variety of infections. CDER 
recognizes the importance of ensuring that antibacterial drugs are 
approved based on sound, informative clinical trials, because the 
clinical use of marginally effective antibiotics can contribute to the 
development of antibiotic resistance. For milder infections that are 
often self-resolving over time, we are recommending different types of 
studies than what were used in the past. The Agency is doing this in 
order to have studies that have the capacity to provide informative 
data to assess an antibacterial drug's effects in these milder 
conditions. It is essential that clinical trials evaluating a new drug 
be performed in a manner that allows for assessment of the benefits and 
the risks of the drug in the condition under study. A better assessment 
of the benefits that a drug may provide and balancing these benefits 
with risks should provide better quality information on antibacterial 
drugs to foster appropriate use and ideally reduce inappropriate use 
that is also contributing to the development of resistance.
    To that end, CDER has been revising its guidance to industry on the 
development of drugs for the treatment of bacterial infections. 
Revision of these guidances is an important first step. In October 
2007, CDER published a draft guidance document on appropriate use of 
non-inferiority trials for antimicrobial drugs. CDER has also recently 
published draft guidance documents on developing drugs for acute 
bacterial sinusitis (October 2007) and acute bacterial otitis media 
(January 2008). These two draft guidance documents were two of the 
three listed in section 911 of the Food and Drug Administration 
Amendments Act (FDAAA) of 2007. The Agency is working on the third of 
the three listed documents; a draft guidance document for acute 
bacterial exacerbation of chronic bronchitis.
    In January of this year, FDA co-sponsored a workshop with the 
Infectious Diseases Society of America on the topic of clinical trial 
designs for community acquired pneumonia (CAP). The workshop provided a 
platform for the discussion of issues in trial designs for CAP. The 
Agency also convened an advisory committee meeting in April 2008 to get 
additional advice and the Agency is now actively engaged in writing a 
draft guidance document that will provide the Agency's thinking on 
informative trial designs in CAP.
    By providing these draft guidance documents on developing drugs for 
these conditions we have provided some clarity on the types of study 
designs that will be informative in these conditions. It is also 
important to keep in mind that these more sophisticated types of trial 
designs are different than the types of studies that have been used 
previously in these conditions. Hence, a company conducting a clinical 
trial that is different than what has been used in the past is faced 
with the uncertainty as to whether their drugs will work, as well as 
the uncertainties that are inherent in utilizing a trial design with 
which there is less experience. Therefore, FDA is working as 
expeditiously as possible to clarify what is needed in a clinical trial 
design as we make it through this necessary transition period.
    Most of the discussion of drug development has focused on 
resistance in common bacterial infections, but resistance is also a 
problem in conditions such as tuberculosis (TB), fungal infections, and 
malaria. CDER has participated in a working group with representatives 
from FDA and the European Medicines Agency to discuss strategies for 
developing drugs for TB. CDER also published a draft guidance document 
describing approaches to the development of drugs for malaria in June 
2007.
    Appropriate use of antibacterial drugs is guided not only by 
understanding the safety and effectiveness of risks and benefits of 
these drugs, but also by having information on whether a particular 
drug is active against a patient's infection when culture results are 
available. Laboratory testing to assess whether a bacterial isolate is 
``susceptible'' to a particular antibacterial drug can provide such 
information. There are a number of antibacterial drug labels that are 
in need of updating of the information on susceptibility testing. FDA 
just recently published a draft guidance document on ``Updating 
Labeling for Susceptibility Test Information in Systemic Antibacterial 
Drug Products and Antimicrobial Susceptibility Testing Devices'' 
(published June 2008). This draft guidance, in compliance with Section 
1111 of FDAAA, describes options for updating the antibacterial 
susceptibility testing information in antibacterial drug product 
labeling and we believe could facilitate the timely updating of this 
information.
    Section 1112 of FDAAA requires FDA to convene a public meeting 
``regarding which serious and life threatening infectious diseases, 
such as diseases due to gram-negative bacteria and other diseases due 
to antibiotic resistant bacteria, potentially qualify for available 
grants and contracts under section 5(a) of the Orphan Drug Act . . . or 
other incentives for development.'' In compliance with section 1112 of 
FDAAA, FDA held a public hearing on April 28, 2008, to discuss, in 
part, potential incentives to encourage pharmaceutical companies to 
develop new antimicrobial drugs.
Center for Biologics Evaluation and Research (CBER)
    Research and regulatory efforts have contributed to the development 
and continued availability of effective vaccines which have eliminated 
or markedly decreased antibiotic resistance by reducing or even nearly 
eliminating some types of infections. Other vaccines contribute by 
reducing the need for use of antibiotics. CBER has initiated a new 
research program to facilitate vaccine development of MRSA and has 
ongoing research programs to foster the development of vaccines to 
prevent other frequent infectious diseases problems such as Salmonella 
or E. coli gastroenteritis, and TB, as multidrug-resistance has emerged 
as a national and international threat to health. In addition, CBER 
works with sponsors to develop safe and effective vaccines against 
emerging infectious diseases problems. Additional efforts at CBER 
address new diagnostic tests and evaluation of emerging technologies 
and test kits for detecting bacteria as it relates to transfusion 
medicine, mechanisms of resistance, alternative therapies for highly 
resistant organisms, and regulatory pathways to assess the potential 
value of probiotics to help reduce the development and spread of 
antibiotic-resistant bacteria.
Center for Devices and Radiological Health (CDRH)
    CDRH leads several efforts to clarify regulatory requirements to 
both industry and the scientific community on clearance of diagnostic 
tests for use in antimicrobial resistance initiatives. For example, 
CDRH assisted device manufacturers in the most efficient way to get an 
alternative method for detecting vancomycin resistant Staphylococcus 
aureus to market and assured timely introduction of this critically 
important new product through use of its expedited review process. CDRH 
has published guidance documents to ensure the safe and effective use 
of in vitro diagnostics for detecting novel influenza A or A/B viruses 
from human specimens. CDRH recently cleared a new assay developed by 
CDC for the detection of human infection with H5 Avian Influenza virus. 
Other recent approvals include a rapid test for confirming methicillin 
resistant Staphylococcus aureus, a rapid DNA test for detecting Group B 
Streptococcus in pregnant women and a rapid test for detecting Shiga 
toxins 1 and 2 produced by E. coli in stools specimens to aid in the 
diagnosis of diseases caused by enterohemorrhagic E. coli infections.
Center for Veterinary Medicine (CVM)
    CVM is addressing potential human health risks associated with the 
use of antimicrobial drugs in food-producing animals. This approach 
uses risk assessment methodologies to quantify the human health impact 
from antimicrobial use in animals, in conjunction with robust 
monitoring, research, and risk management. In addition, the Agency 
participates in public meetings with various stakeholders to strengthen 
and promote science-based approaches for managing the potential human 
health risks associated with the use of antimicrobial drugs in food-
producing animals.
    One of the key components of FDA's CVM strategy to assess 
relationships between antimicrobial use in agriculture and subsequent 
human health consequences is the National Antimicrobial Resistance 
Monitoring System (NARMS). NARMS is a multi-faceted monitoring system 
that takes advantage of the expertise and resources of a number of 
Federal agencies and State public health laboratories. NARMS data 
provides regulatory officials and the veterinary medical community with 
critical data to help assess the risk associated with antimicrobial use 
in food animal production, and to devise policy guidelines for their 
safe use.
                               conclusion
    In summary, the Federal Interagency Task Force on Antimicrobial 
Resistance has been working for several years to develop and implement 
programs to combat or mitigate antimicrobial resistance in all relevant 
sectors--humans, animals and the environment. Progress has been steady 
with notable achievements. The Task Force holds a public meeting 
annually to discuss progress through the previous calendar year, 
receive comments, and redirect efforts for the following year. The 
current Action Plan is 70-plus pages long. The Task Force is now 
revising the plan focusing on those activities that are critical to 
address over the next 3-5 years. The revised plan is expected to be 
ready for public comment in the fall of 2008.
    Antimicrobial resistance is an important public health issue that 
can only be addressed by collaborative efforts of the relevant Federal 
agencies, State health departments, and the private sector. The 
international health community is facing the same issues so it is 
imperative that we work as much as possible with our international 
public health colleagues.
    Thank you for the opportunity to discuss FDA's role with regard to 
antimicrobial resistance. I would be happy to answer any questions.

    Senator Brown. Thank you, Admiral Tollefson. Dr. Tenover, 
you mentioned vaccines in your testimony. With the decreasing 
effectiveness of some antimicrobials, should research be 
focusing on more vaccines? Is that a practical response?
    Mr. Tenover. I think it is because preventing the 
infections in the first place is one of our major strategies.
    Senator Brown. Tell me about the process of how far you 
think we've come on dealing with a lot of these antimicrobials 
in preventing them with vaccines. How far along are we?
    Mr. Tenover. Well the pneumococcus is a really good success 
story in the number of infections we have been able to prevent 
with that. We have been working on staphylococcal vaccines. 
Those are coming along, but they still have a ways to go.
    Again, our strategy is wherever we can prevent the 
infection, that's what we're going to try and do.
    Senator Brown. Are drug companies doing that kind of 
research for vaccines too or is that all public dollars?
    Mr. Tenover. No. Pharmaceutical companies are actively 
involved in vaccines.
    Senator Brown. Do they see potential bottom line success, 
potential profit on vaccines more or less than they do in 
finding some kind of antimicrobials?
    Mr. Tenover. I can't answer that question. I don't have an 
answer on that.
    Senator Brown. Can you look at their behavior and make some 
kind of educated assertion one way or the other about it?
    Mr. Tenover. Dr. Tollefson, can you address that?
    Admiral Tollefson. I think in partnership with the National 
Institutes of Health they've been able to take some basic 
research, the pharmaceutical companies, and then so that their 
expense in the beginning is less. The pneumococcal vaccine is a 
very interesting example because that was approved for infants 
and young children. What we found was that the rate of 
infections in elderly, for example, decreased because the 
carrier population, if you will, was vaccinated.
    Yes, I think in answer to your question, vaccines 
definitely hold promise and even in a marketable sense.
    Senator Brown. Ok. One other question for Dr. Tenover, you 
mentioned anything we can do to prevent the need for 
antimicrobials. The CDC has made simple recommendations, hand 
washing, making sure towels are washed in locker rooms, 
especially if they have Astroturf surfaces on football fields, 
that kind of thing.
    Talk to me about the issue of the widespread use of 
antibacterial hand soaps or hand gels. I've heard that the 
Director of the CDC recommended that they be used. Is there an 
antimicrobial resistance issue there with those?
    Mr. Tenover. There may be. Let me explain. I mean anything 
we can do to get people to wash their hands more is a good 
thing. The question is if your soap contains an antibacterial 
agent, is it more effective than plain soap? The data right now 
say the answer to that is no. It isn't.
    However, what we have seen is some of the antibacterial 
agents that are put into those hand soaps like triclosan, may 
select for resistant organisms in the laboratory. The reason is 
that a bacteria can deal with that disinfectant by pumping it 
out of the cell just like it does an antibiotic. In the 
laboratory there are concerns that if you use those types of 
antibacterials you will select for resistant organisms.
    However, in community studies that have been done where 
they have compared resistance rates with those people using 
plain soap and antibacterial soaps, we haven't seen that 
materialize as a definitive problem.
    Senator Brown. Is there a third soap? There were in the 
antibacterial, the regular soap and the alcohol substance soap, 
if you will, that's not antibacterial, right?
    Mr. Tenover. That's right. Alcohol-based hand gels are 
being recommended by CDC. They are very effective in health 
care settings.
    They reduce transmission of organisms. They also don't dry 
the skin out as much as regular hand soap does. I think we've 
seen widespread acceptance of those in the hospital setting.
    Senator Brown. They have no antimicrobial resistance issues 
because they aren't antimicrobials, right?
    Mr. Tenover. That's correct, not directly. The alcohol is 
bactericidal so it does do that. We've never seen anything that 
amounts to alcohol resistance in an organism and that would be 
very unlikely. That's why they're effective.
    Senator Brown. Admiral Tollefson, my time's running out. I 
wanted to, few people understand the sort of intersection here 
I think of antimicrobial resistance and in the animal 
population. I understand you're an M.P.H. and a doctor and a 
veterinarian, correct?
    The Center for Veterinary Medicine has a $3-million-line 
item in its budget to re-examine the resistance implications 
have already improved antibiotics. What specific activities at 
CVM have been supported by that budget line item and has the 
CVM initiated action to take any drugs off the market as a 
result of those reviews?
    Admiral Tollefson. Thank you, Senator. The $3 million was 
very well received. We appreciate that. It allowed us to do 
quite a few things in the area of antimicrobial resistance that 
we couldn't previously.
    Microbiologist within our Microbiology Safety branch in the 
Office of Food Safety has been looking at the currently 
approved antimicrobials, specifically the penicillin and 
tetracycline products in great detail. They are going through 
the files of the new animal drug applications for each of those 
products. As you're probably aware, there are pioneer products, 
but also many generic versions of the penicillins and 
tetracyclines.
    Looking for information both on efficacy and on safety as 
it regards antimicrobial resistance. They have finished that 
process. They have also undertaken an extensive literature 
search to look to see if there's any new information on either 
the penicillins or the tetracyclines.
    My understanding is that they are close to reaching summary 
evaluation. As far as I know there has been no move to take 
those products off the market.
    Senator Brown. Ok, thank you. Senator Burr. Oh, in that 
case, Senator Hatch is next.
    Alright, one of you two has got to go next.
    [Laughter.]
    You're way more polite--Senator Hatch.
    Senator Hatch. To both of you we appreciate what your 
agencies are doing to try and help with these problems and 
especially domestically on antimicrobial resistance, but would 
each of you please tell the committee what global efforts are 
being done in this case and also what Pan American efforts are 
being done as well? Because we have people crossing the borders 
at all times and I just would like to kind of get caught up to 
speed on that.
    Mr. Tenover. Well I think one of the things to acknowledge 
is that a lot of our antibiotic resistance issues here are home 
grown. One of the things that we've done at CDC is to try and 
develop relationships with other CDC-like organizations around 
the world. We work with the World Health Organization on 
projects to define antimicrobial resistance and to monitor the 
spread of resistant organisms in a variety of the regional 
offices of WHO.
    One of those, of course, is the Pan American Health 
Organization. We have very strong ties with them. We've worked 
with them in terms of developing our surveillance systems, both 
in Central and South America and coordinated those. We've also 
worked on a number of training programs with them to increase 
their laboratory capacity so that they can detect resistant 
organisms as they develop and spread.
    Admiral Tollefson. I'd like to reiterate that the 
antimicrobial resistance is definitely a global problem. We 
can't work alone. When we work very closely with the World 
Health Organization and the Pan American Health Organization--
you may be interested, Senator Hatch in knowing that our Center 
for Veterinary Medicine had an extensive program with Mexico to 
develop an antimicrobial resistant surveillance system in 
carried pathogens from animals and from retail food in Mexico.
    We supported that in 5 States and Mexico for 3 years. It 
was so successful that the Mexican government then picked it 
up. And it's continuing to grow.
    Senator Hatch. That's great.
    Admiral Tollefson. That's a very practical application of a 
global. We did it primarily because of the flow of the food 
across the borders.
    Senator Hatch. Admiral, the FDA has an office for some 
drugs that has a grant program that would help with antibiotics 
particularly for narrowing indications or infrequent 
infections. In Section 1112 of the Drug Administration 
Amendments Act, we discuss ways in which that office's 
activities could be expanded and even publicized. Would you 
discuss what the FDA is doing to encourage or speed the 
development and approval of new antibiotics?
    Admiral Tollefson. Sure. Thank you. We recently held a 
public meeting on that specific provision of the FDA Amendments 
Act on whether the Orphan Drug Act could be used to provide 
incentives for treatment for resistant organisms or new 
antimicrobials for them. We also broadened it to sort of widen 
the questions we ask about antimicrobial resistance.
    The input we got from that meeting was very valuable. They 
talked about various incentives. At this point we don't believe 
that the Orphan Drug Act is a particularly good model for a 
number of legal and practical reasons.
    That isn't to say that those same incentives couldn't be 
used. The Orphan Drug Act----
    Senator Hatch. You're criticizing my bill you know.
    Admiral Tollefson. Yes. I know.
    [Laughter.]
    The Orphan Drug Act has very specific provisions about how 
many people have to be affected with the disease. What we've 
seen with resistant infections, unfortunately, is that that 
number is broadening. It was a valuable meeting and we continue 
to look at incentives. We think that it's key to the overall 
approach to controlling resistance.
    Senator Hatch. Well, I agree with you on that observation. 
Dr. Tenover, in the strategies to address antimicrobial 
resistance in the STAAR Act, Senator Brown and I have suggested 
a holistic approach to the problem of antibiotic resistance and 
establish a network of experts across the country to conduct 
regional monitoring of resistant organisms as they occur and 
get kind of a snap shot, to pick up the problems earlier. Can 
you discuss the importance of augmenting the CDC's current 
surveillance system with some sort of an expert system?
    Mr. Tenover. Our National Health Care Safety Network now is 
growing and our focus is specifically on identifying health 
care associated infections and the resistant microorganisms 
that are causing those infections. Right now we have over 1,500 
hospitals that are participating in a National Health Care 
Safety Network. We plan to expand that to around 2,000 by the 
end of the year. This will help in that sort of surveillance.
    Also we have several surveillance programs in place through 
our emerging infections program at CDC. These are State-based, 
population-based programs designed to do exactly what you're 
talking about which is to try and detect emerging resistance 
problems as quickly as possible.
    Senator Brown. Thank you, Senator Hatch.
    Senator Burr.
    Senator Burr. Thank you, Mr. Chairman. Dr. Tenover, 
welcome. Admiral Tollefson, welcome.
    Doctor, last October a high school student at Virginia died 
after being hospitalized for more than a week with an 
antibiotic resistant staphylococcus infection. This was 
publicized around the country. In North Carolina, the press 
highlighted cases in hospitals and locker rooms and referred to 
it as a superbug.
    Now maybe it was coincidence but on the same day an article 
was published in JAMA estimating the incidence of MRSA 
infections in the United States. In that article the authors 
described differences in MRSA infections by race, socio-
economic status, geographical differences. To what extent do we 
understand those differences today?
    Mr. Tenover. That's a very important question. Thank you 
for asking that. That's a major part of our investigations now 
into our MRSA infections in the community. We found in a pilot 
study that we did several years ago that there were suggestions 
of these. They're very important for us to try and discern. 
Those studies are ongoing at this point.
    Senator Burr. Clearly the results of what we find out will 
be important.
    Mr. Tenover. Yes, very much so.
    Senator Burr. Admiral Tollefson, there's an Interagency 
Task Force on Antimicrobial Resistance that currently exists. 
How often does that group meet and what takes place at those 
meetings?
    Admiral Tollefson. We try to meet about four times a year. 
The entire group, which is composed of many Federal agencies, 
all those that have something in their mission having to do 
with health. We also have smaller group meetings among agencies 
when a particular issue needs to be addressed or discussed, 
like NIH and CDC, FDA and CMS or something like that.
    Also once a year we have a public meeting where we talk 
about the progress that has taken place over the previous 
calendar year. That actually is going to take place tomorrow at 
the National Foundation for Infectious Diseases Conference in 
Bethesda. I would say that we meet fairly frequently.
    We're in the process of extensively revising the action 
plan to bring it more up-to-date and probably most importantly 
to focus on what we can accomplish over the next 3 to 5 years, 
rather than make it this massive blueprint of all types of 
effort.
    Senator Burr. What's the goal of the task force?
    Admiral Tollefson. Well, the goal is to mitigate or combat 
or mitigate antimicrobial resistance. We do that in various 
areas. It's research. It's surveillance. It's prevention and 
control. It's new products being developed.
    Senator Burr. Do you think the FDA has harmed human health 
by approving antibiotics for use in food animals?
    Admiral Tollefson. Well I'll answer that question in one 
way. We recently removed fluoroquinolone for poultry from the 
market because it definitely harmed human health. That action 
took place in 2005, successful action.
    Senator Burr. The legislation that Senator Brown and 
Senator Hatch have proposed calls for the FDA to consult with 
other Federal agencies before acting upon an antibiotic 
submission. Does the FDA currently consult with other Federal 
agencies or outside bodies when reviewing antibiotic drug 
applications?
    Admiral Tollefson. We may, yes. We have a number of 
advisory committees that will advise us on approval of 
antimicrobials. Those advisory committees could contain, you 
know, employees of other agencies or if we have a particular 
question we won't hesitate to ask them.
    Senator Burr. Well that latitude exists.
    Admiral Tollefson. That latitude definitely exists.
    Senator Burr. It's something that is currently utilized.
    Admiral Tollefson. Yes.
    Senator Burr. For example under the FDA process?
    Admiral Tollefson. Exactly, as needed.
    Senator Burr. Let me move just very briefly to vaccines 
where Senator Brown was. Clearly we went through several 
decades of vaccine decline in this country. Not because the 
threats were any less, but because the return on investment 
didn't exist for the manufacturers that were in it.
    When we looked at it almost a decade ago, the primary 
reason for that was the liability exposure.
    Admiral Tollefson. Right.
    Senator Burr. Because the human body processes vaccines 
differently for each person, some percentages were going to 
have an adverse reaction. Do either one of you honestly believe 
that we will return to robust vaccine production and innovation 
in this country without addressing liability for the larger 
population like we have for the children's vaccines?
    Admiral Tollefson. I think the area of vaccines is right to 
address the issue of antimicrobial resistance. I think we could 
have some real success there. Whether we need an indemnity type 
program, I think that's for others to decide, others that have 
more experience in that area.
    I understand your thoughts that you won't get development.
    Senator Burr. Would you disagree that when we've looked in 
the rear view mirror to understand the decline of vaccine 
innovation and production in the United States we found the 
liability exposure to be a major factor in their decision? If 
one used that historical reference to try to design a pathway 
in the future one would conclude that that would have a great 
effect----
    Admiral Tollefson. Yes, I agree.
    Senator Burr [continuing]. Of willingness of manufacturers 
to commit innovation dollars and two, to actually manufacture 
and distribute domestically.
    Admiral Tollefson. Yes, I agree. Fred, do you want to----
    Senator Burr. Thank you. I thank the Chair.
    Senator Brown. Thank you very much, Senator Burr for your 
interest in this. I want to follow up on your comments in 
response to a very good question from Senator Burr about 
baytril in the fluoroquinolone class. I remember I had been 
working in 1999-2000 on the issue of antibiotic resistance in 
prophylactic use of antibiotics in cattle, but mostly if I 
recall from back then, mostly poultry.
    In my understanding was this just removed from the market, 
baytril was removed because there was already evidence of 
antibiotic resistance in humans when in fact, baytril, this 
class of fluoroquinolone had only been used in poultry. It had 
never been used in humans. Is that correct?
    Admiral Tollefson. Not in the United States. We had 
information from other countries that it had never been used in 
humans, had been used in animals. We found fluoroquinolone 
resistant campylobacter in those humans. Our basis for removal 
of that drug from poultry was based on quite a bit of evidence 
of human health harm.
    Senator Brown. No, that's sort of my point. I remember that 
some fast food restaurants----
    Admiral Tollefson. Yes.
    Senator Brown. Farms, large purchasers of poultry, chicken 
especially were already at that point saying that they were no 
longer going to buy poultry----
    Admiral Tollefson. Poultry.
    Senator Brown [continuing]. From farms that used baytril. 
My point is that that is so very clear cut that there is human 
resistance build up and it hadn't been used in humans. It had 
been used in poultry. No agency could come up with any other 
explanation for it.
    Does that suggest, and that's the only time I understand 
that the FDA through CVM has or through--help me with this. The 
CVM, I'm sorry.
    Admiral Tollefson. The Center for Veterinary Medicine.
    Senator Brown. That they've acted to take a drug off the 
market that way. Does that suggest that you're not aggressive 
enough that it only took one that was so, so clear, it took 5 
years to remove it from the market? Are you being aggressive 
enough to--been moving forward as you should be perhaps, on 
those antimicrobials that may in fact cause some problems in 
humans?
    Admiral Tollefson. I think we're being aggressive to the 
point that we can base on other priorities. It's very 
complicated, scientifically.
    Senator Brown. Sure.
    Admiral Tollefson. It's not always as clear cut as it was 
in the case of the fluoroquinolones. So we need to look at each 
approved antimicrobial, look at the risk and then moved either 
to take it off the market or we could do something much less 
than that. You know, we can work with the sponsor to change the 
labeling of the product. We can work with the sponsor to limit 
its use to certain species or certain disease indications or 
even how it's being used.
    We have quite a few options short of withdrawing an 
antimicrobial from the market.
    Senator Brown. Seven or so years ago I had an amendment in 
fiscal year 2001 Appropriations requesting that FDA review the 
safety of non-therapeutic use of antibiotics in farms. In 2004, 
letters were sent from the FDA to the manufacturers of 
penicillin and other drugs requesting more information because 
the FDA reassessed their safety and found that the use of those 
drugs for growth promotion and feed efficiency and weight gain 
proposed a high risk of producing resistant organisms and 
potential harm to human health. To my knowledge these requests 
were never answered? What gives?
    Admiral Tollefson. Some of the companies did actually 
answer with data, submitted data to us. Some of it was 
redundant to what we had in the original new animal drug 
applications. That is the same issue that they, the Center for 
Veterinary Medicine decided to do an extensive literature 
search on. That's the same issue that's ongoing.
    Senator Brown. Ok. Any other questions from Senator Hatch? 
Senator Burr?
    Ok, thank you very much. I very much appreciate Admiral 
Tollefson, your testimony and public service. Dr. Tenover, you 
too. Thank you.
    The Chair calls up the next panel. If they would come 
forward.
    We have a vote at 11:15. Yes. But they called it.
    Thank you. We'll begin the next panel. The vote will be any 
minute and we might have to interrupt at some point. Thank you 
all for joining us.
    Brandon Noble is a 5-year veteran of the National Football 
League. Mr. Noble has seen both sides of one of sports greatest 
rivalries having played on the Washington Redskins and on the 
Dallas Cowboys. He started every game in 2004 and received the 
Redskins Ed Block Courage Award for perseverance through 
injury. He and his wife, Mary Kate, live in Virginia with their 
three children.
    Dr. Patrick Brennan currently serves as the President of 
The Society for Healthcare Epidemiology of America. He is the 
Chief of Healthcare Quality and Patient Safety at the 
University of Pennsylvania Health System and Professor of 
Medicine at the School of Medicine. At the Hospital of the 
University of Pennsylvania he served as Chair of the Healthcare 
Infection Control Practices Advisory Committee for the 
Department of Health and Human Services. Dr. Brennan, welcome 
to you.
    Dr. Jay Graham served as Consultant to the Pew Commission 
on Industrial Farm Animal Production. He is currently a 
research fellow at Johns Hopkins School of Public Health where 
his research focuses on epidemiological and environmental 
health studies of animal production in the United States and 
abroad. In addition he's worked with the United Nations to 
understand risks of avian influenza in farm animal populations 
and might have some comments on Senator Hatch's question a few 
minutes ago. Dr. Graham, thank you for joining us.
    Dr. Lyle Vogel is Assistant Executive Vice President of the 
American Veterinary Medical Association. Dr. Vogel served in 
the U.S. Army Veterinary Corps for 26 years as a food safety 
and public health specialist. He is a diplomat at the American 
College of Veterinary Preventative Medicine, has won many 
awards including the AVMA's President's award and a special 
citation from the FDA's Commissioner in the area of combating 
antimicrobial resistance. Dr. Vogel, thank you for joining us.
    Dr. Barry Eisenstein has served as the Senior Vice 
President of Scientific Affairs for Cubist Pharmaceuticals 
since July 2004. He has previously held management positions at 
ActivBiotics, Inc. and Eli Lily and was Vice President of 
Science and Technology at the Beth Israel Deaconess Medical 
Center in Boston. Dr. Eisenstein currently serves as Clinical 
Professor of Medicine at Harvard Medical School, is editor of 
the Journal of Antimicrobial Agents and Chemotherapy. Dr. 
Eisenstein, welcome.
    Mr. Noble, would you begin?

         STATEMENT OF BRANDON NOBLE, FORMER NFL PLAYER 
             AND MRSA SURVIVOR, CHESTER SPRINGS, PA

    Mr. Noble. Thank you, Mr. Chairman, Senators. I'm pleased 
and very thankful to be here today--fortunate to be here today 
after what I've gone through.
    Thank you for letting me share my story, the story of my 
family as we have dealt with MRSA for the past few years. Four 
or five years ago I couldn't have told you what MRSA was. Then 
playing for the Washington Redskins I blew my knee out, which 
started a chain of events that ended in the end of my football 
career of which MRSA had a huge part.
    In my first year in Washington, I tore my ACL, my MCL, my 
PCL and dislocated my knee cap all in one fell swoop. I thought 
at that point that was probably the most painful thing I would 
ever experience in 20 years of football and I was wrong. As I 
came back from that injury, overcompensating one leg for the 
other, I injured my right knee which required a quick scope, a 
week off of training and I'd be back getting ready for the next 
season.
    Eight days afterwards they took the stitches out I 
developed a ``hot spot,'' started feeling very sick. Felt like 
somebody was lighting me on fire in bed at night. All of these 
symptoms were going on in Washington with the Redskins, some of 
the best medical people around, didn't know what was happening 
to me.
    They put me on keflex which is just your basic antibiotic 
that they give everybody for infections. It had no effect. Two 
days later after the ``hot spot'' developed, it was now 
covering most of my leg.
    My mother in law is a nurse. She came down. It happened to 
be my daughter's second birthday party. She came down and I was 
laying on the couch, in and out of, not necessarily 
consciousness, but waking up, sleeping, moaning, sweating, 
feeling pretty bad. She told my wife, you need to get him to 
the hospital right now.
    I was rushed to the hospital. The doctors that admitted me 
to the emergency room came, talked to me, talked to my parents, 
while my daughter's second birthday party is going on and 
basically informed my parents that another 24 hours and this 
could have potentially been much worse, including loss of life 
or loss of a leg. From there I recovered, 7 days in the 
hospital, only one surgery, thankfully.
    Then I got to take home my first PICC line which is an IV 
that you use at home. It's attached to the inside of your arm. 
It limits you immensely. I had two children at the time and 
none of them are under 5 pounds, nor were they ever.
    [Laughter.]
    You're not allowed to lift anything over 5 pounds or do 
anything strenuous. This is during my off season conditioning 
program which to be a professional athlete, it's a 12-month-a-
year job. I missed a lot of it.
    I suffered through about 3 weeks of vancomycin. Then I 
developed a reaction to that. The dose of vancomycin is 
administered three times a day for an hour and a half.
    You have to go sit down and hook yourself up to an IV. One 
of them went through me too fast. I developed Red Man Syndrome, 
which is where you get a rash that covers your whole body and 
is very uncomfortable, very itchy. From there I recovered. I 
came back. I was ready to play football again.
    I crammed 6 months worth of work into about 3 weeks. I 
wasn't in great shape but, I got back on the field.
    Within 2 weeks I injured my other knee, my reconstructed 
knee. I had a bone bruise because I was overcompensating for a 
weak right knee. And the process started over again. Had 
another surgery, put on injured reserve, went home.
    I found out my wife was pregnant with our third child so 
took the opportunity away from the NFL to take care of my kids 
while she was pregnant. Chasing two little children around, it 
re-injured the knee. Over the course of about a month, draining 
it, draining it, draining it, somehow or another I picked up 
another infection.
    Had emergency surgery on a Thursday night, my wife came in 
on Friday morning to deliver our third child. The doctors, 
thankfully, allowed me to go into the delivery room. Obviously, 
with what I had, that was a risk, but it was one where I needed 
to be there. I was there for the other two and I wanted to be 
there for the third.
    It has affected us in that way and now having three 
children and watching them grow up, two boys and a girl. The 
boys are all boys. They're cut. They're scraped. They're always 
getting dinged. Every little bump, everything we see, because 
of my experience, now affects us because we're keeping an eye 
on it.
    They're in school. They're around other people. I've become 
a complete germaphobe. I'm scared to death to touch anything in 
public places. I'm all over my children about that also.
    It has been something that we're going to live with for the 
rest of our lives. As a father, you know, to watch one of my 
children go through what I went through, scares me to death. 
Working with the IBSA, I've met parents who have lost children 
to MRSA. I couldn't imagine going through that personally. I 
couldn't imagine having my children in the kind of pain that I 
was in physically.
    I'm a tough person. I've broken bones, blown knees out, had 
teeth knocked out. You name it, I've done it. To watch my 
children suffer like I did would be very difficult.
    I thank you for what you're doing here today, for bringing 
light to this issue. I think it's an issue that the American 
public doesn't pay attention to enough. Mostly because it 
affects all of us as opposed to one single group.
    It's very important because it will kill you. It hurts and 
it's painful. It doesn't care if you're old or young or white 
or black. When you get it, it's serious. The medical profession 
needs help taking care of it. Thank you very much.
    [The prepared statement of Mr. Noble follows:]
                  Prepared Statement of Brandon Noble
    Mr. Chairman and Senators, I'm pleased to be with you today to tell 
my story, and that of my family, of living with an infection resistant 
to most antibiotics. Not that long ago, most of us hadn't heard of 
``MRSA.'' However, today, many of us know someone affected by it or at 
least have heard of it. Thank you for giving attention to this 
important issue. I urge you to take action to protect others and 
prevent them from going through what I've been through.
    Being a football player, there are certain things you can expect--
including injuries. But MRSA is the worst and most unexpected thing 
that I have come up against in my 20-year football career. A tiny 
little thing that I cannot see which has hurt me more than any of the 
other injuries combined. MRSA had a hand in ending my career.
    In 2005, while playing for the Washington Redskins, I had routine 
knee surgery and expected to fully recover and to be ready for the 
upcoming season. The surgery was performed and I was fine for about 8 
days, then the stitches were taken out. That night, a hot spot 
developed over the porthole used for the surgery. I began feeling 
sick--flu-like symptoms and my knee hurt like someone was lighting me 
on fire. By the time I was put in the hospital 2 days later, the 
infection had spread from a quarter-sized red spot to cover a good 
portion of my leg. One of the first doctors that I saw told my parents 
that if I had waited another 24 hours we could be talking about the 
loss of my leg or worse. Surgery was performed and the infection was 
washed out.
    But now I had to deal with the rest of the treatment, including 
home IV for 6 weeks on the drug vancomycin--which wears you out. It 
took my energy and appetite. I was told not to lift anything over 5 
pounds with my arm that had the IV port in it. With kids and normal 
activity, that was pretty limiting. Three times a day, for 1\1/2\ 
hours, I had to sit down and get my treatment. Then due to a reaction 
to the vanco, I was taken off that antibiotic and placed on Zyvox, an 
oral med that is very strong and has very uncomfortable side effects. I 
completed my treatment and was given a clean bill of health.
    By this time, I had missed the entire off-season workout program. 
This is my career and livelihood. Now I was playing catch up and tried 
to cram an off-season into 3 weeks. I was able to come back and play 
during pre-season camp, but in compensating for the knee that had been 
infected, I hurt my other leg and required surgery again. I was placed 
on injured reserve and forced to sit out for the season.
    While all this was going on we found out that my wife was pregnant 
with our third child. So, since I was on injured reserve I was able to 
stay home and help my wife out. Chasing two little kids around all day, 
I re-injured my knee and after having the knee drained several times 
over a couple weeks, I started to get sick again. Same symptoms as 
before--burning in the knee and the worst flu symptoms you can imagine.
    I was admitted to the hospital for surgery. The next day, my wife 
was admitted to the hospital and our third child was born. Because of 
my MRSA they were hesitant to let me in the delivery room. But, with 
necessary precautions, my wife's doctor said I could be there. Missing 
the birth of a child is not acceptable and would have been devastating. 
I was scared to hold my son for fear of getting him sick. Again, I was 
sent home with IV antibiotics.
    I continue to live with MRSA. The thing that scares me the most is 
that I could be a carrier of this bug and have to worry about my wife 
and kids getting it. Knowing how painful and serious it is, that is the 
last thing I want to happen. I have three young children who will have 
a lifetime of cuts and scrapes. I will keep a close eye on each child 
because I am incredibly paranoid about them getting MRSA. Any small red 
bump on any of my kids and I am pestering my wife to keep an eye on it, 
ready to go to the doctors at the drop of a hat.
    My wife has been incredible through this experience. In fact, 
because of it, she's gone back to school to become a nurse and to help 
others.
    An unwelcome complication from my last surgery was developing two 
blood clots, one in each lung. Because of the clots and the MRSA, I 
lost my career as a professional football player. This infection has 
had a huge impact on my life and continues to impact me and my family. 
Hopefully, I am not a carrier and will not have to worry about this 
forever.
    Please remember, my story is only one of many, and I'm lucky to be 
here to share it with you. As lawmakers, I urge you to look at the 
growing problem of resistant infections that have few, if any, 
antibiotics to treat them. MRSA outbreaks have impacted sports teams, 
school children, our military, and others. But, there are many other 
infections which antibiotics are failing to treat.
    Mr. Chairman and Senator Hatch, I greatly appreciate your 
dedication to this issue and your recognition that much more needs to 
be done to protect public health. Your legislation, the STAAR Act, 
would better focus the Federal Government on this issue. I understand 
the government has an Action Plan that is nearly 8 years old and much 
of it has yet to be implemented--even those items identified as 
priorities. Your bill makes sure there's a point person, a coach more 
or less to lead the team and hold all the players accountable.
    Also, your bill improves what is known about antibiotic use and 
assist research in this area. We need to learn more about these 
infections and the ability to treat them. Finally, your bill will make 
a difference in prevention. It would monitor new or problematic 
infections and hopefully prevent their spread. It would collect and 
study samples of these emerging infections so that physicians will know 
more about them and help to identify them. For patients like me, it 
makes all the difference if your physician is on the look out for these 
infections and can properly treat them as soon as possible.
    And, of course, we need to make sure new antibiotics are developed 
to keep ahead of these bad bugs. These infections take down the 
strongest and healthiest of us. I hope my experience points out that 
this truly can happen to anyone.
    Thank you.

    Senator Brown. Thank you, Mr. Noble. Dr. Brennan, I 
wouldn't normally go in that order, but since you're going to 
talk about the health acquired infections and health care-
related infections, I'd like you to go next. Thanks.

 STATEMENT OF PATRICK J. BRENNAN, M.D., PRESIDENT, THE SOCIETY 
    FOR HEALTHCARE EPIDEMIOLOGY OF AMERICA, PHILADELPHIA, PA

    Dr. Brennan. Thank you, Senator Brown for inviting the 
Society for Healthcare Epidemiology of America to present our 
views on the challenges of hospital acquired infections in 
light of the emergence of antibiotic resistant infections. I'm 
Patrick J. Brennan, President of the Society for Healthcare 
Epidemiology of America and Chief Medical Officer of the 
University of Pennsylvania Health System. I'm also a fellow of 
the Infectious Diseases Society of America.
    SHEA, as my society is known and IDSA are sister 
organizations, many of whose members overlap and a mutual 
interest in the prevention and elimination of healthcare 
associated infections and the development of better tools 
including antimicrobial agents to combat these infections. 
These infections are diseases caused by microbes primarily 
bacteria, viruses and fungi and their toxins that occur during 
the delivery of healthcare and were not present or incubating 
at the time of entry into the healthcare system. They're often 
related to the delivery of healthcare itself.
    Four diseases are most common: infections of the urinary 
tract, pneumonies, infections that reach recent sites of 
surgical procedures and infections involving the bloodstream. 
Often times these infections are related to the use of a 
medical device such as a urinary/bladder catheter or a 
ventilator to support respiration. Such devices when used 
appropriately are necessary to support patients through their 
recovery from illnesses. However, devices represent double 
edged swords whose beneficial effects must be weighed against 
the risk of infection they pose through proper or improper 
placement, maintenance and unnecessary use.
    As healthcare is delivered more frequently outside the 
hospital, in clinics, surgical oncology centers, extended care 
facilities and even private homes, the line between community 
and healthcare associated infection has become blurred and 
prevention of HAIs has become more challenging. Reducing 
preventable HAIs is a complex challenge that requires multiple 
interventions. No single intervention is a sufficient solution.
    Combinations of strategies or bundles of activities such as 
appropriate hand hygiene during patient care, careful placement 
and maintenance and removal of supported medical devices is 
essential. Isolation practices are often necessary to prevent 
transmission of germs and must be rigorously followed. 
Antibiotic resistance complicates the management of HAIs.
    Since the discovery of antibiotics it has been recognized 
that microbes possess the ability to resist the killing and 
inhibitory affects of these drugs. While most germs possess 
their own native resistance to one or more antibiotics. Germs 
causing infection in healthcare settings have become more 
resistant to our commonly available antibiotics, for example, 
Methicillin-resistant Staph aureus or MRSA infections, thereby 
limiting our therapeutic options.
    Compounding the problem of resistance is the limited 
availability of our antibiotic choices when resistance arises. 
In some situations we have moved beyond second and third line 
choices to the need to re-introduce into common practice agents 
that have been relegated to the pharmacy shelf decades ago 
because of their toxic side effects or limited efficacy. Now as 
our options have been limited by resistance, it has been 
necessary to re-introduce into practice such drugs.
    I've had the experience in my career of seeing a patient 
die of a drug resistant infection when he developed a rare, but 
serious allergic reaction to the only available effective drug 
to treat his infection. We were without therapeutic 
alternatives.
    Hospitals must have flexibility in their choice of 
prevention strategies because they develop their own microbial 
ecology and patterns of infection. As a result must tailor 
their prevention strategies. MRSA is a good example of this. 
This is an extremely important pathogen. And as Mr. Noble has 
described, can have a profound impact on the life and career of 
patients.
    While this is a very virulent and important germ, many 
mistakenly believe it is the only significant cause of HAIs. In 
fact MRSA constitutes approximately 8 percent of healthcare 
associated infections. While we have begun to make progress 
against MRSA, the incidence of which has fallen by more than 50 
percent in the past 10 years in some hospital units, much more 
work remains to be done.
    There are promising options to treat MRSA. However for many 
other types of infections such as gram negatives or 
armamentarium is more limited. Increasing levels of resistance 
are being identified against some classes of antibiotics 
through an analysis by the ID society is apparent that the 
pipeline is in decline. This is an important resource that must 
be restored.
    The drugs in development will not be able to address the 
growing number of antimicrobial resistant infections in the 
various settings. In particular, there are no drugs in the 
pipeline to address many gram negative bacteria. It seems 
likely that it will be necessary for Congress to establish 
measures to ensure the development of new antimicrobials and a 
commission to study to understand the measures should be 
convened by Congress.
    What Federal action is most needed with regard to HAIs? Our 
society supports the conclusions of the recent GAO report in 
coordination among health and human services agencies related 
to HAI prevention. We believe that coordinated action is 
necessary among CDC, CMS and ARC.
    CDC in its division of healthcare quality promotion should 
function as the lead agency, we believe, in surveillance and 
prevention activities related to HAIs at the Federal level 
because of its historic and successful role in this area. It 
has had an enviable record of prevention. Its development and 
management of the foremost surveillance system of its kind, the 
National Healthcare Safety Network has created a national 
resource that many States have now mandated as their public 
reporting tool. Its guidelines developed by the Federal 
Healthcare Infection Control Practices Advisory Committee are 
widely regarded as standards for the field.
    We believe that Federal action would have the greatest 
impact on HAI prevention and antimicrobial resistance by 
supporting and strengthening the infrastructure currently in 
place and by taking the following actions.
    First, to protect and improve resources for implementation 
of programs of standardized measurement and appropriate HAI 
outcomes and performance measures.
    Second, to enact the STAAR Act, to reauthorize the 
Interagency Antimicrobial Resistance Task Force, improve 
coordination and accountability of HHS and its agencies to 
combat resistance, to improve upon and further strengthen 
existing surveillance efforts and create a joint blueprint for 
antimicrobial research.
    Third, Congress should support the development of the next 
generation of experts in this field. Many of the experts in 
this field are now mid-career and beyond and the pipeline there 
is limited as well; create demonstration projects to test real 
world effectiveness of various implementation strategies and 
address the prevention of HAI broadly, rather than focusing on 
specific pathogens.
    Thank you. I'll be happy to answer your questions.
    [The prepared statement of Dr. Brennan follows:]
             Prepared Statement of Patrick J. Brennan, M.D.
    Chairman Kennedy, Ranking Member Enzi and Members of the Senate 
Health, Education, Labor, and Pensions Committee, thank you for 
inviting the Society for Healthcare Epidemiology of America (SHEA) to 
present our views on the challenges of healthcare-associated infections 
in light of the emergence of antibiotic-resistant infections. I am 
Patrick J. Brennan, President of SHEA and Chief Medical Officer of the 
University of Pennsylvania Health System. I am also a Fellow of the 
Infectious Diseases Society of America (IDSA). SHEA and IDSA are sister 
organizations, many of whose members overlap. Our societies have mutual 
interests in the prevention and elimination of healthcare-associated 
infections and in the development of better tools, including 
antimicrobial agents to combat these infections.
    SHEA was organized to foster the development and application of the 
science of infection prevention and control and healthcare epidemiology 
through research and education in such areas as surveillance, risk 
reduction, device and procedure management, and epidemiologic 
investigation. I would like to be clear from the outset that our 
testimony is provided strictly for the good of the public's health and 
the patients we treat. We are not here on behalf of any other interest 
or industry and our advocacy is not financed in any way by industry.
    SHEA and its members are committed to implementing evidence-based 
strategies to prevent healthcare-associated infections. SHEA members 
have scientific expertise in evaluating potential strategies for 
eliminating preventable HAIs. We collaborate with a wide range of 
infection prevention and infectious disease societies, specialty 
medical societies in other fields, quality improvement organizations, 
and patient safety organizations in order to identify and disseminate 
best practice evidence. Our principal partners in the private sector 
have been sister societies such as IDSA and the Association of 
Professionals in Infection Control and Epidemiology (APIC). The Centers 
for Disease Control and Prevention (CDC), its Division of Healthcare 
Quality Promotion (DHQP) and the Federal Healthcare Infection Practices 
Advisory Committee (HICPAC), and the Council of State and Territorial 
Epidemiologists (CSTE) have been invaluable Federal partners in the 
development of guidelines for the prevention and control of HAIs and in 
their support of translational research designed to bring evidence-
based practices to patient care.
                    healthcare-associated infections
    Healthcare-associated infections (HAIs) are diseases caused by 
microbes, primarily bacteria, viruses, and fungi and their toxins that 
occur during the delivery of healthcare and were not present or 
incubating in the patient at the time of entry into the healthcare 
system. They are often related to the delivery of healthcare itself. 
Four diseases represent the most common HAIs. They are: (1) infections 
of the urinary tract; (2) pneumonia resulting from the aspiration of 
the contents of the mouth, throat, or stomach; (3) infections at the 
site of a recent surgical procedure; (4) infections involving the 
bloodstream that are usually related to the use of an intravenous 
catheter. Oftentimes these infections are related to the use of a 
medical device, such as a urinary bladder catheter or a ventilator to 
support respiration. Such devices when used appropriately are necessary 
to support patients through their recovery from illness. However, 
devices represent double edge swords whose beneficial effects must be 
weighed against the risks of infection they pose through proper or 
improper placement and maintenance and unnecessary use.
    As healthcare is delivered more frequently outside the hospital, in 
clinics, outpatient surgical and oncology centers, extended care 
facilities, and in private homes, the line between community-acquired 
and healthcare-associated infection has become blurred, and prevention 
of HAIs becomes even more challenging. Reducing preventable HAIs is a 
complex challenge that requires multiple interventions. No single 
intervention is a sufficient solution. Combinations of strategies, or 
bundles of activity, such as appropriate hand hygiene during patient 
care and careful placement maintenance and removal of supportive 
medical devices, is essential. Isolation practices are often necessary 
once infection occurs and must be carefully followed.
    Accurate measurement of the occurrence of HAIs and the impact of 
preventive strategies is important. Measurement of infection rates and 
the public disclosure of rates can be useful in part because it allows 
hospitals to have a frame of reference for their performance. It 
enables patients, purchasers and payors to hold hospitals accountable, 
and creates the opportunity for dialogue between patients and providers 
on these issues. Transparency enables providers to better understand 
the successes and failures that others have had in process improvement 
related to HAIs and to adopt strategies that have been found to be 
effective in other facilities treating similar patient populations. The 
process of collecting and disclosing HAI rates must be balanced with 
the likelihood that the data collected can lead to actionable 
information and performance improvement. If data are collected that are 
not actionable, scarce hospital resources will be diverted to 
meaningless activities from more valuable interventions.
    Antibiotic resistance complicates the management of HAIs. Since the 
discovery of antibiotics, it has been recognized that microbes possess 
the ability to resist the killing and inhibitory effects of these 
drugs. While most germs possess their own native resistance to one or 
more antibiotics, germs causing infection in healthcare settings have 
become more resistant to our commonly available antibiotics (e.g. 
methicillin-resistant Staphylococcus aureus or ``MRSA'' infections) 
thereby limiting our therapeutic options. Compounding the problem of 
antibiotic resistance is the overuse of antibiotics in humans and 
animals and the limited availability of alternate antibiotic choices 
when resistance arises. In some situations we have we moved beyond 
second and third line drug choices to the need to re-introduce into 
common practice antimicrobial agents that had been relegated to the 
pharmacy shelf decades ago because of their toxic side effects. Now, as 
our therapeutic options have been limited by resistance it has been 
necessary to re-introduce such drugs into practice. I have had the 
experience in my career of seeing a patient die of a drug-resistant 
infection when he developed a rare but serious allergic reaction to the 
only available, effective drug to treat his infection. We were left 
without therapeutic alternatives.
    Hospitals must have flexibility in their choice of prevention 
strategies. There has been a growing interest in legislative mandates 
for action against specific germs. We believe such mandates are 
unfounded and potentially hazardous. Hospitals develop their own 
microbial ecology and patterns of infection and as a result must tailor 
their prevention strategies to their experience. MRSA is a good example 
of this. This is an extremely important pathogen and one that has had a 
serious impact on the life and career of one our panelists, former-
Washington Redskin Brandon Noble, as well as many patients. While this 
is a virulent and important germ, many mistakenly believe is the only 
significant cause of HAIs in the United States. In fact, MRSA 
constitutes approximately 8 percent of HAIs in the United States. While 
we have begun to make progress against MRSA, the incidence of which has 
fallen by more than 50 percent in the past 10 years in hospital 
medical/surgical intensive care units, much more work remains to be 
done. Although there are promising options to treat MRSA, the 
antibiotic pipeline for other types of infections is more limited. 
Mandates for all hospitals to specifically address MRSA may divert 
activity away from the increasing resistance in gram-negative 
infections. Decisions as to appropriate resource allocation can only be 
made by local risk assessment processes. Appropriate institutional 
oversight (``stewardship'') of antibiotic use is an important aspect of 
the prevention of some HAIs and may impact the subsequent development 
of drug resistant pathogens in healthcare settings.
    Increasing levels of bacterial resistance are being identified 
against some classes of antibiotics. Through an analysis done by the 
Infectious Diseases Society of America, it is apparent that the 
antibiotic pipeline is in decline and is not strong enough to meet the 
challenges that we face. Antibiotic research development is an 
important resource that must be restored. The drugs in development will 
not be able to address the growing number of antimicrobial resistant 
infections in the various healthcare settings. In particular, there are 
no drugs in the pipeline to address many gram-negative bacteria. It 
will first be necessary to understand what measures are needed to 
ensure the development of new antibiotics. Congress should commission 
such a study.
    The extent to which HAIs are preventable and the number of lives 
that can be saved remains a matter of debate. What is not debatable is 
that we should attempt to prevent every infection and save every life 
possible through the application of the best evidence to practice. SHEA 
recently provided Congress with a white paper (See Appendix) with a 
range of estimates for the number of infections that can be prevented 
and the potential number of lives saved. Those estimates did not 
conclude that all infections are preventable at this time. There are 
significant limitations to the available information from which the 
estimates are derived but the elimination of HAIs remains an 
aspirational goal.
    Protecting the health of our patients and preventing HAIs in the 
settings where healthcare is delivered in the United States will 
require a multi-faceted approach that includes identification and 
widespread adoption of evidence-based best practices. Where evidence 
does not exist, uniformity in practice should be adopted and studied to 
determine effectiveness. Failed practices should be discarded and 
successes widely disseminated. Prevention and control of HAIs also will 
require better tools in the form of new and novel antimicrobial agents, 
better knowledge of strategies to effect implementation and adherence 
to proven prevention methods, and accountability for performance.
        what federal action is most needed with regard to hais?
    SHEA supports the conclusions of the recent GAO report on 
coordination among Health and Human Services Agencies related to HAI 
prevention. We believe that coordinated action among CDC, CMS and AHRQ 
is critical. CDC and its Division of Healthcare Quality Promotion 
should function as the lead agency in surveillance and prevention 
activities related to HAIs at the Federal level because of its historic 
and successful role in this area. CDC has had an enviable track record 
of prevention and its development and management of the foremost 
surveillance system of its kind, the National Healthcare Safety Network 
(NHSN) has created a national resource that many States have now 
mandated as their public reporting tool. Furthermore, guidelines 
developed by the Federal Healthcare Infection Control Practices 
Advisory Committee are widely regarded as the standards for the field. 
Coordinated activity among the agencies can lead to better informed 
public policy and payment reform.
    SHEA urges enhanced support for CDC and its sister agencies 
including the Agency for Health Care Research and Quality (AHRQ), the 
Food and Drug Administration (FDA), and the National Institutes of 
Health (NIH) to further the goals of prevention and control of HAIs, 
and the establishment of a robust pipeline of effective, new 
antimicrobial agents for treatment and the coordination of efforts to 
improve the health of our citizens.
    SHEA believes that Federal action would have the greatest impact on 
HAI infection prevention and anti-microbial resistance by supporting 
and strengthening the infrastructure currently in place to implement 
evidence-based interventions. Important actions include:

     Protect and improve resources for implementation of 
programs that standardize measurement of appropriate HAI outcomes and 
performance measures. Our most valuable resource in this regard is the 
CDC National Healthcare Safety Network (NHSN). The current 
administration budget proposes to reduce the source of most NHSN 
resources at a time when many States consider NHSN the best option for 
implementing standardized reporting of HAI data. NHSN has now been 
adopted by 17 States and more than 25 percent of all U.S. hospitals for 
the surveillance and reporting of HAIs. It is an enormously important 
national resource and effective funding and support is essential.
     Enactment of the Strategies to Address Antimicrobial 
Resistance (STAAR) Act to reauthorize the Interagency Antimicrobial 
Resistance Task Force, improve coordination and accountability of HHS 
and HHS agencies to combat antimicrobial resistance; improve upon and 
further strengthen existing surveillance efforts; create a joint 
blueprint for antimicrobial research; collect comparable and reliable 
data to allow government to better assess the antimicrobial resistance 
problem including how antibiotic use in humans and animals triggers the 
development of resistance; and establish demonstration projects to 
encourage more appropriate use of existing antibiotics.
     Congress should support the development of the next 
generation of experts in this field. Designate grants to State and 
local health departments, and private organizations to support 
specialized education and training is essential to ensure that 
adequately trained personnel are available to meet the growing needs 
throughout the United States.
     Support standards and HAI preventive measures that assure 
availability of local expertise in infection prevention in every State 
and locality and in every healthcare facility. Such standards might set 
a minimum number of infection control professionals and healthcare 
epidemiologists based on size and acuity level of a facility and/or 
population of a State.
     Create demonstration projects to test the real world 
effectiveness of various implementation strategies for evidence-based 
interventions to prevent infections.
     Support States' efforts to create appropriate statutes to 
ensure optimal HAI prevention activities and, in some cases, public 
reporting standards that fit their own HAI challenges.
     Ensure that unintended consequences of well-intended 
mandates such as public reporting of HAIs (for example, avoidance of 
surgery on patients thought to be at higher risk of infection, or 
inappropriate antimicrobial treatment of asymptomatic patients where 
such treatment is not indicated) are considered prior to adoption of 
surveillance or reporting requirements.
     Address the prevention of HAIs broadly (rather than 
focusing on specific organisms) to ensure that healthcare institutions 
can adequately allocate resources to HAIs of highest priority to local 
needs. As an example, SHEA endorses the emphasis the Joint Commission 
places on conducting a risk assessment in order to target preventive 
efforts effectively. We believe that this strategy allows healthcare 
facilities to use local information to develop and implement optimal 
and individualized prevention plans designed to reduce healthcare-
associated infections that are identified as local problems. Goals 
should be written in such a way to allow hospitals the flexibility to 
identify and target their own safety threats within the domains that 
are considered critical, and healthcare facilities should be expected 
to be able to justify their infection prevention program based on local 
risk assessments.
     Allow flexibility for healthcare facilities to select 
locally appropriate interventions from among ``evidence-based 
practices'' in creating a prevention program that is effective. This 
flexibility recognizes the influence of local conditions on the control 
of healthcare-associated infections, and allows rapid modification of 
strategies as new knowledge is gained.

    Thank you. I will be happy to answer any questions.

    Senator Brown. Thank you, Dr. Brennan. Now I think we will 
recess for 20 to 25 minutes and I will obviously return as 
quickly as I can. Thank you.
    [Recess]
    Senator Brown [resuming the Chair]. Thank you. I again, 
Senator Hatch and I apologize for the interruption. Now Dr. 
Graham, thank you--you're next.

  STATEMENT OF JAY P. GRAHAM, PH.D., MBA, CONSULTANT, THE PEW 
 COMMISSION ON INDUSTRIAL FARM ANIMAL PRODUCTION, BALTIMORE, MD

    Mr. Graham. Thanks a lot. Good morning or good afternoon, 
maybe? My name is Jay Graham.
    I'm a public health researcher at Johns Hopkins Bloomberg 
School of Public Health. In addition I was the co-author of a 
report for the Pew Commission on industrial farm animal 
production titled, Antibiotic Resistance in Human Health. I 
appreciate the chance to speak to you today.
    Antimicrobials play an essential role in the fight against 
infectious bacteria that can cause disease in humans, disease 
and death in humans. Their role however, is being jeopardized 
by the current practice of feeding low doses of antimicrobials 
to billions of animals. This practice facilitates the spread of 
resistant disease causing bacteria and compromises the ability 
of medicine to treat disease.
    Under conditions of constant antimicrobial use, resistant 
bacterial strains have an advantage in terms of reproduction 
and spread. Because of the speed with which bacteria replicate 
these changes can come about quickly. While much of the 
discussion of antimicrobial use centers on the importance of 
human medicine, it is estimated that most antimicrobials used 
in the United States are used as growth promoters in food 
animal production, not in human medicine. A wide range of 
antimicrobial drugs are permitted for use in food animal 
production in the United States. These drugs represent most of 
the major classes of clinically important antimicrobials 
including drugs like penicillin, tetracycline and many others.
    This practice of feeding antimicrobials to animals began 
before we really understood how resistance can spread. We now 
understand that bacteria can share genetic material, DNA, that 
encodes the resistance to antimicrobials. It is estimated that 
this transferable resistance, these resistance genes, account 
for more than 95 percent of antibiotic resistance.
    In our research at the School of Public Health we've 
isolated multi-drug resistant bacteria and resistance genes in 
animal waste stored over long periods of time, in food 
products, in streams downstream from swine confinement 
operations, in people who work with live poultry and in the air 
at swine operations. The food routes are the most well-studied 
exposure route. In the United States, drug resistant bacteria 
are highly prevalent in meat and poultry products including 
disease causing organisms, in meats that are resistant to the 
broad spectrum of antimicrobials, penicillin, tetracycline, 
erythromycin.
    Humans are also exposed through environmental routes. Waste 
disposal is the major source of antimicrobial resistant 
bacteria entering the environment from animal feeding 
operations. Each year confined animals produce more than 40 
times the amount of waste that is produced from publicly owned 
treatment works.
    The difference is that this waste isn't treated. It goes on 
to the land right after production. Antimicrobial resistant E. 
coli and resistance genes have been detected in ground water 
sources for drinking water sampled near hog farms in North 
Carolina, Maryland, and Iowa. As you're likely aware, ground 
water provides drinking water for nearly all U.S. rural 
populations.
    What is most surprising is that the economics don't justify 
the routine use of antimicrobials. There have been two recent 
large scale studies, one with poultry and one with swine, that 
found the actual economic benefits were miniscule to 
nonexistent. These studies just looked at the economic benefits 
at the production level.
    They didn't include the shortened useful life of existing 
antimic-
robials. They didn't include the loss of disease treatment 
options in humans and animals nor the increased health care 
costs, nor the more severe and enduring infections. Those 
weren't included in those economic analysis.
    In closing I would like to reiterate that antimicrobials 
are a precious resource that should be safeguarded. Routine use 
of antimic-
robials in food animal production should be ended. Economic 
analyses demonstrate that there's little to no economic benefit 
from using antimicrobials as feed additives. And that 
equivalent improvements in growth and feed consumption or feed 
conversion efficiency can be achieved by improved management. 
Thank you.
    [The prepared statement of Mr. Graham follows:]
            Prepared Statement of Jay P. Graham, Ph.D., MBA
    Good morning Mr. Chairman and members of the Senate Health, 
Education, Labor, and Pensions Committee. My name is Jay Graham and I 
am a public health researcher at the Johns Hopkins Bloomberg School of 
Public Health. In addition, I was the co-author of a report for the Pew 
Commission on Industrial Farm Animal Production titled Antibiotic 
Resistance and Human Health. I appreciate the opportunity to speak to 
you today.
    Antimicrobials are a critical defense in the fight against 
infectious bacteria that can cause disease and death in humans. Their 
value as a resource in human medicine is being squandered through 
inappropriate use in animals raised for food. The method that now 
predominates in food animal agriculture--applying constant low doses of 
antimicrobials to billions of animals--facilitates the rapid emergence 
of resistant disease-causing bacteria and compromises the ability of 
medicine to treat disease, making it clear that such inappropriate and 
indiscriminate use must end.
    A wide range of antimicrobial drugs are permitted for use in food 
animal production in the United States. (Sarmah, et al. 2006). These 
drugs represent most of the major classes of clinically important 
antimicrobials, from penicillin to third-generation cephalosporin 
compounds. In some cases, new drugs were licensed for agricultural use 
in advance of approvals for clinical use. In the case of quinupristin-
dalfopristin--an analog of virginiamycin, which is used in food animal 
production--this decision by the FDA resulted in the emergence of 
resistance in human isolates prior to eventual clinical registration 
(Kieke, et al. 2006), thus demonstrating how feed additive use can 
compromise the potential utility of a new tool in fighting infectious 
disease in humans. Agricultural use can also significantly shorten the 
``useful life'' of existing antimicrobials for combating human or 
animal disease (Smith, et al., 2002).
    While discussion of the issue of declining effectiveness of 
antimicrobials often centers on the importance of ensuring the proper 
use of antimicrobials in human medicine, the fact is that most 
antimicrobials used in the United States are used as ``growth 
promoters'' in food animal production, not human medicine (Mellon, et 
al. 2001). In North Carolina alone, the use of antimicrobials as a feed 
supplement has been estimated to exceed all U.S. antimicrobial use in 
human medicine. A relatively small percentage of antimicrobial use in 
food animal production is to treat sick animals, and much of what is 
needed for therapeutic purposes is the direct result of the animal 
husbandry practices of crowding large numbers of food animals in small 
confined spaces, thereby increasing the chance that diseases will 
spread through food animal populations.
    Exposure of bacteria to sub-lethal concentrations of antimicrobial 
agents is particularly effective in driving the selection of resistant 
strains, and under conditions of constant antimicrobial use, resistant 
strains are advantaged in terms of reproduction and spread. Because of 
the rapidity of bacterial reproduction, these changes can be expressed 
with great efficiency.
    Exacerbating the problem of using antimicrobials for growth 
promotion of food animals is the fact that bacteria can share genetic 
material that encodes resistance to antimicrobials. It is estimated 
that transferable resistance genes account for more than 95 percent of 
antibiotic resistance (Nwosu, 2001). These events have been frequently 
detected in resistant E. coli isolated from consumer meat products 
(Sunde and Norstrom 2006). At this point, most research has focused on 
specific patterns of resistance in selected disease-causing organisms--
a ``one bug, one drug'' definition of the problem (Laxminarayan, et al. 
2007). But this discounts the fact that it is the community of genetic 
resources that determines the rate and propagation of resistance 
(Salyers and Shoemaker 2006).
    From a public health perspective, it clearly makes good sense to 
remove antimicrobials for growth promotion in food animal production. 
When this is done, resistance in disease-causing organisms tends to 
decrease significantly. Studies carried out in Europe have demonstrated 
a rapid decrease in the prevalence of antimicrobial resistant 
Enterococcus faecium recovered from pigs and broilers after 
antimicrobials were removed (from Aarestrup, et al. 2001). The 
prevalence of resistant enterococci isolates from human subjects also 
declined in the European Union (EU) over the same period (Klare, et al. 
1999).
    Addressing other animal agriculture practices, such as more 
thorough and frequent cleaning of animal feeding operation facilities, 
may also be needed in conjunction with cessation of using 
antimicrobials to eliminate reservoirs of antibiotic resistance 
bacteria from farms.
    Recent studies call into question the assumed economic benefits of 
using antimic-
robials in animal feeds. Historically, economic gains from using 
antimicrobials to promote growth have been thought to justify the 
expense of the drugs. Two recent large-scale studies--one with poultry 
and one with swine--found that the actual economic benefits were 
miniscule to nonexistent, and that the same financial benefits could 
instead be achieved by improving the management of the animals (e.g., 
cleaning out poultry houses) (Graham 2007; Miller 2003). Even when 
improvements from growth promoting antimicrobials have been observed, 
their benefits are completely offset if costs from increased resistance 
are considered: loss of disease treatment options in humans and 
animals, increased health care costs, and more severe and enduring 
infections. These costs are usually ``externalized'' to the larger 
society and not captured in the price of the meat and poultry sold to 
consumers.
    There are industry trade groups that argue that using 
antimicrobials in the food animal production process does not pose a 
threat to public health. But, numerous studies support a strong link 
between the introduction of an antimicrobial into animal feeds and 
increased resistance in disease-causing organisms isolated from humans 
(Silbergeld, et al. 2008). Resistant disease-causing organisms can 
affect the public through food routes and environmental routes.
    Food routes: In the United States, antimicrobial resistant disease-
causing organisms are highly prevalent in meat and poultry products, 
including disease-causing organisms in meats that are resistant to the 
broad-spectrum antimicrobials penicillin, tetracycline and erythromycin 
(Johnson, et al. 2005; Simjee, et al. 2002). Animals given 
antimicrobials in their feed contain a higher prevalence of multidrug-
resistant E. coli than animals produced on farms where they are not 
exposed to antibiotics (Sato, et al. 2005), and the same disparity 
shows up when one compares the meat and poultry products consumers 
purchase from these two styles of production (Price, et al. 2005; 
Luantongkum, et al. 2006).
    Environmental routes: Waste disposal is the major source of 
antimicrobial resistant disease causing organisms entering the 
environment from animal feeding operations. Each year, confined food 
animals produce an estimated 335 million tons of waste (dry weight) 
(USDA), which is deposited on land and enters water sources. This 
amount is more than 40 times the mass of human biosolids generated by 
publicly owned treatment works (7.6 million dry tons in 2005). No 
treatment requirements exist in the United States for animal waste 
before it is disposed of, usually on croplands--even though levels of 
antimicrobial resistant bacteria are present at high levels.
    Antimicrobial resistant E. coli and resistance genes have been 
detected in groundwater sources for drinking water sampled near hog 
farms in North Carolina (Anderson and Sobsey 2006), Maryland (Stine, et 
al. 2007), and Iowa (Mackie, et al. 2006). Groundwater provides 
drinking water for more than 97 percent of rural U.S. populations. In 
addition, antibiotics used in food animal production are regularly 
found in surface waters at low levels (Sarmah, et al. 2006).
    Resistant disease-causing organisms can also travel through the air 
from animal feeding operation facilities. At swine facilities using 
ventilation systems, resistant disease-causing organisms in the air 
have been detected as far away as 30 meters upwind and 150 meters 
downwind (Gibbs, et al. 2006).
    Farm workers and people living near animal feeding operations are 
at greatest risk for suffering the adverse effects of antimicrobial use 
in agriculture. Studies have documented their elevated risk of carrying 
antibiotic-resistant disease-causing organisms (Van den Bogaard and 
Stobberingh 1999; Price, et al. 2007; Ojeniyi 1998; Saenz 2006; Smith, 
et al. 2005; and KE Smith, et al. 1999).
    The rise of antimicrobial resistance in bacteria, in response to 
exposure to antimicrobial agents, is inevitable as all uses of 
antimicrobial agents drives the selection of resistant strains. Thus, 
there is the potential to lose this valuable resource in human 
medicine, which might well be finite and nonrenewable--once a disease-
causing organism develops resistance to an antimicrobial, it may not be 
possible to restore its effectiveness. Declining antimicrobial 
effectiveness can be equated with resource extraction. The very notion 
of antimicrobial effectiveness as a natural resource is a new concept, 
so it is not surprising that there has been very little public 
discussion about the ethical implications of depleting this resource 
for non-essential purposes, such as for growth promotion in food animal 
production.
    In 2003, the American Public Health Association (APHA), in its 
policy statement, said:

          ``the emerging scientific consensus is that antibiotics given 
        to food animals contribute to antibiotic resistance transmitted 
        to humans.'' APHA, the world's largest public health 
        organization, also remarked that ``an estimated 25-75 percent 
        of feed antibiotics pass unchanged into manure waste.''

    For its part, the World Health Organization (WHO) has recommended 
that ``in the absence of a public health safety evaluation, 
[governments should] terminate or rapidly phase out the use of 
antimicrobials for growth promotion if they are also used for treatment 
of humans.''
    For an industry that has become accustomed to using antimicrobials 
as growth promoters, the idea of stopping this practice might seem 
daunting. But, consider the case of Denmark, which in 1999 banned the 
use of antimicrobials as growth promoters. In 2002, the World Health 
Organization reported that:

          ``. . . the termination of antimicrobial growth promoters in 
        Denmark has dramatically reduced the food animal reservoir of 
        enterococci resistant to these growth promoters, and therefore 
        reduced a reservoir of genetic determinants (resistance genes) 
        that encode antimicrobial resistance to several clinically 
        important antimicrobial agents in humans.''

    The World Health Organization also reported there were no 
significant differences in the health of the animals or the bottom line 
of the producers. The European Union has followed suit with a ban on 
growth promoters that took effect in 2006.
    Finally, prudent public health policy thus indicates that 
nontherapeutic uses of antimicrobials in food animal production should 
be ended. Economic analyses demonstrate that there is little economic 
benefit from using antimicrobials as feed additives, and that 
equivalent improvements in growth and feed consumption can be achieved 
by improved hygiene.
                               References
Sarmah AK, Meyer MT, Boxall AB. A global perspective on the use, sales, 
    exposure pathways, occurrence, fate and effects of veterinary 
    antibiotics (VAs) in the environment. Chemosphere 2006; 65:725-59.
Kieke AL, Borchardt MA, Kieke BA, et al. Use of streptogramin growth 
    promoters in poultry and isolation of streptogramin-resistant 
    Enterococcus faecium from humans. J Infect Dis 2006; 194:1200-8.
Smith DL, Harris AD, Johnson JA, Silbergeld EK, Morris JG, Jr. Animal 
    antibiotic use has an early but important impact on the emergence 
    of antibiotic resistance in human commensal bacteria. Proc Natl 
    Acad Sci USA 2002; 99:6434-9.
Mellon M, Benbrook C, Benbrook KL. Hogging it: Estimates of 
    antimicrobial abuse in livestock. Cambridge, MA: Union of Concerned 
    Scientists Publications, 2001.
Nwosu VC. Antibiotic resistance with particular reference to soil 
    microorganisms. Res Microbiol 2001; 152:421-30.
Sunde M., Norstrom M. The prevalence of, associations between and 
    conjugal transfer of antibiotic resistance genes in Escherichia 
    coli isolated from Norwegian meat and meat products. J 
    Antimicrobial Chemotherapy. 2006; 58:741-747.
Laxminarayan R. Extending the cure: policy responses to the growing 
    threat of antibiotic resistance. Washington, DC: Resources for the 
    Future, 2007.
Salyers A, Shoemaker NB. Reservoirs of antibiotic resistance genes. 
    Anim Biotechnol 2006; 17:137-46.
Aarestrup FM, Seyfarth AM, Emborg HD, Pedersen K, Hendriksen RS, Bager 
    F. Effect of abolishment of the use of antimicrobial agents for 
    growth promotion on occurrence of antimicrobial resistance in fecal 
    enterococci from food animals in Denmark. Antimicrob Agents 
    Chemother 2001; 45:2054-9.
Klare I, Badstubner D, Konstabel C, Bohme G, Claus H, Witte W. 
    Decreased incidence of VanA-type vancomycin-resistant enterococci 
    isolated from poultry meat and from fecal samples of humans in the 
    community after discontinuation of avoparcin usage in animal 
    husbandry. Microb Drug Resist 1999; 5:45-52.
Graham JP, Boland JJ, Silbergeld E. Growth promoting antibiotics in 
    food animal production: an economic analysis. Public Health Rep 
    2007; 122:79-87.
Miller GY, Algozin KA, McNamara PE, Bush EJ. Productivity and economic 
    effects of antibiotics use for growth promotion in U.S. pork 
    production. Journal of Agricultural and Applied Economics 2003; 
    35:469-482.
Silbergeld EK, Graham JP, Price LB. Industrial food animal production, 
    antimicrobial resistance, and human health. Annu Rev Public Health 
    2008; 29:151-169.
Johnson JR, Kuskowski MA, Smith K, O'Bryan TT, Tatini S. Antimicrobial-
    resistant and extraintestinal pathogenic Escherichia coli in retail 
    foods. J Infect Dis 2005; 191:1040-9.
Simjee S, White DG, Meng J, et al. Prevalence of streptogramin 
    resistance genes among Enterococcus isolates recovered from retail 
    meats in the Greater Washington, DC area. J Antimicrob Chemother 
    2002; 50:877-82.
Sato K, Bartlett PC, Saeed MA. Antimicrobial susceptibility of 
    Escherichia coli isolates from dairy farms using organic versus 
    conventional production methods. J Am Vet Med Assoc 2005; 226:589-
    94.
Price LB, Johnson E, Vailes R, Silbergeld E. Fluoroquinolone-resistant 
    Campylo-
    bacter isolates from conventional and antibiotic-free chicken 
    products. Environ Health Perspect 2005; 113:557-60.
Luangtongkum T, Morishita TY, Ison AJ, Huang S, McDermott PF, Zhang Q. 
    Effect of conventional and organic production practices on the 
    prevalence and antimicrobial resistance of Campylobacter spp. in 
    poultry. Appl Environ Microbiol 2006; 72:3600-7.
Anderson ME, Sobsey MD. Detection and occurrence of antimicrobially 
    resistant E. coli in groundwater on or near swine farms in eastern 
    North Carolina. Water Sci Technol 2006; 54:211-8.
Stine OC, Johnson JA, Keefer-Norris A, et al. Widespread distribution 
    of tetracycline resistance genes in a confined animal feeding 
    facility. Int J Antimicrob Agents 2007; 29:348-52.
Mackie RI, Koike S, Krapac I, Chee-Sanford J, Maxwell S, Aminov RI. 
    Tetracycline residues and tetracycline resistance genes in 
    groundwater impacted by swine production facilities. Anim 
    Biotechnol 2006; 17:157-76.
Gibbs SG, Green CF, Tarwater PM, Mota LC, Mena KD, Scarpino PV. 
    Isolation of antibiotic-resistant bacteria from the air plume 
    downwind of a swine confined or concentrated animal feeding 
    operation. Environ Health Perspect 2006; 114:1032-7.
van den Bogaard AE, Stobberingh EE. Antibiotic usage in animals: impact 
    on bacterial resistance and public health. Drugs 1999; 58:589-607.
Price LB, Graham JP, Lackey L, Roess A, Vailes R, Silbergeld EK. 
    Elevated risks of carrying gentamicin resistant E. coli among U.S. 
    poultry workers. Journal of Occupational and Environmental 
    Medicine.
Ojeniyi AA. Direct transmission of Escherichia coli from poultry to 
    humans. Epidemiol Infect 1989; 103:513-22.
Saenz RA, Hethcote HW, Gray GC. Confined animal feeding operations as 
    amplifiers of influenza. Vector Borne Zoonotic Dis 2006; 6:338-46.
Smith DL, Dushoff J, Morris JG. Agricultural antibiotics and human 
    health. PLoS Med 2005; 2:e232.
Smith KE, Besser JM, Hedberg CW, et al. Quinolone-resistant 
    Campylobacter jejuni infections in Minnesota, 1992-1998. 
    Investigation Team. N Engl J Med 1999; 340:1525-32.
American Public Health Association. Available at: http://www.apha.org/
    advocacy/policy/policysearch/default.htm?id=1243.
World Health Organization. Available at: http://www.who.int/csr/
    resources/publications/drugresist/en/EGlobal_Strat.pdf.

    Senator Brown. Thank you, Dr. Graham.
    Dr. Vogel, welcome.

 STATEMENT OF LYLE P. VOGEL, D.V.M., M.P.H., DACVPM, ASSISTANT 
     EXECUTIVE VICE PRESIDENT, AMERICAN VETERINARY MEDICAL 
                  ASSOCIATION, SCHAUMBURG, IL

    Mr. Vogel. Thank you, Mr. Chairman and Senator Hatch for 
giving the American Veterinary Medical Association the 
opportunity to speak to you today. I am Dr. Lyle Vogel, 
Assistant Executive Vice President of the AVMA. Because 
veterinarians are ethically charged with promoting public 
health in addition to protecting animal health and welfare, we 
participate in the prevention and control of both human and 
animal disease.
    Antimicrobial resistance is a complex issue that is not 
going to be solved by seemingly simple solutions such as bans 
on certain label uses on antimicrobials without performance of 
a risk assessment on those individual drugs or drug classes. 
Let me first say that not all antimicrobials are equal in their 
probability of it creating a risk to human health. As a result 
non-risked-based bans of approved uses of antimicrobials will 
negatively have an impact on animal health and welfare without 
predictably improving public health and may even harm public 
health.
    The AVMA believes that the current science-based FDA 
approval process for new antibiotics and review of previously 
approved antibiotics under Guidance for Industry provides 
sufficient safeguards for public health. The AVMA advocates for 
improved monitoring systems for foodborne disease and 
antimicrobial resistance such as the Food Net and the National 
Antimicrobial Resistance Monitoring System, sometimes called 
NARMS. Since 1996 NARMS has provided a great deal of useful 
information. For example, NARMS data, when combined with Food 
Net data demonstrates that the case rate of human illness with 
multi-drug resistance salmonella species has decreased by 49 
percent since 1996.
    NARMS data also show that salmonella from humans are one 
half as likely to be resistant in 2004 as they were in 1996. 
Also resistance of enterococci to synercid in the United States 
is 10 times less than that in Denmark where the drug equivalent 
has been banned for almost a decade from use in animals. This 
information indicates that there is not a public health crisis 
related to human pathogens that are thought to originate in 
animals.
    In the late 1990s Denmark began to ban antimicrobials used 
for growth promotion. The use of antimicrobials in feed and 
water for prevention, control and treatment of disease was not 
banned. The results in humans and animals have been very mixed.
    For example, resistance to vancomycin in enterococcus from 
humans stayed at 0 percent from 1997 to 2006. There have been 
dramatic increases in resistance to tetracyclines since 
salmonella from humans. As I mentioned resistance to synercid 
is 10 times greater in Denmark than it is in the United States.
    While the total quality of antimicrobials used in food 
animals in Denmark has decreased by 27 percent, the increase in 
disease has resulted in 143 percent increase in the quantity of 
antimicrobials used for therapeutic purposes. The 
antimicrobials now used more frequently are in classes which 
are also used in humans, such as tetracyclines.
    Even though the results of the Danish ban are very mixed, 
proposals within the United States go beyond the Danish example 
by proposing to ban uses for the prevention and control of 
disease in addition to uses to promote growth. Several risk 
assessments have been performed that demonstrate a very low 
risk to human health from the use of antimicrobials in food 
animals. Some of the models predict an increased human health 
burden if the use is withdrawn. Inappropriate reactions to the 
potential problem could have unintended consequences that 
negatively affect animal health and welfare and ultimately 
could create public health risks.
    The AVMA does not believe that the Food and Drug 
Administration needs new authority to regulate the human safety 
of animal drugs. Instead the FDA needs additional resources to 
fulfill its existing missions. Improved surveillance and 
timelier reporting of resistance, research to better understand 
the causality of resistance, decisions based on risk and 
continued compliance with judicious use guidelines by 
veterinarians and producers are sufficient to protect human 
health against the current small risk associated with 
veterinary medicine and animal agriculture without compromising 
the health of food animals or public health.
    Thank you for the opportunity to appear before you today 
and speak about this important issue. Additional information is 
provided in the written testimony that has been submitted.
    [The prepared statement of Mr. Vogel follows:]
      Prepared Statement of Lyle P. Vogel, D.V.M., M.P.H., DACVPM
    Thank you, Mister Chairman and members of the subcommittee, for 
giving the American Veterinary Medical Association the opportunity to 
speak about antimicrobial resistance.
    I am Dr. Lyle Vogel, Assistant Executive Vice President of the 
American Veterinary Medical Association. The vast majority of my 41-
year veterinary career has been engaged in the practice of protecting 
and advancing public health.
    The AVMA represents more than 76,000 U.S. veterinarians engaged in 
every aspect of veterinary medicine and public health. Among other 
things, our members protect the health and welfare of our Nation's 
animals, help ensure food safety, and protect animal and human health 
through prevention and control of zoonotic diseases.
    As veterinarians, charged ethically with promoting public health in 
addition to protecting animal health and welfare, we have great 
interest in the prevention, control, and treatment of disease. 
Prevention and control of disease are key elements in the practice of 
veterinary medicine, particularly in animal agriculture, where the 
focus is on population medicine. This concept of disease prevention and 
control through herd health is analogous to public health efforts. The 
AVMA supports the use of multidisciplinary approaches to address issues 
affecting public health and food safety. In addition to our support of 
improved animal husbandry practices and the use of biologics, we also 
support the continued availability and use of antimicrobials to ensure 
that we are doing our best to safeguard the Nation's food supply.
    Antimicrobial resistance is a complex problem that is not going to 
be solved by simple solutions. The AVMA opposes seemingly simple bans 
on certain labeled uses of antimicrobials, such as growth promotion, 
feed efficiency, and disease prevention that are not science-based or 
risk-based. Not all antimicrobials nor all their uses are equal in 
their probability of developing resistance or creating a risk to human 
health. The European Union's Scientific Committee on Animal Nutrition 
has agreed that there is insufficient data to support such bans, yet 
possible theoretical human health concerns continue to be the focus 
while probable and scientifically based benefits to human and animal 
health are largely ignored (1).
    Banning approved uses of antimicrobials will negatively impact 
animal health and welfare without significantly or predictably 
improving public health. Based on the results of a limited ban enacted 
in Denmark (i.e., the banning of growth promotants, not uses to prevent 
and control disease), we do not believe the public would benefit from 
such a ban. Non-science based, broad bans of preventive uses of 
antimicrobials have the potential to harm public health, such as 
through increased foodborne disease.
    These significant decisions need to be science- and risk-based 
decisions. Decisions made without the benefit of a thorough evaluation 
of risks and benefits have the potential to further divert resources 
away from more appropriate disease control measures. Additionally, the 
AVMA believes that the judicious and regulated use of antimicrobials--
through scientifically based FDA approvals and post approval review 
under Guidance for Industry #152 of previously approved 
antimicrobials--provides a sufficient safeguard for public health.
              actions addressing antimicrobial resistance
                             avma's efforts
    The AVMA has acted with three objectives in mind:

    1. Safeguarding public health,
    2. Safeguarding animal health, and the
    3. Continued availability of effective therapeutic antimicrobials 
for veterinary medicine, including the retention of currently approved, 
safe drugs and, hopefully, future approvals of new drugs.

    Since 1998, the AVMA has actively worked to mitigate the 
development of antimicrobial resistance related to the use of 
antimicrobials in food animals. The AVMA Guidelines for the Judicious 
Therapeutic Use of Antimicrobials were developed to safeguard public 
health by emphasizing prudent and judicious therapeutic use of 
antimicrobials. With support and input from the Centers for Disease 
Control and Prevention, Infectious Disease Society of America, Food and 
Drug Administration, and the U.S. Department of Agriculture, the 
guidelines were developed in collaboration with our species specific 
allied veterinary organizations. These guidelines were based upon 
carefully reviewed, scientifically sound research, and we believe that 
our members conscientiously adhere to the principles of judicious 
therapeutic use of antimicrobials to ensure the protection of human 
health, as well as animal health and welfare.
    We actively encouraged and assisted our allied veterinary 
organizations to use the AVMA general principles as a template to 
develop more detailed guidelines appropriate to each species, disease 
and type of client. The AVMA also worked with these groups to develop 
and deliver a continuing education program to raise awareness within 
the profession and to encourage utilization of the principles. 
Fundamentally, the guidelines encourage scientifically based 
therapeutic practices, the use of antimicrobials only when needed, and 
compliance with all existing regulatory requirements when 
antimicrobials are used.
    The AVMA has also continually advocated for improved, more robust 
monitoring and feedback systems for foodborne disease and antimicrobial 
resistance such as FoodNet and the National Antimicrobial Resistance 
Monitoring System (NARMS). We have also advocated for more research to 
support scientifically based therapeutic practices, such as 
epidemiological studies that assess the effects of antimicrobial use. 
In addition, we advocate for increased resources for the FDA's Center 
for Veterinary Medicine so the agency can adequately implement its 
regulatory authority.
    The AVMA provided start-up funding for projects to create a 
nationally coordinated laboratory system to test for and report on 
resistance in animal pathogens and to create a decision support system 
to assist veterinarians when making antimicrobial use decisions. 
Unfortunately, while the latter project received follow-on funding by 
the FDA, neither project has been sustained or finished.
                        the fda role and actions
    The FDA approves antimicrobials for four purposes:

    1. Treatment of disease,
    2. Prevention of disease,
    3. Control of disease, and
    4. Growth promotion or feed efficiency.

    The first three uses are classified as therapeutic uses by the FDA, 
AVMA, and Codex Alimentarius Commission (an organization of the World 
Health Organization and the Food and Agricultural Organization of the 
United Nations), and the fourth has also been shown to have health-
promoting effects.
    The FDA process for the evaluation of food animal antimicrobials is 
at least as stringent as, and often more stringent than, the approval 
process for human antimicrobials. In addition to the testing for 
efficacy and safety to the individual (human or animal) receiving the 
drug that is common to the human and animal drug approval process, each 
food animal antimicrobial undergoes an assessment for human and 
environmental safety as part of the review by the FDA. The FDA's Center 
for Veterinary Medicine (CVM) uses a very strict safety assessment 
approval process that requires sponsors to submit data proving the 
antibiotic is safe for both humans and animals. This is a zero-risk 
procedure for human safety--benefits to animals are not weighed to 
offset risks to humans, but rather, drugs that possess risks beyond ``a 
reasonable certainty of no harm'' to human health are rejected.
    Another safety measure was instituted in 2003 (Guidance for 
Industry #152, ``Evaluating the Safety of Antimicrobial New Animal 
Drugs with Regard to Their Microbiological Effects on Bacteria of Human 
Health Concern,'' ) that outlines a comprehensive, evidence-based 
approach to preventing the emergence and selection of antimicrobial 
resistant bacteria that may adversely affect human health. The Guidance 
requires antimicrobial manufacturers to provide information to the FDA 
showing that a proposed animal drug will not harm public health. The 
current FDA risk assessment on a drug-by-drug basis provides a 
scientifically sound process to protect human health. In the event that 
a determination is made that human health is jeopardized, FDA will not 
approve the antimicrobial or may limit the use of the antimicrobial in 
order to mitigate the adverse effect.
    Since the mid-1990s, the FDA has coordinated the National 
Antimicrobial Resistance Monitoring System (NARMS) in cooperation with 
the Centers for Disease Control and Prevention and the U.S. Department 
of Agriculture. NARMS is a multi-agency program that includes 
monitoring for resistant bacteria in retail meats by the FDA, 
monitoring for resistant foodborne pathogens in humans by the CDC, and 
monitoring for resistant bacteria in animals on farms and animal 
products in slaughter and processing facilities by the USDA. NARMS has 
provided a great deal of useful information since 1996.
    Therefore, the AVMA does not believe that The Food and Drug 
Administration needs new authority to regulate the human safety of 
animal drugs. Instead, the FDA needs additional resources to fulfill 
its existing mission. Some of those resources can be furnished through 
passage of the Animal Drug User Fee Act Amendments of 2008.
                                results
United States Monitoring/Surveillance Data
    NARMS data, when combined with FoodNet data, demonstrates that the 
case rate of human infections with multi-drug resistant Salmonella spp. 
has decreased 49 percent between the NARMS baseline years of 1996-1998 
and 2004 (the most current, publicly available human data from NARMS). 
In addition, there has been a 65 percent reduction in the case rate of 
penta-resistant Salmonella Typhimurium infections. The case rate for 
Campylobacter infections in humans that are resistant to ciprofloxacin 
have remained constant over that period (2).
    Additional important resistance trends \1\ reported by NARMS (3) 
(Isolates from humans with clinical disease):
---------------------------------------------------------------------------
    \1\ Odds ratios were calculated based upon available data from 
NARMS assuming the reported isolates were representative of the 
bacterial population.

     Salmonella spp. (non-Typhi)--\1/2\ as likely to be 
---------------------------------------------------------------------------
resistant in 2004 than in 1996.

          a highly significant \2\ improvement in 
        susceptibility \3\ (20 percent relative increase in 
        susceptibility, from 66.2 percent in 1996 to 79.6 percent in 
        2004).
---------------------------------------------------------------------------
    \2\ ``Marginally significant'' indicates a p-value between 0.05 and 
0.10; ``significant'' indicates a p-value between 0.01 and 0.05; 
``highly significant'' indicates a p-value of less than 0.01.
    \3\ No resistance detected to any of 5 subclasses of antibiotics.

     Salmonella Typhimurium--less than \1/2\ as likely to be 
---------------------------------------------------------------------------
resistant in 2004 than in 1996.

          a highly significant \2\ improvement in 
        susceptibility \3\ (60 percent relative increase in 
        susceptibility from 37.9 percent in 1996 to 60.7 percent in 
        2004).

     Campylobacter--only 0.03 times more likely to be resistant 
in 2004 compared to 1997.

          a marginally significant \2\ decrease in 
        susceptibility \3\ (2 percent relative decrease in 
        susceptibility from 47 percent in 1997 to 46.1 percent in 
        2004).
          However, Campylobacter was significantly less likely 
        to be resistant in 2003 when compared to 1997; there was a 
        significant \2\ improvement in relative susceptibility \3\ (8.2 
        percent increase from 47 percent in 1997 to 50.9 percent in 
        2003).

     Enterococcus faecium--Decreased resistance to 
quinupristin/dalfopristin (Synercid) from 20.9 percent in 2001 to 3.7 
percent in 2004.
     E. coli O157--\1/3\ as likely to be resistant in 2004 
compared to 1996.

          a highly significant \2\ improvement in 
        susceptibility \3\ (10 percent relative increase in 
        susceptibility).

    In addition to trends of improved susceptibility, trends regarding 
multi-drug resistance \4\ also showed improvement:
---------------------------------------------------------------------------
    \4\ Resistant to 2 or more antibiotic subclasses.

     Salmonella spp. (non-Typhi)--nearly \1/2\ as likely to be 
---------------------------------------------------------------------------
multi-drug resistant\4\ in 2004 when compared to 1996.

          a highly significant \5\ improvement (44 percent 
        relative decrease) in multi-drug resistance \4\ (decreased from 
        27.0 percent in 1996 to 15.0 percent in 2004).
---------------------------------------------------------------------------
    \5\ ``Marginally significant'' indicates a p-value between 0.05 and 
0.10; ``significant'' indicates a p-value between 0.01 and 0.05; 
``highly significant'' indicates a p-value of less than 0.01.

     Salmonella Typhimurium--nearly \1/2\ as likely to be 
---------------------------------------------------------------------------
multi-drug resistant \4\ in 2004 when compared to 1996.

          a highly significant \5\ improvement (34 percent 
        relative decrease) in multi-drug resistance \4\ (decreased from 
        56.2 percent in 1996 to 37.2 percent in 2004).

     Campylobacter--slightly less likely to be multi-drug 
resistant \4\ in 2004 when compared to 1997.

          a marginally significant \5\ improvement (10 percent 
        relative decrease) in multi-drug resistance \4\ (decreased from 
        15.7 percent in 1997 to 14.1 percent in 2004).
          However, when comparing 1997 to 2003, isolates were 
        half as likely to be multi-drug resistant \4\ and there was a 
        highly significant \5\ improvement (46 percent relative 
        decrease) in multi-drug resistance \4\ (decreased from 15.7 
        percent in 1997 to 8.5 percent in 2003).

    Most foodborne infections do not require treatment with 
antimicrobials. Information shows that there is a decreasing trend of 
foodborne diseases, thereby decreasing the potential numbers of 
treatments (4). The trends of increasing susceptibility/decreasing 
resistance mean more successful treatments when needed. This 
information indicates that there is not a public health crisis related 
to human pathogens that are thought to originate in animals.
Danish Experience
    In the late 1990s, Denmark instituted a voluntary ban on the use of 
antimicrobials for growth promotion (AGPs). (A complete ban of AGPs was 
initiated in 2000.) The use of antimicrobials in feed and water for 
controlling and treating disease was not banned. The following has been 
observed as a result of the ban on the use of antibiotics for growth 
promotion in Denmark:

     There is little evidence to demonstrate a general decline 
in antimicrobial resistance in humans and there is no evidence of an 
improvement in clinical outcomes of antimicrobial treatment of humans, 
the desired consequence of the antibiotic ban in livestock. The results 
have been mixed. In fact, resistance in humans to some of the banned 
drugs has increased dramatically.
     There has been increased death and disease in the swine 
herds, especially at the weaning stage (info inferred from DANMAP 2005 
and other reports on pigs). According to published news reports, there 
was a relative increase of 25 percent in the number of pigs that died 
from illnesses from 1995 to 2005.
     While the total quantity of antimicrobials used in food 
animals has decreased by 27 percent, the increase in disease has 
resulted in a 143 percent increase in the quantity of antimicrobials 
used for therapeutic purposes. And the antimicrobials now used are 
classes such as tetracyclines that are also used in humans (5).
     Resistance to some antibiotics has decreased in some 
animals while resistance to other antibiotics has increased.

    The ban on antibiotic growth promoters in Denmark has not resulted 
in a significant reduction of antibiotic resistance patterns in humans. 
It has, however, resulted in an increase in disease and death in the 
swine herds and an increase in the use of antimicrobials for 
therapeutic uses in swine herds that discontinued the use of antibiotic 
growth promoters.
    Some important resistance trends reported by DANMAP:

     Salmonella Typhimurium from human isolates \6\ has shown 
34-49 percent increase in resistance to tetracycline, sulfonamides, and 
ampicillin from 1997-2006; increases in resistance to nalidixic acid 
and ciprofloxacin were 3.8 percent from 1997-2006.
---------------------------------------------------------------------------
    \6\ Domestically acquired clinical cases.

          In contrast, during the same period of time, poultry 
        isolates have shown only minimal increases (2-6 percent) in 
        resistance to the same antimicrobials.
          Isolates from pigs have also shown a lesser increase 
        (25-27 percent) in resistance to tetracycline and ampicillin 
        than human isolates during that time.

     Campylobacter jejuni from human isolates \6\ has shown 5-
11 percent increase in resistance to tetracycline, nalidixic acid, and 
ciprofloxacin from 1997-2006.
          In contrast, during the same period of time, poultry 
        isolates have shown lesser increases (4-6 percent) in 
        resistance to the same antimicrobials.

     Enterococcus faecium isolates from healthy human 
volunteers has shown no increase in resistance to vancomycin (the 
equivalent of avoparcin) from 1997-2006, and remains at 0 percent.

          However, resistance to virginiamycin (quinupristin/
        dalfopristin, e.g., Synercid) had been steadily increasing (up 
        to 25 percent) from 1997 to 2005 until the definition of 
        resistance was changed in 2006, bringing the level of 
        resistance down to 0 percent.\7\
---------------------------------------------------------------------------
    \7\ The rationale for this change is unknown, but appears to 
introduce bias in reporting. DANMAP decided to use a preliminary 
European Committee on Antimicrobial Susceptibility Testing breakpoint 
instead of the previously used breakpoint established by the Clinical 
and Laboratory Standards Institute.
---------------------------------------------------------------------------
          During the same period of time, Enterococcus faecium 
        isolates from pigs and poultry has shown 8-20 percent decrease 
        in resistance to avoparcin,\8\ virginiamycin, erythromycin and 
        tetracycline from 1997-2006 (using the same definition of 
        resistance as the human isolates from 1997-2005).
---------------------------------------------------------------------------
    \8\ Avoparcin has never been approved for use in the United States.

    Even though the results of the Danish experiment with antimicrobial 
growth promotant drug bans is very mixed, proposals within the United 
States go far beyond the Danish example by proposing to ban uses for 
the prevention and control of disease in addition to uses to promote 
growth and feed efficiency. Evidence shows that the Danish ban (and a 
ban in the United States, if instituted) will cause animal health and 
welfare problems.
                 risk assessments/ human health impact
Antibiotics as a Tool to Prevent and Control Disease in Animals and 
        Humans
    The use of drugs in animals is fundamental to animal health and 
well-being. Antibiotics are needed for the relief of pain and suffering 
in animals. For food animals, drugs additionally contribute to the 
public health by helping keep animals healthy and thereby keeping 
bacteria from entering the food supply. The hypothesis, supported by 
scientific information, is that a reduction in the incidence of food 
animal illness will reduce bacterial contamination on meat, thereby 
reducing the risk of human illness (6), (7), (8), (9), (10) (11), (12), 
(13).
    Several risk assessments have been performed that demonstrate a 
very low risk to human health from the use of antimicrobials in food 
animals, and some of the models predict an increased human health 
burden if the use is withdrawn. The unique farm-to-patient risk 
assessment performed by Hurd demonstrates that the use of tylosin and 
tilmicosin in food animals presents a very low risk of human treatment 
failure because of macrolide resistance, with an approximate annual 
probability of less than 1 in 10 million with Campylobacter infections 
and approximately 1 in 3 billion E. faecium infections (14). Cox 
performed a quantitative human health risks and benefits assessment for 
virginiamycin and concluded that there would be a significant human 
health risk if virginiamycin use is withdrawn. There would be 6,660 
excess cases per year of Campylobacteriosis, which far outweighs the 
0.27 per year reduction of cases of streptogramin-resistant and 
vancomycin-resistant E. faecium (VREF) resulting from the withdrawal 
(15). Cox also performed a risk assessment regarding macrolide and 
fluoroquinolone use and concluded that withdrawal is estimated to cause 
significantly more illness days than it would prevent (11). Cox also 
examined the impact of the use of penicillin-based drugs in food 
animals on penicillin/aminopenicillin resistant enterococcal infections 
and concluded that not more than 0.04 excess mortalities per year 
(under conservative assumptions) to 0.18 excess mortalities per year 
(under very conservative assumptions) might be prevented in the whole 
U.S. population by discontinuing current use of penicillin-based drugs 
in food animals. The true risk could be as low as zero (16). This 
equates to one potentially preventable mortality in the U.S. population 
roughly every 7-25 years. Alban's risk assessment concluded that the 
risk associated with veterinary use of macrolides in Danish pigs 
resulted in a low risk to human health (17). Others have estimated that 
risk management strategies that focus on eliminating resistance are 
expected to create /
members.ift.org/IFT/Research/IFT
ExpertReports/antimicrobial_report.htm).
    3. CDC. National Antimicrobial Resistance Monitoring System: 
Enteric Bacteria. 2004 Human Isolates Final Report. Available at http:/
/www.cdc.gov/narms/NARMSAnnualReport2004.pdf.
    4. CDC. FoodNet. Facts and Figures related to ``Preliminary FoodNet 
Data on the Incidence of Infection with Pathogens Transmitted Commonly 
Through Food--10 States, United States, 2007'' published in the 
Morbidity and Mortality Weekly Report (MMWR) on April 11, 2008. 
Available at http://www.cdc.gov/foodnet/factsandfigures.htm.
    5. DANMAP 2006. Use of antimicrobial agents and occurrence of 
antimicrobial resistance in bacteria from food animals, foods and 
humans in Denmark. ISSN 1600-2032. Available at www.danmap.org.
    6. Singer RS. Modeling the Relationship between Food Animal Health 
and Human Foodborne Illness. Prev Vet Med 2007; 79: 186-203.
    7. Russell SM. The Effect of Airsacculitis on Bird Weights, 
Uniformity, Fecal Contamination, Processing Errors, and Populations of 
Campylobacter spp. and Escherichia coli. Poult Sci 2003 82: 1326-1331.
    8. Russell SM. Ban Antibiotics In Poultry? [Why The Policymakers 
Have It Wrong], WATT Poultry/USA, March.
    9. Dawe J. The Relationship between Poultry Health and Food Safety. 
Poultry Informed Professional 2004; 77:1-6.
    10. Cox LA, Ricci P. Causal Regulations vs. Political Will: Why 
Human Zoonotic Infections Increase Despite Precautionary Bans on Animal 
Antibiotics. Environ Int 2008 (in press).
    11. Cox LA, Popken DA. Quantifying Potential Human Health Impacts 
of Animal Antibiotic Use: Enrofloxacin and Macrolides in Chickens. Risk 
Analysis 2006; 26:135-146.
    12. Cox LA. Potential Human Health Benefits of Antibiotics Used in 
Food Animals: A Case Study of Virginiamycin. Environ Int 2005; 31:549-
63.
    13. Hurd S., et al. Potential Human Health Implications of Swine 
Health, Abstract of Oral Presentation, 2007.
    14. Hurd S., et al. Public Health Consequences of Macrolide Use in 
Food Animals: A Deterministic Risk Assessment. J Food Protection 2004; 
67:980-992.
    15. Cox LA. Potential Human Health Benefits of Antibiotics Used in 
Food Animals: A Case Study of Virginiamycin. Environ Int 2005; 31:549-
63.
    16. Cox LA., et al. Human Health Risk Assessment of Penicillin/
Aminopenicillin Resistance in Enterococci Due to Penicillin Use in Food 
Animals. 2008. In Press.
    17. Alban, L., et al. A Human Health Risk Assessment for Macrolide-
Resistant Campylobacter Associated with the Use of Macrolides in Danish 
Pig Production. Prev Vet Med 2008; 83:115-129.
    18. Cox LA., et al. Quantifying Human Health Risks from Animal 
Antimicrobials. Interfaces. 2007; 37:22-38.
    19. Heuer OE., et al. Prevalence and Antimicrobial Susceptibility 
of Thermophilic Campylobacter in Organic and Conventional Broiler 
Flocks. Letters in Applied Microbiology 2001; 33: 269-274.
    20. Bailey JS., Cosby DE. Salmonella Prevalence in Free-Range and 
Certified Organic Chickens. J of Food Protection 2005; 68:2451-2453.
    21. Wondwossen A. Gebreyes, Peter B. Bahnson, Julie A. Funk, James 
McKean, Prapas Patchanee. Seroprevalence of Trichinella, Toxoplasma, 
and Salmonella in Antimicrobial-Free and Conventional Swine Production 
Facilities. Foodborne Pathogens and Disease. April 1, 2008, 5(2): 199-
203.
    22. M. Bennish and W. Khan. Therapy Guidelines for Enteric 
Infections--A 12-Year Update. 2007. In APUA Newsletter, Vol. 25, No. 3, 
pp. 1-4.

    Senator Brown. Dr. Vogel, thank you for being here.
    Dr. Eisenstein.

 STATEMENT OF BARRY I. EISENSTEIN, M.D., SENIOR VICE PRESIDENT 
            OF SCIENTIFIC AFFAIRS, CUBIST PHARMACEU-
                  TICALS, INC., LEXINGTON, MA

    Dr. Eisenstein. Good afternoon. Mr. Chairman, Senator 
Hatch, thank you for the opportunity to testify before you 
today about the serious consequences of antimicrobial 
resistance. My name is Barry Eisenstein. I am an infectious 
diseases physician as well as Senior Vice President of 
Scientific Affairs at Cubist Pharmaceuticals, a Lexington, MA-
based company focused on research, development and 
commercialization of pharmaceutical products that address unmet 
medical needs in the acute care environment.
    Cubist manufactures CUBICIN for the treatment of skin and 
bloodstream infections caused by certain bacteria including 
MRSA. During the last several decades the prevalence of 
antimicrobial resistant organisms in the U.S. hospitals and 
medical centers has increased to the point where it is a 
serious and frightening threat to public health which must be 
immediately addressed. We have concurrently reached a crisis in 
the lack of available therapies that are still effective 
against many bacterial pathogens as you have already heard.
    As a class of drugs, antibiotics face a perfect storm of 
unique challenges not relevant to other drugs. Which create 
economic disincentives for industry to invest the substantial 
time and resources necessary to develop an antibiotic.
    First, given the rapid evolution of bacteria development of 
resistance is a foregone conclusion. Therefore antibiotics by 
their very nature have a limited clinically effective lifespan.
    Second, when faced with the reality that antibiotics have 
finite lifespan, healthcare providers, not inappropriately, 
engage in the practice of optimizing antibiotic utilization, 
known as antibiotics stewardship, which can result in 
physicians reserving the newest antibiotics for use only as a 
last resort and the most difficult to treat cases.
    Finally, antibiotics are used in acute care setting for 
short duration. To make matters worse, the government's largest 
health care program, Medicare has limited coverage of home 
infusion administration of IV antibiotics which detrimentally 
impacts patient care as well as limits market penetration of 
the antibiotics that are used this way. Taken together these 
realities limit the return on investment for the pharmaceutical 
company, discouraging industry from investing and developing 
new antimicrobial products.
    As we approach the crisis in the lack of available, 
effective drugs, patient care is seriously compromised. One way 
to mitigate the effects of antimicrobial resistance and improve 
patient outcomes is to utilize currently marketed therapies 
rationally. Moreover one of the most significant economic 
disincentives and impediments to state-of-the-art patient care 
is the reluctance by the FDA to apply current standards of 
measuring resistance to older FDA approved antimicrobial 
compounds.
    Congress recognized removal of this impediment as one 
method to combat antibiotic resistance when it required the FDA 
to periodically update and review the ``break points'' of all 
antibiotic drugs. We commend the agency for release of draft 
guidance, which outlines the process for reviewing 
antimicrobial break points and look forward to the public 
comments on the draft guidance.
    Cubist also appreciates the FDA lowering the break point of 
vancomycin, an older commonly used antibiotic. Many experts 
however agree that this is only the first step. An additional 
review and further lowering of vancomycin break points is 
warranted.
    In addition to measures that reduce demand for antibiotics 
it is critically important to establish incentives. As also 
supported by the Infectious Diseases Society of America and 
SHEA to encourage industry to develop a steady supply of new, 
effective antibiotics to ensure therapy is available for 
patients who do develop resistant infections. Such incentives 
could include:
    No. 1, stockpiling in the strategic national stockpile and 
by individual hospitals with antimicrobials to treat resistant 
infections.
    No. 2, R and D tax credits for antimicrobial products to 
offset the enormous, sometimes prohibitive costs of investing 
in antimicrobial R and D.
    No. 3, extension of Orphan Drug Grants and associated 
Orphan Drug exclusivity or some such to antimicrobials or 
development of a parallel grant program specific to 
antimicrobial products.
    No. 4, greater utilization of rapid approval programs at 
the FDA such as fast track and priority review for 
antimicrobials.
    And No. 5, federally guaranteed loans and/or market pull 
mechanisms for advanced purchase of antimicrobials to stimulate 
investment in antibiotic R and D.
    To effectively combat the growing prevalence of antibiotic 
resistance, it will be important to implement practices to 
reduce demand for antibiotics and transmission of infections to 
provide better guidance on older antibiotics, e.g. review 
breakpoints as well as establish incentives to guarantee an 
adequate supply of new products. Risk to investment would also 
be lowered with decreased regulatory uncertainty especially 
clearer FDA guidance.
    I encourage you to refer to my written testimony for 
additional details on all of these proposals. Thank you for 
listening. I look forward to your questions.
    [The prepared statement of Dr. Eisenstein follows:]
            Prepared Statement of Barry I. Eisenstein, M.D.
    Mr. Chairman, Ranking Member, and members of the committee, thank 
you for the opportunity to testify before you today about the need to 
develop and implement comprehensive policy initiatives to address the 
public health impacts of antimicrobial resistant bacterial infections.
    I am Dr. Barry Eisenstein, Senior Vice President of Scientific 
Affairs at Cubist Pharmaceuticals. Cubist is a biopharmaceutical 
company focused on the research, development and commercialization of 
pharmaceutical products that address unmet medical needs in the acute 
care environment. Headquartered in Lexington, MA, we currently market 
CUBICIN (daptomycin for injection), the first intravenous (IV) 
antibiotic from a class of anti-infectives called lipopeptides. CUBICIN 
received FDA approval for the treatment of complicated skin and skin 
structure infections caused by certain susceptible strains of Gram-
positive microorganisms, including methicillin-resistant Staphylococcus 
aureus (MRSA). CUBICIN is also approved in the United States for the 
treatment of S. aureus bloodstream infections (bacteremia), and is the 
only IV antibiotic approved for this indication based on the results of 
a prospective, randomized, controlled registration trial. In the wake 
of a highly successful launch of CUBICIN, the company has a growing 
early stage pipeline of programs which can leverage Cubist's 
scientific, clinical and regulatory expertise as well as its proven 
infectious disease and acute care commercial organization.
    As Senior Vice President of Scientific Affairs, I am responsible 
for leading the efforts at Cubist to understand the medical needs best 
answered by Cubicin, to interact with leading scientists and health 
care providers in the United States and elsewhere, and to advise our 
scientific staff regarding ongoing needs related to infectious 
diseases, particularly those due to resistant bacteria. I am trained in 
internal medicine, infectious diseases, and microbiology. I have been a 
hospital epidemiologist, chief of an Infectious Diseases division, 
chair of an academic department of microbiology and immunology, the 
leader of infectious diseases discovery and clinical development at a 
major pharmaceutical company, and am presently, in addition to my job 
at Cubist, Clinical Professor of Medicine at Harvard Medical School, 
where I teach. I hold leadership positions with the Infectious Diseases 
Society of America, the National Foundation for Infectious Diseases, 
and the American Society for Microbiology, and am currently an editor 
of the journal, Antimicrobial Agents and Chemotherapy. I have been 
studying antibiotic resistance and treating patients with infectious 
diseases for over three decades, have edited major textbooks, and 
published over 100 scholarly articles in the field.
            antimicrobial resistance: a public health threat
    During the last several decades, the prevalence of antimicrobial 
resistant organisms in U.S. hospitals and medical centers has 
increased. According to 2002 data from the Centers for Disease Control 
and Prevention (CDC), more than 1.7 million people acquire bacterial 
infections in U.S. hospitals each year, and 99,000 die as a result. CDC 
estimates that up to 70 percent of those bacterial infections are 
resistant to at least one drug, at a cost of approximately $5 billion 
annually.\1\ A recent study published in the Journal of the American 
Medical Association (JAMA), extrapolated data from nine U.S. 
communities to estimate that there were 94,360 invasive MRSA infections 
alone in the United States in 2005 which resulted in 18,650 deaths 
\2\--to say nothing of the prevalence of other drug resistant 
infections. Antimicrobial resistance is increasingly a public health 
threat: patients who contract a resistant infection require more days 
of antimicrobial therapy than patients who do not; require more days in 
the hospital than those who do not; and generally face worse outcomes 
than those who do not.\3\ We must implement effective measures to 
combat antimicrobial resistance.
---------------------------------------------------------------------------
    \1\ Centers for Disease Control and Prevention at http://
www.cdc.gov/ncidod/dhqp/ar.html.
    \2\ R.M. Klevens, et al., Invasive Methicillin-Resistant 
Staphylococcus Aureus Infections in the United States, JAMA, 
2007;298:1763-1771.
    \3\ A. Shorr et al., Bacteremia Due to Staphylococcus aureus: 
Acquisition, Methicillin Resistance, and Treatment Issues, Medscape 
Clinical Review, October 2004; M.A. Abramson, D.J. Sexton, Nosocomial 
Methicillin-Resistant and Methicillin Susceptible Staphylococcus aureus 
Primary Bacteremia: At What Costs? Infection Control and Hospital 
Epidemiology, 1999;20:408-411.
---------------------------------------------------------------------------
    Unfortunately, given the rapid evolution of bacteria, development 
of antibiotic resistance is almost inevitable, thus policy efforts to 
address antimicrobial resistance must focus on: (1) adoption and 
maintenance of practices that reduce the rates of transmission of 
resistant infections; (2) appropriate use of existing antimicrobials to 
delay development of resistance; and (3) implementation of incentives 
to encourage the continued research and development of new 
antimicrobials to ensure, to the extent possible, a steady supply of 
effective drugs.
      lack of effective antimicrobials is reaching a crisis point
    My testimony today will focus on suggestions for incentives to 
encourage innovative antimicrobial research and development (R&D). We 
are approaching a ``crisis point'' with antimicrobial resistance and 
lack of new therapies, particularly against gram negative bacteria, 
(e.g., Acinetobacter, which is infecting both intensive care patients 
in American hospitals and our troops in the Middle East conflicts at 
alarming rates and which is often untreatable).\4\ Among the gram 
positive bacteria, the disturbing rates of MRSA and the emergence of 
vancomycin-resistant enterococci (VRE) increasingly leave infectious 
disease doctors with few, if any, effective therapies for certain 
strains of bacterial infection.
---------------------------------------------------------------------------
    \4\ L.L. Maragakis and T.M. Perl, Acinetobacter baumannii: 
Epidemiology, Antimicrobial Resistance, and Treatment Options, Clinical 
Infectious Diseases, 2008;46:1254-1263.
---------------------------------------------------------------------------
    Overuse and misuse of antibiotics has contributed to the 
development of resistance and has left hospital shelves increasingly 
barren of effective antimicrobial therapies. In addition, as a class of 
drugs, antibiotics face unique therapeutic challenges, which other 
treatments do not encounter. As I mentioned above, bacteria evolve so 
quickly that development of resistance is inevitable and thus each new 
antibiotic is a ``wasting asset.'' In other words, each therapy has a 
finite period of time during which it will be effective. For example, 
the discovery of penicillin in 1928 was nothing short of a medical 
miracle. Yet only 4 years after the drug became widely commercially 
available during World War II, reports of resistant microbes began 
emerging. This has far reaching consequences for patients and 
physicians who may be left without therapeutic options, but it also 
impacts the willingness of industry to invest in antimicrobial R&D as 
newer agents effective against the most important antibiotic-resistant 
pathogens, like MRSA, are often viewed as niche products to be used 
highly selectively by practicing physicians.
    Industry's hesitancy to invest in antimicrobial development is 
compounded by the consequences of the depreciating nature of 
antimicrobials--when faced with the reality that antibiotics have a 
finite lifespan, health care providers engage in the practice of 
optimizing antibiotic utilization (``antibiotic stewardship''). While 
this can result in more appropriate use of antimicrobials through 
measures that limit exposure to antibiotics (e.g., prescribing 
antibiotics only when necessary, effectively using diagnostic 
techniques to select the most appropriate antibiotic, and acquiring 
appropriate culture and sensitivity data to ensure suitable dosing), it 
can also result in physicians simply reserving the newest antibiotics 
for use only as a last resort in the most difficult-to-treat cases.\5\ 
This apparent virtue of preserving antibiotics (i.e., helping the 
``demand side'') paradoxically hurts the ``supply side'' by making 
commercial return on these antibiotics more difficult to realize, 
thereby causing economic disincentives for industry to engage in 
cutting edge antimicrobial R&D. The consequence is loss rather than 
gain in the antibiotics armamentarium, a fact not well appreciated by 
practicing physicians or by some proponents of antibiotic 
stewardship.\6\
---------------------------------------------------------------------------
    \5\ K. Kaye et al., The Deadly Toll of Invasive Methicillin-
Resistant Staphylococcus Aureus Infection in Community Hospitals, 
Clinical Infectious Diseases, 2008;46:1568-1577.
    \6\ R. Laxminarayan and A. Malani, Extending the Cure: Policy 
Responses to the Growing Threat of Antimicrobial Resistance (2007), 
available at http://www.extendingthecure.org/research
_and_downloads.html.
---------------------------------------------------------------------------
    Finally, antimicrobials are used in acute settings, for limited 
timeframes (7-10 days), rather than daily for the life-time of the 
patient, as with treatments for chronic diseases, making it difficult 
to rely on commercialization of an antimicrobial as a steady source of 
financial returns.
    In addition to challenges inherent to antibiotics as a class of 
drugs (emergence of resistance, prescribing habits, and resulting 
antimicrobial stewardship), over the last decade, regulatory 
uncertainty, including impractical and changing FDA guidelines has had 
a significant negative impact on approval of antibiotics. According to 
Extending the Cure, 14 classes of antibiotics were introduced for human 
use between 1935 and 1968; since then only five have been 
introduced.\7\ While many factors, as discussed above, have contributed 
to this decline, unpredictable approval requirements and timelines only 
add to already existing economic disincentives for industry to invest 
in antimicrobial R&D.\8\
---------------------------------------------------------------------------
    \7\ See, Extending the Cure, Policy Responses to the Growing Threat 
of Antibiotic Resistance, Policy Brief 6: The Antibiotic Pipeline, May 
2008, available at http://www.extendingthecure.org/downloads/
policy_briefs/Policy_Brief6_May08_newdrugs.pdf.
    \8\ See, Docket No. FDA-2008-N-0225-008.1 and -008.2, Comments of 
the Infectious Diseases Society of America, available at http://
www.regulations.gov/fdmspublic/component/main?main=
DocketDetail&d=FDA-2008-N-0225.
---------------------------------------------------------------------------
    Taken together and without further incentives to encourage 
investment in antimicrobial development, both big and small 
pharmaceuticals and biotechnology companies have already begun limiting 
their R&D investment in anti-infectives, preferring instead to focus on 
other, more financially certain therapeutic areas. The consequences of 
this lack of antimicrobial R&D has become devastating for patients, 
leaving us with increasing rates of antimicrobial resistance and fewer 
and fewer available therapies.\9\
---------------------------------------------------------------------------
    \9\ See, Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates . . 
. A Public Health Crisis Brews, Infectious Diseases Society of America, 
July 2004, available at http://www.idsociety.org/WorkArea/
showcontent.aspx?id=5554; G.H. Talbot et al., Bad Bugs Need Drugs: An 
Update on the Development Pipeline from the Antimicrobial Availability 
Task Force of the Infectious Diseases Society of America, Clinical 
Infectious Diseases, 2006;42:657-668; B. Spellberg et al., The Epidemic 
of Antibiotic Resistant Infections: A Call to Action for the Medical 
Community from the Infectious Diseases Society of America, Clinical 
Infectious Diseases 2006;42:155-164.
---------------------------------------------------------------------------
   support for ongoing initiatives to combat antimicrobial resistance
    Cubist supports several ongoing initiatives at the Department of 
Health and Human Services (HHS) to effectively address antimicrobial 
resistance, and encourages HHS to continue to work toward completion of 
these programs, including:

    (1) Activities of the Food and Drug Administration (FDA) to 
implement sections of the Food and Drug Administration Amendments Act 
(FDAAA) (Pub. L. No. 110-85).
    Specifically, Cubist is pleased that the FDA issued a draft 
guidance outlining the agency's proposed procedures for complying with 
section 1111 of FDAAA, which requires the FDA to periodically review 
and update antibiotic ``breakpoints.'' An antibiotic breakpoint is the 
dosing concentration (mcg/mL) after which the drug is no longer 
considered clinically effective. Breakpoints are critical because they 
determine bacterial resistance. During antibacterial susceptibility 
testing to identify which antibiotics will kill or inhibit the growth 
of the isolated bacterial culture, if the bacteria are not inhibited at 
the ``breakpoint'' concentration, it is considered resistant.
    Cubist, as well as the Infectious Diseases Society of America and 
the Clinical Laboratory Standards Institute believe that the 
breakpoints included in the labels of many older antibiotics do not 
reflect emerging resistance. Thus these labels are outdated, 
compromising physicians' ability to appropriately and effectively treat 
patients, often giving them a false sense of confidence about an older 
antibiotic, like vancomycin.\10\ We are pleased that the FDA has 
already revised the label for vancomycin injection to reflect a 
breakpoint of 2 mcg/ML against Staphylococcus aureus.
---------------------------------------------------------------------------
    \10\ G. Sakoulas and R.C. Moellering, Jr., Increasing Antibiotic 
Resistance Among Methicillin-Resistant Staphylococcus Aureus Strains, 
Clinical Infectious Diseases, 2008;46:S360-S367.
---------------------------------------------------------------------------
    However, while we appreciate this first step by the FDA, many in 
the infectious disease community, including academic and clinical 
experts, feel that even this lower breakpoint for vancomycin does not 
reflect true clinical resistance to the drug, putting patients at 
serious risk of receiving ineffective treatment. To quote from a recent 
paper on the topic:

          ``It is becoming clear that vancomycin is losing potency 
        against S. aureus, including MRSA. Serious infections due to 
        MRSA defined as susceptible in the laboratory are not 
        responding well to vancomycin. This is demonstrated by 
        increased mortality seen in patients with MRSA infection and 
        markedly attenuated vancomycin efficacy caused by vancomycin 
        hetero-resistance in S. aureus. Therefore, it appears that our 
        definition of vancomycin susceptibility requires further 
        scrutiny as applied to serious MRSA infections, such as 
        bacteremia and pneumonia.'' \11\
---------------------------------------------------------------------------
    \11\ G. Sakoulas and R.C. Moellering, Jr., Increasing Antibiotic 
Resistance Among Methicillin-Resistant Staphylococcus Aureus Strains, 
Clinical Infectious Diseases, 2008;46:S360-S367. See also, I.M. Gould, 
Editorial, The Problem With Glycopeptides, International Journal of 
Antimicrobial Agents 30 (2007):1-3.

    This apparent reluctance by the FDA to apply current standards of 
measuring resistance to older antibiotic compounds is one of the most 
significant economic disincentives to industry investment in R&D, as 
well as a significant barrier to state-of-the-art patient care. We 
encourage FDA to lower the vancomycin breakpoint and to continue to be 
vigilant in monitoring the efficacy of it and other antibiotics, as 
required under FDA Section 1111.
    Cubist also appreciates that the agency convened a public meeting 
on April 28, 2008 as required by section 1112 of FDAAA, to discuss and 
debate measures to combat antimicrobial resistance. We hope the FDA 
will strongly consider some of the suggestions offered at this 
meeting.\12\
---------------------------------------------------------------------------
    \12\ See e.g., Docket No. FDA-2008-N-0225-0011, Comments of the 
Clinical Laboratory Standards Institute, available at http://
www.regulations.gov/fdmspublic/component/main?main=
DocketDetail&d=FDA-2008-N-0225.
---------------------------------------------------------------------------
    (2) Implementation of the Hospital Acquired Condition (HAC) rule, 
by the Centers for Medicare and Medicaid Services (CMS) as a measure to 
encourage hospitals to engage in proven, evidence-based behavior to 
prevent the transmission of hospital-acquired infections, including 
resistant bacterial infections.
    In the development of these policies, it is critical for CMS to be 
mindful of the challenges that hospitals face in detecting and 
preventing conditions that are often considered hospital-acquired. Due 
to factors outside the control of hospitals, certain conditions are not 
reasonably preventable. In those circumstances, payment policies based 
on the presumption that hospitals can prevent these conditions from 
occurring will not produce the desired results and could impact quality 
of care. CMS must take these factors into account as it implements the 
HAC provisions. For example, while many infections are preventable 
through proper hospital protocols and safety measures, data has shown 
that hospitals lack the ability to reasonably prevent infections caused 
by MRSA. Individuals can become colonized with MRSA in the community as 
well as in health care settings, and while hospitals can take steps to 
prevent MRSA from spreading between patients in the hospital setting, 
they cannot reasonably prevent a patient who is colonized with MRSA 
from developing an active infection in the hospital setting.
    (3) Efforts by Congress to extend Medicare coverage for home 
infusion to include ancillary services associated with home 
administration of IV drugs, including antibiotics.
    Home infusion would allow patients in need of antibiotic treatment, 
including those with MRSA or other resistant bacterial infections, to 
administer the drug themselves, in a non-hospital setting. However, in 
contrast to many private insurance plans, Medicare does not cover 
necessary services related to home administration of injectable drugs, 
such as the supplies, nursing services or equipment. This lack of 
coverage prevents many Medicare beneficiaries from taking advantage of 
these services and forces these patients to remain in the hospital 
longer than necessary simply to receive their antibiotics. Extended 
hospital stays are costly, inconvenient, and most importantly, 
compromise the health of other patients who are at risk of contracting 
the resistant bacterial infection from their neighbors. We encourage 
Congress to extend Medicare coverage to include home infusion services 
as one measure to improve patient care and reduce unnecessary 
transmission of MRSA and other bacterial infections. Extension of 
Medicare coverage would also open additional markets for IV 
antibiotics, providing an incentive to industry to engage in antibiotic 
R&D.
                 additional suggested policy proposals
    In addition to working toward the achievement of the ongoing 
initiatives described above, Cubist also believes that to directly 
address the unique barriers to industry investment in innovative 
antimicrobial research and development, Congress should enact 
additional incentives which will encourage such research. Specifically, 
Cubist proposes the following options:

    (1) Establish research and development tax credits for 
antimicrobials, modeled after bills introduced by Senator Schumer and 
Representative Towns.
    By allowing innovative companies a tax credit equal to a percentage 
of their expenses devoted to research and development of ``qualified'' 
products (e.g., antimicrobials and antivirals), such expenses, which 
can run as high as $1 billion to bring a drug to market, are mitigated, 
thus incentivizing industry to devote more time and resource toward the 
research and development of these critical new products. To ensure that 
the tax credit encourages research and development of innovative new 
products, rather than reformulations or variations on already existing 
drugs or diagnostics, the credit could be limited to research on new 
molecular entities or new diagnostics. The Federal Government, as well 
as several States (including Massachusetts) have in place broader R&D 
tax credits to encourage job creation and cutting edge pharmaceutical 
research. However, a Federal R&D tax credit specific to antimicrobials 
and similar qualified products would focus pharmaceutical and biotech 
R&D on meeting unmet antibiotic medical needs for patients.
    (2) Encourage the CDC and the Department of Homeland Security to 
stockpile antibiotics in the Strategic National Stockpile; similarly 
encourage hospitals to ``stockpile'' antimicrobials.
    The Federal Strategic National Stockpile (SNS) is managed jointly 
through the Department of Homeland Security and the Department of 
Health and Human Services. The SNS is housed at CDC and has large 
quantities of medicine and medical supplies to protect the public if 
there is a public health emergency and local supplies run out. Certain 
antimicrobials are already stockpiled by the SNS, as well as other 
medical countermeasures, but this list could be expanded to include 
additional categories of antimicrobial products effective against 
resistant pathogens. While the SNS is primarily designed to ensure 
sufficient public access to life-saving medicines in the event of an 
emergency, by advance purchasing in large quantities certain drugs and 
biologics, the SNS also incentivizes the research and development of 
such products. Similarly, if hospitals were encouraged to stockpile or 
enter into advanced purchase contracts for antimicrobials for use 
against resistant infections, this would encourage much needed 
antimicrobial R&D.
    (3) Create infectious disease product development grants modeled on 
FDA's successful orphan product development (OPD) grants and provide 
additional 7 years of exclusivity for certain antimicrobial products.
    Orphan development grants are intended to encourage clinical 
development of products for use in rare diseases or conditions. They 
are authorized under current law, and could include antimicrobials, if 
certain infectious diseases meet the statutory criteria for a ``rare 
disease.'' In fact, under Section 1112 of FDAAA, FDA was directed to 
(and did) hold a public meeting to consider which infectious diseases 
would be considered ``rare diseases,'' and thus which products would be 
eligible for OPD grants. In addition to the OPD grants, these 
antibiotics should be eligible for orphan drug status and the 
associated 7-year period of exclusivity to stimulate innovation and 
provide an adequate return on investment. The lengthened exclusivity 
would also take into account the unique, slow uptake of new antibiotics 
into the marketplace based on the usual practices of antibiotic 
stewardship. (By contrast there is no such delay in the use of the 
newest life-saving cancer drugs, which, like antibiotics, work by 
ridding the patient of noxious, life-threatening cells.)
    In the alternative to including antimicrobials/infectious diseases 
under the umbrella of orphan drug grants, similar to the OPD grants, 
Congress could authorize grants specifically directed at antimicrobials 
and other infectious disease products. Like the orphan product grants, 
grants for infectious disease product development would focus on 
targeted Federal dollars in an area of critical public health need but 
limited commercial potential. Additional exclusivity could also be 
granted for these products upon approval if certain criteria were met.
    (4) Continue utilizing rapid approval mechanisms at FDA, such as 
Fast Track and Priority Review; expand the FDAAA Tropical Disease 
Priority Review voucher system to additional categories of 
antimicrobials.
    FDA ``Fast Track'' designation (requested by the sponsor) is a 
process designed to facilitate the development, and expedite the review 
of new drugs or biologics indicated to treat serious or life-
threatening diseases and which fill an unmet medical need. ``Priority 
Review'' is one of two review designations for a product. To hasten 
approval of drugs or biologics that offer major advances in treatment, 
FDA designates such drugs, at the request of the sponsor, as Priority 
Review drugs. The goal for FDA pre-market review of a Priority Review 
drug is 6 months, compared to 10 months for standard review drugs. 
Antibiotics which are indicated to treat serious or life-threatening 
diseases, or which provide major advances in treatment are eligible for 
Fast Track or Priority Review. Cubist encourages product sponsors and 
the FDA to effectively utilize these approval options.
    In addition, to encourage sponsors to engage in innovative 
antimicrobial R&D, Congress could expand the tropical disease priority 
review voucher system enacted under FDAAA to include additional 
categories of antimicrobials (e.g., those that are indicated for 
serious or life threatening diseases). The FDAAA provision establishes 
a system of rewarding priority review vouchers to sponsors who file an 
NDA for a drug indicated for the treatment or prevention of a tropical 
disease. The priority review voucher entitles the holder of the voucher 
to priority review of a single new human drug or biologic application 
(separate from the NDA for the tropical disease product) and is 
transferable. Extension of the provision to include other categories of 
antimicrobials would provide additional incentives for industry to 
engage in cutting edge R&D.
    (5) Provide additional regulatory guidance at FDA for approval of 
antimicrobials.
    In addition to expediting approval times through Fast Track and 
Priority Review, to address the increasing regulatory uncertainty 
antimicrobial sponsors face when submitting a new antibiotic for 
approval, the agency should clarify approval requirements and re-
establish consistency, predictability and timeliness in pre-market 
review of antimicrobials. This should include release and periodic 
review of the guidance on conduct of antimicrobial clinical trials, as 
required by Section 9111 of FDAAA, as well as careful review and 
consideration of the GAO report required by Section 1114 of FDAAA 
examining how certain FDAAA provisions related to antibiotics have 
encouraged development of new antibiotics.
    (6) Authorize study and establishment of guaranteed market 
contracts and other ``pull'' mechanisms.
    Apart from the SNS discussed above, HHS could create advance 
purchase commitments or other ``promised market'' mechanisms (e.g., an 
antimicrobial purchase fund) to encourage the development of future 
antimicrobials. Guaranteed contracts in small amounts (less than $50-
$100 million) could provide an important market foundation to focus 
hospital, private payor and physician attention to novel therapies.
    (7) Establish a Commission on Infectious Diseases Product 
Development, modeled after legislation introduced by Representatives 
Baird and Cubin, to increase public-private development collaboration.
    The Beating Infections through Research and Development Act (H.R. 
1496) requires establishment of a Commission on Infectious Disease 
Product Development to identify the most dangerous infectious disease 
pathogens that are or are likely to become a danger to public health. 
Establishment of such a commission would be beneficial in directing 
limited R&D resources to the most critical areas of need. The 
Commission should include members of relevant government agencies, 
including the Department of Health and Human Services, the Food and 
Drug Administration, CDC, the Department of Homeland Security, and the 
Department of Defense, as well as pharmaceutical and biotechnology 
companies, venture capital firms, financiers, and other experts in the 
economics of drug development. Public sessions and hearings of the 
Commission should be mandated to explore the issues of unmet need as 
well as different mechanisms to better encourage the development of 
innovative antimicrobials.
    (8) Authorize federally-guaranteed loans for product development 
and infrastructure.
    Congress could authorize small business or targeted Business and 
Industry (B&I) Guaranteed Loans similar to those administered by the 
USDA Rural Business-
Cooperative Service (RBS) and the Small Business Administration (SBA) 
Certified Development Company (504) Loan Program. These programs offer 
such maximum loan sizes of $25 million with 30-year terms at market 
advantageous rates. Loans would serve to reduce small, startup 
companies' reliance upon venture capital, and could encourage them to 
innovate creatively on therapeutically significant, potentially higher 
risk development projects. Loan amounts up to $25 million would serve 
to advance drug candidates up to clinical investigation (IND stage); 
additional amounts would be required for early clinical trials.
                               conclusion
    Thank you for the opportunity to testify today. Antimicrobial 
resistance is a very real threat to public health and one that is only 
getting worse. I urge Congress to strongly consider the suggestions I, 
and others, have offered as steps toward managing emergence, 
transmission, and treatment of drug resistant organisms.

    Senator Brown. Thank you, Dr. Eisenstein. Mr. Noble, you, 
as a professional athlete now a college coach, what do you tell 
your players and other coaches to protect them from acquiring 
MRSA.
    Mr. Noble. I think the big thing that we stress right now 
is getting to a doctor quickly. As fast as possible, have them 
culture something that looks like it could be an infection, 
kind of figure out what it is. Obviously, you know, wash your 
clothes, throw your towels in the hamper, make sure everything 
is clean.
    In a locker room setting, it's dirty. Guys are athletes, 
football players, skin to skin contact, it's there. We've had 
kids every year that I've been at West Chester now that we've 
had one or two cases of MRSA.
    The big thing really for me having had it and because of 
the delay that I had in getting treatment and as serious as it 
could have potentially gotten and it did get serious. I always 
tell the kids if you think you have an infection, get to your 
doctor right away. Go see the team doctor, your family doctor 
and get on it as quickly as possible.
    Senator Brown. Thank you. Dr. Graham, you've said that the 
use of antimicrobials apparently yields no appreciable economic 
benefits. Why does agriculture continue to use them and how do 
you change their minds?
    Mr. Graham. I think there's generally a fear that because 
they've been using these for a long time it's sort of a crutch. 
The economic study that I mentioned with swine, they basically 
showed that the better managed operations performed better than 
the operations that were using growth promoting antibiotics. I 
think it's this crutch. It's a low risk in their mind to their 
own operation or to the industries that are promoting this use.
    I think it's more of a fear factor of being just not sure 
that they'll be able to improve management.
    Senator Brown. Does that study apply to, in your mind, 
poultry, pork, beef, if they're confined in large numbers in 
relatively small spaces or does the claim that there is no real 
savings, is that claim disputed by that kind of agriculture 
when it suggest they have to do a different kind of 
agriculture?
    Mr. Graham. Well, I was involved in the poultry study, 
where we looked at the economics of using growth promoting 
antibiotics. It was actually a 3-year study by Perdue, fourth 
largest producer of poultry in the United States. It was 3 
years, 7 million broiler chickens involved.
    During this research they looked at actually cleaning out 
the litter from the house. If they removed the litter from the 
house, which when I worked with farmers in my dissertation 
research and they would actually clean the house about once 
every 5 years, a full cleaning. Now the reason they're doing 
that is because they're pinched.
    They have been getting paid the same amount per pound of 
chicken for a long time. They don't have a lot of free time to 
spend cleaning the chicken houses. They're not cleaning the 
houses and so I think there's this crutch that's available 
which is this constant low dose of antibiotics that we feed the 
animals.
    Senator Brown. Thank you. Dr. Vogel, as we learned from 
Admiral Tollefson, a veterinarian herself, it's been 8 years 
since we passed legislation asking FDA to reassess the safety 
of using some antimicrobials with farm animals. Dr. Tollefson 
told us that FDA is still gathering data.
    The STAAR Act that Senator Hatch and I have worked on 
contains a provision to improve data collection. In your 
assessment, at what point do we have enough data for FDA to 
determine that the use of antimicrobials in animal feed might 
be harmful to human health?
    Mr. Vogel. That's a good question but a difficult question 
to answer. It's very difficult to put a bright line on what 
type of data is needed for these various decisions. You'd have 
to examine what is the actual risk to human health in 
comparison to the benefits to animal health and welfare.
    Each drug is different and acts in a different mechanism 
and can create different circumstances that need to be 
evaluated.
    Senator Brown. Dr. Brennan, are you familiar with Peter 
Pronovost's research in the use of a checklist? Do you know of 
his research, I assume?
    Explain that to us, if you would, in what the Federal 
Government can do. I know that they've done it in Michigan and 
Rhode Island. Pretty much used his checklist to prevent 
hospital infections and other errors for physicians and for 
hospital personnel.
    Run through that and its value in how we promote that 
through a system to cut down on medical errors and the kind of 
hospital infections that Mr. Noble and too many others have 
acquired.
    Dr. Brennan. Well Senator, as I alluded to in my testimony, 
there is no single action that will prevent hospital acquired 
infections. It's really necessary to bundle a number of 
activities. Beginning with the decisionmaking process to use a 
device, the best practices to insert it, decisionmaking about 
the maintenance of the device and then further decisionmaking 
about removal of the device.
    What the checklist does is it groups these bundles of 
evidenced-based activities or groups these activities into 
bundles so that they are addressed on a daily basis and that a 
decision is made in the most timely fashion to mitigate the 
risk. That is, improve the conditions around the site of the 
device by better site maintenance or make a timely decision to 
remove the device. These checklists have been demonstrated 
using these evidenced-based practices that are bundled together 
to reduce the incidence of ventilator associated pneumonies, 
catheter-related bloodstream infections and so on.
    Senator Brown. If these are as effective as I've been 
convinced and by reading Dr. Pogonandi's articles and so much 
that I've seen without being an expert and surely on hospital 
administration. Why are more hospitals not using this checklist 
and adopting these kinds of practices?
    Dr. Brennan. I think many hospitals, Senator, have begun to 
use the checklist. I do think that there's a need for deeper, 
cultural change in hospitals. I think that there is still a 
belief in many segments of the industry that these are the 
costs of doing business.
    I think that slowly but surely we're demonstrating first in 
some hospital units and more often in many hospital units that 
at least some types of infection can be nearly eliminated. 
We've had the most success with central venous catheter 
bloodstream infections. Others I think are more intractable 
such as urinary tract infections and ventilator-associated 
pneumonies are particularly challenging.
    I think that the belief has not penetrated our industry 
deeply enough to embrace this cultural change.
    Senator Brown. Ok. Thank you, Dr. Brennan.
    Senator Hatch.
    Senator Hatch. Well thank you. I appreciate the whole panel 
here today. Mr. Noble, I appreciate you and I am very 
empathetic toward what you've been through and what you and 
your family have had to endure. You know, people look up to you 
and I do certainly, and I'm grateful for your publicizing this 
important issue.
    Did your physician or hospital ever determine the actual 
cause of how you contracted the bacterial infection?
    Mr. Noble. That's kind of the tough thing with it, 
especially in my situation because I had had surgery and 
because I was in a locker room and a training room where MRSA 
is. We had five guys in Washington, the year I had it, contract 
MRSA mostly just in the skin. It never got as serious as mine.
     Theirs were just in the skin, where as mine were in both 
knees. It was treated pretty quickly and it was after mine.
    They were much more aggressive with the treatment. The 
doctors were never able to pinpoint exactly where I got it 
because of my situation--it was just in both. I was in a 
hospital setting and in a community setting, a locker room 
where you can get it.
    Senator Hatch. Well thank you. Dr. Brennan, this has been 
alluded to, but States have begun to require hospitals to 
implement testing programs as a method to identify and 
appropriately care for patients with resistant infections. Is 
there room for the Federal Government to promote testing to 
provide consistency and a higher quality of care? If so, what 
do you envision that role to be?
    Dr. Brennan. Senator, as you know many States have now 
adopted legislation requiring reporting and in some instances 
screening.
    Senator Hatch. This legislation is pending in another six 
States as I understand it.
    Dr. Brennan. Well, Senator, I believe that there are 
actually several other--there are a relatively small number of 
States that have actually begun to collect the data and only, I 
believe, two that have begun to report the data. I think there 
are many others that have actually adopted legislation. And 
still more that have bills pending.
    Furthermore, there are some States that have gone on and 
adopted specific mandates about multi-drug resistant organisms 
such as MRSA, for example and others. I think that what has 
been most striking to us in the field has been the migration 
toward the use of the National Health Care Safety Network at 
the CDC as a solution for the reporting mechanisms and 
surveillance mechanisms that can keep us informed about multi-
drug resistance and about the performance of our hospitals. It 
enables us to have a benchmark for performance.
    Seventeen States have now adopted NHSN out of the division 
for Healthcare Quality Promotion at CDC. Others are considering 
it. Pennsylvania has moved entirely toward that system as 
others have.
    I think that that is an incredibly valuable national 
resource. It is one that I believe is not sufficiently 
supported. When it migrated from its predecessor system, the 
National Nosocomial Infections Surveillance System, there were 
only about 300 hospitals in it.
    As recently as April 2007, there were only about 500 
hospitals in it. Today there are 1,700. It's really growing 
exponentially as more and more States adopt this legislation. I 
fear that its capacity may be outstripped by this movement 
toward its use. I think that support of that will provide us 
great information on surveillance and benchmarking.
    Senator Hatch. Thank you. Dr. Graham and Dr. Vogel, we 
appreciate your testimony and the advice that you've given us 
here today. Let me just ask one last question to Dr. 
Eisenstein. Your testimony acknowledged some of the important 
contributions that were included in the Food and Drug 
Administration Amendment Act of 2007 and suggests some others, 
including a new tax credit.
    In terms of quick results and high impact for the cost, 
will you please highlight some of the incentives that would 
have the highest impact over the very short run?
    Dr. Eisenstein. Well one of them I alluded to would be to 
have the FDA get even more energized toward the provisions of 
FDAAA to go back and re-examine the older antibiotics like 
vancomycin which has been the work horse for the agent that 
we're speaking about most today, namely MRSA. It turns out that 
because this drug was approved by the FDA over 50 years ago, 
about 50 years ago, the standards for what it needed to 
accomplish from an efficacy standpoint were essentially 
minimal. The understanding of resistance for vancomycin was 
quite antique by present standards.
    New drugs that come out that are competing, if you will, 
for vancomycin have a very high hurdle to seem as if they are 
as good, if not better than this old drug. I would suggest that 
a very quick thing that can be done would just be to get the 
FDA to spend even more of its resources, I know they are 
precious. They can depend upon other groups like the CLSI, 
which is a not-for-profit group that examines break points very 
carefully and drug resistance very carefully. Use them as 
essentially the citizens group to enable them to make the 
expert decisions they need to make.
    Senator Hatch. Well, thank you. Mr. Chairman, I appreciate 
your holding this hearing. I appreciate all of you coming here 
to testify. It means a lot to us.
    Senator Brown. Thank you, Senator Hatch.
    Senator Sanders.
    Senator Sanders. Thank you, Mr. Chairman. This is an 
enormously important hearing. I apologize. I'm going to be busy 
running in and out.
    Dr. Graham, I wonder if I could ask you a question. I was 
disturbed to read in your written testimony that the feeding of 
antibiotics to animals in North Carolina alone is estimated to 
exceed human consumptions of antibiotics nationwide. Not only 
does this seem to be a wasteful misuse of a precious resource, 
it appears to be very dangerous.
    You said in your testimony that the practice of constantly 
feeding our livestock low doses of antibiotics for 
nontherapeutic purposes is facilitating the emergence of 
antibiotic-resistant infections. Could you talk a little bit 
more about how you came to that conclusion?
    Mr. Graham. Well in my personal research I focused on 
macro-
lides, lincosamides, streptogramin B resistance. That includes 
ery-
thromycin, clindamycin and also quinupristin, dalfopristin. 
These are all important, clinical drugs.
    Those drugs are also critical because the resistance, the 
genetic material that encodes resistance to those is linked. A 
lot of times it's linked on a certain type of DNA that can be 
transferred to other bacteria that aren't even related species 
or not even the same genera or family. We focused a lot on MRSA 
today. There are a lot of things that are limiting our options.
    One of these is the loss of these drugs that I looked at 
and these resistance genes are present. When we found these 
resistant genes in bacteria that aren't necessarily disease 
causing organisms, which is something that doesn't get factored 
into risk assessments because they look at one specific bug. 
They look at one specific drug. It's this resistance gene that 
can be shared among a whole host of bacteria that's really 
critical.
    That's one of the three antibiotics that I think should 
definitely be removed from food animal production. Of course 
there's a whole host of others, but that was really my focus.
    Senator Sanders. Let me just continue with Dr. Graham. 
You're working with the Pew Commission and the work you're 
doing is important and informative and it clearly is of great 
use to the public health sector. What I would like to know is 
that the Interagency Task Force on which Dr. Tenover and Rear 
Admiral Tollefson both serve, is supposed to be getting input 
from experts like you.
    I have a simple question. That is, has anyone from the Task 
Force actually been in contact with you? The more important 
question, is the research that you're doing being utilized by 
the government in informing our infection, prevention and 
control efforts?
    Mr. Graham. Well, unfortunately in academia we work through 
peer-reviewed process and that's where most of my research is 
focused on getting peer-reviewed manuscripts published. Some of 
my colleagues may have been in contact with them. I personally 
have never received contact from them.
    Senator Sanders. But you are a leading expert on this area, 
are you not?
    Mr. Graham. I've been work----
    Senator Sanders. All modesty.
    [Laughter.]
    Mr. Graham. Maybe.
    [Laughter.]
    Senator Sanders. It does seem surprising that the 
government might not have reached out to you for your thoughts 
in my judgment.
    Mr. Graham. Yes, I think it is surprising.
    Senator Sanders. Mr. Chairman, thank you.
    Senator Brown. Thank you, Senator Sanders for your comments 
and questions. I have a couple more questions before 
adjourning.
    Dr. Eisenstein, explain what gram negative bacteria are and 
why antibiotic development is especially challenged in this 
area. My understanding is that there's a growing number of 
resistant bugs that fall in this category including klebsiella, 
E. coli and acinetobacter. Do we need to consider different 
incentives for these types of infections?
    Dr. Eisenstein. I think we need greater incentives for new 
agents against all of the bugs that you've described, Senator 
Brown. The difference between a gram positive of a gram 
negative organism is relatively straight forward. The gram 
negative has got an extra piece of armor on its outside, in 
simple terms.
    That extra piece of armor also contains additionally 
powerful sump pumps that the gram positives don't contain. 
Given the extra armor plus the extra powerful sump pumps 
they're able to get antibiotics pumped out even more vividly 
than the gram positives can do. That's in part because gram 
negatives are the primary organism in our GI tract and in the 
sewer systems, if you will. They've therefore adapted over 
billions of years to develop the wherewithal to get rid of 
noxious products.
    Senator Brown. Is it safe to say the gram negatives do both 
more good and more bad?
    Dr. Eisenstein. We would not. Yes, exactly right.
    Senator Brown. In verses terms----
    Dr. Eisenstein. We would not be alive today if it weren't 
for the gram negatives in our GI tract. They make very 
important products for us like Vitamin K and other important 
products that we take advantage of. They're actually more 
bacteria in our body by an order of magnitude of tenfold than 
there are human cells in our body.
    The other aspect to the use of antimicrobials is the 
careful, careful use, because we don't want to disturb that 
important flora. So it's not just resistance. It's also 
disturbing that balance of bacteria that live with us.
    Going back to your question about the difficulty of coming 
up with new antimicrobial drugs. It's because these bacteria 
have the extra biological potency to get rid of agents that it 
becomes even more challenging to come up with new agents 
against them. The Infectious Diseases Society and in their 
Journals, Journal of Infectious Disease and Clinical Infectious 
Diseases, I cite in my document, point out some of the real 
issues that we have with many of these gram negative 
infections.
    You've named some. I think acinetobacter has gotten 
particular attention because it has infected many of our brave 
service officers in the Middle East. They've gotten infected 
with this disease in a way that we have, in many cases, great 
difficulty in treating it.
    Senator Brown. Can you always determine if it's gram 
negative or gram positive?
    Dr. Eisenstein. That's a fairly easy distinction. In fact 
it's the gram stand view.
    Senator Brown. Yes.
    Dr. Eisenstein. Yes.
    Senator Brown. Ok. Thank you. One other question, Dr. 
Eisenstein. We talk about incentives for development. Can you 
discuss how development incentives may differ for small 
companies verses pharma-size companies?
    Dr. Eisenstein. Yes. I actually had the experience of 
working in a big pharmaceutical company at Eli Lily, where I 
was head of infectious diseases. Now I work at a small company. 
Big companies essentially can bank roll a lot of their 
programs. What they do is look across the portfolio and decide 
what is the more likely area to have economic return.
    Small companies, in contrast, don't have the luxury of 
having bank rolls. Their barrier to entry to get into the field 
is more difficult. Those incentives that enable a lowering 
event of the entry border is preferable for the small companies 
whereas those that allow greater economic value later in the 
course of the drug use.
    For example, the extension of patent rights or market 
exclusivity actually benefits all. And, so far as market 
exclusivity can be used specifically for antimicrobials through 
the Orphan Drug Act or through some other parallel type 
program, that actually helps all manufacturers get more 
interest----
    Senator Brown. The extension is on the other end when the 
smaller companies need it in the front end.
    Dr. Eisenstein. Right.
    Senator Brown. I'm looking for how we incent small 
companies that doesn't necessarily cost taxpayer dollars that 
are less crucial to large companies.
    Dr. Eisenstein. Well the reason that even the patent 
extensions and marketing extensions help the small companies is 
that the product that they are now working on is viewed as of 
greater value by the bigger companies which will offer partner 
and sometimes buy the smaller companies or the products.
    Senator Brown. What I'm trying to get at, is there anything 
specific we can do that is unique to helping the small 
companies that where those barriers just seem a little bit too 
high to pursue some breakthrough in antimicrobial resistant 
drug.
    Dr. Eisenstein. Well I think----
    Senator Brown. Certain antimicrobial.
    Dr. Eisenstein. Yes, providing assistance to help finance 
some of the ongoing efforts and, as I said earlier, having even 
the present organization we have in place, namely the FDA to 
re-look the potency and resistance patterns of older 
antibiotics to demonstrate that these are actually not as 
powerful drugs as we sometimes presently think. Thereby enable 
physicians to recognize the better value of some of the newer 
drugs does have a value toward helping the smaller companies 
because their products, these newer products then become of 
greater value.
    Senator Brown. Thank you for that. Let me ask a related 
question. When I was in the House there was--we, in the 1990s, 
doubled the NIH budget, as you know.
    Dr. Eisenstein. Yes.
    Senator Brown. Bipartisan agreement, Democratic President, 
Republican Congress. Every member of the Health Subcommittee, 
that on which I sat, seemed to have some relative or friend, 
not to sound a bit cynical, that could be helped by some major 
breakthrough that NIH might find. We didn't see the same 
congressional support by a long shot, on CDC because CDC is 
considered by many to help other people, not people that dress 
like this, but people that might be poor or because it's--but I 
don't think it's that agency. I think it's a public health 
agency that helps everyone.
    When you talk about incenting pharma companies or smaller 
companies, talk if you would about where a billion dollars 
would go and whether it's best FDA would do the research--NIH. 
I hesitate a bit to ask the question whether NIH, FDA or CDC 
would be best at government research on finding out, on 
discovering some of these antibiotics and developing them?
    Dr. Eisenstein. It's a very interesting question and has a 
complex answer. My own view, having been involved in academic 
research for many years and sat on NIH study sections, the most 
recent being less than a year ago where I was extraordinarily 
disappointed to see that we were only able to fund 11 percent 
of the extraordinarily powerful grants that were being 
performed by colleagues like Dr. Brennan and----
    Senator Brown. It was almost twice that 5 years ago.
    Dr. Eisenstein. Yes, exactly. What this is doing and as a 
former chair of an academic department, I recognize this among 
my former colleagues, it's chasing some of our best minds out 
of the field. That's a great worry to me.
    Senator Brown. I'm going to pin you down. Who could do the 
best, understanding that with the fact that in this 2 hours 
we've been hearing this here. We've had this hearing. We spent 
$40 million on the War in Iraq and with the budget situation. 
We're not doing what we ought to do with NIH, CDC or FDA. Where 
would the money best be spent of those three agencies on 
something fairly narrow like finding antibiotics?
    Dr. Eisenstein. I would put as a short-term investment, 35 
cents on the dollar to the FDA so that they can have the 
resources needed to deal with break points. I would put 15 
cents on the dollar to improve the epidemiologic assessments 
from States so that that can be best utilized and normalized 
and communicated. I would give 50 cents on the dollar to trying 
to invest more in the NIH. It's really investing in the 
infrastructure of U.S. academic research.
    Senator Brown. Ok. Thank you for the precise answer. Last 
question. Dr. Graham, unless Senator Sanders has another 
question, you mentioned drinking water and what we're finding 
in drinking water increasing. Are there any other places in our 
environment where antibiotics are showing up where they 
shouldn't be?
    Mr. Graham. Antibiotics or antibiotic-resistant bacteria?
    Senator Brown. Well, one may lead to the other certainly. 
Answer the question how you want.
    Mr. Graham. Ok. We find antimicrobials present in a lot of 
streams. USGS has done a report and they showed a high 
prevalence of streams with antibiotics, mainly looking at 
tetracycline, I believe.
    As far as antimicrobial resistance we're, you know I think 
one of the things we think is that things at the farm stay at 
the farm. We know more and more that that's not the case with 
the E. coli in spinach, that sort of thing. I've seen studies 
where they're finding resistant bacteria, fecal organisms on 
vegetables and fruits.
    We're really linked in this ecosystem so that you apply 
this waste untreated onto land. It ends up in our water supply, 
our ground water and surface water supply. Then that water is 
used as irrigation for our crops that we consume.
    I've actually looked at flies on the Eastern Shore of 
Maryland. I've looked at resistance genes that are in the waste 
at the poultry farms. I've also identified the same resistance 
genes that flies are carrying around the environment.
    There, I mean, it literally seems like they're everywhere 
just like, you know, we all carry a little bit of DDT in us. 
We're likely all carrying some resistant organism. Fortunately, 
most of us are healthy and not going to end up having to take 
antimicrobials. But there is, I guess, that chance.
    Senator Brown. Thank you. Thank you for the enthusiasm for 
what you do too.
    Thank you all for testifying, both the first panel and the 
second panel. Your work is so important for all of us and your 
words today are so important too. Thank you very much.
    The record will remain open for 2 weeks if any of you want 
to submit or the first panel wants to submit additional 
information. Senator Sanders and others, it's open for 2 weeks 
for us too, to ask questions and if you would respond to any 
Senator that does.
    I thank you for being here. The committee is adjourned.
    [Additional material follows.]

                          ADDITIONAL MATERIAL

                  Prepared Statement of Senator Durbin

    I would like to thank the HELP Committee for addressing the 
important issue of antimicrobial resistance and specifically 
the growing emergence of healthcare associated infections.
    Though not a new issue, growing public attention in the 
past year and a half has raised public concerns around 
healthcare associated infections, like methicillin-resistant 
Staphylococcus aureus (MRSA). The Centers for Disease Control 
and Prevention (CDC) estimates that approximately 1.7 million 
healthcare associated infections (HAIs) occur in U.S. hospitals 
and are associated with 99,000 deaths, affecting 5 to 10 
percent of hospitalized patients annually.
    These infections are not only showing up in hospitals, they 
are a threat to our soldiers, to the safety of our community, 
and our entire healthcare system. Approximately half of the 
infections that are treated in a hospital are actually picked 
up in the community. Over the past year, schools in Illinois, 
Connecticut, Maryland, North Carolina, Ohio, Virginia and 
Kentucky have had to close to help contain the spread of an 
infection and others even had to report student deaths. 
Soldiers are increasingly coming back from Iraq with war wound 
infections and osteomyelitis caused by multidrug-resistant 
Acinetobacter species. In addition to the devastating impact on 
human lives, HAIs result in an estimated $20 billion of excess 
healthcare costs every year. Within the Medicare program alone, 
healthcare charges for Staph bloodstream infections exceeded 
$2.5 billion in 2005.
    States are taking important steps to control infections. 
The State of Illinois has been aggressive in its efforts to 
identify the infection before it grows out of control. Illinois 
was the first State to require testing of all high-risk 
hospital patients and isolation of those who carry the bacteria 
called MRSA. With proactive testing and prevention methods a 
group of three hospitals near Chicago reduced MRSA infections 
by 70 percent over 2 years. Since then, 25 States have laws 
that require public reporting of infection rates.
    The Federal Government needs to step up its commitment to 
controlling these infections. Since the rise in reported 
infections, the CDC has seen a dramatic increase in the number 
of hospitals submitting information to the National Healthcare 
Safety Network (NHSN). The NHSN is a secure, internet-based 
surveillance system that collects data from healthcare 
facilities on the emergence of infections and adherence to best 
practices in prevention of HAIs. The NHSN is an effective tool 
that should be sustained and expanded.
    States are actively CDC's recommendations for communities 
and hospitals to help fight the spread of drug-resistant bugs. 
The CDC could do more and should do more to address the growing 
emergence of infections. I introduced the Community and 
Healthcare Associated Infections Reduction Act last year to 
establish a clearer leadership role for the Federal Government 
in improving the prevention, detection, and treatment of 
community and healthcare-associated infections. The bill 
doesn't reinvent the wheel, but instead builds on successes the 
healthcare community and government agencies have created.
    My bill requires hospitals to report infection rates to the 
CDC's NHSN. More complete data will inform policies and 
practices to prevent and treat these dangerous infections. We 
also need comprehensive infection control programs. The bill 
commissions an updated, comprehensive look at best practices 
for hospitals on infection control. The bill also requires the 
Secretary to look into the creation of a Federal payment system 
to acknowledge and reward hospitals that are preventing 
infections. The bill would create a new public health campaign 
to increase awareness about reducing and preventing the spread 
of infections, especially in schools, locker rooms, and 
playgrounds--the areas where we know bacteria can thrive. 
Finally, the bill calls for greater coordination of and greater 
emphasis on research at the Federal level.
    Healthcare-associated infections pose very real health 
risks and cost the healthcare system billions of dollars. But 
they are preventable, and with the proper attention and 
resources, we can control the spread of these infections. I 
look forward to working with my colleagues as the committee 
considers proposals to improve prevention, reporting, and 
research toward minimizing healthcare-associated infections.

Response to Questions of Senator Kennedy, Senator Enzi, Senator Brown, 
               and Senator Burr by Fred C. Tenover, Ph.D.
                      questions of senator kennedy
    Question 1. How might the data collection systems and agencies 
within CDC, FDA, and USDA be improved to more effectively monitor 
sources of antimicrobial resistance?
    Answer 1. The National Antimicrobial Resistance Monitoring System 
(NARMS) was developed in 1996 to monitor changes in susceptibility of 
select foodborne bacteria to antimicrobial agents of human and 
veterinary importance and is a collaboration between three Federal 
agencies including FDA's Center for Veterinary Medicine (CVM), the 
Centers for Disease Control and Prevention (CDC) and the U.S. 
Department of Agriculture (USDA). It is one of the key components of 
the FDA strategy to assess relationships between antimicrobial use in 
agriculture and subsequent human health consequences. NARMS 
surveillance and research data is valuable in identifying the source 
and magnitude of antimicrobial resistance in the food supply and is 
important for the development of public health recommendations for the 
use of antimicrobial drugs in humans and food animals. NARMS provides 
ongoing monitoring data on antimicrobial susceptibility/resistance 
patterns in select zoonotic foodborne bacteria, in particular 
Salmonella, Campylobacter, E. coli and Enterococcus.
    With regard to expanding NARMS into other infection routes besides 
food, NARMS does not currently screen for S. pneumoniae or MRSA but is 
currently working with partners at the University of Maryland to 
conduct a small pilot study looking for MRSA in retail meats in the 
Washington, DC metro area. FDA/CDC is also meeting with FoodNet 
partners to explore the possibility of expanding MRSA testing to a 
larger collection of retail meats obtained through the NARMS retail 
program. Lastly, NARMS scientists have partnered with academic 
investigators at the University of Minnesota in another pilot study 
characterizing potential links between antimicrobial resistant E. coli 
recovered from foods and human extra-intestinal pathogenic E. coli 
infections (e.g., urinary tract infections, septicemia). Overall, the 
NARMS program is yielding information that is valuable in identifying 
the source and magnitude of antimicrobial resistance in the food supply 
and is important for the development of public health recommendations 
related to the use of antimicrobial drugs in humans and food animals.
    For CDC, current surveillance systems for antimicrobial resistance 
are primarily with State health departments, hospitals, and public 
health clinics. There is a need to improve the systems for capturing 
timely and complete surveillance information. In general, there is also 
a need to expand the surveillance systems to include other potential 
emerging sources of resistant microorganisms and to collect isolates of 
bacteria, fungi, and other resistant microorganisms for 
characterization. Characterization studies, such as defining the 
mechanisms of antimicrobial resistance and determining the strain types 
of the organisms for epidemiologic studies, are important activities 
that could be expanded. In addition, more comprehensive data on 
antimicrobial use are needed to understand the drivers of resistance. 
The current databases with this information are expensive to access, or 
are fragmented and in need of updates. These improvements would help 
CDC, working with other HHS Operating Divisions and academic partners, 
to design appropriate interventions to prevent the development of 
resistant organisms and control their spread.

    Question 2. The NARMS program monitors antimicrobial resistance in 
enteric pathogens. In light of the significant and growing threats of 
other resistant pathogens like MRSA or S. pneumoniae, do you feel the 
scope of existing programs should be expanded to include other routes 
of infection such as through the skin, respiratory tract or urinary 
tract?
    Answer 2. The surveillance data provided through NARMS, a 
collaborative effort of CDC, FDA, and USDA, continue to provide key 
information regarding the development and spread of antimicrobial 
resistance among enteric bacteria in humans, animals, and retail foods. 
Control efforts to interrupt the spread of resistant bacteria in the 
food supply may benefit from expanded surveillance for organisms 
including methicillin-resistant Staphylococcus aureus (MRSA) and 
Clostridium difficile in food animals and retail meats. Such studies 
are currently under consideration by NARMS investigators.
    Streptococcus pneumoniae is an example of a major human pathogen 
that is not transmitted through animals nor does it cause infection in 
animals; thus, it falls outside the scope of the NARMS program. S. 
pneumoniae infections, including respiratory tract infections, 
meningitis, and bacteremia, as well as invasive MRSA infections in 
humans are monitored through CDC's Emerging Infections Program. The 
Emerging Infections Program, an intensive surveillance system operating 
in 10 States, tracks serious human infections caused by resistant 
organisms and serves as a research platform that can evaluate the 
impact of prevention measures. Increased capacity of the current sites 
participating in the Emerging Infections Program would allow for 
assessments of the ability of new vaccines to prevent disease caused by 
emerging resistant strains of Streptococcus pneumoniae and to determine 
the effectiveness of new measures to control MRSA infections.
    The need for such expansion is further illustrated by the recent 
detection of the first known cases of ciprofloxacin-resistant 
meningococcal disease reported in North America. The Emerging 
Infections Program provided CDC with strains from its surveillance 
sites to evaluate and describe the scope of the public health problem. 
This information allowed CDC to develop new recommendations for 
antimicrobials to protect individuals who come in contact with such 
cases.

    Question 3. How can regulatory agencies such as the CDC, FDA, and 
Department of Agriculture (USDA) engage in additional data collection 
on how the use of antimicrobials in animal feeds might lead to 
antimicrobial resistance in human diseases? At what level (region, 
State, metropolitan area, farm, etc) is data collection on the use of 
antimicrobials in animal feeds necessary to effectively monitor and 
describe trends in antimicrobial resistance?
    Answer 3. Minimizing the emergence of antimicrobial resistant 
bacteria in animals and the potential spread to humans is a complex 
problem requiring a coordinated, multifaceted approach. More than a 
dozen Federal agencies have an interest in the problem of antimicrobial 
resistance, and several of these agencies have responsibilities 
regarding the use of antimicrobials in agriculture. The strategy 
developed by FDA to address antimicrobial resistance is one component 
of more broad-reaching strategies being developed at the national level 
in the form of the Public Health Action Plan to Combat Antimicrobial 
Resistance.
    CDC, FDA, and the Department of Agriculture (USDA) are currently 
collaborating on the operation and maintenance of the National 
Antimicrobial Resistance Monitoring System (NARMS). NARMS was developed 
in 1996 to monitor changes in susceptibility of select foodborne 
bacteria to antimicrobial agents of human and veterinary importance, 
including food animals and foods of animal origin. It is one of the key 
components of the FDA strategy to assess relationships between 
antimicrobial use in agriculture and subsequent human health 
consequences. NARMS surveillance and research data is valuable in 
identifying the source and magnitude of antimicrobial resistance in the 
food supply, and is important for the development of public health 
recommendations for the use of antimicrobial drugs in humans and food 
animals. NARMS provides ongoing monitoring data to physicians, 
veterinarians, and public health authorities on antimicrobial 
susceptibility/resistance patterns in select zoonotic foodborne 
bacteria, in particular, Salmonella, Campylobacter, E. coli and 
Enterococcus.
    CDC, FDA, and USDA NARMS scientists have been exploring additional 
avenues for data collection. They are currently working with partners 
at the University of Maryland to conduct a small pilot study looking 
for methicillin-resistant Staphylococcus aureus (MRSA) in retail meats 
in the Washington, DC metro area. FDA/CDC are also meeting with FoodNet 
partners to explore the possibility of expanding MRSA testing to a 
larger collection of retail meats obtained through the NARMS retail 
program. Lastly, NARMS scientists have partnered with academic 
investigators at the University of Minnesota in another pilot study 
characterizing potential links between antimicrobial resistant E. coli 
recovered from foods and human extra-intestinal pathogenic E. coli 
infections (e.g., urinary tract infections, septicemia). Overall, the 
NARMS program is yielding information that is valuable in identifying 
the source and magnitude of antimicrobial resistance in the food supply 
and is important for the development of public health recommendations 
related to the use of antimicrobial drugs in humans and food animals.
    In regard to what level of use data collection is necessary to 
effectively monitor and ascertain potential trends in antimicrobial 
resistance, such use data needs to be at a level that will provide 
information relative to use in particular food animal species. Such 
species-specific use data, in conjunction with the data collected as 
part of the NARMS program, enables our epidemiologists to make 
associations between use patterns and emerging antimicrobial resistance 
trends.

    Question 4. As you are aware, recent studies have shown an 
association between community-acquired strains of MRSA and colonization 
of swine and farmers in the Netherlands, Canada and now in the U.S. How 
are the FDA, CDC and USDA working together to understand and contain 
the spread of community acquired MRSA from farm animals such as pigs 
and cattle to humans?
    Answer 4. CDC and others have investigated numerous outbreaks of 
community-associated MRSA infections in the United States, and in none 
of these investigations has animal exposure been identified as a risk 
factor for infection. Recent reports from the Netherlands and Canada 
suggest that human infections caused by MRSA strains of animal origin 
occur predominantly among persons with close proximity to colonized or 
infected animals. CDC has not identified the predominant strain 
identified in pigs in any human disease or colonization isolates in our 
CDC isolate database, suggesting this strain is not a prevalent cause 
of human infection in the United States. CDC works closely with its 
regulatory partners at FDA and USDA on issues affecting the safety of 
the U.S. food supply; further research is needed to understand the 
extent to which MRSA is present in food producing animals in the United 
States and the public health implications of this.
                       questions of senator enzi
    Question 1. You talked extensively in your testimony about the CDC 
surveillance systems. Are there any gaps in your systems that are 
present because of barriers related to the CDC's authority?
    Answer 1. CDC should expand its surveillance of resistant 
microorganisms (bacteria, fungi, viruses, and parasites) among multiple 
life stages, settings, and animals (domestically and internationally) 
to identify populations or communities that require interventions to 
reduce the development or spread of resistance, and to gather more 
nationally representative data. CDC relies on partners such as State 
health departments and hospitals to provide data on resistant 
infections and often such partners lack adequate resources to provide 
complete and timely data. The increasing availability of healthcare 
data in electronic form and recent advances in information technology 
provide new opportunities to accelerate the transition from manual 
healthcare-associated infections (HAI) case finding and reporting to 
computer-based algorithmic case detection and electronic reporting. 
Legislation that encourages collaboration among agencies and requires 
accountability for working together to ensure complementary systems in 
surveillance is helpful in achieving this aim. Privacy and 
confidentiality protections are a barrier that can have useful yet 
still protective legislative solutions. Linked authorization and 
appropriations for systems is important to have the ability to 
implement many solutions to barriers.

    Question 2. Is the coordination of Federal entities currently 
producing the best information and resulting in the most appropriate 
actions that are necessary to take to help reduce antibiotic 
resistance? Are there any legislative barriers that prevent the 
agencies from sharing information or responding to the problem in a 
coordinated manner?
    Answer 2. There is certainly an opportunity for greater data 
sharing among agencies to enhance efforts to monitor the spread of 
antimicrobial resistant microorganisms. For example, sharing of data 
between CDC and the Department of Defense on incidence of antimicrobial 
resistant strains of N gonorrheae could be very useful for selecting 
appropriate treatment regimens in the future. Limited public health 
infrastructure for detecting resistance and the heavy reliance on 
hospital microbiology laboratories around the United States to provide 
the antibiotic resistance data is a barrier. Additionally, 
confidentiality protections create barriers to sharing that need 
creative legislative solutions that both maintain protection and allow 
action.
                       questions of senator brown
    Question 1. CDC appoints a co-chair on the Interagency Task Force 
on Antimicrobial Resistance. Please describe the leadership chain and 
how the many participating agencies and the individuals representing 
them are held accountable for implementation of Action Items in their 
jurisdiction.
    Answer 1. The CDC representative to the Interagency Task Force is 
the Director of the CDC Office of Antimicrobial Resistance, which is 
part of the Coordinating Center for Infectious Diseases at CDC. The 
Office of Antimicrobial Resistance consults with CDC leadership 
regarding issues of policy and clears all policy documents through the 
CDC Office of the Director. The Director of the CDC Office of 
Antimicrobial Resistance is responsible for monitoring and documenting 
progress on the Action Items for the Agency. Annual progress reports 
are posted on the CDC Antimicrobial Resistance Web site on behalf of 
the Interagency Task Force.

    Question 2. Nearly 8 years ago, the Interagency Task Force put out 
an Action Plan identifying 13 (out of 84) elements as ``top priority,'' 
critically necessary to address growing resistance. Shortly after, I 
introduced legislation to authorize such sums as necessary to implement 
these 13 top priority items. The bill didn't pass. How are these action 
items currently funded? According to HHS, in 2006, CDC spent $16.2 
million; FDA $24 million; and NIH $220 million. In your professional 
judgment, please tell me what funding is necessary for each of your 
agencies to implement the Action Plan--especially the top priority 
action items. In addition, what funding is necessary for NIH?
    Answer 2. CDC To fully combat the growing problem of antimicrobial 
resistance, and to fully implement the Action Plan, a significant 
increase in resources would be required. The increase in funding will 
provide resources for expansion and enhancement of networks for 
detection, monitoring and prevention of antimicrobial resistance, both 
domestically and internationally. For example, informatics will be used 
to expand current databases of both antimicrobial use and antimicrobial 
resistance patterns, and expand web based reporting capabilities. 
Antimicrobial use will be improved in multiple settings and populations 
through prevention activities. CDC will conduct new research and 
demonstration projects, and develop software for data and trend 
analysis. Reference laboratories will be expanded and rapid diagnostic 
methods developed to determine the susceptibility of microorganisms to 
new anti-infective agents. Laboratory enhancements will include the 
purchase of state-of-the-art equipment. Finally, the increase in 
funding will provide expanded support for the Antimicrobial Resistance 
Task Force.
    NIH: The National Institute of Allergy and Infectious Diseases 
(NIAID) supports a broad research portfolio dedicated to antimicrobial 
resistance that includes innovative research on new potential 
therapeutics and vaccines, as well as efforts to reduce the pressure on 
the existing arsenal of antimicrobial drugs. The research priorities 
outlined in the Interagency Task Force on Antimicrobial Resistance 
Public Health Action Plan to Combat Antimicrobial Resistance are 
actively being addressed through NIAID-supported research grants and 
contracts. The Action Plan, which is updated annually, is currently in 
the process of being revised to ensure that the document is 
appropriately focused on current priorities. In December 2007, the Task 
Force held a public meeting and received input from experts about 
pressing antimicrobial resistance needs; these issues are being 
considered by the CDC, NIH, Food and Drug Administration and other Task 
Force members as they update the Action Plan.
    FDA: Implementation of the action items, both top priority action 
items and others, are funded through the respective agencies' 
appropriations. There is no dedicated funding for the Interagency Task 
Force or the Public Health Action Plan.

    Question 3. In the late 1990s, the Office of Technology Assessment 
(OTA), the Institutes of Medicine (IOM) and the GAO issued reports to 
Congress on the growing problem of antimicrobial resistance. The 
reports focused on a number of shortcomings of our Federal response to 
antimicrobial resistance. Specifically, it cited the need for 
antibiotic development, enhanced surveillance and data collection. 
Please discuss current data collection related to or specifically 
addressing antimicrobial resistance in this country and in other 
countries--how does the U.S. data effort compare to others, especially 
European countries? Are we doing a better job than our European 
counterparts collecting such data?
    Answer 3. The European Community has established a system for 
monitoring both antimicrobial resistance rates among bacterial species 
[European Antimicrobial Resistance Surveillance System (EARSS)] and 
antimicrobial use. Annual reports are published by EARSS showing 
resistance rates for a wide array of bacterial species in most of the 
countries in the European Union. Comparable data from the United States 
(i.e., population based data) are available only for a few bacterial 
species. The European Union also publishes extensive data on 
antimicrobial use in humans and animals by country. The United Kingdom 
has a national system for MRSA, and has made significant investments in 
this system.
    The United States does not produce comparable data to those listed 
above. The United States has systems such as CDC's Emerging Infections 
Program, the National Healthcare Safety Network (NHSN), and NARMS that 
collect some bacteria and specific infection data. These systems have 
the potential to be national systems with the appropriate investments, 
and could be expanded to include additional bacteria and to have a 
national scope. In contrast to systems in Europe, the United States has 
limited access to comprehensive and timely data on antimicrobial use.

    Question 4. What more does CDC need to do to address antimicrobial 
resistance? What are the barriers to doing more?
    Answer 4. CDC should expand its surveillance of resistant 
microorganisms (bacteria, fungi, viruses, and parasites) among multiple 
life stages, settings, and animals (domestically and internationally) 
to identify populations or communities that require interventions to 
reduce the development or spread of resistance. For example, to reduce 
the potential for widespread failure of primary therapy for gonorrhea 
in the future, surveillance for cephalosporin-resistant Neisseria 
gonorrhoeae should extend beyond men in public health clinics to 
include the men and women in the private sector and military personnel. 
CDC also needs to improve prevention and control activities in all 
healthcare settings such as outpatient centers, hospitals and long-term 
care facilities to stop transmission of resistant microorganisms and to 
reduce inappropriate antimicrobial use. Finally, CDC needs to enhance 
the surveillance infrastructure at both the local, State, and Federal 
levels to improve antimicrobial resistance activities, and to enhance 
laboratory capacity and expand research. Current investments limit the 
capacity to appropriately respond to the emerging problem.

    Question 5. Last year, I introduced S. 2313, the Strategies to 
Address Antimicrobial Resistance (STAAR) Act, a bill targeting the 
problem of antimicrobial resistance. Can CDC tell me how this 
legislation will make an impact on addressing antimicrobial resistance?
    Answer 5. CDC applauds efforts to raise awareness about the problem 
of antimicrobial resistance and to reduce the development and spread of 
resistant microorganisms. It is important that the provisions of The 
STAAR Act compliment the many current activities and programs which 
address microbial resistance.

    Question 6. Within the STAAR Act, can you explain how you think the 
provision on Clinical Research & Public Health Network will compliment 
the current surveillance activities and discuss the importance of 
isolate collection? In short, will these proposed activities better 
prepare physicians to be on the look out for emerging resistance issues 
and help contain them before they spread to other States?
    Answer 6. The proposed mandate for the Clinical Research & Public 
Health Network is very broad. Hopefully, such an activity would be 
designed to enhance and compliment the existing CDC activities of the 
Emerging Infections Program, NARMS, the Prevention EpiCenters, and 
other existing surveillance systems and prevention efforts rather than 
replace these long standing activities. Integrating and leveraging the 
surveillance and research while maintaining existing expertise and 
depth can be useful.

    Question 7. Does CDC have access to the antimicrobial resistance 
data that FDA collects? Do you have access to the data collected by 
Medicare and the VA? In your perspective, do you believe more reliable 
and comparative animal and human usage data would be of value to CDC's 
public health mission? If so, please explain.
    Answer 7. Data collected by CDC, FDA, and USDA as part of the NARMS 
programs is shared among the three agencies. CDC has partnered with 
several VA medical centers to collect limited antimicrobial resistance 
data. However, data are not shared in any consistent manner beyond 
those specific programs. Better access to antimicrobial use data from 
humans and animals would be a tremendous help to CDC's activities to 
monitor and control the development and spread of antimicrobial 
resistant organisms by indicating where selective pressure is highest.

                       questions of senator burr
    Question 1. How does CDC currently decide which organisms to 
monitor for antimicrobial resistance and how does the agency conduct 
surveillance of organisms of concern, such as campylobacter, E. coli, 
gram negative and gram positive organisms, HIV, influenza, malaria, 
tuberculosis and others? Are these surveillance activities conducted by 
State and local public health departments?
    Answer 1. CDC and the Council of State and Territorial 
Epidemiologists provide guidance under the Nationally Notifiable 
Disease Surveillance System and State health departments are 
responsible for determining which microbial species are to be reported 
by physicians and laboratories in their respective States and 
territories. These data contribute to CDC's overall picture of the 
burden of antimicrobial resistance. The selection of which 
microorganisms to monitor for resistance at CDC is based on CDC's 
estimation of the potential public health impact of the development of 
resistance on human and animal health. It also is impacted by CDC's 
need to measure the effectiveness of intervention programs that are 
undertaken. For example, the introduction of the pneumococcal conjugate 
vaccine to decrease invasive pneumococcal infections in children 
required a monitoring system to be in place to measure the 
effectiveness of this multimillion dollar public health initiative. The 
ABCs program, an active laboratory- and population-based surveillance 
system for invasive bacterial pathogens of public health importance 
that is part of CDC's Emerging Infections Program, serves that purpose 
and continues to monitor the development and spread of novel strains of 
pneumococci that cause invasive pneumococcal disease in the United 
States. ABCs also provides an infrastructure for further public health 
research, such as monitoring the impact of the next generation 
pneumococcal vaccine on newly emerging resistant strains not covered by 
the first vaccine and whether new control measures introduced in 
several States can reduce MRSA disease.

    Question 2. How do CDC and NIH decide what research to fund on 
prevention, control and treatment of resistant organisms? Aren't there 
research funds available that academic centers or public health 
departments can apply for? Does CDC have a position on the Brown-Hatch 
legislation and the required establishment of 10 new research centers 
on antimicrobial resistance? How does this change what is already 
occurring?
    Answer 2. To assess scientific opportunities and priorities, the 
National Institutes of Health (N1H) receive input from a range of 
sources, including ad hoc advisory groups, focus groups, conferences, 
and informal discussions with outside scientists. Further, each 
Institute and Center (IC) of the NIH has advisory bodies and a main 
advisory Council that provide recommendations on broad research 
priorities and directions, providing the perspective of the outside 
community. Scientific priorities, especially in emerging areas, can be 
reflected in new research initiatives that an IC issues to solicit 
grant applications or contract proposals to address specific scientific 
questions. In addition, through investigator-initiated research, 
scientists in the extramural community can identify scientific 
opportunities that they feel are important to a particular field. 
Whether research is solicited or investigator-initiated, the most 
important factor in determining funding decisions is scientific merit 
of a proposal or application, as judged by peer reviewers.
    The National Institute of Allergy and Infectious Diseases, a 
component of the NIH, conducts and supports broad research on 
antimicrobial resistance. This research includes innovative research on 
new potential therapeutics and vaccines, as well as efforts to reduce 
the pressure on the existing arsenal of antimicrobial drugs. For 
example, in 2007, NIAID awarded two contracts totaling $19 million over 
5 years to support multisite, Phase II/III clinical trials to study 
whether selected oral, off-patent antibiotics can effectively treat 
skin and soft tissue infection caused by community acquired 
methicillin-resistant Staphylococcus aureus (CA-MRSA). Should the data 
from these studies demonstrate that off-patent antibiotics are 
effective, final option drugs such as vancomycin and linezolid could be 
preserved for treatment of healthcare associated MRSA. These contracts 
were awarded to two groups of researchers qualified to address the 
questions within this specific disease area. These researchers, and the 
multiple sites associated with them for these studies, form a 
``functional network,'' an approach that provides NIAID with a flexible 
structure in which to address specific scientific questions of highest 
priority.
    NIAID has announced a fiscal year 2009 initiative, ``Targeted 
Clinical Trials to Reduce the Risk of Antimicrobial Resistance,'' that 
is soliciting proposals for research to treat a variety of important 
bacterial infections with strategies such as shorter courses of 
antimicrobials drugs and different dosages/frequencies of drugs. NIAID 
anticipates the release of a similar initiative in fiscal year 2010.
    CDC bases funding activities on the Action Plan to Combat 
Antimicrobial Resistance. Academic centers and public health 
departments can apply for funding. The proposed mandate for the 
Clinical Research & Public Health Network is very broad. Hopefully, 
such an activity would be designed to enhance and compliment the 
existing CDC activities of the Emerging Infections Program, NARMS, the 
Prevention EpiCenters, and other existing surveillance systems and 
prevention efforts rather than replace these long standing activities. 
Integrating and leveraging the surveillance and research while 
maintaining existing expertise and depth can be useful.

    Question 3. How much is CDC currently spending on antimicrobial 
resistance research and surveillance activities each year?
    Answer 3. In 2008, CDC's Office of Antimicrobial Resistance 
obligated $16.3 million to antimicrobial resistance activities. In 
addition, divisions within the Coordinating Center for Infectious 
Diseases spent an additional $6.7 million dollars to support 
antimicrobial resistance activities.

    Question 4. When we talk about antimicrobial resistance, are we 
capturing antiviral resistance? If not, do you see this as a separate 
policy issue that should be dealt with differently?
    Answer 4. Resistance to the antiviral agents used to treat Human 
Immunodeficiency Virus infections, influenza viruses, and some 
hepatitis viruses are captured currently by CDC surveillance systems. 
Resistance to other antiviral agents is not monitored.

    Question 5. In your testimony, you talked about a partnership 
between CDC and the VA, which led to a 60 percent reduction in the rate 
of MRSA infections in VA medical centers after a series of infection 
control procedures were implemented. Please tell us more about those 
procedures and how other hospitals and community settings, like gyms, 
can be encouraged to follow suit.
    Answer 5. CDC has collaborated with the VA to demonstrate the 
preventability of healthcare-associated MRSA infections for several 
years. In 2001, CDC funded the Veteran's Affairs Pittsburgh Healthcare 
System (VAPHS) to perform an MRSA infection prevention demonstration 
project. This collaboration, using a prevention strategy consistent 
with CDC's guideline for control of multidrug resistant organisms 
(MDROs), began a pilot study in a single patient care unit within the 
hospital. After a post-intervention reduction in MRSA infection rates 
of over 60 percent was observed in that unit, the intervention was 
implemented in a second unit with similar results. Finally, the 
intervention was implemented across the entire hospital, and an overall 
60 percent decrease in the hospital-wide MRSA incidence was observed. 
The Department of Veteran's Health Affairs (VHA) issued a directive to 
all VHA hospitals nationwide to implement MRSA prevention programs 
using the VAPHS intervention as a model. In addition, the Agency for 
Healthcare Research and Quality and the Robert Wood Johnson Foundation 
have provided funding for hospitals in five States to use innovative 
methods to facilitate implementation of MRSA prevention programs 
modeled closely after the VAPHS demonstration project, and the Maryland 
Patient Safety Center has implemented a voluntary MRSA prevention 
initiative involving 29 healthcare facilities using the VAPHS 
intervention as a model. CDC is helping to measure the impact of 
several of these initiatives, and preliminary data from some of the 
early reporters show successes similar to what was observed following 
the VAPHS intervention, providing encouraging evidence that 
implementing CDC recommendations can result in control of MRSA.
    CDC also has recommendations to prevent transmission of MRSA in 
community settings. CDC has partnered with the National Collegiate 
Athletic Association (NCAA), the National Federation of High School 
Associations, the National Athletic Trainers' Association (NATA), and 
others to develop informational materials and to educate athletes and 
trainers about community associated MRSA and its prevention, and is 
currently developing educational materials for mothers. With 
appropriate investments, these strategies can be implemented on a 
national scale.

    Question 6. I understand a revised Public Health Action Plan is 
going to be released for public comment this fall. Can you please make 
sure we are made aware of this updated action plan?
    Answer 6. CDC will provide the committee with the updated action 
plan.
     Department of Health and Human Services (HHS),
                        Food and Drug Administration (FDA),
                                       Rockville, MD 20857,
                                                September 19, 2008.
Hon. Edward M. Kennedy, Chairman,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, DC 20510-6300.

    Dear Mr. Chairman: Thank you for providing the Food and Drug 
Administration (FDA or the Agency) the opportunity to testify at the 
June 24, 2008, hearing entitled, ``Emergence of the Superbug: 
Antimicrobial Resistance in the U.S.,'' before the Senate Committee on 
Health, Education, Labor, and Pensions. RADM Linda R. Tollefson, 
D.V.M., M.P.H., Assistant Commissioner for Science, testified on behalf 
of FDA. We are responding to your July 17, 2008, e-mail transmitting 
questions for the record.
    We have restated your questions below in bold, followed by our 
response.
 Response to Questions of Senator Kennedy, Senator Brown, and Senator 
  Burr by the Department of Health and Human Services, Food and Drug 
                             Administration
                      questions of senator kennedy
    Question 1. As you mentioned, the FDA has only restricted the use 
of one class of antimicrobial, fluoroquinolones, for subtherapeutic 
doses in poultry feed. Do you believe that other classes of 
antimicrobials used in subtherapeutic doses in animals should be 
reviewed for the risks that they pose to human health, in food, the 
environment and other avenues of potential risk? How are risks of 
penicillin and other older antibiotics being assessed?
    Answer 1. For clarification, FDA has only restricted the use of 
fluoroquinolones for therapeutic uses in poultry. These 
fluoroquinolones were never approved for use at subtherapeutic doses. 
The approved application for sarafloxacin for use in chickens and 
turkeys was voluntarily withdrawn by the pharmaceutical sponsor. The 
approved application for enrofloxacin for use in chickens and turkeys 
was withdrawn following statutory due process procedures for withdrawal 
of an approval of a New Animal Drug Application. Fluoroquinolones are 
approved for other food-producing species; however, they are on the FDA 
list of drugs that are prohibited from extra-label use in food-
producing species. This means that fluoroquinolones may not be used for 
extra-label use in feed or otherwise, e.g. in water.
    FDA monitors all new animal drugs to ensure that the approved uses 
are safe and effective in accordance with the requirements of the 
Federal Food, Drug, and Cosmetic Act (FD&C Act or the Act). The Agency 
has the authority to take action to withdraw an approval on various 
grounds, including that experience or scientific data show that the 
approved new animal drug is unsafe.
    For penicillin-containing products, FDA reviewed all information 
contained in the administrative files, looking specifically for 
microbial food safety information that can be used to assess any 
potential human health risks. Additionally, FDA searched and reviewed 
scientific literature for microbial food safety information for 
penicillin-containing products. The basic tenets of the qualitative 
risk assessment process described in Guidance for Industry #152, 
``Evaluating the Safety of Antimicrobial New Animal Drugs with Regard 
to Their Microbiological Effects on Bacteria of Human Health Concern'' 
(GFI #152 or Guidance) (copy enclosed), were applied by review 
scientists to perform this assessment. A similar review process is 
being applied to other ``older'' approved antimicrobial products (e.g., 
tetracyclines).

    Question 2. Do you feel FDA Guidance for Industry #152 provides a 
sufficient framework for addressing all of the public health risks 
associated with antimicrobial drugs in animal feeds, including 
environmental risks?
    Answer 2. Yes, however, GFI #152 was designed to primarily address 
the foodborne pathway and does not specifically address environmental 
risks. FDA believes that the most likely pathway for the transference 
of antimicrobial resistance in bacteria from animals to humans is 
through foodborne exposures. GFI #152 is a non-binding guidance 
document that provides an approach for the industry to format, 
organize, and present data and other information to FDA for evaluation. 
The Guidance provides suggestions for some risk mitigations that might 
be considered. The Guidance does not bind or constrain FDA in making a 
determination whether a particular animal drug meets the food safety 
standard of a reasonable certainty of no harm. As new scientific 
information causes FDA to consider new or different approaches to 
assessing the microbial safety of new animal drugs, FDA can change the 
Guidance through its administrative procedures outlined in Good 
Guidance Practice regulations.
    GFI #152 provides a framework for sponsors of antimicrobial new 
animal drugs to follow when providing information to FDA on microbial 
food safety. GFI #152 was designed to address public health risks 
associated with antimicrobial drugs primarily through food exposure. 
However, as other avenues of potential public health risk are 
demonstrated, FDA may ask sponsors for additional data and information 
when it is applicable and appropriate.
    Since 2001, FDA has reviewed a variety of antimicrobial animal 
drugs for numerous intended uses. Among these drugs, a number of risk 
mitigations have been implemented. These include modifying the 
conditions of use of the product and applying certain label 
restrictions such as requiring veterinary prescription status.

    Question 3. Does the FDA currently have the authority to collect 
the antimicrobial drug use data needed to manage the risk of 
antimicrobial resistance, such as geographic location and actual 
mechanism of use by producers?
    Answer 3. FDA has the statutory authority to promulgate regulations 
requiring sponsors of approved new animal drugs to submit reports of 
data relating to experience with those new animal drugs. This includes 
experience with extra-label uses of the drug, and other data or 
information the sponsor receives or otherwise obtains with respect to 
the drug as necessary to determine or facilitate a determination of 
whether grounds to withdraw the approval of a new animal drug exist. In 
addition, the act authorizes FDA to issue an order requiring a sponsor 
to submit such reports for those same purposes. Current FDA regulations 
at Title 21, Code of the Federal Regulations (CFR) section 514.80, 
require the sponsor to submit total quantity marketed data annually 
(semi-annually for the first 2 years post-approval) for each new animal 
drug application.

    Question 4. On July 3, FDA issued a prohibition order on extra-
label use of cephalosporin drugs. The order states that ``the 
surveillance data cited [in the order] supports the finding that 
certain cephalosporin use in animals is likely contributing to an 
increase in cephalosporin-resistant human pathogens.'' In my 
understanding, the extra-label uses of cephalosporin are not very 
different from that of labeled uses--which include different species or 
dosing times from on-label uses. Is FDA concerned about on-label uses 
as well? If so, what is FDA doing to understand risks to humans from 
all cephalosporin use?
    Answer 4. FDA believes that the approved cephalosporins are safe 
for on-label uses with respect to microbial food safety. Human food 
safety concerns associated with the approved uses of cephalosporins in 
food-producing animals were evaluated as part of the new animal drug 
approval process. In contrast, we do not have safety information 
relative to extra-label uses. Given the trends of increasing resistance 
cited in the July 3 order, FDA determined that steps were needed to 
help curtail further escalation of cephalosporin resistance. As 
discussed in the July 3 order of prohibition, FDA believes there is 
sufficient evidence to support the conclusion that the extra-label use 
of these drugs is contributing to resistance emergence and thus 
presents a risk to public health. Based on a number of requests to 
extend the comment period and effective date received since publication 
of the July 3 order, FDA has extended the comment period until November 
1, 2008, and has delayed the effective date until November 30, 2008. 
Although FDA does not have specific concerns about the approved on-
label uses of cephalosporins at this time, FDA is continuing to monitor 
resistance trends through the National Antimicrobial Resistance 
Monitoring System.

    Question 5. As you are aware, recent studies have shown an 
association between community-acquired strains of MRSA and colonization 
in swine and farmers in the Netherlands, Canada, and now in the United 
States. What steps will the FDA take to determine the prevalence of 
MRSA on U.S. farms, in farm workers, and in the community at large?
    Answer 5. Methicillin-resistant S. aureus (MRSA) was first reported 
in 1961, soon after the antimicrobial methicillin was introduced into 
human medicine to treat penicillin-resistant staphylococci. MRSA has 
since emerged as an important human pathogen world wide, with some 
epidemic strains spreading between hospitals, countries and more 
recently in people who have not been hospitalized (community acquired 
MRSA or CA-MRSA). More recently, there is concern in the veterinary 
medicine and food safety arenas with regards to MRSA as a possible 
zoonosis (i.e., a disease that may be transmitted from animals to 
humans), in particular those strains belonging to clonal lineage ST398. 
FDA scientists have been following the emergence of MRSA clonal lineage 
ST398 from humans and animals in Central Europe and Canada and are 
monitoring the situation very closely.
    MRSA infections in domestic animals have been reported among 
horses, pigs, cattle, sheep, cats, dogs and rabbits as well as being 
reported as an emerging problem in veterinary teaching facilities. Pig-
to-farmer transmission of MRSA ST398 has been documented in the 
Netherlands and a high prevalence of ST398 was also found in 
slaughtered pigs in Denmark, and in humans, horses, dogs and pigs in 
Austria and Germany. Researchers from the University, of Iowa recently 
presented data at the 2008 International Conference on Emerging 
Infectious Diseases which indicated that MRSA was present among several 
swine farms in Iowa. This data has yet to be published in a peer 
reviewed scientific journal, however, a recent study from Canada 
reported on the prevalence of MRSA colonization in pigs and people that 
work with pigs on South-western Ontario pig farms.\1\ Both human-to-
animal and animal-to-human transmission of MRSA are known to be 
possible; however, it has not yet been adequately determined whether 
animals are an important primary source of MRSA infections for 
populations other than high-risk exposure groups (e.g. swine farmers 
and veterinarians), or if MRSA is colonized in animals after contact 
with human carriers.
---------------------------------------------------------------------------
    \1\ Khanna, T., et al. 2007. Methicillin-resistant Staphylococcus 
aureus colonization in pigs and pig farmers, Veterinary Microbiology, 
doi:10.1016/j.vetmic.2007.10.006.
---------------------------------------------------------------------------
    The National Antimicrobial Resistance Monitoring System (NARMS) is 
one of the key components of FDA's Center for Veterinary Medicine (CVM) 
strategy to assess relationships between antimicrobial use in 
agriculture and subsequent human health consequences. NARMS 
surveillance and research data is valuable in identifying the source 
and magnitude of antimicrobial resistance in the food supply and is 
important for the development of public health recommendations for the 
use of antimicrobial drugs in humans and food animals. NARMS provides 
ongoing monitoring data on antimicrobial susceptibility/resistance 
patterns in select zoonotic foodborne bacteria, in particular 
Salmonella, Campylobacter, E. coli and Enterococcus. NARMS does not 
currently screen for MRSA but is currently working with partners at the 
University of Maryland to conduct a small pilot study looking for MRSA 
in retail meats in the Washington, DC metropolitan area. Overall, 700 
total samples will be tested: 300 of ground pork, 200 of ground beef, 
and 200 of ground turkey. Of the 249 retail meats tested to date, no 
MRSA have been detected. FDA is also meeting with FoodNet partners to 
explore the possibility of expanding MRSA testing to a larger 
collection of retail meats obtained through the NARMS retail program.

    It has come to my attention that the fuel ethanol industry uses 
human therapeutic antibiotics during the fermentation process. I have 
been informed that FDA has found residues of these antibiotics in 
``distiller's grains,'' a bioproduct of fuel ethanol production which 
is sold as animal feed throughout the United States.
    Question 6a. FDA issued a letter in 1993 approving the use of 
virginiamycin in alcohol fermentations at an amount no greater than 6 
parts per million with residuals in the distiller's grains at a level 
no greater than 0.5 parts per million. What are the levels of 
virginiamycin or other antibiotics found at fuel ethanol plants and in 
grain?
    Answer 6a. FDA has been proactive in issuing field assignments to 
collect distillers' grain samples and test for the presence of 
antibiotics; however, FDA will not have data on antibiotic residue 
levels in distillers' grains until the ongoing assay method validation 
is completed.
    Question 6b. Has FDA taken action to prevent contamination of 
distiller's grains with antibiotic residues?
    Answer 6b. The Agency has been very proactive in working with and 
educating the ethanol industry about animal feed requirements. To that 
end, during 2007/2008 FDA spoke at several industry meetings including 
the Renewable Fuel Association's National Ethanol Conference, the 
International Fuel Ethanol Workshop and the Association of American 
Feed Control Officials (AAFCO) BioFuel Symposium. Additionally, FDA is 
a member of several distillers' grain's taskforces including the 
National Grain and Feed Association (NGFA) and AAFCO as well as a 
member of the Department of Energy's (DOE) interagency working group on 
biochemical conversion platform.
    Recently, FDA has worked with the Environmental Protection Agency 
to make clear FDA's regulatory authority over the use of these 
antimicrobials during ethanol production when the distillers' grains 
are used as an animal feed ingredient.
    FDA has been in contact with individual firms to advise them that 
food additive petitions are needed for antibiotics used in ethanol 
production when the distillers grains are used as a livestock feed.
    Question 6c. What are the implications of unregulated antibiotic 
use in fuel ethanol production for animal and human health? Could these 
unknown doses of antibiotics be confounding research on human safety 
aspects of antibiotic use in animals?
    Answer 6c. The use of antibiotics in fuel ethanol production is 
being regulated under the provisions of the FD&C Act as food additives. 
The animal and human health implications of antibiotic residues 
resulting from such use will be addressed in food additive petitions to 
the Agency. As ethanol production increases so does the amount of 
distillers' grain available as an animal feed ingredient. In order to 
use these supplies, distillers' grains are now expanding from the 
cattle market to the swine, poultry, fish, etc. markets. Additionally, 
the use rate of distillers' grains in animal diets has increased. At 
one time, an animal's ration incorporated approximately 10 percent 
distillers' grain. Currently, academic and industrial research is 
supporting levels as high as 50 percent. At this time, FDA has 
requested firms to address the impact of the higher use levels on 
potential exposure antibiotic residues.
                       questions of senator brown
    Question 1. FDA appoints a co-chair on the Interagency Task Force 
on Antimicrobial Resistance. Please describe the leadership chain and 
how the many participating agencies and the individuals representing 
them are held accountable for implementation of Action Items in their 
jurisdiction.
    Answer 1. Each agency develops and internally approves the work 
products resulting from the Public Health Action Plan to Combat 
Antibiotic Resistance. If more than one agency works on a project, 
simultaneous clearance takes place within each of the agencies. FDA 
established the Antimicrobial Resistance Steering Committee, chaired by 
Dr. Tollefson, to coordinate FDA's activities and track action items. 
FDA centers and the Office of the Commissioner are represented on the 
steering committee. Greater than 90 percent of the action items 
represent work that is core to the mission of each of the agencies.

    Question 2. Nearly 8 years ago, the Interagency Task Force put out 
an Action Plan identifying thirteen (out of 84) elements as ``top 
priority,'' critically necessary to address growing resistance. Shortly 
after, I introduced legislation to authorize such sums as necessary to 
implement these 13 top priority items. The bill didn't pass. How are 
these action items currently funded? According to HHS, in 2006, CDC 
spent $16.2 million; FDA $24 million; and NIH $220 million. In your 
professional judgment, please tell me what funding is necessary for 
each of your agencies to implement the Action Plan--especially the top 
priority action items. In addition, what funding is necessary for NIH?
    Answer 2. Work on the action items, both top priority action items 
and others, are funded through the respective agencies' appropriations.

    Question 3. In the late 1990s, the Office of Technology Assessment 
(OTA), the Institutes of Medicine (IOM) and the GAO issued reports to 
Congress on the growing problem of antimicrobial resistance. The 
reports focused on a number of shortcomings of our Federal response to 
antimicrobial resistance. Specifically, it cited the need for 
antibiotic development, enhanced surveillance and data collection.
    Answer 3. The Task Force is aware of these reports on the threat of 
antimicrobial resistance and took each of them into consideration when 
drafting the original Public Health Action Plan to Combat Antimicrobial 
Resistance (Action Plan). The reports were also very influential in 
selecting the four focus areas of the Action Plan: Surveillance, 
Prevention and Control, Research, and Product Development.

    Question 4. Please discuss current data collection related to or 
specifically addressing antimicrobial resistance in this country and in 
other countries--how does the U.S. data effort compare to others, 
especially European countries? Are we doing a better job than our 
European counterparts collecting such data?
    Answer 4. There are several data collection, or surveillance and 
monitoring, efforts in the United States focused on hospital 
infections, community acquired infections, and agriculture or food- 
producing animal-related enteric infections. The National Antimicrobial 
Resistance Monitoring System (NARMS), for example, was modeled after 
the Danish system for monitoring antimicrobial resistance, called 
DANMAP. NARMS monitors antimicrobial resistance in isolates of enteric 
bacteria from ill humans, healthy animals presented for slaughter, and 
retail meat. Several other European countries, as well as Canada, 
Australia and New Zealand, collect information on antimicrobial 
resistance. We work very closely with these countries to harmonize as 
much as possible the methods used to isolate and test the bacteria and 
the reporting of the data.

    Question 5. It's my understanding that FDA currently collects human 
and animal drug distribution data, including for antibiotics. My bill, 
the STAAR Act, would change the date this information is submitted to 
FDA--from anniversary of product approval to a calendar year and in a 
format that allows comparison of data. Also, the bill requires the 
Federal Government to explore opportunities to obtain data from private 
vendors. It is my understanding that other countries purchase data to 
be used in research. What does FDA do with the data currently 
collected? Do you have recommendations regarding ways to improve this 
data collection? Is the data shared with the Interagency Task Force? 
Does it help us understand the relationship between use and resistance? 
Are summaries of this information available for research purposes?
    Answer 5. With regard to the data for human drugs, there are two 
routes through which we have access to these data. First, all holders 
of approved new drug applications (NDAs) are required to include 
distribution data in the annual reports to their NDAs. They are 
required to include quantities of product distributed for both domestic 
and foreign use. These submissions are not shared with parties outside 
FDA without permission from the NDA holder. We use these data as the 
need arises, but do not generally use it to help us understand the 
relationship between use and resistance.
    Secondly, FDA has access to drug distribution data through a number 
of commercial external vendors:

    Outpatient Drug Use--(1) Vendor: Verispan, Database: Vector One 
(contains prescription-level and patient-level data); (2) Vendor: 
Verispan, Database: Physician Drug and Diagnosis Audit (contains 
physician survey data); (3) Vendor: IMS Health, Database: IMS National 
Sales Perspectives, Retail and Non-Retail
    Inpatient Drug Use--Vendor: Premier, Database: RxMarket Advisor

    These databases have proven to be useful in assessing safety 
signals with marketed drugs. They can be used to determine the number 
of prescriptions dispensed as well as the number of patients exposed to 
a particular drug. They can also be used to determine prescribing 
habits, such as which physician specialty prescribes the drug most and 
for what diagnoses, and to determine patient demographics such as age 
and gender. Sales data are used to determine estimated usage of a 
particular product by patients in the United States. They can also be 
used to determine market share in cases of withdrawal or drug shortage. 
Finally, these databases can be used for pharmacoeconomic analyses as 
well as to assess the impact of labeling changes and to monitor changes 
in usage over time for a particular drug.
    Reports from these databases cannot be shared outside FDA (even 
with other agencies within HHS) without permission from the vendor. It 
is rare that information from these databases is made available to the 
public by FDA, and when it is, it is only done so with permission from 
the vendor, and it is presented at a high level (i.e., no detailed 
data).
    FDA's Center for Drug Evaluation and Research has generally not 
used drug distribution data for research regarding antimicrobial 
resistance, and due to the confidential nature of the data, we have not 
made this information available for research outside the Agency.

    Question 6. As I mentioned at the hearing, when I was in the House, 
I made sure language was Included in the fiscal year 2001 Appropriation 
bill requesting that FDA review the safety of non-therapeutic use of 
antibiotics on farms. In 2004, letters were sent from FDA to 
manufacturers of penicillin and other drugs requesting more information 
because the FDA reassessed their safety and found that the use of these 
drugs for growth promotion, feed efficiency, and weight gain posed a 
high risk of producing resistant organisms and potential harm to human 
health. At the hearing, you said that some companies responded to that 
request and that some didn't and that the research is ongoing. Can you 
outline for me specifically what kind of research is ongoing and for 
those companies that did not send you that information, what is being 
done to get that information? Also, please give me a specific date for 
when this assessment will be completed.
    Answer 6. FDA has completed its review of the approved new animal 
drug applications for the use of penicillin in animal feed. FDA 
reviewed all information contained in the administrative files, looking 
specifically for microbial food safety information that can be used to 
assess any potential human health risks. Additionally, FDA searched and 
reviewed scientific literature for microbial food safety information 
for penicillin-containing products. FDA review scientists applied the 
basic tenets of the qualitative risk assessment process described in 
GFI #152 to perform this assessment. A similar review process is being 
applied to other ``older'' approved antimicrobial products (e.g., 
tetracyclines). At this time, we do not have a projected date for a 
report of our review. FDA continues to have safety concerns regarding 
the non-therapeutic use of antimicrobial drugs in food-producing 
animals and is committed to pursuing the appropriate action to address 
those concerns.

    Question 7. The public health community has been concerned about 
the resistance implications of veterinary drugs for decades now. I 
understand that certain classes of antibiotics pose more of a 
resistance threat than others. Which classes of antibiotics approved 
for use in animal agriculture have been reviewed in the last 10 years 
for their impacts on the development of antibiotic resistant disease? 
What is the status of those reviews? Have any drugs or drug classes 
been taken off the market as the result of the reviews?
    Answer 7. FDA is most concerned about those antimicrobial new 
animal drugs or classes of drugs that are approved for use in food-
producing animals and are also important human medical therapies. In 
the past 10 years, FDA has conducted antimicrobial resistance-related 
reviews on a number of approved antimicrobial new animal drugs or 
classes of drugs including fluoroquinolones, streptogramins, 
penicillins, tetracyclines, and cephalosporins.
    FDA's review of data regarding resistance to the fluoroquinolone 
and glycopeptides classes of drugs led the Agency to issue an order in 
May 1997 prohibiting the extra-label use of those classes of drugs in 
food-producing animals. FDA subsequently conducted an assessment of two 
specific fluoroquinolone drugs, enrofloxacin and sarafloxacin, approved 
for use in poultry. Based on concerns raised by this assessment, 
sarafloxacin was voluntarily withdrawn by the pharmaceutical sponsor. 
FDA issued a notice of opportunity for a hearing in October 2000 
proposing to withdraw the approved application for enrofloxacin for use 
in chickens and turkeys. The final decision to withdraw the approval 
was issued in August 2005 following completion of the statutorily 
defined due process procedures.
    In November 2004, FDA completed a draft risk assessment on the 
potential impact that food-animal use of streptogramin antimicrobial 
drugs on the resistance to chemically similar streptogramins used to 
treat human enterococcal infections. CVM conducted a thorough review 
and analysis of all public comments submitted on the draft risk 
assessment and concluded that a number of significant data gaps existed 
that prevented finalization of the assessment. Therefore, CVM decided 
to continue to monitor the scientific literature, the results of 
surveillance studies, the usage patterns of streptogramin drugs in 
hospital and health care settings, and other relevant data that may 
affect the findings of the risk assessment.CVM will revisit the risk 
assessment at a time dictated by the availability of new data and 
scientific developments in streptogramin resistance.
    On July 3, 2008, FDA issued an order prohibiting the extra-label 
use of cephalosporin antimicrobial drugs in food-producing animals. We 
issued this order based on evidence that extra-label use of these drugs 
in food-producing animals will likely cause an adverse event in humans 
and, as such, presents a risk to the public health.
    The Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA) 
amended the FD&C Act to permit licensed veterinarians to prescribe 
extra-label uses of approved animal and human drugs in animals. AMDUCA 
also provided that FDA may issue a prohibition order if it determined 
that extra-label use of a drug in animals presents a risk to the public 
health. As explained in the July 3, 2008, final rule, CVM made the 
decision to prohibit the extra-label use of cephalosporins in food-
producing animals based on information supporting the conclusion that 
such uses are likely contributing to the emergence of cephalosporin-
resistant zoonotic foodborne pathogens. Based on a number of requests 
to extend the comment period and effective date received since 
publication of the July 3 order, FDA has extended the comment period 
until November 1, 2008, and has delayed the effective date until 
November 30, 2008.
    As discussed in the response to Question 6, FDA has completed its 
review of the approved new animal drug applications for the use of 
penicillin in animal feed. In addition, similar reviews are being 
conducted on other ``older'' approved antimicrobial products (e.g., 
tetracyclines).

    Question 8. The Center for Veterinary Medicine (CVM) has a 3 
million line item in its budget to reexamine the resistance 
implications of already approved antibiotics. What specific activities 
at CVM have been supported by that budget line item? Has the CVM 
initiated action to take any drugs off the market as a result of those 
reviews?
    Answer 8. The review of already approved antibiotics is important 
to FDA and these resources have been devoted toward this effort. FDA 
has developed a broad-based approach utilizing a strategic framework in 
place, the interagency Public Health Action Plan to Combat 
Antimicrobial Resistance, tracking resistance patterns through NARMS 
and participating in international activities. The analysis of 
previously approved applications not only includes the activities just 
mentioned but also the review of relevant published literature, 
interactions with scientists in the field, and input from the public. 
Including all these facets in our review provides the best possible 
process for obtaining the scientific information necessary to ensure 
safe antimicrobial new animal drugs are on the market. Please see 
response to Question 7 for a description of actions initiated by CVM as 
a result of reviews conducted on already approved antibiotic products.

    Question 9. FDA currently requires that holders of approved new 
animal drug applications report quantities of drugs distributed on an 
annual basis. Do the current reporting requirements for drug 
distribution data meet the current needs of FDA to adequately track, 
evaluate and control the development of antimicrobial resistance 
related to veterinary drug use? If not, what additional data are needed 
and how, could the reporting requirements be modified to meet the FDA's 
needs?
    Answer 9. FDA receives limited information on the total quantity of 
animal drug products sold as part of Drug Experience Reports (DERs) 
that are required to be submitted annually for new animal drug 
applications. More detailed information relative to the quantity of 
antimicrobial drugs sold that more closely correlates with actual 
amounts used in particular animal species would be helpful in 
conjunction with surveillance data for tracking trends in antimicrobial 
resistance development. Estimates of antimicrobial drug usage in 
animals is difficult data to collect because many drugs are approved 
and labeled for use in multiple species for a variety of purposes. 
Additionally, many drugs come in multi-dose vials and thus while we 
might know how much drug was sold it is difficult to associate this 
amount of drug with the specific number of animals in which it was 
actually used.
    Antimicrobial drug usage data is important for investigating 
potential causes of emerging trends in antimicrobial resistance 
associated with use in animals. Such data enables our epidemiologists 
to make associations between use patterns and emerging trends.

    Question 10. Does the FDA currently have the authority to collect 
the antimicrobial drug use data needed to manage the risk of 
antimicrobial resistance?
    Answer 10. FDA has the statutory authority to promulgate 
regulations requiring sponsors of approved new animal drugs to submit 
reports of data relating to experience with those new animal drugs. 
This includes experience with extra-label uses of the drug, and other 
data or information the sponsor receives or otherwise obtains with 
respect to the drug as necessary to determine or facilitate a 
determination of whether grounds to withdraw the approval of a new 
animal drug exist. In addition, the Act authorizes FDA to issue an 
order requiring a sponsor to submit such reports for those same 
purposes. Current FDA regulations at 21 CFR Sec. 514.80 require the 
sponsor to submit total quantity marketed data annually (semi-annually 
for the first 2 years post-approval) for each new animal drug 
application.
                       questions of senator burr
    Question 1. How does the FDA approve an antibiotic for use in food 
animals? Many people believe the FDA does not consider the impact on 
human health, but 1 know that is completely incorrect.
    Answer 1. FDA approves antimicrobial new animal drugs only after a 
thorough scientific review permits the Agency to conclude that the drug 
is safe and effective. For antimicrobial drugs intended for use in 
food-producing animals, this includes a determination that food derived 
from treated animals is safe for humans.
    Antimicrobial drugs are evaluated for their effectiveness in the 
animal for their intended uses. These studies provide substantial 
evidence of the drug's effectiveness. Effectiveness studies are 
generally conducted at different locations to account for variability 
among animals and geography throughout the United States. Further, 
experimental studies are conducted to determine the safety of the 
animal drug to the animal. The animal drug is evaluated through an 
environmental assessment under the provisions of the National 
Environmental Policy Act.
    With respect to human health, the safety of the animal drug is 
assessed in traditional, nonclinical toxicology studies that address 
both its acute and chronic health effects, leading to the establishment 
of acceptable drug residue levels in animal-derived food products. 
Additionally, microbial food safety (antimicrobial resistance 
development) and effects of antibiotic residues on human intestinal 
bacteria are carefully evaluated through a process that relies on risk 
assessment and/or experimental data.
    FDA communicates its findings at the time of approval: (1) through 
publication in the Federal Register as a final rule (with subsequent 
codification in the CFRs); (2) through a Freedom of Information Summary 
readily available to the public, describing the information FDA 
considered in making its decision; and (3) through the labeling, 
providing important information and direction about the safe and 
effective use of the drug to the user.

    Question 2. Does FDA have a position on the legislation introduced 
by Mr. Brown and Mr. Hatch? Would this legislation make the current 
interagency task force more effective or less effective?
    Answer 2. The administration has not taken a position on the 
legislation.

    Question 3. The Brown-Hatch legislation calls for FDA to consult 
with other Federal agencies before acting upon an antibiotic 
submission. Does FDA currently consult with other Federal agencies or 
outside bodies when reviewing an antibiotic drug?
    Answer 3. FDA often consults with external advisory committees for 
advice related to the review of applications for antibacterial drugs. 
We now bring most NDAs for antibacterial new molecular entities before 
FDA's Anti-Infective Drugs Advisory Committee (Advisory Committee) as 
well as other applications that present unusual or difficult issues. In 
addition to asking this Advisory Committee for advice on specific new 
drug applications, we also bring more general issues to the Advisory 
Committee for discussion. These general issues have included 
antimicrobial resistance and clinical development of drugs for specific 
indications such as community acquired pneumonia.
    FDA's advisory committees are generally the means by which FDA gets 
external advice on drug applications. We generally do not consult with 
other Federal agencies on individual drug approvals; however, we 
sometimes include individuals from other Federal agencies on our 
advisory committee panels.
    In addition to public Advisory Committee meetings, we have 
discussed antibacterial development issues in other public meetings. We 
have cohosted workshops on topics such as drug development issues that 
relate to antibacterial resistance and the development of drugs for the 
treatment of community acquired pneumonia. We also recently convened a 
public hearing in which we solicited feedback from the public regarding 
the use of the provisions of the Orphan Drug Act for the development of 
drugs for serious and life threatening infectious diseases, such as 
diseases due to gram-negative bacteria and other diseases due to 
antimicrobial-resistant bacteria.
    Thank you again for the opportunity to testify. Please let us know 
if you have any further questions or concerns.
                                          Stephen R. Mason,
                     Acting Assistant Commissioner for Legislation.
                                 ______
                                 
 Response to Questions of Senator Kennedy, Senator Brown, and Senator 
                    Burr by Patrick J. Brennan, M.D.
                      question of senator kennedy
    Question. In your testimony, you cited several practices that can 
reduce or eliminate many routes of infection in a hospital environment. 
Would Federal regulations or a mandate of certain guidelines be 
beneficial to hospitals in helping them reduce infection rates, or does 
the unique environment of each hospital prevent standardized guidelines 
from being effective across the Nation?
    Answer. Many guidelines, particularly those from CDC and its 
Healthcare Infection Control Practices Advisory Committee (HICPAC), are 
already widely utilized in healthcare settings throughout the United 
States. Additional guidelines from other professional organizations 
such as The Society for Healthcare Epidemiology of America (SHEA) are 
also integrated into current practices. An additional layer of 
regulatory responsibility for infection control practices is imposed by 
other Federal agencies such as OSHA and, increasingly, by CMS.
    What is uniquely valuable in CDC/HICPAC guidelines is the emphasis 
on rigorous and ongoing evaluation of both infection control practices 
and infectious disease outcomes by each institution. This approach 
facilitates each healthcare facility's ability to direct its response 
to its local infection problems and allows for selection of appropriate 
interventions from among the practices recommended in each guideline. 
To the extent that new Federal legislation would promote the use of 
guidelines in this way, especially if it were to direct much needed 
resources to infection prevention and control programs at the local 
(both State and institutional) level, such legislation might be useful. 
However, new legislative mandates that focus only on reporting without 
providing appropriate resources and flexibility for adaptation to local 
needs and priorities, could have unintended and deleterious 
consequences by diverting resources away from critical infection 
prevention and control efforts based on locally determined needs.
                       question of senator brown
    Question. The IOM report from 1998 reported that the ``most 
critical issues concern the expansion, coordination, and improvement of 
the diverse elements of surveillance.'' The report went on to say that 
investments in research can make a difference. Your organization has 
endorsed the STAAR Act. As State epidemiologists, would you explain how 
you think the provision on Clinical Research & Public Health Network 
will compliment the current surveillance activities and discuss the 
importance of isolate collection? In short, will these proposed 
activities better prepare physicians to be on the look out for emerging 
resistance issues and help contain them before they spread to other 
States?
    Answer. The majority of SHEA members work in both academic and 
voluntary private and public hospitals, although we collaborate closely 
with our colleagues in public health epidemiology at the State and 
local level. Although the CDC and some State health departments have 
already established sentinel monitoring systems for antimicrobial 
resistance, there are geographical and infrastructure gaps that prevent 
a true nationwide network that is nimble and consistent. We concur with 
our colleagues in the Infectious Diseases Society of America (IDSA) 
that additional resources need to be directed to surveillance of 
antimicrobial resistance. The Clinical Research & Public Health Network 
provision in the STAAR Act would anchor its 10 network sites in 
existing centers but focus on overcoming the geographical, 
technological and infrastructure gaps that currently exist. As the 
details of the Network are clarified it is important to emphasize that 
such a network not be duplicative or replace existing activities 
managed by the CDC.
    We note that this surveillance effort needs to be at both a 
national and a global level. Numerous antibiotic-resistant pathogens 
have first appeared outside the United States and subsequently been 
introduced into the U.S. healthcare system. CDC's Morbidity and 
Mortality Reports (MMWR) have been the primary information source for 
physicians about the importation of such pathogens. Other outbreaks 
appear to start locally and may be spread from one healthcare facility 
to another by shared patients and/or healthcare workers. Hence, 
surveillance and expedited sharing of information needs to be supported 
at the international, national, State, and local level. To encourage 
frank reporting and sharing of data which may be perceived as adversely 
affecting a facility's reputation or engendering liability, local, 
State and Federal laws should protect the confidential sharing of such 
information through public health agencies at all levels of government.
                       questions of senator burr
    Question 1. In your testimony, you emphasized the importance of 
accurate measurement of hospital acquired infections and the impact of 
preventive strategies. I agree that data collection and transparency 
can spur progress. How well are we doing at that? Is there a need for 
more guidance?
    Answer 1. Accurate measurement of healthcare associated infections 
is the most important tool available for identifying what problems 
exist (and therefore where to focus improvement work) and for measuring 
improvement over time. This type of measurement is most useful to 
individual institutions working on reducing healthcare associated 
infections, but shared information can be useful on a statewide or 
regional or even national level to understand trends over time, which 
can inform resource allocation decisionmaking and our understanding of 
how preventive strategies are most effectively deployed. Many hospitals 
have used this type of measurement to identify problems with central 
line associated bloodstream infections, ventilator-associated 
pneumonias, and other healthcare associated infections, and to measure 
the success of their interventions. Ultimately, development of 
measurement strategies that extend beyond acute care facilities to 
allow measurement of healthcare-associated infections associated with 
other types of healthcare will enhance our ability to address local 
needs.
    Use of data collected through surveillance programs being used to 
develop internal infection prevention strategies for public reporting 
has become more common in recent years. The impact of using the data in 
this way is less direct, but may have helped in standardizing some data 
collections methods, and to identify regional problems. Although the 
experience is still early, a number of model programs developed by 
States have improved both transparency and accuracy of data regarding 
healthcare associated infections. Importantly, in contrast to several 
years ago, most infection control programs have come to welcome the 
advent of public reporting when instituted with appropriate selection 
of indicators, training, and scale-up. Programs that were ill-conceived 
or over-reaching in their requirements have been abandoned and replaced 
by programs that are more carefully structured in their requirements. 
Model programs already established in several States provide useful 
examples for other States and the Federal Government in developing new 
programs. There is national momentum towards transparency in this area 
that we expect to continue. More than 40 States have considered 
legislation regarding public reporting and 17 have adopted NHSN as a 
mandatory reporting tool. We expect more States to move in this 
direction without further Federal guidance. Our society in 
collaboration with other stakeholders have provided templates for model 
programs of public reporting as well as a toolkit for implementation of 
such programs (accessible at the following links): http://www.shea-
online.org/Assets/files/Essentials_of_Public_
Reporting_Tool_Kit.pdf; http://www.shea-online.org/Assets/files/
Model_Legislation
_-APIC_IDSA_SHEA.pdf.

    Question 2. How do hospitals and other health care providers 
currently decide which organisms to monitor for antimicrobial 
resistance and how do they participate in the surveillance of organisms 
of concern?
    Answer 2. As noted previously, current CDC/HICPAC guidelines 
provide a template for assessment of current antimicrobial resistance 
problems by each institution. Working collaboratively with local 
microbiology and pharmacy professionals, infection control programs 
monitor trends in both resistance and antibiotic utilization in their 
healthcare facility. Using information gained from initial and ongoing 
assessment, programs develop local priorities, design programs, and 
allocate resources so that they most effectively target resistant 
organisms that represent the greatest local threats. Control of 
antimicrobial resistance in any institution rests on this pillar of 
ongoing surveillance and is achieved by a combination of infection 
prevention strategies such as hand hygiene, patient isolation and the 
careful management of medical devices, and, increasingly, through 
programs that enhance antimicrobial stewardship.
    SHEA and IDSA jointly published a paper (attached) addressing 
antimicrobial stewardship in 2008 which offers further insight to our 
society's perspectives on this issue.

    Question 3. When we talk about antimicrobial resistance, are we 
capturing antiviral resistance? If not, do you see this as a separate 
policy issue that should be dealt with differently?
    Answer 3. Although most hospital-based laboratories and clinical 
reference laboratories perform antibiotic resistance testing, viral 
resistance testing is a more specialized procedure usually confined to 
academic or research laboratories. For many viruses, there are no 
specific antiviral therapies, so antiviral resistance is, in general, a 
much less common problem than antibacterial resistance. From the public 
health viewpoint, the viral pathogens of major interest in terms of 
resistance are the influenza viruses and HIV. CDC collaborates with the 
World Health Organization (WHO) to monitor influenza virus resistance 
on an ongoing basis and disseminate this information to physicians and 
public health officials. In addition, CDC and a number of research 
laboratories monitor trends in HIV resistance on a global and national 
level. Importantly, HIV resistance testing through genotyping and 
phenotyping is widely available through commercial laboratories in the 
United States and is an accepted standard of practice when initiating 
or changing therapies for patients with HIV disease.

    Question 4. In our world of limited resources, tell us where you 
think we could get the biggest ``bang for our buck'' in addressing 
antimicrobial resistance. Should we be focusing more on developing new 
antimicrobial drugs and vaccines? Or on educating health care providers 
and institutions on how best to use the ones we have?
    Answer 4. It is critically important that we pursue both drug 
development and education and dissemination of evidence-based practices 
to address antimicrobial resistance. Innovative ways to ensure that 
currently available antimicrobial agents are used carefully and 
appropriately (i.e., stewardship) are needed to maximize their 
effectiveness for as long as possible. In addition, we must face the 
reality that microbes will continue to develop resistance to the drugs 
to which they are exposed. The rapid rate of microbial evolution 
ensures that, as antimicrobial agents are used, resistance will emerge. 
Pathways for the development of antimicrobial resistance have even been 
found in primitive societies where antibiotics have never been used. At 
the same time, there is evidence that inappropriate use of 
antimicrobial agents (due to inappropriate patient demand, efforts to 
promote animal growth, or simply courses of antibiotics that are too 
long, too broad, or not effective) can increase the speed at which such 
resistance emerges. It's important to recognize that even appropriate 
use of antimicrobial agents increases the development of resistance, by 
allowing the growth of resistant organisms.
    To some extent, we are reaping the fruits of our own success in 
treating previously fatal infectious diseases. But ironically, it is 
often the same patients--often with chronic diseases, or suppressed 
immune systems, who survive infection with antimicrobial susceptible 
organisms, which are ultimately most vulnerable to antimicrobial 
resistant pathogens. While clinician and patient education on the 
challenges of antimicrobial resistance and guidance on the most 
appropriate use of currently available agents are clearly important, 
there is an urgent need for new antimicrobial agents to address the 
certain continued evolution of antimicrobial resistance.
                                 ______
                                 
The Society for Healthcare Epidemiology of America 
                                            (SHEA),
                                          Roslyn, VA 22209.

    Dear Chairman Waxman: The Society for Healthcare Epidemiology of 
America (SHEA) is pleased to respond to your request for information on 
estimates of the number of reasonably preventable deaths and cases of 
health care-associated infections (HAIs) in U.S. hospitals, 
particularly ventilator-associated pneumonia (VAP) and bloodstream 
infections (BSI). The enclosed report was developed for the Committee 
on Oversight and Government Reform by SHEA through the support of The 
Center for Evidence-based Practice at the University of Pennsylvania 
Health System.
    Two-thirds of the deaths from HAIs are estimated to be due to 
bloodstream infections (BSI) and ventilator-associated pneumonia (VAP). 
In 2002, there were 1.75 million estimated HAIs and 99,000 deaths 
estimated to be attributable to them. It is important to note that a 
limitation of the data is that current estimates may be lower. From 
1975 to 2002 there was a decreasing trend in HAI incidence.
    In order to arrive at our estimates we used the range of HAI 
reductions in U.S. studies of quality interventions to prevent these 
occurrences multiplied by the 2002 estimate of HAIs and resulting 
deaths. The estimates are as follows:

     Bloodstream infections: 18 percent-82 percent of 
infections preventable, 5,520-25,145 preventable deaths per year;
     Ventilator-associated pneumonia: 46 percent-55 percent of 
infections preventable, 16,545-19,782 preventable deaths per year;
     Urinary tract infections: 17 percent-69 percent of 
infections preventable, 2,225-9,031 preventable deaths per year; and
     Surgical site infections: 28 percent-54 percent of 
infections preventable, 2,297-4,431 preventable deaths per year.

    There is considerable uncertainty in these figures because of the 
numerous assumptions used in their development. Policy decisions should 
take into account the sources of uncertainty which are more fully 
addressed in the attached report. Thank you for the opportunity to 
respond to the Committee on Oversight and Government Reform.
            Sincerely yours,
                                  Patrick J. Brennan, M.D.,
                                                         President.
                                 ______
                                 
GUIDELINES--Infectious Diseases Society of America and the Society for 
   Healthcare Epidemiology of America.--Guidelines for Developing an 
    Institutional Program to Enhance Antimicrobial Stewardship, see 
  www.premierinc.com/safety/topics/guidelines/downloads/CID-Guideline-
                     Antibiotic-Stewardship_b.pdf.
                                 ______
                                 
            PENN CENTER FOR EVIDENCE-BASED PRACTICE ADVISORY
   Mortality From Reasonably-Preventable Hospital-Acquired Infections

   (Craig A. Umscheid, MD, MSCE; Matthew D. Mitchell, PhD; Rajender 
Agarwal, MD, MPH; Kendal Williams, MD, MPH, and Patrick J. Brennan, MD, 
        for the Society for Healthcare Epidemiology of America)*
---------------------------------------------------------------------------

    * Author affiliations: Center for Evidence Based Practice (CAU, 
MDM, RA, KW) and the Office of the Chief Medical Officer (PJB), 
University of Pennsylvania Health System, Philadelphia PA.
---------------------------------------------------------------------------
                                Summary
     Survey data from the National Nosocomial Infections 
Surveillance (NNIS) system, National Hospital Discharge Summary, and 
American Hospital Association report the incidence of hospital-acquired 
infections (HAIs) and the mortality resulting from them.

          In 2002, there were 1.74 million HAIs and 99,000 
        attributable deaths.
          Two-thirds of those deaths are the result of 
        bloodstream infections and ventilator-associated pneumonia.
          There was a decreasing trend in HAI incidence from 
        1975 to 2002.

     An Agency for Healthcare Research and Quality (AHRQ) 
report published in 2007 surveyed the evidence on various interventions 
to reduce HAIs.

          The AHRQ reviewers found that the quality of evidence 
        was low, and that there was little consistency in patient 
        populations and interventions examined. Therefore, they did not 
        combine the results of the studies into a single numeric result 
        estimating the ability of interventions to reduce HAIs.

     We used the 2002 estimate of HAIs and resulting deaths 
from the NNIS survey and the range of HAI reductions observed in the 
AHRQ report to calculate the number of preventable HAIs and HAI deaths 
per year:

          Bloodstream infections: 18 percent-82 percent of 
        infections preventable, 5,520-25,145 preventable deaths per 
        year;
          Ventilator-associated pneumonia: 46 percent-55 
        percent of infections preventable, 13,667-25,537 preventable 
        deaths per year;
          Urinary tract infections: 17 percent-69 percent of 
        infections preventable, 2,225-9,031 preventable deaths per 
        year; and
          Surgical site infections: 26 percent-54 percent of 
        infections preventable, 2,133-4,431 preventable deaths per 
        year.

     There is considerable uncertainty in these figures because 
of the numerous assumptions going into them. One should not base policy 
decisions on these figures without understanding the sources of 
uncertainty.
                               background
    To inform policy discussions regarding the reduction of infections 
in hospitals, the Center for Evidence-based Practice at the University 
of Pennsylvania Health System was asked to estimate the number of 
annual deaths in U.S. hospitals from reasonably-preventable cases of 
hospital-associated infections (HAIs), particularly bloodstream 
infections (BSI) and ventilator-associated pneumonia (VAP).
                                methods
    An accurate estimation of this figure requires accurate estimates 
of two underlying figures: the current total of annual deaths from HAIs 
and the proportion of these deaths that are ``reasonably preventable.'' 
Uncertainty in either of these components will necessarily lead to 
uncertainty in the final estimate.
    A best-evidence approach was used to obtain the source data for 
this calculation. To estimate the number of HAIs and resulting 
mortality, we used estimates from the National Nosocomial Infections 
Surveillance (NNIS) system, National Hospital Discharge Summary, and 
American Hospital Association as reported by Klevens and colleagues.\1\ 
To estimate the proportion of HAIs that could be prevented, we used the 
estimates of HAI risk reductions resulting from quality improvement 
strategies as reported in an Agency for Healthcare Research and Quality 
(AHRQ) Evidence-based Practice Center (EPC) report.\2\ Given the 
limited quality of the studies reviewed by the AHRQ report, we only 
used HAI risk reductions reported from U.S. studies that were graded as 
good quality by AHRQ, and that examined risk reductions in BSI, VAP, 
urinary tract infections (UTI) and surgical site infections (SSI). When 
there were fewer than three studies that met these criteria, we also 
included studies graded as moderate quality.
    Because the patient populations and interventions tested in the 
published studies of HAI prevention varied from study to study, it was 
not appropriate to combine the risk reductions into a single summary 
estimate. Thus, to calculate a range of possible risk reductions for 
each HAI, we simply used the highest and lowest infection reductions 
for each HAI as listed in the AHRQ report. We then multiplied this 
range of risk reduction for each HAI by the frequency of that HAI as 
reported by the NNIS survey to calculate a range for the number of 
preventable infections for each HAI. To estimate a range for the number 
of preventable deaths for each HAI, we multiplied the risk reduction 
for each HAI by the reported frequency of deaths for that HAI.
                        number of annual deaths
    A comprehensive estimate of annual incidence of and mortality from 
hospital-
acquired infections was reported by Klevens and colleagues of the 
Centers for Disease Control and Prevention (CDC) in 2007.\1\ (Table 1) 
This estimate was based on broad surveys of U.S. hospitals so the risk 
of uncertainty from measuring an unrepresentative sample is low. 
However, the survey data is from 2002, so changes in infection rates 
and mortality resulting from improved care practices implemented 
between 2002 and today are not captured in these figures. If care has 
improved since that time, the current number of infections and deaths 
will be lower than observed in 2002. That would continue the trend 
observed since 1975-76, when the total number of hospital-associated 
infections estimated by the CDC's SENIC project was 2.15 million.\3\ 
Infection-related deaths were not estimated in that project.
    The survey data show that BSI and VAP cause more than two-thirds of 
the deaths resulting from HAIs, and that they are five times more 
deadly than the other infections. Thus it may make sense to target 
these two types of infections first for reduction measures.

             Table 1.--Hospital-Acquired Infections in 2002
------------------------------------------------------------------------
                                     No. of      Deaths from    Percent
       Type of infection           infections     infections   of fatal
                                     (2002)         (2002)    infections
------------------------------------------------------------------------
BSI............................         248,678       30,665        12.3
VAP............................         250,205       35,967        14.4
UTI............................         561,667       13,088         2.3
SSI............................         290,485        8,205         2.8
Other..........................         386,090       11,062         2.9
                                ----------------------------------------
  Total........................       1,737,125       98,987         5.7
------------------------------------------------------------------------
Data from Klevens (1).

               proportion of deaths that are preventable
    We based our estimates of the preventability of infection-related 
deaths on the evidence tables of the AHRQ EPC report.\2\ An earlier 
review by Harbarth and colleagues,\4\ done in much less detail, has 
similar findings.
Description of Studies Included in the AHRQ Report
    The quality of the evidence base reviewed in the AHRQ report was 
poor. For example, half of the BSI studies met none or one of the 
reviewers' three internal validity standards. The AHRQ report divided 
the before-after studies into ``good,'' ``moderate,'' and ``poor'' 
quality categories (Table 2) but did not explain how the categories 
were defined. They did not grade the quality of controlled and 
interrupted time series trials.
    The AHRQ investigators reported that there was little consistency 
among patient groups studied or among interventions tested. Therefore 
they could not perform any quantitative synthesis of the data, and they 
did not attempt to make a summary estimate of the proportion of 
infections or deaths that could be considered preventable.
    The highest quality studies in the AHRQ report examined 
interventions to reduce BSI, VAP, UTI and SSI. For prevention of other 
HAIs, the evidence bases were even weaker and any numeric conclusions 
are even more speculative.

                  Table 2.--Description of Infection Prevention Studies Examined in AHRQ Report
----------------------------------------------------------------------------------------------------------------
                                                                                   Simple before-after studies
                Infection type                     N      Controlled     Time   --------------------------------
                                                            trials      series      Good     Moderate     Poor
----------------------------------------------------------------------------------------------------------------
BSI..........................................         19           2          1          6          2          8
VAP..........................................         12           0          0          3          4          5
UTI..........................................         10           3          0          0          6          1
SSI..........................................         28           4          2          1          6         15
----------------------------------------------------------------------------------------------------------------
Not all studies in this table were used to calculate results, since they did not all report infection results.
Data from AHRQ EPC report (2).

Estimates of Preventable Deaths
    Our estimates for the ranges of potential reductions in HAIs are 
found in the fifth column of Table 3 and the resulting estimates of 
preventable infections and deaths are found in the seventh and last 
columns of Table 3 respectively.
    There is nothing novel about trying to estimate the number of 
infections that could be prevented or lives that could be saved if 
hospitals followed best practices in infection control. The SENIC 
project made such an estimate in 1975. They considered 30 to 35 percent 
of most HAIs preventable with effective surveillance and control 
programs, and 22 percent of pneumonia cases preventable. In a 1985 
follow-up survey, they found that only a fraction of those infections 
were actually being prevented, because many hospitals still had not 
implemented recommended infection control measures.\5\ This was still 
the case in the present decade.\6\ Our estimated ranges of potential 
reductions in HAIs is in line with the estimates in Kaye's review.\7\

                                                Table 3.--Estimates of Preventable Infections and Deaths
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                      Reduction
                                                                          in
                                                            Case      infection   Projected no. of                    Projected no. of
                                   No. of        No.      fatality    risk with    infections with    Estimated no.      deaths with    Estimated no. of
         Infection type            HAIs\1\    Deaths\1\   rate  [in       QI        institution of   of preventable    institution of      preventable
                                                          percent]   programs\2\    QI  programs       infections        QI programs         deaths
                                                                          [in
                                                                       percent]
--------------------------------------------------------------------------------------------------------------------------------------------------------
BSI............................     248,678      30,665        12.3        18-82    44,762-203,916    44,762-203,916      5,520-25,145      5,520-25,145
VAP............................     250,205      35,967        14.4        38-71    72,559-155,127    95,078-177,646     10,430-22,300     13,667-25,537
UTI............................     561,667      13,088         2.3        17-69   174,117-466,184    95,483-387,550      4,057-10,863       2,225-9,031
SSI............................     290,485       8,205         2.8        26-54   133,623-204,959    75,526-156,862       3,774-6,072       2,133-4,431
--------------------------------------------------------------------------------------------------------------------------------------------------------
HAI--hospital-acquired infection.
QI--quality improvement.
\1\ NNIS 2002 estimates.
\2\ Range from U.S.-based QI studies of good or moderate quality in AHRQ report.

                              limitations
    There is considerable uncertainty in our estimate of preventable 
HAI-related deaths. Uncertainty stems from both the component numbers 
and the calculation itself. Here we discuss some of those sources of 
uncertainty.
Number of Deaths Caused by HAIs
    While our estimate of the number of annual deaths caused by HAIs is 
based on a broad national survey, that survey data is more than 5 years 
old. It does not reflect improvements in infection control practice 
that hospitals have implemented since the time of the survey. The true 
number of annual HAI deaths at present may be lower. The estimate of 
HAI-related deaths is also uncertain because there is no definite way 
to attribute a death to HAI. Patient deaths frequently have multiple 
causes, and there exists a blurred line between a patient whose death 
was caused by an HAI and a patient with an HAI whose death was due to 
another cause.
Proportion of HAIs That Are Preventable
    The key uncertainty in the estimate of preventable HAIs is the 
limited quality of the HAI reduction studies. In particular, none of 
the studies are randomized, and few of the studies are controlled, so 
the validity of the risk reductions reported are limited, and may be 
exaggerated. For example, most of the studies are of a simple before-
after study design, comparing outcomes after the HAI intervention was 
implemented in a patient population with results from the same 
population during a time period prior to the HAI intervention. This 
study design cannot control for other changes in patient care that took 
place between the control period and the experimental period, making it 
difficult to attribute the results reported in the study to the study 
intervention rather than to random variation, patient selection, or 
other uncontrolled variables, like changes in staffing structures or 
the implementation of other quality/safety initiatives.
    In addition, some of the published studies date back a decade or 
more, so the infection control practices used in them may have already 
been implemented at some hospitals, making large HAI reductions less 
likely in today's hospitals. Another source of uncertainty is 
generalizing from the results of specialized study populations like the 
ICU population to more general populations like a general hospital 
ward.
Number of HAI-caused Deaths That Are Preventable
    The key uncertainty here is the fact that we are not estimating 
preventable deaths from studies that have directly measured death as an 
outcome. Instead, we are extrapolating reductions in death from the 
above estimates of reductions in HAIs, and these above estimates have 
their own limitations. In addition, in multiplying the estimated 
fraction of HAIs that are preventable by the fatality rate for a given 
HAI, we assume that the fatality rate for preventable infections is the 
same as the rate for those infections that weren't prevented. The true 
effect on deaths could be larger or smaller, depending on the extent to 
which preventive measures affect the severity of HAIs and the extent to 
which preventive measures work for the kinds of patients who are more 
susceptible to fatal HAIs.
                               References
    1. Klevens RM, Edwards JR, Richards CL Jr, Horan TC, Gaynes RP, 
Pollock DA, Cardo DM. Estimating health care-associated infections and 
deaths in U.S. hospitals, 2002. Public Health Rep. 2007 Mar-Apr; 
122(2):160-6. PMID: 17357358.
    2. Ranji SR, Shetty K, Posley KA, Lewis R, Sundaram V, Galvin CM, 
Winston LG. Prevention of Healthcare-Associated Infections. Vol 6 of: 
Shojania KG, McDonald KM, Wachter RM, Owens DK, editors. Closing the 
Quality Gap: A Critical Analysis of Quality Improvement Strategies. 
Technical Review 9 (Prepared by the Stanford University-UCSF Evidence-
based Practice Center under Contract No. 290-02-0017). AHRQ Publication 
No. 04(07)-0051-6. Rockville, MD: Agency for Healthcare Research and 
Quality. January 2007.
    3. Haley RW, Culver DH, White JW, Morgan WM, Emori TG. The 
nationwide nosocomial infection rate. A new need for vital statistics. 
Am J Epidemiol. 1985 Feb; 121(2):159-67. PMID: 4014113.
    4. Harbarth S, Sax H, Gastmeier P. The preventable proportion of 
nosocomial infections: an overview of published reports. J Hosp Infect. 
2003 Aug;54(4):258-66. PMID: 12919755.
    5. Haley RW, Culver DH, White JW, Morgan WM, Emori TG, Munn VP, 
Hooton TM. The efficacy of infection surveillance and control programs 
in preventing nosocomial infections in US hospitals. Am J Epidemiol. 
1985 Feb;121(2):182-205. PMID: 4014115.
    6. Braun BI, Kritchevsky SB, Wong ES, Solomon SL, Steele L, 
Richards CL, Simmons BP; Evaluation of Processes and Indicators in 
Infection Control Study Group. Preventing central venous catheter-
associated primary bloodstream infections: characteristics of practices 
among hospitals participating in the Evaluation of Processes and 
Indicators in Infection Control (EPIC) study. Infect Control Hosp 
Epidemiol. 2003 Dec;24(12):926-35. PMID: 14700408.
    7. Kaye KS, Engemann JJ, Fulmer EM, Clark CC, Noga EM, Sexton DJ. 
Favorable impact of an infection control network on nosocomial 
infection rates in community hospitals. Infect Control Hosp Epidemiol. 
2006 Mar; 27(3):228-32. PMID: 16532408.

                                                                     Evidence Tables
  Table 4.--BSI Prevention Studies Reviewed by AHRQ Suggest an 18 to 82 Percent Reduction in BSIs Depending on the Intervention and Population Examined
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                         Risk before       Risk after     Risk Reduction
         Author, Year            Study Design         Setting        Intervention       Comparison       intervention     intervention     [in percent]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Provonost, 2006..............  Interrupted time  ICU patients      Preventive: Hand  Previous care...  7.7 per 1,000    1.4 per 1,000    82
                                series.           (United States).  hygiene;                            catheter days.   catheter days.
                                                                    maximum sterile
                                                                    barrier;
                                                                    insertion site
                                                                    selection;
                                                                    chlorhexidine
                                                                    disinfection;
                                                                    removal of
                                                                    unnecessary
                                                                    catheters; QI:
                                                                    Clinician
                                                                    education,
                                                                    audit and
                                                                    feedback,
                                                                    clinician
                                                                    reminder,
                                                                    organizational
                                                                    change.
Higuera, 2005................  Before-after      ICU patients      Preventive: Hand  Previous care...  46.3 per 1,000   19.5 per 1,000   58
                                study.            (Mexico).         Hygiene; QI:                        catheter days.   catheter days.
                                                                    Clinician
                                                                    education,
                                                                    audit and
                                                                    feedback,
                                                                    organizational
                                                                    change.
Berenholtz, 2004.............  Controlled        ICU patients      Intervention: /   Previous care...  Intervention     Intervention 0   100
                                before-after      (United States).  Preventive:                         11.3 per 1,000   per 1,000
                                study.                              Hand hygiene,                       catheter days.   catheter days.  82
                                                                    maximum sterile                    Control 5.7 per  Control 1.6 per
                                                                    barrier,                            1,000 catheter   1,000 catheter
                                                                    insertion site                      days.            days.
                                                                    selection,
                                                                    chlorhexidine
                                                                    disinfection,
                                                                    removal of
                                                                    unnecessary
                                                                    catheters; QI:
                                                                    Clinician
                                                                    education,
                                                                    audit and
                                                                    feedback;
                                                                    Control:
                                                                    Clinician
                                                                    education only.
Coopersmith, 2004............  Before-after      ICU patients      Preventive: Hand  Previous care...  3.4 per 1,000    2.8 per 1,000    18
                                study.            (United States).  Hygiene,                            catheter days.   catheter days.
                                                                    maximum sterile
                                                                    barrier,
                                                                    insertion site
                                                                    selection; QI:
                                                                    Clinician
                                                                    education.
Warren, 2004.................  Before-after      ICU patients      Preventive: Hand  Previous care...  9.4 per 1,000    5.5 per 1,000    42
                                study.            (United States).  hygiene,                            catheter days.   catheter days.
                                                                    maximum sterile
                                                                    barrier,
                                                                    insertion site
                                                                    selection; QI:
                                                                    Clinician
                                                                    education,
                                                                    audit and
                                                                    feedback.
Warren, 2003.................  Before-after      ICU patients      Preventive:       Previous care...  4.9 per 1,000    2.1 per 1,000    57
                                study.            (United States).  Maximum sterile                     catheter days.   catheter days.
                                                                    barrier;
                                                                    insertion site
                                                                    selection; QI:
                                                                    Clinician
                                                                    education,
                                                                    audit and
                                                                    feedback.
Coopersmith, 2002............  Before-after      ICU patients      Preventive: Hand  Previous care...  10.8 per 1,000   3.7 per 1,000    66
                                study.            (United States).  hygiene; QI:                        catheter days.   catheter days.
                                                                    Clinician
                                                                    education,
                                                                    audit and
                                                                    feedback.
Eggiman, 2000................  Controlled        ICU patients      Intervention:/    Previous care...  Intervention     Intervention     -13 (increase)
                                Before-after      (Switzerland).    Preventive:                         (MICU) 11.3      3.8 per 1,000
                                study.                              Hand hygiene,                       per 1,000        catheter days.
                                                                    maximum sterile                     catheter days.  Control 11.6
                                                                    barrier,                           Control (SICU)    per 1,000
                                                                    chlorhexidine                       10.3 per 1,000   catheter days.
                                                                    disinfection,                       catheter days.
                                                                    removal of
                                                                    unnecessary
                                                                    catheters; QI:
                                                                    Clinician
                                                                    education;
                                                                    Control: No
                                                                    additional
                                                                    measures.
Sherertz, 2000...............  Before-after      ICU patients      Preventive: Hand  Previous care...  4.51 per 1,000   2.92 per 1,000   35
                                study.            (United States).  hygiene,                            catheter days.   catheter days.
                                                                    maximum sterile
                                                                    barrier; QI:
                                                                    Clinician
                                                                    education.
--------------------------------------------------------------------------------------------------------------------------------------------------------

                                                                     Evidence Tables
  Table 5.--VAP Prevention Studies Reviewed by AHRQ Suggest a 38 to 71 Percent Reduction in VAPs Depending on the Intervention and Population Examined
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                 Risk
                                                                                                             Risk before       Risk after      Reduction
         Author, Year              Study Design         Setting         Intervention       Comparison       intervention      intervention        [in
                                                                                                                                               percent]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Good quality:
  Babcock, 2004...............  Before-after       ICU patients       Preventive: Hand  Previous care...  8.75 per 1,000    4.74 per 1,000            46
                                 study.             (United States).   hygiene; HOB                        ventilator days.  ventilator days.
                                                                       >30, daily
                                                                       interruption of
                                                                       sedation; QI:
                                                                       Clinician
                                                                       education.
  Zack, 2002..................  Before-after       ICU patients       Preventive: HOB   Previous care...  12.6 per 1,000    12.6 per 1,000            55
                                 study.             (United States).   >30; QI:                            ventilator days.  ventilator days.
                                                                       Clinician
                                                                       education.
Moderate quality:
  Rosenthall, 2006............  Before-after       ICU patients       Preventive: Hand  Previous care...  51.3 per 1,000    35.5 per 1,000            31
                                 study.             (Argentina).       hygiene; QI:                        ventilator days.  ventilator days.
                                                                       Clinician
                                                                       education,
                                                                       audit &
                                                                       feedback.
  Salahuddin, 2004............  Before-after       ICU patients       Preventive: Hand  Previous care...  13.2 per 1,000    6.5 per 1,000             51
                                 study.             (Pakistan).        hygiene,                            ventilator days.  ventilator days.
                                                                       HOB>30; QI:
                                                                       Clinician
                                                                       education,
                                                                       audit &
                                                                       feedback.
  Lai, 2003...................  Before-after       ICU patients       Preventive:       Previous care...  SICU: 45.1 per    SICU: 27.9 per            38
                                 study.             (United States).   HOB>30; QI:                         1,000             1,000
                                                                       Clinician                           ventilator days.  ventilator days.         48
                                                                       education,                         MICU: 22.4 per    MICU: 11.6 per
                                                                       audit &                             1,000             1,000
                                                                       feedback.                           ventilator days.  ventilator days.
  Kelleghan, 1993.............  Before-after       Not reported       Preventive: Hand  Previous care...  17 per 1,000      5 per 1,000               71
                                 study.             (United States).   hygiene,                            ventilator days.  ventilator days.
                                                                       HOB>30; QI:
                                                                       Clinician
                                                                       education,
                                                                       audit &
                                                                       feedback.
--------------------------------------------------------------------------------------------------------------------------------------------------------

                                                                     Evidence Tables
  Table 6.--UTI Prevention Studies Reviewed by AHRQ Suggest a 17 to 69 Percent Reduction in UTIs Depending on the Intervention and Population Examined
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                 Risk
                                                                                                             Risk before       Risk after      Reduction
         Author, Year              Study Design         Setting         Intervention       Comparison       intervention      intervention        [in
                                                                                                                                               percent]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Good quality:
  Huang, 2004.................  Before-after       ICU patients       Preventive:       Previous care...  11.5 per 1,000    8.3 per 1,000             29
                                 study.             (Taiwan).          Removal of                          catheter days.    catheter days.
                                                                       unnecessary
                                                                       urinary
                                                                       catheters; QI:
                                                                       Clinician
                                                                       reminder.
  Greco, 1991.................  Before-after       ICU patients       Preventive:       Previous care...  12.9 per 100      11.9 per 100               8
                                 study.             (Italy).           Aseptic                             catheters.        catheters.
                                                                       insertion and
                                                                       catheter care;
                                                                       QI: Audit and
                                                                       feedback,
                                                                       clinician
                                                                       education,
                                                                       clinician
                                                                       reminder.
Moderate quality:
  Topal, 2005.................  Before-after       Ward patients      Preventive:       Previous care...  36 per 1,000      11 per 1,000              69
                                 study.             (United States).   Reduction in                        catheter days.    catheter days.
                                                                       placement of
                                                                       catheters,
                                                                       removal of
                                                                       unecessary
                                                                       catheters; QI:
                                                                       Clinician
                                                                       education,
                                                                       clinician
                                                                       reminder,
                                                                       organizational
                                                                       change.
Rosenthal, 2004...............  Before-after       ICU patients       Preventive: Hand  Previous care...  21.3 per 1,000    12.4 per 1,000            42
                                 study.             (Argentina).       hygiene,                            catheter days.    catheter days.
                                                                       aseptic
                                                                       catheter care;
                                                                       QI: Audit and
                                                                       feedback,
                                                                       clinician
                                                                       education.
Dumigan, 1998.................  Before-after       ICU patients       Preventive:       Previous care...  SICU: 10.3 per    8.6 per 1,000             17
                                 study.             (United States).   Aseptic                             1,000 catheter    catheter days.
                                                                       insertion and                       days.                                      29
                                                                       cathter care,                      MICU: 15.8 per    11.2 per 1,000
                                                                       removal of                          1,000 catheter    catheter days.           45
                                                                       unecessary                          days.
                                                                       catheters; QI:                     CICU: 15.1 per    8.3 per 1,000
                                                                       Clinician                           catheter days.    catheter days.
                                                                       education,
                                                                       organizational
                                                                       change.
--------------------------------------------------------------------------------------------------------------------------------------------------------

                                                                     Evidence Tables
  Table 7.--SSI Prevention Studies Reviewed by AHRQ suggest a 26 to 54 Percent Reduction in SSIs Depending on the Intervention and Population Examined
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                 Risk
                                                                                                             Risk before       Risk after      Reduction
         Author, Year              Study Design         Setting         Intervention       Comparison       intervention      intervention        [in
                                                                                                            [in percent]      [in percent]     percent]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Good quality:
  Van Kasteren, 2005..........  Interrupted time   Not reported       Preventive:       Previous care...  5.4.............  4.6.............          15
                                 series.            (Netherlands).     Appropriate use
                                                                       of
                                                                       perioperative
                                                                       antibiotics;
                                                                       QI: Audit and
                                                                       feedback,
                                                                       clinician
                                                                       education,
                                                                       clinician
                                                                       reminder.
  Gastmeier, 2002.............  Controlled study.  ICU (Germany)....  Preventive: Hand  Previous care...  2.2.............  1.6.............          26
                                                                       hygiene,
                                                                       appropriate use
                                                                       of
                                                                       perioperative
                                                                       antibiotics,
                                                                       decreasing use
                                                                       of preoperative
                                                                       shaving,
                                                                       improving
                                                                       perioperative
                                                                       glucose
                                                                       control; QI:
                                                                       Audit and
                                                                       feedback,
                                                                       clinician
                                                                       education.
  Weinberg, 2001..............  Interrupted time   Not reported       Preventive:       Previous care...  Hospital A: 10.5  0...............         100
                                 series.            (Columbia).        Appropriate use                    Hospital B: 6.1.  4.4.............          28
                                                                       of
                                                                       perioperative
                                                                       antibiotics;
                                                                       QI: Audit and
                                                                       feedback,
                                                                       organizational
                                                                       change.
  Greco, 1991.................  Before-after       ICU (Italy)......  Preventive:       Previous care...  7.8.............  6.2.............          21
                                 study.                                Appropriate use
                                                                       of
                                                                       perioperative
                                                                       antibiotics,
                                                                       decreasing use
                                                                       of preoperative
                                                                       shaving; QI:
                                                                       Audit and
                                                                       feedback,
                                                                       clinician
                                                                       education,
                                                                       clinician
                                                                       reminder.
Moderate quality:
  Dellinger, 2005.............  Before-after       Not reported       Preventive:       Previous care...  2.3.............  1.7.............          26
                                 study.             (United States).   Appropriate use
                                                                       of
                                                                       perioperative
                                                                       antibiotics,
                                                                       decreasing use
                                                                       of peroperative
                                                                       shaving,
                                                                       improving
                                                                       perioperative
                                                                       glucose
                                                                       control; QI:
                                                                       Audit and
                                                                       feedback,
                                                                       clinician
                                                                       education,
                                                                       clinician
                                                                       reminder.
  Borer, 2004.................  Before-after       Operating room     Preventive: Hand  Previous care...  4.2.............  0...............         100
                                 study.             (Israel).          hygiene,
                                                                       appropriate use
                                                                       of
                                                                       perioperative
                                                                       antibiotics,
                                                                       decreasing use
                                                                       of preoperative
                                                                       shaving,
                                                                       improving
                                                                       perioperative
                                                                       glucose
                                                                       control; QI:
                                                                       Clinician
                                                                       education.
  Lutarewych, 2004............  Before-after       Not reported       Preventive:       Previous care...  7.58............  3.47............          54
                                 study.             (United States).   Improving
                                                                       perioperative
                                                                       glucose
                                                                       control; QI:
                                                                       Audit and
                                                                       feedback,
                                                                       clinician
                                                                       education,
                                                                       patient
                                                                       education.
  Rao, 2004...................  Before-after       Not reported       Preventive:       Previous care...  2.1.............  1.5.............          29
                                 study.             (United States).   Appropriate use
                                                                       of
                                                                       perioperative
                                                                       antibiotics,
                                                                       decreasing use
                                                                       of preoperative
                                                                       shaving,
                                                                       improving
                                                                       perioperative
                                                                       glucose
                                                                       control; QI:
                                                                       Clinician
                                                                       education,
                                                                       clinician
                                                                       reminder.
  Won, 2004...................  Before-after       Not reported       Preventive: Hand  Previous care...  0.33 per 1,000    0.84 per 1,000          -154
                                 study.             (Taiwan).          hygiene; QI:                        patient days.     patient days.    (increase)
                                                                       Clinician
                                                                       education,
                                                                       audit and
                                                                       feedback.
  Larsen, 1989................  Before-after       Operating room     Preventive:       Previous care...  1.1.............  0.7.............          36
                                 study.             (United States).   Appropriate use
                                                                       of
                                                                       perioperative
                                                                       antibiotics;
                                                                       QI: Audit and
                                                                       feedback,
                                                                       clinician
                                                                       reminder.
--------------------------------------------------------------------------------------------------------------------------------------------------------

                                 ______
                                 
     Response to Questions of Senator Kennedy and Senator Burr by 
                       Jay P. Graham, Ph.D., MBA
                      questions of senator kennedy
    Question 1. Dr. Graham, you mentioned the public health risks 
associated with antimicrobial resistance in many classes of 
antimicrobials. Would a review of previously approved labeled 
subtherapeutic doses of antimicrobials under a risk assessment 
framework such as FDA Guidance #152 effectively determine which 
antimicrobial uses pose a risk to human health?
    Answer 1. FDA Guidance #152 does not sufficiently address the 
potential spread of resistance genes and resistance determinants. 
Guidance #152 focuses solely on foodborne pathogens and disregards 
resistance in other human pathogens. For example, resistance genes that 
encode resistance to macrolides, lincosamides and streptogramins (e.g., 
erythromycin, clindamycin and quinupristin-dalfopristin, respectively) 
are relatively mobile, since they are commonly found on conjugative 
transposons. These transposons can transfer resistance to different 
genera of bacteria, many of which are human commensals. Guidance #152 
should consider the medical implications of increasing the reservoir of 
specific resistance genes that are augmented by the use of 
subtherapeutic doses of antimicrobials.

    Question 2. Is Guidance #152 stringent enough to adequately assess 
the full risk to human health posed by non-therapeutic uses of 
antibiotics on farms, including risks in addition to food safety such 
as environmental contamination?
    Answer 2. No. Historically, research has focused on occupational 
and food-borne exposure pathways. Environmental pathways of exposure, 
however, are increasingly documented as surveillance of infectious 
diseases improves. The spread of resistance could occur in a number of 
ways: (1) crops fertilized with manure or irrigated with water 
contaminated by land-disposed manure; (2) aerosolized particles of 
waste emitted from confinement or waste storage facilities, or 
emanating from fields fertilized with manure or trucks transporting 
live animals for processing; (3) runoff of waste into groundwater and 
surface water; and (4) contamination and carriage by other organisms 
(e.g., flies). All of these pathways have been documented in the peer-
reviewed literature. For example, antimicrobial-resistant enteric 
bacteria have been found in surface water and groundwater supplies near 
confined animal feeding operations. And, groundwater makes up 40 
percent of the water used for public water supplies and provides 
drinking water for more than 97 percent of rural U.S. populations.

    Question 3. You mentioned that your studies have shown that animal 
producers would not experience a significant increase in costs if they 
ceased using subtherapeutic doses of antimicrobials. Are alternative 
treatments, such as probiotics, diet acidification, enzymes, or immune 
system modulators including antibodies and spray-dried plasma cost 
effective when compared with subtherapeutic antimicrobials?
    Answer 3. The research that I referenced in the hearing was based 
on data published by the Perdue Company, in which a non-randomized 
controlled trial of growth promoting antibiotic use was conducted with 
7 million broiler chickens to evaluate the impact of removing growth 
promoting antibiotics (GPAs). The company did not look at alternative 
treatments in this study; it just looked at the results of removing 
growth promoting antibiotics from feed. The results of the economic 
analysis showed that positive production changes were associated with 
GPA use, but were insufficient to offset the cost of the antibiotics. 
Interestingly, the Perdue study showed that mortality rates dropped 
following a full clean-out of the poultry houses. There are likely 
alternative treatments that could replace subtherapeutic 
antimicrobials, however, it appears that improved hygiene and 
management could suffice (Graham et al. 2007; Miller et al., 2003).

    Question 4. Is there a connection between MRSA outbreaks and the 
use of subtherapeutic doses of antimicrobials in animal feeds?
    Answer 4. Research in Denmark showed that MRSA on pig farms was 
associated with use of tetracycline in the feed. However, more research 
in the United States is needed to better understand what is driving 
MRSA at U.S. swine operations.

    Question 5. On July 3, FDA issued a prohibition order on extra-
label use of cephalosporin drugs. The order states that ``the 
surveillance data . . . supports the finding that certain cephalosporin 
use in animals is likely contributing to an increase in cephalosporin-
resistant human pathogens.'' In my understanding, the extra-label uses 
of cephalosporin are not very different from that of labeled uses--
which include different species or dosing times from on-label uses. Do 
you think there should be a concern about on-label uses of 
cephalosporins as well?
    Answer 5. Yes, I do think there should be concern about the on-
label uses of cephalosporins. Of particular concern are the 
increasingly isolated plasmidencoded resistance genes associated with 
cephalosporin resistance (Li et al., 2007). There are 12 other 
antimicrobials that are still effective for bovine respiratory disease, 
so it doesn't seem appropriate to approve cefquinome for on-label uses, 
when this is so important in human medicine. Bacteria from agricultural 
settings can make their way to clinical settings and the complexity of 
the spread of resistance should be more fully integrated into the FDA 
risk assessment of Guidance #152.
                       questions of senator burr
    Question 1. How did the Pew Commission come up with the definition 
for non- therapeutic? Mr. Vogel said the AVMA considers ``therapeutic 
use'' to be disease control, prevention and treatment. The AVMA 
definition is consistent with the FDA, 0IE, Codex and other 
international authorities. Can you please explain your definition and 
why it is different?
    Answer 1. The Pew Commission used information from the World Health 
Organization (WHO) and consulted with officials at the Centers for 
Disease Control and Prevention (CDC) to establish the definition for 
non-therapeutic. The Commissioners wanted to craft a more narrow 
definition to help reduce the potential spread and impact of 
antimicrobial resistance in human medicine. The current definitions 
have not reduced drug-resistant infections, and it is, in fact, a 
growing problem. Pew also based its definition on peer-reviewed studies 
and a commissioned technical report on farm animal production and 
antimicrobial resistance (available at: http:/Awmf.ncifap.org/reports/
). The Commission was also able to draw upon the expertise of three of 
its members: Drs. Mary Wilson, James Merchant, and Michael Blackwell. 
Dr. Wilson is a faculty member at the Harvard School of Public Health 
and has more than 30 years experience in infectious diseases. Dr. 
Merchant is a medical doctor and a Doctor of Public Health. He recently 
retired as Dean of the College of Public Health at the University of 
Iowa. Dr. Blackwell is a veterinarian and recently retired as Dean of 
the College of Veterinary Medicine at the University of Tennessee/
Knoxville. He has a Masters of Public Health and served as Assistant 
Surgeon General of the United States. Pew decided on a definition for 
therapeutic that is more in line with human usage and more protective 
of the public's health.
    Currently, there is unrestricted access for purchasing 
antimicrobials for use in animal agriculture, which can be bought in 
feed stores, online or directly from distributors; no prescription or 
veterinarian oversight is needed. Some antimicrobials, such as 
penicillins and tetracyclines, are used routinely, without any sign of 
disease. It is important to know how antimicrobials are used (i.e. how 
much goes for routine use in the absence of disease?) so that we can 
determine the level to which this use is leading to an increase in 
drug-resistant infections in humans.

    Question 2. Your written testimony states that ``in North Carolina 
alone, the use of antimicrobials as a feed supplement has been 
estimated to exceed all U.S. antimicrobial use in human medicine.'' Who 
has estimated that? And were you aware that, according to the N.C. 
Dept. of Agriculture, in 2007 8.9 billion chickens and 10.1 million 
pigs were born in N.C.? In comparison, the U.S. population is 304 
million people.
    Answer 2. The State and county estimates of antibiotics in 
agricultural feed and animal waste were derived using data from the 
U.S. Department of Agriculture's 2002 Census of Agriculture, along with 
per-animal estimates of antibiotic feed-additive use developed by the 
Union of Concerned Scientists (UCS) for broiler chickens, hogs and beef 
cattle. The UCS estimates were used because they are the most detailed 
and transparent figures on antibiotic use now available. The report 
referenced can be found at:http://www.edf.org/documents/
4301_AgEstimates.pdf.
    I understand that it is difficult to believe that more 
antimicrobials go to food animals in North Carolina than are used in 
all of human medicine in the United States. However, food animals are 
fed a constant, low-dose of antimicrobials, and humans are not. For 
example, 1 billion chickens consume roughly 5 million tons of feed (a 
five-pound chicken consumes roughly 10 pounds of feed). Each ton of 
feed has 0.22-0.44 pounds (100-200 grams) of antimicrobials. Thus 5 
million tons of feed multiplied by the 0.22-0.44 lbs of antimicrobials 
is equal to 1.1-2.2 million pounds of antimicrobials. This calculation 
is just for 1 billion poultry, so it easy to see how the low doses of 
antimicrobials on a per-animal basis can at first appear deceptively 
small.

    Question 3. I have an article written by an N.C. State University 
researcher stating ``there is a fallacy that more than 70 percent of 
the life-saving antibiotics and related drugs produced are used in food 
animal production . . . The reality is that, annually, humans and our 
pets consume 10 times more antibiotics per pound of body mass than food 
animals do.'' Who is right? You or him?
    Answer 3. An important point is being overlooked here: The issue is 
not the amount of use ``per pound of body mass'' but total drug use. Of 
the total amount of antimicrobials used, including humans, pets, and 
food animals, the best estimates we have available report that the 
majority of antimicrobials are used at subtherapeutic concentrations to 
raise food animals. These constant low doses of antimicrobials are a 
major driver in the development of drug-resistant bacteria, and a 
number of studies have shown this. These bacteria then end up in our 
food supply and in our environment.

    Question 4. Are you not concerned with the 143 percent increase in 
the quantity of antimicrobials used for therapeutic purposes in Denmark 
post-ban? Isn't this a case of chopping off your nose to spite your 
face?
    Answer 4. This is a skewed way of looking at the results of the 
ban. Total consumption of antimicrobial drugs by food animals in 
Denmark declined after the ban, by 36 percent between 1996 and 2003. 
After the ban in Norway, antimicrobial use in food animals dropped 45 
percent between1995 and 2003. In Sweden, total antimicrobial use in 
food animals in 2003 amounted to only one-third of the amounts used in 
1984--a 35-ton decrease. Termination of antimicrobials for growth 
promotion was only a temporary risk factor for increased use of 
therapeutic antimicrobials in food animals in Sweden and Denmark; 
however, an exception might be use in weaning piglets in Denmark.
    In Denmark, there is a program (VetStat) that monitors all 
veterinary use of medicines for animals. It is based on reporting from 
the pharmacies and from veterinary practitioners and contains detailed 
information, such as animal species, reason for prescription, and 
dosage on each prescription. In Denmark, antimicrobial drugs can be 
obtained only by prescription and only at pharmacies. We need something 
similar in the United States to protect the public's health.

    Question 5. Please cite the science that illustrates the risk to 
public health that antibiotic use in food animals creates.

    Answer 5. World Health Organization Strategy for Containment of 
Antimicrobial Resistance. 2001. (Available at:http://www.who.int/csr/
resources/publications/drugresist/en/EGlobal_Strat.pdf).
     Silbergeld EK, Graham JP, Price LB. Industrial food animal 
production, antimicrobial resistance, and human health. Annu Rev Public 
Health 2008; 29:151-169. (Available at: http://
arjournals.annualreviews.org/doi/pdf/10.1146/annurev
.publhealth.29.020907.090904?cookieSet=1).
     Van den Bogaard AE, Stobberingh EE. Epidemiology of 
resistance to antibiotics. Links between animals and humans. 
International Journal of Antimicrobial Agents 2000; 14(4):327-335.

    Question 6. What proof do you have that public health in the EU has 
benefited from the ban of antibiotic growth promoters in animals?
    Answer 6. One of the most important issues regarding antimicrobial 
resistance is that the principle of proof requires that resistance has 
already emerged, by which time the ``genie is out of the bottle.'' 
Another important fact is that all use of antimicrobials leads to the 
development of resistance in bacteria. The number of drug-resistant 
bacteria and resistance genes in our food supply and in the environment 
is an important part of the risk of exposure for humans. Adopting 
precautionary measures, as the EU has done, reduced the opportunities 
to find out how risky this practice is. The benefit of the ban in 
Europe is that policymakers there reduced the human health risk by 
reducing the prevalence of resistant bacteria in Europe's food supply. 
Even when transmission to humans is infrequent, amplifying resistant 
bacteria still makes transmission via food and other pathways more 
likely (Turnidge, 2004).

    Question 7. While antibiotic resistance is a public health threat, 
does your report include an estimate of how much of the total human 
burden is caused by antibiotic use in humans and how much by use in 
animals?
    Answer 7. The antimicrobial resistant bacteria that we select in 
food animal production are often indistinguishable from those that we 
select from other uses (e.g., hospital use). Therefore, once resistant 
bacteria are disseminated into the human population from their point of 
origin, it is nearly impossible to attribute them to a particular 
source. In contrast to hospital-selected resistant bacteria, many of 
those selected in the food animal setting are distributed into the 
community on food animal products such as meat and poultry. Peer-
reviewed studies of meat and poultry products have shown that they are 
regularly contaminated with antibiotic resistant bacteria. Most of our 
U.S. population is exposed to meat and poultry products, whereas only 
those entering hospitals have direct exposure to the antibiotic 
resistant bacteria that are selected in that setting. Thus, while it is 
currently impossible to determine what percentage of antimicrobial 
resistant infections in humans can be traced to food animals, the 
science points to a substantial proportion of these human diseases 
being attributable to antimicrobial use in food animal production. 
Thus, as Smith et al. (2005) conclude, a large number of people exposed 
to a low risk may generate more cases than a small number of people 
exposed to a high risk. Evidence for the increasing prevalence of 
community sources of multidrug resistance is found in a study of 
incoming patients at a tertiary care hospital in Boston: From 1998/9 to 
2002/3, the likelihood of multidrug resistance in E. coli increased 
from 2 percent to almost 20 percent (Pop-Vicas, 2005).
                               references
Graham JP, Boland JJ, Silbergeld E. Growth promoting antibiotics in 
    food animal production: an economic analysis. Public Health Rep 
    2007; 122:79-87.
Miller GY, Algozin KA, McNamara PE, Bush EJ. Productivity and economic 
    effects of antibiotics use for growth promotion in U.S. pork 
    production. Journal of Agricultural and Applied Economics 2003; 
    35:469-482.
Li XZ, Mehrotra M, Ghimire S, Adewoye L. B-Lactam resistance and B-
    lactamase in bacteria of animal origin. Veterinary Microbiology 
    2007; 121:197-214.
Turnidge J. Antibiotic use in animals--prejudices, perceptions and 
    realities. Journal of Antimicrobial Chemotherapy 2004; 53:26-27.
Smith DL, Dushoff J, Morris JG. 2005. Agricultural antibiotics and 
    human health. PLoS Med. 2:e232.
Pop-Vicas AE, D'Agata EM. 2005. The rising influx of multidrug-
    resistant gram-negative bacilli into a tertiary care hospital. 
    Clin. Infect. Dis. 40:1792-98.
                                 ______
                                 
           American Veterinary Medical Association,
                                                     July 31, 2008.

    Dear Members of the Senate Health, Education, Labor, and Pensions 
Committee: Thank you for the opportunity to respond to your questions 
concerning the use of antimicrobials in food animals.
    However, I cannot respond to the questions regarding ``non-
therapeutic'' use in that same terminology. The term ``non-
therapeutic'' has no meaning in Federal regulation or common usage. The 
Food and Drug Administration approves antimicrobials for four purposes: 
disease treatment, disease prevention, disease control, and growth 
promotion/feed efficiency. The FDA does not approve antimicrobials for 
``non-therapeutic'' uses. Also, the various organizations and people 
who use the term ``non-therapeutic'' use it inconsistently to mean 
different things. For example, the Pew Commission on Industrial Farm 
Animal Production (PCIFAP) provides an unclear definition of ``non-
therapeutic'' that is different from that found in S. 549, the 
Preservation of Antibiotics for Medical Treatment Act of 2007 (PAMTA). 
Additionally, the definitions include terms that themselves are 
undefined such as ``routine preventive uses and other routine uses.'' 
As a result, the language is not commonly understood. The use of 
exclusionary terms, such as ``non-therapeutic,'' that are ill-defined 
and not commonly understood, is confusing. We caution against the use 
of the term ``non-therapeutic'' for the sake of clear communication and 
understanding.
    Instead we urge that FDA terminology, which appears on labeled uses 
of antimicrobials, be used. Specifically, these terms are: 
``treatment,'' ``prevention,'' ``control,'' or ``growth promotion/feed 
efficiency.'' Alternatively, use the classifications of the Codex 
Alimentarius Commission (an organization of the World Health 
Organization and the Food and Agricultural Organization of the United 
Nations) and the American Veterinary Medical Association. Both 
organizations classify treatment, prevention, and control of disease as 
therapeutic uses.
    In the responses below, I do not use ``non-therapeutic'' 
terminology for clarity.

                        Lyle Vogel, D.V.M., M.P.H., DACVPM,
                                Assistant Executive Vice President.
 Response to Questions of Senator Kennedy, Senator Brown, and Senator 
               Burr by Lyle Vogel, D.V.M., M.P.H., DACVPM
                      questions of senator kennedy
    Question 1. Dr. Vogel, you mentioned in your testimony that the 
AVMA has ``a great interest in the prevention, control, and treatment 
of disease.'' How would a reduction in the use of antimicrobials for 
non-treatment or non-therapeutic purposes, such as ``feed efficiency,'' 
prevent veterinarians from using their discretion to prescribe 
antimicrobials for sick animals or a sick herd when an infection is 
diagnosed.
    Answer 1. We will presume that this question pertains to 
antimicrobials that are labeled for feed efficiency or growth 
promotion. While often used under the supervision or guidance of a 
veterinarian, the use of antimicrobials for feed efficiency or growth 
promotion does not require a veterinary prescription. As a result, 
legislative restrictions on such uses have no direct effect on the 
ability for veterinarians to prescribe antimicrobials for therapeutic 
uses, such as treatment of ``sick'' animals, control of disease within 
a ``sick'' herd, and prevention of disease when animals are at high 
risk of becoming ill.
    However, if our presumption is incorrect and the question also 
pertains to antimicrobials that are labeled for prevention of disease 
(as does PAMTA), then the veterinarian's ability to prevent disease in 
herds or flocks will be seriously compromised. If veterinarians are 
required to wait until animals are sick and dying from disease, then 
this will significantly and adversely affect health plans established 
by veterinarians. If veterinarians cannot use antimicrobials until 
animals are sick and dying from disease, animal welfare will be greatly 
harmed.
    The Danish experience has shown us that the use of antimicrobials 
for growth promotion had the added benefit of preventing or controlling 
disease.

    Question 2. How have European countries dealt with the 
ramifications of the EU ban on antimicrobial use for growth promotion?
    Answer 2. Based upon reports from Denmark (the most complete data 
that is available for evaluating trends of antimicrobial use), the ban 
on antimicrobial use for growth promotion has caused a substantial 
increase in therapeutic use of antimicrobials to maintain food animal 
health. While the total quantity of antimicrobials used in food animals 
decreased, the therapeutic use increased greatly The total quantity of 
antibiotics used in food animals decreased by 24 percent between 1997 
(160 tons) (the year closest to the start of the ban in 1998) and 2007 
(121.1 tons), while therapeutic use increased by 152 percent (from 57.3 
tons in 1996 to 121.1 tons in 2007) (1996 is the year closest to start 
of the ban in 1998 for which therapeutic use data is available).
    The antimicrobials now being used for therapy are in classes such 
as tetracyclines that are also used in humans. This compares to 
previously used drugs such as avilamycin, salinomycin, monensin, 
flavomycin, and bacitracin that are not used in human medicine or are 
not important for human medicine. Tetracycline use in food animals has 
increased from 12,900 kg of active compound in 1996 to 32,650 in 2006 
(153 percent increase), 13-lactamase sensitive penicillins from 7,200 
to 22,600 (214 percent increase), cephalosporins and other penicillins 
from 5,800 to 11,550 (99 percent increase), macrolides from 11,400 to 
22,050 (93 percent increase), and sulfonamides + trimethoprim from 
4,800 to 13,800 (188 percent increase). Hence, as a result of the ban, 
we have seen a significant increase in the use of classes of 
antibiotics that are used in humans.
    During this same period of time, resistance to tetracycline of 
Salmonella Typhimurium isolated from clinically ill humans in Denmark 
increased from 18 percent in 1997 to 53 percent in 2006, and resistance 
of Salmonella Typhimurium isolates to ampicillin increased from 11 
percent to 56 percent. Resistance of Campylobacter jejuni to 
tetracycline increased from 3 percent to 7 percent. It is unknown if 
these increases are associated with the increased food animal use of 
the antibiotics or increased use of antibiotics in humans themselves. 
Tetracycline resistance of Enterococus faecium, Enterococcus faecalis, 
and Escherichia coli from healthy humans stayed the same for the first 
two organisms and decreased for E. coli.
    In the early years, swine producers substituted zinc oxide to deal 
with the ramifications of discontinuing antimicrobial growth promoters. 
However, because of potential adverse environmental impact, the use of 
zinc oxide was stopped.
    The swine producers also delayed weaning piglets so they were older 
and better able to adjust to a non-milk diet. While successful, later 
weaning has created other health risks. For example, piglets are now 
subjected to prolonged exposure to pathogens from the sow. This occurs 
while protection from maternal antibodies received through nursing is 
waning, resulting in increased risk of disease. Increased quantities of 
antimicrobials are now used to prevent disease in piglets. In addition 
to the disease concerns, delayed weaning also impacts efficiency of 
production.

    Question 3. Since there are alternatives to non-treatment uses of 
antimicrobials such as certain minerals, enzymes or probiotics, is the 
issue with restricting non-treatment uses of antimicrobials a matter of 
animal health, or mainly about costs and expenses?
    Answer 3. The use of alternatives including vaccines and 
probiotics, are always strongly encouraged as a part of the AVMA 
judicious use guidelines, regardless of costs and expenses.
    While I am not an expert in the effectiveness of these 
alternatives, my impression is that there is not a good science-base 
that demonstrates predictable efficacy of these alternatives. As 
mentioned above, Denmark initially used zinc oxide as an alternative, 
but withdrew it because of potential environmental impacts.

    Question 4. How often do producers use antibiotics without a 
prescription?
    Answer 4. Currently, there is no accurate system to obtain 
information on the quantity of use of over-the-counter antibiotics by 
producers. While there have been estimates of veterinary and human use 
of antimicrobials, the estimates vary greatly. Also, there is not a 
system to determine use by producers or any other specific group of 
individuals. This is one of the many reasons why we discourage broad 
based bans on antimicrobial use in food animals. Without further 
information, there is no way of determining public health impact based 
upon a specific use. Thus, we encourage further evaluation, research, 
monitoring and surveillance of antimicrobial use.
    The USDA National Animal Health Monitoring System (NAHMS) provides 
some information that addresses the question in terms of frequency of 
use and involvement of veterinarians.
    The Feedlot '99--Part III: Health Management and Biosecurity in 
U.S. Feedlots, 1999, provides the following information:

     Antimicrobials are added to feed or water of feedlot 
cattle for a number of purposes, such as a therapeutic response to an 
outbreak of respiratory disease, disease prevention, to aid in 
controlling liver abcessation, or to increase average daily gains and/
or improve dry matter conversion.
     Nearly 17 percent of feedlots used no antimicrobials in 
feed or water. (83.2 percent did use antimicrobials in feed or water 
for some purpose.)
     Tetracyclines were fed between 4 and 12 days, on average, 
whereas tylosin was fed for a longer time period, likely because the 
desired purpose differs depending on which antimicrobials were 
administered. Tetracyclines are often used to treat or prevent 
outbreaks of respiratory disease, while tylosin is fed to reduce the 
occurrence of liver abscessation. Tylosin is fed on average 138-145 
days.
     Almost all feedlots (99.8 percent) used an injectable 
antimicrobial as part of an initial therapeutic regimen for an animal 
believed to be suffering from a respiratory disease.

    The Swine 2006 Report (Part I: Reference of Swine Health and 
Management Practices in the United States, 2006 and Part II: Reference 
of Swine Health and Health Management Practices in the United States, 
2006) provides the following information:

     Nursery pigs
       Approximately 8 of 10 sites (79.6 percent) used 
antibiotics in feed as a preventive practice for nursery pigs. 40.4 
percent of the sites used injectable antibiotics. On the nursery pig 
sites that used antibiotics in the specified way (in feed or 
injectable), 89.5 percent of the nursery pigs received antibiotics in 
the feed and 64.7 percent of the nursery pigs received injectable 
antibiotics.
       The most common reason for giving antimicrobials in feed 
was disease prevention (50.9 percent of sites). The second most common 
reason was for disease or parasite treatment (39.3 percent of sites). 
The third most common reason was for growth promotion (24.5 percent of 
the sites).
       Antimicrobials were administered via feed to nursery-age 
pigs for growth promotion for an average of 32.4 days, for disease 
prevention--28.6 days, enteric disease treatment--26.1 days, and 
respiratory disease treatment--20.3 days.
       Regarding treatment for disease of nursery-age pigs, the 
percentage of sites where the owner of the operation was the primary 
decisionmaker regarding antimicrobial use in sick nursery-age pigs 
decreased as size of site increased. The owner of the operation was the 
primary decisionmaker in 75.8 percent of the small sites and 35.0 
percent of the large sites. The local veterinary practitioner was the 
primary decisionmaker for treatment of sick nursery-age pigs in 6.1 
percent of the small sites and 14.2 percent of the large sites. The 
company veterinarian or company nutritionist was the primary 
decisionmaker in 4.4 percent of the small sites and 20.0 percent of the 
large sites. A consulting or second-opinion veterinarian was the 
primary decisionmaker in 0.3 percent of the small sites and 5.2 percent 
of the large sites.
       8.2 percent of the sites did not use antimicrobials for 
growth- promotion in nursery-age pigs. Of those that did use 
antimicrobial growth promoters, the primary decisionmaker was the owner 
in 75.7 percent of the small sites and 37.4 percent of the large sites. 
The local veterinary practitioner was the primary-decision maker at 3.2 
percent of the small sites and 17.9 percent of the large sites. The 
company veterinarian or company nutritionist was the primary 
decisionmaker at 6.7 percent of the small sites and 34.7 percent of the 
large sites. A consulting or second-opinion veterinarian was the 
primary decisionmaker at 0 percent of the small sites and 3.3 percent 
of the large sites.

     Grower/finisher pigs
       68.1 percent of grower/finisher sites used antibiotics 
in feed as a preventive practice. 38.8 percent of the sites used 
injectable antibiotics. On the grower/finisher pig sites that used 
antibiotics in the specified way (in feed or injectable), 78.2 percent 
of the grower/finisher pigs received antibiotics in the feed and 52.7 
percent of the grower/finisher pigs received injectable antibiotics.
       The most common reason for giving antimicrobials in feed 
was for growth promotion (55.1 percent of sites). The second most 
common reason was for disease treatment (46.1 percent of sites). The 
third most common reason was for disease prevention (37.5 percent of 
the sites).
       Antimicrobials were administered via feed to grower/
finisher pigs for growth promotion for an average of 62.3 days, for 
disease prevention--38.4 days, enteric disease treatment--40.8 days, 
and respiratory disease treatment--27.3 days.
       Regarding treatment for disease of grower/finisher pigs, 
the percentage of sites where the owner of the operation was the 
primary decisionmaker regarding antimicrobial use in sick nursery-age 
pigs decreased as size of site increased. The owner of the operation 
was the primary decisionmaker in 67.9 percent of the small sites and 
29.0 percent of the large sites. The local veterinary practitioner was 
the primary decisionmaker for treatment of sick grower/finisher pigs in 
7.5 percent of the small sites and 11.0 percent of the large sites. The 
company veterinarian or company nutritionist was the primary 
decisionmaker in 6.6 percent of the small sites and 28.8 percent of the 
large sites. A consulting or second-opinion veterinarian was the 
primary decisionmaker in 2.7 percent of the small sites and 3.8 percent 
of the large sites.
       6.7 percent of the sites did not use antimicrobials for 
growth-promotion in grower/finisher pigs. Of those that did use 
antimicrobial growth promoters, the primary decisionmaker was the owner 
in 67.0 percent of the small sites and 33.9 percent of the large sites. 
The local veterinary practitioner was the primary-decision maker at 3.8 
percent of the small sites and 7.5 percent of the large sites. The 
company veterinarian or company nutritionist was the primary 
decisionmaker at 12.9 percent of the small sites and 49.9 percent of 
the large sites. A consulting or second-opinion veterinarian was the 
primary decisionmaker at 1.2 percent of the small sites and 1.2 percent 
of the large sites.

     Piglets
       60.0 percent of piglet sites used antibiotics in feed as 
a preventive practice before or at weaning. 51.4 percent of the sites 
used injectable antibiotics. On the piglet sites that used antibiotics 
in the specified way (in feed or injectable), 30.8 percent of the 
piglets received antibiotics in the feed and 68.7 percent of the 
piglets received injectable antibiotics.

     Sows
       47.7 percent of sow sites used antibiotics in feed as a 
preventive practice. 40.8 percent of the sites used injectable 
antibiotics. On the sow sites that used antibiotics in the specified 
way (in feed or injectable), 46.1 percent of the sows received 
antibiotics in the feed and 51.9 percent of the sows received 
injectable antibiotics.

     Boars
         34.5 percent of boar sites used antibiotics in feed as 
a preventive practice. 23.2 percent of the sites used injectable 
antibiotics. On the boar sites that used antibiotics in the specified 
way (in feed or injectable), 41.1 percent of the boars received 
antibiotics in the feed and 32.0 percent of the boars received 
injectable antibiotics.

    Question 4. Without directly consulting with a veterinarian?
    Answer 4. Veterinarians strongly encourage a Veterinarian-Client-
Patient Relationship (VCPR) (required for any veterinary prescription 
drug) and veterinary consultation when implementing any treatment 
regimen.
    NAHMS also provides some information for this question. For 
example, Beef '97--Part II: Reference of 1997 Cow-Calf Health and 
Health Management Practices reports that the veterinarian is a key 
information resource for cow-calf producers. The veterinarian may 
provide many services to operations such as diagnosis and care of sick 
animals, disease prevention, consultation on production practices, and 
financial analysis. Veterinarians were most commonly used for disease 
diagnosis and treatment (42.0 percent of operations) and 39.1 percent 
of producers consulted a veterinarian for disease prevention 
information. There were differences in the use of veterinary services 
by herd size, both in terms of overall use and also what services the 
veterinarians were being asked to provide. There was more overall use 
of veterinary services in larger operations (83.4 percent) compared to 
the smallest operations (48.6 percent).
    Feedlot '99--Part I: Baseline Reference of Feedlot Management 
Practices, 1999, reports that all large operations and nearly all (96.5 
percent) small operations used the services of a veterinarian. Large 
operations were more likely to use a veterinarian that made regular or 
routine visits or employ a full-time veterinarian on staff than small 
operations. Conversely, small operations were more likely to use a 
veterinarian when the need for one arose. Veterinarian recommendations 
had strong or moderate influence on selection of an antimicrobial for 
nearly 100 percent of feedlots. Veterinarian recommendations and 
laboratory test results were more likely to strongly influence 
selection of antimicrobials on large feedlots than small feedlots. 
Almost three out of four feedlots provided formal training in areas 
related to antimicrobial use.
    The USDA Swine 2006 reports that a higher percentage of large and 
medium sites (88.1 and 85.0 percent, respectively) used a veterinarian 
during the previous year compared to small sites (60.8 percent). Nearly 
5 of 10 large sites (46.8 percent) used an on-staff veterinarian. A 
similar percentage of large sites (42.5 percent) used a local 
practitioner. Overall, approximately half of the sites (49.5 percent) 
used a local veterinarian during the previous 12 months. About one of 
four sites (24.7 percent) were visited by a veterinarian five or more 
times. Producers used the services of a veterinarian for many purposes 
during the previous 12 months. A higher percentage of large sites used 
a veterinarian for blood testing, production record analysis, employee 
education, and quality assurance compared to small sites. For sites 
that had at least one veterinary visit during the previous 12 months, 
the highest percentage of sites used a veterinarian to treat individual 
pigs (63.8 percent). These are followed by vaccination consultation 
(48.6 percent), quality assurance (47.9 percent), blood testing (47.6 
percent), nutritional consultation (19.8 percent), environmental 
consultation (19.0 percent), and employee training/education (18.0 
percent).

    Question 5. Are antibiotics easy to purchase without a 
prescription?
    Answer 5. The older antimicrobials are available in medicated feeds 
that can be purchased without a veterinary prescription. These are 
called over-the-counter or OTC drugs. A newer category of drugs, the 
Veterinary Feed Directive (VFD) Drug category, was created by the 
Animal Drug Availability Act of 1996 to provide veterinary control for 
certain animal pharmaceuticals for use in feed that are not suitable 
for OTC status. Any animal feed bearing or containing a VFD drug shall 
be fed to animals only by or upon a lawful VFD issued by a licensed 
veterinarian in the course of the veterinarian's professional practice.
                       questions of senator brown
    Question 1. Given your comments on the need for more data, do you 
support the collection and review of safety and use data for non-
therapeutic uses of antimicrobials?
    Answer 1. We support the collection and review of data for all uses 
of antimicrobials and other pharmaceuticals in humans and animals to 
protect both human and animal health. We hope that the collection is 
done correctly so the data is meaningful and not a waste of resources. 
We urge that such data be collected in concert with other data that is 
necessary to explain or inform fluctuations in use, e.g., disease 
prevalence, populations of animals, etc. An example is the USDA 
program, Collaboration for Animal Health, Food Safety and Epidemiology, 
that is attempting to study the use of antimicrobials on farm 
correlated with disease occurrence, and the effects of antimicrobial 
use on antimicrobial resistance as measured both on the farm and during 
processing of the meat from the specific farm. Unfortunately, the 
program has not received adequate funding. We urge for adequate 
funding.
    We also support adequate funding and improvement of food safety 
programs such as FoodNet and the National Antimicrobial Resistance 
Monitoring System (NARMS). It is unfortunate that reporting by NARMS is 
not timelier. For example, the most recent Centers for Disease Control 
and Prevention NARMS report that is available to the public is for 
2004--4 years ago.

    Question 2. Do you believe that we should be reassessing all 
previously approved antimicrobials through the science-based risk 
assessment outlined in Guidance #152?
    Answer 2. No, not ALL previously approved antimicrobials need to be 
reassessed, only the priority antimicrobials (antimicrobials important 
to humans) that have not had a risk assessment performed by FDA or 
academicians. Some have already been concluded. If FDA is expected to 
perform the reassessments, the Agency must be given adequate resources 
to perform the reassessment so that this effort does not detract from 
its many other priority missions.
    The priority for reassessment must be established based on the 
potential for a negative impact on human health. A drug, such as 
bacitracin, that is not classified as an important human antibiotic by 
either the World Health Organization or the FDA should not be 
reassessed. Also, there is no need to reassess bambermycin or 
ionophores because they are not used in humans. FDA has already 
performed a risk assessment of virginiamycin. Academicians have 
performed risk assessments on other antimicrobials such as the 
macrolides. These assessments do not need to be repeated unless new 
information becomes available. Finally, we understand that the FDA is 
reassessing the penicillins and tetracyclines and are waiting for the 
report of the FDA findings.
    Reassessment of all previously approved antimicrobials may or may 
not provide useful information. However, it will require additional FDA 
resources and has the potential to divert current resources away from 
the development and approval of new antimicrobials based on the current 
system of science based risk assessments that evaluate human risks.

    Question 3. If yes, and if such a review were to show that there 
was a potential risk to humans, should we restrict the non-therapeutic 
use of antimicrobials in animals?
    Answer 3. Any restrictions on antimicrobial use should be based on 
a carefully constructed, science-based risk Assessment that thoroughly 
weighs risks and benefits to both humans and animals. Restrictions 
should also be focused upon specific antimicrobials and specific uses 
of the antimicrobials supported by scientific data that demonstrates a 
significant public health risk.
    AVMA policy supports this approach: ``Risk analysis should continue 
to evaluate the risks and benefits to animal health and welfare in 
addition to the risks and benefits to human health attributed to 
[antimicrobial] uses in animals.'' Because veterinarians are ethically 
charged with promoting public health in addition to protecting animal 
health and welfare, we participate in the prevention of both human and 
animal disease. The public health community and physicians do not need 
to consider the risks to animal health and welfare and therefore are 
free to recommend precautionary restrictions on animal drugs based on 
theoretical or minimal risks to human health. However veterinarians 
must balance the need for animal health and welfare with the need of 
human health. Sometimes we believe that the balance should fall in 
favor of animal health and welfare if the decision will result in a 
small or insignificant impact on human health but a large or 
significant impact on animal health and welfare.
    But if the human health impact is significant, then we are 
supportive of measures to mitigate the risk to human health. Those risk 
management measures can include any of the following: FDA advisory 
committee review of an existing approval or application for a new 
animal drug approval; post-approval monitoring through systems such as 
NARMS; limitations on the extent of use (e.g., individual animals only 
for short duration of use); targeted extra-label use restrictions; 
antimicrobial use through prescription or Veterinary Feed Directive 
Drugs only; and finally non-approval or withdrawal of a previously 
approved antimicrobial.

    Question 4. The AVMA policy states that ``regulatory action should 
be transparent and based on scientific risk analysis.'' Does AVMA 
consider Guidance #152 a scientifically sound framework for making 
decisions about the safety of new animal antimicrobials?
    Answer 4. Yes, the AVMA supports the use of Guidance for Industry 
#152 as a scientifically sound framework for evaluating the safety of 
new applications for approval and the safety of previously approved 
antimicrobials.
    We support GFI #152 while recognizing that it is very conservative 
in ensuring the protection of human health without consideration of 
benefits to animal health and welfare. We also recognize that the 
ranking of antimicrobial drugs according to their importance in human 
medicine adds additional difficulty for approving animal drugs because 
the ranking design includes treatment of human diseases that are not in 
any manner associated with food animals. These diseases include 
gonorrhea, tuberculosis caused by Mycobacterium tuberculosis, 
neurosyphillis, meningitis, neutropenic fever, and Legionnaire's 
disease. Antibiotics used to treat these diseases in humans are ranked 
critically important which creates additional barriers to approval of 
drugs for animals even though the pathogens that cause the human 
disease are not present in animals.
    In addition, we also recognize that the design of GFI #152 makes it 
extremely difficult or impossible for FDA to approve antibiotics that 
are used in humans for use in feed or water for treatment or other use 
in groups of animals. This is because the extent-of-use limitations 
table assigns a high ranking for intended administration to flocks or 
herds of animals regardless if the duration of use is short (less than 
6 days) or long (more than 21 days).
                       questions of senator burr
    Question 1. Can you please give us some more detail on what 
happened in Denmark after the government banned the use of 
antimicrobials for growth promotion?
    Answer 1. The ban on antibiotic growth promoters in Denmark 
resulted in an increase in disease and death in swine herds, especially 
in newly weaned pigs, and an increase in the use of antimicrobials for 
therapeutic uses in swine herds. At the weaning stage, farmers noted an 
increase in piglet diarrhea, higher mortality rates, decreased weight 
gains, and greater weight variations. Initially, farmers generally 
reported few health problems in the finishing stage of pork production. 
Some farms noticed negative impacts in average daily gain and 
mortality. Many farms adjusted production practices to address these 
negative impacts, but some farmers have not been able to make the 
adjustments.
    There is little evidence to demonstrate a general decline in 
antimicrobial resistance in humans, and there is no evidence of an 
improvement in clinical outcomes of antimicrobial treatment of humans, 
the desired effect of the antibiotic ban in Denmark. If the measure of 
success is resistance in humans, then the results have been mixed and 
disappointing.
    In fact, resistance in humans to some of the banned drugs has 
increased dramatically. For example, when resistance is measured by 
using the same resistance definition as is used by CDC, the resistance 
of Enterococcus faecium from healthy humans to quinupristin/
dalfopristin (Synercid) increased from 29 percent in 1997 to 35 
percent in 2004, 54 percent in 2005, and 37.5 percent in 2006. The 
animal equivalent drug (virginiamycin) was banned in Denmark in 1998. 
While virginiamycin is still approved and used in the United States, 
the level of resistance in humans (3.7 percent) in the United States is 
10 times less than in Denmark.
    In another situation, resistance of Enterococcus faecium to 
vancomycin in healthy humans has remained at 0 percent. This may be 
associated with the ban on the use of avoparcin in animals. (Avoparcin 
has never been approved for use in the United States). Alternatively, 
this may also be associated with a different pattern of vancomycin use 
in human medicine in Denmark.

    Question 2. Wasn't there a significant increase in the quantities 
of antimicrobials used for therapeutic purposes?
    Answer 2. Yes, the increase in disease, or the need to prevent 
disease that was previously prevented by antimicrobial growth promoters 
has resulted in a 152 percent increase in the quantity of 
antimicrobials used for therapeutic purposes. Unfortunately, the 
antimicrobials now used are at higher doses and in classes that are 
also used in humans, such as tetracyclines.\1\

    Question 3. What is the difference between what Denmark and other 
EU countries have done compared to what Senator Kennedy proposes in his 
legislation?
    Answer 3. Even though the results of the Danish experience with 
antimicrobial growth promotant drug bans is very mixed, proposals 
within the United States, such as PAMTA, go beyond the Danish example 
by proposing to ban uses for the prevention and control of disease, in 
addition to uses to promote growth and feed efficiency. Evidence shows 
that the Danish ban (and a ban in the United States, if instituted) 
will cause animal health and welfare problems.

    Question 4. Many people have never spoken to animal producers to 
understand what non-therapeutic uses of antibiotics means. Can you 
please explain why animal producers use antibiotics for non-therapeutic 
uses and what ``non-therapeutic uses'' means exactly?
    Answer 4. The terms non-treatment or non-therapeutic have no true 
definition and often cause confusion. Treatment, control, and 
prevention of disease are classified as therapeutic uses by the FDA, 
AVMA and Codex Alimentarius Commission (an organization of the World 
Health Organization and the Food and Agricultural Organization of the 
United Nations). The use of exclusionary terms, such as non-
therapeutic, that are ill-defined and have no clear definition only 
serves to further confuse the issue. We caution against the use of 
these terms, as it is defined by some groups, because it could 
potentially disallow veterinary discretion in control or prevention of 
disease and consequently interfere with the practice of veterinary 
medicine.
    In addition to treatment, control, and prevention of disease, the 
FDA also approves antimicrobials for growth promotion or feed 
efficiency. The antimicrobials that have been approved for growth 
promotion or feed efficiency are sometimes not in the same classes as 
antimicrobials that are used in human medicine and thus do not 
contribute to human resistance concerns. In addition, antimicrobials 
approved for growth promotion or feed efficiency have been shown to 
have health-promoting effects.

    Question 5. Have non-therapeutic uses of antimicrobials negatively 
impacted human health?
    Answer 5. We don't know if growth promotion and feed efficiency use 
has impacted human health but we believe that any impact is minimal if 
it exists. Because the human health impact is not known is the reason 
why we recommend that risk assessments be performed to aid the risk 
management decision process.
    It is clear that any use of antimicrobials, whether in humans or 
animals, can foster resistance. However, what is not clear is whether 
resistance in animals results in an impact on human health. While there 
has been much speculation, there has been little evidence indicating a 
negative impact on human health as a result of antimicrobial use in 
animals. And the Danish experience has not demonstrated an improvement 
in human health that resulted from the ban. However, there is a fair 
amount of evidence indicating that broad based bans on antimicrobial 
use has resulted in significant declines in animal health and could 
potentially harm human health.
    Information from resistance monitoring systems, such as NARMS, 
indicates that there is not a public health crisis associated with 
resistant pathogens that may originate in animals. For example, NARMS 
data, when combined with FoodNet data, demonstrates that the case rate 
of human infections with multidrug resistant Salmonella spp. has 
decreased 49 percent between the NARMS baseline years of 1996-98 and 
2004 (the most current, publicly available human data from NARMS). In 
addition, there has been a 65 percent reduction in the case rate of 
penta-resistant Salmonella Typhimurium infections. Non-typhi Salmonella 
spp. are one-half as likely to be resistant in 2004 than in 1996. 
Resistance of Enterococcus faecium to quinupristin/dalfopristin 
(Synercid) decreased from 20.9 percent in 2001 to 3.7 percent in 2004. 
As mentioned earlier, the resistance rate in 2004 is 10 times less than 
the resistance rate in Denmark, where the animal equivalent 
antimicrobial, virginiamycin, has been banned for 10 years. Resistance 
of E. faecium to other antimicrobials or antimicrobial classes, such as 
vancomycin and aminoglycosides, also decreased from 2001 to 2004. 
Escherichia coli 0157 is one-third as likely to be resistant in 2004 
compared to 1996.
    Several risk assessments have been performed that demonstrate a 
very low risk to human health from the use of antimicrobials in food 
animals, and some of the models predict an increased human health 
burden if antimicrobial use is withdrawn. The unique farm-to-patient 
risk assessment performed by Hurd demonstrates that the use of tylosin 
and tilmicosin in food animals presents a very low risk of human 
treatment failure because of macrolide resistance, with an approximate 
annual probability of less than 1 in 10 million with Campylobacter 
infections and approximately 1 in 3 billion E. faecium infections.\2\ 
Cox performed a quantitative human health risks and benefits assessment 
for virginiamycin and concluded that there would be a significant human 
health risk if virginiamycin use is withdrawn. There would be 6,660 
excess cases per year of campylobacteriosis, which far outweighs the 
0.27 per year reduction of cases of streptogramin-resistant and 
vancomycin-resistant E. faecium (VREF) resulting from the 
withdrawal.\3\ Cox also performed a risk assessment regarding macrolide 
and fluoroquinolone use and concluded that withdrawal is estimated to 
cause significantly more illness days than it would prevent.\11\ Cox 
also examined the impact of the use of penicillin-based drugs in food 
animals on penicillin/aminopenicillin resistant enterococcal infections 
and concluded that not more than 0.04 excess mortalities per year 
(under conservative assumptions) to 0.18 excess mortalities per year 
(under very conservative assumptions) might be prevented in the whole 
U.S. population by discontinuing current use of penicillin-based drugs 
in food animals. The true risk could be as low as zero.\4\ This equates 
to one potentially preventable mortality in the U.S. population roughly 
every 7-25 years. Alban's risk assessment concluded that the risk 
associated with veterinary use of macrolides in Danish pigs resulted in 
a low risk to human health.\5\ Others have estimated that risk 
management strategies that focus on eliminating resistance are expected 
to create 
Aminopenicillin Resistance in Enterococci Due to Penicillin Use in Food 
Animals. 2008. In Press.
    5. Alban, L. et al. A human health risk assessment for macrolide-
resistant Campylobacter associated with the use of macrolides in Danish 
pig production. Prey Vet Med 2008; 83:115-129.
    6. Phillips I. et al. Does the use of antibiotics in food animals 
pose a risk to human health? A critical review of published data. J of 
Antimicrobial Chemotherapy 2004: Vol 53, pp 28-52.
    7. Cox LA. et al. Quantifying Human Health Risks from Animal 
Antimicrobials. Interfaces. 2007; 37:22-38.
    8. Animal Medicinal Drug Use Clarification Act (AMDUCA) Compliance 
in Drug Use--The therapeutic administration of any approved dosage form 
drug in a manner that is not in accordance with the drug's labeling 
requires additional management. AMDUCA regulations are in force for all 
approved therapeutic dosage form drugs if administered in a manner not 
in accordance with the drug's labeling. For such usage, the FDA 
specifies that the following criteria must be met:

     Make a careful diagnosis and evaluation of the conditions 
for which the drug is to be used.
     There is no approved animal drug that is labeled for such 
use, or that contains the same active ingredient in the required dosage 
form and concentration. Alternatively, an approved animal drug exists, 
but a veterinarian finds, within the context of a veterinarian/client/
patient relationship, that the approved drug is clinically ineffective 
for its intended use.
     Assure that the identity of the treated animal(s) is 
carefully maintained.
     Establish a substantially extended withdrawal period 
supported by appropriate scientific information prior to marketing 
milk, meat, eggs, or other edible products from the treated animal(s).
                                 ______
                                 
                      Cubist Pharmaceuticals, Inc.,
                                       Lexington, MA 02421,
                                                     July 30, 2008.
Hon. Edward M. Kennedy, Chairman,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, DC 20510.

ATTN: Laura Kwinn, Ph.D.

    Dear Chairman Kennedy: Thank you for convening the June 24, 2008 
hearing on ``Emergence of the Superbug: Antimicrobial Resistance in the 
U.S.'' and for inviting me to participate as a witness.
    As you know, antimicrobial resistance presents a serious threat to 
the public health which must be immediately addressed. Cubist 
appreciates your leadership in this area and your willingness to work 
with all stakeholders to find the appropriate legislative solutions.
    Enclosed, please find my answers to the questions for the record. I 
look forward to continuing the dialogue with you and your staff and I 
am happy to provide additional materials as needed. Please feel free to 
contact me at any time.

                                  Barry I. Eisentein, M.D.,
                                             Senior Vice President,
                         Scientific Affairs Cubist Pharmaceuticals.
                                 ______
                                 
Response to Questions of Senator Kennedy, Senator Brown, Senator Burr, 
             and Senator Hatch by Barry I. Eisenstein, M.D.
                      question of senator kennedy
    Question.  You mentioned Federal incentives to increase research 
into biodefense agents such as Project Bioshield and the Biomedical 
Advanced Research and Development Authority. Do you think research into 
development of new antimicrobials should be included in those programs?
    Answer. Antimicrobials are clearly an important category of 
therapeutic countermeasures against select agents such as anthrax. The 
Biomedical Advanced Research and Development Authority (BARDA) provides 
Federal funding for the development of new vaccines, diagnostics and 
therapeutics to combat health threats. BARDA also manages Project 
Bioshield, which focuses on advanced development for bioterrorism 
countermeasures through expedited procedures and guarantee purchase 
agreements. These initiatives serve as existing opportunities that 
should be explored in regards to spurring new antimicrobial research 
and development, as antimicrobial resistance is a clear public health 
threat.
                       question of senator brown
    Question.  Fifteen years ago, the Office of Technology Assessment 
urged Congress to develop new antibiotics specifically to treat 
infections caused by antibiotic-resistant bacteria. Not much has 
happened since then to address this growing problem. Can you discuss 
how development incentives may differ for small companies versus big 
PhRMA companies?
    Answer. As you may know, I was part of the expert panel of 
consultants involved in this Office of Technology Assessment report. 
Large pharmaceutical companies generally have a scope of resources and 
a stable risk profile that can tolerate the high-cost, high-risk 
research targeted to relatively small populations, such as anti-
microbial research and development. Investigative and small biomedical 
companies operate in an arena far more challenging: these emerging 
companies have no revenue stream; depend on venture funding with pre-
established investment windows; and face large intellectual property 
and scientific start-up costs. Incentives which would lower these 
barriers to entry in order to attract private funding are integral for 
small companies. Tools such as research and development tax credits, 
orphan drug tax credits, orphan product designations, net operation 
loss carry-forwards and priority review vouchers can act to help infuse 
capital into early- and mid-market companies. Incentives that allow 
greater economic value later in the course of drug development life, 
such as extension of patent rights and market exclusivity, will benefit 
large companies.
    Regulatory hurdles also exist; the removal of which may spur 
innovation and interest in the antimicrobial field for both small and 
large companies. As you may know, the effectiveness of older 
antibiotics were reviewed and approved with technology that is now 50 
years old. Reviewing these older lines of antibiotics to examine their 
modern effectiveness would help new antibiotic products gain a greater 
appreciation, and thus assist innovative small and large companies.
    Specifically, older antibiotics reflect standards of measuring 
antibiotic resistance which are decades old and now outdated. Newer 
compounds must meet more rigorous tests of resistance but must still 
compete against the older, already approved drugs. This compromises 
patient safety since the effectiveness of older antimicrobials is 
called into question, but also puts newer compounds at a competitive 
disadvantage--they face higher barriers to market entry. Periodic 
review by the FDA of the ``breakpoint'' (labeled concentration at which 
a compound is considered resistant) for older compounds will benefit 
patients as well as ensure a fair playing field for approval of newer 
antibiotics.
    In addition to the outdated ``breakpoints'' of these older 
compounds, approval standards necessary to demonstrate safety and 
effectiveness for older antimicrobials were less rigorous than modern 
standards, allowing approval of a broad array of indications for older 
antibiotics with comparatively less scientific data. New antibiotics 
cannot be approved for a broad array of indications without meeting 
significantly more rigorous scientific standards, making these drugs 
appear, by comparison to older drugs, to be weaker, less potent, and 
less broadly effective. Clinical guidelines often follow approved, 
labeled indications to set standards of care, thus the commercial 
opportunities for newer compounds are more limited and lead to lower 
returns on investment. This is particularly true in light of current 
``antibiotic stewardship'' practices which conserve use of new 
antimicrobials to delay emergence of resistance. Adherence to exacting 
scientific standards is, of course, appropriate. These standards should 
be applied to new drugs as well as older compounds, not only for the 
purposes of commercial fairness, but also to ensure patients are 
receiving the most effective drugs available.
                        question of senator burr
    Question.  In your testimony, you identified some possible 
incentives to encourage the development of antimicrobial products by 
pharmaceutical and biotech companies. You mentioned encouraging HHS and 
individual hospitals to stockpile antimicrobials. You also suggested 
guaranteed market contracts similar to Project Bioshield. In the 
Bioshield arena, we learned there needed to be a stronger emphasis on 
advanced development, which is why we created the Biomedical Advanced 
Research and Development Authority (BARDA). You suggested small 
contracts of $50 million could provide the incentive necessary for 
antimicrobial R&D. That figure seems low to me. From a business 
standpoint, how much impact can a $50 million development contract 
have? Are there other things that provide an even greater disincentive 
for companies that we need to focus on?
    Answer. Contracts of $50 million would be at the lower end of the 
spectrum for small and mid-sized biopharmaceutical companies; such sums 
would provide a small, but not substantial, incentive for research and 
development. Additionally, the earlier such an investment is made, the 
greater the potential benefits to a start-up company without marketed 
products or revenue. As I have witnessed first hand, antimicrobial R&D 
is an expensive endeavor and the marketplace is challenging even for 
successful products.
    Again, the current regulatory environment may provide the greatest 
disincentive to antimicrobial development as it tilts the playing field 
toward older, less-effective products. The Infectious Disease Society 
of America as well as the Clinical Laboratory Standards Institute 
determined that the labels of many older antibiotics are outdated and 
fail to reflect current anti-infective resistance. Additionally, these 
labels reflect approval for indications that may not be appropriate 
under today's scientific standards. I strongly agree with these 
findings and feel these outmoded labels give a false sense of 
confidence to physicians and the public. FDA recently addressed these 
concerns by partially lowering the breakpoint for vancomycin--but the 
persistent loss of drug potency requires continued review by the FDA.
                       question of senator hatch
    Question.  Dr. Eisenstein, you discussed in your testimony your 
concerns regarding the lack of Medicare coverage for home infusion of 
intravenous antibiotics. In some instances, Medicare beneficiaries 
either stay in the hospital longer in order to continue receiving their 
IV antibiotics or they travel to the hospital for daily infusions. Both 
scenarios cause difficulties for Medicare beneficiaries and encourage 
additional spending in the Medicare program. Additionally, if the 
Medicare beneficiary has Methicillin-resistant Staphylococcus aureus, 
better known as MRSA, shouldn't we be discharging these patients from 
the hospital as soon as possible to reduce the spread of MRSA to other 
patients?
    Answer. In general, yes, we should be discharging patients from the 
hospital ASAP. Medicare coverage of home infusion services would allow 
patients to receive a daily dose of IV antibiotics safely and 
effectively at home. Home infusion, a medical service carried by many 
private insurers, has been found to be easier and more convenient for 
patients, safer for patients and hospital providers, and good public 
health policy as it removes infected patients from the hospital and 
reduces the risk of its spread. Home infusion can also be far less 
costly for patients and payers. In fact, many private health plans, 
including those provided to Senators and their staff through the 
Federal Employees Health Benefits program, recognize the benefits of 
home infusion and provide comprehensive coverage and reimbursement for 
all necessary home infusion components.
    Unfortunately, Medicare--unlike the overwhelming majority of other 
health plans--provides fragmented and limited coverage and 
reimbursement for home infusion. Some parts of Medicare, like Part C, 
do a good job of providing coverage and reimbursement for all the 
component parts of medical treatment necessary for a comprehensive home 
infusion benefit, including the drug/ingredient supplies; and the 
administration service fee to the provider. Medicare Part B, however, 
pays for some but not all of these components. Missing from Medicare 
Part B reimbursement is the fee for the administration service. This 
situation is akin to Medicare paying for a topical anesthetic for the 
removal of a skin mole in a doctor's office but not paying for the 
doctor to actually perform the service.
    The lack of an administration fee for home infusion services under 
Medicare Part B is a significant problem that Congress should remedy. 
In fact, included in the 2008 MedPAC Report to Congress this March, 
MedPAC identified ``hospital discharge problems'' for those patients 
requiring on-going IV antibiotic infusions.
    In such situations, patients are often kept in the inpatient 
setting longer than necessary simply to assure continued IV antibiotic 
treatment--an obvious cost to Medicare. Other patients who are 
discharged from inpatient care may be required to return to the 
hospital outpatient department for daily IV antibiotic infusions 
because there is no coverage of the administration fee under the home 
infusion benefit. Daily back and forth travel to the hospital is often 
inconvenient and even impossible for Medicare beneficiaries living in 
rural areas. Finally, as your questions note, keeping infected patients 
in the inpatient setting or having them return for daily infusions 
increases the risk of spread of MRSA infection to other patients.
    If home infusion of IV antibiotics were comprehensively covered 
under Medicare Part B, including the administration service fee, this 
would make financial sense for the Medicare program, it would be more 
convenient for beneficiaries (particularly those in rural areas), and 
it would be safer for other patients.

    [Whereupon, at 12:38 p.m. the hearing was adjourned.]


```