[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
__________
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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
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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 < 1 percent of the public health benefit of
strategies that focus on reducing microbial loads in animals or on
foods (1). In another paper, the authors concluded,
``We came to some surprising conclusions that were robust to
many uncertainties. Among these were that antimicrobials that
benefit animal health may benefit human health, while
regulatory interventions that seek to reduce antimicrobial
resistance in animals may unintentionally increase illness
rates (and hence antimicrobial use and resistance rates) in
humans. . . . In conclusion, our analysis suggests that the
precautionary-principle approach to regulatory risk management
may itself be too risky (18).''&
Information derived from studies of organic or antibiotic-free
production practices compared to traditional production practices is
inconclusive, but there are indications that organically grown meat may
have less-resistant organisms but greater prevalence and quantities of
pathogens on the meat. So the greater risk of foodborne illness is
somewhat offset by an increased likelihood of treatment success if
treatment is necessary (2), (19), (20), (21).
The question of what the nature and magnitude of the risk to humans
is can only be answered by performing systematic risk assessments. Such
risk assessments must include identification of the endpoints of
concern (e.g., increased illness or mortality caused by bacteria
resistant to antibiotics used to treat the disease in humans), the
nature of the treatment protocols in food animals, the potential routes
of exposure, characterization of the population at risk, and the
probability of occurrence.
Just because resistant bacteria may develop in animals that then
are transferred to the environment or humans does not necessarily
equate to a human health risk. First, the pathogen may not colonize in
humans to create a foodborne disease. Second, if disease does occur,
antimicrobial therapy may not be needed. In the majority of cases,
treatment is not needed. Supportive therapy, such as fluids, is all
that's needed for most Salmonella, Campylobacter and E. coli
infections. In fact, antimicrobial therapy of E. coli O157 infections
is contra-indicated because such treatment makes the effects of the
disease worse. Third, if antimicrobial therapy is needed, the pathogen
may be susceptible to the drug of first choice. The Therapy Guidelines
for Enteric Infections for non-typhi Salmonella are:
``In uncomplicated infections antimicrobial therapy is not
indicated because it has no effect on clinical illness and
prolongs carriage and excretion of the organism. . . .
Treatment recommended only for young infants (< or = 6 m) and
immunocompromised individuals. Resistance is common. Agents
that can be used include a fluoroquinolone or a third-
generation cephalosporin such as ceftriaxone for 5-7 days.
Ampicillin and co-trimoxazole can be used if the infecting
organism remains susceptible (22).'' NARMS (3) reports the
following resistance percentages of non-typhi Salmonella to
fluoroquinolone (ciprofloxacin)--0.2 percent; third-generation
cephalosporin (ceftriaxone)--0.6 percent; ampicillin--12.0
percent; and co-trimoxazole (trimethoprim-sulfamethoxazole)--
1.8 percent. These resistance levels do not indicate a public
health crisis associated with foodborne Salmonella.
conclusion
The American Veterinary Medical Association is committed to
ensuring judicious veterinary use of antimicrobials. To further
safeguard public health and to maintain the long-term effectiveness of
antibiotics, the AVMA established a profession-wide initiative to
create and implement judicious use guidelines for the therapeutic use
of antimicrobials by veterinarians, and we launched an educational
campaign to raise the awareness of the profession to the issue.
The spread of antibiotic resistance is a public and animal health
concern. There is no question that the human medical profession is
facing extreme challenges because of hospital- and community-acquired
resistant human pathogens. The human medical problem with resistant
nosocomial and community-acquired infections has increased the concern
of possible development of resistant pathogens in animals that could be
transferred to humans through the food supply or environment.
The AVMA shares the concerns of the human medical community, the
public health community, governmental agencies and the public regarding
the potential problem of resistant zoonotic pathogens developing in
animals and then being transferred to humans. However, we emphasize the
importance and primacy of using these medicines to prevent and treat
diseases before they enter our food supply. Passing legislation that
would ban the use of these antibiotics before science-based studies and
risk-based evaluations are done would be detrimental to animal and
human health. Inappropriate reactions to the potential problem could
have unknown and unintended consequences that negatively affect animal
health and welfare, and ultimately, could create other public health
risks, such as increased foodborne disease.
The AVMA is committed to working in concert with CDC, FDA, and USDA
to provide consumers--not only in the United States, but all over the
world--with the safest food possible. The judicious use of
antimicrobials is but one of the essential components of the process
that enables animal agriculture to meet that demand. Other components
include veterinary care, good management practices, biosecurity, proper
nutrition and good husbandry.
The AVMA supports the ongoing scientific efforts of monitoring and
surveillance of foodborne disease and resistant foodborne pathogens,
education, development of new antimicrobials, and other research to
better define the challenges presented by antimicrobial resistance. We
also support adequate funding for such efforts to combat antimicrobial
resistance. These efforts were high-priority tasks in the 2001 version
of the Public Health Action Plan to Combat Antimicrobial Resistance
that was created by a Federal Interagency Task Force on Antimicrobial
Resistance. The Action Plan reflected a broad-based consensus of
Federal agencies and stakeholders on actions needed to address
antimicrobial resistance and provided a blueprint for specific,
coordinated Federal actions that included the full spectrum of
antimicrobial use: human medicine, veterinary medicine and animal
agriculture. We are disappointed that the Action Plan was not
adequately funded and prioritized by Congress. We are also concerned
that the new Action Plan under development appears to not be as
collaborative, broad-based and acceptable to the diverse community of
stakeholders.
The AVMA does not believe that additional legislation is needed to
regulate the uses of antimicrobials in veterinary medicine and animal
agriculture. Additional legislation can put animal health and welfare
and public health at risk. FDA has adequate authority for oversight but
lacks the resources to accomplish its many priorities.
An analysis that compared the regulatory strategy of the European
Union to ban or restrict animal antibiotic uses with the United States'
approach of continued prudent use to prevent and control animal
infections, together with measures to improve food safety, has some
pertinent conclusions. Among these, prudent use of animal antibiotics
may actually improve human health, while bans on animal antibiotics,
intended to be precautionary, inadvertently may harm human health (10).
Increased surveillance of resistance, as well as continued
compliance with judicious use guidelines for veterinarians and
producers, may be sufficient to protect human health against the
current small risks without compromising the health of food animals.
Thank you for the opportunity to appear before you today and speak
about this important issue.
References
1. 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.
2. Antimicrobial Resistance--Implications for the Food System,
Institute of Food Technologists Expert Report, Comprehensive Reviews in
Food Science and Food Safety, Vol 5, 2006 (Available at http://
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.
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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\
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\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.
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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\
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\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\
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\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.
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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.
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\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\
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\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\
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\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.
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(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.
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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 <1 percent of the public health benefit of strategies that
focus on reducing microbial loads in animals or on foods.\6\ Programs
such as farm-to-fork pathogen reduction are much more effective than
antimicrobial restrictions or bans in mitigating human health risks. In
another paper, the authors concluded, ``We came to some surprising
conclusions that were robust to many uncertainties. Among these were
that antimicrobials that benefit animal health may benefit human
health, while regulatory interventions that seek to reduce
antimicrobial resistance in animals may unintentionally increase
illness rates (and hence antimicrobial use and resistance rates) in
humans. . . . In conclusion, our analysis suggests that the
precautionary-principle approach to regulatory risk management may
itself be too risky.'' \7\
Question 6. Please explain how a veterinarian prescribes
antibiotics.
Answer 6. Dispensing or prescribing a prescription product
(including antimicrobials) requires a veterinarian-client-patient
relationship (VCPR). The VCPR is the basis for interaction among
veterinarians, their clients, and their patients. Veterinary
prescription drugs are to be used or prescribed only within the context
of a VCPR.
The veterinarian must have sufficient knowledge of the animal(s) to
initiate at least a general or preliminary diagnosis of the medical
condition of the animal(s). This means that the veterinarian has
recently seen and is personally acquainted with the keeping and care of
the animal(s) by virtue of an examination of the animal(s), or by
medically appropriate and timely visits to the premises where the
animal(s) are kept.
Veterinarians making treatment decisions must use sound clinical
judgment and current medical information and must be in compliance with
Federal, State, and local laws and regulations. The veterinarian must
also include consideration of: judicious use principles; food safety
and public health; and producer education as a part of the treatment
plan.
After considerations have been made for both animal and human
health impact, veterinary authorization is required prior to dispensing
of the prescription product.
Question 7. What happens if a veterinarian is complicit in an off-
label use of animal drugs? Are there penalties for this? Who enforces
these rules? In recent years have there been any enforcement actions
taken? What were the outcomes?
Answer 7. The Animal Medicinal Drug Use Clarification Act \8\
(AMDUCA) made extra-label drug use (ELDU) (off-label use) legal when
the ELDU regulations are followed by the veterinarian. Without a valid
veterinarian-client-patient relationship (VCPR), extra-label use of any
pharmaceutical is unethical and is illegal under Federal law. Given the
numerous animal species and diversity of disease conditions that affect
animals, the indications for FDA approved drugs are severely limited.
The numbers of FDA approved drugs are inadequate to meet veterinary
medical needs, placing both animal health and potentially human health
at significant risk. As a result, extra label drug use is a medically
necessary provision authorized by the U.S. Congress through AMDUCA to
relieve the pain and suffering of millions of animals. The ELDU of
medicated feeds is strictly prohibited. The FDA, in conjunction with
the State boards of veterinary medicine (which license veterinarians),
enforce ELDU and prescribing regulations. Penalties for violation of
these regulations range from investigations and warning letters to
suspension and loss of licensure. There is also the potential for civil
and criminal penalties for violation of these regulations. However,
AVMA does not enforce ELDU regulations and therefore does not have
record of enforcement actions or outcomes of any violations.
endnotes
1. 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.
2. Hurd S. et al. Public Health Consequences of Macrolide Use in
Food Animals: A Deterministic Risk Assessment. J Food Protection 2004;
67:980-992.
3. Cox LA. Potential human health benefits of antibiotics used in
food animals: a case study of virginiamycin. Environ Int 2005; 31:549-
63.
4. Cox LA. et al. Human Health Risk Assessment of Penicillin/
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.]