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S. HRG. 110–989 

EMERGENCE OF THE SUPERBUG: ANTIMICROBIAL 

RESISTANCE IN THE UNITED STATES 

HEARING 

OF THE

COMMITTEE ON HEALTH, EDUCATION, 

LABOR, AND PENSIONS 

UNITED STATES SENATE 

ONE HUNDRED TENTH CONGRESS 

SECOND SESSION 

ON

EXAMINING THE PUBLIC HEALTH IMPACTS OF ANTIMICROBIAL RESISTANT BACTERIAL INFECTIONS IN THE UNITED STATES, FOCUSING ON 

CURRENT ANTIMICROBIALS AND CONTINUED DEVELOPMENT OF NEW 

SOLUTIONS FOR THE FUTURE PROTECTION AGAINST INFECTIOUS 

DISEASES 

JUNE 24, 2008 

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

( 

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

COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS 

EDWARD M. KENNEDY, Massachusetts, Chairman 

CHRISTOPHER J. DODD, Connecticut 

TOM HARKIN, Iowa 

BARBARA A. MIKULSKI, Maryland 

JEFF BINGAMAN, New Mexico 

PATTY MURRAY, Washington 

JACK REED, Rhode Island 

HILLARY RODHAM CLINTON, New York 

BARACK OBAMA, Illinois 

BERNARD SANDERS (I), Vermont 

SHERROD BROWN, Ohio 

MICHAEL B. ENZI, Wyoming 

JUDD GREGG, New Hampshire 

LAMAR ALEXANDER, Tennessee 

RICHARD BURR, North Carolina 

JOHNNY ISAKSON, Georgia 

LISA MURKOWSKI, Alaska 

ORRIN G. HATCH, Utah 

PAT ROBERTS, Kansas 

WAYNE ALLARD, Colorado 

TOM COBURN, M.D., Oklahoma 

J. MICHAEL MYERS, Staff Director and Chief Counsel 

ILYSE SCHUMAN, Minority Staff Director and Chief Counsel 

(II) 

C O N T E N T S 

STATEMENTS 

TUESDAY, JUNE 24, 2008 

Page 

Brown, Hon. Sherrod, a U.S. Senator from the State of Ohio, opening statement ...................................................................................................................... 1 

Tenover, Fred C., Ph.D., Director of the Office of Antimicrobial Resistance, 

Centers for Disease Control and Prevention, Atlanta, GA ............................... 3 

Prepared statement .......................................................................................... 5 

Hatch, Hon. Orrin G., a U.S. Senator from the State of Utah, statement ......... 11 

Tollefson, RADM Linda R., D.V.M., M.P.H., Assistant Commissioner for 

Science ................................................................................................................... 12 

Prepared statement .......................................................................................... 14 

Noble, Brandon, Former NFL Player and MRSA Survivor, Chester Springs, 

PA .......................................................................................................................... 27

Prepared statement .......................................................................................... 29 

Brennan, Patrick J., M.D., President, The Society for Healthcare Epidemiology of America, Philadelphia, PA .................................................................... 30 

Prepared statement .......................................................................................... 32 

Graham, Jay P., Ph.D., MBA, Consultant, The Pew Commission on Industrial 

Farm Animal Production, Baltimore, MD .......................................................... 36 

Prepared statement .......................................................................................... 37 

Vogel, Lyle P., D.V.M., M.P.H., DACVPM, Assistant Executive Vice President, 

American Veterinary Medical Association, Schaumburg, IL ............................ 41 

Prepared statement .......................................................................................... 42 

Eisenstein, Barry I., M.D., Senior Vice President of Scientific Affairs, Cubist 

Pharmaceuticals, Inc., Lexington, MA ............................................................... 49 

Prepared statement .......................................................................................... 51 

ADDITIONAL MATERIAL 

Statements, articles, publications, letters, etc.: 

Durbin, Hon. Richard J., a U.S. Senator from the State of Illinois ............. 66 

Response by Fred C. Tenover, Ph.D. to questions of: 

Senator Kennedy ....................................................................................... 67 

Senator Enzi .............................................................................................. 69 

Senator Brown ........................................................................................... 70 

Senator Burr .............................................................................................. 72 

Response by the Department of Health and Human Services, Food and 

Drug Administration, to questions of: 

Senator Kennedy ....................................................................................... 74 

Senator Brown ........................................................................................... 77 

Senator Burr .............................................................................................. 80 

Response by Patrick J. Brennan, M.D. to questions of: 

Senator Kennedy ....................................................................................... 81 

Senator Brown ........................................................................................... 82 

Senator Burr .............................................................................................. 82 

Response by Jay P. Graham, Ph.D., MBA to questions of: 

Senator Kennedy ....................................................................................... 98 

Senator Burr .............................................................................................. 99 

(III) 

(IV) 

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 

(1) 

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 

2 

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 hospitalbased 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. 

3 

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 

4 

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. 

5 

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 

6 

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 trimethoprimsulfamethoxazole. 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 antiVerDate Nov 24 2008 10:51 Feb 03, 2010 Jkt 035165 PO 00000 Frm 00010 Fmt 6633 Sfmt 6621 S:\DOCS\43267.TXT DENISE
7 

microbial 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. 

8 

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 

9 

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 cephalosporins, 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 disVerDate Nov 24 2008 10:51 Feb 03, 2010 Jkt 035165 PO 00000 Frm 00013 Fmt 6633 Sfmt 6621 S:\DOCS\43267.TXT DENISE
10 

ease. 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 

11 

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 

12 

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. 

13 

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 

14 

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. Communityacquired 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 

15 

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. 

16 

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. 

17 

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 

18 

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 gramnegative 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. 

19 

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. 

20 

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. 

21 

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 laboraVerDate Nov 24 2008 10:51 Feb 03, 2010 Jkt 035165 PO 00000 Frm 00025 Fmt 6633 Sfmt 6601 S:\DOCS\43267.TXT DENISE
22 

tory 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? 

23 

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. 

24 

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. 

25 

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 

26 

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. 

27 

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. 

28 

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. 

29 

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 11⁄2 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. 

30 

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 uriVerDate Nov 24 2008 10:51 Feb 03, 2010 Jkt 035165 PO 00000 Frm 00034 Fmt 6633 Sfmt 6601 S:\DOCS\43267.TXT DENISE
31 

nary/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 

32 

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 prevenVerDate Nov 24 2008 10:51 Feb 03, 2010 Jkt 035165 PO 00000 Frm 00036 Fmt 6633 Sfmt 6621 S:\DOCS\43267.TXT DENISE
33 

tion 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. methicillinresistant Staphylococcus aureus or ‘‘MRSA’’ infections) thereby limiting our theraVerDate Nov 24 2008 10:51 Feb 03, 2010 Jkt 035165 PO 00000 Frm 00037 Fmt 6633 Sfmt 6621 S:\DOCS\43267.TXT DENISE
34 

peutic 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 

35 

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 

36 

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 

37 

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 antimicrobials. 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 antimicrobials 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 quinupristindalfopristin—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). 

38 

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 antimicrobials 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 multidrugresistant 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 

39 

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 diseasecausing 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. 

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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. 

40 

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 Campylobacter 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. 

41 

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. 

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policy/policysearch/default.htm?id=1243. 

World Health Organization. Available at: http://www.who.int/csr/resources/publications/drugresist/en/EGloballStrat.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 draVerDate Nov 24 2008 10:51 Feb 03, 2010 Jkt 035165 PO 00000 Frm 00045 Fmt 6633 Sfmt 6601 S:\DOCS\43267.TXT DENISE
42 

matic 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 

43 

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, 

44 

1Odds ratios were calculated based upon available data from NARMS assuming the reported 

isolates were representative of the bacterial population. 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. 

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 multiagency 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): 

• 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). 

• Salmonella Typhimurium—less than 1⁄2 as likely to be resistant in 2004 than 

in 1996. 

45 

4 Resistant to 2 or more antibiotic subclasses. 

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. 

• 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: 

• Salmonella spp. (non-Typhi)—nearly 1⁄2 as likely to be multi-drug resistant4 in 

2004 when compared to 1996. 

• a highly significant 5 improvement (44 percent relative decrease) in multidrug resistance 4 (decreased from 27.0 percent in 1996 to 15.0 percent in 

2004). 

• 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 multidrug 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 

46 

6Domestically acquired clinical cases. 

7The 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. 8 Avoparcin has never been approved for use in the United States. 

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 in- crease 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. 

• 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

• 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). 

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 

47 

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 

48 

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/antimicrobiallreport.htm). 

49 

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 PHARMACEUTICALS, 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 

50 

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 stateof-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 

51 

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 

52 

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. 4L.L. Maragakis and T.M. Perl, Acinetobacter baumannii: Epidemiology, Antimicrobial Resistance, and Treatment Options, Clinical Infectious Diseases, 2008;46:1254–1263. 

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. 

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. 

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 diVerDate Nov 24 2008 10:51 Feb 03, 2010 Jkt 035165 PO 00000 Frm 00056 Fmt 6633 Sfmt 6621 S:\DOCS\43267.TXT DENISE
53 

5K. 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 landldownloads.html. 7See, 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/policylbriefs/PolicylBrief6lMay08lnewdrugs.pdf. 8See, 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. 9See, 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. 

agnostic 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

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

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

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 

54 

10G. Sakoulas and R.C. Moellering, Jr., Increasing Antibiotic Resistance Among MethicillinResistant Staphylococcus Aureus Strains, Clinical Infectious Diseases, 2008;46:S360–S367. 11G. Sakoulas and R.C. Moellering, Jr., Increasing Antibiotic Resistance Among MethicillinResistant 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. 12See 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. 

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. 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

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 stateof-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

(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 necVerDate Nov 24 2008 10:51 Feb 03, 2010 Jkt 035165 PO 00000 Frm 00058 Fmt 6633 Sfmt 6621 S:\DOCS\43267.TXT DENISE
55 

essary 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 

56 

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 BusinessCooperative Service (RBS) and the Small Business Administration (SBA) Certified 

57 

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, 

58 

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 evidencedbased 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 

59 

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 

60 

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. 

61 

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 macrolides, lincosamides, streptogramin B resistance. That includes erythromycin, 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. 

62 

[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. 

63 

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. 

64 

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. 

65 

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.] 

66 

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. 

67 

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. CharacterizaVerDate Nov 24 2008 10:51 Feb 03, 2010 Jkt 035165 PO 00000 Frm 00071 Fmt 6633 Sfmt 6621 S:\DOCS\43267.TXT DENISE
68 

tion 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 broadreaching 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 

69 

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 extraintestinal 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 communityassociated 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? 

70 

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 antiinfective agents. Laboratory enhancements will include the purchase of state-of-theart 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 

71 

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 

72 

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. 

73 

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. 

74 

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 extralabel 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 penicillincontaining 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 

75 

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 

76 

1Khanna, T., et al. 2007. Methicillin-resistant Staphylococcus aureus colonization in pigs and 

pig farmers, Veterinary Microbiology, doi:10.1016/j.vetmic.2007.10.006. 

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. 

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. 

77 

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 

78 

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 teVerDate Nov 24 2008 10:51 Feb 03, 2010 Jkt 035165 PO 00000 Frm 00082 Fmt 6633 Sfmt 6621 S:\DOCS\43267.TXT DENISE
79 

nets 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? 

80 

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 broadbased 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 § 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 careVerDate Nov 24 2008 10:51 Feb 03, 2010 Jkt 035165 PO 00000 Frm 00084 Fmt 6633 Sfmt 6621 S:\DOCS\43267.TXT DENISE
81 

fully 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 

82 

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 develVerDate Nov 24 2008 10:51 Feb 03, 2010 Jkt 035165 PO 00000 Frm 00086 Fmt 6633 Sfmt 6621 S:\DOCS\43267.TXT DENISE
83 

oped 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/EssentialsloflPublicl ReportinglToollKit.pdf; http://www.shea-online.org/Assets/files/ModellLegislation l-APIClIDSAlSHEA.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. 

84 

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. 

85 

* 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. 

GUIDELINES—INFECTIOUS DISEASES SOCIETY OF AMERICA AND THE SOCIETY FOR

HEALTHCARE EPIDEMIOLOGY OF AMERICA.—GUIDELINES FOR DEVELOPING AN IN- STITUTIONAL PROGRAM TO ENHANCE ANTIMICROBIAL STEWARDSHIP, see www.premierinc.com/safety/topics/guidelines/downloads/CID-Guideline-Antibiotic-Stewardshiplb.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)* 

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 

86 

as reported in an Agency for Healthcare Research and Quality (AHRQ) Evidencebased 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 hospitalacquired 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 

Type of infection No. of infections 

(2002) 

Deaths from 

infections 

(2002) 

Percent 

of fatal 

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. 

87 

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 

Infection type N Controlled 

trials Time series 

Simple before-after studies 

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

88 

Table 3.—Estimates of Preventable Infections and Deaths 

Infection type No. of HAIs1 No. Deaths1

Case 

fatality rate 

[in percent] 

Reduction in 

infection risk 

with QI 

programs2

[in percent] 

Projected no. of 

infections with 

institution of QI 

programs 

Estimated no. 

of preventable 

infections 

Projected no. of 

deaths with 

institution of QI 

programs 

Estimated no. of 

preventable deaths 

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. 

89 

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. 

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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 

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121(2):159–67. PMID: 4014113. 

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PMID: 12919755. 

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TM. The efficacy of infection surveillance and control programs in preventing 

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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. 

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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. 

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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 

Author, Year Study Design Setting Intervention Comparison Risk before intervention Risk after intervention Risk Reduction [in percent] 

Provonost, 2006 ............................ Interrupted time 

series.

ICU patients 

(United States).

Preventive: Hand hygiene; 

maximum sterile barrier; insertion site selection; chlorhexidine disinfection; removal of unnecessary catheters; QI: Clinician education, audit and feedback, clinician reminder, organizational change.

Previous care ........ 7.7 per 1,000 catheter 

days.

1.4 per 1,000 catheter 

days.

82 

Higuera, 2005 ............................... Before-after study ICU patients (Mexico). Preventive: Hand Hygiene; QI: Clinician education, 

audit and feedback, organizational change.

Previous care ........ 46.3 per 1,000 catheter days. 19.5 per 1,000 cath- eter days. 58 

Berenholtz, 2004 ........................... Controlled beforeafter study. ICU patients (United States). Intervention: /Preven- tive: Hand hygiene, maximum sterile barrier, insertion site selection, 

chlorhexidine disinfection, removal of unnecessary catheters; QI: Clinician education, audit and feedback; Control: Clinician education only.

Previous care ........ Intervention 11.3 per 

1,000 catheter days.

Control 5.7 per 1,000 

catheter days.

Intervention 0 per 

1,000 catheter days.

Control 1.6 per 1,000 

catheter days.

100 82 

Coopersmith, 2004 ....................... Before-after study ICU patients 

(United States).

Preventive: Hand Hygiene, 

maximum sterile barrier, insertion site selection; QI: Clinician education.

Previous care ........ 3.4 per 1,000 catheter 

days.

2.8 per 1,000 catheter 

days.

18 

Warren, 2004 ................................ Before-after study ICU patients 

(United States).

Preventive: Hand hygiene, 

maximum sterile barrier, insertion site selection; QI: Clinician education, audit and feedback.

Previous care ........ 9.4 per 1,000 catheter 

days.

5.5 per 1,000 catheter 

days.

42 

92 

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 

Author, Year Study Design Setting Intervention Comparison Risk before intervention Risk after intervention Risk Reduction [in percent] 

Warren, 2003 ................................ Before-after study ICU patients 

(United States).

Preventive: Maximum sterile barrier; insertion site selection; QI: Clinician education, audit and feedback. Previous care ........ 4.9 per 1,000 catheter days. 2.1 per 1,000 catheter days. 57 

Coopersmith, 2002 ....................... Before-after study ICU patients 

(United States).

Preventive: Hand hygiene; 

QI: Clinician education, audit and feedback.

Previous care ........ 10.8 per 1,000 catheter days. 3.7 per 1,000 catheter days. 66 

Eggiman, 2000 ............................. Controlled Beforeafter study. ICU patients (Swit- zerland). Intervention:/Preven- tive: Hand hygiene, maximum sterile barrier, 

chlorhexidine disinfection, removal of unnecessary catheters; QI: Clinician education; Control: No additional measures.

Previous care ........ Intervention (MICU) 

11.3 per 1,000 catheter days.

Control (SICU) 10.3 

per 1,000 catheter days.

Intervention 3.8 per 

1,000 catheter days.

Control 11.6 per 1,000 

catheter days.

–13 (increase) 

Sherertz, 2000 .............................. Before-after study ICU patients 

(United States).

Preventive: Hand hygiene, 

maximum sterile barrier; QI: Clinician education.

Previous care ........ 4.51 per 1,000 catheter days. 2.92 per 1,000 cath- eter days. 35 

93 

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 

Author, Year Study Design Setting Intervention Comparison Risk before intervention Risk after intervention 

Risk 

Reduction 

[in percent] 

Good quality: 

Babcock, 

2004.

Before-after study ...... ICU patients (United 

States).

Preventive: Hand hygiene; 

HOB >30°, daily interruption of 

sedation; QI: Clinician education.

Previous care .............. 8.75 per 1,000 ventilator days 4.74 per 1,000 ventilator days 46 

Zack, 2002 ... Before-after study ...... ICU patients (United 

States).

Preventive: HOB >30°; QI: 

Clinician education.

Previous care .............. 12.6 per 1,000 ventilator days 12.6 per 1,000 ventilator days 55 

Moderate quality: 

Rosenthall, 

2006.

Before-after study ...... ICU patients (Argentina). Preventive: Hand hygiene; QI: Clinician education, audit 

& feedback.

Previous care .............. 51.3 per 1,000 ventilator days 35.5 per 1,000 ventilator days 31 

Salahuddin, 

2004.

Before-after study ...... ICU patients (Pakistan). Preventive: Hand hygiene, HOB>30°; QI: Clinician education, audit & feedback. Previous care .............. 13.2 per 1,000 ventilator days 6.5 per 1,000 ventilator days 51 

Lai, 2003 ...... Before-after study ...... ICU patients (United 

States).

Preventive: HOB>30°; QI: 

Clinician education, audit & feedback.

Previous care .............. SICU: 45.1 per 1,000 ventilator days.

MICU: 22.4 per 1,000 ventilator days.

SICU: 27.9 per 1,000 ventilator days.MICU: 11.6 per 1,000 ventilator days.

38 48 

Kelleghan, 

1993.

Before-after study ...... Not reported (United 

States).

Preventive: Hand hygiene, 

HOB>30°; QI: Clinician education, audit & feedback.

Previous care .............. 17 per 1,000 ventilator days 5 per 1,000 ventilator days ... 71 

94 

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 

Author, Year Study Design Setting Intervention Comparison Risk before intervention Risk after intervention 

Risk 

Reduction 

[in percent] 

Good quality: 

Huang, 2004 Before-after study ...... ICU patients (Taiwan) Preventive: Removal of unnecessary urinary catheters; 

QI: Clinician reminder.

Previous care .............. 11.5 per 1,000 catheter days 8.3 per 1,000 catheter days .. 29 

Greco, 1991 .. Before-after study ...... ICU patients (Italy) ..... Preventive: Aseptic insertion 

and catheter care; QI: Audit and feedback, clinician education, clinician reminder.

Previous care .............. 12.9 per 100 catheters .......... 11.9 per 100 catheters .......... 8 

Moderate quality: 

Topal, 2005 .. Before-after study ...... Ward patients (United 

States).

Preventive: Reduction in 

placement of catheters, removal of unecessary catheters; QI: Clinician education, clinician reminder, organizational change.

Previous care .............. 36 per 1,000 catheter days ... 11 per 1,000 catheter days ... 69 

Rosenthal, 2004 Before-after study ...... ICU patients (Argentina). Preventive: Hand hygiene, aseptic catheter care; QI: 

Audit and feedback, clinician education.

Previous care .............. 21.3 per 1,000 catheter days 12.4 per 1,000 catheter days 42 

Dumigan, 1998 Before-after study ...... ICU patients (United 

States).

Preventive: Aseptic insertion 

and cathter care, removal of unecessary catheters; QI: Clinician education, organizational change.

Previous care .............. SICU: 10.3 per 1,000 catheter 

days.

MICU: 15.8 per 1,000 catheter 

days.

CICU: 15.1 per catheter days

8.6 per 1,000 catheter days ..11.2 per 1,000 catheter days 8.3 per 1,000 catheter days ..

17 

29 

45 

95 

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 

Author, Year Study Design Setting Intervention Comparison Risk before intervention [in percent] Risk after intervention [in percent] Risk Reduction [in percent] 

Good quality: 

Van Kasteren, 

2005.

Interrupted time series Not reported (Netherlands). Preventive: Appropriate use of perioperative antibiotics; 

QI: Audit and feedback, clinician education, clinician reminder.

Previous care .............. 5.4 ........................................... 4.6 ........................................... 15 

Gastmeier, 

2002.

Controlled study ......... ICU (Germany) ............ Preventive: Hand hygiene, 

appropriate use of perioperative antibiotics, decreasing use of preoperative shaving, improving perioperative glucose control; QI: Audit and feedback, clinician education.

Previous care .............. 2.2 ........................................... 1.6 ........................................... 26 

Weinberg, 

2001.

Interrupted time series Not reported (Columbia). Preventive: Appropriate use of perioperative antibiotics; 

QI: Audit and feedback, organizational change.

Previous care .............. Hospital A: 10.5 ......................

Hospital B: 6.1 .......................

0 ..............................................4.4 ...........................................

100 

28 

Greco, 1991 .. Before-after study ...... ICU (Italy) ................... Preventive: Appropriate use 

of perioperative antibiotics, decreasing use of preoperative shaving; QI: Audit and feedback, clinician education, clinician reminder.

Previous care .............. 7.8 ........................................... 6.2 ........................................... 21 

96 

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 

Author, Year Study Design Setting Intervention Comparison Risk before intervention [in percent] Risk after intervention [in percent] Risk Reduction [in percent] 

Moderate quality: 

Dellinger, 

2005.

Before-after study ...... Not reported (United 

States).

Preventive: Appropriate use 

of perioperative antibiotics, decreasing use of peroperative shaving, improving perioperative glucose control; QI: Audit and feedback, clinician education, clinician reminder.

Previous care .............. 2.3 ........................................... 1.7 ........................................... 26 

Borer, 2004 .. Before-after study ...... Operating room 

(Israel).

Preventive: Hand hygiene, 

appropriate use of perioperative antibiotics, decreasing use of preoperative shaving, improving perioperative glucose control; QI: Clinician education.

Previous care .............. 4.2 ........................................... 0 .............................................. 100 

Lutarewych, 

2004.

Before-after study ...... Not reported (United 

States).

Preventive: Improving 

perioperative glucose control; QI: Audit and feedback, clinician education, patient education.

Previous care .............. 7.58 ......................................... 3.47 ......................................... 54 

Rao, 2004 .... Before-after study ...... Not reported (United 

States).

Preventive: Appropriate use 

of perioperative antibiotics, decreasing use of preoperative shaving, improving perioperative glucose control; QI: Clinician education, clinician reminder.

Previous care .............. 2.1 ........................................... 1.5 ........................................... 29 

Won, 2004 .... Before-after study ...... Not reported (Taiwan) Preventive: Hand hygiene; 

QI: Clinician education, audit and feedback.

Previous care .............. 0.33 per 1,000 patient days .. 0.84 per 1,000 patient days .. -154 

(increase) 

97 

Larsen, 1989 Before-after study ...... Operating room 

(United States).

Preventive: Appropriate use 

of perioperative antibiotics; QI: Audit and feedback, clinician reminder.

Previous care .............. 1.1 ........................................... 0.7 ........................................... 36 

98 

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— 

99 

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 nontherapeutic? 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/4301lAgEstimates.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. 

100 

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/EGloballStrat.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 

101 

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 ‘‘nontherapeutic’’ 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. 

102 

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 

103 

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 nontreatment 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 comVerDate Nov 24 2008 10:51 Feb 03, 2010 Jkt 035165 PO 00000 Frm 00107 Fmt 6633 Sfmt 6621 S:\DOCS\43267.TXT DENISE
104 

pany 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 secondopinion 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. 

105 

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, 

106 

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 

107 

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 classiVerDate Nov 24 2008 10:51 Feb 03, 2010 Jkt 035165 PO 00000 Frm 00111 Fmt 6633 Sfmt 6621 S:\DOCS\43267.TXT DENISE
108 

fied 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 nontherapeutic, 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 

109 

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. 

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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 

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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 antimicrobial 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? 

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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 startup 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. 

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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.] 

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