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Jane E. Henney, Ph.D - Royal Society of Medicine

"This text contains Dr. Henney's prepared remarks. It should be used with the understanding that some material may have been added or deleted during actual delivery."

Remarks by:
Jane E. Henney, Ph.D
Commissioner of Food and Drugs
U.S. Food and Drug Administration
for

FDA Perspective on Antimicrobial Resistance
Royal Society of Medicine Conference
On
Anitimicrobila Resistance

Washington, D.C.

May 5, 2000

I'm pleased to be here today to talk about FDA's perspectives on antimicrobial resistance. Our goal is to be sure that practitioners have a continued supply of safe and effective antimicrobials available to protect the health of both humans and animals. But that is becoming increasingly difficult.

Antibiotics are different from most of the other drugs approved by FDA, because their effectiveness is so fragile. We need to protect that effectiveness by using them in a thoughtful way, based on science and not on the most current advertising strategy. If drugs are overused, or misused...they won't be there for us when our patients need them.

We should look at our array of antibiotics as a valuable resource that deserves careful protection. And, as with most issues that involve fragile resources, this one has global ramifications. With frequent and wide-ranging air travel and extensive immigration, we are able to pass our pathogens to one another with frightening speed. That means that in order for us to succeed in our effort to use antibiotics wisely, similar steps must be taken by nations around the world.

Many factors are involved in the development of antibiotic resistance, and in managing it. Many of these are working at cross-purposes. We all must concede the fact that individually and collectively we are a part of the problem, and acknowledge that it will take all of our efforts to arrive at the solution.

First of all, the medical profession plays an important role in this issue. Physicians tell us that patients often pressure them to prescribe antibiotics. They may have limited time to explain the rationale for NOT using an antibiotic, or for using an alternative treatment. They may not have rapid access to antibiotic sensitivity testing. It can be far too tempting to go ahead and prescribe an antibiotic.

And since this is often a shot in the dark, because the bacteria have not been identified, the physician is further tempted to prescribe a blockbuster antibiotic that will have the greatest chance of working.

A colleague of mine told an interesting story. She was waiting in line at the pharmacy in a hospital in the Washington area. This was just outside the outpatient surgery area. She was the fifth person in line. Now this was shortly after a particular fluoroquinolone was approved. I won't mention the name of the product. The point is that, believe it or not, every single person in the line in front of her was given this new fluoroquinolone. And so was she. It was the blockbuster antibiotic of the day. One might conclude that it was being pushed a little too hard and perhaps used when it wasn't necessary.

Now, once the antibiotic is prescribed, a lack of patient compliance may also contribute to resistance. Patients, either by omission or commission, often don't take the antibiotic according to directions, and frequently fail to take the entire course of antibiotics. Instead, they stop taking it when they feel better, and then save the rest for the next time...or share the leftover drug with a sick friend.

It's not easy to accurately establish the extent of overuse and/or inappropriate use of antibiotics by the medical profession, but several studies have given estimates that present a picture of substantial overuse of these products. Office-based physicians in the U.S. write more than 100 million antibiotic prescriptions each year. According to the CDC, as many as half of those prescriptions-a total of 50 million-are unnecessary. They're prescribed for the common cold and other viral infections, including influenza.

A recent study of paid Medicaid claims for treatment of respiratory tract infections in Kentucky found that 60 percent of adults received antibiotics to treat the common cold(1).

A survey of the prescribing patterns of office-based physicians in the U.S. in 1992 found that approximately 12 million antibiotic prescriptions, or 21% of all antibiotic prescriptions for adults, were written to treat colds, upper respiratory tract infections and bronchitis, even though 90% of these diseases are caused by viruses(2).

Clearly, these unnecessary prescriptions can have serious consequences in terms of increasing the selective pressure on bacteria to develop and spread resistant strains.

Adding to the problem are the marketing practices of pharmaceutical companies, which are geared to persuading health professionals to buy and use their products. And with well over 50,000 detail people, there are effective means to get a message out. A recent article in USA Today commented that, "Physicians must be honest with themselves and with their patients. Decisions on which prescriptions to write must be made in accordance with the best scientific evidence, not on the best marketing campaign."

Even if all antibiotic use were prudent and appropriate, the problem of antibiotic resistance would not go away entirely.

We need to educate physicians and the public about the resistance problem and encourage more judicious use of antimicrobial drugs. To this end, we believe it's important to include additional information in the labeling of prescription antibiotics.

This summer we'll be proposing a regulation that will require statements on prescription antibiotic labeling that discuss the appropriate use of antibiotics and how to reduce the development of drug-resistant microorganisms.

The recently approved antimicrobial, Zyvox®, has some of this language in its package labeling. Under Indications and Usage, the labeling states, "Due to concerns about inappropriate use of antibiotics leading to an increase in resistant organisms, prescribers should carefully consider alternatives before initiating treatment with Zyvox® in the outpatient setting."

It goes on to say, "Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to linezolid [Zyvox®]. Therapy may be instituted empirically while awaiting the results of these tests. Once these results become available, antimicrobial therapy should be adjusted accordingly."

Under Precautions, the Zyvox® label states, "The use of antibiotics may promote the growth of nonsusceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken."

We believe that having more of this type of information on product labeling will influence prescribing behavior, and that the Zyvox® labeling is a step in the right direction.

As another example of what's happening in the human antimicrobial area--we're using the accelerated approval process for critical antibiotics, so that these products can be brought to market in a shorter time. Two of the most recent approvals--Synercid® and Zyvox® --were reviewed using this process.

We're also encouraging the development of new vaccines to help reduce the need for antibiotics. By the same token, we want to facilitate the development of new diagnostic tests that can determine with certainty whether an infection is bacterial, and if it is, help identify an appropriate antibiotic for treatment.

Let me next address our effort in the area of antimicrobial use in food-producing animals-an area of controversy that has spanned the past 30 years.

Antibiotics have, for decades, played a key role in ensuring the health of food animals. And, as you know, producers have used these same products as growth promoters, and as a result, consumers have enjoyed safe food products at reasonable prices.

In 1999 FDA developed the "Framework document," to address these concerns. Actually, the complete title is "A Proposed Framework for Evaluating and Assuring the Human Safety of the Microbial Effects of Antimicrobial New Animal Drugs Intended for Use in Food-Producing Animals."

The proposed Framework is a discussion document that describes the agency's best thinking as to how to evaluate the microbial safety of antimicrobials for use in food animals. Using the concepts described in the framework we will be able to assess not only new antibiotics, but also previously approved antibiotics.

In establishing the framework, we've developed a sound science and risk-based approach to the antimicrobial resistance issue. We are well on our way to implementing the concepts articulated in the framework. We're currently requiring companies to conduct a microbial hazard assessment for all new antimicrobials to be used in food animals.

Depending on the results of this assessment, the drug sponsor may need to conduct pre-approval studies to assess the rate and extent of resistance development in pathogens or commensals of human health concern. We'll be issuing a guidance document in the near future to more specifically outline the pre-approval study requirements. In addition, we'll hold a scientific workshop this October to outline our approach and seek public input on the establishment of resistance and monitoring thresholds.

I'd also like to note that the veterinary medical profession is developing prudent use guidelines, and we're actively supporting their efforts.

So that we'll have a workable mechanism for regulating these drugs, the Framework sets out three categories of antimicrobial drugs. The categories will be based on the drug's unique or relative importance to human medicine.

The first category would include antimicrobial drugs that are:

  1. essential for treating a serious or life-threatening disease in humans, and for which there is no satisfactory alternative treatment,
  2. important for the treatment of foodborne diseases in humans where resistance to alternative antimicrobial drugs may limit therapeutic options, or
  3. in a class of drugs for which the mechanism of action and/or the nature of resistance-induction is unique, resistance to the antimicrobial drug is rare among human pathogens, and the drug holds potential for long-term therapy in human medicine.

Any microbial that can induce or select for cross-resistance to a Category I drug would be considered a Category I drug. At the same time, if an antimicrobial is not used in human medicine, and if it does not induce cross-resistance to any antimicrobials in the same class used in human medicine that are Category I, then it would not be considered a Category I drug.

Some examples of Category I drugs would be:

  1. Quinolones for serious infections caused by multi-drug resistant Salmonella.
  2. Vancomycin for serious infections caused by methicillin-resistant S. areus, and ampicillin-resistant enterococci.
  3. Synercid® for vancomycin-resistant enterococcal infections, and
  4. Third generation cephalosporins used to treat foodborne infections.

Category II drugs are those drugs that don't meet the criteria for Category I, They're drugs of choice or important in the treatment of a potentially serious disease, whether foodborne or otherwise, but for which there are satisfactory alternative therapies.

Again, any antimicrobial that can induce or select for cross-resistance to a Category II drug would be considered a Category II drug. And, if an antimicrobial is not used in human medicine, or does not induce cross-resistance to any antimicrobials in the same class used in human medicine that are Category II, then it would not be considered a Category II drug.

Some examples of Category II drugs would be:

  1. Ampicillin for treating Listeria moncytogenes infections. This disease IS life-threatening but alternative treatments are available.
  2. Cephalosporins that are not in Category I, and do not induce cross-resistance to those in Category I.
  3. Erythromycin for treating Campylobacter infections, and
  4. Trimethoprim-sulfamethoxasole for treating serious enteric infections including susceptible Salmonella and Shigella infections.

The final category, Category III, includes drugs that do not meet the criteria for Category I or Category II and have little or no use in human medicine, and are not the drug of first choice or a significant alternative for treating human infections including foodborne infections.

Examples of Category III drugs would be the ionophores (such as Monensin®), which currently have no use in human medicine. Another example would be the polymixins (such as Polymixin B® and colistin) since they are rarely, if ever, used in human medicine today.

As you know, the chain of events that leads to the transfer of antimicrobial resistance from animals to humans is complex. It includes the ability of the drug to induce resistance in bacteria, and the likelihood that use of the drug in food-producing animals will promote resistance. It also includes the likelihood that any resistant bacteria in or on the animal will then be transferred to humans. The final link in this chain of events is the likelihood that such transfer will result in loss of availability of human antimicrobial therapies.

As part of the framework, we would characterize the likelihood of human exposure to resistant, foodborne pathogens as HIGH, MEDIUM or LOW. To do this we look at the drug's attributes-for example, its mechanism and rate of resistance induction, and its induction of cross-resistance to other related or unrelated drugs. We also evaluate how the product is used, and other relevant factors such as animal and manure management practices, environmental contamination, and food processing.

The extent of data required before and after approval of a new antimicrobial drug will depend upon the categories into which the drug falls, and what the potential is for human exposure. So, for example, approval of a Category I drug with HIGH potential for human exposure, would require the most data-that is, pre-approval studies on resistance and pathogen load, and the establishment of resistance and monitoring thresholds. On the other end of the spectrum, for a Category III drug with LOW potential for human exposure, pre-approval data on antimicrobial resistance would not be necessary.

To make this Framework operational we depend upon an effective resistance surveillance system and scientifically sound risk assessments. We can now obtain valuable resistance data through the National Antimicrobial Resistance Monitoring System (NARMS). NARMS was developed in 1996 as a collaborative surveillance effort by FDA's Center for Veterinary Medicine, the Centers for Disease Control and Prevention, and the U.S. Department of Agriculture. This system allows us to prospectively monitor changes in the antimicrobial susceptibility of selected zoonotic, enteric pathogens.

Currently, NARMS monitors the susceptibility of Salmonella and E. coli to 17 antimicrobial drugs, including ciprofloxacin, ceftriaxone, and ceftiofur, and tetracycline, and others. NARMS also monitors susceptibility of Campylobacter isolates to eight antimicrobial drugs-among them--azithromycin, ciprofloxacin, clindamycin, erythromycin, and tetracyline.

Seventeen state and local health departments submit human clinical isolates of non-typhoid Salmonella and E. coli. Eight state health departments submit human clinical Campylobacter isolates. And four states submit Campylobacter isolates from retail poultry. In 1998, NARMS was expanded to include sentinal sites at veterinary diagnostic laboratories.

The U.S. Department of Agriculture conducts animal isolate testing is done at their Agricultural Research Service Russell Research Center. And the Centers for Disease Control and Prevention conducts testing on human isolates at their National Center for Infectious Diseases Foodborne Disease Laboratory.

NARMS is proving to be a valuable source of resistance data, and is helping us characterize the scope of the resistance issue, and monitor changes.

Now...to the issue of risk assessment. Last December, FDA released a draft quantitative risk assessment that modeled the human health impact of fluoroquinolone-resistant Campylobacter infections associated with the consumption of chicken. We used data from NARMS, CDC's case control studies, FoodNet, and other sources, for the risk assessment. We'll finalize the results of the risk assessment by early this summer, but the results did indicate that there is an impact on human health from fluoroquinolone-resistant Campylobacter acquired from chickens.

And we've initiated a second risk assessment. This one will examine the indirect transfer of resistance from animals to humans. The focus will be on the impact of virginiamycin use in food animals and on the ability to treat Enterococcus faecium in humans with the recently approved human antimicrobial, Synercid® .

Ultimately, we want to ensure that significant human antimicrobial therapies are not compromised or lost due to use in animals. At the same time, we want to provide for the use of safe and effective antimicrobials in food animals. There's been a lot of discussion lately about the human health impact associated with the use of fluoroquinolones in chickens. We're looking at this issue carefully--using a science-based, risk-based approach to dealing with these questions. In addition to including fluoroquinolones among the drugs to be monitored under the NARMS surveillance system, in 1997 we issued an order to prohibit all extralabel use of fluoroquinolones in food animals to limit the development of resistance. We're also working with drug sponsors to explore what can be done to curb a further increase in fluoroquinolone resistance in Campylobacter.

The other major issue related to the use of antimicrobials in food-producing animals is their subtherapeutic use in livestock. While this use of antimicrobials is decreasing, it is still a widespread practice. We're taking a renewed look at this practice, and are focusing our efforts on those uses that seem to pose the greatest potential risk to public health. As in all of our decision-making, science will be used to ground and guide our actions.

These are some of the FDA's initiatives and the continued tasks that lie ahead. Let me once again underscore that to adequately address this public health issue, it will take responsible action by more than just federal agencies. It's going to take energy and determination on the part of the medical and veterinary professions, and the pharmaceutical and animal health industry.

Our highest priority should be to ensure that we have safe and effective antimicrobials to protect human and animal health today and in the future. FDA is committed to doing our part to ensure that this happens.

--------------------------------------------------------------------------------

1 Mainous, A.G. III, W.J. Hueston, and J.R. Clark, "Antibiotics and Upper Respiratory Infection. Do Some Folks Think There is a Cure for the Common Cold?" The Journal of Family Practice 1996; 42: 357-61.

2 Gonzales, R., Steiner, J.F., and M.A. Sande, "Antibiotic Prescribing for Adults with Colds, Upper Respiratory Tract Infections, and Bronchitis by Ambulatory Care Physicians," JAMA1997; 278: 901-904.