ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **ANTI-INFECTIVE DRUGS ADVISORY**
>
> **COMMITTEE (AIDAC) MEETING**
>
> Wednesday, March 5, 2003
>
> 9:00 a.m.
>
> Marriott Washingtonian Center
>
> Grand Ballroom
>
> 975 Washington Boulevard
>
> Gaithersburg, Maryland
>
> PARTICIPANTS
>
> James E. Leggett, Jr., M.D., Acting Chair
>
> Tara P. Turner, Pharm.D., Executive Secretary
>
> MEMBERS
>
> David M. Bell, M.D.
>
> Alan S. Cross, M.D.
>
> Mary P. Glode, M.D.
>
> Celia J. Maxwell, M.D.
>
> Jan E. Patterson, M.D.
>
> Ellen Wald, M.D.
>
> ACTING INDUSTRY REPRESENTATIVE (NON-VOTING)
>
> Kenneth R. Brown, M.D.
>
> CONSULTANTS
>
> John S. Bradley, M.D.
>
> James H. Jorgensen, Ph.D.
>
> Donald M. Poretz, M.D.
>
> Michael Proschan, Ph.D.
>
> L. Barth Reller, M.D.
>
> Keith A. Rodvold, Pharm.D.
>
> Maria H. Sjogren, M.D.
>
> GUEST SPEAKER (NON-VOTING)
>
> Francis Tally, M.D.
>
> FDA
>
> Renata Albrecht, M.D.
>
> Edward Cox, M.D., M.P.H.
>
> Mark Goldberger, M.D., M.P.H.
>
> John Powers, M.D.
>
> Janice Soreth, M.D.
>
> [C O N T E N T S]{.underline}
>
> [PAGE]{.underline}
>
> Call to Order:
>
> James E. Leggett, Jr., M.D. 4
>
> Introduction of Committee 4
>
> Conflict of Interest Statement:
>
> Tara P. Turner, Pharm.D. 6
>
> Opening Comments:
>
> Mark Goldberger, M.D., M.P.H. 9
>
> Linkages of Resistance Determinants in Bacteria: 17
>
> James H. Jorgensen, Ph.D.
>
> Questions from Committee 41
>
> Industry Perspective on List of Pathogens:
>
> Francis P. Tally, M.D. 51
>
> Questions from Committee 69
>
> List of Pathogens of Public Health Importance:
>
> John H. Powers, M.D. 76
>
> Questions from Committee 116
>
> Open Public Hearing:
>
> Dr. Jerome Schentag 175
>
> Dr. Richard Gesser 179
>
> How Clinicians Use data for Clinical
>
> Decision Making:
>
> John Bradley, M.D. 182
>
> Relating Clinical Data from One Disease to Another:
>
> Edward Cox, M.D., M.P.H. 195
>
> Committee Discussion 211
>
> Summary 291
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order**
>
> DR. LEGGETT: Good morning. I would like to welcome everyone for
> today\'s March 5th\'s meeting of the Anti-Infective Drugs Advisory
> Committee.
>
> A little housekeeping since it is now 9 o\'clock, committee members,
> you have a little green menu in front of you. That menu needs to be
> filled out and passed to Tara, so we can get it in by 9:30 if you want
> to have lunch. Lunch will be served next-door in Salon D today, but we
> will need your menus.
>
> Can we begin the day by having everyone introduce themselves. I guess
> I will start down at that corner.
>
> **Introduction of Committee**
>
> DR. GOLDBERGER: Mark Goldberger from the Office of Drug Evaluation IV,
> FDA.
>
> DR. COX: Ed Cox, Deputy Director, Office of Drug Evaluation IV, FDA.
>
> DR. SORETH: Good morning. I am Janice Soreth. I am the Division
> Director for Anti-Infectives.
>
> DR. ALBRECHT: Hello. I am Renata Albrecht, Director of Division of
> Special Pathogen and Immunologic Drug Products.
>
> DR. PORETZ: I am Don Poretz in private practice of infectious disease
> in Fairfax, Virginia.
>
> DR. PATTERSON: Jan Patterson, Medicine- Infectious Diseases,
> University of Texas Health Science Center, San Antonio.
>
> DR. RODVOLD: Keith Rodvold, University of Illinois at Chicago.
>
> DR. TURNER: Tara Turner, Executive Secretary for the committee.
>
> DR. LEGGETT: Jim Leggett, Infectious Diseases, Oregon Health Sciences
> University and Providence Portland Medical Center.
>
> DR. WALD: Ellen Wald, Pediatric Infectious Diseases, University of
> Pittsburgh School of Medicine.
>
> DR. GLODE: Mimi Glode, Pediatric Infectious Disease, Children\'s
> Hospital, University of Colorado.
>
> DR. BRADLEY: John Bradley, Pediatric Infectious Diseases, Children\'s
> Hospital, San Diego.
>
> DR. RELLER: Barth Reller, Infectious Diseases, Director of Clinical
> Microbiology, Duke University.
>
> DR. CROSS: Alan Cross, Infectious Diseases, Center for Vaccine
> Development at the University of Maryland.
>
> DR. BELL: David Bell, National Center for Infectious Diseases at the
> CDC in Atlanta.
>
> DR. JORGENSEN: Good morning. I am Jim Jorgensen from the University of
> Texas Health Science Center.
>
> DR. PROSCHAN: I am Mike Proschan from the National Heart, Lung, and
> Blood Institute.
>
> DR. BROWN: Ken Brown, Infectious Disease, University of Pennsylvania,
> representing industry.
>
> DR. LEGGETT: Welcome, everyone.
>
> Now, Dr. Turner, could you read the conflict of interest statement,
> please.
>
> **Conflict of Interest Statement**
>
> DR. TURNER: The following announcement addresses the issue of conflict
> of interest with respect to this meeting and is made a part of the
> record to preclude even the appearance of such at this meeting.
>
> The topics of today\'s meeting are issues of broad applicability.
> Unlike issues before a committee in which a particular product is
> discussed, issues of broader applicability involve many industrial
> sponsors and academic institutions.
>
> All special Government employees and Federal participants have been
> screened for their financial interests as they may apply to the
> general topics at hand. The following participants have reported no
> current financial interests with regards to pharmaceutical companies:
> Drs. Mary Glode, David Bell, and Michael Proschan.
>
> Dr. Donald Poretz has reported a financial interest in a
> pharmaceutical company covered under CFR 2640.202(b) deminimus
> exemption.
>
> The following participants have reported interests in pharmaceutical
> companies and the Food and Drug Administration has granted general
> matters waivers to the following SGEs which permits them to
> participate in today\'s discussions: Drs. James Leggett, Ellen Wald,
> Alan Cross, Celia Maxwell, Jan Patterson, John Bradley, Donald Poretz,
> L. Barth Reller, Judith O\'Fallon, James Jorgensen, and Keith Rodvold.
>
> A copy of the waiver statements may be obtained by submitting a
> written request to the Agency\'s Freedom of Information Office, Room
> 12A-30 of the Parklawn Building.
>
> Because general topics impact so many institutions, it is not prudent
> to recite all potential conflicts of interest as they apply to each
> member and consultant.
>
> FDA acknowledges that there may be potential conflicts of interest,
> but because of the general nature of the discussion before the
> committee, these potential conflicts are mitigated.
>
> With respect to FDA\'s invited speakers, there are reported interests
> which we believe should be made public to allow the participants to
> objectively evaluate their comments. Dr. Francis Tally is Chief,
> Scientific Officer, at Cubist Pharmaceuticals. Dr. Tally also owns
> stock in Cubist.
>
> In addition, we would like to disclose that Dr. Kenneth Brown is
> participating in this meeting as an acting industry representative,
> acting on behalf of regulated industry. Dr. Brown owns stock in Merck
> and in his rollover retirement account he owns shares in Pfizer,
> Genentech, and Johnson & Johnson, as of December 31, 2002. Dr. Brown
> also serves as a consultant to Wyeth and Merck and works one to four
> days per month.
>
> In the event that the discussions involve any other products or firms
> not already on the agenda for which FDA participants have a financial
> interest, the participants involvement and their exclusion will be
> noted for the record.
>
> With respect to all other participants, we ask in the interest of
> fairness that they address any current or previous financial
> involvement with any firm whose product they may wish to comment upon.
>
> Thank you.
>
> DR. LEGGETT: Thank you.
>
> Dr. Goldberger, could you please provide us with some opening
> comments.
>
> **Opening Comments**
>
> DR. GOLDBERGER: Yes. I would like to welcome everybody to the second
> day of this advisory committee. Yesterday, we had a very interesting
> discussion focused around a product. Today, we are going to continue
> what has been an ongoing effort stretching over a few years at least
> and actually more intensively over the last year or so to look at
> issues related to the development of antimicrobial drugs including
> antimicrobial drugs for resistant indications.
>
> We have had a major two-day advisory committee in early February of
> 2002, another meeting in the summer, a meeting with IDSA, PhRMA, and
> ourselves this past fall, and now today\'s meeting to talk about a
> variety of issues that we hope will lead to encouraging the
> development of new antimicrobial drugs and to also thinking about ways
> that we can really facilitate that approach, encourage companies by
> perhaps reducing the overall amount of resources that are necessary,
> but at the same time, at the end of the day, get information that is
> at least is of high quality, if not higher quality, than what we have
> been accustomed to in the past.
>
> Today\'s meeting is going to focus on two issues that have come up as
> part of some of these meetings. One issue could be summarized briefly
> by referring to it as the list, that is, the list of microbial
> organisms, and today really we are concentrating on bacterial
> organisms that are of public health interest for which we should
> really be encouraging the development of drugs.
>
> Again, the organisms on this list generally tend, in fact, to be those
> that have demonstrated some level of resistance to therapies that have
> been commonly used to, for instance, treat.
>
> We have had some discussions about this. Industry has expressed a
> great interest in having a little more in the way of something defined
> as to what organisms we believe are important, so that they can look
> carefully to decide whether or not these things I think represent
> appropriate opportunities for them.
>
> We are certainly in agreement that providing guidance to industry
> about these things is useful. On the other hand, a list per se, simply
> making up a lot of organisms does require one to then be thinking
> about updating it, you know, on a regular basis, and one of the things
> we want to talk about today is how one sort of decides the kind of
> things that ought to be on some list, what are the parameters that are
> appropriate, so that the list can be dynamic and yet not overly
> burdensome in terms of thinking about what ought to be on it, and more
> to the point, if we can define some parameters, then that gives
> industry a little more flexibility.
>
> Should a new issue come up, industry will not be in the position of
> looking to see is this on the list, is this not on the list. They will
> be able to use parameters that have been discussed and defined to make
> an argument about why such organisms are appropriate targets for
> antimicrobial drug development.
>
> So, that is going to occupy discussion I think most of the morning,
> and we have several presenters who will be talking about this issue.
> We hope to have a fair amount of committee discussion.
>
> In the afternoon, we are going to talk about another topic that we
> hope will lead to more expedited drug development, and that is sort of
> looking at the overall package that many companies submit as part of,
> you know, development of a new antimicrobial.
>
> As most of you are probably aware, it is uncommon although not by any
> stretch unheard of for a new antibacterial drug to come in for a
> single indication. Generally speaking, drugs come in for a variety of
> indications.
>
> To give you a good example, fluoroquinolones is one example, as well
> as some macrolides, often will come in for a variety of respiratory
> indications, in part because from a purely business point of view, it
> makes much more sense to have this package when you are trying to get
> drugs on formulary, so when you can promote them of having related
> indications, and in some cases, the breadth of indications will be
> even broader.
>
> There will be respiratory indications, sometimes intra-abdominal
> indications, skin, complicated skin, et cetera, so the packages can be
> fairly large.
>
> In general, multiple studies have been submitted for each of these
> indications. There are\--and we will be talking about this, this
> afternoon\--clear exceptions to the idea that you need multiple
> studies for each indication.
>
> One of the things we really want to talk about is can we advance the
> model as to how indications could support one another to a point where
> it will facilitate overall development by perhaps reducing the size of
> a development program, and at the same time will provide a rational
> approach both to the general issues of development over a broad range
> of indications and to the related and very important issue that
> companies have addressed with us in meetings on a one-on-one basis, et
> cetera, I think has come up at open meetings like this, as well as, we
> want to get an indication for a resistant organism.
>
> Sometimes it is difficult to acquire adequate numbers of those
> organisms from a study or studies in a single body site, what is the
> latitude, how much pooling across body sites can be done. As you can
> see, that is related to the overall issue of how indications support
> one another.
>
> We think this is an important issue. We think from a practical point
> of view, and I go back to the years that I have spent in practice,
> that clinicians are prepared to make inferences as to how a drug is
> likely to perform based on how it performs in other settings, and I
> certainly think that a drug that one feels more comfortable\--this is
> my own personal opinion\--about how a drug will perform in a seriously
> ill patient if there is already data suggesting that in other serious
> illnesses or infections, the drug has performed well.
>
> I think that at times, although as a clinician we are comfortable
> doing that, from a regulatory point of view, we don\'t clearly have
> that laid out as to how that might occur, and I think that that is an
> area that is worth talking about in some detail, talking about the
> parameters that might help us in deciding what indications could
> support one another, so that we can put out some guidance that will be
> helpful to industry in thinking about what a package might look like.
>
> So, in any case, we are going to have some discussion about this in
> the afternoon with the hope of again facilitating antimicrobial drug
> development, as well as development for resistant indications, and we
> hope that at the end of day, that we will have enough ideas here that
> will assist us in writing some guidance that will be helpful to
> industry.
>
> There has been a great desire, not surprisingly, and this goes across
> many areas in FDA and far outside anti-infectives, for industry to get
> some type of guidance as to how to proceed since they are much more
> comfortable, they can sit and look at what is required or suggested as
> opposed to having to depend on individual interactions, et cetera,
> although there is always an issue about getting guidances done because
> of the amount of people you have available to sit and write them.
>
> Here, we actually have a somewhat different issue, which is not always
> quite as common. I actually believe one of the obstacles to writing
> some of the guidances, particularly what I was speaking about for the
> afternoon, how indications support one another, is that there are
> unresolved scientific questions about how far one can really go.
>
> The one thing you learn about, you know, when you are writing a
> guidance or when you are writing a letter to a company, et cetera, if
> you are not really clear what it is you can do, what it is you are
> trying to say, what you actually write will turn out to be, you know,
> really kind of semi-disastrous or at least not useful.
>
> So, before we embark on trying to get some sort of draft guidance out
> for comment, we would like to see how far we can get in resolving some
> of the underlying issues, so that everybody at least understands those
> issues, and then it is simply a matter of taking that and trying to
> put it into some clear English.
>
> That in and of itself is no small achievement, but at least you
> understand what it is you think you trying to say, so that\'s what our
> goals are for today. Again, we don\'t expect this to be the end of
> this process.
>
> We expect to continue to have meetings like this, hopefully, another
> meeting, as well, with IDSA, PhRMA, et cetera, just to continue
> talking about these issues and to work through the variety of
> scientific issues that we think we need to do, but we are hopeful at
> the end of today, we will be a little closer to being able to provide
> the advice we would like to.
>
> Thank you.
>
> DR. LEGGETT: Thank you.
>
> John, could I ask you to introduce yourself.
>
> DR. POWERS: John Powers, Lead Medical Officer for Antimicrobial Drug
> Development in 04.
>
> DR. LEGGETT: Thank you.
>
> The first speaker of the day will be Jim Jorgensen who is going to
> talk to us about linkages of resistance determinants in bacteria.
>
> **Linkages of Resistance Determinants in Bacteria**
>
> **James H. Jorgensen, Ph.D.**
>
> DR. JORGENSEN: Good morning, everyone.
>
> I seem to have failed the first test and that is how to run the laptop
> computer up here.
>
> \[Slide.\]
>
> What I would like to speak with you about this morning is about
> antibiotic resistance and the era that we find ourselves in, in
> emerging resistance among a number of very common hospital-acquired
> and also now community-acquired bacterial pathogens.
>
> I think everybody recognizes that we are in this very unusual era that
> none of us have ever seen or lived through before, and that is the era
> of emerging or evolving antibiotic resistance.
>
> As you can see on the upper part of my slide, some would argue that
> this is really the era of emerging acronyms as we find new names for
> all of these different resistant organisms.
>
> I think what is clear as we talk about VRE, VISA, and VRSA is that
> these organisms are of clinical significance and are becoming more
> frequent, and we have relatively few therapeutic options today.
>
> Certainly, these organisms compromise the utility of some of our most
> important compounds, such as the extended spectrum cephalosporins, the
> macrolides, as well as the fluoroquinolones.
>
> Certainly, the obvious need that will be discussed today is exactly
> which organisms are of greatest importance and where do we need help
> in developing new compounds.
>
> Now, what I have been asked to talk about specifically is this concept
> that I would call \"associated resistance.\" That is some of the
> resistance mechanisms possessed by these organisms affect multiple
> members of the same class or family or subclass.
>
> That is, for example, beta-lactam resistance in staph affects not only
> the semisynthetic penicillins, but also the cephalosporins and the
> carbapenems. But the second thing is those resistance mechanisms that
> may be genetically linked, that may be on the same plasmid or on the
> same transposon and are therefore transferred in mass from one strain
> to another.
>
> The latter part of that is the fact that there are some frequently
> associated resistance mechanisms that are not co-transferred in the
> sense of being truly linked in the same cassette, but simply are very
> frequently found in the same clones or same derivatives of clones.
>
> \[Slide.\]
>
> I think everybody has seen these data and I wanted to start here
> because it illustrates our point that in the era of the \'90s, we went
> from almost no VRE in the United States or essentially case reports of
> VRE to, by the end of the \'90s, about 1 out of 4 enterococcal
> isolates were vancomycin resistant. I could have used other examples,
> but I thought VRE would be a very good place to begin.
>
> \[Slide.\]
>
> VRE also illustrates the problem, that in the United States, almost
> all of our VREs occur in Enterococcus faecium. Inherent in most
> strains of Enterococcus faecium is also penicillin, ampicillin, and,
> for that matter, carbapenem resistance.
>
> Now, these are not genetically linked events, but they are present in
> the background of that species. Many of these isolates also produce
> inactivating enzymes that affect multiple aminoglycosides, so most of
> these have high-level aminoglycoside resistance.
>
> Despite the fact that we do have some newer antibiotics that have
> proven very useful in therapy of VRE infections, we already have
> experienced resistance developing during therapy with some of the
> newer agents including linezolid and quinupristin-dalfopristin. So, it
> also illustrates the point of not putting all of our eggs in one
> basket, I believe.
>
> \[Slide.\]
>
> Now, this is a partial list and a lot of these organisms are where I
> want to delve a little bit deeper in the next few minutes.
>
> For example, the last organism, Enterococcus faecium, as I mentioned,
> most of the time, probably 90 percent of isolates produce a
> low-affinity, penicillin-binding protein that provides resistance, not
> only to penicillin, but to other relevant beta-lactams.
>
> I am going to spend a few minutes talking about methicillin-resistant
> staph and then I think there are some new things that are worthy of
> consideration, but methicillin-resistant staph or resistant to
> multiple members of that same major class, the beta-lactams.
>
> Then, I think extended spectrum beta-lactamases are a significant
> problem, and I believe they will become more frequent in the near
> future, and these enzymes have hydrolytic activity against all of the
> current penicillins, true cephalosporins, and also aztreonam.
>
> Then, I will say a few words about resistance in Strep pneumoniae
> including emerging fluoroquinolone resistance.
>
> \[Slide.\]
>
> To begin with, MRSA, I think there are some new things here. MRSA have
> been around for a long time, and I think it is noteworthy that within
> about a year or so of the introduction of methicillin for clinical
> use, the first strain was recognized in the United Kingdom that was
> resistant to methicillin.
>
> In the 1960s, there were some hospital outbreaks in Europe and the UK
> and certainly in the 1970s in this country. From the 1970s until
> today, I think you are all aware MRSA have become a major problem of
> health care institutions.
>
> Now, one point I would like to make at this point is that these
> conventional MRSA or healthcare-associated MRSA strains have been
> multidrug resistant. Here, I mean in addition to other beta-lactams,
> other drug classes.
>
> \[Slide.\]
>
> However, what is new and I believe rapidly emerging is
> community-acquired MRSA and that probably most of us first heard about
> this in Detroit among the injection drug users in that city in 1980
> and \'81, in which MRSA was quite prevalent among that population.
>
> But then in the early \'90s, community-acquired MRSA was described in
> Western Australia and also in New Zealand, and what was different
> about these strains and what should have raised our awareness was that
> these were not multidrug resistant strains. For the most part, they
> were resistant only to penicillin and oxacillin.
>
> Then, the CDC reported four children in the \'90s in the upper Midwest
> who had very serious community-acquired MRSA infections, and once
> again, these were not conventional hospital-acquired MRSA isolates.
>
> The CDC has also done a great deal of work along with several state
> health departments to characterize community onset MRSA in Native
> American populations in Alaska, Minnesota, and also the State of
> Washington.
>
> Also, I think during this period, MRSA has become a very frequent
> cause of skin infections in incarcerated individuals, both in
> penitentiaries and in jails. Then, in the San Francisco Bay area of
> California, workers there have described that among the homeless
> populations, skin infections due to these community-acquired strains
> of MRSA have become quite frequent.
>
> \[Slide.\]
>
> What this means I guess is we need a new definition of MRSA or a new
> subdefinition and what the CDC is currently using is
> healthcare-associated MRSA, and that means to many of us the
> hospital-acquired strains that we are most familiar with.
>
> These are patients who have recently been in the hospital where they
> acquired their strain or perhaps they have been in a rehab center or
> they have undergone or continue to undergo hemodialysis, or perhaps it
> has been communicated to them directly by a home or other healthcare
> worker.
>
> However, we need some new definitions for these community strains, and
> I have used the term \"community-acquired now a few times. CDC prefers
> the term \"community-onset\" meaning that the infection originates in
> the community, and it may have been through some conventional risk
> factor, such as recent antibiotic use or perhaps a hospitalization,
> not recently, but in the distant past, and prolonged colonization, but
> there is still a number of patients who do not have any of the
> conventional risk factors, illustrating that this organism now does
> appear to be a true community-acquired pathogen.
>
> \[Slide.\]
>
> Now, there are several differences between the healthcare-associated
> and community-onset isolates, and they include the fact that I have
> already stated, the healthcare-associated strains usually are
> resistant to multiple drug classes.
>
> Usually, this includes macrolides and lincosamides, usually
> aminoglycosides and also fluoroquinolones. In contrast, the
> community-acquired strains usually are only resistant to penicillin
> and oxacillin although some strains now are resistant also to
> macrolides and some to fluoroquinolones, but this is not predictable,
> this is not in most cases the majority of strains.
>
> As I will show you a second, they contain a different version of the
> mec element, a much smaller element and much more easily transmitted
> among the community-acquired isolates.
>
> These strains in the hospital usually do not have this toxin called
> Panton-Valentine leukocidin, whereas, the community-acquired strains
> usually produce this. At least the currently feeling is that PVL
> explains why these strains are so prone to cause skin or subcutaneous
> infections and also severe necrotizing pneumonia.
>
> Also, these strains often produce as many, well, I should say as many
> as 19 different toxins or superantigens including staphylococcal,
> enterotoxins, possibly toxic shock toxin I.
>
> \[Slide.\]
>
> So, these strains phenotypically look different and they have, as I
> said, a different staphylococcal chromosomal cassette of SCCmec
> variety. Now, there are four types and, in fact, Type IV is now being
> subdivided.
>
> What I want to show you, and I use this slide very reluctantly, is
> that the Type I is now considered an archaic version, and that is, it
> is not found in most current MRSA isolates.
>
> Type II and Type III, which are found in the healthcare-associated
> isolates, are really very large and often carry with them transposons
> that code for other antibiotic resistance including macrolides,
> lincosamides, and also aminoglycoside-modifying enzymes.
>
> So, that SCCmec Type II or III, I think helps explain the MDR
> phenotype of the healthcare-associated strains. What is different is
> the Type IV is a much smaller piece of DNA, in fact, some would argue
> small enough to fit in the head of a phage and perhaps be transmitted
> through transduction.
>
> This Type IV mec cassette does not include any of those transposons
> for multidrug resistance, so it appears that that is a transferable
> element that is now finding its way into very fit community-acquired
> clones of Staph aureus and contains only the essential information for
> methicillin or oxacillin resistance.
>
> \[Slide.\]
>
> Now, one of the things that is sometimes challenged is this concept
> that we should view MRSA as resistant to all beta-lactams, and I am
> aware that there are some beta-lactams under development that have
> high affinity for this PBP-2A or altered special penicillin-binding
> protein of methicillin-resistant staphylococci.
>
> However, I decided to go back to the origin, and that is, one of the
> first studies that helped to illustrate that beta-lactams, even if
> they appear active in vitro, do not provide adequate therapy in vivo.
>
> This was a paper by Jacques Acar in Paris, published in Antimicrobial
> Agents in Chemotherapy in the early \'70s. Illustrated in that early
> experience with MRSA in France, physicians did try to use
> cephalosporins to treat patients who were bacteremic or who had
> endocarditis, and when used alone, and these were cephalothin or
> cephaloridine, both agents that I think have among the best activities
> against staphylococci of all of the cephalosporins, what you find is
> that very few patients were cleared of their bacteremia using a
> cephalosporin alone, and if you added to it an aminoglycoside, you did
> somewhat better, but it was not really very successful therapy.
>
> Recall that these strains did have aminoglycoside resistance
> determinants. When you looked at endocarditis, even though the number
> of patients was very small, these patients\' bacteremias could not be
> cleared using either a cephalosporin or an aminoglycoside alone.
>
> Now, certainly there are more modern data than this, but I thought it
> might be useful to go back to the beginning just for a moment.
>
> \[Slide.\]
>
> Now, other resistance mechanisms that are commonly found or
> co-transferred in these healthcare-associated strains, as I have
> alluded to, include the macrolide and lincosamide determinants. They
> may be ermA or more frequently ermC, and they may be either
> constitutively produced or they may be inducible.
>
> This TN554, which is commonly found in the SCCmec Types II or III,
> codes for this kind of resistance, and is co-transferred with
> methicillin resistance.
>
> Aminoglycoside-inactivating enzymes can be produced by these organisms
> including this important so-called bifunctional enzyme which has both
> an acetylating and phosphorylating end or activity, and is the same
> enzyme found in many enterococci that have high-level aminoglycoside
> resistance.
>
> Then, most of these healthcare-associated strains today are resistant
> to fluoroquinolones either because of gyrase A mutations or because
> they have an active efflux pump that removes the drugs from the cells.
>
> Then, they may have the ribosomal protection mechanism of tetM for
> tetracycline resistance or they may have an efflux pump that removes
> most members of that class.
>
> \[Slide.\]
>
> The other problem, however, that I think is more urgent and of greater
> concern is the fact that in this background of MRSA, we have seen
> either diminished susceptibility to vancomycin in the form of VISA or
> vancomycin-intermediate Staph aureus, in which about 8 times as much
> vancomycin is required to inhibit these strains as a normal strain, or
> recently, in 2002, in the U.S., we have seen the first true VRSA
> isolates.
>
> Both of those isolates contain the vanA gene sequences from
> Enterococcus, and in the first case, the patient in Michigan, it was
> fairly clear that that was transferred from vancomycin-resistant
> Enterococcus faecalis, not faecium.
>
> \[Slide.\]
>
> Now, let me shift gears and talk for a moment about gram-negatives and
> about extended spectrum beta-lactamases. Most of the ESBLs that we are
> familiar with in North America are derivatives from either the TEM-1
> or SHV-1 enzymes.
>
> These are the beta-lactamases ordinarily found in E. coli and
> Klebsiella that generally just code for ampicillin resistance, but
> when mutations occur, they may then hydrolyze at least at high
> inoculum all of the currently available penicillins, cephalosporins,
> and aztreonam.
>
> As you can see on this slide, as of last Friday, there were a huge
> number of different TEM and SHV enzymes that have a different
> molecular structure or a different spectrum of activity. In fact, some
> of these strains appear susceptible to some cephalosporins, but
> resistant to others.
>
> \[Slide.\]
>
> Now, the molecular basis for this are point mutations that probably
> occur spontaneously in the genes that encode either TEM-1 or SHV-1,
> and even a 1 or 2 amino acid sequence change can take a strain from
> being very susceptible to a drug like ceftazidime to being highly
> resistant, so these are fairly subtle point mutations that occur every
> day.
>
> \[Slide.\]
>
> Some of these enzymes provide very obvious resistance to a compound
> like ceftazidime as in the case of TEM-10, while retaining very low
> MICs to cefotaxime, so the argument has been, well, this is a
> potential difference between these compounds that perhaps could be
> taken advantage of.
>
> \[Slide.\]
>
> However, at very high inoculum, that is, if you increase the number of
> cells, the amount of enzyme present, you can see even the latest
> generation cephalosporins are hydrolyzed by these enzymes.
>
> On the other hand, the structure of the carbapenems tends to resist
> hydrolysis by the ESBL and they tend to remain susceptible to that
> class.
>
> \[Slide.\]
>
> Now, again, clinical significance is very important. David Paterson
> from Pittsburgh, I think has done some of the most important work to
> illustrate the clinical significance of these strains, and in a 2001
> publication, he reported a multi-country, multi-continent study
> looking at Kleb pneumoniae bacteremias, and about 18 percent or so of
> these organisms were found to produce ESBLs.
>
> Nine of those were treated with a cephalosporin that, by conventional
> testing and conventional breakpoints, were either intermediate or
> susceptible to a cephalosporin, however, among those 9, 3 patients
> died and 5 required additional therapy.
>
> Overall, there were 32 patients that were treated with a cephalosporin
> that we would, based on testing of that drug by itself, consider
> either susceptible or intermediate to a particular drug. Among those
> that were classified as intermediate, all 4 failed therapy and 15 of
> 28 of the strains considered susceptible, meaning they had fairly low
> MICs, also failed therapy.
>
> Among those were 5 patients treated with cefepime, to illustrate the
> last point, and 4 of those also failed.
>
> \[Slide.\]
>
> Now, ESBL-producing strains carry their gene for beta-lactamase
> production on a plasmid, and that plasmid can be easily shared among
> different isolates of the same species or between species.
>
> Located on the same plasmid in most of the ESBL are genes that also
> code for trimethoprim sulfa and for gentamicin resistance, so here is
> an example of co-transfer of genes that affect more than one class of
> drug.
>
> Unrelated to that is the fact that many and I would guess maybe 40 or
> 50 percent of isolates also were fluoroquinolone-resistant, but that
> is not a plasmid-mediated event in these strains and it is not
> co-transferred.
>
> \[Slide.\]
>
> Then, there are many other gram-negative rods, too many to mention in
> my limited time, but I just want to make a brief pitch for the
> importance of Pseudomonas aeruginosa and the fact that Pseudomonas
> isolates may have a number of different beta-lactamases including the
> ability to hyperproduce the ampC or Bush group 1 beta-lactamase to
> code for resistance to a variety of beta-lactams, but they may also
> have plasmid-mediated enzymes, such as PSE-1, -3, or -4, and also the
> less common ESBLs, such as the OXA group of enzymes that are not yet
> very common in this country, but are in some other parts of the world.
>
> Many of these strains produce enzymes that chemically inactivate in
> aminoglycosides or they may have outer membrane protein changes which
> essentially close the door to penetration by the aminoglycoside group
> of drugs.
>
> Fluoroquinolone resistance is now relatively common among Pseudomonas
> isolates often due to mutations in the gyrA gene.
>
> Very interesting I think is this class of efflux pumps, often the Mex
> B, D, or F pumps that can be found in Pseudomonas, that every
> effectively remove fluoroquinolones and cephalosporins from these
> strains before they can have any activity.
>
> \[Slide.\]
>
> Now, I will say a few words about pneumococci to wrap up my remarks.
> First of all, everyone is aware of penicillin resistance in
> pneumococci. The point of this slide, the upper portion at least, is
> that there are several different penicillin-binding proteins that can
> be modified through self-transformation, that is, taking in DNA from
> another pneumococcal strain or even from a viridan strep that might be
> an oropharyngeal colonizer.
>
> Pneumococci can then build so-called mosaic genes that code for
> penicillin-binding proteins of lower affinity.
>
> For high-level penicillin resistance, there may need to be as many as
> 3 of these penicillin-binding proteins modified, but for cephalosporin
> resistance, that is, extended spectrum cephalosporins, it is really
> only necessary to have 2 of these PBPs altered.
>
> So, there are now some strains that are more resistant to
> cephalosporins than to penicillin.
>
> \[Slide.\]
>
> Now, looking at CDC surveillance data from the active bacterial core
> surveillance program published by Cindy Whitney in 2000, I would like
> to simply illustrate the point that penicillin-susceptible
> pneumococci, in this column, are rarely resistant to other drug
> classes, that is, they rarely have genes that would affect the
> macrolides, tetracycline, or the fluoroquinolones.
>
> As you move to strains that have diminished susceptibility to
> penicillin, you see it is more frequent that those isolates may carry
> genes for other drug classes, and as you move to the
> penicillin-resistant Strep pneumos, it is quite common to see
> macrolide resistance, trimethoprim sulfa resistance, and indeed there
> is a statistically significant association between penicillin and
> fluoroquinolone resistance in these strains.
>
> Now, that is not because these genes are all co-transferred, but
> rather these are clones of pneumococci that have become repositories,
> if you will, for many different resistance genes, and the fittest of
> these clones have now circulated throughout the world.
>
> \[Slide.\]
>
> So, macrolide resistance in the United States is most often coded by a
> gene called mefA or mefE, which is an efflux pump. A smaller number, a
> small percentage of strains have the erm gene, which codes for
> clindamycin, as well as macrolide resistance.
>
> What is interesting to me is it is the reverse in Europe. The erm
> strains are much more common than the efflux strains.
>
> Many of these strains also have tetM or an efflux pump, and many of
> the strains now, particularly the pen-resistant ones, have altered
> enzymes needed in the folate pathway that affect trimethoprim or sulfa
> or both to code for trimeth sulfa resistance.
>
> \[Slide.\]
>
> Quinolone resistance in pneumococci has become a major concern. The
> study published in 2002 by Davies and colleagues looked at strains
> that had borderline susceptibility to levofloxacin, but found that
> about 4.5 percent of these strains actually contain a first-step
> mutation of the parC locus that would code for higher MICs to drugs
> like ciprofloxacin, but not so much so for levo.
>
> The second step or double mutants, on the other hand, become quite
> obviously resistant to the currently used fluoroquinolones, and those
> are estimated between 0.2 and 0.5 percent of strains in the U.S., so a
> very small percentage as of today.
>
> However, when those mutations occur, as we have showed in this earlier
> study, those mutations, particularly those that involve both the parC
> and gyrA loci, also are the same targets used by the later, more
> potent fluoroquinolones and raise the MICs of those compounds, as
> well.
>
> So, the concern here is that despite the greater potency of the newer
> fluoroquinolones, they still affect the same drug targets.
>
> \[Slide.\]
>
> Now, I think the real concern and where we ought to look is the data
> that have emanated from Hong Kong and have been published by Ho and
> colleagues, in which they showed in 1995, a very small percentage of
> their pneumococci were fluoroquinolone resistant, essentially, the
> same as we currently see in the United States.
>
> However, a few years later, that percentage had increased and then by
> 2000, it was more than 13 percent of all of their isolates, and if
> they looked specifically at the more resistant clones, that is, the
> penicillin-resistant strains, it was more than one-fourth of those.
>
> Now, what is unique here is that this is a single clone or, if you
> will, single strain of pneumococcus that has been shared throughout
> patients in Hong Kong, so it is not dissemination of genes in the
> sense of transmissible elements, but rather a single, very fit clone
> that originated originally from Spain and is a serotype 23F clone, has
> now become very common in that area of the world.
>
> So, the concern I think is could we see this sort of thing in North
> America.
>
> \[Slide.\]
>
> Now, my final slide is maybe food for thought more than firm data.
> That is, Elaine Tuomanen and colleagues in Memphis have illustrated a
> few strains, one at least associated with a meningitis treatment
> failure in a 10-month-old that they describe as being tolerant to the
> bacteriocidal effect of vancomycin and also the bacteriocidal effect
> of beta-lactam antibiotics.
>
> This child had recurrent meningitis after a full course of both
> cefotaxime and vanc therapy. They have been working to identify a
> particular gene associated with this defect, but this is a totally
> different aspect of a failure of the autolytic system of this strain
> or these strains which is triggered by both the beta-lactams and
> vancomycin.
>
> So, this is I think a point of concern, but it as yet a fully
> clarified area.
>
> So, those are my feelings on this and I guess I would say the reasons
> for this are that there are mechanisms that we recognize that affect
> closely related compounds, such as the beta-lactams with MRSA.
>
> Also, there are mechanisms, some of which I have described, that are
> co-transferred, that are genetically tied together and go with one
> gene into a different strain.
>
> Lastly, as I attempted to illustrate with pneumococci, there may be
> multidrug resistant strains due to the fact that there are clones that
> over time have collected these resistance genes and maintain them for
> fitness in an environment of antibiotic use.
>
> So, with that, I think I will conclude and I appreciate your
> attention.
>
> Mr. Chairman, do we have questions?
>
> **Questions from Committee**
>
> DR. LEGGETT: Yes. Why don\'t we open it up for questions.
>
> I have a quick one, I may have missed it. The vanco tolerance, was it
> pneumococci?
>
> DR. JORGENSEN: Yes.
>
> DR. LEGGETT: Jan.
>
> DR. PATTERSON: Jim, would you like to comment on the linkage of
> resistance in Acinetobacter, multidrug-resistant Acinetobacter?
>
> DR. JORGENSEN: Acinetobacters certainly can be multidrug resistant
> including penicillin, cephalosporins, and can acquire resistance to
> carbapenems, and I think that has been the concern, is that some of
> those strains, because of resistance to other classes, have been
> treated with carbapenems only to later become carbapenem resistant.
>
> DR. LEGGETT: Don.
>
> DR. PORETZ: In our hospital, the tertiary care facility, MRSA
> continues, we still continue to be active with the sulfa trimethoprim,
> 80 percent of MRSA sensitive to sulfa trimethoprim, doxycycline,
> minacycline still very, very active yet. Those particular drugs are
> completely worthless against E. coli, Strep pyogenes.
>
> Is it just because those drugs have not been used that often in the
> hospital in the past or why do we continue to have 80 percent
> sensitivity with sulfa and semisynthetic tetracyclines?
>
> DR. JORGENSEN: I think that\'s a good question. The vancomycin
> intermediate and vancomycin-resistant Staph aureus strains have all
> been susceptible to trimeth sulfa and would seem even to be perhaps
> the drug of choice for those strains in terms of a good susceptibility
> profile.
>
> Many MRSAs are susceptible to minacycline and perhaps the reason for
> that is minacycline is not so well pumped by the tetracycline efflux
> pump that many of those strains have.
>
> I think you are right about the potential utility of those agents
> against those strains, but not against the gram-negatives, and I am
> not sure I can explain why except that organisms like E. coli and
> other gram-negatives are part of our normal GI flora and are exposed
> every day to any antibiotic we would take for any reason and perhaps
> that is a partial explanation.
>
> DR. LEGGETT: John.
>
> DR. BRADLEY: I think the complicated nature of resistance, the
> multiple mechanisms of resistance, the ability of organisms to develop
> new resistances highlight something that we have been talking about on
> a number of occasions, about the difficulty in assigning a drug
> approval for an organism resistant to one particular drug, and that as
> your presentation really predicts for the future, that the situation
> is going to get far more complicated than simple and not only will we
> have to deal with Strep pneumo that is resistant to penicillin,
> cefuroxime, clarithromycin, et cetera, but we are going to have to
> deal with pseudomonads that have multiple drug resistances,
> acinetobacter, and are we going to be needing to deal with drug
> approvals for drugs that are active against each and every one of
> those antibiotics that are resistant on your list, requiring that the
> sponsor produce treatment successes for each of those sets of
> resistances.
>
> So, you have done a beautiful job of painting the future for us.
>
> DR. JORGENSEN: I wish it were more optimistic.
>
> DR. LEGGETT: Barth.
>
> DR. RELLER: Jim, your presentation raises many questions that I have.
> I will restrict it, if I might, to two.
>
> First, you mentioned the development unequivocally of resistance while
> on therapy with linezolid, quinupristin-dalfopristin where if one did
> PFGE, it is clearly the same organism.
>
> Of these mechanisms of resistance, and time wouldn\'t permit all of
> them, which ones are recognized, of the more common ones, to develop
> on therapy and which ones has that not been observed? For example, my
> understanding is with penicillinase with Staph aureus, going way back,
> that on long-term observations that the development or acquisition of
> that plasmid in vivo doesn\'t occur.
>
> But what about these other mechanisms, and the importance of it is
> where one might be on secure ground with a susceptible organism at the
> initiation of therapy, but see it change right under your eyes.
>
> DR. JORGENSEN: Enterobacter.
>
> DR. RELLER: Well, Enterobacter, the D-repression with this is enough,
> but are any of the others, is there a pitfall, is it actually even
> more complicated than what you say having to do with you think you are
> okay, but then the ground shifts even in the course of therapy of an
> individual patient?
>
> DR. JORGENSEN: I think you are right with penicillin-resistant or I
> should say penicillin-susceptible Staphylococci. In order to become
> penicillin-resistant, your organism would have to go out and find the
> plasmid and the beta-lactamase gene somewhere else, so it is not
> likely to change during therapy.
>
> In the case of the Bush Group I or ampC beta-lactamase, you have an
> enzyme present in virtually every isolate of Enterobacter, Citrobacter
> freundii, Serratia marcescens, et cetera, that is just sitting there
> waiting to have a mutation in its represser sequences to a very high
> level of resistance. So, that can occur in maybe a couple of days
> during therapy.
>
> VRSA represents acquisition of a gene group again from outside, so it
> is not likely to happen commonly. It had to go and find that gene in
> the right environment of those two patients.
>
> VISA, on the other hand, represents acclimatization to the presence of
> vancomycin over a long period of time, this thickened cell wall that
> is developed and been described in these strains, which seems to be an
> adaptation to the pounding away of that strain by vancomycin over a
> period.
>
> So, I think in many cases, these are genes that are acquired,
> transferred, et cetera, or may be kept by a strain when spontaneous
> mutations occur, such as in the case of ESBL, that those spontaneous
> mutations do not have value in an environment that is not saturated
> with antibiotics, so we see those strains mostly in intensive care
> unit patients where there is value to maintaining those mutations for
> production of a very high potency beta-lactamase.
>
> DR. RELLER: The second question that is related is with the different
> cassettes with Staphylococcus aureus MRSA, hospital-associated
> community-associated, is there a difference in the common detection
> mechanisms used in laboratories, salt screen plate, latex
> agglutination, PCR for mecA, are there differences in the ability to
> detect accurately methicillin resistance among these strains?
>
> The analogy is with the resistance and the use of cephalosporins, in
> other words, are there pitfalls in detection that are related to the
> different cassettes?
>
> DR. JORGENSEN: Well, first of all, all of the variants of MRSA contain
> the mecA gene whether there is a big piece of DNA that goes along with
> it or a small piece, so genetic tests, such as PCR, that detect the
> presence of the mecA gene would pick all of those up very effectively.
>
> All of those code for PBP-2a, so tests that would detect the protein
> product of mecA also would be positive with all of those.
>
> I think some of the hospital-acquired strains are more likely to have
> the heterogeneous expression of oxacillin resistance that is more
> difficult to detect by phenotypic tests, such as distifusion or MIC.
>
> The detection, however, is somewhat compromised I think in the
> community-acquired strains because microbiologists have been trained
> to look for multidrug resistance as a secondary key that a strain
> might be an MRSA. Even some of our instrument systems have been
> programmed with expert systems to look for resistance to
> aminoglycosides, tetracycline, et cetera, as a marker for MRSA.
>
> So, I guess I worry a little bit that the community-acquired strains
> might be underappreciated because they don\'t have that additional red
> flag that I\'m an MRSA.
>
> DR. LEGGETT: Celia.
>
> DR. MAXWELL: Excellent summary, Dr. Jorgensen.
>
> I have two questions on your next to the last slide with the
> 10-month-old and the meningitis. Was it Strep pneumo, the organism?
>
> DR. JORGENSEN: Yes.
>
> DR. MAXWELL: An earlier slide, looking at the differences between
> healthcare-associated and community-associated MRSA, was the outcome
> in those patients that were treated or what was the outcome?
>
> DR. JORGENSEN: Well, in the community-associated or community-onset
> isolates, many of these patients had skin or subcutaneous infections,
> boils especially. Many of these were severe enough that they didn\'t
> improve without surgical drainage. As long as they were drained
> surgically, the limited data, and the data are not extensive, seemed
> to suggest it didn\'t really make a lot of difference which antibiotic
> was used.
>
> On the other hand, if you used an effective antibiotic without
> surgical drainage, they didn\'t do all that well. There are some
> groups, such as some of the physicians who manage jail and prison
> settings, that favor use of either trimeth sulfa or doxycycline or
> clindamycin to treat those strains, but the limited data suggest they
> make very bad subcutaneous infections that may require surgical
> drainage.
>
> DR. LEGGETT: Dr. Jorgensen, could you comment upon the growing data
> about cross-linkage between detergents and antibiotic resistance?
>
> DR. JORGENSEN: Well, I can tell you that in two of the mec cassettes,
> there are genes for resistance to heavy metals like mercury and things
> of that sort, and may also have to do with iodine and other
> disinfectants, but that is all I could comment on.
>
> DR. LEGGETT: John.
>
> DR. BRADLEY: Just a quick extra piece of information on that
> 10-month-old with Pneumococcal meningitis because it created quite a
> stir in the pediatric community, and Dr. Tuomanen has done beautiful
> molecular diagnostic dissection of the resistance mechanisms. This is
> an autolysin-resistant, a deficient organism.
>
> Normally, with pneumococcus, once you hit it with an antibiotic and
> cripple it, it kills itself. Well, this organism won\'t kill itself
> and there is no antibiotic, not vancomycin, not beta-lactams, not
> fluoroquinolones, nothing that will kill this organism. It can prevent
> it from growing, so antibiotics are static, but you need more than a
> static agent in the central nervous system.
>
> So, the implication isn\'t just for vancomycin resistance, but it\'s
> for resistance across all antibiotic classes for this organism, and we
> are just thankful that it hasn\'t seemed to have spread outside of
> Memphis or continued to increase in its prevalence there. Is that
> correct?
>
> DR. JORGENSEN: Yes.
>
> DR. LEGGETT: Thank you, Dr. Jorgensen.
>
> The next speaker will be Frank Tally, who is going to give us an
> industry perspective on a list of pathogens.
>
> From the first speech, it looks like the list of pathogens is all our
> common pathogens is all I can say.
>
> **Industry Perspective on List of Pathogens**
>
> **Francis P. Tally, M.D.**
>
> DR. TALLY: Mark Goldberger set the stage for today\'s meeting with the
> two major themes of what is the list and do we need, can one
> particular study in one system support studies in another system, but
> I think in the documentation that was sent out via the Internet, there
> was also a third issue I saw in there, is the problem of decreasing
> research in the area of developing new antimicrobial agents, and I
> would like to kind of wind that into the discussion today.
>
> \[Slide.\]
>
> Why develop drug for resistant pathogens? Well, as you have heard,
> resistant pathogens kill people, and I will delve into some of that
> data. It was nicely discussed by Dick Wenzel at the November workshop
> meeting that we have talked about.
>
> For a pharmaceutical company or a biotech company, one has to justify
> the expenditure of a large amount of money to develop a drug for a
> particular area, so that drug should have specific advantages which
> allow the drug to penetrate into the marketplace and return the
> investment that the company has made.
>
> An alternative, which I spoke about at sessions a couple years ago, if
> we are not going to do that, then, one should possibly even think
> about developing another institute at the National Institutes of
> Health to actually look at drug discovery for some of these, what we
> would call orphan pathogens, and do the basic work to come up with
> targets and particular lead molecules, and then turn it over to
> industry to go off with the development.
>
> That is something I think we possibly should consider down the pike.
>
> The problem in industry right now is that anti-infectives are
> competing with CNS drugs, cardiovascular drugs, and GI drugs that
> people have to take for the rest of your life, so there are huge
> markets and huge sales, and the anti-infective drugs are being
> prioritized down, and not going into development pipelines.
>
> Most companies need a potential market of \$500 million to bring a
> drug forward into development.
>
> That shifted the burden actually out to the biotech industry and there
> are a lot of companies out there trying to develop antimicrobial
> agents, but I can tell you the cost of developing is a problem in
> raising funds, and if you have been in this particular area or even
> had any stock whatsoever, you will understand what I am saying because
> at times, like three years ago, it was easy to raise funds. It is
> nearly impossible to raise funds this year even to start-up companies
> with very good ideas, that two or three years ago you could start.
>
> So, we are in what I would call almost a nuclear winter of funding for
> biotech companies at this point in time, and you are going to see a
> number of those companies go under.
>
> So, I think what is happening in the November workshop and with what
> Mark said will happen in the future, I think is absolutely imperative,
> that is, regulatory bodies, academia, and the pharmaceutical industry
> have got to get together to streamline this process, so we can develop
> life-saving drugs coming now.
>
> What you need is microbiological superiority, you have to be active
> against the resistant organisms, and you would like to have a drug
> that is not going to develop resistance very fast. You would also
> develop something that had a distinct pharmacological advantage, and
> finally, something that had a safety advantage.
>
> \[Slide.\]
>
> We have a well worked out paradigm. There are some scientific holes in
> it, but we do have the paradigm that you work first in the test tube
> to see if the bug is active, how it works, what its mechanism of
> action is, is it a cidal drug, is there low induction resistance, and
> is it active against both susceptible and resistant pathogens because
> you can\'t determine a priori whether the patient has a resistant or a
> susceptible pathogen.
>
> The next step is efficacy and appropriate animal models, and this is
> hotly debated, with the key pathogens, both the resistant and
> susceptible pathogens, and also bringing in the elements of
> pharmacodynamics in developing what levels of drugs that you need. I
> know Bill Craig and George Drusano have discussed that at many of
> these meetings.
>
> The pharmacokinetic requirements can be worked out ahead of time also.
> You need an I.V. drug for serious infections. Many times you can
> switch over to an oral drug if you have it once the infection comes
> under control.
>
> We need to know if the drug penetrates into the site of infection.
> John was talking about that strain in the central nervous system. You
> need to be able to penetrate into the central nervous system.
>
> You need to be able to penetrate into the alveolars to get aspiration
> pneumonia or aerosol pneumonia. These are topics I think will be
> discussed this afternoon.
>
> Finally, there is the risk-benefit analysis with the safety database.
>
> \[Slide.\]
>
> I borrowed a slide that Ed Cox showed at the meeting on the 19th of
> November on how you get on the list, and I know this is going to be
> gone into in detail a little later by John Powers, but I think there
> are two or three themes here, is there sufficient prevalence, because
> if there isn\'t sufficient prevalence, you are not going to be able to
> study it.
>
> Two, is the organism virulent, does it really have the public health
> importance that we are talking about.
>
> Then, you go down to look at other sufficient therapeutic alternatives
> to really justify going forward.
>
> So, what I would like to do for the rest of the talk, is kind of set
> some of the themes on how you go forward.
>
> \[Slide.\]
>
> First, the list. This is what David Ross presented a couple of years
> ago in a briefing document. This list is notable in that some of the
> newer resistant bugs, the Acinetobacters don\'t appear here, and I
> think this is a class that probably should be added to these lists.
>
> \[Slide.\]
>
> We do have very potent pathogens here. When you look at the
> community-acquired, Jim just went over a number of them. We have some
> other areas outside the gram-positives and the salmonellas and N.
> gonorrhea areas, so this is a list that has to go forward.
>
> We have talked about the vancomycin-resistant Staph aureus and the
> looming problem that may be coming.
>
> \[Slide.\]
>
> Jim has gone into the multidrug resistance. This is a study we
> actually had the Focus people do for us, to look at the incidence of
> multidrug resistance in common and gram-positive pathogens, and you
> can see it is significant when you sample 50 different centers around
> the United States, so it is a major problem coming and it\'s a problem
> that is changing over time, so a system has to be put in place to be
> able to track this in order to identify the problem bugs.
>
> We see the case reports as we are hearing about some new resistances,
> but people have to pay attention now to make sure they don\'t become a
> dominant pathogen.
>
> \[Slide.\]
>
> I would like to use Staph aureus as a model on how you would get onto
> the list, and you go back to some work, Chip Chambers published this
> actually in Emerging Infectious Disease in 1999.
>
> This is what happened with penicillinase-producing Staph aureus. It
> appeared almost after penicillin appeared. It became a real problem in
> the \'50s in hospitals. When I was in training in the early \'60s,
> penicillin resistance was not a problem out in the community. Yes, you
> would see it occasionally, but you can see very rapidly over the next
> two decades it became a major problem, and now the penicillin
> resistance is out there.
>
> \[Slide.\]
>
> We saw the emergence of MRSA. It was low. Jim reviewed the history of
> it. It is up to almost 50 percent now in many hospitals, and this
> actually drove the use of vancomycin. You can see the tonnage of
> vancomycin used as the incidence of methicillin-resistant Staph aureus
> came about. So, it does have an impact on the way the physicians treat
> patients.
>
> \[Slide.\]
>
> In the community now, are we seeing again what was seen with
> penicillin resistance? We have high levels of methicillin resistance
> in hospitals in nosocomial infections. We are starting to see it, and
> by word of mouth, we are hearing from almost every city in the United
> States that a significant percentage of patients coming into emergency
> rooms now have MRSA, so I think this is one area that has to be
> monitored very closely, and it has been seen in many different
> countries.
>
> These organisms are fully virulent, actually, they are probably a
> little virulent than some of the hospital strains, and they have
> caused fatal infections in children. It varies as high as 21 percent
> in Finland, and in some of the localized communities, Indian American
> communities, there was actually an incidence of 55 percent in the
> children.
>
> As Jim pointed out, these community-acquired strains are much
> different and they are not the multidrug-resistant strains, but they
> have something else that is much scarier. There was a recent study
> presented at ICAAC with 32 community-acquired MRSA isolates, of those
> 32 isolates, 31 were producing the superantigens Enterotoxin B and C
> which causes toxic shock.
>
> So, these are organisms that have high virulence factors that we may
> be seeing as a major problem coming forward.
>
> \[Slide.\]
>
> Finally, the VRSA that Jim has already talked about, the two strains,
> one from Detroit, the other one from Hershey, Pennsylvania. It turned
> out the Hershey patient also had a vancomycin-resistant enterococci in
> the wound, but the strain was lost, so you really couldn\'t tell
> whether or not that\'s where the vanA gene came in the Staph aureus in
> Hershey, Pennsylvania, and the organisms are not related, which is
> another scary factor.
>
> So, I think this is what is starting to dictate is that we are going
> to need some new classes of drugs to drive on for some of these
> resistances because, as Jim pointed out, they are resistant to a lot
> of different compounds.
>
> \[Slide.\]
>
> We just heard a little bit about the development of resistance, and
> this is a slide Bob Moellering showed at a meeting I was at, and he
> looked at the rate of resistance to vancomycin versus linezolid. It
> took a long time for vanco resistance to come about.
>
> That is probably because it wasn\'t used much, because we had many
> other anti-staphylococcal drug in the \'70s and \'80s, but when that
> tonnage went up to treat MRSA, the bugs had to do something, and they
> did an architectural, an engineering feat of putting eight genes
> together to overcome vancomycin resistance, but once that genetic
> bridge was built, it can be traded around, but it took 30 years for
> resistance to develop to vanco, but with linezolid, it developed
> actually while the clinical studies were being done.
>
> \[Slide.\]
>
> There was a paper in CID in January of this year of the compassionate
> use where they had 19 cases emerge while on therapy, so it is a
> problem, and this comes back to the question about the U.S., and those
> are point mutations giving the resistance to linezolid in the
> ribosome, so they can emerge during therapy.
>
> \[Slide.\]
>
> But, unfortunately, it has also emerged in Staph aureus, and I am
> aware of three different isolates now of Staph aureus. Well, what is
> the problem with the Staph aureus?
>
> We just heard maybe if you just drain it, it\'s okay, but if you look
> at bacteremia, probably one of the worse infections you can get with
> Staph aureus, and you look at the mortality, it is in the second set
> of bars, it\'s 30 percent. This is bugs that they kill people in a
> high percentage.
>
> Indeed, the mortality rate with MRSA is even higher than with MSSA,
> but it is not only true for Staph aureus, but coag-negative staph,
> enterococci, and Candida also when it is in bacteremia, the mortality
> is high. This is studies coming out of Dick Wenzel\'s group published
> in 1999. So, these are organisms that cause a lot of mortality.
>
> \[Slide.\]
>
> What about the pre-antibiotic era? This is a paper by Skinner & Keefer
> back in 1941. Staph aureus bacteremia had an 82 percent mortality.
> This is a real killer organism, and as the patient population got
> older, as you can see on the graph, the mortality was 100 percent. So,
> with our aging population and Staph aureus, this is a major problem.
>
> \[Slide.\]
>
> How about if inadequate therapy is given? Another slide that Dick
> Wenzel presented on data from Ibrahim in Chest in 2000. If you look at
> patients with intensive care unit bloodstream infections, and the
> numbers of patients are fairly large here, if you get inadequate
> therapy, the mortality is great, it doubles more than 50 percent.
>
> If you look at the patients, the organisms that were causing this
> mortality with inappropriate therapy, it was two main pathogens, Staph
> aureus and Pseudomonas aeruginosa. So, given the appropriate therapy
> early on, it empirically, really changes the outcome overall.
>
> So, I think these are the type that have to be put together for
> different pathogens to get them onto the list.
>
> Dick has also written a prospective article in JID in \'99, looking at
> the impact of therapy and attributed mortality, and as he says in that
> article, the resistance genes just add to that mortality, so if you
> have a drug that treats the resistant organisms, you can bring the
> mortality back down.
>
> \[Slide.\]
>
> Well, what are some of the problems? We talked about this a lot at the
> February meeting and at the meeting in November. I am just using some
> of my old slides there, but one of the problems that we have right in
> the development of drugs is there is very limited drugs in the
> pipeline.
>
> The promise that genomic sequencing in combinatory chemistry was going
> to cure it has failed to date. We still think that those new targets
> will yield some compounds in the future, but I think it is going to be
> another 5 to 10 years before you start seeing those compounds come
> down the pike, and we need substantial funding to continue that.
>
> \[Slide.\]
>
> I am not going to go into the detailed drugs on the next two slides.
> You have those that you can look at. There are two approved drugs
> here, and then there are five drugs being evaluated for gram-positive
> infections listed. They are in different phases of development.
>
> \[Slide.\]
>
> Following up on the ICAAC, and from data in the literature, there is
> another group of drugs. These are all analogs of beta-lactams with
> activity against Staphylococcus aureus. What it is, is these compounds
> were engineered to bind to PBP-2a.
>
> They do it much better than most other cephalosporins and carbapenems,
> and there are a number of them now going into development both in the
> United States and in Japan. That is the cephalosporins. The
> carbapenems have not made it to development yet, there is major
> problems in synthesis of those compounds and whether or not they are
> going to be brought forward, and I included these just for
> informational purposes.
>
> What is missing from the list? There is no drugs for gram-negatives,
> and gram-negatives are a looming problem in the hospital, and there is
> nothing that I see in the pipeline that is really going to add to the
> armamentarium, and that\'s why we need to encourage the development of
> drugs in this particular area.
>
> \[Slide.\]
>
> So, what about development of drugs for resistant pathogens? You need
> to promote development and appropriate use of them and the appropriate
> labeling. If you get restricted labeling, it is okay for an MRSA, but
> for a more focused product like a VRE, it is going to really
> negatively impact people developing drugs for that particular area.
>
> But basically, what you come down to is with enough safety database if
> there are safety issues, but there is activity against resistant
> pathogens. That will actually control the use of drugs, and I.V. drugs
> only are going to be controlled in hospital or in home I.V. use
> anyway.
>
> \[Slide.\]
>
> I.V. drugs are a problem to develop. You need serious infections
> because patients have to be in the hospital. Selection of comparative
> agents, I don\'t think is that much of a problem because there is a
> lot of drugs out there which are considered the drugs of choice.
>
> One should select the best agent, though, and I think this is a part
> of the monitoring by the FDA and Human Studies Committees to ensure
> that the best therapy is given as a comparative agent.
>
> I think the criteria for oral switch are being developed with
> different partners.
>
> \[Slide.\]
>
> With serious infections, there was a lot of talk about using surrogate
> markers with clearing of the cerebral spinal fluid in meningitis,
> clearing the blood with pathogens, but, of course, you need clinical
> outcome also, but the importance of clearing pathogens out of the CSF
> has been brought up before.
>
> Another question on what is the number of pathogens that you need, and
> I think we are going to be discussing that this afternoon, and the
> requirement for two well-controlled studies, this is one of the major
> topics of this conference, but there is another initiative that has
> been initiated at the FDA, which I think industry should use more, and
> that is use the target package insert initiative to really increase
> the communication and to clear up exactly what has to be done, and
> increasing the use of that particular initiative may actually help in
> the development of drugs.
>
> \[Slide.\]
>
> Finally, how do we incentivize drug development? This is really more a
> biotech field than a Big Pharma field. For expanded access, there is
> the possibility of charging fees just to cover your expenses or to
> augment what you are raising on the marketplace.
>
> There was a lot of talk about patent term extension at the November
> 19th meeting, and this is the initiative talked about by Mark
> Goldberger, about extending and giving a wildcard patent extension,
> that for developing drugs for niche products, you would then put the
> patent extension onto another product, and that drew a tremendous
> amount of enthusiasm from the Pharmaceutical Manufacturers
> Association.
>
> How about funded consortiums? I think that is a model, also cancer and
> AIDS has already had it, and we should move forward.
>
> One of the other areas that was brought up by one of my colleagues at
> Cubist is possibly the development of a loan system or government
> guaranteed loans. This would facilitate biotech companies being able
> to access different types of funds than just the stock market, and
> being able to develop funds.
>
> There are small business loans, but most biotech companies are too big
> to really get into that particular area. That particular thing could
> be modified also.
>
> You then repay the loans based upon once you have commercialized the
> product.
>
> \[Slide.\]
>
> The final incentives are tax credits or deductions. Right now it is
> only valuable for profitable companies, and there are things to extend
> tax losses to carry them forward, so you do become profitable, you can
> apply them.
>
> But the biggest thing, they actually have this in Canada and some
> countries in Europe, you have a transferable tax loss. A nonprofitable
> biotech company can transfer that to another company that is
> profitable and some mechanism of raising funds.
>
> These are just some of the ideas that have to be developed in the
> future, and many of these ideas cannot be worked on by this committee,
> but really have to be worked on by Congress to pass some laws to get
> into this area for funding.
>
> We do have drugs coming down the pike to treat some of the pathogens.
> There are areas of problems particularly with gram-negative where we
> need more research, and I think having the clear guidelines of how to
> develop these drugs and then encouraging companies to get into this
> area will help us in the future because of the emergence of these
> resistant pathogens.
>
> Thank you.
>
> DR. LEGGETT: Thank you.
>
> I will open for questions at this point. Don.
>
> **Questions from Committee**
>
> DR. PORETZ: Frank, it is common for certain organisms to use
> combinations of drugs, like Pseudomonas, people have been using double
> agents for a long period of time, tuberculosis we always do, and in
> the antiviral world with HIV disease we do.
>
> Should we be more commonly using combinations of drugs to hopefully
> prevent the emergence of resistance for other organisms than the
> classic ones that we have used?
>
> DR. TALLY: I think that is something that is going to come, and you
> point to Pseudomonas for combination therapy, and studies that were
> done a long time ago at UCLA for gram-negative bacteremia combinations
> seem to work better also in the neutropenic patient.
>
> So, yes, it is a point in the future where combination drugs will
> probably be employed. It is something that would come in a Phase IV
> type of procedure, because in registering a drug, you need to show
> that the drug, one, works, and, two, that it is safe in an adequate
> number of patients, and it is very hard to do that when you are doing
> combination studies initially.
>
> So, you need to do the first steps to show that you have a drug that
> is safe and effective in treatment, and then for the resistant ones in
> the sicker patients, in Phase IV, you could do the combination
> therapy, so I think you are going to see a lot more of that.
>
> DR. LEGGETT: Alan.
>
> DR. CROSS: At our hospital, because of our resistance problem, we have
> been, in fact, using more colistin than I have ever seen used since I
> started training. In our last talks, someone asked about the status or
> feasibility of detergent type antibiotics, and I was just wondering
> given the resistance mechanisms we heard about in the last talk, are
> there any resistance mechanisms we know about for detergent drugs,
> number one, and, number two, these drugs have been developed a long
> time ago and since then we have acquired increased skill in
> understanding the structure-function relationships, and are there any
> efforts or do you think there is any utility in perhaps going back to
> a drug like colistin, making some modifications, and at least perhaps
> mining that area?
>
> DR. TALLY: That is an area that I actually mined a while ago
> particularly to try and change the molecule, the colistin molecule of
> polymyxa B, to take off the part of the molecule that was binding LPS
> to see if I could use it in septic shock.
>
> There has been a lot of work on polymyxins and colistin to try and
> come up with better molecules, and I haven\'t seen any data that they
> have been able to do it.
>
> The inherent problem with those drugs, as you know, is the
> nephrotoxicity and that they really stay in the vascular space and
> don\'t penetrate much. I think there are other efforts to look at
> those molecules.
>
> Now, the detergent-like drugs, you get to a point where you can\'t
> give them because they are indiscriminate on all membranes, so it is a
> fine line. I know there are two or three efforts out there now that
> people are looking at those types of molecules.
>
> DR. CROSS: Do we know anything about the resistance mechanisms that
> may develop with those type drugs?
>
> DR. TALLY: No, not that I am aware of. Barth, do you know?
>
> DR. RELLER: No.
>
> DR. BELL: Frank, that was an excellent talk as usual. You have to some
> extent bridged the topics to be addressed in the morning session and
> the afternoon session, and I wonder if you could help me right now, in
> response to my question addressing the morning session, this concept
> of criteria for pathogens or I might call it drug-resistant pathogens
> of public health importance.
>
> What is the relative importance of the two topics this morning and
> this afternoon to the industry? In other words, I can well understand
> the afternoon\'s importance because it impacts on the way you would do
> studies and the materials you would have to submit for approval.
>
> How useful is it to you to have a list of criteria for drug-resistant
> pathogens of public health importance stamped by some government
> agency, is that not something you could figure out anyway or you and
> your investors could surmise anyway, do you really need some sort of
> criteria like that or is it really only as it might relate to this
> afternoon\'s discussion that that is of interest of you?
>
> DR. TALLY: I think I hear what you are saying, David. It is important
> for us. One, it is important for the discovery scientist to know what
> organisms we will be working on. That is at one level, that are going
> to result in a compound that would have a commercial potential.
>
> The second part of the question is your ability to raise money. It is
> easier to raise money from very skeptical investors, and they are all
> very skeptical, it is easier to convince them if there is some type of
> broad criteria that you can then fit your compound into or your
> organisms you are working into to increase the likelihood that you can
> get funding. So, it is important to the industry.
>
> Now, for Big Pharma, it is important for the discovery scientists in
> Big Pharma to convince their upper management that they can develop a
> drug in this particular area, so I think it is important in both
> areas.
>
> DR. LEGGETT: Frank, you made mention of you first have to prove your
> drug alone works. In that regard, could you mention some of the efflux
> pump attempts in terms of looking at inhibitors?
>
> DR. TALLY: There has been a huge effort on trying to develop pump
> inhibitors. It is an area I personally have kept my research out of
> because when you look at the genomes of many of the bugs, the
> versatility of their pumps is such that when you turn one off, another
> one turns on, and so it has been very difficult.
>
> You can show for select strains that you can inhibit the pump and
> restore the activity of ampicillin or one of the quinolones or
> fluconazole back to what it was in fungi, but as soon as you start
> going out and do a survey, another pump turns on at about 10^-7^,
> 10^-8^, and you are right back to where you were with another pump
> pumping in molecule.
>
> I was into this area also when I worked at Lederle with the pumps for
> pumping tetracycline. Again, there is a tremendous genetic ability of
> the organisms to manipulate these pumps to handle all the toxins
> because that is the way they make their living.
>
> So, there have been very good pump inhibitors, but none of them has
> reached the stage of commercial development that I am aware of at this
> point.
>
> DR. LEGGETT: Thank you.
>
> If there is no further questions, we will take a break here and
> reconvene at 10:45.
>
> \[Break.\]
>
> DR. LEGGETT: The next speaker will be John Powers, who is going to
> talk to us about a list of pathogens of public health importance.
>
> **List of Pathogens of Public Health Importance**
>
> **John H. Powers, M.D.**
>
> DR. POWERS: Thanks, Dr. Leggett.
>
> This is a continuation of our discussion that we started yesterday
> when we talked about labeling for multidrug-resistant pathogens.
>
> \[Slide.\]
>
> What I would like to show you today is some background on the requests
> that we have had from folks in the industry to list resistant
> pathogens of public health importance and why we even want to engage
> in this endeavor.
>
> The second thing I would like to go over is to elaborate on the
> criteria for listing pathogens of public health importance, and you
> saw that on one of the Dr. Tally\'s slides this morning, and then try
> to go into some information that we at the agency have been trying to
> obtain on looking at those criteria and how to obtain that data on
> looking at those things for each of the pathogens, and then finally,
> some future plans for populating that list.
>
> \[Slide.\]
>
> As I said, today is a continuation of previous discussions on
> development of drugs for pathogens resistant to antimicrobials. There
> were several Advisory Committee meetings on this topic in the late
> 1990s, but most recently, there was a meeting of this committee about
> a year ago, in February of 2002, and then a workshop in November of
> last year co-sponsored by the Infectious Disease Society of America,
> the pharmaceutical industry, and the FDA.
>
> It is very clear from these meetings that one of the main topics is
> that increasing in vitro resistance among many of these pathogens is
> becoming a public health problem. In some cases already, this in vitro
> resistance is translating into clinical failures, and even if we
> aren\'t seeing clinical failure at this point, it may signal a
> decrease in the future usefulness of that drug or drug class.
>
> \[Slide.\]
>
> In November, at the workshop, there were discussions on the shifting
> of resources within the pharmaceutical industry to the treatment of
> more chronic diseases, something Dr. Tally already brought up again
> today, and there was a recent Wall Street Journal article, and
> somebody sent this to me, and unfortunately, it didn\'t have the date
> at the top of the clipping, so I can\'t tell you which issue it was,
> but it listed the top 10 selling antimicrobials in the United States.
>
> I just sort of condensed them all together and looked at the drug
> classes. There was not a single antimicrobial on that list of top 10
> selling drugs, and on those were antidepressants, anti-ulcer
> medications, cholesterol-lowering drugs, and two drugs for anemia, but
> none of them were antimicrobials.
>
> So, as Dr. Tally elucidated for us this morning, antimicrobials are
> not the moneymakers for the pharmaceutical industry. So, why even put
> together this kind of a list?
>
> \[Slide.\]
>
> Well, at last year\'s meeting of this Advisory Committee,
> representatives of the pharmaceutical industry requested that the FDA
> develop a list of pathogens for which drug development was deemed of
> public health importance. Again, this same issue was brought up in
> November of 2002 by both representatives of the Infectious Disease
> Society of America and the pharmaceutical industry.
>
> At that point, we discussed, well, what would the criteria be for
> developing such a list, and we felt it was important to come up with
> the criteria before we just started putting names of pathogens on a
> long list, the reason being that obviously, as Dr. Tally brought up
> this morning, this list would probably change over time, therefore, it
> would be nice to have some uniform criteria, and one of the other
> things Dr. Tally brought up is when a company wants to go develop a
> drug, they want to be able to sort of plug this in for their
> particular drug and the particular organism that they are looking at.
>
> We could take an example of this. For instance, in the 1950s, in
> hospital-acquired infections, penicillinase-producing Staphylococcus
> aureus was a scourge at that point.
>
> One could argue that there are plenty of drugs available now to treat
> just penicillinase-producing Staphylococcus aureus, and one would not
> put just that drug on a list at this time. However,
> methicillin-resistant Staphylococcus aureus is a different story.
>
> So, you can see that some of these pathogens will change over time as
> to what would be considered of public health importance.
>
> \[Slide.\]
>
> How would we use such a list? Well, there is a couple of points that
> are important to bring up, and that is to get on this kind of a list,
> a pathogen would not need to fulfill every one of the criteria to be
> on this list. We are just using this as a kind of template.
>
> The other issues that we need to discuss would be the drug sponsors
> would still need clinical data on treatment of resistant pathogens, as
> we discussed yesterday in our discussion on multidrug-resistant
> Streptococcus pneumoniae, and the reason we feel this is important is
> that there may be differences in patient characteristics of those who
> harbor resistant organisms versus susceptible organisms, and we feel
> it is still important to actually see clinical information on the
> treatment of those patients.
>
> One of the other reasons that this may be important to have a list for
> the pharmaceutical industry, that came up in November, was the idea
> that perhaps these drugs could be given priority review.
>
> Now, it is almost impossible to designate priority review upfront in
> the development process because as Dr. Goldberger brought up in
> November, whether a drug gets priority review or not depends upon the
> results of the clinical trials, but at least it would be designated
> that perhaps the drug might get designated as a priority review.
>
> For instance, just recently\--now, this is public
> knowledge\--daptomycin has been designated for priority review, as
> well.
>
> Also, drugs may still be approved, but not garner a resistance claim
> until there is sufficient clinical data, and this is addressed as
> another important point. The issue here is the drug will be on the
> market and available for clinicians to use in their patients, but
> until there is a sufficient clinical database, they don\'t necessarily
> need to have a resistance claim.
>
> The example of this is levofloxacin, which was approved in late 1996,
> but didn\'t garner a claim for penicillin-resistant Streptococcus
> pneumoniae until 1999, when there was sufficient clinical data to
> support its efficacy in the treatment of those organisms.
>
> The other important point here is that this is a list for
> prioritization, and Dr. Leggett already pointed out in our discussions
> so far, we have essentially talked about every bug you could possibly
> think of, but since this is for prioritization, what we are trying to
> look at is what do we consider most important.
>
> So, because an organism isn\'t on the list doesn\'t mean it is not
> important, but we are trying to prioritize these things.
>
> \[Slide.\]
>
> So, what we did, there were seven initial criteria that you saw on Dr.
> Tally\'s list, and we condensed them down to six because it appeared
> to us that two of them essentially were the same thing, and I will go
> through these.
>
> The first is that the organism is of sufficient prevalence in the
> population with the disease under study, and I will talk about these
> in more detail through the talk.
>
> The second is that the organism causes severe or serious disease. We
> changed this from virulence because we didn\'t want to get into the
> issue of virulence factors as much as that those virulence factors
> actually translate into high morbidity and mortality for patients.
>
> The third is that the drug to which the organism is resistant is
> commonly used in the disease under study.
>
> The fourth is that there is limited available therapies due to
> multidrug resistance, and we had separated these out into two separate
> criteria before, but then we figured, well, if it\'s multidrug
> resistant, that is why there is limited available therapies, and we
> condensed that into one criteria.
>
> Finally, a drug is used to control spread of the disease in the
> population, and I will give some examples of that, and then lastly,
> that there is a clinical correlation of in vitro resistance with poor
> clinical outcomes.
>
> \[Slide.\]
>
> So, let\'s go through each one of these, and I will try to show you
> some of the information we have tried to put together for some
> organisms to put on this list.
>
> The first is that the organism is of sufficient prevalence in the
> population with the disease under study. The first point here is that
> this speaks to the current burden of the public health problem. If an
> organism is really, really uncommon, not to say that it is still not
> important, but what is its relative importance compared to some to
> some of the other organisms which may be more common for which we
> might desire drug development.
>
> Dr. Tally also brought this up this morning. If an organism is very,
> very uncommon, then, it is almost impossible to get clinical
> information and to study it, as well.
>
> As we said, less prevalent organisms may still be important or they
> may become more prevalent over time, and again this list should be a
> dynamic thing where we will update this as time goes on.
>
> Also, this brings up an initial point here about linking the disease
> under study and the organism, and most resistance labeling claims are
> related to efficacy in a particular disease, so one could argue that
> perhaps an organism is important in treating hospital-acquired
> pneumonia, but that same organism may not be as big a deal when
> treating an uncomplicated urinary tract infection.
>
> Also, this provides the most helpful information to clinicians to show
> where the drug actually works in which particular disease, and we will
> talk some more about this issue of difficult diseases supporting each
> other this afternoon.
>
> \[Slide.\]
>
> So, let\'s try to look at some information on how common are some of
> these organisms. I am going to show this again for some of the
> committee members that weren\'t here yesterday.
>
> The FDA has tried to obtain surveillance data in several ways, and one
> of the things we have done is to obtain this information from Focus
> Technologies through a contract that we issued last year.
>
> We got this contract for the purposes of identifying and tracking
> resistant organisms of public health importance really for the
> purposes of drug development. The Surveillance Network of Focus
> Technologies includes 317 U.S. laboratories, and this information is
> updated continuously. I will you some information today as Dr.
> Jorgensen showed, something about penicillin-resistant Strep pneumo
> and 14 percent of those organisms being multidrug resistant. That
> number is a lot higher now than when that was published in 2000.
>
> This includes community, government, and university laboratories, and
> hospitals that range from bed size of below 99 to over 500 beds.
>
> \[Slide.\]
>
> This Surveillance Network also includes greater than 65 million
> antimicrobial susceptibility testing results for various bug-drug
> combinations. It is not an active surveillance network, and it is
> based on cultures which clinicians order.
>
> We looked at this in several ways. One way we could look at this is
> per isolate, one way we could look at it is per patient, and when we
> did it, essentially, the results come out the same. So, all the
> information that you will see today is on a per patient basis, and we
> also looked at only one isolate per patient.
>
> When we looked at that isolate, we looked at it from a first isolate
> per patient, last isolate per patient, and it came out to be the same
> in most of the cases, which brings up I guess an important point that
> Dr. Reller raised this morning, about development of resistance on
> therapy, but for the vast majority of what we looked at, the first
> isolate and the last isolate, the susceptibilities were not different.
>
> This database includes over 500 microbial taxa and greater than 100
> individual drugs, and covers almost 3 million patients who are both
> inpatients and outpatients, which gives us access to an estimated 2.6
> percent of all isolates tested per year in the United States, and some
> of the other surveillance data is about less than 1 percent.
>
> \[Slide.\]
>
> Here is some of the information that we tried to get to address this
> idea of how common is an organism in the population. As you can see,
> interestingly, of these greater than 500 taxa that are in this
> database, only 27 of those taxa account for 95 percent of the
> clinically encountered bacterial species.
>
> So, if you look at this, as Dr. Tally pointed out, Staph aureus seems
> to be a fairly important organism here, 16.1 percent of Staph aureus
> make up this 95 percent, and the interesting thing is that the
> inpatient-outpatient split is starting to get closer and closer, 9
> percent of these are inpatients, 6.5 are outpatients.
>
> Although we discussed Streptococcus pneumoniae at great length, you
> can see that Streptococcus pneumoniae only account for 1.3 percent of
> this, with 0.7 percent being inpatients and 0.6 percent outpatients.
>
> There is an obvious bias in this, and that is that the kinds of
> diseases in which Streptococcus pneumoniae is most common, things like
> sinusitis, are also the kinds of diseases where clinicians may not
> choose to culture patients, so again there are some limitations in
> this data.
>
> \[Slide.\]
>
> I apologize for this being very hard to read, but it is awful hard to
> squeeze 27 taxa onto one slide and to try to show you some of the
> quantitative information, as well.
>
> What we have here are 27 taxa listed from most common to less common
> on this list, and here is a point that Dr. Tally brought up this
> morning. If we look at the overall burden of disease, the
> Enterobacteriaceae account for almost half of it, and yet we see very
> little drug development for these gram-negative organisms.
>
> When we split them up by the top 10 Enterobacteriaceae, we have E.
> coli leading the list, Klebsiella pneumoniae, Proteus mirablis,
> Enterobacter cloacae, Serratia marcescens, Enterobacter aerogenes,
> Citrobacter freundii, Klebsiella oxytoca, Citrobacter, Morganella on
> here.
>
> Then, we get down to some of the gram-positives with Staph aureus
> accounting for 16.4 percent, and as Dr. Tally pointed out in that
> Chest article, it was Staph aureus and Pseudomonas that were the ones
> that had the excess mortality.
>
> The organisms that come up next are coagulase-negative Staphylococci,
> Pseudomonas aeruginosa, and Enterococcus faecalis. Enterococcus
> faecium again, although we have talked a lot about
> vancomycin-resistant E. faecium, is 0.9 percent down here. Again, this
> isn\'t saying that these organisms aren\'t important, we are just
> trying to put this on a relative scale compared to some of the other
> things that we are seeing.
>
> So, the organisms for which we are seeing drug development, like
> Enterococcus faecium and Staph aureus really the question is how do
> they fit in compared to these gram-negatives where we are not seeing a
> whole lot of drug development.
>
> Some of the other things we see down here, Acinetobacter,
> stenotrophomonas, and then we get to Streptococcus pneumoniae, viridan
> strep, group A and B streptococci, Haemophilus influenzae, and
> anaerobes at the bottom.
>
> \[Slide.\]
>
> There are some limitations to this data, as I said, as it is limited
> to what clinicians actually order tests for. One can make a case that
> penicillinase-producing and quinolone-resistant Neisseria gonorrhea is
> an organism of public health importance, and yet when we went to look
> for this, over this five-year span, we could only find 1,500 isolates
> of Neisseria gonorrhea in this database.
>
> Again, I am not saying that this is unimportant, it just shows that
> unfortunately, that we can\'t obtain much information and there are
> other mechanisms and I believe the CDC has an active surveillance for
> looking for resistance in Neisseria gonorrhea.
>
> \[Slide.\]
>
> So, one of the other things that we can do with this database is to
> try to track the proportions of infections over time to try to see
> which are increasing, as well. So, what we have here is the percent of
> all patients with bacteremias, and this goes from 1998 to 2002.
>
> You can see that there is a slight increase in all Staph aureus and
> plateaus out from 1999 to 2002, but what you can see, at least from
> the data that we have obtained, is that the number of
> methicillin-resistant Staph aureus bacteremias is going up, and there
> has been a slight decline in methicillin-susceptible Staph aureus
> bacteremias, so again this is just one way of trying to look at the
> burden of disease.
>
> \[Slide.\]
>
> One of the other things that bears discussing here is something that
> we talked about yesterday, about trying to put into the label
> information on helping clinicians to make treatment decisions.
>
> One of the things that still clinicians will need to look is what
> their individual patterns of susceptibility are in their particular
> institution or their particular community because when you look at the
> spread of methicillin-resistant Staph aureus across 111 institutions
> in this database, it is enormous, so if you practice over here on the
> far left, you have a less than 10 percent incidence of
> methicillin-resistant Staph aureus and perhaps you don\'t need to
> worry about that when you are making treatment decisions.
>
> If you practice over here, you have got a big problem. You need to
> consider Staph aureus probably every time you see a person who is
> infected with a gram-positive.
>
> So, looking at this information on drug-resistant pathogens isn\'t
> going to obviate clinicians still needing to know what the resistance
> pattern is in their own community.
>
> \[Slide.\]
>
> So, let\'s move on to the second criteria. Do the organisms cause
> serious and severe disease? This is really information that we can
> just garner from the clinical literature and what we know about the
> natural history of disease caused by these pathogens.
>
> Again, resistance claims are usually linked to the disease under
> study. For instance, we have up to date granted penicillin-resistant
> Streptococcus pneumoniae indications for community-acquired pneumonia,
> but not acute bacterial sinusitis or acute exacerbations of chronic
> bronchitis.
>
> It is also important about the range of organisms that cause various
> disease. If one were to grant an indication that said for all
> resistant Streptococcus pneumoniae infections, that may not be very
> informative to clinicians, and it also doesn\'t impact on things like
> Strep pneumo causes respiratory tract infections, but it\'s an
> uncommon cause of something like urinary tract infections.
>
> Again, these diseases range from fatal to self-resolving diseases, and
> it may be that the impact of resistance is most likely to be important
> and relevant to public health in the diseases which are not as likely
> to resolve spontaneously.
>
> This gets to an issue of making public health decisions versus
> decisions in individual patients, so when we are approving a drug, we
> are looking at is this drug going to be used in millions and millions
> of people to treat that particular infection. That doesn\'t mean we
> are telling a clinician that if they see a patient that has been
> treated over and over again and has failed numerous antibiotics that
> they can\'t make a treatment decision based on what they are seeing in
> front of them.
>
> \[Slide.\]
>
> So, when we look at some of the stuff of splitting it up by source,
> this database gives us the ability to actually try to look at where
> are these organisms most commonly occurring. In this graph, what you
> will see is splitting up the data on Staph aureus infections by
> source.
>
> In here, we will see the yellow bars are all Staph aureus, the pink
> bars are methicillin-susceptible, and the orange bars are
> methicillin-resistant Staph aureus. What you can see is that from all
> sources, that we still see that MSSA outnumbers MRSA, but you can see
> that there is big differences across these.
>
> When you look at bloodstream infections, they are pretty much getting
> equal to each other. Upper respiratory tract infections, it seems that
> methicillin-susceptible outnumbers methicillin-resistant, and in UTI,
> actually, surprisingly, methicillin-resistant actually outnumbers
> methicillin-susceptible although the overall numbers are quite small.
>
> \[Slide.\]
>
> So, the third criteria is that the drug to which the organism is
> resistant is commonly used in the disease under study, and this really
> speaks to the clinical relevance of drug resistance. Again, I gave
> this example yesterday.
>
> One could argue that trimethoprim sulfa resistance is a problem when
> one goes to treat an uncomplicated urinary tract infection because
> that drug is very commonly used. On the other hand, if someone gave
> you the information that this young woman had an E. coli resistant to
> Streptomycin, causing her UTI, that information is not very clinically
> relevant since people don\'t use that drug to treat uncomplicated
> urinary tract infections.
>
> We are attempting to gather information on drug usage for various
> diseases from a number of sources, and actually it is quite difficult
> to split this up when you try to look at what clinicians are using for
> a particular disease.
>
> There are a number of databases, like the IMS database, which look at
> overall drug usage, but it is a lot more difficult when you want to
> piece it down to what people are actually using it for. So, we are
> trying to look at the IMS database, medical literature, and we are
> also trying to contract with some other folks to actually obtain
> sources of information from their practices about what folks are using
> for various diseases, and this is because variations in medical
> practice and resistance patterns in various geographic areas and
> patient populations may differ.
>
> It is interesting, when I was listening to the discussion yesterday, I
> think one of the committee members said I don\'t think cefuroxime
> should even be on here, it is not a problem, and the person sitting
> next to me said gee, that is the drug of choice we use at our hospital
> for community-acquired pneumonia. So, I think there is differences
> across the practices that may impact on this, as well.
>
> \[Slide.\]
>
> The fourth issue is limited available therapies due to multidrug
> resistance. This is what we have tried to get a lot of information on.
> So, we have tried to use surveillance data to examine the
> relationships of cross resistance within a given bacterial taxa.
>
> I showed you this data yesterday for Streptococcus pneumoniae, that
> the way we are trying to look at this is if an organism is resistant
> to one drug class, is it resistant to the other and vice versa,
> looking at it in both directions.
>
> We also plan to do similar analyses for other organisms, as well for
> fungi, and what I am going to show you is some preliminary analyses
> today that we have done for some of these organisms that we are by no
> means complete yet.
>
> We assume that organisms which are resistant to multiple drugs are
> more likely to have fewer available drugs for treatment, as well,
> which would seen to place them higher on the list.
>
> \[Slide.\]
>
> So, like I did yesterday, I want to show you a blank graph, so that we
> will have an idea of what we are looking at. What we have done is we
> have placed on the X axis the number of agents to which the isolates
> are resistant.
>
> On the Y axis is the number of agents to which the isolates were
> susceptible, so if you are right here, it means that these particular
> isolates that you will see, and we put a number of dots across this
> here, each dot representing one isolate usually, and so if an organism
> falls right here, it means that it is resistant to nothing and
> susceptible to six different drugs.
>
> If an organism falls right here, it means it is resistant to one drug
> and susceptible to five drugs, and then you will see these dots that
> kind of trail off down here. What that means is that an organism that
> falls right here is susceptible to four drugs, resistant to one, and
> intermediate to one, just so you understand what you are looking at
> when we do this, and then we will trail down here to the point when
> you get to see these dots down here, these particular isolates are
> resistant to seven different antimicrobials and susceptible to
> nothing.
>
> So, obviously, what we are really interested in is the organisms that
> are falling down on this end. If we see cross-resistance in these
> organisms, what we will then look for is clustering of organisms here
> and clustering of organisms somewhere down here, as well.
>
> \[Slide.\]
>
> Let me give you two examples of an organism that appears to be
> multidrug resistant with linked cross-resistance pattern and one that
> does not.
>
> Here, we did the same analyses in almost 8,000 isolates of
> Acinetobacter baumannii. The antimicrobials tested across these seven
> things here are gentamicin, ceftazidime, imipenem, ciprofloxacin,
> cefepime, ampicillin- sulbactam, and piperacillin. So, that is the
> seven isolates that run across both of these isolates.
>
> What you can see is that the organisms either cluster right here where
> there are the darkest dots, and that means that the organism is either
> susceptible to all seven drugs and resistant to none, but right here
> is where we see the other clustering of the organisms.
>
> So, if you have a resistant Acinetobacter, it is most likely to be
> resistant to five or six other drugs and susceptible to only one or
> two at that particular point. So, this way, we are looking at it in
> both directions of not just starting out with, say, gentamicin
> resistance and seeing how many are resistant to gentamicin, we are
> looking at it in two directions.
>
> \[Slide.\]
>
> Let\'s look at an organism that doesn\'t fit this pattern. This is
> Streptococcus pyogenes group A beta-hemolytic streptococci. Here, we
> looked at penicillin, vancomycin, erythromycin, clindamycin,
> ceftriaxone, and levofloxacin.
>
> What you see here is that multidrug resistance is not a problem with
> group A strep. So, you will see that these organisms are, for the most
> part, susceptible to all six of these antimicrobials, and there is
> very few of them that are resistant. Again, this trailing down here is
> a few of them will end up being intermediate, as well, but when you
> look out here, there is almost none that are multidrug resistant or
> very few when we get out to this point.
>
> So, if we are looking at this criteria at least of multidrug
> resistant, Acinetobacter is clearly an issue here, but group A strep
> is not, and that there are a number of other drugs that may be
> effective.
>
> \[Slide.\]
>
> Then, we can actually take this information and do more detailed
> analysis on the resistance patterns by taking these particular cells
> and actually looking at the seven different drugs and trying to see
> whether they are resistant or not.
>
> If you just take this group right here where we are talking about
> organisms that are resistant to six different drugs and only
> susceptible to one, that is across this line here. The beauty of this
> is you can actually look as we increase, you can see when you start to
> lose particular drugs. I will show you this for Streptococcus
> pneumoniae where it is a little easier because there are not so many
> drugs across the bottom here.
>
> But what you can see is that once you get to this point with an
> Acinetobacter, that you are talking about 98 percent resistance to
> aminoglycosides, 91 percent to ceftazidime, 99 percent to quinolones,
> 97 percent to cefepime, 86 percent to ampicillin-sulbactam, and 99
> percent to piperacillin, and all you are left with is imipenem, and
> even there, a third of the organisms are resistant.
>
> So, this is the kind of information we are trying to look at to say
> would an organism go on such a list of public health importance
> because of the lack of available therapies here.
>
> If you did the same thing with group A streptococci, you would see
> that 100 percent are still susceptible to penicillin, and a few of
> them are macrolide resistant, but that most of them are still
> susceptible to all those other drug classes.
>
> Let\'s do the same kind of analyses with Streptococcus pneumoniae, and
> I just want to show you this to complete the thought that we did
> yesterday because I didn\'t show you these when we were talking about
> multidrug resistance, but the question came up yesterday of, well,
> most of these organisms probably aren\'t resistant to two or three
> things.
>
> Well, at this point, it looks like they are, and you can see that if
> we split this up, and we split this up just because if you overlay
> these two graphs on top of each other, you can\'t see anything, so we
> split them up into penicillin-susceptible isolates on the left and
> penicillin-resistant on the right.
>
> If you susceptible to penicillin, most of these organisms still
> cluster right here, meaning they are susceptible to erythromycin,
> third generation cephalosporins, clindamycin, levofloxacin, and
> trimethoprim- sulfamethoxazole.
>
> On the other hand, if you start out with the penicillin-resistant
> isolate, you can see most of these organisms cluster out here meaning
> they are resistant to at least two other drugs in addition to
> penicillin, so it is not that if you are resistant to penicillin,
> well, some of them are macrolide resistant and some of them are just
> resistant to trimethoprim-sulfa, they are resistant to at least three
> things.
>
> \[Slide.\]
>
> So, again, we can do the same kind of information where we take this
> and look down at this, and actually, we did it right here just to show
> the extreme case of what\'s out here, but if we took this right here,
> you can do this for any of the lines, so if you look at the two drug
> resistance line, you can see that 94 percent are resistant to
> erythromycin, 95 percent to trimethoprim-sulfa.
>
> Again, if you look down this list, you can see when you start to lose
> things, and you can see that the first drug to go is
> trimethoprim-sulfa, the second class to go looks like macrolides, and
> then the third class to go looks like clindamycin here, but yet we
> maintain susceptibility of third generation cephalosporins until we
> get way out here, and then you see that even there is 100 percent
> resistance to this, as well.
>
> The reason I am showing you this is that what we would like to do is
> get your input today on what kind of organisms we should run through
> this kind of analysis to try to look at.
>
> We plan on doing this for the 27 different taxa that I showed you in
> the beginning, but are there some other organisms that the committee
> would consider important to try to do this analyses, as well.
>
> \[Slide.\]
>
> The fifth criteria was that the drug is used to control the spread of
> the disease in the population, and this is important for things like
> sexually transmitted diseases like gonorrhea and tuberculosis where we
> don\'t have good vaccines available, and really the means of limiting
> that spread of the organism in the population is the drug therapy
> itself as opposed to, say, things like vaccines.
>
> \[Slide.\]
>
> The last criteria is perhaps the trickiest one, and that is trying to
> draw a clinical correlation between in vitro resistance with poor
> clinical outcomes, and this really raises the question of is
> resistance in the test tube clinically relevant.
>
> The reason why we also feel this is important is there are recent
> examples where in vitro resistance does not correlate with poor
> outcomes in the majority of cases, and there are other methodological
> issues when we expand this beyond just bacteria, such as things with
> like tuberculosis where we know that clinical outcomes don\'t
> correlate with some of the in vitro testing for some of the anti-TB
> drugs.
>
> But, for instance, we know that some of the data we are seeing now on
> penicillin resistance in Streptococcus pneumoniae at least in
> community-acquired pneumonia shows that until we get up to MICs of at
> least four for Streptococcus pneumoniae against penicillin, that there
> doesn\'t appear to be an impact.
>
> Again, this is the issue of the disease in question because for
> meningitis, there appears to be that this may be more of an issue than
> for community-acquired pneumonia.
>
> On the other hand, there is also some information in macrolide
> resistance in Streptococcus pyogenes pharyngitis that perhaps that
> doesn\'t make a whole lot of difference either.
>
> So, the clinical impact of resistance may be more important, as I said
> before, and more apparent in more serious diseases which are less
> likely to resolve spontaneously.
>
> \[Slide.\]
>
> It is difficult to get information on clinical treatment outcomes.
> First of all, as Dr. Tally said, the organism must be prevalent enough
> to even study and it takes time to accumulate that data.
>
> The Pallares study that was published in the New England Journal of
> Medicine was 10 years\' worth of data from Spain. Also, some drugs are
> not used to treat a severe disease where the difference between
> susceptible and resistant isolates are more likely to occur, and Dr.
> Tally showed that slide about the attributable mortality between these
> things.
>
> So, for instance, in hospital-acquired pneumonia, it may be more
> apparent that susceptible, and the data that Dr. Tally showed from the
> Ibrahim article in Chest is about hospital-acquired pneumonia where
> you this big difference between susceptible and resistant isolates.
>
> On the flip side of that, though, the cure rate for hospital-acquired
> pneumonia is about 50 percent, so the overall cure rate is going to be
> lower although the difference between susceptible and resistant
> isolates may be bigger.
>
> On the other hand, suppose you look at a study of community-acquired
> pneumonia in PORT Class 1 patients, who are the least severely ill
> patients. The mortality in those people is about 0.1 percent. How are
> going to be able to show a difference between susceptible and
> resistant isolates when a number of the\--now, obviously, that is
> treated patients, so we are not saying that everybody would get better
> if they didn\'t get treated\--but it is difficult to show a difference
> in that.
>
> We can extend this to even other diseases like acute bacterial
> sinusitis where the spontaneous cure rate is higher, it is a lot more
> difficult to show this.
>
> The other issue is where is your drug used, and we had this discussion
> back in January about macrolide- resistant Streptococcus pneumoniae.
> Again, macrolides are usually used in these people for things like
> community-acquired pneumonia in the outpatient setting who are likely
> to do well anyway.
>
> What is the impact of macrolide resistance on that disease, it may be
> very difficult to tell. The flip side of that is that macrolides are
> very rarely used as sole therapy in the treatment of someone with
> severe community-acquired pneumonia. They are usually part of a
> combination regimen, so again it becomes very difficult to determine
> what the impact of macrolide resistance is in that organism.
>
> \[Slide.\]
>
> The other issue is when we see increasing case reports, can we really
> call this mounting clinical evidence, and there is a couple of issues
> that make that difficult to evaluate.
>
> The first is that there is a publication bias, people are less like to
> publish the fact that they put the person on a macrolide and they got
> better.
>
> The second thing is the natural history of the disease, such as
> community-acquired pneumonia, where severe disease carries a mortality
> of approximately 30 percent regardless of therapy. So, if you see
> somebody who has severe community-acquired pneumonia and they were
> given a macrolide and they didn\'t do well and they had a resistant
> organism, is it because they had the resistant organism or is it
> because they were going to die anyway from their underlying disease?
>
> The third thing is there are some data showing no effect of
> antimicrobial therapy on mortality in the first five days of
> bacteremic pneumococcal pneumonia, and this is data that Dr. Astrian
> did at Penn back in the 1960s, and there is no reason to believe that
> that would be different. In fact, that is the reason why the Feikin
> article in the American Journal of Public Health excluded patients in
> the first four days of treatment because they wanted to take this into
> account, as well.
>
> The problem with all these case reports is they lack comparative data
> showing a higher rate of failure in resistant isolates versus
> susceptible isolates. So, for instance, when we looked at the data for
> tolithromycin, we showed at that advisory committee that three of the
> five patients who received clarithromycin, who had macrolide-resistant
> organisms, one of whom was bacteremic, got better.
>
> So, when we look at this in a comparative way, the question is can we
> show that these resistant isolates have a worse outcome, and this
> data, like I said, is very hard to obtain.
>
> \[Slide.\]
>
> Some people have done it, though, and I would like to show you some
> examples. This committee is pretty familiar with the discussions about
> Streptococcus pneumoniae, so I wanted to use a different example here
> of group A streptococcal pharyngitis.
>
> This was a study that was done in Italy in a four-month span in 1997.
> In Italy, their macrolide resistance is actually quite high, it is
> almost about 50 percent of group A strep are resistant to macrolides.
>
> So, they did throat swabs prior to treatment at the end of therapy in
> these children all under the age of 14, and they looked at both the
> clinical resolution and the bacteriologic eradication rate in these
> children.
>
> Out of those 3,000 kids who got cultured, 1,048 or about a third of
> them had a positive test for group A beta-hemolytic streptococci. 934
> of them were tested for susceptibility, and all of those kids got
> looked at for clinical cure.
>
> Only 668 out of the 934 came back for follow-up and that were able to
> be assessed for bacteriologic cure by a second culture. The macrolide
> resistance in their isolates at baseline was 46.3 percent of the
> isolates, and one of the phenomenon I find very interesting is that
> penicillin resistant was zero percent.
>
> So, I constantly ask myself this question - penicillin is used all the
> time for various infections, why hasn\'t this bug become resistant to
> penicillin, and I think that is a very interesting, if unanswered
> question.
>
> \[Slide.\]
>
> What they showed was that the macrolide-susceptible organisms, which
> comprised 57 percent of them, the bacteriologic cure rate which was
> done at the end of treatment, at 10 days, was about 80 percent of
> those people. Even though 42 percent of the organisms were
> macrolide-resistant, almost 60 percent of them had a bacteriologic
> cure anyway. So, there is a big discrepancy, 20 percent more kids who
> had a resistant isolate still eradicated the organism from their
> throat.
>
> Now, this goes to two different points here. Is this because this is
> pharyngitis, which is a self-limited, self-resolving disease in a lot
> of people anyway, or does it say that we are defining these
> breakpoints in some wrong way and that the drug is still having
> efficacy?
>
> If you look at the penicillin-susceptible isolates, 100 percent of
> these were susceptible, and yet the penicillin only eradicated the
> organism in 84 percent of the cases, so it shows that even in all
> susceptible isolates, that the drug isn\'t completely effective all
> the time, and there is a whole body of literature on this, too, that
> some people argue that perhaps other organisms in the mouth secrete
> beta-lactamases which inactivate penicillin when you are trying to
> treat group A strep, et cetera.
>
> When they looked at the clinical cure rates, it was low no matter
> which way you sliced it, and, in fact, the failure rate with all these
> drugs was less than 2 percent at day 3 to 5 no matter which drugs you
> looked at, and they looked at penicillins, cephalosporins, and
> macrolides in this disease.
>
> \[Slide.\]
>
> So, what are some of the organisms that we have previously granted
> resistance claims for that would seemingly be easy to put on this
> list? Well, we have talked at length today about methicillin-resistant
> Staph aureus, vancomycin-resistant Enterococcus faecium.
>
> In the past, we have granted claims for penicillinase-producing
> staphylococci, but one could argue that at this point in time, that
> doesn\'t really represent an organism of public health importance, and
> it is probably subsumed under MRSA anyway.
>
> We have granted indications in the past for beta-lactamase-producing
> Haemophilus influenza and Maraxella, and most recently, for
> penicillin-resistant Streptococcus pneumoniae, and we had the
> discussions yesterday of should we now, knowing what we know, be
> calling this multidrug-resistant Streptococcus pneumoniae.
>
> Just to reiterate some of the things we brought up yesterday, some of
> the committee members talked about why don\'t we just turn back the
> clock and remove this and just say community-acquired pneumonia due to
> susceptible pathogens and forget about putting these resistance things
> in there.
>
> Two of the points I brought up yesterday I think we need reiterating
> today. The one is not everybody who reads this label is an infectious
> disease specialist, so we want to convey this information to
> clinicians, and what do we want to convey, because somebody else said
> yesterday, well, the label shouldn\'t be an educational tool.
>
> It says in the Code of Federal Regulations that the label is actually
> supposed to show how the drug is supposed to be used for its intended
> use. The intended use is not for a bacteria, it is for a disease, and
> those diseases for the most part are treated empirically especially
> when we talk about Streptococcus pneumoniae, so what we are writing
> this label for is not so just infectious disease physicians know how
> to use it, but so how general practitioners and family practitioners
> and other people also are aware of this cross resistance pattern
> between these organisms and what they should be doing when they are
> going to treat people especially in an empiric setting.
>
> \[Slide.\]
>
> So, our future plans then will be to try to look at some of this
> information we have gathered, examine the epidemiology of organisms
> and causing these various diseases, obtain data on drug usage for some
> of these various indications to see what folks are actually using for
> these, look at the cross-resistance patterns in various organisms, and
> as I said, we would like some guidance from the committee of\--we will
> show that slide again of the 27 different taxa and are there things
> you think should be excluded from that, that aren\'t important, are
> there things you think should be added to that list.
>
> Finally, to try to obtain some data on clinical correlations with
> clinical outcomes and resistance wherever possible.
>
> \[Slide.\]
>
> So, what we would like to do is based on today\'s discussions, to at
> some point in the future, and today we are not expecting to come up
> with a list coming out of this meeting, what we are trying to do is to
> have the committee comment on these six criteria for us that would
> make up such a list and see if there is anything that we should add or
> subtract to that list, and then try to go back and populate the list
> based on those criteria.
>
> This afternoon\'s discussions are actually going to talk about some
> other aspects of drug development for resistant pathogens, which
> actually dovetail into this. Then, we talked about yesterday this idea
> of multidrug-resistant organism claims, which I hope we can expound on
> again today, and finally, all of this in the end what we are trying to
> do is use it to formulate a guidance for drug development for
> resistant pathogens.
>
> DR. LEGGETT: Thank you very much.
>
> It is now a little bit later, but we still have at least an hour or so
> of discussion. So, go ahead. We have some questions first. Alan.
>
> **Questions from Committee**
>
> DR. CROSS: John, that was a very elegant presentation of the
> multi-resistance. I wonder if you actually wrote down any of those
> organisms, for example, the Acinetobacter, by site of isolation, and,
> if so, is there any difference in terms of the likelihood of
> resistance at a specific site for a specific organism.
>
> DR. POWERS: We are going to try to do that. For some of the organisms,
> we are going to try to split it up by inpatient and outpatient basis.
> We are going to try to actually look at it by bed size of the
> hospitals. We are going to try to look at it by geographic area, by
> census tract within the United States to see if it varies across the
> country.
>
> So, we have got all of these planned analyses, and I was just trying
> to sort of give you the tip of the iceberg today to see what it looks
> like.
>
> DR. CROSS: Certainly, in terms of the organism by site, it may dictate
> the pharmacokinetics of the desirable drug that you want.
>
> DR. POWERS: Right, and the other thing is that when I put up some of
> those sites, like CNS, central nervous system includes shunts,
> cerebral spinal fluid, so I just sort of gave you the broadest brush
> approach today because some of those things may be more important than
> others.
>
> You may complete ignore a coagulase-negative staph coming out of CSF,
> but not out of a shunt.
>
> DR. LEGGETT: David.
>
> DR. BELL: The FDA, I believe is to be commended for its continuing
> efforts to facilitate the process of new antimicrobial drug
> development.
>
> I think I can understand the potential usefulness of developing a list
> of criteria for drug-resistant pathogens of public health importance.
> I have some comments, that I am going to defer until later, the most
> important of which is I think that the currently proposed criteria
> need to be amended to include trend information.
>
> I, however, have serious reservations about the Federal Government
> actually developing a specific list of pathogens stamped with FDA or
> Public Health Service approval, and I wonder if it might be acceptable
> just to list criteria that then could be evaluated as the drugs or
> brought forth.
>
> Let me outline my reservations about the specific list. One of them is
> that, of course, the list is going to change over time or should
> change over time. Who would develop the list and how would it be
> changed in a timely manner?
>
> What would be the impact on the industry and on efforts at new drug
> development if the list changes over time particularly if a pathogen
> were to come off the list because let\'s just say there were some
> wonderful new drugs developed or a new vaccine that eliminated
> transmission to zero, or something like that?
>
> Would pathogens ever come off the list or would the list basically
> only grow and become so long as to become meaningless?
>
> My biggest concern, however, is what about the pathogens not on the
> list? One issue is could work on these pathogens not yield insights to
> help contribute to pathogens that are on the list. But my biggest
> concern about pathogens not on the list is that the fact that they are
> not on the list might compromise essential control measures to deal
> with drug resistance that, as we all know, require approaches in
> addition to new drug development.
>
> Let me give you an example. Currently, the FDA Center for Veterinary
> Medicine is engaged in a legal proceeding to try to withdraw approval
> for fluoroquinolone use in poultry. We fortunately don\'t have much
> fluoroquinolone-resistant salmonella in this country, unlike other
> parts of the world, but we have considerable fluoroquinolone-resistant
> Campylobacter that is linked to fluoroquinolone use in poultry, and it
> is the Campylobacter that is serving as the basis for the FDA\'s legal
> proceeding to withdraw the fluoroquinolones.
>
> Now, the FDA\'s legal proceeding is being fought tooth and nail by
> industry, tooth and nail, and my question is suppose Campylobacter
> didn\'t turn up on this list of priority pathogens for public health
> importance. I think it is virtually certain that the industry would
> use that in contesting efforts to withdrawn fluoroquinolones from
> poultry, and they would say, I think it likely, this is burdensome
> regulation, see, it is not even an important pathogen, it is not even,
> et cetera, et cetera, and I think has to be considered.
>
> There are other approaches to drug resistance in addition to new drug
> development, and what would be the implications of a pathogen not
> being on the list?
>
> So, I wonder, in closing, if it\'s possible to develop criteria,
> perhaps even with some examples, but stopping short of actually
> enshrining some sort of specific list.
>
> Thanks.
>
> DR. LEGGETT: Ellen.
>
> DR. WALD: Just to make two comments. One is that although
> antimicrobials may not be on the list of drugs that you generated for
> overall, certainly as you look at hospital formularies, they are
> usually right there on top. Now, I suspect that the hospital-based
> dollars is relatively small compared to all dollars, but nonetheless,
> I think important.
>
> Secondly, I would just like us to not exaggerate the nonsignificance
> of drug resistance because I think that in reality, it is probably
> almost all significant and that the fact that some infections do okay
> on drugs to which they are reported to be resistant, really reflects
> the relevance of the breakpoints for the particular sites of
> infection, and that, you know, when you get to central nervous system
> disease or you get to an empyema or you get to middle ear disease
> where you have a significant stepdown of antibiotic concentration from
> blood to site of infection, then, in fact, you see very clearly that
> these drug-resistant organisms are important and pathogenic.
>
> DR. LEGGETT: Barth.
>
> DR. RELLER: I like the criteria that John condensed for the developing
> list and I wonder a couple of things, whether the caveats that Dr.
> Bell has articulated could not be encompassed by a wording \"including
> but not limited to\" on this list, and with specific examples.
>
> One could argue, for example, for Campylobacter, that it is important
> to clearly certain antimicrobials curtail resistance, issues of day
> care, public health interest in containing infection.
>
> But in addition, I wonder, John, on the scattergrams that you did, and
> given the utility of the TSN database as being one of the better,
> perhaps the best currently available, that monitors, is a good
> sampling because of the diversity of hospitals involved, so that one
> doesn\'t get biases of the high concentration of resistant organisms
> in tertiary care hospital, but doesn\'t ignore their importance
> because of the past trends of what appears first in these centers
> eventually wends its way to communities. It is just a matter of how
> quickly.
>
> And the complexity of dissecting out all of those shadows and dots is
> to develop subset data, and I am thinking about Item No. 2 on the
> list, organisms that cause serious and severe disease, of using the
> bacteremia isolates in that database as a first cut for rank ordering
> of pathogens with multidrug resistance.
>
> The utility of that I think is more than what is immediately obvious.
> In complicated urinary tract infections, resistance may not be
> important or uncomplicated or not as important, but if one has
> bacteremia, I mean by definition, one has upper tract disease and a
> complicated infection.
>
> So, you pick up those pathogens that in different sites may be
> important, and you also deal with the issue of an organism means
> different things in different places. Similarly, most
> coagulase-negative staphylococci that are isolated and in the
> database, many are rubbish, whereas, the ones out of blood,
> particularly if one follows the newer guidelines in hospital-acquired
> infections, catheter-associated infections where there is a
> reproducible isolate of coagulase-negative, given how frequent they
> are, even though 80 percent may be contaminants, the 20 percent that
> aren\'t can cause serious disease including the occasional
> community-acquired endocarditis with coagulase-negative staphylococci,
> so that you have a natural selecter, if you will, that everyone would
> accept as serious and severe disease.
>
> There is also some additional regulatory support for that approach in
> that some of the surrogates, with the emergence of resistance, for
> example, in VRE, one of the things that was important in the
> consideration when quinupristin-dalfopristin came before the committee
> was the use of cessation of bacteremia, and I think of Dr.
> Jorgensen\'s portrayal of the persistence of bacteremia from the Acar
> publication with third generation cephalosporins and
> methicillin-resistant staphylococci of the early data of where despite
> aberrant or inappropriate testing, that now doesn\'t happen in any
> good laboratory, one could have been misled by in vitro
> susceptibility, but clinical failure.
>
> So, I think mining the data that gives a cross-section of the country
> would be perhaps much more valuable than all of those numbers and all
> of those points that may obscure the central issue of these or by
> definition important organisms associated with serious disease.
>
> You can actually cover, not only one, but some components of more than
> one of the six points in doing that.
>
> DR. LEGGETT: John, what do we do about the not prevalent pathogens
> that we can\'t study that are of immense public health interest? For
> instance, anthrax, or viruses.
>
> DR. POWERS: Some of the things we have done with anthrax, there has
> also been a recent animal rule where we are trying to get information
> in things that cannot be studied at all, to try to get that
> information.
>
> The original anthrax approval was based on a study done in Rhesus
> monkeys, that looked at the efficacy of ciprofloxacin, doxycycline, or
> penicillin versus placebo.
>
> DR. LEGGETT: Yes, Mark.
>
> DR. GOLDBERGER: I think that brings up, you know, sort of the broader
> issue, which is related to some of the things we are going to also
> talk about this afternoon, but in terms of thinking about how to study
> organisms that are hard to study.
>
> An example that came to mind, I was just looking, you know, at the
> Acinetobacter data, to actually do a study to really determine if a
> new antimicrobial worked against the Acinetobacter would be a major
> undertaking.
>
> So, the question comes up how does one go about making inferences,
> what are the other components of information you can use to get a
> feeling of whether a new antimicrobial is going to perform.
>
> As a starting point, obviously, that includes looking at in vitro
> data, perhaps commonality of resistance mechanisms, the use of animal
> data, the study of the drug in perhaps serious indications analogous
> to where you would find the pathogen you are concerned about with
> other serious gram-negative organisms including those that have
> similar resistance mechanisms, but it may be worth, at some point,
> whether we do it now or in part in the afternoon or at a subsequent
> meeting, talking about this concept of how one draws inferences from a
> variety of types of data to allow one to be reasonably comfortable
> that even if the number of actual isolates is not that high of the
> organism in question, the totality of the data that you have collected
> makes it reasonable to presume that this drug is likely to perform.
>
> I think that that is an important issue because even beyond the
> Acinetobacter, I mean we have had concerns about resistant
> gram-negatives in a variety of settings, to ask companies to come up
> with enough of each of the types of gram-negatives to get that clearly
> put in the label is no small undertaking, and the question is at what
> point, when you have looked at serious infections due to a couple of,
> say, major gram-negatives, say, a klebsiella, an anaerobacter, a
> pseudomonas, and you have shown the drug performs well, do you begin
> to get enough confidence to be able to say you will label this for,
> say, this type of a disease, due to gram-negative organisms more
> broadly.
>
> But I think at some point we are going to need to have a type of
> discussion about how one draws inferences because there will be many
> examples of these hard-to-study, very resistant organisms that we need
> to collect useful information in some organized fashion about.
>
> DR. LEGGETT: John, one follow-up question, can I play devil\'s
> advocate for a second. Since we first saw penicillin resistance and
> sulfa resistance, hasn\'t all drug discovery been driven by
> resistance? In other words, criteria No. 4, isn\'t that self-evident?
>
> That sort of gets a little bit back to David\'s question, but in a
> different way.
>
> DR. POWERS: My answer would be sort of in that we are actually in the
> process now of working\--one of the things that came out of that
> November workshop was this idea that some of this has to be changes in
> the law.
>
> The IDSA is actually trying to go to Congress to actually lobby to do
> some of these changes, and we are working in cooperation with them to
> try to look at what are companies actually submitting to us, not by
> drug name, but just sort of broad categories.
>
> What we are seeing, and this has not been completed yet, though, is
> that the number of new molecular entities is actually quite small,
> yet, the number of changes in formulations, such as extended releases
> or increasing the dosage of a particular drug, is what we are seeing a
> lot of.
>
> So, when you say isn\'t all drug development driven by resistance,
> partly, yet, it is changing your dosage formulation from the tid drug
> to a q.day drug, is that driven by resistance or something else?
>
> DR. LEGGETT: Money.
>
> Alan.
>
> DR. CROSS: I was just going to re-emphasize Dr. Goldberger\'s point
> that we are not simply talking about organisms like Acinetobacter that
> are hard to study. Over the last 15 years, we have been involved in
> the preparation of hyperimmune globulins and vaccines for things like
> Pseudomonas and Klebsiella, which were high on John\'s list, and it is
> a major undertaking to find enough centers that have enough of this
> disease to actually do a study.
>
> So, it is not just the Acinetobacters and stenotrophomonas, that is of
> concern, and perhaps looking at common resistance mechanisms and being
> able to perhaps pool that data may be of some use.
>
> DR. LEGGETT: Celia.
>
> DR. MAXWELL: Yes. As I was looking at the six criteria for developing
> the list, I was a little bit concerned that I didn\'t know where I
> would fit an organism like falciparum malaria. That is not prevalent
> in this country, but certainly it is deadly, it is prevalent worldwide
> in areas of the world, and we have an increasing risk of, let\'s say,
> sending troops or something like that, that are going to have an
> immediate exposure.
>
> Where would we fit something like that?
>
> DR. POWERS: I don\'t think we put the moniker in this country on the
> end of prevalent, so certainly you could argue that might be the
> prevalence of the disease in study. Falciparum malaria within the
> disease malaria is very common and very prevalent. I don\'t think in
> any way we meant to say just in the United States.
>
> DR. LEGGETT: Jan.
>
> DR. PATTERSON: I think the idea of a list is helpful. I think that
> would be helpful to industry to have some specifics, and it could be
> reviewed periodically to keep it up to date.
>
> I have a little bit of reservation about prioritizing just the
> bloodstream isolates because, for instance, a lot of the
> catheter-related infections, taking the catheter out is the major
> therapeutic maneuver particularly for things like coag-negative staph,
> and for an infection, say, like Pseudomonas pneumonia, I mean a lot of
> times that is a lot more severe infection, but you don\'t have a
> bacteremia from it.
>
> One way we have kind of gotten around, you know, giving us an out for
> just certain organisms on a list per se, for instance, at our
> hospitals, for the use of contact precautions, we say it\'s for
> multidrug-resistant and epidemiologically significant organisms, so
> that kind of gives us an out.
>
> Like, for instance, Clostridium difficile, which we don\'t really
> think of as multidrug resistant, it epidemiologically significant and
> has some of the same implications, and maybe some of the bioterrorism
> organisms could fit in the same way.
>
> I don\'t know if Salmonella and Campylobacter were on your list, but I
> think that probably fluoroquinolone resistant, foodborne pathogens
> like that should be included.
>
> DR. LEGGETT: Did you want to say something, John?
>
> DR. POWERS: I just wanted to answer Jan\'s question. That\'s the kind
> of thing we are actually looking for, because when you realize most
> people don\'t culture when they have foodborne disease, so that is not
> going to show up on our list, but clearly you can make a case that
> that should be on there, as well.
>
> There is a list of bioterrorism things, and sort of get this idea of
> making a list and the Federal Government making a list, the Federal
> Government has made a list. This is a list for bioterrorism-related
> agents. So, it is not as if we are doing something that is completely
> out of the realm of possibility here.
>
> DR. LEGGETT: Mike.
>
> DR. PROSCHAN: I am taking a risk here because I am just a country
> statistician. I am from Heart, Lung, and Blood, but I am trying to
> understand why the drug resistance doesn\'t correspond to poor
> outcomes necessarily. Actually, I don\'t even know the exact
> definition of drug resistance, but I am assuming that that is entirely
> in vitro. Is that right, the definition?
>
> DR. LEGGETT: Yes.
>
> DR. PROSCHAN: So, is it possible that the body, you know, is able to
> handle a certain amount of infection, so that even if the drug kills
> half the bacteria instead of all of it, now your own body is able to
> fight the rest. Is that a possible?
>
> DR. LEGGETT: That has been the major problem of trying to compare
> antibiotics to other drugs, because there is three parts of the
> equation instead of just two, so, it is not drug and us, it\'s drug,
> us, and bug.
>
> David.
>
> DR. BELL: I had a few comments on Table 1, the criteria that I just
> wanted to mention. The title, I would suggest that the title encompass
> the concept of drug resistance as opposed to just saying criteria for
> pathogens of public health importance, because, you know, there is
> influenza and there is anthrax, there is all kinds of things, and this
> is really about drug resistance, something in the title to that
> effect.
>
> Point No. 1, I wonder if it should be \"or\" in the disease under
> study rather than \"and.\"
>
> Point No. 4, a few alternatives to treat the pathogen, I wonder if
> there should be some concept of ease of treatment, oral therapy,
> empiric therapy\--
>
> DR. LEGGETT: Dave, could I interrupt a second?
>
> DR. BELL: Yes.
>
> DR. LEGGETT: Are there any more questions for John\'s talk before we
> jump over, because, John, were you going to lead the discussion? No?
> Okay. So, we can jump on over. Finish what you were going to say, and
> then we have this page here of Points of Discussion.
>
> DR. BELL: Okay.
>
> DR. LEGGETT: It\'s not that I want to shut you up.
>
> DR. BELL: The agenda kind of looked like it all went together, and I
> apologize, I didn\'t see that.
>
> DR. LEGGETT: I know. That\'s a trouble we are all having.
>
> DR. BELL: Do you want me to just\--
>
> DR. LEGGETT: Go ahead, jump in.
>
> DR. BELL: Well, I will just finish. I mean ease of treatment, oral,
> empiric. No. 5, there is no vaccine for that pathogen. I would suggest
> delete that parenthetical phrase because even when there is a vaccine,
> there is still going to be people getting sick and they are going to
> need to be treated, and the vaccine won\'t be offered for everybody or
> efficacious for everybody.
>
> But the most important thing, something about trend information. We
> have run into this situation a lot where criteria for regulatory
> action, preventive action, whatever, tend to focus on rates rather
> than the trend.
>
> Thanks. Sorry.
>
> DR. LEGGETT: No, no, if you look at the bottom the page, that is
> exactly where we want to start, so that was fine. I just thought John
> was going to lead.
>
> DR. POWERS: The slide I showed about the Staph aureus bacteremias that
> we were intending to look at trend information over time, as well, but
> we could certainly add that in, be a part of criteria No. 1.
>
> DR. LEGGETT: Go ahead, Jim.
>
> DR. JORGENSEN: I would like to suggest adding to these criteria. So
> far, we have talked about resistant organisms and the need for new
> agents, but I am also concerned about infections in which very
> effective agents may no longer be available or may cease to be
> available.
>
> Specifically, I am thinking about gonorrhea in which the four
> recommended agents currently, two fluoroquinolones in which resistance
> is common in some parts of the world and becoming more so in this
> country, and where the only other oral agent is no longer going to be
> available, so it may leave only one injectable drug that is
> predictably active against gonorrhea.
>
> DR. LEGGETT: You mean by the pharmaceutical agents.
>
> DR. JORGENSEN: Yes.
>
> DR. LEGGETT: John.
>
> DR. BRADLEY: Just a concept that unfortunately adds to the problem,
> not solving it, and it\'s in response in part to Dr. Frank Tally\'s
> presentation earlier this morning.
>
> It takes several years once you identify a problem to actually bring a
> drug to the clinicians, so that they can use it. So, in putting
> together these criteria, and I think you have done a really nice job,
> I suggest that we cast a wide net because you don\'t know which of
> these resistances 10 years down the road is going to be giving us lots
> of problems, and if you restrict your criteria, then, someone will say
> 10 years from now, gee, you were shortsighted and only look at the
> most prevalent likely pathogens.
>
> As our ability to determine molecular mechanisms of resistance
> improves, it complicates things further. When I was in my fellowship,
> there is resistant Pseudomonas to ceftazidime and now it can be
> beta-lactamase, PORN \[ph\] deficiency, efflux pumps, and God knows
> what else is going to come up, and now we know these mex pumps can
> pump out not only beta-lactams but fluoroquinolones and probably a lot
> of other agents.
>
> So, it becomes more difficult predicting which of these mechanisms of
> resistance is actually going to be a problem, and the time to
> development of agents is huge.
>
> Secondly, and in addressing one of the points for discussion regarding
> not having enough patients with a particular organism, I think with
> the animal models that have been developed, that you were involved
> with, with Dr. Craig, with neutropenic mouse, Rhesus monkey models
> where you can actually model drug exposure for a pathogen in a
> particular issue and get an idea of the Cmax to MIC or AUC to MIC that
> is required in the animal model.
>
> I believe a lot of that information can be extracted into the clinical
> situation, so you don\'t need nearly as many patients to prove that a
> drug at a certain dose will work if you have laid all your groundwork
> with the animal model and then just a very few patients to confirm
> that the animal model is predictive will net you more information on
> fewer patients for these very resistant organisms which may be very
> rare.
>
> DR. LEGGETT: John.
>
> DR. POWERS: Could I ask you a question about animal models because,
> Jim, you asked this now, and, John, you brought it up a second time.
>
> I want to refer to something we saw yesterday. One of the thing Mark
> was talking about was sort of building this body of information to
> show that the drug may be effective for a resistant organism.
>
> What we saw yesterday was a drug which claimed to be effective for
> quinolone-resistant organism, and Pete Dionne, our microbiologist,
> showed an animal study where even though the dose was doubled, that it
> still did not eradicate the organism from the mouse\'s lungs.
>
> I was interested to hear, then, as we went around and talked, several
> of the committee members said, well, this is a drug effective against
> quinolone-resistant organisms, so it gets to be the point of how does
> one interpret that animal data when you see it and extrapolate that to
> what might happen in people.
>
> DR. LEGGETT: That is the point of contention that one of the speakers
> at the open session is probably going to address.
>
> Mimi.
>
> DR. GLODE: I have two comments. I just wanted to reinforce what Dr.
> Reller brought up and then comment on Dr. Patterson\'s comment on
> that. I do believe that some patients\--and also referring to Dr.
> George McCracken at an earlier meeting\--some patients are more
> informative than others, so bacteremic isolates, CNS isolates, and
> therapy for those patients is more informative to me than many sputum
> cultures with the resistant organism.
>
> But then I certainly took your point that perhaps more in adults than
> pediatric patients, catheters are removed when there is a
> catheter-associated bacteremia. In most of our oncology patients, the
> first issue, if one is not desperately ill, is to treat through.
>
> So, the catheters are left in place, repeat cultures are obtained, and
> antibiotics are provided, and this is a real challenge at the
> neutropenic host, et cetera, but that would be the standard in our
> hospital for pediatric oncology patients, so one has the opportunity
> then to say can this drug eradicate this organism in this setting,
> which is a significant challenge. One could then argue that that is a
> pretty informative situation.
>
> My second comment goes back to the Wall Street Journal and anti-ulcer
> medications, but I just have to say this. I haven\'t read the labeling
> for any of these anti-ulcer medications, but with regard to physician
> education and perhaps patient education if you can get your hands on
> the PDR, I mean I hope they all say that the patient should be
> evaluated for the infectious organism that causes ulcers and then
> treat it appropriately with the antibiotics to eradicate it and be
> cured.
>
> DR. LEGGETT: They are all getting them anyway for their viral upper
> respiratory tract infections.
>
> Jan.
>
> DR. PATTERSON: Well, I just wanted to clarify. I was thinking more
> about short-term catheters and ICU patients. We also treat through in
> adults for the long-term catheters.
>
> DR. LEGGETT: Barth.
>
> DR. RELLER: Fusing the amplification of this information about the
> catheters, to me, a critical issue here is separating out the ones
> that, by definitions that have come up at the FDA having to do with
> what documentation would be required for studies and indication for
> catheter-associated bacteremia, because if one had an agent that
> actually was effective in clearing the bacteremia with the catheter in
> place by whatever mechanism, the new agent, given the frequency and
> the increasing importance of this organism and the increasing
> importance of these catheters as lifelines for the kinds of patients
> that are growing exponentially in healthcare in this country, and with
> home I.V. therapy, et cetera, a really rigorous definition of
> catheter-associated bacteremia and something that would work with or
> without, and clearly the discussions of guidelines for that include
> whether or not the catheter is removed would be very helpful.
>
> I didn\'t mean in any way to imply that only bacteremia would be a way
> to get at this, but rather that it would be perhaps the most efficient
> first cut at what everyone would accept as important, plus recognition
> that in, for example, CNS infections, a very high proportion of those
> patients, if they were done, would have concurrent bacteremia, perhaps
> a higher association than with any other entity apart from infective
> endocarditis in terms of the proportion who would have a positive
> blood culture to deal with, Listeria or, in the old days, Haemophilus
> influenza type B or the pneumococcus.
>
> DR. LEGGETT: What I would like to do is talk a little bit more these
> criteria until people have discussed it under 10 minutes, and then go
> on for 10 minutes and talk about sort of the second point about the 27
> taxa and the other sort of analyses before 12:30.
>
> Before we go off the criteria portion of this, I would like to ask,
> where do you fit in, say, in drug development, something that alters
> things, so, for instance, we know P-glycoprotein, that we never even
> thought much about in terms of HIV is now probably more important than
> what we used to think of as the cytochrome p450 in terms of making
> drugs ineffective.
>
> Where do you tie in, and then sort of the whole efflux pumps in bugs
> are sort of equivalent to the MDR in cancer sort of chemotherapy, and
> I am sure, I can envisage a new drug development not at a particular
> pathogen, but at something that would enable the drug to work much
> better in the body.
>
> Where is that subsumed in this or is that just sort of in a parallel
> universe in terms of deciding that something is important, because
> theoretically, I could think of a process by which a drug that
> inhibits P-glycoprotein would be of immense importance for a bunch of
> drugs.
>
> DR. POWERS: I think what you are getting at is the bigger issue that
> we always talk about, and that is what we are really trying to treat
> here is a disease. It just so happens that in anti-infectives, that
> that disease is associated with an infecting pathogen.
>
> Since a lot of these diseases are treated empirically, we usually ask
> that that drug show efficacy against the most common organisms that
> are likely to be encountered.
>
> So, for instance, if you were developing a drug for meningitis and it
> had absolutely no activity against the pneumococcus, but was a great
> Neisseria drug, what do you do with that, because, you know, the
> people are going to apply it empirically.
>
> I guess if somebody came in with a drug like that, that had some kind
> of effects, it would depend how the drug works, but I would assume it
> would have to have some effect on the bacteria, or if it doesn\'t,
> they would have to show that leaving the bacteria alone still somehow
> cures the disease.
>
> DR. LEGGETT: Ellen.
>
> DR. WALD: I just wanted to make one comment about group A strep and
> which I think is an organism in which looking at antibiotic resistance
> is particularly difficult especially, currently, you know, in part,
> because it is definitely a self-limited disease, so from the clinical
> perspective, you might never notice that there was antibiotic
> resistance, we are in an era now where almost no one is collecting
> isolates certainly from patients with pharyngitis because they are
> doing so many rapid diagnostic tests.
>
> Again, even the availability of organisms and testing them, you know,
> has diminished. So, I think that we might not notice that as a problem
> unless there was an increase either in invasive disease or acute
> rheumatic fever, so that might be something that we need to keep our
> eye on even though it might be harder to do and harder to interpret
> what\'s happening clinically.
>
> DR. POWERS: I think what that gets at, though, what I was trying to
> draw there in that, was the link between resistance and a
> self-limiting disease, and how it is to show that resistance has an
> impact.
>
> Again, getting back to this issue we talked about yesterday of the
> drug label actually trying to convey some important information to
> clinicians, I guess you could sort of use the other upper respiratory
> tract issues that we have, are the diseases like acute bacterial
> sinusitis and acute exacerbations of chronic bronchitis where we are
> dealing with again a self-resolving disease, and yet drug sponsors
> have asked us several times for resistance labeling claims for those
> diseases, but pharyngitis is the example of where there is data
> available to show that, gee, perhaps the resistance doesn\'t impact on
> that disease.
>
> That is not to say that for something like community-acquired
> pneumonia that it would.
>
> DR. LEGGETT: Ken.
>
> DR. BROWN: I have no idea what the topic under discussion is right
> now, so I thought I would raise a couple of points of my own.
>
> I would like to focus on something Frank Tally said because I think it
> goes far beyond the scope of most of our comments, and that is, that
> several things which have occurred and the state of things as they
> are, there is little to no hope that the drug companies are going to
> be able to develop adequate answers to these problems.
>
> I think if you look at the fact that most of the available
> antibiotics, and I think all of the antituberculous drugs were
> discovered by or before 1975, and since that time we have had almost
> no new classes of compounds discovered.
>
> That is frightening if you knew the numbers, and I wish we would give
> them to the statisticians, the numbers of soil samples that have been
> screened in the last 45 or 50 years by the pharmaceutical companies.
>
> I think it is fair to say that there is essentially no chance that the
> pharmaceutical industry by itself can come up with the answer to this
> problem. I wish I could say Frank were the first person to suggest
> this kind of a consortium, but actually, the president of the IDSA, in
> 1978 or so, in his closing remarks, suggested that the very formation
> of such an institute which would be responsible for the discovery and
> development of new anti-infectives.
>
> I think all this is complicated by something you just mentioned, Jim,
> which a lot of us haven\'t come to fully appreciate, and that is the
> role of P-glycoprotein, and some of us don\'t even know what it is,
> and MDR, and the interesting problem that some of us want the
> protection of P-glycoprotein to keep drugs like ivermectin out of the
> CNS, and others of us who treat cancer want to get rid of
> P-glycoprotein, so we can get the drugs into the CNS.
>
> When you then combine that with the multiple drug that the patients
> who are being treated for HIV and have an effect or are affected by
> p450 or have an effect on P-glycoprotein, this geometric increase in
> the need for knowledge is horrendous, and I think that to say that we
> are going to have a productive result from this small part of the
> discussion is a little bit scary, especially when, as Mark points out,
> we can\'t expect to really get even a list today and the slow rate at
> which we function as organizations contributes to this, and I don\'t
> know that there is an adequate way to get around the speed of our
> ability to do things, but I don\'t think it is going to be within the
> purview of the industry to do this, period.
>
> DR. LEGGETT: Barth. Didn\'t you have your hand raised? You are too
> depressed after that.
>
> \[Laughter.\]
>
> DR. RELLER: I was trying to digest it. Just a follow-up to Dr. Wald\'s
> comment, and I realize why virulence was taken out of this and
> embodied in the serious, and how one could minimize the importance
> possibly in those places where it is a self-limited disease, but if
> one had to pick among the common bacteria, one that intrinsically is
> virulent, I would choose a group A streptococcus because of how
> quickly and how devastating it can be in certain clinical pictures.
>
> If we were to have resistance in group A streptococcus, we would have
> a real pathogen on our hands, and I think that one should be on the
> list because of what Dr. Bradley mentioned earlier of this timeline of
> how long it takes. I think it is second to none in its intrinsic
> virulence.
>
> DR. LEGGETT: I would like to expound a little on that if I can,
> bringing it back to the point of trying to get back to the
> Campylobacter issue and my sort of pet peeve is Neisseria gonorrhea.
>
> I think if you are dealing with a pathogen that only has a human
> reservoir, that has immense potential pathogens we want to be
> preventive and that might have to be either another criteria or folded
> into the ones that are in that list, to talk about what if type
> things.
>
> We have sort of done it with Staph aureus because we now we are all
> nervous about being in the pre-antibiotic era again, but what happens,
> the same thing could be applied to group A strep or to the Neisseria
> or bring those things into this discussion.
>
> Alan.
>
> DR. CROSS: I wanted to ask the FDA or perhaps John, what types of
> contacts do you have with other organizations, not just here, but
> around the world, the globalization issue. Part of that is we have
> talked about not having enough glue-based strep, but in the military,
> they have really some serious outbreaks every few years even recently.
>
> I don\'t know if there is any sharing of those isolates with the
> nonmilitary organizations. Similarly, we heard about the resistant
> pneumococci in Hong Kong. Is there any type of surveillance program
> for bacteria that we have for influenza in terms of sampling around
> the world and trying to find out what\'s on the horizon, perhaps
> getting access to those organisms?
>
> Then, there is the other issue in terms of trends, what David talked
> about, is that MRSA actually started in Europe and was there for a
> number of years before it occurred here. It was rather benign there
> when it first started, and then once we had MRSA here, it was a more
> significant clinical problem.
>
> My understanding is it is less of a problem in Europe now. So, the
> point is that there are some global trends associated with these
> organisms that may be instructive in terms of how we deal with things.
>
> Is there any actual sharing of either data or specimens, for example,
> comparing your data under contract with perhaps what is going on
> elsewhere?
>
> DR. POWERS: We are also part of an interagency task force on drug
> resistance that had a meeting prior to ICAAC last October or
> September, and where this issue was discussed\--David, you set that
> up\--about trying to get\--and there is a whole section on
> surveillance, in fact, David is probably better equipped to answer
> this than me because he was the chair of that section.
>
> But we are trying to get that kind of information. Focus Technologies
> tells me that we have the ability to get some information from outside
> the United States, as well, although we haven\'t tapped into that as
> yet to try to see, but that is one thing we could do would be to try
> to compare.
>
> DR. LEGGETT: To follow up on Alan\'s question, is this sort of a
> project that is also undergoing discussion in Europe and abroad, sort
> of like along with the harmonization sort of globalization and that
> sort of thing, or is this just solely a U.S. initiative?
>
> DR. POWERS: David Bell is probably better to answer this because we
> were talking about all of this stuff.
>
> DR. BELL: Is what in particular under discussion?
>
> DR. LEGGETT: This project to try to come up with a list, in other
> words, the fact the United States prioritizes it or somehow allows
> industry to do what they want.
>
> DR. BELL: You know, this is a particularly opportune discussion
> because I am actually about to go for a three-month detail to WHO to
> help them identify ways to implement their global strategic plan on
> containment of antimicrobial resistance.
>
> Of course, surveillance is a major issue. There are a lot of major
> obstacles to good surveillance. We have had discussions both a CDC and
> I know elsewhere, for example, the EU, their surveillance system.
>
> They phrase it in terms of marker pathogens, and we have looked at
> this concept also to try and get away from this idea that some are
> more important than others for the reasons I mentioned, but just
> marker pathogens, and it would be Staph aureus and pneumococci.
>
> The EU has a very nice sentinel surveillance system in their
> countries, and they have I guess it\'s pneumococci, VRE, I believe
> it\'s Staph aureus, and I think they just added E. coli, something
> like that.
>
> Again, they are not trying to say these are the targets for drug
> development, they are trying to harmonize surveillance efforts in
> different countries in their jurisdiction and use these as, quote
> \"important,\" unquote, marker pathogens, and I suspect we will see
> more of that around the world, but this is actually a very interesting
> discussion to me because WHO is kind of looking for what to do next.
>
> DR. LEGGETT: Ken, it sounds as it you are pretty pessimistic even if
> there was this production of a list and there were incentives, as
> Frank talked about, in terms of providing money or those sort of
> things, you are basically saying even if there were much more
> incentives to come up with drugs with new mechanisms rather than
> me-too\'s or extensions of patents by, you know, increasing the
> milligram dosage, you are pretty pessimistic that that is even
> possible, is that the gist of what you were saying?
>
> DR. BROWN: If you try to count the number of rational drugs which have
> been put together, trimethoprim sulfa, that makes one. That was really
> based on permesamine \[ph\] and sulfa, which preceded it. That is
> actually the only one I can think of\--
>
> DR. CROSS: Influenza drugs.
>
> DR. BROWN: And then if I look at the number of isolates which people
> look at, it is not that people have stopped looking at isolates, but
> 25 years ago, in a screen of 3,000 soil samples a month, 99.9 percent
> of the compounds which were isolated were already known.
>
> So, what I am saying is the discovery of perhaps ivermectin from a
> soil sample next to a sludge sewer in a Japanese golf course grew
> Streptomyces, but we haven\'t had a lot of additional new compounds
> since that class.
>
> So, all I am saying is statistically, we need to do several things
> better, and I don\'t think that just depending on companies that have
> to try to make money to keep themselves in business is going to be an
> adequate situation knowing what we know and the increasing demands of
> the scientific community, which are appropriate, and the additional
> information.
>
> When I think about the use of the macrocyclic lactones in combination
> of HIV drugs in Africa, where the CYP450 is not the same for people
> who live in Ethiopia and the southern tip of the Arabian peninsula
> versus the rest of the world.
>
> It seems to me the complexity is frightening, and we need an
> institution bigger than any pharmaceutical group that I know of to
> participate and probably to lead it.
>
> DR. LEGGETT: John.
>
> DR. BRADLEY: I think the pessimism about industry not developing new
> drugs is certainly in part based on the fact that the financial
> incentives, the disincentives to develop a drug and lose money are
> huge, and there are both pharmaceutical company funded and NIH funded
> studies in looking at mechanism of resistance, so on the one hand, we
> are moving forward quickly in developing information on why the drugs
> are resistant, but the other side of the coin, moving forward quickly
> in developing drugs to meet the resistance has been the problem.
>
> I think there are several ways that were brought up in November,
> brought up again today on how to get rid of the financial
> disincentive. I am sure that PhRMA has incredible resources to be able
> to approach these problems if given the right incentives, so I don\'t
> share the pessimism of Dr. Brown that it can\'t be done, I just think
> that the equation of how progress is put together needs to change.
>
> In addition, there as we get more involved in mechanisms of
> resistance, perhaps on this list somewhere, knowing that many of these
> mechanisms of resistance cross between organisms by cassettes or
> plasmids, that as a mechanism of resistance of public importance goes
> on this particular list, like efflux pumps, that that can be a target
> for facilitating pharmaceutical industry development of drugs, as
> well.
>
> DR. LEGGETT: Barth.
>
> DR. RELLER: Dr. Brown, the pessimism, I wonder, as a provocative
> question, the problem that the home runs of the past, what is found in
> sewage, that the problem is a repetition of a failed or nonproductive
> model as opposed to an entirely different approach, in other words,
> the success of the past may be an inhibitor for the future.
>
> In other areas, non-antimicrobials, I mean the advances have come by
> an understanding of receptors and blockers, et cetera, so that maybe
> the approach is not looking in sewage or natural compounds, but rather
> an investment, and it may require, as Dr. Tally pointed out, a leap
> forward in terms of an institute that looks at basic science, that
> these cassettes, for examples, that Dr. Jorgensen, to actually
> understand the components, what turns them on and off, et cetera, and
> that the model for new drugs would be at that level as opposed to
> finding the needle in the immense haystack that has been part of the
> past discovery approach.
>
> What do you think?
>
> DR. LEGGETT: And then can we then come from a firmament and then go
> right to the very concrete before we go to lunch.
>
> DR. BROWN: I think it is important for me to reflect that I didn\'t
> believe that diesels would replace steam engines with which I grew up.
> I was working in Ethiopia at the time of the smallpox eradication
> program, and I didn\'t think it would work.
>
> So, while I had great hopes for the new information we have about
> genetics, I have to look realistically and say we thought we would
> have great advances in sickle cell disease from what we have known
> about the genetics of that disease or those 29 changes, and not a
> whole lot has come out of that, so I don\'t have as great hope for the
> wonders that we were going to get from the knowledge of the human
> genome yet, and it may take a while and I may be hopefully shown to be
> very wrong.
>
> The final example I would give, we were told maybe seven or eight
> years ago, boy, once we get combinatorial chemistry going, it is just
> going to revolutionize things and we will have so many new things that
> you don\'t know what to do with them.
>
> Of course, there is always a bottleneck after that, so I hope that I
> am wrong, however, I would love to see better ideas, and I think
> Frank\'s is a great one, that we need to pull together and get our
> heads together, and I agree with Barth that we should probably stop
> looking at just sewage sludge.
>
> DR. LEGGETT: David.
>
> DR. BELL: I have one other question. It might still be in the
> firmament, but recently, there have become enormous amounts of new
> resources available for issues related to the bioterrorism agents,
> diagnosis, treatment, and so on, I mean really enormous, and I am
> wondering if somebody from the pharmaceutical industry might comment
> on how they see, if they do, attention to the bioterrorism agents,
> which are microorganisms, after all, how some of that research might
> be leveraged into antimicrobial drugs for more common pathogens, I
> think the mechanisms have to be, you know, if we are talking basic
> research in drug development.
>
> DR. LEGGETT: Do you want to say something, Frank?
>
> DR. TALLY: There are a couple of points. It is in the firmament, this
> could go on for four or five hours talking about it. What we have to
> do is think out of the box. What Ken is saying is the old methods have
> wringed all the water out, and that is you still wring the thing, you
> are just not going to get any more, so you have to think of a new way
> to do it, and I think that is what we have to do with the genetic
> information we have, and the next round is the financing, and it is
> look not just for drugs, but for vaccines for stimulating the immune
> system, and that type of thought has to start going in.
>
> For the bioterrorism, people are working on that area, and there is
> now being grants coming into companies to try and look at new targets,
> and you can use anthrax as one of the ways to do that, a lot of common
> genes between anthrax and other gram-positives, the same as with
> gram-negatives.
>
> DR. LEGGETT: What I took away from your talk was one of the basic
> things is that the science of antimicrobial drug discovery has to go
> back in a sense and be validated by the NIH, which kept telling us for
> years, oh, there is already a way to do that, we are not going to fund
> it, so in terms of getting back to the government and pharmaceutical
> agencies.
>
> DR. PORETZ: Could I just ask one quick question about the surveillance
> network? Your contract to Focus Technologies, what was it, 317 labs,
> are those all in-hospital labs?
>
> DR. POWERS: They are in-hospital labs, but they are hospital labs that
> also function as central labs for communities, as well.
>
> DR. PORETZ: So, you get outpatient cultures in addition?
>
> DR. POWERS: Yes.
>
> DR. PORETZ: And you have been doing that for a period of time? Is that
> recent or what?
>
> DR. POWERS: Is our contract recent or has Focus been doing this for a
> while?
>
> DR. PORETZ: I mean that information, who is getting the information,
> is it just going to the FDA or is it being disseminated to anyone
> else?
>
> DR. POWERS: Well, if you want to go pay Focus to get it, I guess you
> can get it for anyone else.
>
> DR. PORETZ: No, but you get it.
>
> DR. POWERS: Yes, the information that we get from them, we contracted
> from them to obtain.
>
> DR. PORETZ: And what do you do with that information, just keep it
> internally?
>
> DR. POWERS: One of the things we are doing here is trying to use it to
> make this list. The other thing is once we get your input, we actually
> plan on publishing some of this information in cooperation with them,
> as well.
>
> DR. GOLDBERGER: But it is important, just to mention, this is a
> contract that became effective only this past October, so some of the
> data you have seen is data we have only just started to get within the
> last month or two.
>
> DR. LEGGETT: Speaking to that point, has anybody been able to come up
> with other bugs they would like to have the sort of analyses we were
> shown done with in, for instance, group A strep was mentioned, and I
> see that is on the list of beta-hemolytic strep.
>
> DR. POWERS: I heard Salmonella and Campylobacter as two other
> organisms.
>
> DR. LEGGETT: Salmonella and Campylobacter, which I did not see there.
>
> DR. POWERS: No, they are not on there. Neisseria gonorrhea is not on
> there, which was one of the questions, I wanted to see if people
> thought that that was important to put on there.
>
> DR. LEGGETT: Go ahead, John.
>
> DR. BRADLEY: That\'s a pretty long list. Did you want to prioritize
> them the way the government did with bioterrorism agents, like A, B,
> C?
>
> DR. POWERS: If you would like to. I mean one of things I didn\'t want
> to come across is saying I didn\'t think group A strep was important,
> that wasn\'t what I was trying to say. One of the points I tried to
> make about the list is what do we see in the pipeline for development
> for E. coli, which is way at the top of the list? Almost nothing.
>
> So, I guess the idea would be prioritization. I look at group A strep
> and I think, gee, that\'s a really severe disease, but then I look at
> the cross-resistance pattern and I see six other drugs to which that
> organism is susceptible including penicillin and clindamycin, which
> are the recommended drugs for severe group A strep necrotizing
> fasciitis. So, not to minimize its importance, but how does that
> compare to a Pseudomonas that\'s resistant to seven drugs, and I
> guess, John, that\'s your question about prioritization.
>
> DR. LEGGETT: The logical first step in going through that is to take
> your criteria number\--whichever one is that there is few options
> available and go that way, so you work your way back from zero drugs
> to one drug, to two drugs.
>
> DR. POWERS: I guess one of the things we might address then, rather
> than putting the bugs in first, is go back to the criteria and say
> which of those criteria should we rank in such a way as to be more
> important.
>
> DR. LEGGETT: Go ahead.
>
> DR. GESSER: Richard Gesser from Merck Research.
>
> I would like to suggest along the lines that John is thinking, ESBL,
> Klebsiella, E. Coli, to start the conversation perhaps.
>
> DR. LEGGETT: Good.
>
> Anybody have any other suggestions? Go ahead.
>
> DR. PORETZ: I couldn\'t see that list very well. We Mycobacteria and
> tuberculosis on that list?
>
> DR. LEGGETT: No, I think this is just typical bacteria.
>
> DR. POWERS: That is actually a good point. This is all typical
> bacteria. We didn\'t try to branch out yet into those other things.
> Like I said, we are going to probably do this kind of analysis for
> fungi and other things, but this was our first pass. As Mark said, we
> just got a lot of this information.
>
> DR. LEGGETT: Go ahead, Jan.
>
> DR. PATTERSON: I guess with regard to prioritizing the criteria, I
> might see No. 4 as one of the higher priority criteria, limited
> available therapies due to multidrug resistance, and that is kind of
> what has driven a lot of our concerns in recent years.
>
> DR. LEGGETT: I think in terms of prioritizing the list, where you
> could get your most bang for your buck is similar to the ESBL thing,
> where you could take care of both klebs and E. coli sort of at the
> same time, you know, sort of a common resistance mechanism, and then
> go from there.
>
> I think, in general, another of the reasons to have this is I think it
> is going to give us lots of information about the cross-reaction of
> resistance mechanisms that we don\'t appreciate. We may think we know
> them in the abstract, but we don\'t really see how interwoven they
> are.
>
> Go ahead, John.
>
> DR. BRADLEY: I think the fact that Jan pointed out that multidrug
> resistance is a priority amplifies the fact that if it\'s multidrug
> resistant, there are likely multiple mechanisms of drug resistance
> including PORN changes, ESBLs, other beta-lactamases, efflux pumps,
> the whole nine yards.
>
> DR. LEGGETT: Alan.
>
> DR. CROSS: Just to re-emphasize the point that is made, we have had a
> whole series of, quote \"new\" antibiotics based on combining
> inhibitors of a resistance mechanism with existing drug, so perhaps
> something aimed at at least a few identified mechanisms mixed with the
> existing good agents we have, would also start a new class of drugs.
>
> DR. BRADLEY: How do you exactly want us to do this right now?
>
> DR. LEGGETT: I don\'t know. The first I saw what we were supposed to
> be doing\--
>
> DR. BRADLEY: Is someone supposed to be putting a list up here?
>
> DR. LEGGETT: I don\'t know that this morning we want to come up
> necessarily with the dominant list unless you guys tell us, I mean I
> didn\'t think that was the purpose.
>
> DR. POWERS: I think the things we would like to know are - we have six
> criteria up there, Dave Bell, you commented on some of the things we
> should add into this or subtract out, and that is the kind of comments
> we were looking for, are there some changes that we should make to
> this criteria, and then one of the clear things I am hearing is No. 4
> should be No. 1.
>
> Is there any other way that we should prioritize those? What I thought
> I heard was it sounds like No. 2 ought to stay No. 2 from what I heard
> from Drs. Wald and Reller about group A strep. Any other ranking of
> those things, should we change that?
>
> DR. LEGGETT: No. 1 should be No. 6.
>
> DR. PATTERSON: I would probably put the clinical correlation, I would
> probably put that higher up, like 3 or 4.
>
> DR. BRADLEY: I think we should assume for purposes of the discussion
> that if it\'s resistant in vitro, that you will have a poor clinical
> outcome. In terms of linking the two, I think that\'s a completely
> different discussion how closely they are linked, but I think as we
> prioritize, to make it simpler, if it\'s in vitro resistance, in
> making the list, we should assume that you can\'t treat them with
> standard doses of drugs in the clinical arena, and then this afternoon
> talk about that other issue perhaps.
>
> I would take it off the list.
>
> DR. LEGGETT: I think I sort of would, too, because whether it\'s not
> the case now, it may be. I am not sure how that really helps us cull
> out things that we are not going to look for even though you have got
> some of the examples.
>
> DR. POWERS: Maybe I should clarify a little bit, and this has to do
> with the discussion we had yesterday. When we come down to it, what
> end up doing with this is putting a bug-drug combination in the label,
> and that ends up being for a specific disease.
>
> The reason why No. 6 is really there is this idea about suppose
> somebody comes in with a new drug, say, for instance, for
> macrolide-resistant group A strep, and they say, look, we are great
> for pharyngitis, does that really help the public health?
>
> So, I guess what is missing from this list or I didn\'t make clear
> enough was the idea that this resistance claim that we are going to
> the label is an organism linked to a specific disease, much like we
> were talking about yesterday, multidrug-resistant Streptococcus
> pneumoniae for community-acquired pneumonia.
>
> So, that is why No. 6 is there, to try to lean it towards the diseases
> where resistance is more likely to be apparent instead of telling a
> drug company to spend all their money studying pharyngitis.
>
> DR. LEGGETT: Okay. Barth.
>
> DR. RELLER: I would be interested in Dr. Jorgensen\'s comments on Item
> No. 6, but thinking about that, one could consider 6 an NCCLS issue
> and indeed the committee is constantly trying to make sure that the
> detection of resistance is clinically important.
>
> I think as an excellent example, Dr. Bell\'s comment earlier about
> resistance to fluoroquinolones among Salmonella is not that big of an
> issue here in the United States. Actually, I wonder about that, by
> what criteria. Most of the resistance, if not all of the resistance to
> fluoroquinolones, which is a major problem in typhoid fever, at least
> as drugs are currently used in some parts of the world, and as
> reviewed by Dr. Perry in his New England Journal review a couple of
> weeks ago, and under discussion and a working group in NCCLS is that
> the organisms look susceptible, but relative to yesterday\'s
> discussion, when there is a single mutation, they are nalidixic acid
> resistant, and the discussion of whether the criteria are appropriate
> or even the breakpoint criteria for Enterobacteriaceae with ESBLs, if
> we had the breakpoint criteria that the Europeans have, whether or not
> they are ESBLs in the phenotypic strict sense, organisms would look
> resistant based on dropping the MICs that constitute susceptibility.
>
> The prevalence of single mutations in typhae strains in the United
> States, many of which are acquired abroad, about 80 percent, but also
> in foodborne salmonella, the single mutations that are nalidixic acid
> resistant as presented at the IDSA this autumn, are actually
> substantial.
>
> What does that mean clinically? Well, perhaps the most important thing
> it means is that you have got one hit, and when you get that second
> hit, they are probably not going to work, and it\'s easier to get
> maybe the second hit if you have already got the first hit.
>
> So, I think it is an event waiting to happen, and that may be where
> you can get the mileage on this whole business about the quinolones in
> poultry and the feeds is that first hit although it is silent by NCCLS
> criteria currently, and maybe silent clinically with appropriate
> duration and dosage of fluoroquinolone in the therapy of typhoid
> fever.
>
> It is a failure waiting to occur with an additional hit. So, I think
> the main importance of No. 6 in my mind is reinforcing the importance
> of keeping the clinical laboratory on which all surveillance is based,
> be it bioterrorism or hospital infection control practices, or therapy
> of the individual patients, or the database on which the targets for
> future drug development are prioritized, to keep the scientific
> integrity including being linked, not only with phenotypic
> characterization, but as Dr. Jorgensen so eloquently presented,
> keeping that matched with the basic science underlying the mechanism
> of resistance is a fusion that is critical to maintain and to
> recognize that in some infections with some organisms, you can get
> clinical success because of the nature of the disease itself despite
> resistant other organisms, but in some infections like meningitis, you
> get autolysis-deficient pneumococcus.
>
> We want to make sure that the in vitro recognition of that keeps in
> sync with the clinical reality of it. So, I think actually this is a
> very important issue to keep the clinical and laboratory things,
> getting the same answer, so to speak.
>
> Jim, what do you think?
>
> DR. JORGENSEN: Well, I think while it is very complicated to do so, it
> is important or we are finding it more important to index the
> interpretive breakpoints with the site of infection or the type of
> infection.
>
> Clearly, that is the case with penicillin and the cephalosporins with
> pneumococcus. But I think there are other resistance mechanisms that
> we have debated. For example, it has been debated whether macrolide
> efflux-resistant Strep pneumos are really significant in
> community-acquired pneumonia.
>
> The argument has been made that those drugs achieve very high levels
> in the epithelial lining fluid. The MICs for those strains are not
> unreasonably high, they are maybe in the range of 4 to 32.
>
> So, the argument has been made that this is an in vitro phenomenon, it
> is not significant. I would cite to the contrary, the four patients
> that were reported from the University of North Carolina, who were
> treated as outpatients for community-acquired pneumonia with oral
> macrolides and who came back to the hospital bacteremic and had failed
> that therapy, and all four of those had efflux-resistant strains.
>
> Moreover, the CDC has had an ongoing study of persistent positive
> blood cultures in patients who have bacteremic pneumococcal pneumonia,
> and if you look at the agents they are treated with, most of them are
> macrolides, most of them have efflux mechanism.
>
> So, I think one thing that is clear is not everybody that has a strain
> we would define as resistant is going to die or is even going to fail
> in a dramatic sense, but there will be a percentage of patients who do
> not do well, and I think that percentage is worth paying attention to.
>
> DR. LEGGETT: Alan.
>
> DR. CROSS: I think in Item 6, it is important, but there has to be a
> huge caveat there, and I would like to talk on behalf of the host. The
> point has been made about informative patients, and I think that is
> really critical, and I would like to just remind everyone that we were
> unable to show that antibiotics, that appropriate antibiotics were
> effective in gram-negative bacteremia, which ought to be fairly
> straightforward, until the McCabe-Jackson criteria tossed out the
> uninformative patients who were destined to die anyway.
>
> So, what happens is how we define the informative patient in Item 6 is
> really critical. It has to be done in a very careful way if Item 6
> will have any futility at all.
>
> DR. LEGGETT: Do you think focusing a study on neutropenic sepsis,
> getting back to the positive blood cultures, that is the only two
> things you have got, is the bug and the drug.
>
> DR. CROSS: Well, I mean when Dr. McCracken was here last time talking
> about meningitis, I think that also is an idea situation. We have the
> experience which we discussed yesterday of levofloxacin in bacteremia
> with penicillin-resistant Strep pneumo. We had 15 cases of that. So,
> those were highly informative, good patients, and it does not have to
> be a huge study, but it is a lot easier to evaluate.
>
> This becomes particularly relevant for the ESBLs because the patients
> that tend to have serious infections with those organisms are very
> complicated patients, many of whom, even under the best of
> antimicrobial care, will not have a good clinical outcome, and those
> have to be really separated out carefully.
>
> DR. LEGGETT: We can continue to talk over lunch, but those comments
> take us perfectly into the discussion we are going to have this
> afternoon about one study versus the other and the quality of the
> data.
>
> Since we are running a little behind time, why don\'t we just break
> for lunch, and we are scheduled to be back here at 1:30 for the open
> public hearing. At 2 o\'clock, John Bradley is going to talk to us
> about how clinicians use data for clinical decisionmaking.
>
> \[Whereupon, at 12:45 p.m., the proceedings were recessed, to be
> resumed at 1:30 p.m.\]
>
> [A F T E R N O O N P R O C E E D I N G S]{.underline}
>
> \[1:40 p.m.\]
>
> **Open Public Hearing**
>
> DR. LEGGETT: The first speaker is Jerry Schentag. I hope you can
> introduce yourself and give us your two cents worth.
>
> DR. SCHENTAG: I will introduce myself. There may be someone in this
> committee I haven\'t spoke in front of yet.
>
> Jerry Schentag from the University of Buffalo. I have working
> relationships with most of the pharmaceutical companies in the area of
> PK/PD and I will declare that upfront. If I missed anybody, you know
> where to find me.
>
> But I think I would like to just make one or two small points, some of
> which is to answer things that are already talked about this morning
> and a couple of questions that have been asked that I think I have
> some information to help with.
>
> Then, in another more central point, which perhaps I will state first,
> and that is, that with AUIC or any other index of pharmacokinetics and
> pharmacodynamics, we have had a pretty good run here working with
> clinical correlations and also explaining I think one of the most
> important things which we have talked about today, which is bacterial
> killing rate and also bacterial resistance.
>
> The point I want to make about that is that it is the same number that
> describes the threshold of killing and the prediction pretty reliably
> of resistance. So, whatever you think of the absolute value, whether
> you agree with me that it should be pretty much 100 for everything or
> whether you think it should be different by different drug class
> doesn\'t matter in this statement.
>
> The point is, it is always a predictor of resistance if you set your
> drug dose against an MIC of an organism right where you see the
> threshold at the beginning of your good effect.
>
> Now, why is that important? Well, it answers the most fundamental
> question of all, which is that PK/PD actually predicts the effect of
> the drug on the organism. It may not have much to do in some clinical
> scenarios with what happens to the patient, but it has a lot to do
> with the organism, so that is the territory that we wish to stay in,
> and your pathogen list can actually be resorted against the drug
> classes and predict which ones are going to develop resistance based
> on their current therapies, because this is selection pressure you are
> talking about.
>
> So, for instance, John earlier asked why group A strep is not a
> problem for pharyngitis while the macrolides do have a problem. It is
> very simple. You are always over 1,000 for your AUIC even with the
> lowest dose of Pen-V K against strep group A.
>
> With the macrolides, you are never much above 20 or 30, numbers which
> we normally associate with resistance or at least a prediction of it
> fairly soon. Vancomycin, which Frank talked about, he talked about it
> in the context of why it took so long it develop resistance.
>
> Well, there are actually two scenarios of vancomycin resistance that
> are worth talking about. One is, of course, VREF, which happened
> first, and then MRSA. Well, with staphylococcus, vanco always had
> values of 4- to 500 because the MICs were down around 0.5 or lower,
> and the blood levels were always high enough on the AUC side, so that
> 0.5 into 250 or so would give you 400 to 500.
>
> Now, why did E. faecium go first? Very simple. Sensitive E. faecium
> run around with MICs of 4. Well, if you divide that into 250, that is
> approximately 62, it drops below 100, and quite a few years ago
> already, we did a small analysis of our patient population and sure
> enough, all the E. faeciums that start out 4 and sensitive were
> selected to develop resistance by vancomycin treatment.
>
> Then, if you do that in a hospital population with just about any
> drug, you should see the same thing, so it\'s predictable.
>
> This is perhaps a bit more pertinent, and this is my last point today,
> because yesterday, we went after the question of the quinolones
> finally targeting Strep pneumo with a high number. That\'s the first
> time we have actually formally targeted a PK/PD value around 250 or
> higher for the pneumococcus.
>
> Up until now, we have been working on a situation where the dosing
> gives us 40 most of the time against Streptococcus pneumonia, so I
> mean we will see whether that is soon enough to help, but my view is,
> is that all of this is predictable, and the pathogen list ought to be
> set with some thought in mind for the drug and the dose and how that
> interacts with the MIC of the organism population.
>
> So, you sort your organism population in such a say that you see the
> easy-to-kill bacteria where you are over 1,000 like the quinolones
> against Haemophilus, for instance, and the hard-to-kill ones, like
> Streptococcus pneumonia and pseudomonas, and then is you set your dose
> in the range where you are always low or just at the threshold for
> animal models that suggest bacteria static activity, which is, what,
> 30 years for most quinolones against gram-negatives and
> gram-positives, your resistance can be predicted from there.
>
> I mean technology is available I think to make these decisions from
> the perspective of both pharmacokinetics and pharmacodynamics
> integrated.
>
> That is what I have to say.
>
> DR. LEGGETT: Thank you very much.
>
> Richard Gesser is here, who I believe was part of the PhRMA task force
> with the November meeting.
>
> DR. GESSER: Thanks very much. Jim, I guess invited me to speak. I am
> not speaking for the PhRMA group per se, but I was part of the PhRMA
> group at the meeting in November, and IDSA, as well, participated in
> that meeting.
>
> First, I just want to echo some of the points that Frank Tally made. I
> think the points that he made were really pertinent to Big Pharma, as
> well as to Little Pharma, and the main issues, what we face.
>
> I am in the Division of Antibacterial Clinical Research at Merck
> Research Lab, and we are competing for resources within the company as
> Frank competes for resources in the outside world. Those resources are
> all used. They are used for one purpose or another as the company
> decides.
>
> I just want to focus on the purpose of the meetings today, and the
> meeting in November, I think it was Dave Cachetto \[ph\] from the
> PhRMA group who brought up the issue of the list, and there was some
> debate back and forth of the value of a list and people weren\'t
> prepared to make a list, and the list was brought up really in the
> context of just sort of general guidance, acknowledging that we are
> competing for resources, that drug development takes a long time, and
> what we were asking for as pharmaceutical research group was more
> guidance and clarity earlier on as to what was considered important in
> the field of bacterial resistance.
>
> I think that the members of the group, I think IDSA supported this, as
> well, but I don\'t want to speak for them here, but a lot of people
> felt that a targeted list of pathogens acknowledging all the caveats
> associated with that list, particularly the concept of trends over
> time, the limitations of the list, the meaning of the list of people
> outside the purview of this group, all things considered, that type of
> a list and the guidance around that list, and what could be achieved
> with that list, I think part of the discussions this afternoon, how
> you would, for lack of a better term, streamline or use information,
> such as Dr. Schentag mentioned, PK/PD information, in vitro testing
> information, to go after uncommon pathogens, and again a focused list
> that was never presumed to be comprehensive entirely and always was
> presumed to be a working document, something to reflect the current
> environment was perceived as something that was very important in
> allowing us to devise development resources, to use those development
> resources, and to really campaign for resources either within our
> company or outside of our company if the clear importance of
> developing new drugs for these pathogens was stated, I think it would
> go a long way to moving this along.
>
> One last point. At that meeting, it was expressed with some concern
> that less resources were being able to apply in this area, and so that
> we were facing situations of increasing bacterial resistance and
> concern in an environment where it takes a long time to develop new
> products, and resources, at least new resources weren\'t easily being
> relegated to that area of development.
>
> DR. LEGGETT: Thank you very much.
>
> Is there anyone else who would like to take advantage of the open
> portion?
>
> \[No response.\]
>
> DR. LEGGETT: Thank you.
>
> I think we will move on and have John Bradley address us on how
> clinicians use data for clinical decisionmaking.
>
> **How Clinicians Use Data for Clinical**
>
> **Decision Making - John Bradley, M.D.**
>
> DR. BRADLEY: Thanks very much, Jim.
>
> I received a call from Dr. Powers earlier this week that there was
> another clinician who was supposed to be giving this lecture about how
> clinicians use data for clinical decision making, and since I was one
> of the clinicians on the committee, he decided to ask me if I could
> perhaps put together my thoughts on clinical decision making.
>
> It is certainly nothing unique that I do, and any clinician on this
> committee could certainly give exactly the same talk, but the purpose
> of what I am trying to do is to demonstrate publicly all the sources
> of information that we use in actually taking care of patients, and
> how we take all of this data and use the data in order to cure the
> patients, which is, of course, our most important goal.
>
> \[Slide.\]
>
> We certainly use clinical information about the patient being treated,
> what are the characteristics of the patient, what are the
> characteristics of the infection that we are treating. We get organism
> information from the cultures including identification and
> susceptibility data, so we depend on our hospitals\' microbiology lab
> giving us an NCCLS guidelines approved ID and susceptibility piece of
> information, so that we can select from those antibiotics to which the
> organism is susceptible which ones to choose for the patient.
>
> Obviously, the list of antibiotics that are tested by the micro lab
> happen to be those that are FDA-approved and available to us. We can
> certainly go to some research labs and get unapproved investigational
> antibiotics tested against the organism, but the vast majority of what
> we do has to do with FDA-approved therapies.
>
> We take into account information on pharmacokinetics and
> pharmacodynamics now, as Dr. Schentag had mentioned, the toxicity
> characteristics of these FDA-approved agents which are active in
> vitro.
>
> \[Slide.\]
>
> So, we do clearly use the information that the FDA reviews and
> publishes in the package insert and on their web site. They certainly
> look at data on safety and efficacy, but they have approvals only for
> the particular indications that are submitted by the sponsor, and they
> have gone on record as saying that if there is an indication for which
> they have not been given data, that they are not saying yes or no,
> they just haven\'t been given data on which to make a recommendation.
>
> So, it is unlikely that we will get new indications for ampicillin
> because it is unlikely that a group will put all the financial
> resources requires into a sort of package labeling submission to go to
> the FDA and have them actually review it and approve ampicillin for
> something, and this certainly goes for virtually any other drug that
> is generic.
>
> We also use the medical literature for the preferred antibiotic
> therapy, and certainly when the FDA approves a drug, they approve it
> with all the information they have, the best information at the time
> of the approval, but then a year or two or three later, unless there
> is more information that comes back to them, they don\'t keep annually
> updating all of the package inserts for every drug that they have
> approved.
>
> That is something that we find from the medical literature. We have
> guidelines that clinical societies put together, like the IDSA, which
> is very involved in trying to tell physicians which is the preferred
> therapy for which particular infections and organisms.
>
> In pediatrics, the American Academy of Pediatric\'s Red Book
> Committee, the Infectious disease Committee comes out with
> recommendations on preferred therapies. There is the Sanford Guide,
> which is put together by a number of very prominent infectious disease
> clinicians who are internists, published clinical trials, some of
> which are excellent, some of which are not so good, some of which are
> downright misleading, but we are taught to evaluates these clinical
> trials in the literature and take the information from these trials
> that is valuable and extrapolate it to each individual patient, each
> individual infection that we are treating.
>
> \[Slide.\]
>
> Back to the patient. This situation was raised a number of times
> earlier today. The immune competence of the patient is very important
> in whether that patient can clear the infection. The extremes of age,
> the newborn and the elderly don\'t have the same immunologic
> capabilities as people in the middle.
>
> The are comorbidities, associated illnesses, sickle cell disease was
> raised earlier in childhood, chronic bronchitis from the smokers in
> adult life, diabetes, there is a whole host of comorbidities which
> impact the progression of the infection and the ability of the host to
> clear this infection. These are just a few of the things. In the time
> allotted, there is no way we can go into all of them.
>
> Of course, we like to have an examination of the patient. That
> sometimes gives you clues on to where the infection is and what other
> problems that you may have facing you. We look at the laboratory
> information from the patient which includes organ dysfunction
> information, which impact antibiotic toxicity decisions.
>
> So, if I have two antibiotics that are equally effective, one has
> renal toxicity, and I have a patient who has got pre-existing renal
> toxicity, I am not going to want to use that, I will want to use the
> one with less renal toxicity. Then, of course, we use imaging studies,
> as well.
>
> \[Slide.\]
>
> Now, trying to put together how we take all of this information to
> make the decision, I have tried to put together this Ven diagram,
> which includes circles from the FDA, the NCCLS, the CDC, and the IDSA,
> and other clinical organizations.
>
> The FDA is certainly expert at evaluating the safety and efficacy of
> submitted data. That is their job. They tell me where the drug will
> work and where it will not work, where to be cautious in the group of
> patients for which data have been submitted to them. They also caution
> me on where to look out for safety considerations, and I take their
> advice very seriously.
>
> The NCCLS looks at the organism identification, that is their job, and
> interpretations of susceptibility, and they use those interpretations
> based on both in vitro testing and, of three years ago,
> pharmacodynamic considerations.
>
> Now, the FDA is also historically involved in looking at breakpoints
> and what is susceptible in vitro, and there are FDA microbiologists
> who are certainly present at the NCCLS meetings, and it is an open
> forum for discussion, but the NCCLS puts together the guidelines which
> virtually every hospital in the U.S. and many in the world use in
> order to determine what is susceptible and what is not.
>
> Things can change. The fact that third generation cephalosporins are
> now considered a bit more active against pen-resistant pneumococci.
> Beta-lactam-resistant pneumococci is one example of that. Their
> guidelines keep getting updated, so if there is new information on
> resistance that impacts my being able to use a drug, it shows up in
> their documents.
>
> The CDC is involved in epidemiologic evaluation of pathogens,
> particularly resistant ones, ones which are of public health concern,
> and I know the FDA and the CDC have some interconnection. There is
> probably a dotted line that goes between these two, but the CDC
> certainly feeds information on organisms to the NCCLS and feeds
> information on epidemiology to the IDSA and other clinical
> organizations.
>
> So, everyone is involved in this decision making process, no one can
> do it by themselves. The IDSA and the other clinical organizations
> that I mentioned are responsible for recommendations for clinicians
> for actually treating patients for all infections with all
> antibiotics, so if there is an organism that the FDA has approved for
> a certain drug and a certain indication, then, if there is another
> infection that that organism causes, and a clinician wants to know if
> there is any data to treat this other infection, then, they will go to
> these societies to get some advice on extrapolating information from
> what the FDA has, again hopefully based on clinical studies which give
> us good, useful, evidence-based information.
>
> \[Slide.\]
>
> Just to give you a couple of examples briefly, if there is a
> 12-year-old with leukemia and neutropenia, who has x-ray defined
> pneumonia, and grows a Pseudomonas aeruginosa that is ceftazidime
> resistant, but meropenem and ciprofloxacin susceptible from the bronch
> wash, we are supposed to decide what is the appropriate therapy for
> this particular child.
>
> So, based on the susceptibility data, I will treat with meropenem
> based on the safety and efficacy data of meropenem in pediatric
> meningitis. So, I take the data from just as serious an infection,
> although perhaps a more immune competent host, and extrapolate with a
> high dose of drug, tissue penetration, killing of organisms that I
> will hopefully get a success using this drug to treat pneumonia in an
> immune-compromised host.
>
> So, again, the FDA hasn\'t approved of meropenem for Pseudomonas
> pneumonia in neutropenic children, I am sure, but that doesn\'t stop
> me from using the drug in that scenario.
>
> Now, if it\'s meropenem resistant, then, I would go to ciprofloxacin,
> and there are clearly even less data in pediatric populations on
> quinolone therapy of Pseudomonas pneumonia, but I also use data that
> is published in the adult literature to help guide me on efficacy in
> these certain populations, but in kids perhaps I have to worry more
> about safety rather than efficacy for fluoroquinolones, so all of
> these things are going around all at the same time, and hopefully I
> come up with a reasonable recommendation for therapy.
>
> \[Slide.\]
>
> Another example, and this is something that we talked about earlier
> with respect to serious infections versus non-serious infections. Dr.
> Reller brought up meningitis, Dr. Glode brought up meningitis where if
> you don\'t treat it with an effective antibiotic, you don\'t cure the
> infection, in contrast to otitis media where there is a fairly high
> spontaneous resolution rate even without antibiotic treatment.
>
> This is a real case which occurred in the pre-Haemophilus type B
> vaccine era, an 18-month-old with periorbital cellulitis and
> bacteremia, who was being treated with ceftriaxone, and I am asked by
> the resident why I don\'t use I.V. trimethoprim sulfa, which was
> available at the time, because he frequently used the drug PO for
> treatment of H. flu and otitis, and the susceptibilities of type B H.
> flu and non-typeable H. flu are very, very similar.
>
> Because no published series existed on bacteremic infections with H.
> flu treated with I.V. trimethoprim sulfa, I felt very uncomfortable
> extrapolating from otitis efficacy to sepsis and cellulitis efficacy,
> so I would not use otitis data to convince me that I can treat
> bacteremic disease, whereas, I would probably go the other direction
> if there were previous data on I.V. therapy of Haemophilus in
> bacteremia and cellulitis, would I feel comfortable using that drug in
> otitis, probably more comfortable, but I would also like to see data
> in otitis.
>
> \[Slide.\]
>
> So, when can you extrapolate efficacy? If you can successfully treat a
> difficult infection, you should be able to treat a simple infection.
>
> \[Slide.\]
>
> Certainly some infections are harder to treat based on penetration of
> antibiotic to the site of infection, intra-abdominal abscesses is one
> case, meningitis is another, versus infections in which there is
> excellent penetration like urinary tract infections, you have huge
> concentrations of antibiotic in the urine, or pneumonia where you have
> got excellent blood flow to the lung.
>
> The seriousness of the infection and spontaneous resolution of the
> infection, as I just mentioned, meningitis, or a pneumonia Fine Class
> 5 versus acute exacerbation of chronic bronchitis or acute otitis
> media where there is controversy in the clinical community as to how
> important treatment is in the first place. And then comorbidities, I
> have already mentioned, healthy young adults versus neutropenia states
> or old age or neonates in which you need to ask the antibiotic to do
> more in curing the infection.
>
> \[Slide.\]
>
> When can you extrapolate safety? Well, If I have a tough infection in
> a patient who is not responding, and the in vitro susceptibilities are
> sort of borderline, I will push the dose, and most of my colleagues
> would, as well.
>
> We watch for toxicity certainly because there may not be as much data
> in the literature on toxicity at a higher dose, but in pediatrics,
> where we have the luxury of having meningitis studies where almost
> double the dose has been used for a number of infections, and we have
> plenty of safety data, I feel comfortable then increasing the dose in
> other non-CNS difficult-to-treat infections feeling that the safety
> data for meningitis can be extrapolated to the safety data in a bad
> pneumonia empyema or a bad pyelonephritis with a perinephric abscess.
>
> So, that\'s one situation again where I can extrapolate safety from a
> severe serious infection to treating less severe infections.
>
> \[Slide.\]
>
> So, to summarize, we use published data from the FDA and clinical
> trials on safety and efficacy for infections caused by a certain
> pathogen, considering the host and location of the infection, the
> antibiotic toxicities, and the in vitro susceptibilities, as well as
> the risk of failure, to extrapolate efficacy in using an antibiotic
> which has not been previously studied for the type of infection or the
> patient population that we are treating. I should have broken that
> sentence up into two or three, I apologize, but all the stuff is in
> there.
>
> So, that is basically a nutshell of clinical approach that I take.
>
> DR. LEGGETT: Thank you, John.
>
> Moving right along, Ed, could you please tell us about relating
> clinical data from one disease state to another.
>
> **Relating Clinical Data from One Disease**
>
> **State to Another**
>
> **Edward Cox, M.D.**
>
> DR. COX: Good afternoon. It is a pleasure to follow Dr. Bradley. A lot
> of the principles that he has been discussing will be parallel with
> some of the items that I will be discussing as I discuss data from
> studies in one indication supporting studies in a different
> indication.
>
> \[Slide.\]
>
> Just to start out, and I know a number of the folks that have been
> present at these meetings, but there have been a number of FDA
> meetings on resistance, both meetings discussing the general topic of
> drug development for antimicrobial-resistant pathogens, and then also
> we have had discussions with regards to resistant pathogens in the
> setting of product-specific meetings that have occurred over the last
> couple of years.
>
> \[Slide.\]
>
> The topic that I am talking about today stems from one of these
> meetings, the February 20th meeting, where we discussed drug
> development for resistant pathogens. One of the suggestions that came
> out of that meeting was to consider the degree to which a study
> performed in one indication could be used to support safety and
> efficacy in another indication, so that multiple studies would not be
> required within a multi-indication new drug application.
>
> \[Slide.\]
>
> Just to mention the Public Health Service Action Plan and some of the
> items in there with regards to product development. This overall
> approach of streamlining the regulatory process and identifying ways
> to promote the development of antimicrobial-resistant drug products is
> consistent with some of the action items that are within the PHS
> Action Plan.
>
> \[Slide.\]
>
> I also turn and just give a brief excerpt from our labeling
> regulations as to what guidance or what information or requirements, I
> should actually say that our regulations provide us with regards to
> the types of data that we need in order an indication in the label.
>
> The regulations say that, \"All indications shall be supported by
> substantial evidence of effectiveness based on adequate and
> well-controlled studies,\" and then goes on to define these studies.
>
> \[Slide.\]
>
> You will notice that is adequate and well-controlled studies in the
> plural form, and I think the word choice here in part reflects some of
> the considerations with regards to clinical trials, the
> reproducibility of observations that are made in clinical trials,
> there are inherent variabilities that can occur in clinical trials.
> There is the potential for bias both recognized and unrecognized that
> may occur in clinical trials. Chance findings can also lead to results
> in clinical studies.
>
> So, by performing more than one clinical study, essentially looking
> for reproducibility, you may be able to, with a greater degree of
> certainty, determine what it is that you are see in the clinical
> studies that you are conducting.
>
> \[Slide.\]
>
> Today, we have been talking mostly about bacterial infections, and we
> also recognize the importance of resistance in non-bacterial
> infections, but we will, in fact, focus on some of the indications
> here for bacterial infections.
>
> You will notice there is essentially a number of different indications
> that I put up here. I won\'t go through the abbreviations, but there
> is a wide variety of indications that one can study.
>
> In looking across these indications, you will notice that some are
> more related to each other than others, as are the microbes that cause
> these infections.
>
> \[Slide.\]
>
> I think really what we hope to do here today\--and Dr. Bradley has
> helped us tremendously I think in already elucidating some of the
> criterion and principles that he uses in his practice\--is really to
> explore the science behind the practice of considering data that comes
> from outside of a specific target indication within a multi-indication
> NDA.
>
> We have heard from Dr. Bradley some of the principles and practices
> that he uses, and that serves as a very good starting point for
> understanding how we might approach this problem, but we also have to
> recognize, too, that as we move from the individual patient to a
> broader public health decision, one that would have regulatory impact,
> there is certainly a higher degree of rigor that one would be inclined
> to use as opposed to what one would use with a single individual
> patient.
>
> The issue of using data from related indications is not something that
> is brand new. It is actually something that is recognized and has been
> in some of the prior guidances and draft guidance documents with
> regards to developing antimicrobial agents.
>
> Our goal here is if we can clearly describe the rationale for the use
> of the evidence from studies in other indications, that raises the
> question can we develop criteria as to how such information may be
> used to support clinical studies in other indications for the purpose
> of drug development.
>
> \[Slide.\]
>
> Just to review some of the guidance documents that have provided some
> information with regards to the issue of using data from other
> indications. The 1992 Points to Consider guidance document discussed
> circumstances within a multi-indication NDA where one trial within an
> indication, that is part of an overall drug development program that
> includes multiple indications, might be used.
>
> It describes relationships between uncomplicated UTI and complicated
> UTI, acute prostatitis relying upon complicated UTI, uncomplicated
> intra-abdominal infections, such as mild diverticulitis, relying upon
> data from a complicated intra-abdominal infection study, and then also
> an intra-relatedness between complicated intra-abdominal infections
> and also GYN infections.
>
> \[Slide.\]
>
> Around the same time, the IDSA/FDA guidelines that came out in 1992
> and published in CID, have some further comment on this issue that I
> found quite informative, so I will just briefly mention that here.
>
> That is, the IDSA/FDA guidelines state that whenever possible, there
> should be more than one comparative randomized study for a proposed
> indication. They do go on to note that, however, in certain
> circumstances, a single, well-controlled study may suffice.
>
> The single trial may be sufficient for additional indications when a
> new agent has been shown to be effective in more than one trial for a
> major indication existing within the same anatomic location or organ
> system and caused by similar microorganisms.
>
> So, I think these are, in part, some of the principles that John has
> been talking about and that also are part of the criteria that I will
> get to.
>
> They do also provide some examples that are informative as to their
> thought processes back then. They talk about CAP trials and if you
> have a CAP trial that shows efficacy for Strep pneumo and H. flu,
> then, in that circumstance, perhaps a single trial for otitis media,
> bronchitis, or sinusitis would be a reasonable approach.
>
> Then, they go on to provide sort of a contrasting example where they
> talk about uncomplicated urinary tract infections being cause by E.
> coli and noting that this would not really provide much assurances to
> the drug\'s efficacy and the treatment of bacteremia caused by E.
> coli.
>
> \[Slide.\]
>
> The draft guidances 1998 describe some relationships between
> complicated UTI and prostatitis are similar to what we have seen
> before. They also talk about concordant microbiology data being
> derived from CAP or HAP studies being able to support AECB, and also
> note a relationship between CAP and HAP.
>
> \[Slide.\]
>
> This list just mentions a couple of NDAs where, in fact, these
> principles are relying upon data from one indication to support
> another, and this is not meant to be an exhaustive list. Certainly, a
> more extensive search could probably turn up more examples, but
> Sporanox injection, oral solution was improve for empiric antifungal
> therapy for febrile neutropenia based upon one trial and supportive
> data from treatment trials of fungal infections including treatment of
> aspergillosis and also esophageal candidiasis.
>
> Other examples include the studies for prevention indications for
> Pneumocystis carinii pneumonia and Mycobacterium avium, which were
> supported by data from treatment studies of illness caused by these
> same pathogens.
>
> \[Slide.\]
>
> Just to get people thinking about this a little bit, the rhetorical
> questions of the relationship between CAP and HAP, same tissue site or
> same anatomic location, and then a contrasting example of
> uncomplicated urinary tract infection support CAP, and then
> complicated skin supporting HAP, and these are really just meant to be
> provocative examples and really not to ask the question of yes or no,
> but more to say why are people saying yes, why are people saying no,
> what is going through people\'s minds that is leading them to say that
> either one can support or one cannot.
>
> \[Slide.\]
>
> I think the factors that people are probably considering are the
> things that John has mentioned and also that we have here on this
> slide with microbial etiologies, tissue penetration, severity of
> disease, and host in which the infection occurs.
>
> \[Slide.\]
>
> So, this really leads us to the proposed criteria for when data from
> one indication might be able to support another indication within a
> multi-indication NDA. I will read through this because they are the
> subject of what we would like folks to discuss, and we will talk about
> more with regards to the questions.
>
> 1\. The natural history of the disease under study\--and that is the
> first criteria\--what is the spontaneous resolution rate and what is
> the morbidity/mortality without treatment?
>
> So, this issue gets to the degree to which you can understand the
> treatment effect within a particular indication.
>
> No. 2. Factors other than the antimicrobial which may affect outcome
> in a given indication, for example, in complicated intra-abdominal
> infection, part of the therapy would be the surgical debridement, and
> another example, ABECB, where there therapy is not only the
> antimicrobial agent, but also can be corticosteroids, can be beta
> agonists, and other interventions that may influence the outcomes.
>
> No. 3. The characteristics of the study drug. Here, for example, we
> are talking about the pharmacokinetics of the drug, does it reach the
> site of the infection, what are the levels within those tissues, and
> are there any other effects that need to be considered, such as the pH
> at the site of action of the antimicrobial agent.
>
> \[Slide.\]
>
> No. 4. Then, other criteria that may influence the data that can be
> inferred from a particular indication is whether the infection is a
> monomicrobial or a polymicrobial infection. An example here would be
> enterococci in the setting of a polymicrobial intra-abdominal
> infection where surgical attention would usually be needed, and then
> also antimicrobial therapy directed at the spectrum of microbials
> infecting, and not necessarily including enterococci would probably
> affect effective therapy.
>
> No. 5. Similar sites of infection, for example, the lung where both
> community-acquired pneumonia and hospital-acquired pneumonia would
> occur, so another consideration as whether one can use data from one
> indication to support another.
>
> No. 6. As Dr. Bradley has already mentioned, too, the host effects.
> Certainly, there are host differences as we move from one indication
> to another. For example, the patient who gets community-acquired
> pneumonia may have different host factors than those patients who get
> hospital-acquired pneumonia.
>
> No. 7. Then, importantly, the seventh criteria, the similarity in
> spectrum of organisms causing disease, and while there may be some
> overlap with the organisms causing community-acquired pneumonia and
> hospital-acquired pneumonia, there are significant differences as one
> moves from CAP and HAP and gets more to gram-negative pathogens and
> also more Staph aureus.
>
> So, these are the factors that we have come up with, that we are
> proposing, that we would like the committee to discuss with regards to
> using these criteria to determine when it might be appropriate to use
> data from one indication to support another indication.
>
> \[Slide.\]
>
> Some of the other considerations, and Dr. Bradley has also mentioned
> these, is almost sort of a directionality of support, can a severe
> disease support a less severe disease? How about vice versa?
>
> Some examples here would be an I.V. CAP study in relationship to I.V.
> HAP, and then to contrast that oral CAP versus I.V. HAP.
>
> Other considerations might be the similarity of dose, duration and the
> formulation. If one study uses a different dosing regimen, how does
> that help us in inferring efficacy with regards to another indication.
>
> And then an underlying question here, too, is also if data from one
> indication is to be used to support another indication, what is the
> weight of evidence that that supporting data can provide.
>
> \[Slide.\]
>
> Some practical issues that I think deserve mention are if there is a
> greater dependence on a single study in a subject indication, reliance
> upon other supporting data, with regards to that single study, it is
> important that that be a high-quality study, have a rigorous study
> design, and that it be well performed and have very well done clinical
> and microbiologic endpoints since there is a greater reliance upon
> that data from a single study within the overall multi-indication NDA.
>
> Some other practical considerations are that within a highly
> interdependent program, such a program may have less resiliency if
> unexpected findings are encountered within the program. That can be
> either in a supporting clinical study, for instance, if efficacy is
> not demonstrated in the supporting study or that would certainly
> create some difficult questions that would need to be answered about
> the overall indication.
>
> Then, it is also important that the more streamlined approach also
> still provide sufficient quantity of data to adequately characterize
> safety, and then we really sort of already mentioned this, and that
> is, in situations where there is a more streamlined program, if an
> unexpected safety finding does come up, it may be more difficult to
> address that within the more limited clinical program.
>
> Then, I have got as the last bullet, other issues here just because as
> we discuss this, there may be other things that become apparent in the
> discussions today for other practical issues that need to be
> considered within a multi-indication NDA that is planning to use a
> single study within a particular indication.
>
> \[Slide.\]
>
> Then, just to put out a hypothetical example of a dependent
> development program for a drug that was being developed for more
> serious infections, just a hypothetical example of two studies in
> community-acquired pneumonia, one study in hospital-acquired
> pneumonia, and one study in complicated skin and skin structure
> infections along with supportive data.
>
> Important to remember is that this data would provide both the
> efficacy data and then should also be able to provide the necessary
> safety data for the drug development program.
>
> \[Slide.\]
>
> Because there are numerous indications, as we showed on an earlier
> slide, I put this up really just to get people thinking about this
> question, and have sort of put down some of the thoughts so far.
>
> This is not meant to limit the discussions and all, but maybe just
> sort of focus the discussions initially by providing some indications
> where there appears to be a relationship by organ system, and you will
> notice that some of the arrows are one directional and others are
> bidirectional, and then also other relationships that might be used in
> relating indications, and these are a little more based on the
> microbiology than they are the anatomic location.
>
> \[Slide.\]
>
> What I will do just to give folks an impression of where we are headed
> to is just to run through the questions and then I will sit down and
> take questions if folks have questions, and then we can move from
> there on into the discussion.
>
> \[Slide.\]
>
> So, the first question and just so people know where we are headed is
> to please discuss the concept of data from studies in one indication
> supporting studies in a different indication.
>
> It would be helpful to have a conceptual discussion about this use of
> data from one study supporting studies in a different indication
> within a multi-indication NDA. It would also be helpful in your
> discussions if you could please also discuss the proposed criteria
> that are intended to identify factors which should be evaluated when
> considering the evidence from studies in one indication supporting
> studies in a different indication, and from the list of factors, are
> there factors that should be added, modified, or removed.
>
> Question 2. Please discuss which indications may provide supportive
> evidence for a single clinical study in another indication.
>
> Question 3. Please discuss whether data for a more serious indication
> can support safety and efficacy in a less serious indication, and are
> there situations where the converse could be considered, that is, a
> less serious disease supporting a more serious disease.
>
> As we get to the questions, we can put up some other slides just to
> remind people what those criteria were, but at this point, I will take
> my seat and be happy to take questions.
>
> DR. LEGGETT: Are there any questions for Dr. Cox?
>
> \[No response.\]
>
> DR. LEGGETT: Obviously, an entirely lucid presentation. Let\'s hope
> our discussion can come someplace close.
>
> **Committee Discussion**
>
> It is now about 2:30, so we have a couple hours at least to come to
> these proposed criteria and discuss this.
>
> So, why don\'t we just jump off with Point No. 1, and I would like to
> hear some people\'s ideas about the concept of using data from one
> indication to support studies in a different indication.
>
> I think that the points that were brought up in the final page,
> looking at the relating indications on that final page that Ed talked
> about. Why don\'t we use those as sort of specific example to try to
> flesh out what we like, don\'t like, or other thoughts we have.
>
> Since a lot of yesterday\'s meeting was devoted to community-acquired
> pneumonia, why don\'t we start with can we use community-acquired
> pneumonia data into the hospital, or can we go the other way around?
>
> Go ahead, Barth.
>
> DR. RELLER: To help get the discussion started, there was a reason
> that we have community-acquired pneumonia and hospital-acquired
> pneumonia. Earlier, it was lower respiratory tract infections and
> upper respiratory tract infections, and I think the reason for the
> delineation and the arduous discussion of the past, that to lump
> everything in lower respiratory tract infections did not give
> sufficient delineation about severity of disease, about differences in
> pathogens and that one might take easy ones and inappropriately
> extrapolate to the more difficult ones led to these basic splits.
>
> I think the natural spectrum of organisms in community-acquired and
> hospital-acquired infections, and the added complications in many of
> the hospital-acquired infections also being associated with
> ventilatory assistance, makes these sufficiently disparate that there
> is very little that one can extrapolate in one direction or the other,
> not because if you had a hospital-acquired pneumococcus, it wouldn\'t
> act like both of them bacteremic with a community-acquired
> pneumococcal pneumonia, but just that the frequency with which that
> happens is insufficient to put much effort into the extrapolations
> with these two entities.
>
> There was a reason why they were split into this, and not lumped into
> lower respiratory tract infection.
>
> DR. LEGGETT: Michael.
>
> DR. PROSCHAN: But what you are talking about is not\--I mean you are
> talking about just requiring one study rather than two, and then using
> information from other similar diseases, right? You are not talking
> about relying entirely on the other diseases, but on not requiring
> quite as strong evidence for the particular one.
>
> DR. LEGGETT: That was my understanding, that it would not be two
> community-acquired pneumonias studies, but one required
> community-acquired pneumonia, but then if you wanted to get a
> hospital-acquired pneumonia, what would you have to do, what kind of
> data could be transferred or could it be transferred at all.
>
> I don\'t think we are talking so much of safety at this point although
> there is some degree of that. I think at least right now we should
> focus on the efficacy part of it. What sort of that sort of data can
> we transfer?
>
> Ellen.
>
> DR. WALD: Well, it seemed like in general that you could feel
> comfortable going from the more complicated infections to the less
> complicated, so if you are talking about urinary tract infection or
> soft tissue skin infections, then, you established efficacy in the
> more complicated, that you could feel I think assured that the
> uncomplicated would do as well.
>
> DR. LEGGETT: By that, do you mean that if, for instance, taking this
> hospital-acquired pneumonia that is more complicated, the patient is
> more complicated, and it\'s Staph aureus, could you the extrapolate to
> pneumococcus in the community?
>
> DR. WALD: I would make my remarks confined to the two things I
> suggested, that is specifically soft tissue and skin, as well as
> urinary tract infection.
>
> DR. LEGGETT: Go ahead, John.
>
> DR. BRADLEY: In look at getting a good study for both CAP and HAP, Dr.
> Powers and I talked about this a little bit yesterday. In setting up a
> clinical study for, say, community-acquired pneumonia, there are
> certain criteria that we have in order to enroll a patient in the
> study, and we are looking for a certain percentage of bacteremic
> pneumonias, and certainly if there is a very motivated investigator to
> get sick bacteremic consolidated pneumonias and the number of
> enrollments is actually fairly small, to target that group.
>
> If, on the other hand, the investigators are just there to enroll
> every child with abnormalities on chest film, knowing, as Dr. Wald had
> said yesterday, the viral pneumonias are far more common, then the
> number of children enrolled in that CAP study with viral disease, not
> true bacterial disease, will be excessive and the quality of the study
> won\'t be sufficient for us to feel good, so if there is a
> community-acquired pneumonia study where 10 percent of the children,
> 20 percent have bacteremic pneumonias, I will feel really good that
> that high quality study in community-acquired pneumonia with one study
> in hospital-acquired pneumonia would make me comfortable with not
> doing a second community-acquired pneumonia study.
>
> My point in all of that is to say it\'s not just how many studies you
> do, but it is the quality of the study.
>
> DR. LEGGETT: I have a caveat to that. I agree that the harder your
> target, the small the N you need, but on the other hand, if you are
> only going to use a single study, the more comprehensive your analysis
> and correct your analysis has to be as was allowed with the animal
> data.
>
> It is not the animal model, it\'s how your good your analysis is of
> that animal model. For instance, while we were talking about numbers
> of 15 or 25, that is good to know that for that particular bug, say,
> pneumococcus, that we can sterilize 25 out of 25 bacteremic sick
> hospital patients, but unless you have got some data that will
> extrapolate those 25 cases to 5,000 people that you have done Monte
> Carlo simulation on, so that you know the kinetics are going to be the
> same in the 70-year-old liver failure, ICU patient as my 18-year-old
> pneumococcal bacteremia, I am not going to buy that. In other words,
> we can\'t extrapolate too far.
>
> Mike.
>
> DR. PROSCHAN: Part of this business about two studies is really sort
> of artificial. I mean if you took one huge study and then you just
> broke it into two and said, oh, here, here are two studies, I mean
> that shouldn\'t be regarded as any stronger evidence than the one
> study.
>
> It doesn\'t make sense from a statistical point of view to just break
> it into two. So, part of the reason it\'s more convincing to add two
> studies is that they were done in perhaps slightly different patient
> groups and maybe there are other factors that were somewhat different.
> Otherwise, it wouldn\'t make sense to require two.
>
> DR. LEGGETT: What would you say about the N in each of those two
> studies? If it\'s one big study, should it have the same N as the two
> smaller studies or, quote, \"two separate studies?\"
>
> DR. PROSCHAN: Well, what I was saying is like suppose you had one
> study and you used the number of people such that if you cut it in
> half, each one of those would have high power, 90 percent power, say.
>
> Then, in that situation, it is certainly not more convincing to break
> the study into two and run two separate tests and say yes, look what
> happened than it is to just put all the data together and compute the
> test statistic on the full data. I mean it just wouldn\'t make sense
> to do it any other way.
>
> That is what I am saying, that one of the reasons why it is a good
> idea to require two different studies is because they are usually in
> different patients or, you know, somewhat different anyway, and there
> are other things that are slightly different. That makes it more
> convincing.
>
> DR. LEGGETT: What is you required a priori that you had to have a
> certain percentage of folks that would give you those two populations,
> could you then have one study, you have to analyze it knowing that
> your population was heterogeneous. Does that make it stronger or
> weaker?
>
> DR. PROSCHAN: I am sorry, if you did what?
>
> DR. LEGGETT: You said you have two studies, you have got one of old
> folks in the nursing home and one of adolescents on the street. If you
> put both of those into one study and analyzed them as one group, is
> that stronger or weaker?
>
> DR. PROSCHAN: No, that\'s weaker. I mean in that situation, to me,
> that situation is different because I want to know separately whether
> it is working in both groups. You put them all together, you could
> increase the variance to such an extent that you may not see anything.
>
> DR. LEGGETT: And if we use one study in a hospitalized pneumonia with
> a larger study in community, and then try to go across it, aren\'t we
> doing the same thing?
>
> DR. PROSCHAN: If you go across?
>
> DR. LEGGETT: If you try to use your data from your community-acquired
> pneumonia to then tell you something about hospital-acquired
> pneumonia, isn\'t that doing the same thing?
>
> DR. PROSCHAN: What I would do, to me it seems like a reasonable
> approach is you already have some results on community-acquired
> pneumonia, and I would still require a study in hospital-acquired
> pneumonia, but then if I had that study that was positive, then, I
> would also try and use the information from the community-acquired, as
> well.
>
> So, I think you still, you know, you have got to have a study that
> shows it in the particular one that you are interested in, but perhaps
> not two. I mean you could borrow the evidence from the other one to
> help corroborate the results.
>
> DR. LEGGETT: Dave, you look like you want to say something.
>
> DR. BELL: I just wanted to add that I am not in disagreement with the
> general tone of this, but I think there is value in two studies that
> goes beyond just different population groups studied. I mean the
> investigators are different, the institutions are different,
> geographic region of the country, of the world is different. It adds a
> certain robustness in terms of whether there might be biases.
>
> DR. LEGGETT: You knew that was a surrogate for all variability.
>
> DR. BELL: Okay.
>
> DR. PROSCHAN: I agree with that. I just was struck, one time I
> reviewed something where they said yes, we have done these two
> different protocols and, you know, they were done exactly alike, they
> had the same investigators, and to me, they did what I said you
> probably shouldn\'t do, you know, they basically just cut one study in
> two, and that is not more convincing. But I agree with you that all
> those things are important, the fact that, you know, there other
> differences, as well.
>
> DR. LEGGETT: Alan, you looked like you wanted to say something.
>
> DR. CROSS: We saw yesterday, I think that there were four control
> studies presented off of the same indication, and one of the four was
> markedly at odds with the other, so I do think what everyone else has
> been saying.
>
> First of all, that no studies are done exactly alike and that there is
> a greater confidence when we see that there is at least more than one
> study going in the same direction, and also in terms of comparability,
> I agree with Barth that it is very hard to extrapolate
> hospital-acquired to community-acquired because of the obvious
> multiple differences between the two syndromes.
>
> DR. LEGGETT: Could you elaborate on what kind of differences you are
> talking about, differences in the host, not just different pathogens?
>
> DR. CROSS: First of all, the organisms and comorbidities, and
> therefore perhaps how the drug has to be delivered.
>
> DR. LEGGETT: Orally rather than I.V., you mean.
>
> DR. CROSS: Yes.
>
> DR. LEGGETT: In terms of the analogy that Ellen made about going from
> complicated to uncomplicated, wouldn\'t you think that that same
> analogy could be from complicated to hospitalized sick patients to
> folks with less, quote, \"complicated\"?
>
> DR. CROSS: If they have the same organisms, but I don\'t think what we
> are talking about are two completely different organisms, but, in
> general, if one were to have a more severe hospital-acquired pneumonia
> and extrapolated to perhaps lesser severity, that is obviously
> acceptable.
>
> DR. LEGGETT: Go ahead, John.
>
> DR. POWERS: Alan, let me ask you for a more specific example here,
> because clearly, there are different pathogens between community- and
> hospital-acquired pneumonia, but suppose the drug sponsor came in
> with, say, a carbapenem type drug, which looked like it had, in the
> test tube, activity against Pseudomonas, Acinetobacter, and Strep
> pneumo, H. flu, Moraxella, and the common ones, and they did first a
> community-acquired pneumonia trial, and they got, unlike what we saw
> yesterday, a whole lot of Fine Class V people in there, severely ill
> people.
>
> This is probably assuming this is going to be I.V. drug. Then, you
> get, as John pointed out, a high-quality, hospital-acquired pneumonia
> trial, one of them, and assuming it works, because that\'s the other
> issue, what we saw yesterday. If your one trial was that one
> gemifloxacin trial that didn\'t work, you have got a problem.
>
> But suppose that that trial actually shows it works, are you convinced
> by that one hospital-acquired pneumonia trial, based on what you saw
> in a community-acquired pneumonia trial?
>
> DR. CROSS: Well, I think a real wildcard is certainly in
> hospital-acquired pneumonia, one of the variables you don\'t have in
> community onset is the appliance, the endotracheal tube, and the
> situation is, first of all, that it is much more difficult to clear
> organisms in the presence of a trach tube.
>
> But the other aspect of it is that, as I see it, there is a lot of
> disagreement in terms of just defining the bacteriology of
> ventilator-associated pneumonia, for example, is Staph epi truly a
> pathogen, and if so, do we have to evaluate a drug efficacy there,
> which you would never do for community onset.
>
> DR. POWERS: I guess what we are getting\--maybe if I can make it
> clear\--we are not saying that you do no trials for hospital-acquired
> pneumonia, that is not even on the table, so let me phrase the
> question another way.
>
> Somebody does a CAP trial for this carbapenem type drug or let\'s say
> they do two of them, like Ed used in his example, and then they have
> one hospital-acquired pneumonia trial, and it works, and the drugs
> works, and it is a well done trial.
>
> What is the second hospital-acquired pneumonia trial going to tell
> you?
>
> DR. CROSS: You mean aside from the reproducibility of that.
>
> DR. POWERS: Exactly, because that is the question we are asking. So,
> you have got two CAP trials with a drug and it works, and now you have
> got one hospital-acquired pneumonia trial, and what we are asking is
> assuming all those things, that is a well-done trial, and that the end
> results show the drug is actually effective and safe, what does the
> second trial in that indication actually add to that?
>
> Now, there are a lot of ifs in there, that is what I am saying, and,
> of course, the risk there, too, if your one HAP trial and the drug
> fails, you have got a problem.
>
> DR. CROSS: If what you are saying is on the community onset one, that
> you have sufficient number Klebsiellas, Pseudomonas, et cetera, then,
> I might not have as much difficulty, but it seems that most of the
> drugs which we have evaluated for CAP are really looking at the
> atypicals plus Strep pneumonia, so I think it depends how much
> emphasis you wish to place on, let\'s say, gram-negatives, in that
> situation.
>
> DR. POWERS: So, I guess what I am hearing, then, to sort of summarize
> that, would be that perhaps in a single hospital-acquired pneumonia
> trial, you would still need an adequate number of organisms more
> commonly seen in HAP than community-acquired pneumonia to give you
> some confidence of what was going on.
>
> So, that would go to sort of the size of the HAP trial and again the
> quality of the data that you are getting.
>
> DR. CROSS: Well, again, it might be size, but I think also what we
> have been discussing is, is there an intrinsic value to having a study
> done under one protocol by certain investigators reproduced at least a
> second time, and I should say it does not have to be a huge trial if
> the patients included are, as we say, informative.
>
> DR. LEGGETT: Keith.
>
> DR. RODVOLD: Actually, your comment in the beginning is what I
> actually observe out in the field, is that most of the pharmaceutical
> companies, no matter what kind of compound it is, go two CAPs and come
> to one HAP, and despite the compound, it is probably better for HAP
> than it is for CAP, because when they get through and get their
> numbers for safety, as well as build up a database off the CAP and
> then make the flip to HAP, and kind of come through smaller.
>
> When you look at those pathogens, and I think the message came up
> pretty strong this morning, and I agree, that there is nothing in the
> pipeline for gram-negatives, and really nothing, that if it was in the
> pipeline, has really been developed for serious gram-negative
> infection indications.
>
> If it has got enough gram-positive coverage, which they almost slip in
> on the compound today, so they can get into the community indications
> first, that is where they go, and here is no incentive for them to
> kind of come the other way.
>
> My point is that I think you need to think, I agree with everything,
> that the diseases are different, the patients are different, that
> there is no doubt that the bugs are different, but if you really want
> to be serious about getting people to develop drugs and
> gram-negatives, and get nosocomial type infections on board, you have
> got to do something to make them come that way, because they are not
> coming that way, and they are not going to come that way at the price
> of drug development and delays they could face.
>
> So, that is where you are going to have to get the caveat or carrots
> out there to get them to come and to hopefully develop drugs that give
> us that, because I don\'t think there is any incentive for them to do
> it, and that\'s just what I am constantly seeing, and I think the
> example you put is one that is out there already, a big carbapenem,
> but it doesn\'t have nosocomial, and they are teasing now with how to
> get it in CAP guidelines. I am like going really.
>
> DR. COX: It sounds like what I am hearing is that people are thinking
> really in terms of the criteria and essence, but it seems that
> efficacy within the lungs is not enough, there is reservations about
> using that information derived from a CAP study with regards to HAP,
> and it sounds like the point there is actually, really to the
> microbiology and the host factors.
>
> So, those are a couple of the criteria that we have there, but it
> sounds like there is some reservation with regards to that use of
> supporting information from, say, two CAP studies to a HAP study.
>
> Do I characterize that correctly?
>
> DR. LEGGETT: Especially the lack of bacteriologic data that seem to be
> coming of CAP studies.
>
> John.
>
> DR. BRADLEY: I am still supportive of one CAP and one HAP, and there
> is an example that I can give you right now. We are in Phase III
> trials of ertapenem with CAP, and ertapenem is a very potent
> antibiotic, and I don\'t know if I am going to use ertapenem for CAP
> for the routine, run-of-the-mill well child that comes into the
> hospital with pneumonia, assuming the drug is approved.
>
> So, I don\'t want to do two CAP studies with ertapenem when I see the
> value of the drug being one for hospital infections and outpatient
> infections. So, I don\'t you to ask the company to do extra studies in
> an area where, at least in pediatrics, it may not have its strength.
>
> So, a CAP study, which is one, well-done, well-powered with
> high-quality study, where the HAP study, I think will help me.
>
> Now, the gram-negatives that we are talking about, that cause HAP, if
> there are other supportive data in treatment of those gram-negatives
> in other tissues, such as complicated urinary tract infections, I will
> feel better about using the drug for those gram-negatives when they
> appear in the lung for HAP, especially if I have CAP data to show that
> I have got good drug penetration, and we are actually doing a
> complicated UTI study, as well, with the same drug.
>
> So, I use drugs, the studies, to help complement my confidence in
> using the drug for pathogens in the lung when they come from another
> tissue site.
>
> DR. LEGGETT: Mark.
>
> DR. GOLDBERGER: Just to follow up what Drs. Rodvold and Bradley said.
> I think we would agree that in the perfect world, we would want, for
> each indication, multiple studies. I think everybody would feel most
> comfortable about that.
>
> But we live in a world, of course, that has various constraints. One
> of the constraints is that it takes a certain amount of resources in
> order to perform all these studies. So, the question really we are
> sort of asking is, in part, in order to encourage and facilitate the
> development of new antimicrobials, you know, recognizing the fact that
> companies have to make decisions about how to apply their resources,
> what are the things that we can do to sort of expedite the development
> program, and the big clinical trials are ultimately fairly expensive
> to perform.
>
> So, we are sort of asking this question, not in the perfect world, but
> also in the constrained world in which we live, to try to understand
> what things might conceivably be reasonable.
>
> We acknowledge, of course, this issue that was raised, that the
> microbiology in HAP is different than the microbiology in CAP, and how
> much overlap there is depends on a lot of factors, but clearly it is
> different as well as the patients themselves.
>
> Now, we have, for instance, the opportunity in a multi-indication
> development program to also, for instance, explore complicated
> intra-abdominal infection, which gives us the opportunity to look at
> fairly sick patients over a wide variety of ages, who will have
> significant gram-negative infections.
>
> Now, arguably, surgical intervention is a component there, and that is
> an issue, as well. We also have the opportunity to look at complicated
> skin including diabetic infections, again where there are issues of
> significant gram-negatives.
>
> Now, are these perfect surrogates, for instance, what goes on in the
> lung? No, it depends in part on how much information you have acquired
> about comparative tissue levels as part of your development plan, but
> we are faced with dealing at one level with a somewhat constrained
> environment, and the question is what can we do with that environment
> recognizing that this is less than what we would normally do perhaps
> in the perfect world, and in those circumstances, what is our level of
> comfort and what is the things we really want to sort of look at and
> think about in order to make reasonable accommodations.
>
> DR. LEGGETT: Mike.
>
> DR. PROSCHAN: We have been making it kind of simple here by
> considering only HAP and CAP, but there might be several related bugs,
> and the question is should you take into account information on the
> other ones. I think definitely, you would have to say yes.
>
> I mean if you found one clinical trial that showed efficacy for HAP,
> but all the other things that you think ought to be similar, the drug
> doesn\'t work for, then, you would probably want to see another study.
> On the other hand, if it is consistent, all four are showing the same
> thing, then, that might be a situation where you would be happy with
> just the one.
>
> DR. LEGGETT: Again, I come back to my point of how good the study is.
> My view of studies of complicated skin and soft tissue infections
> close up is it looks pretty bad. You can swab somebody\'s open foot
> ulcer and its complicated skin and soft tissue, but that is not at all
> what I would worry about if I was treating somebody with nosocomial
> pneumonia who had the same pathogen in their lung.
>
> Then, the question I get to is can we redefine the criteria of how
> many people or what kind of person you have got, and how much has to
> be bacteriologic hard data in your CAP trial.
>
> DR. POWERS: Let me switch out of indications where this might even be
> more relevant, because this committee has discussed this only a few
> months ago.
>
> If you take a look at one of the things we have on the bottom there,
> of sinusitis compared to otitis media, now, those are two infections
> where the organisms are almost identical for those things, but we
> could make the case of what kind of quality data do we see for those
> kind of indications.
>
> As you are saying, Jim, when one is going to use those to support the
> other, does the kind of clinical-only trials that we saw in the past,
> with no microbiology, or a microbiology trial with no clinical
> information along with it that is open and non-controlled, what does
> the committee think about that if we are then going to use that to
> relate one disease to the other?
>
> DR. LEGGETT: I don\'t like it.
>
> DR. RELLER: No numbers can make a lousy study a good one. I have no
> problems whatever extrapolating from otitis media to sinusitis and
> vice versa if we have got sinus taps and tympanocenteses with
> microbiology and eradication of the organism.
>
> Coming back to CAP and HAP, it is not that they could never be
> extrapolated one to the other. It is just that the probability of
> having comparable organisms is so small, and even if one had a drug
> that was active against Enterobacter in HAP, and it was active against
> the Pneumococcus in CAP, I am not willing to extrapolate drug X\'s
> data for the Pneumococcus to the Enterobacter in HAP even though they
> are both susceptible organisms to this putative compound that you
> mention.
>
> When we come to two studies/one study, I am actually much more
> interested in the numbers that I know that they have the entity, the
> bacteremic pneumococcal pneumonias in CAP, the ones that had an
> expectorated sputum where the organism was seen on Gram stain, and it
> was grew and it was devoid of epithelial studies, the HAP studies that
> have quantitative cultures obtained by endoscopy and bronchial brush.
>
> I mean those where you have got the best possible chance to be sure of
> what you have got, and then those, of course, accompanied by
> bacteremia, to me, mean a lot more, and these clinical studies that we
> have had in the past with otitis and sinusitis, they don\'t tell us
> very much, and they certainly don\'t tell us very much with the kinds
> of organisms that Dr. Jorgensen described earlier.
>
> DR. LEGGETT: Keith.
>
> DR. RODVOLD: I agree with Barth in the type of patients, and I think
> the agency themself has used this as an example. It\'s the
> levofloxacin data, when that came through to us. I was on the
> committee, Barth was there, and what was convincing was the story, the
> whole story. I mean they had a reasonable number of patients, the
> quality of the patients, and what they had recovered, but they also
> had the kinetics, the dynamics, the in vitro models with it, and the
> story was very consistent to get into a smaller group of numbers of
> quality people, and it rolled along.
>
> What I would throw on top of that these days would be what Jim brought
> up, was doing some simulations on top of that information to kind of
> project out of the worse scenarios, the people that have a very fast
> clearance to a slow clearance, to someone with a high MICs to low
> MICs, to again give people comfortability levels, just like what they
> have been doing at NCCLS more recently of 80 percent of the time, you
> are going to hit the target even if it\'s someone that is a poor
> eliminator or a fast eliminator.
>
> I think that building that whole story around one good study that has
> good quality patients that are really sick, that have the real
> pathogens, is more convincing that two trials that have kind of some
> numbers, and I think that is still the best example you have to share
> with people.
>
> DR. LEGGETT: Mimi.
>
> DR. GLODE: I just wanted to comment on the issue of trying to
> establish safety and efficacy in the same study, so sort of torn
> between we want to enroll a lot of people, so we have some safety
> data, but then really, often inadvertently, if you will, contaminating
> the population and sacrificing quality of the study.
>
> So, particularly, I know it is very hard for everybody, whether in
> pediatrics or internal medicine, but community-acquired pneumonia,
> trying to figure out who has got a viral respiratory disease that is
> going to get better no matter what you give them, who has got
> mycoplasma that is going to get better no matter what you give them,
> and who actually has bacterial pneumonia that presumably will
> definitely get better faster and needs an antibiotic, you know, means
> the best microbiology, it means pneumococcal urinary antigen, as Barth
> mentioned yesterday, potentially, I mean quantitative CRPs, I think
> there are better ways to narrow that population and then study that
> population, because if you inadvertently contaminate them, you create
> this effect of making the drug look fabulous in this population, and
> that is not the critical information you really want.
>
> So, as long as you are inadvertently contaminating them, it is
> elevating the efficacy of the drug inappropriately and misleading
> everybody.
>
> DR. LEGGETT: Ellen.
>
> DR. WALD: I think the infections in which you would have the greatest
> ability to extrapolate one to the other are the ones in which the
> microbiology is the same, and so, you know, acute sinusitis and acute
> otitis media are identical for all intents and purposes.
>
> Some have made the observation that the middle ear is a paranasal
> sinus, and I think there is truth to that when you think about the
> eustachian tube as a sinus ostea.
>
> I think a question that you could ask from there is how similar is
> that bacteriology to the microbiology of acute exacerbations of
> chronic bronchitis, and then at least in children, for the
> bacteriology of a community-acquired pneumonia, which, of course, is
> something we don\'t exactly know what the bacteriology of
> community-acquired pneumonia is in children short of the pneumococcus,
> because that is the only thing that we grow from blood cultures in
> pleural effusions, although it may not be the only cause of bacterial
> pneumonia.
>
> So, I think where you have similar microbiology, you have the greatest
> ability to extrapolate, and I think, though, it puts a tremendous
> burden on the quality of the first study that you do for any of those
> for it to be really high quality, and to have as much microbiology as
> possible.
>
> DR. POWERS: Could I ask a follow-up question about that, because you
> named three respiratory diseases and two of them are a little
> different, and that for otitis media and sinusitis, they are both
> normally sterile body sites where we can get that microbiology by
> tympanocentesis or sinus puncture.
>
> On the other hand, acute exacerbations of chronic bronchitis is a
> disease where, if you culture those people when they are not having
> exacerbations, you are going to find those bacteria there, as well.
>
> So, does the certainty of diagnosis of what that microbiology means
> also play into part of this?
>
> DR. WALD: Well, I think if we are willing to suspend certainty for a
> moment, since we really talked yesterday and I think everybody was
> sincere about the need to do an antibiotic versus placebo study, but
> if for the moment, we accept that it is a real entity that is caused
> by bacteria at least in some proportion of the cases, then,
> microbiology is really very similar to the others. Maybe there is a
> little shift in proportion of the organisms, but they are really
> pretty much the same organisms.
>
> DR. LEGGETT: Would you be willing, assuming that acute exacerbation of
> chronic bronchitis or bronchitis, assuming antibiotics help, would you
> be wiling to go from community-acquired pneumonia to that indication
> with the one study?
>
> DR. WALD: Yes, I would, because again, I think going from the more
> complicated to the less complicated is a direction that has an ease
> associated with it. So, in a more stringently, better defined
> infection, i.e., CAP, a drug proves to be effective, then, I think
> that one could comfortably conclude that in a lesser infection, acute
> exacerbations of bronchitis, that it would perform equally well.
>
> Again, if we have bacteriology that includes non-typeable Haemophilus
> and Streptococcus pneumoniae as being probably the major players in
> both of those infections.
>
> DR. POWERS: Let me extend that a little bit, asking about the
> directionality question. So, if you had otitis or sinusitis, that
> might be supportive of acute bacterial exacerbations of chronic
> bronchitis.
>
> I am assuming that these trials are doing at different times because a
> lot of what we see is they are done simultaneously and we can use them
> to support each other, but suppose the ABECB trials gets done first,
> how supportive do you think that is in the other direction of, say,
> sinusitis or otitis media?
>
> DR. LEGGETT: None.
>
> DR. POWERS: Because that is the stuff we are dealing with is, you
> know, is there a directionality to this, and the CAP one is clearer,
> better, ABECB is a little different.
>
> DR. LEGGETT: Jan.
>
> DR. PATTERSON: I was going to say I agree with Ellen, and that I think
> you can go from CAP to ABECB, but not the other way around, and also
> from acute bacterial sinusitis to acute otitis. In adults, I have a
> little reservation about going from otitis media to acute bacterial
> sinusitis because I think adults have staph sinusitis sometimes, but
> if you had an acute otitis media study and you knew that the compound
> had good staphylococcal activity, then, I might go for that.
>
> That kind of gets to the point of, you know, with some of these
> resistant organisms, they have had sort of pathogen-directed
> indications like VRE, bacteremia, and that kind of thing, and I think
> if you had an antibiotic that was successful in treating bacteremia,
> that it would most probably be successful in treating UTI and lesser
> sorts of things, but I don\'t know how much you want to go for
> pathogen directed indications.
>
> DR. LEGGETT: People are trying to get multiple indications. If they
> are only trying to get one, is it still two studies and supporting
> data?
>
> DR. POWERS: Yes.
>
> DR. LEGGETT: I just wanted to make that clear.
>
> Could the two studies, one is controlled, and could the other be one
> of these enriched pneumococcal antigen, or do they have to be
> controlled, blinded, the variability problem?
>
> DR. POWERS: That goes to the reproducibility of the information.
> Whether one could then do two studies and then some other kind of
> open-label trial trying to accrue more resistant pathogens might be
> one way to go.
>
> DR. LEGGETT: Barth.
>
> DR. RELLER: One example of this question about one study/two studies,
> if you had a good efficacy demonstrated for the pneumococcus Moraxella
> catarrhalis, I mean the respiratory pathogens with the
> community-acquired pneumonia study, and one had a single acute
> exacerbations of chronic bronchitis that was placebo-controlled, I
> don\'t think anybody would have any trouble extrapolating.
>
> I mean that would be one nice example of a single study would be all
> you would need if it was a good one, on the one side, and it was a
> good one on the other, and then the transfer of the information. I
> would like to see more of those.
>
> DR. POWERS: I think one of the issues we are trying to get at is what
> I think I heard yesterday a couple of times was what is the incentive
> for anyone in industry to go out and do a placebo-controlled study of
> acute bacterial exacerbations of chronic bronchitis, so in this way,
> it sounds like this might be some incentive if it streamlines the drug
> development process in some way.
>
> The other issue I think that we didn\'t talk about much yesterday is a
> placebo-controlled ABECB trial has fewer patients in it than a
> non-inferiority trial of ABECB does, therefore, there is two benefits
> to a company doing this. Do I think we are going to see this? I am a
> little skeptical from what I have heard, but at least we can at least
> hold out that there is some benefit to industry to actually do things
> this way.
>
> If there is not, why should anybody do this?
>
> DR. RELLER: Yesterday, I would have to pull out the books, but, what,
> 2- to 300 in three different trials with acute exacerbation, or were
> there four? There were three or four trials for acute exacerbations of
> chronic bronchitis.
>
> DR. COX: You mean in yesterday\'s discussion?
>
> DR. RELLER: Yes, yesterday. I mean at least three, three, four or
> five. Let\'s take four trials, 250, 300 patient apiece, I mean one
> good trial would have I think given us more useful information than
> all of the material that we wrestled with yesterday with acute
> exacerbations of chronic bronchitis.
>
> DR. POWERS: You are hitting on my pet topic here, so I have another
> question for the committee related to this. So, if it\'s okay to
> expose 800 people to a non-inferiority trial in ABECB, one of the
> things we hear is it is unethical to do a placebo-controlled trial.
>
> Well, how ethical is it to expose all those people if we don\'t even
> know if the drugs have any efficacy in that disease?
>
> DR. LEGGETT: Correct, but they are not going to die. I think that
> people draw the line at when you are going to die.
>
> DR. POWERS: I am trying to address the question of why is it unethical
> to do a placebo-controlled trial in ABECB.
>
> DR. WALD: Who says that it is unethical?
>
> DR. POWERS: Ever since we had this discussion in November, we have
> tried to ask drug sponsors saying based on what we heard, that we
> think that these trials should be placebo-controlled. No one has
> expressed a willingness to do so, and one of the reasons we hear is
> that IRBs have a problem with this and that it is not ethical or
> supposedly not ethical to do a placebo-controlled trial in this
> disease.
>
> DR. LEGGETT: Barth.
>
> DR. RELLER: What a wonderful opportunity for a sponsor. We have got
> the Infectious Disease Society of America participating in the meeting
> saying that placebo-controlled trials are necessary, and even the
> Institute of Medicine saying this is something that should be brought
> up to the NIH for funding because this is important.
>
> I mean I would think that there are sufficient published consensus
> bodies experts, I mean it should be a slam dunk within IRB. I mean we
> have emphasized here the tympanocentesis study with the
> demonstrations, the taps, that it can\'t be done, the amount of useful
> information in what the potential benefit of knowing what somebody
> actually has as opposed to the pitfalls of empiricism in a world of
> unexpected resistance, I think the time has never been better to
> tighten the science and thereby achieve also economies of having more
> useful information involving smaller numbers.
>
> DR. PROSCHAN: Would you expect the drug companies to say we don\'t
> want to do that because our drug might not be any better than the
> placebo? Of course, there is an incentive to say it is unethical.
>
> DR. LEGGETT: Ellen.
>
> DR WALD: I think it may help. You know, there are certainly some
> published statements from recommending agencies suggesting that these
> things are ripe for investigations, and I think the timing is right,
> but I have to say that the IRBs now are particularly skittish.
>
> I think that they are feeling a lot of pressure because of the kinds
> of things that have recently been reported in the press about mistakes
> of protocol implementation, whatever, and we just had an experience at
> Pittsburgh where, in fact, our IRB has declined approving a
> placebo-controlled trial of acute otitis media, and we are going to be
> sending it to the FDA to get their ruling on that.
>
> I think that is despite the fact that, you know, there is a lot of
> media now looking at watchful waiting as a strategy. So, I think that
> maybe in the minutes of this meeting, if we can make a formal
> statement about how important these studies are, that it will create a
> sense of equipoise, which I think is what is necessary to engage in
> any of these kinds of investigations.
>
> I think that we can, in fact, state that equipoise, because I think we
> don\'t know the answer.
>
> DR. LEGGETT: Keith.
>
> DR. RODVOLD: I agree, that, you know, being a past IRB member plus
> dealing with the IRB constantly, that every IRB is its own animal
> basically, and the only way you get through it, especially where a lot
> of people do trials, they go through IRBs that are way different than
> the ones that I think most of the people sitting around this table go
> through as an IRB, and you would need to not only gather the
> literature, but I think you probably would have to make a statement
> that would go right in the packet.
>
> That does lend credence, a lot of credence, in areas of untouched
> territories or uncomfortable territories, and I can tell you one of
> our IRBs, when you bring up placebo-controlled, are just like what
> Pittsburgh is running into, it\'s almost a no go until you can just
> really show them with convincing data and convincing endorsement from
> the Federal Government that this is a possibility.
>
> DR. LEGGETT: Go ahead, John.
>
> DR. POWERS: Having been on an IRB myself, I agree that it is the
> quality of the data that gets presented to the IRB that sways them,
> and one of the things that always comes to my mind now when we talk
> about levels of evidence is the trial that was done on hormone
> replacement therapy in women that was published just last year.
>
> Loads of observational data saying that that therapy actually
> prevented cardiovascular disease, one very well-done
> placebo-controlled trial shows it does not, and those are the kinds of
> things that I think are convincing to IRBs, look, we have all these
> trials done in the past that prove absolutely nothing to us, we want
> to do a kind of trial like the hormone replacement trial to answer
> this question definitively.
>
> Jim, could we maybe look at some of those criteria?
>
> DR. LEGGETT: Sure. Don wanted to say something and we will do it.
>
> DR. PORETZ: In certain areas like cardiovascular disease, you look at
> endpoints with events like how many myocardial infarctions you are
> going to have or how many deaths you are going to have if a person
> does or does not take a certain drug.
>
> In infectious diseases, when you are doing drug studies, antimicrobic
> studies, who determines the total number of patients for validity of a
> study, is the pharmaceutical company and their statisticians, is it
> the FDA and their statisticians, who determines?
>
> DR. POWERS: That is something we usually work on together and it
> usually depends upon what the endpoint is and how effective you
> estimate that your drug is going to be, and then it gets into the
> dreaded delta issue of how effective you want your drug to be relative
> to whatever control that you are happening to use, but that is usually
> something we talk about, that the FDA and the pharmaceutical sponsor,
> we talk about together.
>
> DR. LEGGETT: So, what we are saying basically is if we are going to be
> able to change things and improve the single trials, that you guys are
> going to have to require more stringent criteria on your part.
>
> Ken.
>
> DR. BROWN: If I understand the discussion, I am a little uncomfortable
> with the idea of CAP to HAP or reverse, unless we are absolutely
> stringent on the organism, be a case-by-case by organism. The
> pathology of Pseudomonas pneumonia is so dramatically different from
> the pathology of Pneumococcal pneumonia that I can\'t conceive that we
> could let anybody get a claim for both regardless of where they came
> from.
>
> I think a parallel exists in my discomfort with otitis media and
> sinusitis. After the first or second bout of sinusitis, I believe that
> you no longer have acute sinusitis, you have acute exacerbations of
> chronic sinusitis.
>
> Joe Fredericks showed in around 1964 that if you do cultures for
> obligate anaerobes, and not just facultative anaerobes, you always get
> anaerobes in those sinuses, which means to me that the drainage
> procedure may be more important than the antibiotic in those cases,
> but certainly we shouldn\'t be using antibiotics which don\'t have
> anaerobic coverage for those people.
>
> DR. LEGGETT: I think one would have to specify there are big
> differences between adult and pediatric populations in terms of
> sinusitis.
>
> Here are the proposed criteria. No. 1, the natural history of the
> disease under study - what is the spontaneous resolution rate and what
> is the morbidity/mortality without treatment? This is where we have
> been talking about acute exacerbation of chronic bronchitis.
>
> Are there some others in terms of we are talking about various
> different models where that might apply other than the otitis that we
> have just mentioned?
>
> Go ahead, Ed.
>
> DR. COX: One of the things that might be helpful would be this
> morning, some of the criteria were actually ranked as far as level of
> importance, and I think that might help us get a better feel. I think
> we had some discussions about where there are criteria that are more
> important than others at least from the discussions we had going on
> here.
>
> That would actually be helpful to us, I think, if we had some
> discussion of the criteria, which of these are of the most importance
> and which ones are of lesser importance.
>
> DR. LEGGETT: The diseases that we get the most irrelevant data on are
> the ones that have the fewest hard endpoints, and that is the upper
> respiratory tract type problems. That, to me, is probably the
> strongest argument for a placebo-controlled trial in a disease of that
> nature.
>
> Don.
>
> DR. PORETZ: Another example of 1 would be chronic bacteriuria, chronic
> urinary tract infection in elderly women where most people now would
> not treat asymptomatic bacteria. I mean you can put them on an
> antimicrobic, get rid of the organism, just like chronic bronchitis,
> it means nothing.
>
> DR. LEGGETT: What about something like skin and soft tissue
> infections, whether it\'s complicated or uncomplicated, we are going
> to let clinical data go where we can\'t get bacteria? That is another
> example of two things that I can think of where we don\'t really get
> reliable data, but we know from antibody studies that 90 percent of
> them are group A strep, at least in uncomplicated.
>
> What kind of numbers do we need for that? Are those going to resolve
> by themselves, does anybody think?
>
> Go ahead, Alan.
>
> DR. CROSS: Not with group A strep or Staph aureus.
>
> DR. LEGGETT: Or Staph aureus.
>
> DR. CROSS: But perhaps I can take this opportunity to ask a question,
> and that is, we heard from the pharmacokineticists and dynamics folks
> that if we had an AUC of greater than 100, it is highly predictive of
> efficacy, so I am just wondering, in the case of like a skin
> infection, if we actually were able to measure the antibiotics in the
> skin and actually calculate how much of a dose actually gets in the
> skin.
>
> Can that type of data be extrapolated to other organisms?
>
> DR. LEGGETT: So, in other words, the question is sort of will you guys
> allow in vitro or in vivo model extrapolations.
>
> DR. POWERS: That is actually No. 3, the characteristics that is up
> there about looking at the pharmacokinetics of the drug. How to use
> pharmacodynamics is something that we have been discussing internally
> and that got brought up in November, and the FDA has an internal
> exposure response working group, which is actually trying to look at
> this information of how can we actually apply some of that data.
>
> DR. COX: I think, too, I mean we are focusing here today on clinical
> data and really the reliance and inference that can be drawn from
> other indications, so I think it is more clinical that we are talking
> about here today.
>
> DR. LEGGETT: To finish up with the natural history stuff, does anybody
> here believe that prostatitis or urinary tract infection is going to
> go away by itself, and what are we going to do? Uncomplicated urinary
> tract infection, you know, post-coital cystitis, do we need placebo
> control is what I am saying or do we have to have controlled data? I
> am just making sure that we flesh this whole thing out before we go.
> No.
>
> The only thing I can think of unless somebody tells me otherwise that
> we are going to have placebo control is that upper respiratory tract.
>
> DR. POWERS: But our real question is how they would be supportive of
> another disease. So, I guess what I was hearing was acute bacterial
> exacerbations of chronic bronchitis trials wouldn\'t be supportive of
> anything else unless you did a placebo-controlled trial.
>
> DR. LEGGETT: Right. That is the lowest on the totem pole, everything
> is above that.
>
> A question that sort of jumps back in terms of what do you propose. If
> you have a very good, tight puncture of the ear trial with data, and
> you have one puncture trial of the sinus data in kids, can you use
> them back and forth, or do you need two in the ear and then one in the
> sinus?
>
> If we have just made the argument that they are the same, why do you
> need two in one and in the other except for the best possible world
> validation?
>
> DR. COX: I think it gets to the issue of level of evidence, and having
> the one indication or anchoring the initial indication in a couple of
> studies, and then moving on to use that information to support other
> studies, so it is all level of evidence question, and we have had some
> discussion about the number of studies, one big study versus smaller
> studies.
>
> John mentions another good point, too, and that is, you know, accruing
> sufficient numbers of patients in order to be able to adequately
> characterize the safety of the drug, too.
>
> DR. LEGGETT: Right, the same globalization.
>
> Jan.
>
> DR. PATTERSON: Just in terms of priorities, you were asking about
> priorities. I think one of the things that have spent a lot of time
> talking about is that No. 7, similarity in spectrum of organisms
> causing disease. I think I would put that pretty high, like towards
> No. 1.
>
> Then, No. 5, similar site of infection, you know, respiratory versus
> urinary versus skin and soft tissue, complicated versus uncomplicated,
> we have been talking about that, too, so I think that would also be
> pretty high up, maybe No. 2.
>
> I would see those two as being a couple of the more high-priority
> ones.
>
> DR. LEGGETT: So, what you are saying, for No. 5, was we don\'t really
> seem to like the CAP/HAP thing. You are saying that urinary,
> complicated/uncomplicated, skin, complicated/uncomplicated, and how
> about urine and prostate?
>
> DR. PATTERSON: Complicated UTI.
>
> DR. LEGGETT: Yes, complicated UTI.
>
> DR. PATTERSON: Complicated UTI, then, I would go for prostatitis, yes.
>
> Go ahead, John.
>
> DR. BRADLEY: In extrapolating between the same site of infection, but
> different scenarios, like HAP and CAP, knowing that they are different
> types of organisms, in my suggesting that all you would need is one
> study of each, the implication was that you would need to study a
> certain number of Pseudomonas infections either in that HAP trial, so
> that you would know that it would work in Pseudomonas,
> hospital-acquired pneumonia, or have just a few in hospital-acquired
> pneumonia and then Pseudomonas in another complicated tissue site that
> you would not expect any spontaneous resolution, so some sort of
> complicated urinary tract infection, hospital-acquired urinary tract
> infection, or deep surgical wound infection, a mediastinitis.
>
> There are certainly situations where you can collect information on
> the drug\'s effect on the organism, so what I am trying to build is
> taking a certain amount of information on efficacy at a tissue site,
> but requiring a certain amount of microbiology that is either from
> that site or a comparable site.
>
> So, if you can treat Pseudomonas or Enterobacter or Klebsiella in a
> complicated intra-abdominal infection, because even though you require
> surgery, the antibiotics are part of the whole treatment process, if I
> can get efficacy data in those pathogens in another tissue site, I
> will feel comfortable extrapolating into a pneumonia site and
> requiring fewer of those cases in a pneumonia.
>
> You had in the other slide complicated intra-abdominal infection
> towards complicated skin and skin structure. Well, you don\'t get
> Staph aureus very often in a ruptured appendix, but it\'s a deep
> tissue space where there is a low pH, lots of white cells that
> requires drainage, so the same thing would be true of a cervical
> adenitis that requires drainage caused by staph in terms of the
> environment, but the organisms would be different.
>
> So, I wouldn\'t go from intra-abdominal into complicated skin and skin
> structure unless I had data on Staph aureus supporting skin and skin
> structure, and where you would get that other data, I don\'t know,
> certainly not in intra-abdominal infections.
>
> Then, you have got complicated skin and skin structure supporting
> complicated intra-abdominal, and again the same concept is there. The
> organisms are completely different even though the types of tissue
> environment would be similar, both deep tissue, both requiring
> drainage.
>
> DR. LEGGETT: To follow up on that, what about monomicrobial and
> polymicrobial, so staph is one of your polymicrobial in your
> intra-abdominal, whatever process, and then your skin and soft tissue
> is staph, do you think you can extrapolate?
>
> DR. BRADLEY: I think it would be difficult to extrapolate
> polymicrobial to a single drug simply because in the abdomen and in
> deep head and neck space infections where you have got so many
> different organisms, the quality of pathogenesis and rapidity of
> spread seems to be a function of the multiple organisms rather than
> the single, and it may be easier to treat a single organism than once
> you get them all together, and their separate pathogenicities add or
> are synergistic with each other.
>
> DR. LEGGETT: To face the other issue, what about an enterococcus in a
> polymicrobial versus an enterococcus someplace else? I am not sure I
> would buy that either. So, I am not sure we can use this
> polymicrobial/monomicrobial in terms of going from one to the other,
> if that is what you guys were trying to get at.
>
> DR. POWERS: I guess what we are asking is suppose you had some
> complicated intra-abdominal cases, and some of those were, say,
> abscesses that grew pure enterococcus versus you had another drug that
> studies the same thing, and then you get enterococcus and a whole
> bunch of other stuff.
>
> DR. LEGGETT: Nope.
>
> DR. POWERS: But would the pure cases of enterococcus be more
> convincing to you?
>
> DR. LEGGETT: Yes, to me, yes. I will defer to everybody else. Go
> ahead, Alan.
>
> DR. CROSS: If you had a pure case of enterococcal abscess in the
> belly, I would be impressed. I just recall early on when the coverage
> for intra-abdominal sepsis used to be Keflin and kanamycin and, you
> know, absolutely no enterococcal coverage. People have studied it,
> including Dr. Tally in his earlier days, it just hasn\'t been a
> problem in patients or animal models, so I would be hard pressed.
>
> DR. LEGGETT: The same applies to clinda/gent.
>
> DR. PATTERSON: I guess one comment about enterococcus is kind of
> getting back to the pathogen-specific issue. If I knew something
> worked in enterococcal bacteremia, then, I would use it for an abscess
> or skin and soft tissue, and I think there are times you see
> significant intra-abdominal infections, for instance, in liver
> transplant patients, so I mean I think you do see them sometimes.
>
> DR. POWERS: And that is the point. I have seen pure enterococcal
> abscesses, but it is in somebody that is throwing bucketloads of
> antibiotics, you know, in their third operation after they get it.
>
> DR. LEGGETT: Right, where it is in their liver.
>
> DR. POWERS: Exactly. I think it can exist, it is just unusual.
>
> Mike.
>
> DR. PROSCHAN: Could the FDA say, you know, ordinarily you need two
> well-controlled clinical trials, but if you think you can make the
> case based on related bugs, then, you are welcome to try, and then the
> advisory committee sees if they made the case.
>
> DR. POWERS: What we are trying to do here is outline the criteria that
> decides whether you make the case. Rather than have the company come
> in and just have to de novo make this up, we are trying to outline
> this of the things that would allow them to say we meet these criteria
> that the advisory committee outlined, which is what we are asking you
> guys today, so that they have some template upon which to build their
> case.
>
> DR. LEGGETT: I would think it pertinent in terms of that, in your No.
> 1, the natural history of the disease, it is not only the disease, it
> is natural history of the bug disease complex. As we were saying, that
> enterococcus melts away when you don\'t treat it in the presence of a
> bunch of other stuff, but VRE bacteremia, if it\'s persistent, you
> know, if somebody is looking for a VRE thing, they have got a VRE
> liver abscess, and then a VRE bloodstream, and then a VRE someplace
> else, could they lump those together and say yes, I would think you
> could make a case for saying yes.
>
> Barth.
>
> DR. RELLER: That is basically what was done with
> quinupristin-dalfopristin.
>
> DR. LEGGETT: That is an example, going forward to drug-resistant
> pneumococcus, or VRSA, or something like that.
>
> DR. RELLER: To me, the critical issue is the rigor of the database,
> and I would add a little caution in trying to get things too
> delineated because then if those things are met, you still may be
> uncomfortable.
>
> I think about yesterday\'s discussion, well, the company did what they
> were supposed to do, but, you know, the lingering discomfort of the
> solidity of the science, so that I think maybe 95 percent of the way
> there, but just checking them off shouldn\'t be\--it should be
> defensible, not only there, but also rigorous, and I think some of the
> attempts here is to raise the bar, or put another way, you get what
> you ask for, and it also applies to the agency what is required.
>
> DR. LEGGETT: Going back to how hard the sort of persistence question
> of the pathogen can be applied, not when you are only trying to do one
> bug, but when you are trying to do nosocomial-acquired pneumonia.
>
> Lots of the times, MRSA in the sputum, I deliberately don\'t do
> anything with in the ICU with somebody who has got an infiltrate. That
> data has to be tightened up. The not normally sterile site, you know,
> but the data that I am aware of, and that we have tried, looking at
> all the sort of protected specimens in the quantitative, is if anybody
> has had a whiff of antibiotics, you don\'t get anything.
>
> It is only in France where they don\'t give antibiotics to anybody
> before they do the bronchoscopy that they get anything, and it is only
> in those one or two places that could publish those studies, nobody
> else can replicate that.
>
> DR. POWERS: So, it sounds like what I am hearing is there should be an
> eighth criteria on here, and that has to do with the quality and rigor
> of the trial.
>
> DR. LEGGETT: Definitely.
>
> John.
>
> DR. BRADLEY: Looking at 7, thinking of organisms, in most of the
> studies that I have done, and in what you said earlier, John, that the
> FDA looks to treat infections, when there is a clinical trial, when a
> patient comes into the hospital, we are looking for infectious disease
> diagnoses, and then we look to see if that patient qualifies in terms
> of the types of pathogens that we are interested in treating, but what
> Dr. Reller is saying, and you seem to have agreed with, particularly
> with dalfopristin-quinupristin, is supplementary data that is
> organism-specific, not site-specific.
>
> Am I hearing you say that if there is a particular indication like
> pneumonia, and a company would like Pseudomonas as an indication for
> pneumonia, that you would accept my screening from the micro lab and
> taking Pseudomonas infections other than pneumonia, so bacteremias,
> endocarditis, prosthetic joint, you know, all range of things that are
> not pneumonia\--
>
> DR. LEGGETT: Except UTI.
>
> DR. BRADLEY: Except UTI, you know, the quality of data, serious
> infections that you need the drug, and provide you with supplemental
> data for the organism that is organism-driven, not infection-driven.
>
> DR. GOLDBERGER: I think that basically we recognize, and this is
> something we have sort of touched on a couple times, that for some of
> the more difficult-to-study organisms, including some that despite the
> fact that they are difficult to study, in no way means that they are
> not important. We talked about an Acinetobacter, there are other
> examples.
>
> It is going to be necessary, I think, to be able to pool data across
> more than one indication, and I think you can recognize that much of
> the discussion that we have had today about how indications support
> one another is the kind of discussion that is necessary as part of
> thinking conceptually how we can take organisms across the different
> sites and pool them, but I think it is inevitable if we are going to
> be able to draw some kinds of conclusions about whether a drug works.
>
> You can argue, on one hand, the goal from the pharmaceutical company
> is, of course, to get this in their product labeling, which is fine
> because they need to have an incentive in order to do all this work,
> but realistically, that is hopefully intimately tied to the idea that
> we can actually draw some meaningful conclusions about whether the
> drug actually performs.
>
> In order to do that, it is clear it is going to be necessary to do
> this, so in addition to a lot of obviously the traditional indications
> and listing some organisms, it is clear in certain circumstances we
> will need to be able to grant some sort of organism-specific approval
> that will utilize data across more than one indication. I think it is
> inevitable.
>
> What we want to do is to do it as well as we can. I think if you think
> about what everybody is saying here, what everybody is saying is and
> almost irrespective of whether we were having the discussion we are
> having, is that there are issues still in how the clinical trials are
> performed, and they could be done better.
>
> We have talked about it for sinusitis, we have talked about it for
> otitis, we have talked about it for pneumonia, we have talked about it
> for almost every\--well, and that is what we are moving toward.
>
> On the other hand, what we are also hopefully moving towards is
> providing an incentive for industry to be interested in doing it
> better because instead of doing a lot of trials that are at best
> so-so, ultimately, the goal is to move to a fewer number of trials
> that are better performed with better endpoints, with better
> microbiology, and the link to that is this further incentive of how
> organisms can sort of be used across more than one indication.
>
> That is really what we are trying to do.
>
> DR. LEGGETT: Could I go back to sort of the real world situation? I
> don\'t know if, say, piperacillin or piperacillin-tazobactam, or some
> drug, for instance, that did not get intra-abdominal and went for
> pneumonia, or got intra-abdominal and then did not go for a pneumonia
> trial, but you knew the MIC and the susceptibility data in real life,
> do you not use your pip-whatever it is in the belly after you have
> used it before in the pneumonia, and vice versa?
>
> So, how much higher does the hurdle have to be, which is I think what
> you are trying to get at, so we should think about the way we actually
> treat people with antibiotics when we are discussing this.
>
> DR. POWERS: Can I sort of follow up on that for a second, because one
> of the things I think that came out of the last meeting we had in
> February was a misunderstanding of what we were saying when we were
> saying accepting pooled information.
>
> That would still need to be held down by efficacy data in the disease
> in which that resistant pathogen is most likely to be found. So, in
> other words, suppose you wanted to go for methicillin-resistant Staph
> aureus, the two places you would most likely see that would be
> complicated skin and, say, hospital-acquired pneumonia.
>
> So, if you did a hospital-acquired pneumonia trial and only came up
> with a few MRSAs, you could then do this other trial, pooling the
> information, but if you just come to us with all that pooled
> information and no hospital-acquired pneumonia trial, that is not very
> helpful.
>
> DR. LEGGETT: Jan.
>
> DR. PATTERSON: I was just going to say about extrapolating from the
> non-pneumonia infections to pneumonia. I think that is where Criteria
> No. 3 would come in as pretty high priority about making sure you had
> tissue levels, because not all antibiotics get into the lung equally
> well, so that would become important.
>
> Then, just thinking about Pseudomonas pneumonia, I mean even if you
> had a complicated skin and skin structure infection due to
> Pseudomonas, I think Pseudomonas pneumonia is harder to treat. For
> instance, you would definitely use combination therapy for Pseudomonas
> pneumonia, whereas, with the other one, if you combined it with
> surgery, you might not need combination therapy for as long at least.
>
> So, I think for that particular pathogen, you would have to be a
> little bit careful going from non-pneumonia to pneumonia.
>
> DR. LEGGETT: To bring No. 2 back into this, Pseudomonas, would you
> accept an intra-abdominal abscess that got drained, that had the
> resistant Pseudomonas in it, if you had lung data or vice versa?
>
> In other words, a good study in pneumonia that cleared the resistant
> Pseudomonas, and then you had other supportive data, say, an
> intra-abdominal abscess drained or had surgery, would that be
> acceptable? Trying to get at No. 2.
>
> DR. PATTERSON: Going from pneumonia to the abscess, you mean?
>
> DR. LEGGETT: Yes.
>
> DR. PATTERSON: Yes, I would accept that.
>
> DR. LEGGETT: And is it a directionality, would you not go the other
> way?
>
> DR. PATTERSON: Well, that is what I am saying. I don\'t know that I
> would necessarily go the other way for Pseudomonas, I might for some
> other pathogens, but I would want to know about the tissue levels if I
> was going the other way.
>
> DR. LEGGETT: Back to No. 3, there are some significant differences in
> the surface-to-volume ratio in the abdomen than there is in the lung,
> so I would be very hesitant going from the belly to the lung
> personally.
>
> Keith, what is your take on what can be done in terms of No. 3, in
> terms of helping with resistance trials and in vitro, in vivo, and
> stuff?
>
> DR. RODVOLD: Well, in 3, where you are looking at basically tissue
> levels or concentrations of fluids, is that again I think, as you are
> putting the whole package together, it lends you support in that
> disease state.
>
> The problem in the area is that tissue samples, I have never been
> hooked to efficacy to a significant degree, and someone that does
> research in the area that I do, I mean that is the common criticism we
> get, you know, elegantly designed study, data is really meaningful,
> but there is no link to showing that those samples and those levels of
> concentrations prove that efficacy is going to occur.
>
> It gives people a comfortability level, I think that is what it does,
> and supports, as you trying to say I have got 10 Pseudomonas and I
> have concentrations in the lung that equivalent or higher in the
> plasma, and it works in the plasma, it is going to probably work
> there, as well.
>
> DR. POWERS: Let me give you an example of where we encounter something
> like this. Norfloxacin is indicated for urinary tract infections. Do
> you feel real good about using it for pneumonia, and if not, why not?
>
> DR. RODVOLD: Well, in that case, it doesn\'t have any systemic levels
> in the blood, in the first place.
>
> DR. POWERS: That\'s what we are talking about. Maybe we didn\'t phrase
> this like tissue levels is not the right word. I guess maybe we should
> broadly say gets to the site of infection at all.
>
> DR. RODVOLD: I think that most people believe that it needs to be in
> the site of infection, but if it\'s there, it doesn\'t necessarily
> still link you to efficacy.
>
> DR. POWERS: Right, not relative concentrations, just the fact that it
> has to get there at all.
>
> DR. RODVOLD: But, again, I think it\'s a supportive tool, and
> especially for the industry, from the industry perspective for them,
> is that you are trying to make them fast-track to get an approval or
> get it in their package, it\'s another thing if they have it, it
> allows you to be a little bit more comfortable, but they still need
> efficacy data in the indication.
>
> If you have 10, 15, or however many pathogens, I think most people
> feel more comfortable with it. The whole kicker with that is, though,
> I can tell you from the number of phone calls I get and the
> conversation with people is that the quality of those studies have got
> to be done right, as well.
>
> Most people call me to ask me how we do the studies, and they are not
> sure what they are going to do and how they do them, and there is only
> a few sites around the area that really know, in a specific tissue,
> how to do them.
>
> We do lung, but I don\'t do a lot of the other ones, so I am very
> cautious in jumping over there until we make sure we have the
> methodology done right. So, the methodology, again, good data is going
> to come to you.
>
> DR. LEGGETT: Barth.
>
> DR. RELLER: Maybe a comprehensive way of putting this is the
> necessary, but not sufficient concept, the necessity of having
> adequate concentrations at the site of infection, and this also
> extends\--well, there are high concentrations in urine, but it is also
> the recognized published quantitative relationships that are
> necessary.
>
> NCSF, the 10-fold margin of bactericidal activity, that many drugs get
> into the urinary tract, but not all drugs get into the urinary tract,
> and the ones that don\'t get in there are not good agents for urinary
> tract infections, so without which, you can\'t expect efficacy and
> that alone doesn\'t necessarily constitute efficacy of adequate
> concentration, and adequate has some quantitative concentrative
> relationships that are recognized in some sites that are more
> important than others.
>
> Coming back to what we haven\'t discussed a lot is complicated
> intra-abdominal infections. The integrity of the database and what you
> can rely on microbiologically, I think there is more recent published
> data in this area, as well.
>
> For example, the microbiology that you can rely on in intra-abdominal
> collections of pus, drainage or not, are the initial CT-guided
> aspirates, not what is draining out of the pigtail catheter on the
> fourth, fifth, sixth day, but what is achieved initially. That is one
> point.
>
> Secondly, if one has multiple, which is frequently the case,
> collections in the abdomen, that we know that they need to be drained,
> you know, over a certain size, but I mean if there are multiple
> collections, there are multiple sites that need to be drained, but
> they also need to be sampled.
>
> There are also good published data on the lack of complete correlation
> between one collection and another collection in terms of the
> microbiology, so that clearly, drainage is necessary, but I think with
> some of these organisms, it is not sufficient, and what used to be
> true is not necessarily, as Jan and others have pointed out, for
> example, with the enterococcus that may have been dismissed 20 years
> ago in a polymicrobial collection, it is not necessarily dismissed in
> a post-liver transplant with a collection of pus.
>
> We know that it is real when it\'s associated with bacteremia, but it
> is probably real even without always demonstrating the bacteremia when
> it is got by CT-guided aspirate. So, I think the techniques for
> getting the microbiology are better than they used to be, and we need
> to look at first tap and each one drained tap information in the
> microbiology and the correlation with efficacy of these agents in
> complicated intra-abdominal infection.
>
> And then having those data and what the response is adds support to
> the potential, not the automatic, but the potential in the resistant
> organisms of some extra utility in considering the efficacy of the
> compound against a given resistant pathogen across body sites.
>
> DR. LEGGETT: In terms of across body sites, I was looking there. I
> don\'t think I would allow that resistant pathogen in bronchitis or
> just a sputum without some illness at all, ever, unless it was part of
> a trial that was placebo-controlled.
>
> What about the situation in which you have a pathogen that is hard to
> come up with like drug-resistant pneumococcus, and you use
> penicillin-susceptible pneumococcus with great data, bacteremic
> pneumonias, and then you do your animal model trial that tells you
> that you are going to kill it dead from your PK/PD modeling, how much
> more data do you think is reasonable before you are going to use that
> in real life, in other words, is this a situation where you would
> allow 15 bacteremic pneumonias that are treated with this drug when
> you had all that supporting data and PK/PD modeling?
>
> DR. RELLER: Well, I think if you have the PK/PD data, the animal
> model, a relatively small number, but those are golden cases, you
> know, accompanied by bacteremia, and you have got the NV drode \[?\],
> legitimate, NCCLS methodology data that the, quote, \"resistant\"
> organisms are susceptible to compound X, and the mechanism of
> resistance, there are good data in vitro, that there is no
> cross-resistance whatsoever, the resistance mechanism isn\'t totally
> different, you know, you don\'t need 100 cases of resistant when you
> put all of the components together.
>
> I think Keith was talking about that earlier. I mean if you have got a
> beautiful package that passes muster based on what is known about
> mechanisms of resistance, doing everything that you have done
> first-class, you don\'t need the numbers.
>
> DR. LEGGETT: The reason I brought that up again is because I want to
> go back to the one dose azithromycin for the ear.
>
> Suppose we get into a situation where you have got dueling PK/PD
> stuff, are we going to hence forward say you are going to have to show
> us more data, or what happens if the company comes up with some
> clinical points or has a few bugs, but the PK/PD says it shouldn\'t
> work or, as Dr. Schentag said earlier, they aim at 25, and we know we
> want 100 if we are not going to see resistance in a couple of months,
> I think those things need to be fleshed out in terms of your criteria
> for allowing resistant pathogens.
>
> You were going to say something, John?
>
> DR. BRADLEY: I was just going to support the statement that you made
> when there was that long pause that no one was saying anything and
> Barth agreed with you, and I think everything Barth said regarding the
> package, the complete package, is absolutely correct.
>
> DR. POWERS: One of the things that we deal with is when the package
> doesn\'t hold together. I think this brought this up earlier today.
> What we saw yesterday was some information on quinolone-resistant
> organisms in a drug that had zero anti-pneumococcal quinolone isolates
> in its clinical development package, and showed an animal study that
> showed lack of eradication when the drug was given twice a day
> compared to when it was given once a day in an animal model.
>
> So, what we do we do when that information package doesn\'t hold
> together?
>
> DR. LEGGETT: I personally, if it comes across again, I am going to be
> much harder than I was yesterday. That was a terrible model. It
> wasn\'t a model of infection, it was a preventive, prophylactic model,
> and you could see the dropoff right at 0.25, you know, 0.5 was
> certainly a dropoff, but I didn\'t want to go too far down the NCCLS
> road because you are going to be doing that later, but that was really
> very disturbing to me especially with them trying to say that they
> were going to get quinolone-resistant\--no way in m view.
>
> Alan.
>
> DR. CROSS: I think we also have to be careful when we talk about
> animal models between the PK/PD models versus infection models. I
> think certainly in terms of the latter, it is very difficult to have a
> uniformly accepted model that everyone is comfortable with the data
> that is collected and how it is interpreted.
>
> I just have to always harken back to in the area of sepsis where there
> really isn\'t one uniformly accepted animal model, and I would
> probably hazard that is probably the same in terms of the\--
>
> DR. LEGGETT: Yes, in that little package, that was definitely just an
> animal model, and not a PK/PD model, which to me what you take from
> that is the goal that you are going to use in your clinical studies,
> not that it works or not, and that you can then sort of use it as a
> surrogate endpoint, no.
>
> DR. BRADLEY: You said that you have got a PK/PD working group, and I
> think when a sponsor comes to you with a request for an indication,
> you can share with them the animal model that you think would best fit
> the types of indications that they are ultimately looking for.
>
> As I understand it, you know lots of the information that the sponsor
> is looking for ultimately when they come to you, and there is much
> more dialogue upfront rather than waiting for a sponsor to just come
> up with data, dump it in your lap, and say, \"and here is the animal
> model we used,\" and have that not be the appropriate one that you
> feel is the best and most predictive model.
>
> DR. POWERS: I think in the future, at some point we will need to have
> a more detailed discussion about this issue of pharmacodynamics, but
> some of the issues of how these studies are done are important in that
> realm, as well, as far as when you actually measure it, how long you
> wait, et cetera.
>
> Although we have heard several times from people at this advisory
> committee, there are other folks within that field that feel
> differently about how those studies should be done, and we need to
> probably address that at some point in the future.
>
> DR. LEGGETT: Ellen.
>
> DR. WALD: In the practice of clinical medicine, one of the things that
> makes interpretation of microbiologic data difficult, especially in
> things like intra-abdominal infections, is that the patient has often
> received a few doses of antibiotics before the material is available
> for culture.
>
> I am participating in a pneumonia study now, and it really surprised
> me, but I presume that you guys okayed this, which allows me to enroll
> patients 24 hours after they have received another antibiotic. Now, I
> can\'t do that in good conscience, and so I am not doing it, but I
> suspect that other investigators who are entering patients in this
> trial are.
>
> What do you learn from that and what should be the posture?
>
> DR. POWERS: This goes to something Dr. Goldberger said earlier. In a
> perfect world, one would obviously like to enroll pristine patients
> that didn\'t get any antibiotic. It becomes very difficult, though, to
> enroll people that way especially\--you know, when I was an infectious
> disease fellow trotting in at 3 o\'clock in the morning to enroll
> those people in those trials.
>
> The flip side of that, though, is that would you expect one dose of a
> different antibiotic to cure the patient, and in the long run, what we
> want to look at is, you know, what was the actual effect. So, if a
> person gets one dose of ceftriaxone and then gets nine more days of
> drug X, is it the ceftriaxone that cured them or not.
>
> This goes to a bigger issue, though, and that is, you know, when the
> perfect becomes the enemy of the good, where if we require people to
> do trials that way, and the companies say forget it, it\'s too hard to
> do it, and then we get no data.
>
> DR. WALD: Well, I would say that ceftriaxones are a pretty powerful
> drug, and I would really not know the answer to the question that you
> posed, is the clinical outcome a consequence at least in great part
> from one very powerful drug and some other not so powerful drug.
>
> DR. LEGGETT: I think people are going to have to be a little bit more
> inventive of trying to enroll people\'s pathogens. If you use your
> pneumococcal urine antigen after you have received one dose of
> ceftriaxone, and then you use your drug X for 10 days, I will buy
> that, but just allowing clinical data because, quote, \"you had this
> infiltrate,\" and you enrolled somebody on ceftriaxone is a much
> weaker endpoint. I think that is what Ellen is getting at.
>
> Whether this would have a lot of bearing on anything except
> drug-resistant pneumococcus is unclear in that example, but I mean I
> could think of other situations.
>
> I had a question. In the proposed criteria for resistant pathogens,
> No. 6, host effects, what sort of things were you guys thinking about
> in terms of the criteria?
>
> DR. COX: I think what we are talking about here are if we are looking
> to take data and use that to support another indication, if there were
> significant differences in host factors, say, for instance, one
> indication was in the study of immunocompromised patients, patients
> who were ventilated or other factors, I mean it would certainly seem
> reasonable to have some degree of reservation about extrapolating that
> data from a more immunosuppressed host to a less immunosuppressed
> host.
>
> So, I think that is sort of what we are trying to get at there and
> trying to characterize that, and we are looking for comment on that.
>
> DR. LEGGETT: Do you want to start, Alan?
>
> DR. CROSS: I am sorry, I am not sure I followed your comment. Are you
> saying or asking is it possible to extrapolate from a more compromised
> to a less compromised patient?
>
> DR. COX: What we are getting at is the host factors. If you had a more
> immunocompromised patient, it would seem reasonable to have some
> degree of hesitancy to extrapolate that data to a less
> immunocompromised host, so we are looking at this as sort of criteria
> that would allow us to assess whether one indication could support
> another one, and host factors seem to be important.
>
> So, yes, I mean I guess we are asking the question of in what
> situations would host factors give you hesitation to extrapolate data
> or not extrapolate, but using supportive data from one indication to
> support another indication.
>
> DR. POWERS: If a drug was indicated for febrile neutropenia, bacterial
> drug for febrile neutropenia, how good would that make you feel about
> hospital-acquired pneumonia in non-immunocompromised population?
>
> DR. CROSS: I will give you a different example. I see lots of patients
> who are neutropenic, who have VRE, so they have host defenses that are
> compromised, there are a bunch of other immunosuppressive drugs. If I
> have an agent that is effective in clearing the VRE in that patient, I
> would have no hesitation going in the other direction.
>
> DR. POWERS: But remember we are talking about a different indication.
> We are not talking about the same indication in neutropenic versus
> non-neutropenic. We are trying to extrapolate across different disease
> states.
>
> That is why I used the example of two different diseases all together,
> of empiric therapy for bacterial infections in neutropenic patients
> compared to some other completely different disease, not
> empiric\--well, you don\'t give empiric therapy to non-neutropenic
> patients.
>
> DR. LEGGETT: How about you grow Pseudomonas out of the bloodstream
> when you are neutropenic, and then you have got a normal host with a
> complicated skin and soft tissue infection, would that data, if you
> cleared that, would you like to hear that at this meeting?
>
> DR. CROSS: Yes, I would feel pretty comfortable with that because I
> know the importance, let\'s say, of neutrophils in Pseudomonas
> infections, and if it worked in the absence of it, I would think in
> someone who had it\--
>
> DR. POWERS: How about the other way around, complicated skin
> infections with Pseudomonas, and then referring that to the
> neutropenic compromised host?
>
> DR. CROSS: I wouldn\'t know what the contribution of the neutrophils
> is in that situation.
>
> DR. POWERS: So, there would be a directionality to this.
>
> DR. LEGGETT: What about Pseudomonas bacteremia from presumed GI tract
> in your neutropenic with no infiltrate to Pseudomonas pneumonia in a
> hospitalized patient who is not immunocompromised?
>
> DR. CROSS: I think as Jan pointed out, at least historically,
> Pseudomonas pneumonia with bacteremia is a horse of a completely
> different color.
>
> DR. LEGGETT: I don\'t think I would feel comfortable going from a
> neutropenic bacteremic patient no matter what\--unless it was the
> pneumonia, the source, to the lung in a non-compromised person.
>
> Barth.
>
> DR. RELLER: The issue is the enormous numbers of organisms and what
> you are asking the antibiotic to do. Maybe there is one place, not
> that this comes up very commonly even though it is occasionally seen,
> and that is the sort of stringency required for Pseudomonas
> meningitis, so if it worked in Pseudomonas meningitis, maybe you could
> have some benefit to the lung.
>
> John asked earlier, and I want to not miss the opportunity to be a
> little provocative on this one, you said what do we do when the data
> don\'t hang together in a package. Well, I would hope you would
> exercise your regulatory responsibility and consider the advisory
> committee exactly what the name says, advisory, and that you would
> give no broader indication than what the substantive scientific data
> allowed until additional information was forthcoming that would allow
> expansion of the indication as regards organism or site of infection.
>
> DR. LEGGETT: Are you implying a ruling committee or advisory
> committee?
>
> DR. RELLER: What I am saying is that the agency is privy to the entire
> package. I mean there are limitations to what any advisory committee,
> no matter what its composition and how hard they work and how
> carefully they think, can do in the course of a few hours relative to
> the detail that the agency is privy to. That is all I am saying.
>
> DR. LEGGETT: Beyond that, there is all the information that is not yet
> done when we are meeting, that comes up later, for instance, as well
> as all the stuff that went on before.
>
> One thing maybe to consider would be another\--well, I don\'t know if
> you guys can even do this\--but another venue to then get secondary
> feedback if more information comes in, but the package still doesn\'t
> look good, you know, without going through the whole process, is there
> any way of getting a \"second\" look or something like that, or what
> is the rules?
>
> DR. POWERS: Usually, we can bring it back here a second time.
>
> DR. LEGGETT: Are there any of these other criteria that you want to
> run through more at length?
>
> DR. POWERS: I think we can probably sum this up. It sounds like what
> we heard was that these seven criteria are pretty good, they need to
> be arranged in a certain way, putting the microbiology of the disease
> and the similar site up at the top as No. 1 and 2, and then we need to
> add an eighth criteria to this, to say that these studies need to be
> also of high quality and rigor.
>
> DR. LEGGETT: That is close. I will tell you the way I did it.
>
> No. 1 is the similarity in spectrum, which you guys have as 7. No. 2
> is the rigor of the trial. No. 3 is the similar site, and then it gets
> less. No. 4 is the characteristics, which you guys have as No. 3.
> Then, No. 5 is the similar\--sorry, I am getting lost because I
> numbered them again\--at some point, No. 5 or 6, or whatever the next
> number is, is your guys No. 2, the factors other than the
> antimicrobial.
>
> The final two, the next to the last would be the host effects, and the
> last one is the monomicrobial versus polymicrobial.
>
> Jan, you were the original re-arranger of the list.
>
> DR. PATTERSON: I think I had put No. 5 as No. 2, but I think the rigor
> of the trial is very important, so I think that is very important to
> have up there.
>
> **Summary**
>
> DR. LEGGETT: Any other comments by anyone? Okay.
>
> I think basically, this morning we heard about linkage of resistance
> determinants in bacteria and we looked at and basically didn\'t have
> much to say about a draft of criteria of listing pathogens of public
> health importance, so I think that means they are probably pretty
> close, and we heard an industry perspective.
>
> We spent lots of time discussing the criteria that was presented, but
> I think we came up with a little fundamental change and lots of
> tweaking that may or may not be useful. I think the FDA\'s list is
> coming close to being finished and the pathogens of priority further
> analyzed to get more data.
>
> This afternoon we heard about being sure to incorporate PK/PD concepts
> not only into the new drug approval process, but also in prioritizing
> the list of pathogens for targeting drug development, the complexities
> of relating clinical data from one disease state to the other, and
> then some, and how clinicians eventually try to make sense of the
> bug-drug host interactions in treating people after all the above is
> said and done and behind us.
>
> I think that you might want to draw upon your own clinical experiences
> as you guys start thinking about the clinical trials things, and
> thinking more the way we were talking there in real life, if you know
> the drug works against the bug in one situation, would you use it in
> another, and I think let reality sort of filter into regulation in
> terms of trying to come up with what you feel comfortable with.
>
> In the few minutes we had today, I don\'t think we spent enough time
> thinking about all the permutations of that.
>
> Anybody else have anything to say?
>
> \[No response.\]
>
> DR. LEGGETT: Thank you all for putting up with a long day. Tomorrow,
> we are going to start at 8:00. Thank you.
>
> \[Whereupon, the committee was adjourned at 4:05 p.m., to reconvene at
> 8:00 a.m., Thursday, March 6, 2003.\]
>
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