DEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **ANTI-INFECTIVE DRUGS ADVISORY**
>
> **COMMITTEE (AIDAC) MEETING**
>
> **Discussion of Issues Related to Clinical**
>
> **Trial Design and Analysis in Studying Bacteremia**
>
> **Due to Staphylococcus aureus and**
>
> **Catheter Related Bacteremia**
>
> Thursday, October 14, 2004
>
> 8:20 a.m.
>
> Hilton Gaithersburg
>
> The Ballroom
>
> 620 Perry Parkway
>
> Gaithersburg, Maryland
>
> PARTICIPANTS
>
> James E. Leggett, Jr., M.D., Chair
>
> Shalini Jain, PA-C, MBA, Executive Secretary
>
> MEMBERS
>
> Alan S. Cross, M.D.
>
> Celia J. Maxwell, M.D.
>
> Jan E. Patterson, M.D.
>
> Joan F. Hilton, Sc.D., MPH
>
> John S. Bradley, M.D.
>
> Donald M. Poretz, M.D.
>
> Samuel D. Maldonado, M.D., MPH
>
> (Industry Representative)
>
> John E. Edwards, Jr., M.D.
>
> CONSULTANTS, SPECIAL GOVERNMENT EMPLOYEES (VOTING)
>
> Thomas R. Fleming, Ph.D.
>
> Christopher A. Ohl, M.D.
>
> L. Barth Reller, M.D.
>
> Nathan M. Theilman, M.D., MPH
>
> CONSULTANT, FEDERAL EMPLOYEE (VOTING)
>
> Patrick R. Murray, Ph.D.
>
> FDA
>
> Mark Goldberger, M.D.
>
> Sumathi Nambiar, M.D.
>
> John H. Powers, M.D.
>
> Alfred Sorbello, D.O.
>
> Janice Soreth, M.D.
>
> [C O N T E N T S]{.underline}
>
> Call to Order and Opening Remarks:
>
> James E. Leggett, Jr., M.D. 5
>
> Conflict of Interest Statement:
>
> Shalini Jain, PA-C, MBA 8
>
> Opening Comments:
>
> Janice Soreth, M.D. 11
>
> Regulatory History of Bacteremia Indications:
>
> Alfred Sorbello, D.O. 23
>
> Questions from Committee 40
>
> Epidemiology of S. aureus Bacteremia:
>
> Sumathi Nambiar, M.D. 55
>
> Questions from Committee 74
>
> Microbiological Considerations in Diagnosing
>
> S. aureus Bacteremia:
>
> Patrick Murray, Ph.D. 82
>
> Questions from Committee 103
>
> Open Public Hearing\--Extra Session 109
>
> Francis P. Tally, M.D.,
>
> Cubist Pharmaceuticals Inc.
>
> Clinical Trials Issues with Studies of S. aureus
>
> Bacteremia:
>
> John H. Powers, M.D. 131
>
> Questions from Committee 173
>
> Open Public Hearing 208
>
> Tim Henkel, M.D., Ph.D., Vicuron
>
> Pharmaceuticals 209
>
> Charles Knirsch, M.D., MPH, Pfizer
>
> Pharmaceuticals 222
>
> [C O N T E N T S]{.underline} (Continued)
>
> David Shlaes M.D., Ph.D., Idenix

# Pharmaceuticals 242

> Issues in Studying Catheter-Related Bacteremia:
>
> Janice Pohlman, M.D. 247
>
> Questions from Committee 269
>
> Questions to Committee and Discussion 272
>
> Summary 366
>
> [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 and Opening Remarks**
>
> DR. LEGGETT: Good morning. Today we are gathered to discuss issues
> related to clinical-trial design and analysis in studying bacteremia
> due to Staphylococcus aureus as well as issues related to
> clinical-trial design or analysis in studying catheter-related
> bacteremia.
>
> It is going to be, I hope, not a terribly eventful day but eventful,
> nonetheless. I think that the problem that we are faced with, as
> clinicians, I faced on Friday when I was asked to see two patients,
> one a recently end-stage renal-disease patient with diabetes who has
> had three MRSA hemodialysis catheter infections since July when she
> started dialysis requiring the removal of the catheter and, at the
> same time, was called to see a patient because they had Gram-positive
> cocci in clusters from their one of two blood cultures and it turned
> out to be coagulate-negative Staph and who cared.
>
> So I think that is going to be sort of the crux of a lot of the
> problems today.
>
> To get started, why don\'t we go around the table and have everyone
> introduce themselves.
>
> DR. MAXWELL: I\'m Celia Maxwell, the Assistant Vice President for
> Health Sciences at Howard University, an adult infectious diseases
> specialist.
>
> DR. BRADLEY: I am John Bradley, Pediatric Infectious Diseases, from
> Children\'s Hospital in San Diego.
>
> DR. OHL: Chris Ohl, Section on Infectious Diseases, Wake Forest
> University School of Medicine.
>
> DR. HILTON: Joan Hilton. I am on the Biostatistics Faculty at
> University of California, San Francisco.
>
> DR. MURRAY: Pat Murray, Director of Microbiology at the NIH Clinical
> Center.
>
> DR. RELLER: Barth Reller, Division of Infectious Diseases and
> International Health and Director of Clinical Microbiology, Duke
> University Medical Center.
>
> DR. LEGGETT: Jim Leggett, Infectious Diseases, Providence Portland
> Medical Center and the Oregon Health and Sciences University.
>
> DR. CROSS: Alan Cross, Center for Vaccine Development, University of
> Maryland.
>
> DR. FLEMING: Thomas Fleming, Department of Biostatistics, University
> of Washington.
>
> DR. MALDONADO: Sam Maldonado, Global and Regulatory Affairs, Johnson &
> Johnson. I am the industry representative to this committee.
>
> DR. PATTERSON: Jan Patterson, Medicine Infectious Diseases, University
> of Texas Health Science Center, San Antonio and South Texas Veterans
> Healthcare System.
>
> DR. THEILMAN: Nathan Theilman, Division of Infectious Diseases and
> International Health, Duke University Medical Center.
>
> DR. PORETZ: Donald Poretz, Infectious Diseases in Fairfax, Virginia.
>
> DR. NAMBIAR: Sumathi Nambiar, Division of Anti-Infective Drug
> Products, FDA.
>
> DR. SORBELLO: Fred Sorbello, Medical Officer, FDA.
>
> DR. POWERS: John Powers, Lead Medical Officer for Antimicrobial Drug
> Development and Resistance Initiatives in ODE IV at FDA.
>
> DR. SORETH: Good morning. I am Janice Soreth, the Division Director
> for Anti-Infectives. Let me take the opportunity to introduce in
> absentia our Office Director, Dr. Mark Goldberger, who is on his way.
> But another person who is actually here and who directs a sister
> division, that of Special Pathogens and Immunologic Drugs which also
> regulates antibiotic development. That would be Dr. Renata Albrecht
> who sits behind me here.
>
> MS. JAIN: I am Shalini Jain, Executive Secretary for the
> Anti-Infective Drugs Advisory Committee.
>
> **Conflict of Interest Statement**
>
> MS. JAIN: Before we begin the meeting, I need to read a
> conflict-of-interest statement. The following announcement addresses
> the issue of conflict of interest issues associated with this meeting
> and is made a part of the record to preclude even the appearance of
> such.
>
> Based on the agenda, it has been determined that the topics of
> today\'s meeting are issues of broad applicability and there are no
> products being approved. Unlike issues before a committee in which a
> particular product is discussed, issues of broader applicability
> involve many industrial sponsors in academic institutions.
>
> All Special Government Employees have been screened for their
> financial interests as they may apply to the general topics at hand.
> To determine if any conflict of interest existed, the agency has
> reviewed the agenda and all relevant financial interests as reported
> by the meeting participants.
>
> The Food and Drug Administration has granted general-matters waivers
> to the Special Government Employees participating in this meeting who
> require a waiver until Title 18 United States Code Section 208. A copy
> of waiver statements may be obtained by submitted a written request to
> the agency\'s Freedom of Information Office, Room 12A-30 of the
> Parklawn Building.
>
> Because general topics impact so many entities, it is not practical to
> recite all potential conflicts of interest as they may apply to each
> member, consultant and guest speaker. FDA acknowledges that there may
> be potential conflicts of interest but, because of the general nature
> of the discussions before the committee, these potential conflicts are
> mitigated.
>
> With respect to FDA\'s invited industry representative, we would like
> to disclose that Dr. Samuel Maldonado is participating in this meeting
> as a non-voting industry representative acting on behalf of regulated
> industry. Dr. Maldonado\'s role on this committee is to represent
> industry interests in general and not any one particular company. Dr.
> Maldonado is employed by Johnson & Johnson.
>
> In the event that the discussions involve any other products or firms
> not already on the agenda for which FDA participants has 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 all persons making statements or presentations disclose
> any current or previous financial involvement with any firm whose
> products they may wish to comment upon.
>
> Thank you.
>
> DR. LEGGETT: Janice, would you like to start?
>
> **Opening Comments**
>
> DR. SORETH: Good morning, Dr. Leggett and special thanks for the
> academic quarter this morning, members of the advisory committee, FDA
> and industry colleagues and other members of the audience.
>
> (Slide.)
>
> I would like to begin today\'s talks by telling you what we are going
> to talk about today followed by actually talking about it, then
> summarizing what we already told you as a segue to the discussion. I
> promise we will finish before midnight.
>
> This is the story of blood and guidance going a bit bad, that of
> bacteremia as an indication.
>
> (Slide.)
>
> I am going to take us first through the District of Columbia,
> Rockville and White Oak\--you will understand what I mean in just a
> moment\--followed by a tour, very briefly, of Hollywood, the
> Washington Redskins, the NHL lockout, Monday morning
> quarterbacking\--that would be the discussion period\--and wrapping up
> with credits. I promise you I have not yet lost my mind.
>
> (Slide.)
>
> We are back in the District of Columbia. It is pre-1965. I am in
> second grade. We have been talking about bacteremia, sepsis,
> bacteremic sepsis, septicemia, primary bacteremia and secondary
> bacteremia for a long, long time, ever since the FDA was solely
> located in the District.
>
> As far as the Org chart goes back then, and this is all oral history,
> we were the Bureau of Biological and Physical Sciences, the Division
> of Pharmacology and we were a branch, I think, of Antibiotics. As I
> said, my knowledge of this era is entirely derivative.
>
> (Slide.)
>
> Let\'s fast-forward to Rockville of the \'70s and the \'80s where the
> language for bacteremia and septicemia began to make it into package
> inserts. We will hear more about this historical framework and its
> details through to the 1990s and the present from Dr. Fred Sorbello
> this morning.
>
> The Org chart was changing. We were becoming the Bureau of Biological
> and Physical Sciences, Division of Pharmacology to the Bureau of Drugs
> and Biologics, Division of Anti-Infective and, finally, the Center for
> Drug Evaluation and Research. I realize only now I forgot to put
> Crystal City on there because, once we went from the District, we went
> to Crystal City which is in Virginia and then, ultimately, to
> Rockville and Gaithersburg, which is where we are now.
>
> The Division was morphing at the same time. It was growing. Back in
> the \'70s and \'80s, we were the Division of Anti-Infectives. We were
> one entity that took care of regulation of antibiotics,
> anti-infectives, anti-parasitics, topical antiseptics, dermatologics,
> ophthalmologics, anti-fungals, T.B. drugs and antivirals. I am sure I
> left something out. Let me know at the break.
>
> There was a split, then, that happened in the latter \'80s. I think it
> was about \'88 when the development of HIV therapies took off, as it
> should. So we split and became the Division of Antiviral Drugs as well
> as the Division of Anti-Infectives. The Antiviral therapies together
> with the Antifungals and the TB drugs, then, went to the Division of
> Antivirals.
>
> This is the late \'80\'s, early \'90\'s.
>
> (Slide.)
>
> By the time we hit mid-\'90\'s, maybe about 1996, we, as two
> divisions, were large again. Portfolios were growing. So we decided to
> morph at that point into a third division. So the Ur-Division, as I
> like to call it, of Anti-Infectives then became Anti-Infectives,
> Antivirals and Special Pathogens and Immunologic Drug Products
> directed by Dr. Renata Albrecht.
>
> The portfolio from Anti-Infectives of quinolones split off to Special
> Pathogens. I believe chronic fatigue and AIDS wasting type of drugs
> and transplant products and antifungals and antiparasitics also went
> to Special Pathogens.
>
> So we are now three divisions under the leadership of Dr. Mark
> Goldberger. It is pertinent\--the background is pertinent to today
> because the topics really touch all of us within the office and
> particularly Anti-Infectives and Special Pathogens. We need to be
> careful as we write the music that we sing from the same sheet of
> music.
>
> I think more on the history of what we have struggled with as a word,
> bacteremia, septicemia, will be discussed later today not only by Dr.
> Fred Sorbello but also, in terms of clinical-trial design
> considerations by Dr. John Powers, by Dr. Janice Pohlman as well as
> Dr. Sumathi Nambiar.
>
> (Slide.)
>
> As to the future, we are moving in 2005, we are told, to White Oak.
> Shalini, correct me if I am wrong, but I think all that AC meetings
> will take place there.
>
> MS. JAIN: Actually no. They won\'t be able to actually accommodate the
> size.
>
> DR. SORETH: Wonderful. Okay. To be determined later. Shalini was just
> saying that we won\'t necessarily have the AC meetings at White Oak.
> It is our combined campus, a dream that we have maintained at FDA for
> a long, long time. Some would say a nightmare, but whatever. It is off
> New Hampshire around the Beltway for Washingtonians.
>
> This is the laboratory building. Our building is off to that side. I
> am a little challenged directionally. I would submit to you that we
> sincerely hope to have the guidance in this arena tucked away by the
> time we move to White Oak. So, see, we have a challenge.
>
> (Slide.)
>
> Hollywood, where we are told nothing is impossible, where every
> scientist should remove the word \"impossible\" from his lexicon.
> Christopher Reeve. Nothing is impossible.
>
> (Slide.)
>
> Except maybe when it comes to the breakdown of skin, invasion of the
> blood stream and infection of the patient followed by cardiac arrest,
> heart failure, coma and death, for Superman was no match for a
> bloodstream infection.
>
> (Slide.)
>
> I think our meeting today will highlight that it takes extraordinary
> individuals to recognize that investment and effort in the discovery
> of new antibiotics and in the treatments for serious infections, like
> Staphylococcus aureus bacteremia, are indeed worth it in the long run.
> And I know that some of these extraordinary individuals are in this
> room today.
>
> They are prescribing physicians. They are academicians. They are
> industry colleagues. They are FDA colleagues. They are support staff
> all of whom have, at heart, the same mission.
>
> (Slide.)
>
> So what do the Skins have to do with this? Well, you have to ask
> yourself the question what do Joe Gibbs, who is the Head Coach of the
> Washington Redskins, and the FDA have in common? I will preface my
> comments by saying I am a die-hard Eagles fan but it is not why I say
> this.
>
> Just like Joe Gibbs, we thought we had put all the right pieces
> together on the team with the catheter-related blood-stream infection
> guidance. That is 1999 and Dr. Janice Pohlman will tell us a lot more
> about that later today. And, just like Joe Gibbs, we watched as the
> monster just wouldn\'t get up.
>
> (Slide.)
>
> We discussed the catheter-related blood-stream infection guidance
> hereafter known as CRBSI at a 1999 advisory committee meeting. Most of
> you were probably not here then because we had a different committee
> there. But I know Dr. Barth Reller was there. The U.S. stats would
> tell us that roughly there are 200,000 or 400,000 episodes per year.
> We should be able to study it.
>
> Mortality attributable somewhere between 10, 25 percent; we thought a
> definable case definition\--we thought. Lo and behold, sponsors, many
> of them, now tell us there are numerous reasons why they have hit the
> boards. But I would ask, don\'t blame it on my heart; blame it on my
> youth.
>
> (Slide.)
>
> The NHL lockout is pertinent here because success, beyond being tied
> to this year\'s salary cap, is determined not by knowing where the
> puck is, rather knowing where the puck is going to be, which is
> sometimes, maybe often, unpredictable which is probably why they
> don\'t want a salary cap in the first place. But the increasing
> incidence of Staph aureus bacteremia paralleled by a rise in infective
> endocarditis, I think, foreshadows where major players need to
> position themselves to win, to develop effective therapies whose
> risk/benefit ratio we think we understand so that, ultimately,
> patients and their prescribing physicians can benefit from this.
>
> (Slide.)
>
> The issues for discussion are many. Dr. John Powers will cover these
> in great detail. I have made some excerpts and highlights from his
> talk that will come later today. But I want you to bear them in mind
> as you go through today\'s discussions and talks. Should primary
> bacteremia due to Staph aureus, PBSA, be an indication? And what
> exactly would a healthy development program look like? What patient
> populations would be included in such a program?
>
> And, just as importantly, would there be populations that should be
> excluded, because we are not really sure they have an infection? Do
> they have a lab finding? Should endocarditis due to Staph aureus be a
> separate indication?
>
> (Slide.)
>
> More issues for discussion. Should we grant a separate
> catheter-related blood-stream infection indication in its own right?
> Does it have merit? Does it lack merit? Or, do we fold it into a more
> general clinical-trial experience and product label under the rubric
> of primary bacteremia due to Staph aureus or under the rubric of
> complicated skin infections?
>
> If we go the separate way, what additional information would you
> suggest be collected before, or while, treating other serious Staph
> aureus infections?
>
> (Slide.)
>
> Finally, what role do preclinical and early clinical studies play in
> setting the stage for faster, larger clinical trials? We are cognizant
> of the fact that, in many ways, in drug development, as in life, time
> and money are our enemies. We sweat the small stuff and we ask you
> today to do the same.
>
> How many positive blood cultures are required prior to entry into a
> primary bacteremia due to Staph aureus clinical trial?
>
> (Slide.)
>
> Last, screening patients for admission into these clinical trials
> appears to be complicated. Do you have any thoughts or advice for us
> as to a general approach?
>
> (Slide.)
>
> I would like to thank Shalini Jain, our Exec Sec contact and organizer
> for today\'s meeting who answered numerous phone calls, E-mails and
> cell-phone calls way later than anyone should have made them, myself
> included; our Office Director, Mark Goldberger; John Powers; Ed Cox:
> and Leo Chan; and, at the Division level, my ever supportive reliable
> deputy, Lilian Gravrilovich and members of the division, Sumathi
> Nambiar, Janice Pohlman and Fred Sorbello.
>
> I will stop there and turn the podium back over to Dr. Leggett.
>
> DR. LEGGETT: Thank you.
>
> Let\'s move on to the Regulatory History of Bacteremia Indications
> which will be done by Dr. Sorbello.
>
> **Regulatory History of Bacteremia Indications**
>
> DR. SORBELLO: Good morning. I am Fred Sorbello, Medical Officer at the
> Division of Anti-Infective Drug Products at FDA.
>
> (Slide.)
>
> My presentation today will focus on the regulatory history of
> bacteremia and some of the early regulatory history of
> catheter-related blood-stream infections as labeled blood-stream
> infection indications.
>
> (Slide.)
>
> I wanted to start with an historical time line to help to focus a
> little bit on the history of the development of this whole issue from
> a regulatory perspective. It really began prior to 1992, 1993. As Dr.
> Soreth had described, there were various types of terminology that
> were being used in the setting of labeling for blood-stream
> infections.
>
> In 1992, the FDA developed a document called Points to Consider. This
> was a very important document because it was designed to assist
> investigators on how to formulate drug-development plans for infective
> agents. Since that time, there have been several anti-infective drug
> advisory committee meeting where the issue has been discussed,
> including 1993, 1998 and 1999 and, obviously, at the meeting today.
>
> (Slide.)
>
> Just to give you a little bit of a perspective on the terminology that
> has been used for blood-stream infections in antimicrobial, I just
> have a chart to kind of compare the historical terminology versus what
> is used currently. Historically, labels would include terms such as
> bacteremia or septicemia or bacteremia/septicemia, bacterial
> septicemia or septicemia (including bacteremia.)
>
> Today, what is used currently is terminology that is in accordance
> with the Points to Consider document which is basically site-specific
> indications with bacteremia included if bacteremic patients were
> involved and assessed adequately within the particular trials.
>
> To give you a little more perspective on the labeling indications
> prior to 1992, 1993, the terms \"bacteremia\" and \"septicemia\" were
> those that were used most commonly. These were defined as infections
> that were accompanied by certain types of laboratory criteria.
>
> Bacteremia related to the evidence of one positive blood culture,
> septicemia with two positive blood cultures. It is important to note
> that, at that time, there were no specific clinical-trial protocols
> that were really relevant to those indications. The data was derived
> by pooling data on bacteremic patients from trials that involved
> different sites of infection; for example, trials that might have
> looked at pneumonia or urinary-tract infections where bacteremic
> patients may have been enrolled.
>
> Also the clinical context was bit varied in that patients with either
> transient bacteremias or, as I mentioned, bacteremias where there may
> be an identifiable focus or even bacteremias of unknown origin could
> have been included amongst this pooled data.
>
> (Slide.)
>
> 1992, Points to Consider, a very critical document that was developed.
> Again, it did contain relevant information on the agency\'s
> perspective on specific indications for anti-infective drugs. It
> really was an attempt to recognize that different types of infections
> had different pathophysiology.
>
> The way labeled indications were indicated was they were referred to
> as the treatment of an infection at a specific body site due to a
> specified susceptible microorganism. Drug-development guidelines were
> provided with the document so that accurate information could be
> complied on both the efficacy and safety of the drug and that
> information could later be described in product labeling.
>
> (Slide.)
>
> The 1993 Anti-Infective Drug Advisory Committee focused a bit on this
> issue of bacteremia in the setting of two issues. Number one, the
> consensus document developed by the American College of Chest
> Physicians and the Society of Critical Care Medicine where definitions
> were published regarding terms such as sepsis and multi-organ failure.
> In addition, a pharmaceutical sponsor had proposed a new indication
> termed bacteremic sepsis in an attempt to try to both add some
> specificity and clarify some of the previous terminology in order to
> do a particular drug-development study. The definition of bacteremic
> sepsis included some of the material from the consensus document.
>
> (Slide.)
>
> Just to review briefly the consensus-document definitions, infection
> was described as a microbial phenomenon characterized by an
> inflammatory response to the presence of microorganisms or the
> invasion or normally sterile host tissue by those organisms.
>
> Bacteremia was defined as a laboratory finding associated with the
> presence of viable bacteremia in the blood. The systemic inflammatory
> response was a response that can occur with a multitude of clinical
> entities and it was basically manifested by two or more of the
> criteria that were listed which was temperature greater than 30
> degrees C or less than 36 degrees C, an elevated heart rate of greater
> than 90 beats per minute, respiratory rate greater than 20 beats per
> minute or a PA-CO2 of less than 32, an elevated white count of 12,000
> or a low white-blood count of less than 4,000 or 10 percent bands.
>
> Sepsis, then, was defined as an infected patient who exhibited a
> systemic inflammatory response.
>
> (Slide.)
>
> This is a Venn diagram which is adapted from the paper in Critical
> Care Medicine which described the consensus document in the
> definitions. But it was an attempt to try to show how some of these
> concepts merge, again illustrating that there is a large focus of
> infected patients and some of those patients will exhibit a systemic
> inflammatory response syndrome. Those that do are considered septic.
>
> Bacteremia essentially refers to the laboratory finding of bacteremia
> in a blood culture. Again, just keep in mind that there can be other
> non-infectious causes that can produce a systemic inflammatory
> response including burns, ischemia, pancreatitis and others.
>
> (Slide.)
>
> So, getting back to bacteremic sepsis with the consensus definitions
> and concepts in mind, bacteremic sepsis was defined at the time as
> SIRS, systemic inflammatory response syndrome, due to an infection
> that was associated with positive blood cultures but was without
> hypotension, hypoperfusion or any evidence of organ dysfunction.
>
> The definition implied, but it didn\'t state, that the patient would
> have an identifiable focus of infection. Now, when this concept was
> discussed by the 1993 Anti-Infective Drug Advisory Committee, there
> were a number of issues that were reviewed. I am just going to mention
> some of them here at this point.
>
> One is bacteremic sepsis really a clinically meaningful entity. Could
> we, really, on a clinical basis, identify patients who had that
> entity. Number two, there were concerns that the population would be
> rather heterogeneous because you might be looking at patients with
> different types of underlying diseases, different states of
> immunosuppression, immunocompetence, for instance.
>
> Positive blood cultures; it was certainly felt that they do add
> confirmation and specificity in identifying an infecting organism but
> there was some discussion about whether positive blood cultures could,
> in some way, be a marker of prognosis.
>
> Another issue was the efficacy of a drug in treating a blood-stream
> infection and whether it would be possible to extrapolate the efficacy
> in clearing a blood-stream infection to being comparable effective in
> treating an infection that is, for example, deep within a certain body
> tissue or site that might be the source for that bacteremia.
>
> (Slide.)
>
> So, amongst the discussion at the time in 1993, it was felt that the
> terms bacteremia and septicemia as had been used lacked specificity of
> definition. Again, there were concerns about the patient populations
> that would be studied. There were concerns about the whole concept of
> pooling data from various sites of origin, effective origin for
> bacteremias and, lastly, whether or not it would be possible on a
> clinical basis to actually identify a person who had sepsis infection
> with a systemic inflammatory response who would have a positive blood
> culture versus those who would have clinical findings without a
> positive blood culture, was it really clinically meaningful and could
> it be identified on the clinical basis.
>
> (Slide.)
>
> The recommendations from the Anti-Infective Drug Advisory Committee at
> the time in \'93 was, again, to focus labeling related to the site of
> infection, site-specific labeling as had been described through the
> Points to Consider Document and then including bacteremia within that
> context if it was applicable rather than using terms such as
> bacteremia or bacteremic sepsis.
>
> (Slide.)
>
> Now over the following five years, there were no new drugs that had
> been approved with the indication of bacteremia. But bacteremia and
> this whole concept of blood-stream-infection indications resurfaced
> again back in 1998 at the Anti-Infective Drug Advisory Committee.
>
> In particular, the main topic referred to catheter-related
> blood-stream infections. The issues that brought the issue up for
> discussion included the observed rising incidence of bacteremia due to
> resistant Gram-positive bacteria in particular, the increased
> incidence that was noted of intravenous catheter-related bacteremia
> and well as bacteremia without an identifiable focus and the whole
> concept of how to really utilize data from bacteremic patients in
> order to analyze and supplement clinical-trials data since there were
> really no clinical trials directly developed with protocols to look at
> bacteremia specifically.
>
> (Slide.)
>
> Regarding the issue of bacteremia as an indication, the committee
> reaffirmed, again, using the concept of site-specific labeling for
> secondary bacteremias but also had some discussion about the concept
> of a primary bacteremia as a potential new indication and a fair
> amount of discussion focusing, again, on catheter-related blood-stream
> infections, catheter-related blood-stream bacteremias as a focus for
> future studies and potentially an area for future drug development.
>
> (Slide.)
>
> To give some follow up regarding the committee\'s thoughts on
> catheter-related blood-stream infections, the issues, again, of the
> increased incidence of those types of infections that were noted, the
> problems of growing antimicrobial resistance and also the limited
> antimicrobial armamentarium that would be available for treatment, but
> also the lack of the controlled clinical trials for drug development
> for agents to treat path-related blood-stream infections.
>
> There were a number of topics that were discussed including issues of
> what types of criteria should there be for catheter removal, what
> types of both clinical and microbiologic criteria should be
> considered, the number and the source of blood cultures for this
> potential indication as well as what types of laboratory studies might
> be considered to verify concordance of blood culture and catheter
> culture isolates such as DNA subtyping was discussed for
> Staphylococcus epidermidis.
>
> (Slide.)
>
> So, following the Anti-Infective Drug Advisory Committee meeting in
> \'98, a working group was formulated at FDA, the CRBSI Working Group,
> and a draft guidance was developed regarding drug development for
> catheter-related blood-stream infections. This guidance was then
> presented the following year at the 1999 Anti-Infective Drug Advisory
> Committee meeting.
>
> (Slide.)
>
> There was extensive discussion about the draft guidance and a number
> of issues were mentioned. I just wanted to point out some of these
> discussion issues because I think they are very pertinent to today\'s
> discussion and a number of them are, as yet, undefined and not clearly
> resolved.
>
> Number one was the issue of a heterogenous patient population, again
> the concept that, looking at catheter-related blood-stream infections
> you would potentially be looking at a large population of patients,
> different types of underlying diseases, different types of catheters,
> tunnel/non-tunnel, short-term/long-term, and a whole variety of
> potentially causative microorganisms.
>
> Number two was the sample size that might be required. Again, the
> thought was it may require a number of patients to screen to actually
> identify those who were felt to have a catheter-related blood-stream
> infection. In particular, there were concerns, and in studies such as
> this, it would be important to get catheter data, if catheters are
> indwelling in the patient and what is more frequently done is they are
> just pulled and discarded without being cultured, the lack of catheter
> data may be a limiting finding.
>
> The other issue is the concept of doing microbiologic evaluation and
> test-of-cure; is it necessary, what situations would it be necessary
> and would the lack of test-of-cure microdata, again, limit evaluation
> of this type of a study.
>
> There were also concerns about the lack of a standardized disease
> definition for catheter-related blood-stream infection and also the
> lack of demonstrable treatment effect for certain types of organisms,
> especially organisms that are low virulence that are associated with
> skin sites such as coag-negative Staph, Bacillus, Corynebacterium,
> some of those types of bacteria.
>
> (Slide.)
>
> Another main area was the lack of standardized procedures as to how to
> manage an infected catheter. It was recognized that there was
> basically a lack of standard criteria to provide proof of a catheter
> infection, should the types of cultures be catheter-drawn and
> peripherally blood-drawn blood cultures, should it be based on two
> blood cultures, should it be based on quantitative catheter tips, hub
> cultures. A number of different options were discussed without any
> apparent consensus.
>
> The other issue is, in management, what would be the criteria to
> remove the catheter since it was recognized that patients can have
> different types of catheters that can be in for different periods of
> time and also you can have different infecting microorganisms as there
> was some discussion of organisms such as Staphylococcus epidermidis
> that may not always require removal of the catheter. Again, what types
> of criteria should be thought about in trying to address the
> catheter-removal issue.
>
> (Slide.)
>
> Last, microbiological issues that were discussed and I alluded to
> these a little bit. Number one, the issue of quantitative blood
> cultures and the fact that they are rather limited in their
> availability. Most hospitals are not able to do quantitative blood
> cultures and what would be some other options to take a look at. One
> that was mentioned was the possibility of looking at differential
> blood-culture time-to-positivity.
>
> Again, concordance of catheter and blood-culture isolates, what type
> of catheter-related isolates would be felt to be valid and how would
> it be possible to document that there would be concordance and, again,
> certain types of coagulase-negative Staph would probably be organisms
> where that would be an important issue.
>
> As I alluded to previously the concept of test-of-cure blood cultures;
> do you need to do a test-of-cure blood culture in someone who studied
> in the context of the clinical trial for a catheter-related
> blood-stream infection. If the patient is well and stable and doing
> fine, is that really a requirement or should it be reserved basically
> as a secondary endpoint for patients where the catheter is retained
> and they are basically treated through.
>
> (Slide.)
>
> So, in summary, I have tried to summarize for you the regulatory
> history of bacteremia and some of the early developmental history
> regarding catheter-related blood-stream infections. I have tried to
> hit on some points such as the revisions and the changes that have
> occurred in terminology that has been used in labeling, the Points to
> Consider document which has the label-indication concept as basically
> what is employed currently and some of the multiple issues that have
> been discussed at previous Anti-Infective Drug Advisory Committees in
> attempting to discuss and grapple with a lot of the issues about how
> to study bacteremia, catheter-related infections and what some of the
> appropriate criteria will be.
>
> This afternoon, Dr. Janice Pohlman is going to provide some additional
> historical and current perspectives on catheter-related blood-stream
> infections, in much greater detail provide more recent information to
> you.
>
> Thank you for your attention.
>
> DR. LEGGETT: Thank you, Dr. Sorbello.
>
> **Questions from Committee**
>
> Does anyone have any questions? Don?
>
> DR. PORETZ: I imagine that the majority of these patients are
> hospitalized but not all of them. There are certainly plenty of
> patients who have cultures obtained on an outpatient basis and are
> treated on an outpatient basis. But, if a patient is in the hospital,
> when they are discharged, the diagnoses are put on the front of the
> chart and coded. Is that information accurate many times and who has
> access to that information, and when you are trying to figure out the
> total number of these patients, is there a central way that
> information is gathered? Can you explain that me?
>
> DR. SORBELLO: I don\'t know that there would be a central clearing
> house or anything for that type of information.
>
> DR. PORETZ: Does anyone know?
>
> DR. SORBELLO: I don\'t know.
>
> DR. POWERS: Are you asking about ICD9 codes and their use in
> diagnosis?
>
> DR. PORETZ: Yes, essentially. Where does that information\--does it
> get entered somewhere?
>
> DR. POWERS: In terms of for us to use, the FDA to use?
>
> DR. PORETZ: Central reporting group.
>
> DR. POWERS: No; we have actually gone\--Janice, you may want to add to
> this, but we have actually had to go and actually pay to get that data
> from people like large HMOs and other folks to be able to actually
> collate that information. However, the CDC has done some studies on
> the accuracy or lack of accuracy with some of these diagnoses.
>
> The probably with ICD9 codes is they are used for billing and people
> often code them in terms of the highest amount that they can bill for
> so that the accuracy sometimes is not 100 percent, certainly not to
> the level, the specificity, we would like in terms of enrolling people
> in a clinical trial.
>
> Janice, do you want to add something?
>
> DR. POHLMAN: You know, I did look into this and was going to speak to
> this a little bit in the afternoon, but I think largely the numbers
> that are in the literature, you know, you get this wide range\--I
> tried to look for the ICD9 codes or, I guess, we are heading towards
> ICD10. It is really hard to\--they are not coded specifically for
> that. A lot of the numbers come from nosocomial surveillance systems
> that actually may miss patients that are treated in an outpatient
> arena as some of these patients don\'t even get hospitalized when the
> bacteremia is discovered as well as patients that\--some of the
> surveillance systems will just pick up\--it depends on how the
> hospital is doing surveillance on whether or not they are doing
> non-critical-care units. It may just be they are getting critical-care
> numbers so the estimates are really subject to a lot of variation.
>
> DR. LEGGETT: Alan?
>
> DR. CROSS: At one point, the arguments in the infectious-disease
> community were really on, for example, the length of therapy for Staph
> aureus bacteremia based on whether or not there was either a
> non-removable or removable focus. It sounds like, going through your
> discussion, that really was never a viable discussion.
>
> I think if one thinks back on that type of discussion, obviously
> catheter-related infections would be a subset of removable foci. On
> the other hand, the nonremovable focus would encompass Staph aureus
> bacteremia of a multitude of primary foci, whether it was from the
> skin, the urine or elsewhere.
>
> That has never entered into any of the discussions, it sounds like.
>
> DR. SORBELLO: There had been some discussions about treatment although
> there was not a great focus on duration of treatment. I think part of
> that was because of the discussion about how do you really manage the
> catheter? Who do you identify and can you identify some type of
> uniform guidelines of who has a catheter removed, what kind of
> catheters remain; is it related to the type of organism; do you treat
> them differently if you keep the catheter in versus you take the
> catheter out.
>
> So it had been discussed but I think it was kind of folded into some
> of the other more structural constructs of how to really go about
> formulating some type of, if you could, a uniform management guideline
> for catheters.
>
> DR. CROSS: But, looking at the other end of it, though, of the
> nonremovable foci, it sounds like a discussion of the origin of the
> bacteremia seemed to make a difference in terms of the
> recommendations. I don\'t know whether there is any data presented at
> those meetings to actually support that point of view.
>
> DR. SORBELLO: Not specific data that I remember from the transcripts
> but, again, the previous Anti-Infective Drug Advisory Committees felt,
> overall, that going with site-specific indications and then tying the
> terminology of bacteremia to an identifiable focus was most
> appropriate for labeling.
>
> I think part of grappling with catheter-related infections was there
> was really no standardized uniform accepted definition of what a
> catheter-related infection was let alone best management because
> everybody has somewhat of a different way to kind of tailor their
> approach, again depending on the organism, the type of catheter, the
> type of patient.
>
> So I think treatment is an extremely important aspect of all this and
> I think it really folds in as a very important aspect of management.
> But I think some of the other constructs of actually how to put the
> clinical trial together and develop a population appeared to be
> somewhat more of a priority in the prior discussions.
>
> DR. LEGGETT: It has also been a moving target looking at the new drugs
> we have looked at that are treating five days for pneumonia, et
> cetera.
>
> Chris?
>
> DR. OHL: Could you outline how the discussions went parallel to all
> of\--in this time line related to endocarditis and diagnosis of
> endocarditis for trials?
>
> DR. SORBELLO: Actually, there was not much discussed regarding
> endocarditis at the prior Anti-Infective Drug Advisory Committee
> meetings as far as criteria for a clinical trial, criteria for
> labeling. There was not really an in-depth discussion about that.
>
> As I say, the \'93 Anti-Infective Drug Advisory Committee meeting was
> basically grappling with the new definitions that were published of
> how do you define what sepsis is, how do you fit that in to the
> clinical setting and how do you tie that in, then, to the labeled
> indications that were used at the time which were bacteremia and
> septicemia where there was still a lot of confusion and discussion
> about whether they are specific enough and appropriate enough for a
> label.
>
> But there was not really an in-depth discussion about endocarditis as
> an indication.
>
> DR. LEGGETT: Jan?
>
> DR. PATTERSON: I wonder if you could clarify for me what we mean when
> we say primary bacteremia because, as a hospital epidemiologist, in
> doing nosocomial infection surveillance, when we look for
> catheter-related infections, we want to make sure that there is not
> another identifiable site so that it is not a secondary infection.
>
> So we call it a catheter-related infection and sometimes we even use
> the term primary bacteremia. With Staph aureus, as clinicians, we very
> often find a source, whether it is endocarditis or an abscess or the
> catheter. So I am just wondering if you could clarify for me what we
> mean by primary bacteremia versus catheter-related.
>
> DR. SORBELLO: The context that those terms were used in the historical
> setting was the primary bacteremia either referred to the patient with
> endocarditis or the catheter-related infection and that bacteremias,
> secondary bacteremias, were where you had some other identifiable
> focus, whether it was along with the urinary tract or whatever.
>
> But primary bacteremia in the historical sense here was used either in
> the setting of endocarditis or catheter-related.
>
> DR. LEGGETT: Barth?
>
> DR. RELLER: I have had the great privilege of actually, I think, being
> at every one of the meetings that Dr. Sorbello\--and the comment that
> I wanted to make was that he has done a masterful and accurate capture
> of the essence of that decade.
>
> I think history is very important if we are to learn from it. And a
> few additions. Dr. Cross brought up the question of role of removal.
> In fact, that has been discussed because\--not that the answers are
> in, but the discussion, because the recognition that removal is of
> varying degrees of facility in importance in the outcome but must be
> considered and that was captured here; that is, whether it is a
> peripheral catheter, indwelling, tunneled, et cetera, and also the
> organism and the interplay between the organism so that a catheter
> that has Candida or Bacillus or a coagulase-negative Staph, the
> actions may be quite different based on recognized outcome.
>
> Dr. Ohl\'s query about endocarditis; one of the hesitancies, the
> caution, about an indication for catheter-associated bacteremia or
> that the organism makes a huge difference and the recognition that
> particularly\--not exclusively but particularly\--with Staph aureus,
> the specter of endocarditis which is a segue to Dr. Patterson\'s
> comment of usually finding a source if the source is endocarditis but
> also grappling with the reality that I am sure will be more discussion
> today when there is Staphylococcal bacteremia, is the source
> endocarditis or is endocarditis a consequence, one of the many
> consequences, of the bacteremia regardless of what the initiating
> source was.
>
> So one gets into a chicken-egg phenomenon and the organism, the
> source, the relative role of removal, the kind of intervention,
> drainage, removal, extirpation in terms of valve replacement, that
> these things are incredibly complicated.
>
> Again, for starting points, as Dr. Sorbello said, I mean it is a very
> complicated history but it is a complicated topic and he has really
> captured the main points. Some of these other things that have come
> up, it is not that they were ignored during the time but it is one of
> the reasons that the end conclusions were reached at the different
> points sequentially because, clearly, the patient population and the
> options have also evolved, I mean whether the patient is
> granulocytopenic and the chemotherapy and the kinds of catheters and
> the spectrum or organisms and the resistance mechanism\--I mean, it is
> a very different world in 2004 from 1992.
>
> The last thing, very briefly, is I was not in second grade in 1965
> like Janice Soreth. On the other hand, I was not on the committee in
> 1965. (Laughter.)
>
> DR. LEGGETT: Tom and then John and then, unless there is anything
> really urgent, let\'s move on.
>
> DR. FLEMING: Fred, back on your Slide 12, I had a follow-up question
> that was related to Jan\'s question. Basically, on Slide 12 is you are
> referring to catheter-related BSI. You have noted in that
> second-to-the-last point that we have got catheter-related bacteremia
> and bacteremia with unknown source.
>
> It is my understanding that your guidance document for CRBSI focuses
> exclusively on the former while, when we are going to go on this
> afternoon and talk about PBSA, will be inclusive to both. Is that
> correct?
>
> DR. SORBELLO: Yes, because there was discussion, actually, at the \'98
> Anti-Infective Drug Advisory Committee as to whether some proportion
> of the patients who have an unidentifiable focus but have catheters in
> place could actually have been catheter-related. So there was a fair
> amount of discussion about that and how to really view them and how to
> consider them within the total spectrum.
>
> DR. LEGGETT: John?
>
> DR. BRADLEY: In stepping back for a moment and looking at some of the
> questions that Dr. Soreth had asked at the very beginning, in trying
> to get a protocol with inclusion and exclusion criteria that will
> work, the whole issue of the patient who has a fever and looks
> bacteremic is one that I think is an even more important issue than
> drilling down to how many blood cultures because that defines a small
> sub-segment of those who look bacteremic.
>
> Rule out sepsis is a very common admitting diagnosis in pediatrics,
> certainly, and probably in the adult world as well so, to me, one of
> the biggest hurdles is to try and figure out empiric therapy for
> bacteremic disease, suspect bacteremic disease, and then contrast that
> with how we are going to define the treatment, the drugs, the
> duration, for documented infection whether it be with the catheter in,
> with the catheter out, with endocarditis, without endocarditis.
>
> So the approach to empiric therapy, to the septic patient, I think, is
> a huge program and, in the April of 2004 hearing, the details of one
> of the pharmaceutical companies trying to study this, it is clear that
> we need to further define what empiric operational definitions we can
> use so that we can enrich for evaluable patients.
>
> The critical-care community with I.D. and pulmonary and surgical help
> made the first attempt to define SIRS and the septic patient. They
> were unhappy with their definitions. They are in the process of
> redefining them. Three weeks ago in Boston, a group of us got together
> to try and redefine what is the septic patient because they all look
> septic. You just don\'t know which ones are actually infected or not.
>
> As you had said, Jim, it is a moving target so those definitions from
> 1992 have been changed for adults. We are changing them for kids. We
> are not the only ones that want to study the septic patient. There are
> biologics, pressers, all sorts of other people who are with us in
> trying to get our arms around what is this patient and what is the
> underlying process and how can we study it.
>
> DR. LEGGETT: Celia?
>
> DR. MAXWELL: Just one brief question on Slide 16. While I know that a
> large sample-size requirement would be an issue, was there any
> speculation as to what kind of a sample size you would need to begin
> to answer the question?
>
> DR. SORBELLO: An actual numerical sample size was not something that
> was directly discussed, but I think the core issue really regarding
> sample size is how do you define a catheter-related blood-stream
> infection, what criteria do you need to make that identification and,
> again, if you are dealing with a clinical study where there may not be
> uniformity in capturing catheter data because catheters are pulled and
> discarded without being cultured or there are not exit-site cultures
> done, et cetera, you are losing a major piece of information, at least
> microbiologic information, that is needed to properly do the study.
>
> So I think the size of the sample really dovetails with how you define
> it and what your criteria are to prove it, that it actually is a
> catheter-related blood-stream infection. I think that tends to
> restrict the number of patients that can be enrolled because there are
> some rather strict microbiologic data that needs to be collected to do
> that.
>
> DR. LEGGETT: Thank you, Dr. Sorbello.
>
> Janice, before we go on?
>
> DR. SORETH: Just a quick comment to follow up on Celia\'s point. I
> think we are going to hear more about this from the companies who are
> going to speak in the Open Public Hearing setting with regard to their
> experience with trying to do the trial, the number of patients
> screened versus the number of patients evaluable as it is, no pun
> intended, a sticking point for catheter-related blood-stream-infection
> trials.
>
> DR. LEGGETT: We are now going to hear from Dr. Nambiar who is going to
> talk to us about the epidemiology of Staph aureus bacteremia.
>
> **Epidemiology of Staph aureus Bacteremia**
>
> DR. NAMBIAR: Thank you, Dr. Leggett and good morning everybody.
>
> (Slide.)
>
> In the next twenty minutes or so I will briefly discuss some salient
> epidemiology characteristics of Staph aureus bacteremia. The clinical
> implications of this cumulative epidemiologic evidence as it relates
> to clinical-trial design will be discussed by Dr. John Powers in a
> subsequent presentation.
>
> (Slide.)
>
> Although staphylococci were first described about 125 years ago by Sir
> Alexander Ogston, it continues to evoke immense interest and respect
> among members of the medical community both because of its tendency to
> cause severe disease and its tendency to develop resistance to
> antimicrobials.
>
> (Slide.)
>
> Staph aureus is an important cause of bacteremia in hospitals both
> within and outside the United States. Data from the SCOPE project from
> 1995 to 1998 showed that Staph aureus was the second-most common
> blood-stream isolate and it caused 16 percent of all hospital-acquired
> bacteremias.
>
> Data from pediatric institutions over a slightly longer time period
> showed that Staph aureus caused 9 percent of all hospital-acquired
> bacteremias. In a seven-year study from a single institution in
> Switzerland which was an acute-care facility, it was noted that 14
> percent of all bacteremias were caused by Staph aureus.
>
> Limited data is available on the incidence of community-acquired Staph
> aureus bacteremia. In a study from four metropolitan areas in
> Connecticut in 1998, it was noted that the incidence of
> community-acquired Staph aureus bacteremia was about 17 per 100,000
> persons.
>
> (Slide.)
>
> The increasing incident of Staph aureus bacteremia is paralleled by an
> increase in the incident of infective endocarditis due to Staph
> aureus. About 25 to 40 percent of native value endocarditis is now
> caused by Staph aureus. In a series of 329 patients with infective
> endocarditis from a tertiary-care facility, 40 percent of all
> endocarditis was caused by Staph aureus and the frequency of infective
> endocarditis due to Staph aureus increased from 10 percent in 1993 to
> 68 percent in 1999.
>
> (Slide.)
>
> Why is Staph aureus bacteremia different from other causes of
> bacteremia? It can present with a wide spectrum of clinical
> manifestations ranging from uncomplicated bacteremia to severe
> fulminant and often fatal disease. Complications are common and are
> often difficult to identify or to predict.
>
> Given its protein manifestations, it is difficult to standardize the
> extent of diagnostic procedures. There is significant overlap of
> infective endocarditis and the two are often difficult to
> differentiate clinically. Mortality from this disease remains high.
> Additionally, it poses there issues both related to its development of
> resistance to common antimicrobials and uncertainty regarding the
> optimum length of therapy.
>
> (Slide.)
>
> The common risk factors identified for Staph aureus bacteremia include
> the use of intravascular catheters, hemodialysis, intravenous drug use
> and the presence of underlying illnesses such as diabetes mellitus and
> immunosuppression.
>
> (Slide.)
>
> Staph aureus bacteremia has been classified several different ways in
> the literature. It can be classified as community- or
> hospital-acquired. It is classified as primary or secondary depending
> on the absence or presence of an apparent primary focus of infection.
> It is classified as complicated versus uncomplicated depending on the
> presence or absence of certain clinical characteristics.
>
> (Slide.)
>
> Although all patients with Staph aureus bacteremia necessarily have a
> focus of infection, it is not always apparent. How often there is an
> obvious focus of infection depends upon the series of investigations
> performed, the presence or absence of an intravascular catheter,
> whether the population consisted primarily or intravenous drug uses
> versus non-drug uses, whether the disease was acquired in the
> community or in the hospital.
>
> On an average, there is no obvious focus of infection in about 20
> percent of cases.
>
> (Slide.)
>
> This is a graph I have taken from a recent paper by Jensen describing
> the importance of focus identification in patients with Staph aureus
> bacteremia. The line in red represents how often an unknown focus was
> reported. This is data compiled from 14 published studies. The line in
> blue depicts how often intravascular catheter was reported as the
> focus of infection.
>
> So, in the \'90s, the two cross and the frequency of an unknown focus
> being reported has significantly decreased while that due to
> intravascular catheters is on the rise.
>
> (Slide.)
>
> In 1976, Nolan and Beaty reported in a retrospective study of 105
> cases with Staph aureus bacteremia. This is one of the earlier
> descriptions of two fairly distinct clinical populations, the first
> group consisting of 63 patients, all of whom had an apparent primary
> focus in infection. These patients were more likely to have
> hospital-acquired disease. They tended to be older with a mean age of
> 55 years. They were more likely to have significant underlying
> illnesses. Secondary foci were less likely and only two out of the 26
> patients with infective endocarditis belonged to this group.
>
> In the second group of patients, none of them had an apparent primary
> focus of infection. They were more likely to have community-acquired
> disease. They were younger with a mean age of 37 years. They were more
> likely to use intravenous drugs, more likely to have secondary foci
> and 24 out of the 26 cases of infective endocarditis belonged to this
> group.
>
> (Slide.)
>
> Subsequent studies have also documented that patients with
> community-acquired Staph aureus bacteremia are more likely to have an
> unknown portal of entry, more likely to develop metastatic disease and
> have a poorer prognosis. All of these most likely reflect the fact
> that medical attention is sought later probably after the onset of
> bacteremia and before the institution of effective therapy.
>
> How often Staph aureus bacteremia is community-acquired differs
> between studies essentially because of differences in definition. Most
> investigators would classify it to be community-acquired if a positive
> culture developed within 48 hours of admission to the hospital.
> However, other investigators have used longer cutoffs of 72 to 96
> hours.
>
> Using a 48-hour cutoff to define community-acquired disease, Jensen,
> et al., in their series of 278 cases of Staph aureus bacteremia from
> Denmark noted that just under 50 percent had community-acquired
> disease.
>
> Another important factor to consider in the definition of
> community-acquired Staph aureus bacteremia is if there was any prior
> contact with the healthcare system. In the series by Morin, et al.,
> from Connecticut that I referred to earlier, 192 patients had
> community-acquired disease and 62 percent of them had some prior
> healthcare contact.
>
> (Slide.)
>
> Staph aureus bacteremia is classified as complicated versus
> uncomplicated by different investigators using various definitions.
> Some authors would classify it as complicated if a focus of infection
> was not identified or it was non-removable while others would classify
> complicated Staph aureus bacteremia if there was evidence of
> metastatic disease, deep-seated infections or other complications such
> as acute respiratory-distress syndrome, or DIC.
>
> In a series of 724 cases described from Duke University Medical
> Center, complicated Staph aureus bacteremia was defined as the
> presence of attributable mortality, evidence of infection extension or
> metastasis, embolic stroke or recurrent Staph aureus infection within
> the 12-week follow-up period.
>
> The authors noted the following four risk factors to predict the
> presence of complicated Staph aureus bacteremia; a positive blood
> culture at 48 to 98 hours later; community-acquired disease; skin
> findings such as petechia or vasculitis suggesting acute systemic
> infection; and persistent fever at 72 hours.
>
> (Slide.)
>
> We have already heard some discussion about Staph aureus bacteremia
> and catheters and, needless to say, it is very controversial. Reports
> of increasing association of catheters and Staph aureus bacteremia
> pertain both to hospital-acquired and community-acquired disease and
> the increasing association with community-acquired disease may just be
> a reflection of changing medical practices.
>
> As with everything else I have presented so far, the definitions,
> really, vary between studies. By and large, catheter is usually
> considered the focus of infection if there is no evidence of an
> alternate source and there is evidence of inflammation or infection at
> the catheter-insertion site or a catheter-tip culture is positive for
> Staph aureus.
>
> However, in the absence of catheter microbiologic data, either because
> the catheter was not removed or the catheter was not cultured, it is
> often a diagnosis of exclusion.
>
> (Slide.)
>
> Steinberg, et al. reported on the association between catheters and
> Staph aureus bacteremia over two time periods from Atlanta. In the
> first time period, from 1980 to 1983, they noted that 25 percent of
> all hospital-acquired Staph aureus bacteremia were related to the use
> of intravascular devices. There were no documented catheter-related
> community-acquired Staph aureus bacteremia during this time period.
>
> However, from 1990 to 1993, they noted that 56 percent of all
> hospital-acquired Staph aureus bacteremia and 22 percent of
> community-acquired Staph aureus bacteremia were associated with
> intravascular devices.
>
> In a larger series of patients, again from Duke University Medical
> Center, it was noted that about 50 percent of patients with Staph
> aureus bacteremia had an intravenous catheter as the focus of
> infection.
>
> (Slide.)
>
> The incidence of infective endocarditis in patients with Staph aureus
> bacteremia were really depending upon the patient population studied
> and the extent of evaluation performed.
>
> Traditionally, the following three bedside criteria, as proposed by
> Nolan and Beaty, in 1976 were used to predict to presence of infective
> endocarditis in patients with Staph aureus bacteremia,
> community-acquired disease, the absence of a primary focus of
> infection and evidence of metastatic disease. However, subsequent
> studies have shown that infective endocarditis can occur in patients
> with hospital-acquired disease. It can occur in patients who have an
> obvious primary focus of infection and can occur in a population of
> non-drug users.
>
> In a series of 59 patients with Staph aureus infective endocarditis,
> Fowler, et al., reported that 46 percent, in fact, had
> hospital-acquired disease. In a series of 76 patients with Staph
> aureus bacteremia all of whom were non-I.V.-drug users 59 had an
> obvious portal of entry and 13 of these 59 patients had evidence of
> infective endocarditis.
>
> (Slide.)
>
> Infective endocarditis is often missed based on clinical findings
> alone. In a ten-year study from Denmark, it was noted that
> endocarditis was missed clinically in over half of the 152
> pathologically confirmed infective endocarditis due to Staph aureus.
>
> In a prospective series of 103 patients with Staph aureus bacteremia
> that was studied, 26 were noted to have infective endocarditis using
> the Duke criteria. Clinical evidence was, however, seen in only seven
> patients, five of whom had peripheral emboli and two had new murmurs.
> Transesophageal echocardiogram identified vegetations in 22 patients,
> abscess in two, perforation and new regurgitation in one each.
>
> (Slide.)
>
> Risk factors for Staph aureus infective endocarditis include the
> presence of native value disease which historically was associated
> with rheumatic heart disease. However, structural abnormalities such
> as mitral-valve prolapse, degenerative disease such as aortic-valve
> sclerosis and congenital heart disease also predispose to development
> of infective endocarditis.
>
> Other risk factors include the presence of a prosthetic valve, history
> of intravenous drug use or prior infective endocarditis and
> community-acquired disease.
>
> (Slide.)
>
> How often patients with Staph aureus bacteremia will develop
> metastatic disease again varies between studies. On average, about a
> third of patients will develop one or more metastatic foci. In a
> retrospective study of 281 patients with Staph aureus bacteremia from
> Switzerland, 27 percent developed metastatic disease. Common sites
> included the joints, kidneys, nervous system, skin and intervertebral
> disc. Half the patients had more than one metastatic focus of
> infection.
>
> In a more recent prospective study of 68 patients published in 2000 by
> Ringberg, et al., and this was very appropriately titled \"To Seek is
> to Find.\" They noted that 53 percent of patients, in fact, had
> evidence of metastatic foci. Patients underwent a fairly extensive
> evaluation including one or more of the following; X-rays,
> echocardiogram, bone or leukocyte scintigraphy.
>
> (Slide.)
>
> Risk factors for metastatic disease include community-acquired
> bacteremia, primary Staph aureus bacteremia, presence of prosthetic
> devices including orthopedic devices, implantable pacemakers and
> defibrillators. The study also suggested that persistent bacteremia
> would be an important risk factor for developing metastatic disease.
>
> Among 104 patients with Staph aureus bacteremia, 59 percent of
> patients with a positive blood culture, more than 24 hours after
> starting effective therapy, developed metastatic disease compared to
> 17 percent without sustained bacteremia.
>
> (Slide.)
>
> The two important issues that come up in the discussion of metastatic
> disease is development of metastatic disease always represent lack of
> drug efficacy. If not, from what time point after institution of
> effective therapy can we always attribute it to lack of drug efficacy.
> And this will come up again in the discussion by Dr. Powers later this
> morning.
>
> There is some evidence in patients with infective endocarditis that
> suggests that once you institute effective therapy, the rate of
> embolic phenomenon seems to decline. So, in a retrospective study of
> 207 patients with left-sided infective endocarditis, it was noted that
> the rate of embolic events decreased from 13 per 1000 patient days
> during the first week of therapy to less than 1.2 per thousand patient
> days after completion of the second week of therapy.
>
> However, in my review of the literature, I found there is only limited
> data available about inpatients with Staph aureus bacteremia regarding
> the time to development of metastatic disease. In a small series of
> patients, of 39 patients with Staph aureus bacteremia, Libman, et al.,
> reported that nine developed metastatic complications, one within the
> first week and eight after the first week of positive blood culture,
> two of whom developed metastatic disease four weeks after institution
> of therapy.
>
> (Slide.)
>
> This has already been brought up for discussion this morning; what is
> the optimum length of therapy. It really depends on the extent of
> disease and the presence of host risk factors. Generally complicated
> infections such as infective endocarditis and deep-tissue abscesses
> need prolonged duration of therapy somewhere in the range of four to
> six weeks.
>
> However, the appropriate length of therapy for patients with
> uncomplicated disease is still controversial. Some investigators
> propose 14 days of therapy while others propose longer duration based
> on higher complication rates seen with shorter therapy.
>
> (Slide.)
>
> Acute systemic complications such as the acute respiratory distress
> syndrome, disseminated intravascular coagulation and septic shock
> usually occur within the first 48 hours. Mortality in patients with
> Staph aureus bacteremia in the pre-antibiotic era was as high as
> 82 percent as reported by Skinner and Keefer in 1942.
>
> Currently, though, the mortality rates are much lower. They still
> remain fairly high, between 16 to 35 percent. Risk factors for
> morality include the severity of illness at onset of bacteremia,
> presence of an unknown source of infection, older age and
> noneradicable foci.
>
> About 12 to 15 percent of patients with Staph aureus bacteremia will
> develop recurrent disease. Risk factors for recurrence include the
> presence of persistent bacteremia, a retained intravascular device and
> the presence of noneradicable foci.
>
> (Slide.)
>
> So, in summary, these are some of the important challenges we have
> identified with Staph aureus bacteremia most of which have a bearing
> on the design and conduct of clinical trials. Clinically, it is
> classified several ways; community- versus hospital-acquired, primary
> versus secondary, complicated versus uncomplicated. Due to its overlap
> with infective endocarditis, there is often a need for
> echocardiographic evaluation.
>
> Because of its propensity to cause metastatic disease, there is often
> a need for extensive diagnostic procedures and as metastatic disease
> always due to drug effect is still unclear. The association with
> intravascular catheters is sometimes based on stringent laboratory
> criteria but often is a diagnosis of exclusion.
>
> Treatment issues posed with Staph aureus bacteremia include the need
> to initiate empiric therapy given the nature of the disease, the
> choice of initial therapy which often is based upon the resistance
> patterns in any given institution and the uncertainty regarding the
> need for short versus long-course therapy.
>
> Thank you.
>
> DR. LEGGETT: Thank you, Dr. Nambiar.
>
> **Questions from Committee**
>
> DR. LEGGETT: Does anyone have any questions? Tom?
>
> DR. FLEMING: I am trying to understand the sequelae for what might be,
> in fact, a PBSA cohort. We have seen that there are several important
> clinical consequences that you have referred to that are mortality,
> endocarditis, metastatic disease. And the evidence that you have
> shown, if I am understanding it, would suggest that effective
> antimicrobial therapies delivered sufficiently early in time could
> have an important benefit in reducing the metastatic-disease rates.
>
> Is that also true for the ability to reduce the rate of I.E. and
> mortality and would we be able to see those effects, particularly on
> mortality, by only following a moderate period of time because, as I
> understand from this, a lot of the mortality is, in fact, within 30
> days.
>
> DR. NAMBIAR: Even though there is some evidence to suggest that once
> you institute appropriate therapy, the likelihood or the risk of
> developing metastatic disease is decreased. I think what is not clear
> at this point is is there a difference if metastatic focus manifests
> for the first time in the first week of illness, whether it manifests
> in the second week or in the fourth week, especially some metastatic
> foci like bone infections may not be evident early on.
>
> So what is not clear to us, and we are seeking help from the
> committee, is from what point on do we attribute it completely to lack
> of drug efficacy. The other important issue that comes up is this drug
> that we are going to develop to treat Staph aureus bacteremia, should
> it have penetration to every potential site where Staph aureus can
> develop a focus of infection.
>
> DR. FLEMING: Just to follow up on that, certainly some of these events
> are events that would have been seeded prior to the initiation of the
> antimicrobial therapy. Some, however, presumably will be prevented
> which I would think would be a major benefit of such therapy.
>
> So, for infective endocarditis, is it reasonable to presume that we
> would be able, because of this chicken and egg\--presumably some of
> this is, in fact, caused by Staph aureus bacteremia\--is it plausible
> to think that, with effective therapy, we should be able to detect a
> reduction in the incidence cases post-therapy of I.E.?
>
> DR. NAMBIAR: Yes, provided you have done everything to exclude I.E.
>
> DR. FLEMING: Certainly, that would mean, and I follow you on
> that\--that would reduce the diluting if we have done as much as we
> could to exclude cases that are already preexistent.
>
> DR. NAMBIAR: I think, in my understanding, that would be a fair
> assumption.
>
> DR. LEGGETT: Tom, there is the other problem of effective treatment
> and losing, nonetheless, because a good proportion of folks who have
> endocarditis lose their valve four to six weeks into therapy when
> cultures are sterile. So that just further complicates that.
>
> Jan?
>
> DR. PATTERSON: It was a nice review. I just wanted to comment that
> since that Jensen review, there has been the emerging problem of
> community MRSA which has affected the rate of community Staph aureus
> in general. Indeed, it does appear to be a different epidemiology in
> terms of the invasiveness of the infection and the fact that people
> may even stay bacteremic on bactericidal therapy for Staph aureus.
>
> So, probably, it is with the PBL talks that those particular strains
> have\--that would probably be considered a risk factor, I think, for
> morbidity and mortality as well.
>
> DR. LEGGETT: As well as an incentive for drug companies to produce new
> drugs.
>
> Joan?
>
> DR. HILTON: It seems to me that, in trying to decide whether a therapy
> is effective, it would be great if there is time to evaluate a
> patient\'s baseline status, then treat, then evaluate the effective
> therapy. I am wondering if there are patients in whom there is not
> time to evaluate that baseline status that it is imperative that you
> start therapy right away.
>
> If there might be a different group of patients in whom you actually
> can take a number of days or whatever time is needed prior to starting
> therapy, I think this leads into clinical-trial design.
>
> DR. NAMBIAR: I think that would be an issue because I think, given the
> nature of the beast, I don\'t think we have the luxury of waiting for
> a few days before you actually initiate therapy. In fact, you are more
> likely to have a situation where most patients would have received
> some empiric therapy, I think like the example Dr. Leggett said. All
> that you would know is that there are Gram-positive cocci in clusters.
>
> If you all those risk factors, you are going to assume it is Staph
> aureus and, more than likely, I, as a clinician, wouldn\'t hold back
> treatment. So I think having the luxury of waiting for some time and
> then evaluating the patient\--and, again, the other issue that comes
> up is how much evaluation is good enough. Do you subject every patient
> to every test that is known because this particular organism has a
> propensity to seed in multiple sites.
>
> So I think part of it is going to be a clinical judgment issue because
> I think it is hard to mandate that every patient be subjected to every
> radiologic procedure available to detect a potential occult focus.
>
> DR. LEGGETT: Certainly expensive. Joan, I think part of the problem is
> we are trying to get at a final common pathway, final common
> denominator, and there are multiple ways to go there. So we oftentimes
> tell our residents to sit tight and don\'t start antibiotics until you
> know what is going on.
>
> But then there are the other people who are deathly ill that we start
> right away.
>
> Don?
>
> DR. PORETZ: Just in answer to your question, also, there are
> significant medical-legal questions because I have reviewed multiple
> files and, if you suspect a bacteremia and you don\'t act on it, and a
> patient is bacteremic, the medical-legal repercussions are very, very
> significant.
>
> DR. LEGGETT: As long as the outcome is bad.
>
> John?
>
> DR. BRADLEY: I was going to mention, as Jan did, that, as we move
> forward, looking at PVL-positive community-acquired MRSA is going to
> be incredibly important because the disease is firmly within
> pediatrics right now and at the IDSA meetings a week or two ago, the
> warning was put out that children get it first and watch out, adults;
> you are next.
>
> The other issue that had to do with waiting to start antibiotics, it
> is the standard of care right now in a child who has fever to start
> antibiotics while your blood cultures are pending. In order to go
> through a human research committee to present to a parent, mother or
> father, that we are withholding antibiotics and the potential
> complications is death I don\'t think would go over very well.
>
> DR. LEGGETT: Chris?
>
> DR. OHL: Just one other comment to add on that. I think that we are
> also discovering that Staph aureus in its resistance has become
> somewhat heterogeneous. More difficult to predict what and whom might
> respond to therapy that would thought to be sufficient based on
> microbiological MIC data. We are still learning on this issue and it
> will be some time before that comes to fruition.
>
> DR. LEGGETT: Thank you, Dr. Nambiar. If there are no further
> questions, we will move on.
>
> Dr. Patrick Murray is now going to talk to us about Microbiological
> Considerations in Diagnosing Staph aureus Bacteremia.
>
> Dr. Murray?
>
> **Microbiological Considerations**
>
> **in Diagnosing Staph aureus Bacteremia**
>
> DR. MURRAY: Thank you.
>
> (Slide.)
>
> John Powers asked me if I would give an overview of the microbiology
> of the issues that we are discussing today. I notice we are running a
> few minutes overtime. Hopefully, I won\'t exacerbate that problem. I
> think that I would be able to cover this material within the allotted
> 20 minutes or so.
>
> (Slide.)
>
> What I am going to do is divide my presentation into three components.
> I will start off with an overview of the blood-culture systems and I
> think the theme that I want to get across in that portion of the
> presentation is that not all negative cultures are created equally. We
> tend to think that a negative culture means really there are no
> bacteria there. I think what I can do, when I finish this
> presentation, is emphasize where, in fact, we can go wrong and miss
> the opportunity to detect organisms in the bloodstream.
>
> I will then talk a little bit about interpretation of the culture
> results and then, finally, the last maybe half of the presentation
> will be on identification of staphylococci, both the traditional
> methods for identifying the staphylococci as well as the newer genetic
> approaches to this.
>
> (Slide.)
>
> If we start off with an overview of blood-culture systems, the first
> thing that we have to do is collect an uncontaminated blood sample.
> Skin antisepsis is pretty well defined, what should be done. The
> surface to the skin should be cleaned with 70 percent alcohol. It
> should be allowed to dry, air dry. Then that is followed by either a 2
> percent tincture of iodine, povidone iodine, or chlorhexadine.
>
> Of the three disinfectants that I just mentioned, the povidone iodine
> which is traditionally the disinfectant that has been used most
> commonly is probably the least effective and that is because it needs
> to be on the skin surface for about two minutes for it to kill the
> bacteremia that are there.
>
> 2 percent tincture of iodine or chlorhexadine both work much faster
> and, for that sense, it is probably more effective at least based on
> traditional practices.
>
> The other question that could be raised is what is considered an
> acceptable rate of contaminated blood cultures. I would say that there
> is no acceptable rate. We don\'t want to have contaminated blood
> cultures. But, generally, the goal of institutions is to keep the
> contamination rate below 3 percent.
>
> In my experience, what we find is that, although you may have a rate
> of less than 3 percent, in certain parts of the hospital, you may have
> much higher rates. Emergency departments is a good example of that
> where the contamination rate can be much higher.
>
> I think in any sort of a program for reducing contaminated blood
> cultures, it is important for the institutions to know where their
> problems are and address those specifically.
>
> The volume of blood is the most important aspect of collecting a
> successful blood culture. Most septic patients have less than 1
> organism per milliliter of blood, whether that be bacteremia or fungi,
> that theme applies. So the more blood you collect, the greater the
> chance of getting a positive blood culture. There have been a number
> of studies that have looked at that.
>
> Those studies, then, form the foundation for the current
> recommendations that, for an adult patient between 20 to 30
> milliliters of blood should be collected for each blood culture and
> that volume of blood is divided into two or three bottles. For
> children and for infants, there is proportionately less blood that
> would be collected.
>
> The dilution of blood in the broth is also important. The minimum
> dilution is a 1 to 5 ratio between the blood to the broth that is in
> the culture systems. Now, there are resin media that are available
> that allow you to have a more concentrated amount of blood in the
> broth. I tend to think that that is not a good practice. I think what
> we want to do is maximize the amount of growth medium that is
> available to support the growth of the organisms.
>
> The number and timing of cultures really depends on the type of\--I am
> almost afraid to use the term bacteremia or septicemia right now, so I
> will use it in a more generic sense of bacteremia. The number and
> timing is really dependent on the type of infection. If it is a
> continuous infection, and that would be an intravascular infection
> like an infection localized on the heart valve or on a catheter, then,
> really, the timing is not critical because the bacteremia will always
> be present in the bloodstream.
>
> The key, then, is to collect enough blood to detect to organisms that
> are there. On the other hand, if it is a localized focus, say, a lung
> or urinary tract or an abscess, then we would expect that, for many of
> those patients, you are going to have intermittent spillage of
> organisms into the blood and so the timing becomes critical and the
> number of cultures that are collected becomes critical.
>
> The recommendations are that two to three blood cultures should be
> collected within a 24-hour period of time. Additional blood cultures
> really are not terribly useful unless you are looking for specific
> fastidious organisms.
>
> The methods that we use to culture bacteria and fungi in the blood
> have evolved over a number of years. The manual methods, which
> consisted of bottles of nutrient media, really have been replaced by
> automated methods today. I think there are very few laboratories that
> would have a manual method where they would inoculate the bottles and
> then periodically look at the bottles to see if there is evidence of
> microbial growth in those bottles.
>
> The lysis centrifugation system is a technique where you draw blood
> into a vacuum tube. It has a lysine reagent in the tube which lyses
> the blood cells. You concentrate the organisms by centrifugation and
> then you take the pellet and you inoculate solid media with that. The
> advantage of that system is that you can do a quantitative blood
> culture.
>
> The disadvantage is the lysine solution can lyse some organisms that
> you are interested in. Staphylococcus pneumoniae is a good example of
> that. In addition, there is a higher incidence of contamination of
> those cultures because of the manipulations.
>
> Most laboratories today use an automated method for processing blood
> cultures. There are three major players on the market today in the
> United States. Each of them are detecting growth or organisms by the
> metastatic activity of those organisms and that could be the
> production of carbon dioxide, the consumption of oxygen, and both of
> those can be detected by sensors or it could be detected by changes in
> pressure within the bottles.
>
> Those systems are comparable. There are subtle differences between
> them, or among them. I think each laboratory has their preference in
> what they would like to use but I would say all of those are superior
> to the manual methods that existed before.
>
> (Slide.)
>
> If we look at the interpretation of the culture results, the first is
> the time to detect the positive culture. I could say that most
> positive cultures, probably 90 percent of more of the positive
> cultures that are detected in the laboratory are detected within the
> first 48 hours of incubation. That is one of the advantages of the
> automated systems. The manual systems took longer in order to detect a
> positive culture.
>
> Organisms like Staph aureus, the Enterobacteriaceae, betahemolytic
> streptococci, all of those will grow generally within the first 24
> hours of incubation. In contrast, organisms like the
> coagulase-negative staphylococci can take more than 24 hours on the
> average before you detect their growth.
>
> So one way of separating those organisms just within the laboratory is
> that if it grows quickly and it looks like a staphylococcus there is a
> greater chance that that is going to be Staph aureus compared with the
> other staphylococci.
>
> Cultures are routinely held in laboratories five to seven days. There
> are some laboratories that hold bottles for a shorter period of time.
> I think that does compromise their success in isolating some
> organisms, particularly on patients that have been started on
> antibiotics before the blood cultures were collected from those
> patients.
>
> Extension beyond seven days is generally unnecessary unless you are
> looking for more fastidious organisms such as those that may cause
> subacute bacterial endocarditis.
>
> The spectrum of organisms recovered blood cultures, this has been
> touched on already in one of the earlier presentations; about 10 to 15
> percent of blood-culture bottles\--blood cultures\--are going to be
> positive, and they can be positive in one or both bottles that would
> be inoculated.
>
> The most common isolates are the coagulase-negative staphylococci,
> Staphylococcus aureus, Escherichia coli, the Enterococci, Klebsiella
> and Streptococcus pneumoniae and probably in that order, although that
> does vary from hospital to hospital depending on your patient
> population.
>
> The key point, though, is the most common organism that we will see in
> the laboratory will be the coagulase-negative staphylococci. Most
> isolates of Staph aureus, Streptococcus pneumoniae, the beta-hemolytic
> streptococci, Enterococci, Enterobacteriaceae, Pseudomonas, the
> Gram-negative anaerobes and yeast are going to be significant. So, if
> we see those in the blood culture, generally that is a significant
> finding.
>
> In contrast, most isolates of the coagulase-negative staphylococci,
> Corynebacterium, Propionibacterium and Bacillus are clinically
> insignificant. Each of those are organisms that can colonize the skin
> surface and contaminate blood cultures.
>
> So the important point that I would make there is that the
> coagulase-negative staphylococci are the most common organisms we see
> and also are commonly insignificant. In contrast, Staph aureus is the
> most common significant organism that we see but it is\--again, we
> have to be able to differentiate that from the coagulase-negative
> staphylococci.
>
> The other point that I would make is that the coagulase-negative
> staphylococci do cause significant infections but almost always they
> are associated with either a contaminated line or another foreign body
> that is present in the patient such as the prosthetic heart valve,
> prosthetic joint and so forth.
>
> (Slide.)
>
> Identification of staphylococci has evolved over the years and I
> think, in the last three or four years, we are getting more
> sophisticated and I think, also, offer opportunities here to help with
> some of the issues that are under discussion today.
>
> What I would like to do, though, is to mention that, for blood
> cultures, the way we approach identifying organisms is different from
> how we do with other types of cultures. Other cultures traditionally
> we are going to have the organisms isolated on a plate. We can pick
> the colonies, set up the biochemical test and be able to identify the
> organisms.
>
> Because, in blood cultures, there are so few organisms in the
> patient\'s blood, we are forced to inoculate the blood into a large
> volume of broth and grow the organisms initially in that manner. So
> what we are faced with, then, is a bottle with 50 to 100 milliters of
> broth and blood with the organisms present.
>
> Now, we can take those bottles. We can subculture them and the next
> day pick isolated colonies and go ahead and do identification tests,
> but that is going to introduce a one-day delay. So, traditionally,
> what most microbiology laboratories attempt to do are some rapid tests
> using procedures where we can concentrate the organisms from the broth
> and perform our test that way.
>
> Now, that subculture plate\--traditionally, microbiologists will take
> a plate. They will subculture the organisms onto the plate. They put
> it into an incubator and they don\'t look at it until the next day. In
> fact, if you go and you take that plate after four to six hours, you
> can see growth is present there, growth that you can use to set up
> your biochemical test and identify your organisms or set up your
> antimicrobial susceptibility test and have the results available the
> next day.
>
> Another approach would be to concentrate the organisms that are in the
> blood. But, again, the first approach was to use differential
> centrifugation, a low-speed centrifugation, to remove the erythrocytes
> that are present and then a high-speed centrifugation to concentrate
> the organism. You would take that pellet of organisms and use that to
> inoculate your test.
>
> A different approach to do that is to use the serum-separator, or clot
> tube, which are commercially available and you centrifuge your blood
> in that tube. Your blood cells would be concentrated in the bottom of
> the tube. The organisms, either bacteria or fungi, are concentrated on
> the top of the plug that is there and, above that, would be the rest
> of the blood.
>
> You can remove the organisms with a pipette and go ahead and set up
> your test from that. Now, you can also take the broth, itself, and set
> up tests without concentrating the organisms. The broth can be used
> for what I will talk about in a few minutes, the FISH test, or
> fluorescent in situ hybridization test, can also possibly be used with
> molecular probes and I will discuss that also in a few minutes.
>
> But you need a heavier inoculum from a subculture plate or from a
> concentrated pellet of organisms to perform the coagulase test and the
> protein-A test. The coagulase test is the ability of a staphylococcus
> to clot plasma, a very simple test. It has been historically used to
> identify Staph aureus for many, many, many years.
>
> The recommended plasma that should be used is EDTA rabbit plasma,
> commercially available and readily available. The coagulase
> enzyme\--there are actually two enzymes that we are interested in. One
> is bound to the surface of the bacteria and it is called, very
> originally, bound coagulase also referred to as clumping factor. The
> other one is freely excreted by the bacteria.
>
> It makes a different which coagulase you are looking at. For the bound
> coagulase, you can use a slide test or a commercial or latex
> agglutination test to detect the presence of that coagulase where the
> free coagulase is detected by a tube test.
>
> Now, let me explain what each of those tests are. The slide
> test\--what that means is you take your organisms from that pellet or
> from a plate. You suspend it in a small drop of water and then you mix
> with that the plasma. If Staph aureus is present, the organisms will
> clump together and it happens within about ten seconds.
>
> Another version of this test is commercial latex-agglutination test
> where, on latex particles, they have immobilized the antibodies to the
> bound coagulase as well as antibodies to protein-A which is specific
> for Staph aureus. If the latex particles clump in the presence of the
> organism, then that is considered a definitive positive test for Staph
> aureus.
>
> The slide test is positive in about 85 percent of the isolates of
> Staph aureus. That percent actually will fall if you don\'t have a
> heavy enough inoculum to be able to perform the test properly. The
> latex test has a very good sensitivity and specificity. It approaches
> 97 to 98 percent sensitive and specific.
>
> There are some organisms that will give you a false positive slide
> test. I have listed them here on this slide. There are also some
> organisms that will give you a false positive tube test. The tube test
> is that you take a tube of about a half a milliliter of plasma. You
> suspend your organism in that and you incubate it for four to
> 24 hours.
>
> Almost all Staph aureus isolates will be positive within four hours
> with that test. Some, though, require extended incubation and you have
> to incubate them overnight before you can have a definitive negative
> test.
>
> What all this means for the coagulase test is that, if the slide test
> is positive, in general, you consider that definitive for Staph aureus
> and you report that. If the slide test or latex test is negative, then
> you have to confirm that negative reaction with the tube test which
> would take four to 24 hours. Again, the protein-A is just a variation
> of the latex agglutination test.
>
> (Slide.)
>
> Genetic probes for Staph aureus; GenProbe has developed the probe they
> market as AccuProbe that is used to identify Staph aureus. It is a
> single-stranded DNA probe with a chemiluminescence label on it that is
> complementary to the ribosomal RNA in Staph aureus. The advantage of
> targeting ribosomal RNA is there are about 10,000 copies of the RNA
> that is present so you have an inherent amplification of the test
> using this approach.
>
> The test inoculum is recommendedly prepared from a subcultured plate
> or, again, from that pellet of the broth. It can be prepared from a
> broth culture. The recommendation by the manufacturer is the turbidity
> has to be a McFarland 1 standard which is very heavy inoculum for
> practical purposes, much heavier than what you would see when a blood
> culture is initially detected as positive.
>
> The test time to perform this cell-lysis hybridization and detection
> is less than one hour. So this would truly be considered a rapid test.
> Marlow, last year, reported that the limit of detection with seeded
> blood cultures was approximately 10,000 colony-forming units per
> milliliter with this method. That is at least 10-fold to 100-fold more
> sensitive than the limit of detection for the blood culture
> instruments.
>
> In other words, with a seeded study, it appears that you could use the
> blood culture broths directly to do this test. I think additional
> tests have to be performed to confirm this but if this, in fact, is
> true, this would be an attractive alternative for identifying Staph
> aureus rapidly from a blood-culture broth.
>
> Still, the way that you can get around the possible problems of
> sensitivity here would be to pellet the organisms in a concentrate and
> use that to perform the test. That should work very successfully.
>
> (Slide.)
>
> The last technique for identification of staphylococcus that I wanted
> to mention is fluorescent in situ hybridization or FISH test. Applied
> Biosystems, which used to be called Boston Probes, developed a FISH
> test using synthetic peptide nucleic-acid probes that target, again,
> the messenger RNA of the specific bacteria, in this case, Staph
> aureus.
>
> They have a number of probes for different bacteria but the one that
> we are interested in today is the one for Staph aureus. The peptide
> nucleic-acid probe is a synthetic pseudopeptide that hybridizes
> complementary nucleic-acid targets. Essentially, it is a synthetic
> peptide backbone with nucleic acids attached to it that would match up
> and be complementary to the nucleic-acid target.
>
> The probes have the advantage of a higher specificity and more rapid
> hybridization kinetics compared with traditional DNA or RNA probes. In
> addition, the hybridization can be performed in a wide variation of
> salt concentrations which allows the speed in which this reaction can
> be performed.
>
> The probes also have a fluorescent label on them which allows
> detection by fluorescent microscopy.
>
> (Slide.)
>
> I apologize for this picture. This wasn\'t really what I wanted to
> show you. What I wanted to show you is what is here in this lower
> right-hand corner but I am not sophisticated enough with computer to
> figure out how to cut that little picture out and show that alone.
>
> So this is from one of Boston Probe\'s research articles that were
> published. It showed a series of different organisms. There was an E.
> coli. Salmonella is No. 2. No. 3 was Pseudomonas auruginosa and No. 4
> was Staph aureus.
>
> The first two columns going down showed auto-fluorescence. The next
> four columns, they used specific probes. So, under C, it was the
> specific probe that was for the E. coli and only the E. coli is
> fluorescing. The second one was for Salmonella. The third one was for
> Pseudomonas and the last one, in the lower corner here, was the
> specific probe for Staph aureus.
>
> Truly, that is what it looks like when you perform these tests. They
> really do jump out at you. The organisms can auto-fluoresce and they
> have corrected with special filters for the auto-fluorescence. So it
> really is a fairly nice, in my experience, and we have used this now
> for about three months; it is a system that works fairly nicely.
>
> The downside of this is the total test time is approximately
> two-and-a-half hours. It is not a problem if your blood cultures are
> detected early in the day but if it is detected late in the day and,
> because of the, I think, relative sophistication of the interpretation
> of the reaction, it is not a test that can be performed off-hours.
> There have been three studies using these probes; specifically, the
> Staph aureus probe with positive blood-culture broths and the
> sensitivity and specificity for each of the studies was 100 percent.
> So it appears that this is a very sensitive and specific reaction when
> used with blood-culture broths.
>
> I think that was my last slide.
>
> DR. LEGGETT: Thank you, Dr. Murray.
>
> **Questions from Committee**
>
> DR. LEGGETT: Are there any questions? Don?
>
> DR. PORETZ: Through the years, it is obvious that we are seeing more
> and more blood cultures being reported back as coagulase-negative
> Staph. Not all those patients have lines in place. Do you think it is
> because of the way the blood is collected? Do you think it is because
> what is happening in the laboratory? Why are we seeing so much
> coagulase-negative Staph in blood cultures?
>
> DR. MURRAY: I could probably make one comment about the laboratories.
> In my opinion, one of the advantages for the new blood-culture systems
> is they are noninvasive systems. Once you have inoculated the blood
> into those, you don\'t go back into those bottles where traditionally,
> either with manual systems or with the early automated systems, there
> are multiple entries into the bottles. So it is most likely the
> collection problems.
>
> DR. PORETZ: I get the impression, after watching our laboratory
> technicians draw blood, at least in my hospital, they are not as
> careful as they were several\--they are being\--you know, it is a
> matter of dollars and cents. They speed these people up from person to
> person. I think that is probably the major reason and we are getting
> what we are paying for. We are, therefore, treating more patients than
> we need to treat, unfortunately.
>
> DR. MURRAY: Very clearly, and there have been, I think, excellent
> studies that have looked at this, if you have a dedicated phlebotomy
> team that collects blood cultures, you get much better results. If you
> have technicians that have other responsibilities, if you have nurses
> that have other responsibilities, you have medical house staff that
> are doing a lot of different things, they are not trained well and
> they don\'t take the time to do it properly.
>
> Again, my experience is if you look at where you have problems, you
> can usually identify key areas. That is really where the laboratories
> need to focus their attention in getting the proper cultures
> collected.
>
> DR. LEGGETT: John?
>
> DR. BRADLEY: It is wonderful to see the progress in molecular
> techniques in increasing how quickly we can identify organisms once
> they have come out of culture. However, at the bedside, for enrollment
> in a study, what we would really like is a test, a molecular test, we
> can do on plasma of the sick patient so that, within two-and-a-half
> hours of entering the hospital, we would have something to let us know
> whether they are infected or not. Can you comment on progress in that
> direction?
>
> DR. MURRAY: I think that the difficulty that, if you look from the
> microbiology perspective, the difficulty that you are working with is
> there are very small numbers of organisms present in the blood and
> that you have to amplify that. Not every company that makes molecular
> probes has targeted blood cultures as the place to go because, if you
> come up with a successful system, it is wonderful because there are a
> lot of people that would want to run those tests.
>
> I am not optimistic about that, but possibly that will happen. Other
> approaches would be to look at a patient\'s response to the organisms,
> and so you look at cytokine profiles. There is a lot of work that is
> being done with that as well. And that is part of problem. It is not
> specific.
>
> DR. LEGGETT: Barth?
>
> DR. RELLER: I would like to add three more reasons, Don, why there are
> more positives. One is where the blood is collected from. There are
> more and more catheter draws because it is convenient. Two is time is
> money, and the speed. If one uses povidone iodine, as Pat pointed out,
> it takes time so that you have\--and the Gram-positives are the
> hardest ones to kill or to disinfect.
>
> The third thing that is, I think, unequivocal and has been shown in
> controlled clinical trials is the newer instruments including media
> for institutions that use charcoal and resin-containing bottles. They
> are more sensitive. But they are also more sensitive at picking up
> that solitary coagulase-negative staphylococcus that is derived from
> the first two issues.
>
> So there is a tradeoff. You get more reals but you unequivocally get
> more contaminants. I would reinforce Pat\'s assessment of John\'s
> query about PCR. PCR, or nucleic amplification, is fantastic for some
> entities where the number of targets is large; acute HIV infection,
> hepatitis C, HSV, et cetera. Pat emphasized it is unequivocally true,
> many, and shown by Washington, Murray, others, at least half, more
> than half, of real staphylococcal bacteremias were less than one
> organism per ml, so that one would have a large volume.
>
> There are currently not yet processes in place, not that it couldn\'t
> be developed, that one could extract the 20 to 30 mls of blood,
> because if you don\'t have a target, you don\'t have a positive
> nucleic acid.
>
> DR. LEGGETT: Dr. Murray, a question. On your slide about
> interpretation of culture results, it stated that Staph aureus is
> detected in less than 24 hours and other Staph greater than 24 hours.
> Are you implying less inoculum or slower growth?
>
> DR. MURRAY: It probably is not the inoculum effect. It is probably
> more related to the rate of growth of the organisms. If you just look
> at colonies of Staph aureus and colonies of coagulase-negative Staph
> on a plate, generally the Staph aureus is a much larger organism, the
> colonies. So it is growing faster.
>
> The inoculum is an important issue though because the time to
> detection is influenced by the number of bacteria that are present.
> One way of assessing whether a catheter is the source of a positive
> culture, or a septic patient, is to look at how fast the
> organisms\--how fast the cultures collected from a catheter group
> compared with cultures collected at the same time from a peripheral
> vein.
>
> DR. LEGGETT: Any further questions? Thank you, Dr. Murray.
>
> Do we want to take a fifteen-minute break now? I think so. I was
> chided by one of the speakers last time because I wasn\'t accounting
> for older bladders. So it is now 10:15. Let\'s come back at 10:30 for
> the Open Public Hearing.
>
> (Break.)
>
> **Open Public Hearing\--Extra Session**
>
> DR. LEGGETT: This will begin our extra session of an Open Public
> Hearing which was not on the Federal Register Announcement.
>
> Before we have Dr. Tally speak to us, I would like to make the
> following announcement. Both the Food and Drug Administration and the
> public believe in a transparent process for information gathering and
> decision making. To insure such transparency at the Open Public
> Hearing session of the Advisory Committee meeting, FDA believes that
> it is important to understand the context of an individual\'s
> presentation. For this reason, FDA encourages you, the Open Public
> Hearing speaker, at the beginning of your written or oral statement to
> advise the committee of any financial relationship that you may have
> with any company or any group that is likely to be impacted by the
> topic of this meeting.
>
> For example, the financial information may include a company\'s or
> group\'s payment of your travel, lodging or other expenses in
> connection with your attendance at the meeting. Likewise, FDA
> encourages you at the beginning of your statement to advise the
> committee if you do not have any such financial relationships.
>
> If you choose not to address this issue of financial relationships at
> the beginning of your statement, it will not preclude you from
> speaking.
>
> Dr. Tally?
>
> DR. TALLY: In the spirit of what Jim just said, I am the Chief
> Scientific Officer of Cubist and I am a stockholder of Cubist.
>
> (Slide.)
>
> I would like to thank the agency for inviting Cubist to present at
> this important advisory committee meeting. We are currently in trial
> in a study of Staphylococcus aureus bacteremia endocarditis. I would
> like to present some of the experience we have had with this
> particular study.
>
> I will give you the summary up front using the old teacher attitude of
> I am going to tell you what I am going to tell you, tell you, and then
> review it at the end.
>
> (Slide.)
>
> Staphylococcus aureus bacteremia, as we have heard from the previous
> speakers, is a significant unmet medical need. It is a heterogenous
> population which includes endocarditis and in these heterogeneous
> populations, there are different outcomes. There is a lack of a
> placebo effect with Staphylococcus aureus bacteremia and I will
> address that during this talk.
>
> It is a difficult study to do, a bacteremia endocarditis study, but it
> is possible and we will look at that today. However, when we look at
> this, traditional noninferiority assessment may not be best or the
> only association of efficacy in this seriously ill group of patients.
>
> (Slide.)
>
> What is the high unmet medical need? We have heard, from the earlier
> speakers, that Staph aureus is a leading cause of bacteremia. It is a
> virulent organism. Indeed, it is one of the premier pathogens to
> infect man. It was discouraged in the preantibiotic era. It leads to
> endocarditis, metastatic infections and/or death.
>
> As we have heard this morning, Staphylococcus aureus bacteremia is
> both a cause and a result of endocarditis. Finally, there is changing
> epidemiology, as we have heard today and, in that changing
> epidemiology, it is a therapeutic challenge and that is compounded by
> the increasing resistance to beta-lactam drugs and the increasing
> tolerance to vancomycin.
>
> (Slide.)
>
> What is the mortality and what is the frequency of Staph aureus
> bacteremia? This is data just published in August from the SCOPE study
> looking at 20,000 isolates of nosocomial bacteremia published in CID.
> When you look at coag-negative Staph, it is 31 percent of the
> isolates, the coag-negative Staph, with a crude mortality of 21
> percent.
>
> With Staph aureus, incidence of the 1999 survey, SCOPE survey, was 16
> percent in 2004. It has jumped to 20 percent of the isolates. So Staph
> aureus as a cause of nosocomial bacteremia is increasing. The intended
> mortality, the crude mortality, with Staph aureus, in this particular
> study was 25 percent.
>
> (Slide.)
>
> What about the placebo effect. This is data that was mentioned
> earlier. The Skinner study published in the Archives of Internal
> Medicine in 1941 looked at the outcome in patients with Staph aureus
> bacteremia and the case-fatality ratio was 82 percent. You will notice
> if you are 50 or older, which most of us are in the room, the
> mortality goes up to almost 100 percent.
>
> With this, when you look at Staph aureus endocarditis non-treated, it
> is 100 percent fatal as are other endocarditises in the preantibiotic
> era. So the placebo effect in Staph aureus bacteremia or endocarditis
> is little or none.
>
> (Slide.)
>
> The next confounder in Staph aureus bacteremia is whether the patient
> has a MSSA bacteremia or an MRSA bacteremia. This is a slide from
> Sarah Cosgrove\'s meta-analysis looking at that. If you look at
> mortality with MSSA, it is 23.4 percent. With MRSA it is 36.4 percent.
> She controlled for confounding variables in clinical backgrounds. So
> there is a consistent finding that mortality is increased when you
> have MRSA causing the infection.
>
> (Slide.)
>
> When you do have MRSA, the main therapeutic modality has been
> vancomycin. The problem emerging from vancomycin has been the emerging
> resistance. We saw VRE outbreaks in Europe in \'86. It continues to
> today. VISA was first reported from Japan in 1996. We still see it
> albeit it is very low. Heteroresistance in vanco was noticed by the
> CDC in 2001 and it continues to be a rising problem.
>
> More recently, we have had vancomycin-resistant Staphylococcus aureus
> albeit there are only three isolates known at this time.
>
> (Slide.)
>
> When you do look at vancomycin in this particular area of therapy for
> MSSA and MRSA, two things come out. One, Chang, in an analysis of over
> 500 cases of bacteremia, looked at MSSA, whether it was treated with
> vancomycin or nafcillin. In that study the conclusion was that
> nafcillin was superior to vanco in the treatment of MSSA bacteremia
> and why most people recommend switching off vanco to nafcillin when
> you have nafcillin-susceptible.
>
> More recently, there has been disturbing data with these
> heteroresistent strains and vancomycin has been known to fail in MRSA
> bacteremia back into the early 90s in studies coming from San
> Francisco.
>
> The heteroresistance and tolerance problem probably is the most common
> problem we are seeing now and it has increased and heteroresistance is
> noted to be associated with increased failures.
>
> The most recent paper in JCM in June of this year looked at a biased
> sample of failure patients, looking specifically at the MIC of the
> organisms to vanco, came up with a surprising result. By NCCL
> criteria, an isolate with an MIC or 4 or less to vancomycin is
> considered susceptible. However, when the group at the Deaconess
> looked at 30 isolates, it had some rather disturbing outcome when you
> broke up the isolates based upon the MIC.
>
> Those isolates with an MIC of 0.5 or less, there was a successful
> outcome in this group of 55 percent. The overall group of 30 patients,
> it was a 23 percent favorable outcome. However, if the isolate had an
> MIC of 1 to 2, the favorable outcome was 9.5 percent and that is
> approaching what we saw with the placebo effect that Keefer published
> in 1941.
>
> So one has to look at vancomycin in this group of patients and
> particularly wonder about these ones with MICs of 1 to 2.
>
> (Slide.)
>
> So, with that background, when we were looking at our drug,
> daptomycin, and how to guide physicians in treating, and,
> particularly, what we were asked is how do we treat bacteremia, we
> made the decision back in 1999 to look at patients with bacteremia and
> endocarditis because, at that time, endocarditis is a registerable
> indication according to FDA guidelines.
>
> In consultation with the FDA, we undertook at study of daptomycin and
> infective endocarditis and bacteremia to specifically Staph aureus.
> The criteria to get into the study is you had to have a positive blood
> culture for Staph aureus. It is multicenter, both in the U.S. and
> Western Europe. It was randomized. But, because of safety concerns, it
> was an open-label study which adds complexity that I will talk about
> in a minute.
>
> We did add a blinded external adjudication committee. It is a
> comparative control and it was nafcillin versus vancomycin. In the
> beginning, we just treated bacteremia and right-sided endocarditis.
> There was an amendment of the protocol in April of 2004 to include a
> left-sided endocarditis.
>
> (Slide.)
>
> What were the challenges in this study? You have heard this morning
> that Staphylococcus aureus bacteremia is a heterogeneous group of
> patients. We use the modified Duke criteria to try and give some
> semblance of what type of patient we had at admission criteria. This
> is the phenomenon. The clinician is confronted with a positive Staph
> aureus blood culture and you don\'t know which group they are going to
> fall into. You only determine that during the course of therapy with
> many diagnostic tests.
>
> What we did is we classified our patients by the Duke criteria into
> definite or possible or not infective endocarditis. Part of that was a
> centralized reading of our echos, not leaving it to the original site.
> Finally, at the end, there will be an overall determination of
> responses in each subgroup; that is left-sided endocarditis,
> right-sided endocarditis and bacteremia.
>
> This is a difficult study to enroll and I will show you the magnitude
> in the next couple of slides.
>
> (Slide.)
>
> So what we did is enrolled numerous sites. There were some ethical
> considerations and that was you are treating patients with a high
> mortality if they have endocarditis. So the treating physician has to
> know. We looked at that open-label design. We also put in place a
> safety data-monitoring committee to make sure there was not a safety
> issue in the ongoing study.
>
> What about the bias due to an open-label design? We addressed that
> somewhat with the blinded independent external adjudication committee.
> It is composed of ID experts that are experts in infective
> endocarditis. They will determine diagnosis and outcome.
>
> Finally, with the type of study here, we have heard about relapse, you
> need long-term follow ups. So the test of cure is actually out at six
> weeks and a post-study visit is actually out three months. So the
> length of the study is rather long.
>
> There are extensive inclusion and exclusion criteria which affect the
> conduct of the study and it is related to the drugs used and the
> patients being enrolled.
>
> (Slide.)
>
> How did we make out in this study? When we looked at our diagnosis,
> and we are over 200 patients which is what are target was, and we
> looked at, by the Duke criteria, at these patients, about a third of
> them did not have IE based upon the Duke criteria and would consider
> those having bacteremia.
>
> We had a large group that were possible IE. They met the Duke criteria
> but they did not have a positive echo. Finally, we also had a smaller
> group that had definite infective endocarditis. It is proven by
> echocardiography.
>
> (Slide.)
>
> How many patients did we have to screen to get this over 200 patients?
> We screened over 5,000 patients to get this over a two-and-a-half-year
> period. But it is doable. And we are, at this point\--right now, we
> are in discussions with the FDA on going forward with this particular
> study.
>
> (Slide.)
>
> So I am back to the summary from the beginning. There is a significant
> unmet medical need. I think it has been brought out time and again
> this morning. The heterogeneous population includes patients with
> endocarditis and these heterogeneous populations all have different
> outcomes. So you are going to have to do some type of subanalysis of
> those groups.
>
> There is a lack of a placebo effect in this so it raises some
> questions we will get to. It is a difficult study to do, expensive,
> but it is possible to do these studies as we have shown.
>
> Finally, traditional noninferiority assessment may not be best in this
> serious illness or the only assessment of efficacy and I would throw
> that open for discussion at the end.
>
> Thank you.
>
> DR. LEGGETT: Thank you, Frank. We will take some questions. Alan?
>
> DR. CROSS: When you said that you screened over 5,000 patients, was
> that 5,000 patients with positive blood cultures or with Gram-positive
> positive blood cultures?
>
> DR. TALLY: It was 5,000 patients with positive blood cultures.
>
> DR. LEGGETT: Jan?
>
> DR. PATTERSON: I was wondering on that Sakoulas JCM 2004 study, the
> vancomycin\--we know that physicians tend to underdose vancomycin. I
> was wondering, did they use a 10 milligram per kilogram dose and/or
> were there any trough levels measured?
>
> DR. TALLY: There were trough levels and they were, I think, above 15.
> So they took that into consideration with these.
>
> DR. LEGGETT: Frank, could you elaborate a little bit about the
> exclusion\--was it mostly the inclusion-exclusion criteria that you
> had the 5,000 but only 200 enrolled?
>
> DR. TALLY: I have my Dave Letterman list of ten reasons. The biggest
> reason, in our study, turns out to be creatinine clearances below 30.
> Our drug is cleared by the kidney. We didn\'t have guidance in that
> area so it was a major exclusion criteria in this. And, indeed, that
> is something we are working on now to try and include patients in the
> future with ongoing studies of patients with renal failure being
> evaluated with a specific dosing regime.
>
> It was not the only reason. That was a primary reason and, in those
> patients, they probably had other reasons for being excluded also.
> But, also, there were a whole bunch of other reasons. One, they were
> already on the drug for greater than 48 hours, it was effective. Two,
> you couldn\'t get the consent in this serious illness. Three, there
> was renal failure. Four, they were in imminent threat of death so we
> didn\'t want to put morbid patients in. Fourth\--let me pull out my
> sheet, my cheat-sheet for that.
>
> A large group where they intravascular material that couldn\'t be
> removed were excluded. Severe neutropenia. Elevated bilirubins above
> 3. So there were a number of these criteria to try and focus on the
> disease and get it. We are not giving out the exact numbers on that.
> We have submitted all of that data to the FDA. We will be discussing
> that and it will come out sometime when we complete the study.
>
> DR. LEGGETT: Tom?
>
> DR. FLEMING: Could you clarify your last point? It is somewhat vague.
> You haven\'t gone into any details about what type of noninferiority
> assessment was planned.
>
> DR. TALLY: Excuse me?
>
> DR. FLEMING: Could you clarify your last point about the
> noninferiority assessment.
>
> DR. TALLY: Not being a statistician, I can\'t. I don\'t know what type
> of analysis should be done and that would be something we should talk
> about. But I think with the number of patients that you have to
> enroll, you would have to screen, to enroll just 200 patients. And
> then you have to do a subset. If you want to look at the subset
> analysis of the different groups of patients within here. It is going
> to make it an impossible study to do if we are doing a noninferiority
> study.
>
> So one would like to know if there are alternate ways to study this
> group of patients that, one, do not have a placebo effect; two, have a
> definite endpoint of you either clear the bacteremia or you don\'t.
> Third, to take into those the effect of not being able to do a study
> to assess all of these subgroups.
>
> So I, personally, don\'t know what type of analysis should be done and
> would throw that out.
>
> DR. FLEMING: Just to lay out the principles here, though, the analysis
> that you would do should allow you to conclude that you have an
> efficacious intervention.
>
> DR. TALLY: Correct.
>
> DR. FLEMING: And in a setting that you are referring to here as\--you
> are calling it lack of a placebo effect. I think what you are saying
> is a setting where you are going to have very few favorable outcomes
> in the absence of effective therapy.
>
> DR. TALLY: Correct.
>
> DR. FLEMING: But where there are effective therapies then a critical
> question is to ensure that an intervention isn\'t clinically
> meaningfully worse than what, in fact, you could achieve with existing
> therapies which also is, in fact, addressable through a noninferiority
> paradigm.
>
> DR. TALLY: I think you hit on it. It is the clinical evaluation of it
> and that is what we are in discussion with the FDA right now.
>
> DR. FLEMING: Celia?
>
> DR. MAXWELL: On your Slide 12, on the diagnosis of enrolled patients
> by the modified Duke criteria at baseline, I had a question\--two
> questions, actually, of the definitive and the possible infective
> endocarditis, what was that in actual numbers and also, of these two
> populations, were any or what percentage of them in each of these
> categories were shown to have vegetations, let\'s say, on echo.
>
> DR. TALLY: The definites had echo evidence of vegetation.
>
> DR. MAXWELL: All of them. And what number was that?
>
> DR. TALLY: Oh; we are not giving out the numbers at this point in
> time.
>
> DR. MAXWELL: Okay.
>
> DR. TALLY: Because the numbers are not complete. We are on an ongoing
> study where there are a number of patients where we haven\'t
> determined\--they are under analysis. So I am constrained from giving
> out numbers because, in addition to being regulated by the FDA, I am
> also regulated by the SEC. And I don\'t want to give out any
> misleading information.
>
> DR. LEGGETT: Don?
>
> DR. PORETZ: Frank, do you anticipate, if this drug is of value and is
> approved, is one going to be, when they are treating infective
> endocarditis, obligated to get serum levels of the drug?
>
> DR. TALLY: Since I haven\'t seen the data and the study is still
> ongoing, I think we have to wait to draw that conclusion. We had built
> into the study a pharmacokinetic study on all patients that we will be
> able to use when we look at the outcomes when the study is closed down
> and the blind is broken.
>
> DR. LEGGETT: Barth?
>
> DR. RELLER: I just wanted to comment that, at first, it seems the 200
> out of 5,000 is a small number. But it is exactly what one would
> expect given the physiologic exclusions. I base that on the largest
> review published in the \'90\'s on bacteremia; exactly 9 percent of
> all positive blood cultures grew Staph aureus assessed by an
> infectious-disease clinician to be true, which were almost all of the
> Staph aureus.
>
> What it is telling you is that half of all blood cultures obtained in
> tertiary-care hospitals in the United States are contaminants or
> unknown. So you do the numbers and, if you took 1,000 reals relative
> the positive, same institution, it is 9 percent. So basically it is
> capturing half of the ones who really have it.
>
> DR. LEGGETT: Yes.
>
> DR. FETZER: (Inaudible comments.)
>
> DR. LEGGETT: Could I ask you to speak into the microphone, please, and
> identify yourself.
>
> DR. FETZER: Olaf Fetzer, senior vice president, Cubist
> Pharmaceuticals, responsible for R&D. I just wanted to mention to
> Frank, as a correction; of the 5,000 screened, these were all Staph
> aureus confirmed.
>
> DR. RELLER: It wouldn\'t make it much different if it were all
> staphylococci in coming down to\--but then there are other reasons why
> people chose not to enter someone into the trial apart from the
> exclusion criteria mentioned.
>
> DR. TALLY: In response to Bob\'s question, one, and to clarify, the
> only patients that were screened has positive Staph aureus cultures.
> So that has been eliminated right away. There are a whole list\--there
> are about 30 reasons why patients didn\'t get into the study. I gave
> you some of the top ones and I don\'t have the full list right with
> me.
>
> If somebody drops out for one of the higher reasons, it doesn\'t mean
> they have a lower reason for exclusion. What it is saying is that
> this\--and it is a very sick patient population\--when you build in
> your exclusion and inclusion criteria, it eliminates a lot of
> patients. It is just getting that proper window where they haven\'t
> had other therapies and getting a patient to consent to your study and
> to get the physician to take out devices is problematic in this group
> of patients.
>
> DR. RELLER: I was just running the numbers based on the earlier
> question and on the comment that it was all positive cultures, not all
> cultures obtained. If one did all positive cultures, you could count
> on, at most, 9 percent.
>
> DR. LEGGETT: Thank you. Let\'s move on. Thank you, Frank.
>
> Our next speaker is Dr. Powers who is going to talk to us about
> clinical-trials issues with studies of Staphylococcus aureus
> bacteremia which will be followed, again, by questions from the
> committee.
>
> **Clinical Trials Issues with Studies**
>
> **of Staph aureus Bacteremia**
>
> DR. POWERS: Thanks, Dr. Leggett.
>
> (Slide.)
>
> I think that is a good introduction because what Dr. Tally brought
> up\--
>
> DR. LEGGETT: Excuse me, John. I have to close the Open Session.
>
> DR. POWERS: Oh; go ahead.
>
> DR. LEGGETT: The open session is closed.
>
> DR. POWERS: That took care of that. What Dr. Tally brought up was that
> it was very hard to evaluate the endocarditis subset within the group
> of people with Staph aureus bacteremia. But what they did find was
> 5,000 people with Staph aureus bacteremia.
>
> So what I would like to talk about today is can we define a new
> indication of primary bacteremia due to Staphylococcus aureus and then
> maybe look at subsets within that to try to evaluate those patients.
>
> (Slide.)
>
> So the first thing we are going to talk about is actually defining
> this indication and ask the committee whether they think that this is
> a worthwhile indication for people to pursue and does it actually add
> some information for clinicians.
>
> Then we would talk about the place of this potential indication in a
> clinical-development program and what kinds of preclinical and prior
> clinical-trials work would be helpful in evaluating a drug that would
> be potentially helpful in this disease and then, finally, go through
> some of the issues in designing and analyzing clinical trials of this
> potential indication.
>
> We will go through some of those issues of selecting the appropriate
> patient population to study, talk about how would we evaluate
> endpoints with what Dr. Nambiar brought up about how would one
> evaluate metastatic disease that may occur on treatment, talk about
> this issue of selection of duration of therapy, the issue with
> controlled drugs\--and we will go into a little bit about this dictum
> of vancomycin and nafcillin and how they compare to each other, and
> then some of the statistical considerations including the question Dr.
> Fleming asked about noninferiority.
>
> (Slide.)
>
> So the first question we would like the committee to ask here, and I
> am going to do this talk in terms of questions and then put some of
> the pertinent information underneath it. So, should primary bacteremia
> due to Staph aureus constitute a separate indication?
>
> Before we answer that, we actually have to say what is an indication.
> Well, an indication and the patients actually studied should be
> something that we can clearly define. That is for two reasons. One,
> obviously, we need to be giving some information to clinicians about
> how they appropriately select patients for treatment with that drug
> once it is determined to be safe and effective. Also, we need to be
> able to write that into prescription product labeling so that people
> can understand who was studied and where the drugs should be used.
>
> So what we are suggesting is that maybe one definition of primary
> bacteremia due to Staph aureus, and this gets back to what Dr.
> Patterson asked, we are not defining in the same way as it was defined
> in some previous trials. What we saw was that it is variously defined
> depending upon how you look at it.
>
> So our suggestion here would be that it is evidence of systemic signs
> and symptoms with positive blood cultures for Staph aureus and no
> other identified source of infection at the time of enrollment. The
> reason why we brought up signs and symptoms is something that Dr.
> Reller just brought up, that maybe as much as 50 percent of positive
> blood cultures don\'t represent real disease.
>
> What the committee had discussed in the past, in 1998 and 1999, was
> that bacteremia alone is not an illness. We need to link that to some
> signs and symptoms that the patient actually has.
>
> It shouldn\'t be that hard because, usually, clinicians draw a blood
> culture when the person is having some systemic signs and symptoms. So
> then the question comes up is should one differentiate from secondary
> bacteremias\--that is, patients who have a known source of infection
> such as pneumonia, complicated skin infections, et cetera.
>
> What the committee had told us back in 1999 was they were concerned
> that there may be differential efficacy of drugs based on the site of
> infection. We have certainly seen recent drugs that were effective in,
> say, complicated skin but did not look effective in other body sites
> like pneumonia. So, depending upon where the patient\'s original site
> of infection is may be important in determining drug efficacy.
>
> Also, bacteremia related to an intravascular catheter\--when we looked
> through a lot of this literature\--is often really a diagnosis of
> exclusion. Sometimes it is based on a positive catheter tip but,
> again, when we went back to the 1970s and tried to evaluate where does
> that information come from on positive catheter tips, again, there
> really is no gold standard to say what were those things compared to
> to determine that a positive catheter tip actually implied that the
> person had a true catheter-related infection.
>
> So the question came up, since it is often a diagnosis of exclusion
> and what we have heard from people in industry that we will go over
> this afternoon is that it is very often difficult to get that piece of
> information from the catheter because it has often been discarded by
> the time you get around to the patient.
>
> So could we devise an indication where intravascular-catheter-related
> infections were subsumed under this primary bacteremia indication.
> But, really, the question is would this indication provide useful
> information to clinicians. If we already know that a drug is effective
> in Staphylococcus aureus infections with a primary source of
> infection, would this provide this some additional data to knowing
> that the drug is effective in pneumonia, complicated skin, et cetera.
>
> That brings up something Dr. Tally just talked about. Would this
> indication provide us the opportunity to study patients that would not
> be included in those with a primary source of infection. Namely
> patients with endocarditis would be the big issue there.
>
> (Slide.)
>
> In fact, it is such an important issue that does efficacy in primary
> bacteremia due to Staph aureus imply that the drug is effective in
> endocarditis. Clinically, what we always worry about when you see a
> person with a Staph aureus in their bloodstream, especially if they
> don\'t have an identified initial focus of infection, is they may have
> an occult case of endocarditis.
>
> So why is that important in terms of a clinical trial as well as
> clinically? Because, first of all, it implies different outcomes in
> the patient and, in fact, Dr. Tally referred to a paper by Chang in
> Medicine. There is another paper by the same authors in that same
> journal that looked at risk factors for outcome in people with Staph
> aureus bacteremia, 31 percent mortality in the people who had
> endocarditis versus 20 percent in the people who didn\'t. So big
> difference in outcome if you have endocarditis or not.
>
> It also may imply a different duration of therapy as well, and that
> remains controversial; two weeks, four weeks, six weeks, what would be
> the appropriate duration in these people.
>
> So then the question comes up is can these drugs be studied without
> examining efficacy in endocarditis and, even within endocarditis, are
> there differences between right- and left-sided disease. So one of the
> things we would like to ask the committee is can these drugs be
> studied in a staged approach of first studying uncomplicated Staph
> aureus bacteremia or at least people unlikely to have a complication;
> then study right-sided endocarditis; then study left-sided disease.
>
> In addition, how would we approach drugs that may not demonstrate some
> potential efficacy for endocarditis based on either in vitro or animal
> testing but still may be effective in patients who have a primary
> source without endocarditis.
>
> (Slide.)
>
> So the next question that comes up is where would these kinds of
> studies fit in the overall clinical-development plan for a new drug.
> We brought these issues up in April of 2004 at a public workshop
> co-sponsored by FDA, the Infectious Disease Society of America and the
> International Society for Antimicrobial Pharmacologists.
>
> Some of the participants, when we brought this up, a little to our
> surprise, were very hesitant about going forward with studying drugs
> without some prior information that the drug may be effective given
> the serious nature of this disease and the potential for development
> of endocarditis.
>
> (Slide.)
>
> One of the things that the folks at that meeting suggested was that
> there should be some data from trials in this indication and that this
> kind of indication probably would not be the sole basis for approval.
> In other words, if a new drug came forward and this is the only thing
> they wanted to study, that that might be problematic and that we would
> probably look at this in terms of the overall efficacy of a drug in
> treating serious Staph aureus infections.
>
> So, again, they expressed this view of that we needed some more
> infection. So then the obvious question is what kinds of information
> would be helpful prior to studying a drug in a serious disease like
> this.
>
> (Slide.)
>
> The first question is what kinds of preclinical studies would be
> helpful in forming these hypotheses about potential efficacy and
> safety in this indication. And that would include both in vitro data
> and animal models. The in vitro data would consist of looking at the
> biological activity against isolates of Staph aureus and that brings
> up another interesting question about what is the clinical
> significance of bacteriostatic versus bactericidal drug.
>
> Dr. Pankey and colleagues wrote a very interesting review of this just
> recently in March 2004 in Clinical Infectious Diseases where they
> actually proposed the hypothesis that no drug is really all
> bactericidal or all bacteriostatic, that the way in which we define
> these things is really 80 percent or so killing with a bacteriostatic
> and 99 percent of so with bactericidal and that, by altering the
> conditions of inoculum, pH, et cetera, that you can actually alter
> whether a drug is bacteriostatic or bactericidal in the test tube.
>
> The real question, though, is what is the clinical significance of
> bactericidal versus bacteriostatic. We have all been taught that, in
> serious diseases where the antibiotic may not penetrate or there is
> little help from the host immune system such as meningitis and
> endocarditis, that at least, in animal models, it appears that
> bactericidal drugs look more effective in those models.
>
> So the question is what do you do, then, with a drug that appears
> bacteriostatic in the test tube. Would that be something that folks
> would be able to study in this indication or could we use that staged
> approach that we talked about earlier.
>
> Again, could we look at, then, some animal models of infection to give
> us a better idea of how these drugs may work given that in vitro may
> not reflect clinical outcomes perfectly and what kind of animal models
> would we need. Endocarditis would seem to be an obvious one but are
> there other potential metastatic sites of infection like bone that we
> would want to look at animal models as well.
>
> (Slide.)
>
> Then what clinical experience would be helpful in evaluating a new
> drug for this indication? We know that spontaneous generation in the
> bloodstream was done away with a number of years ago as a potential
> reason why people have organisms so, obviously, these people have a
> primary site. It is just that we don\'t find it. So patients with no
> primary site, it is still coming from somewhere although it may be
> occult.
>
> The serious nature of this illness and, again, those potential
> differences in efficacy of drugs based on the primary site of
> infection, again, would weigh against this being the sole basis of
> approval for a new drug.
>
> So one of the things we would like the committee to address is what
> kinds of data from clinical trials of infections of sufficient
> severity where Staph aureus would be a potential pathogen would be
> helpful in evaluating in new drugs for this indication.
>
> Some of the ones we thought of were hospital-acquired pneumonia,
> community-acquired pneumonia sometimes especially after influenza
> outbreaks can occur due to Staph aureus, complicated skin and
> skin-structure infections and are there some others that the committee
> might suggest where Staph aureus is a common pathogen that we may be
> able to look at.
>
> So I would like to go into now a bit of\--now that we have gone into
> the natural history of the disease, how will we actually design and
> analyze clinical trials for this indication. One of the reasons we did
> the talks the way we did today was it is very important to look at the
> natural history of a disease and to design trials based upon that
> natural history.
>
> These clinical trials obviously need to provide information that is
> useful in clinical practice but it is a very important distinction to
> realize that clinical trials are not clinical practice. We do lots of
> procedures to people in a clinical trial that are not routinely done
> in clinical practice but, perhaps, the biggest difference is that, in
> clinical practice, we give a drug and we don\'t care why the patient
> gets better as long as they recover.
>
> However, in a clinical trial, what we are trying to do is to ascribe
> causality of results to the drug that was administered, a very
> different thing than what we do in clinical practice. So, to allow us
> to do that, we use the scientific method and that is we hold as many
> factors constant as possible other than the drugs administered to the
> patients so that we can ascribe the causality of those results to
> those drugs that were administered.
>
> The Code of Federal Regulations actually says this in a very nice way.
> It says; the purpose of performing any clinical investigation is to
> distinguish the effects of the drug from other influences such as
> spontaneous change in the course of the disease, placebo effect or
> biased observations. There are a number of other things such as
> potential confounders that may come into the trial like concomitant
> medications, et cetera, that also impact on that as well.
>
> (Slide.)
>
> So I wanted to sort of show this as a map and talk about the places
> where potential bias may creep into a trial and then try to address
> some of these in terms of primary bacteremia due to Staph aureus
> indication.
>
> So what we first do is we obviously take a group of people as a whole
> who have the disease or even, more importantly, that we think might
> have the disease and then try to define the patients who would enter
> into the trial. Clearly, the first step there is we want to make sure
> they have the illness that we are trying to study.
>
> The issue here, too, is that this population needs to be heterogeneous
> enough to extrapolate to the people we are going to treat in practice
> but homogeneous enough to be able to make some conclusions about drug
> efficacy. Then we randomize people and, hopefully, blind this as well,
> talk about things that may occur while patients are on therapy,
> appropriate endpoints and how we analyze the data.
>
> (Slide.)
>
> So the first issue there is defining the patients who would actually
> come into the trial which is based upon the inclusion and exclusion
> criteria. Again, as I said, we need to strike a balance between a
> homogeneous enough population to study so that outcomes are not
> related to the differences in the natural history of the disease just
> like the Code of Federal Regulations said we are not trying to measure
> and that they are related to drug effects, but has to be heterogenous
> enough to be able to extrapolate this to clinical practices.
>
> One of the first issues is we would need to differentiate among
> patients with Gram-positive cocci in the blood. Dr. Murray gave us a
> good talk this morning about how we may be able to do this.
>
> One of the issues we have seen is that if you go to the microbiology
> laboratory and try to use that as the way to screen for patients in
> these trials, what is going to happen is, a, you are going to get a
> lot of Staph epidermidis and, even if they have Staph aureus, those
> people are likely to have received some amount of therapy by the time
> you get back to the patient who is up on the floor.
>
> So the question we like to ask the committee here is are there better
> ways of screening for patients than just getting the breakdown of who
> comes out of the microbiology lab. More and more, as we see these
> trials, we are beginning to see that especially in shorter-term
> illnesses that that one or two days of antibiotic that people get up
> front may have a big influence on the outcome at the other end. So
> that may not be an insignificant problem.
>
> Again, these newer diagnostic tests that Dr. Murray talked about may
> allow us to differentiate Staph epidermidis from Staph aureus prior to
> enrollment which would be a huge benefit because, otherwise, the
> drop-out rate from these trials may be considerable.
>
> (Slide.)
>
> Again, we know that there are different natural histories for various
> populations of patients in whom subsequent testing after randomization
> may show a source or a metastatic site of infection, such as
> endocarditis. Again, I mentioned the difference success rates and the
> different durations of therapy that may be necessary depending upon
> what infection site the patient ultimately has although it may be
> difficult prior to enrollment to differentiate those people.
>
> As Dr. Nambiar presented, even patients with what may be considered
> uncomplicated disease such as catheter-related infections may
> subsequently develop metastatic disease. So all of these things we are
> looking at are risk factors for metastatic illness but does not
> obviate that the patient may then develop those sites of infection on
> therapy.
>
> (Slide.)
>
> One of the things that we always find very important at the FDA is
> what you call something and the name of an indication. So I wanted to
> be clear about some of the definitions that we are using here today.
> One of them was complicated versus uncomplicated disease. Again,
> looking through the literature, we found various definitions of what
> you would call this. In fact, in the study by Small and Chambers that
> Dr. Tally referred to, what we found is that what they called
> complicated was just somebody that continued to have fever which is a
> very different issue than what we saw as complicated in some other
> trials.
>
> So what we put out as a trial definition for you folks to discuss is
> complicated disease would be patients who develop further clinical
> manifestations that were not present at the time of initial diagnosis
> that may portend a worse prognosis and/or need for prolonged therapy.
>
> As Dr. Nambiar said, these can be divided into two categories; severe
> sepsis, ARDS and DIC which usually occur within 48 hours but then that
> issue of metastatic sites of infection which may occur early on, may
> occur later, and some preliminary evidence that we found says may
> actually decrease with the institution of effective therapy. But you
> saw the limitations of the data that we were able to find.
>
> What we haven\'t really found to be very useful is this distinction
> between community-acquired versus nosocomially-acquired infections.
> When we look through the literature, what we saw is this really
> wasn\'t referring to the geography of where you got the infection. It
> was really trying to refer to different host populations.
>
> Although we have defined community-acquired versus nosocomial with
> diseases like pneumonia, the question is does it really help us here.
> When we went back and analyzed our data from the Focus Technologies
> database, we saw that these PVL-containing community-acquired MRSAs
> which usually remain susceptible to clindamycin, tetracycline and
> trimethoprim sulfa were really mixed in with the multi-drug-resistant
> Staph aureus that you would normally think of as nosocomial when we
> evaluated only outpatient isolates of Staph aureus.
>
> So what that tells us is sicker people are going home, getting mixed
> up out there in the community with the people who have
> community-acquired MRSA and so, when somebody gets sick in the
> outpatient setting, which one of those do they have. It is not really
> the fact that they got it as an outpatient that determines what is
> happening. It is really the host factors that determine it.
>
> So our looking at this says this may not be as useful a distinction in
> clinical trials for labeling given that there is such overlap in the
> populations. If we tell a clinician, use this for community-acquired
> and that is a dialysis patient who is in and out of the hospital every
> day, that becomes very confusing to the clinician.
>
> (Slide.)
>
> So one of the issues here, obviously, is it is very difficult to
> stratify these patients at the time of enrollment. We brought up this
> morning this issue of could you wait a little while, see what happens
> to these patients and then treat them later. Well, that data that
> shows that DIC, ARDS and severe complications can occur within 48
> hours would really argue against waiting for any period of time.
>
> But, since we can\'t wait, these metastatic complications may occur
> after enrollment. So, how well do these risk factors that have been
> cited in the literature select patients who have complicated disease
> and uncomplicated and, therefore, with uncomplicated, could these
> people receive what has been called short-course therapy.
>
> Nathan Fieldman and I did our fellowship at Virginia. One of our
> co-fellows, John Jernigan, did a study while we were there, or a
> meta-analysis, looking back at all the studies that have been in the
> literature up to that point in time on evaluating short-course therapy
> for Staph aureus bacteremia.
>
> What John and Barry Farr found was that many of these studies
> differentiating complicated from uncomplicated infection were
> retrospective and 10 of the 11 trials that they looked at that time
> were uncontrolled. It is very difficult to be able to make any real
> good assumptions about whether short-course versus long-course has any
> differences associated with it.
>
> We, then, went back and tried to pull all the studies from 1993 to the
> present to see if there were any differences and all we found, again,
> was either observational studies or retrospective studies. So, again,
> even since 1993, there is not much new information that would allow us
> to be able to draw any firm conclusions about short-course therapy in
> this disease even if you had uncomplicated disease.
>
> So one of the questions we are going to ask the committee today is how
> do we deal with that in terms of setting the duration of therapy.
>
> (Slide.)
>
> How useful are these risk factors that have been enumerated in the
> literature in the past in the clinical-trials setting. Well, these may
> be useful in clinical practice but some of these risk factors, like
> duration of fever and duration of bacteremia actually occur after the
> patient has been randomized.
>
> The other thing is these are all based upon the fact the you have a
> known effective drug. So, if a person is on nafcillin and remains
> bacteremic for three or four days, you could say, well, I think that
> person has endocarditis but I feel comfortable leaving them on
> nafcillin. This is a different situation where we are now testing an
> experimental drug in this setting, so does duration of fever and of
> bacteremia say something about how well the drug is working.
>
> So how could we then use an outcome to define who the patients are at
> the beginning of the trial. It seems like very circular reasoning.
>
> (Slide.)
>
> The other issue I wanted to bring up is, since these risk factors are
> based on outcomes with known effective therapy\--I brought that up
> already about experimental drugs\--how should patients who develop a
> site of infection after randomization be handled. I think Dr. Fleming
> asked this question earlier. Could patients with no signs or symptoms
> at the primary site be left in the trial when they develop a site of
> infection on therapy and does that have something to do with the
> timing of when they develop that site of infection.
>
> So, if a person ends up in the trial and, within three or four days,
> develop pneumonia, can we assume that that pneumonia was there? If
> they develop pulmonary emboli, does that mean it was there at the
> time? Even if it was there at the time, should we still call those
> people failures of therapy in order to actually analyze people evenly
> between the arms of the trial.
>
> In the past, we have evaluated\--in empiric febrile neutropenia
> trials, we have set a breakpoint of calling people baseline versus
> breakthrough infections. But that presents another conundrum. If you
> set that breakpoint, suppose somebody gets the infection one day
> before versus the person who gets an infection one day after that
> breakpoint. Are those people really different. That is a real
> conundrum we are going to ask you to comment on today.
>
> What is really important here, though, is patients would need some
> kind of standardized evaluation at the time of enrollment so that
> there are no potential differences between arms of the study in
> determining who has baseline infections and who does not.
>
> So, if one study center decides, we are only going to do chest X-rays
> and another study center says, we are going to do chest X-rays, bone
> scans and CAT-scan everybody from head to toe, the total body
> \"groapgram,\" then how would we match those two up. So there would
> need to be some standardized way. We realize you have to be practical
> about what you can do here and that we can\'t ask for every test in
> every person.
>
> But, as Dr. Nambiar pointed out this morning, that one study actually
> showed that you find what you look for. The harder you look, the more
> likely you are to find the primary site of infection.
>
> So we are going to ask you today what tests would be appropriate and,
> given this issue that endocarditis is such a concern, would every
> patient need some kind of echocardiography to evaluate those patients
> for endocarditis given that even patients with catheter-related
> bacteremias may go on to develop subsequent endocarditis.
>
> (Slide.)
>
> So, again, should patients who develop a site of infection be
> considered clinical failures on therapy? Should one differentiate
> baseline from breakthrough infections? And, again, can that be part of
> what we consider as part of the endpoints in this disease.
>
> When we actually evaluated this, and I will go back to the paper that
> Dr. Tally brought up by Small and Chambers that was published in
> Antimicrobial Agents and Chemotherapy in 1990. What they did was they
> took patients and, if their blood cultures were negative, and yet they
> remained persistently febrile, they called those people failures.
>
> If they had some other complication, even in the face of a negative
> blood culture, they were called failures. It is interesting that we
> use that data to say vancomycin may not be so effective. But now, when
> we are talking about clinical trials on the other end, how are we
> going to handle that and call those people.
>
> So it seems, when we were discussing this, that a negative blood
> culture doesn\'t always tell you that the person is not going to go on
> to have some clinical complication down the line. So would a proper
> endpoint include not only negative cultures, which we clearly think
> are important, but also some other evaluation of how the patient is
> actually doing down the line.
>
> The other issue is this idea of time to negative blood cultures. This
> has been commented on several times in the literature and probably
> goes back originally to the Kourzanowski paper in the Annals of
> Internal Medicine in 1982 wherein patients with right-sided
> endocarditis, they tested nafcillin plus gentamicin versus nafcillin
> alone.
>
> I put this in my category of urban legends of infectious diseases
> because we are always told that we should use gentamicin up front for
> the first five days. The first issue is that is now how the study was
> done because the patients got gentamicin plus nafcillin all along
> during the therapy and what they showed was that, in a subgroup
> analysis of only non-addicts, eliminating all the addicts, which
> consists of 11 patients on nafcillin and 19 on the combination, they
> showed 3.4 days of bacteremia in nafcillin and 2.9 days in nafcillin
> plus gentamicin.
>
> A, is that a real difference anyway that is clinically significant,
> about a half a day\'s worth of difference and then, after that trial
> was done, people say, well there was more toxicity in the gentamicin
> arm, obviously renal insufficiency. They said, well, since it causes
> renal insufficiency, let\'s just give the gentamicin for five days up
> front.
>
> And that is what we recommend. And that is actually recommended in the
> American Heart Association guidelines. But that is not how it was
> studied. So that becomes an issue, too, for selecting control regimens
> which we will get to down the line.
>
> But the real point here, in terms of this problem here, is that time
> to negative cultures didn\'t correlate with either morbidity or
> morality in that Kourzanowski study. So, even if you can make the
> blood cultures turn negative faster, what does it mean clinically for
> the patient down the line.
>
> (Slide.)
>
> The next issue is how should the duration of therapies in studies of
> this indication be determined. The first question is why is that even
> important to discuss. Again, the problem here is we leave this up to
> investigator discretion, we may introduce a potential bias that
> similar groups of patients may be being treated with two weeks worth
> of treatment at one center and four weeks worth of treatment in the
> other and how would we compare those.
>
> So this is a big issue because we know that there is significant
> variation in clinical practice even for uncomplicated disease. I know
> every time we brought this up when I was a fellow and we would have a
> Monday conference about this, the attendings would be throwing stones
> at each other back and forth about whether everybody should get four
> weeks regardless just because they have Staph aureus in their blood
> versus others who thought that you could select a population that
> should get shorter-course therapy.
>
> In the terms of clinical trial, this would really need to be specified
> up front as to what duration of therapy would be appropriate for what
> patients.
>
> (Slide.)
>
> So the next question is how would appropriate control regimens be
> designed for this indication. Let me go back, since I didn\'t hear
> this until Dr. Tally presented his, I want to talk a little bit about
> this vancomycin versus nafcillin distinction.
>
> When we went back and actually looked through this data, there are no
> randomized controlled trials that actually compare those. The first
> study or the most recent one is the one by Chang which was published
> in Medicine in 2003. The problem there is that we need to really
> understand the limitations of some of this data.
>
> While that study evaluated 505 patients in a prospective manner, it
> was an observational trial. An observational trial is not randomized
> and the problem with that is that it may not, then, account for some
> of the differences between the patient populations. Since it is also
> observation, they have no influence on how the patients actually are
> treated which means that things like management of the catheter is not
> controlled for in that population.
>
> So what they did, then, was come up with a relative risk for
> vancomycin. It doesn\'t mean that vancomycin is inferior because there
> is no direct comparison between vancomycin and nafcillin within that
> trial. So, again, there are some limitations in looking at that.
>
> The study by Small and Chambers published in 1990 in Antimicrobial
> Agents and Chemotherapy evaluated all of 13 patients who received
> vancomycin and they were I.V.-drug abusers. Five of those 13 patients
> were considered failures. And, again, we know that 100 percent of
> patients are not cured when they have endocarditis. So what you really
> need is some control, which that trial did not have.
>
> What they then did was they went back and they pulled several papers
> which had essentially between 10 and 25 patients, pooled them all
> together and tried to get an effect estimate for nafcillin. That,
> essentially, is an historically controlled trial. Again, the people
> that they called failures, I will just give you two examples.
>
> One of their patients, the only complication was fever. The patient
> was doing fine, was put on oral cefradine and was sent home and
> lost-to-follow-up. So that patient was called a failure. The question
> is you could legitimately ask, well, did that patient have fever
> because of drug fever or because the person actually wasn\'t getting
> better from their endocarditis. With the lost-to-follow-up, it is hard
> to tell.
>
> The other patient received nafcillin and tobramycin for four days,
> then got vancomycin for 12 days, then was switched to cefazonlin and
> then has a surgery down the line even though there were organisms
> found in the valve at the time of surgery. The question is, again, is
> that a failure and which drug failed? That person got four different
> regimens along the way and yet that was considered a failure of
> vancomycin in that study.
>
> The reason I am bringing this up is I think we need to be cognizant of
> limitations in the data when we start talking about these.
> Nonetheless, clinicians have these perspectives out in practice of
> whether they are going to feel comfortable using vancomycin or
> nafcillin or whether they are going to want to use gentamicin in
> combination with either one of those drugs.
>
> The issue in a clinical trial is, again, leaving this up to
> investigator discretion may introduce a potential bias even though we
> know all the limitations of this data. So, again, could we
> protocol-define switches from vancomycin to an antistaphylococcal
> penicillin once the determination of the susceptibilities of the
> organisms is made.
>
> The issue here is drawing the distinction between something that is
> specified in the protocol versus something that is left up to
> investigator discretion.
>
> The last issue we would like to address is what would be an acceptable
> loss of efficacy relative to controlled drugs for this indication. Let
> me take a step back and, again, address something that Dr. Tally
> brought up. If what we are going to try to determine is is that drug
> effective or not, the legal requirement is you need a control.
>
> If what we are going to do is say, we are just to look at how patients
> did on our drug and compare that to some external analysis of how
> patients in 1942 did, that essentially is an historical control. The
> Code of Federal Regulations says one of the appropriate controls that
> you can use in clinical trials is an historical control.
>
> But, remember, that is exactly what we have for vancomycin and we
> still don\'t know the answer for some of those questions now. So our
> question for the committee is would something like an historically
> trial be something that you folks, as clinicians, would want to see.
> We may get an ability to evaluate whether the drug is effective, yes
> or no, relative to placebo but that would probably not give us the
> data to evaluate how a new drug would compare to an already approved
> therapy such as vancomycin or an antistaphylococcal penicillin.
>
> We would assume, though, in lieu of an historically controlled trial,
> that most of these would be noninferiority trials which gets us to the
> issue of what would be an appropriate noninferiority margin.
>
> We agree that that study by Skinner and Keefer actually shows a very
> large mortality in Staph aureus bacteremia. Again, we need to
> recognize the limitations of that data. That pools together patients
> from all sorts of sites of bacteremia including pneumonia,
> complicated-skin, et cetera. In 1941, there were no central lines so
> that is a different population of patients today than what we would
> have had back then. But it still argues that this can be a very lethal
> disease.
>
> So the real issue here is not what is the benefit over placebo. The
> real issue here is what would be the clinically acceptable loss of
> efficacy relative to drugs that we already know are effective in this
> particular setting.
>
> So the issue then is a larger noninferiority margin translates into a
> smaller sample size and makes the trial easier to do. But that larger
> noninferiority margin also translates into more uncertainty regarding
> the results with that particular drug especially when it comes to
> comparing it to the control drug.
>
> (Slide.)
>
> So what I wanted to do was to sort of show you, since somebody asked
> the question earlier, what do the numbers actually look like, just
> take a second and go through some of this.
>
> I am going to use that number of 31 percent mortality from the 2003
> Chang paper and say let\'s just use that as the success rate in these
> trials. We don\'t know where that would be but let\'s just say that
> success rate comes out to be 70 percent.
>
> Over here is the noninferiority margin. So the narrower the margin
> means the more certainty you have that the drug is effective. In other
> words, a 5 percent margin would say, we are going to say that this
> drug has to be at least within 5 percent of the control or we are not
> going to say that that is useful clinically. 10 percent would be
> within 10 percent of the control, 15 percent within 15 percent of the
> control.
>
> So what you see is that if you have a really stringent criteria of
> saying, we are only going to say this drug is clinically useful if it
> is within 5 percent of what we already have out there, that you are
> talking about a trial that has about 1,300 patients per arm. That
> doesn\'t count the dropout rate which may be significant in these
> kinds of trials so you are talking probably in the order of 3,000
> patient trials.
>
> There are only about 10,000 patients with endocarditis in the United
> States yearly and, given all the issues with inclusions and exclusions
> that Dr. Tally brought up, you have to ask whether that is even a
> doable thing. On the other hand, if you are willing to accept more
> uncertainty\--namely, on the order of 15 percent\--then we are talking
> about 150 patients per arm which, again, you would have to figure in
> that there would also be that issue of dropout and the not
> insignificant issue of screening for these people up front as well. As
> Dr. Tally brought up, that is not an insignificant issue when it comes
> to actually trying to find people to put into the trial.
>
> So, hopefully, this gives you some numbers to be able to frame what we
> are actually talking about. We can put this back up here again if we
> need to.
>
> (Slide.)
>
> So let\'s just go through the issues for discussion here that we would
> like the committee\--I am going to go back to the beginning and talk
> about the questions that I had as the headers for those slides.
>
> Should patients with primary bacteremia due to Staph aureus constitute
> a separate indication and do these patients constitute a clinically
> relevant group of patients that we could describe in product labeling
> for clinicians. Does efficacy in primary bacteremia due to Staph
> aureus imply efficacy in endocarditis and can drugs be studied without
> examining the efficacy in endocarditis using some kind of staged
> approach with appropriate labeling to tell clinicians where the drug
> had and had not been studied?
>
> (Slide.)
>
> What preclinical information and information from other clinical
> trials would be helpful in evaluating drugs that may be appropriate
> for study in this indication?
>
> What evaluations should patients have prior to enrollment or shortly
> thereafter to rule out a known focus of infection? Are we talking
> chest X-ray, echocardiogram or anything beyond that?
>
> How should patients who develop a site of infection after
> randomization be handled? Should they be left on the study drug?
> Should they be considered failures of study medication?
>
> (Slide.)
>
> How should the duration of therapy in these studies be designated and
> what would appropriate control regimens for this indication be?
> Finally, what would be an acceptable loss of efficacy relative to
> controlled drugs trying to balance that certainty of the results with
> the practicality of sample size.
>
> Let me add on to the end of this, would an historically controlled
> trial be something that you, as clinicians, would find acceptable.
>
> I\'ll stop there. Thanks very much.
>
> **Questions from Committee**
>
> DR. LEGGETT: Thank you, John. I know there are going to be some
> questions. What I would like to do\--we are behind schedule\--is take
> questions and discussion until just about noon. So please make your
> questions succinct and important. Tom, would you like to start?
>
> DR. FLEMING: I have got a lot of issues and I am not ready yet to get
> them boiled down to a succinct summary. So I would rather go a little
> bit later.
>
> DR. LEGGETT: Joan?
>
> DR. HILTON: I will just ask one question to clarify at this point.
> When we are talking about efficacy, I assume that you are going to
> measure that using the endpoints listed on Slide 16. You have two
> listed there. One is metastatic disease and one you talked about,
> negative cultures, or time-to-negative-cultures. Are those what you
> are focused on when you think in terms of measuring efficacy?
>
> DR. POWERS: That would probably be part of the definition. We didn\'t
> want to get into today actually defining what the endpoints would be
> because, obviously, there are some things we left out of there, like
> people who die while they are on treatment.
>
> What we wanted to say is should that be a part of the appropriate
> definition of endpoints. But, given all the issues we needed to
> discuss today, we didn\'t want to get into specifically defining what
> an endpoint would constitute.
>
> DR. LEGGETT: Don.
>
> DR. PORETZ: I think you are right that physicians in practice are
> looking for guidelines and would like specific entities. So why not,
> for argument sake, start out with one primary bacteremia in and of
> itself; number two, bacteremia associated with a metastatic focus of
> infection; and number three, bacteremia associated with infective
> endocarditis and then start discussions from that so we have three
> separate categories.
>
> I think doctors in practice would appreciate that.
>
> DR. LEGGETT: So let\'s take some questions about Staph aureus
> bacteremia without endocarditis. One of my problems that I see
> immediately coming up is most of the time, even though we think we
> have an endovascular focus, Staph aureus is acute enough that we
> don\'t see the vegetations. A lot of the transesophageal studies are
> done in more subacute situations where the sensitivity is much higher.
>
> DR. PORETZ: Don\'t you believe\--at least it is my feeling that we
> tend to significantly overtreat a lot of these patients? I mean,
> people\--based on the dogma of what we are taught, we treat for four
> to six weeks sometimes and people have no reason in the world to
> really think they have endocarditis but doctors are scared not to do
> that.
>
> DR. LEGGETT: Agreed, totally. On the other hand, we are doing that in
> the face of drugs with what we think have known efficacy. Here we are
> talking about a drug we don\'t even know if it works.
>
> Alan?
>
> DR. CROSS: I would point out that, at least based on our earlier
> teachings, one of the reasons that I would treat for four to six weeks
> is the fact that the morality with simple Staph aureus bacteremia,
> unquote, was almost as forbidding as with an endocarditis. Part of the
> reason for that is the establishment of metastatic infections. We
> treat for a long period of time not simply to clear the blood but to
> treat the metastatic foci in the spleen, kidney, wherever. That takes
> time.
>
> Actually, you may recall the whole issue of teichoic acid antibodies
> was an attempt by the infectious-disease community to really separate
> out that issue to decide who may have a significant or metastatic
> focus that merited long-term therapy\--you can say four weeks, five
> weeks, six weeks\--versus those who didn\'t.
>
> Obviously, that is in the dust heap of unrealized tests, but the
> principle remains the same. I would say that the significant
> forbidding mortality of Staph aureus bacteremia, even in the absence
> of endocarditis, demands that we at least approach Staph aureus
> bacteremia a little differently than we do with bacteremia of other
> organisms.
>
> DR. LEGGETT: I would follow up on that with this question about only
> leaving a 48-hour window of prior antibiotics because what you are
> implying is that to say 72 hours of therapy, no matter what it is, is
> not going to make a difference in the long run. So I think that this
> is different than what Dr. Powers was talking about of therapy early
> on and short course of treatment.
>
> We are not talking five days of therapy for sinusitis after 48 hours.
> Now we seem to be talking four to six weeks.
>
> John?
>
> DR. BRADLEY: I think Dr. Powers has done a really nice job of
> detailing how complex these studies would be. He has brought up at
> least 20 different questions. For you to say, \"Oh; do you have any
> comments?\" I am rather paralyzed. I don\'t know which one to comment
> on first and, if I don\'t comment, does that mean I agree with
> something?
>
> DR. LEGGETT: You have got 18 minutes.
>
> DR. BRADLEY: So if you could go by each point that he requested, one
> by one, I think it would be easier for us to comment.
>
> DR. LEGGETT: Sure. Number one; should primary bacteremia due to Staph
> aureus constitute a separate indication? Any thoughts? My thought is
> no.
>
> DR. BRADLEY: Yes.
>
> DR. LEGGETT: John?
>
> DR. BRADLEY: I would agree. I think that if, the harder you look, the
> more you find the associated occult focus\--so I would agree.
>
> DR. PORETZ: But does that mean someone needs to be treated with
> parenteral antibiotics during that whole period of time?
>
> DR. LEGGETT: I don\'t think so. I think it just depend on the
> antibiotic. It doesn\'t have to be parenteral. If we have a drug that
> is 100 percent bioavailable with the same levels P.O. and I.V., there
> is no reason to give it I.V.
>
> DR. PORETZ: I agree.
>
> DR. PATTERSON: Could I ask\--Dr. Maxwell brought up a question. You
> are agreeing with what? We weren\'t sure what you were saying.
> Agreeing no, it shouldn\'t be a primary\--it should not be an
> indication?
>
> DR. BRADLEY: Yes, Dr. Leggett, I was agreeing with you that primary
> bacteremia, itself, should not be considered its own diagnosis.
>
> DR. LEGGETT: Any disagreement or clarifications of things? Jan?
>
> DR. PATTERSON: I was just going to say if we are including
> catheter-related bacteremia in the definition of primary bacteremia, I
> am inclined to say yes to that question.
>
> DR. LEGGETT: John?
>
> DR. POWERS: Could we ask people to give their reasons why yes or no? I
> think, John, you said it is the complexity of actually studying it
> that would be\--and, if the answer to this is no, what would you think
> would be useful in lieu of this?
>
> DR. LEGGETT: So he is jumping ahead to another question.
>
> DR. BRADLEY: If I can comment on Jan\'s question first. I think
> catheter-related bacteremias should not be considered in the primary
> bacteremias. I think if someone comes in with fever, has a blood
> culture and the blood culture is positive with no other associated
> focus\--and I would consider a foreign body, the catheter, in this
> case, a focus\--they should be considered separately.
>
> And I forgot what your question was.
>
> DR. LEGGETT: You have explained it. Celia, can you give some
> explanation about why you think primary bacteremia should or should
> not be a separate indication?
>
> DR. MAXWELL: I think it would be hard to determine what primary
> bacteremia is because, as everyone agrees, if you look hard enough,
> you are going to find something. So when do you stop looking? So it
> would be hard for me to say what primary bacteremia is.
>
> DR. LEGGETT: Chris?
>
> DR. OHL: Given the complexity of the definitions and how the trials
> would have to be constructed in order to get this indication, I would
> say no. I would agree.
>
> DR. LEGGETT: Joan, did you want to make any comments?
>
> DR. HILTON: No.
>
> DR. LEGGETT: Barth?
>
> DR. RELLER: No. But Staph aureus bacteremia is, I think, much more
> difficult for this rubric than coagulase-negative staphylococcal
> associated with catheters because, without association with catheters,
> it is problematic. It doesn\'t mean that there couldn\'t be
> differentiation of persons who have bacteremia with Staph aureus and
> that the indications could be different.
>
> But it depends on the definition. Where I am coming from are three
> avenues. They are very familiar to all the infectious-disease
> clinicians here. There is a huge difference by organism in what the
> site of infection is. Now, I am not fast enough to do this subset
> analysis by Staph aureus bacteremia as well, but just to give an
> example.
>
> Bacteremia with acute pyelonephritis in a young woman\--I mean the
> bacteremia is there but that is not the issue, and there is no
> intervention. That is different from Staph aureus bacteremia with a
> phlegmon with discitis which is different from bacteremia with an
> intra-abdominal abscess, not with Staph aureus, or a catheter-related
> bacteremia with Staph aureus is very different whether it is
> complicated by endocarditis or complicated by osteomyelitis or a joint
> infection because of this issue of what are the ancillary\--they are
> not ancillary\--or the adjunctive or, in terms of outcome, the primary
> determinants.
>
> For example, when we looked at all bacteremias in that thousand
> confirmed real bacteremia studies, on the role of removal, excision
> and drainage of a primary focus of infection, the associated mortality
> and the rank order was, if there was a removable focus and it was
> removed, the mortality was 6 percent. If it was a catheter-associated,
> sort of the purist, it was 4 percent. So it was even less.
>
> But if there either wasn\'t something that you could remove or if
> wasn\'t removed\--now, this is, you know, all real bacteremias, not
> just Staph aureus. One of the things that came out of this session is
> to go back and look at the cohort of Fowler and colleagues at our
> place. We have got now 1500\--is to go back and try to assess this,
> the mortality\--when you couldn\'t, it was 16 percent.
>
> So, in other words, there is a huge effect, regardless of the
> bacteremia. So it is where the complication is and whether you can do
> something about it, and whether you do something about it. Then you
> take endocarditis. Let\'s take Staph aureus endocarditis, treat it
> with a good drug that is effective, regardless of what that is. Well,
> the outcome is also, everyone here knows, critically dependent on if
> one develops a surgical complication or not and whether you have
> surgery.
>
> So the real outcome depends on whether the valve is attacked, if it
> needs to be attacked. So it is not just the antibiotic. This
> confounder of prior antibiotics, I think, with Staph aureus
> bacteremia, given the incredible frequency of complications and
> especially with endocarditis, that intervention needs to be swift to
> preserve life but the outcome depends on some of these other things so
> that if you had a confounding antibiotic for two, three, four, five
> days, that is not going to make any difference in the outcome of
> endocarditis or even complicated staphylococcal bacteremia.
>
> In other words, I don\'t think you would have to exclude patients. But
> if you take overall, and I don\'t have this for Staph aureus, another
> thing that could be done and I would like to do is that when one looks
> in that, let\'s say, for round figures, thousand patients about the
> influence on mortality, attributable mortality, based on
> time-of-intervention, of getting the right antibiotic, the relative
> risk of one was you got the right antibiotic empirically; that is, you
> were thought to be going to be bacteremic, you got the right
> antibiotic\--you had someone who was an experienced clinician that
> gave you the right antibiotic from the get-go. Relative risk of 1.
>
> Of you didn\'t get the right antibiotic until the Gram stain was
> called, it went up a little bit but not much, 1.2. But if you didn\'t
> get the right antibiotic until susceptibility\--this is taking all
> thousand; okay? Real\--that is where the big jump came and it was
> about a relative risk of 3.
>
> If you never got the right antibiotic, which is infrequent, very
> infrequent, it was, you know, very\--I mean, it was ninefold or more.
> Now, this is attributable to the extent possible with a multivariate
> analysis, et cetera. So the point is it makes a difference overall. I
> am not sure with subsets with Staph aureus it would make a difference
> acutely to get the right antibiotic, but the real test of
> antimicrobial component, when one separated out the role of excision,
> drainage, surgery, endocarditis, whether there is\--so I think that,
> for me, the answer to this is complicated or not, removable focus or
> not and whether it was done and then that endocarditis is in a
> different category\--this gets into duration of therapy\--from the
> other complications.
>
> But, even with the other complications, I think most of them are going
> to have four weeks of therapy and the other intervention. So it is not
> sort of avoiding the issue, but this maybe is really crucial and
> whether or not the numbers allow it to be done is something else. But
> I think the biggest danger is to facilely group as a primary
> bacteremia or catheter-related bacteremia because you have got a
> catheter, even if you remove it, it grows Staph aureus, et cetera, and
> say, okay, you can have short-course therapy.
>
> That can be and is a catastrophe if you have not sought hard enough
> for the complications.
>
> I know that is a long answer, but it is the only way you can fairly do
> it because these things, and I gave some numbers to show the relative
> importance of these other factors in making this decision.
>
> DR. LEGGETT: Succinct, as usual.
>
> I have trouble with a primary bacteremia because, as has been
> mentioned, they usually come from somewhere. So we have got to make
> sure that the drug works elsewhere than in the bloodstream if we are
> going to try to treat these upcoming complications. I think what we
> want to do in a clinical trial is try to avoid lumping as many things
> in there as possible. I think throwing a catheter-related into the
> primary bacteremia just makes it that much harder to group people so
> that you are actually sort of having some scientific looking at it.
>
> The problem, of course, is that we are looking at the final common
> denominator of something that came from many different directions. But
> I think that trying to look at clinical endpoints of metastasis,
> endocarditis, those sorts of things, as one of the outcomes is much
> more important to me than just whether the blood culture was negative
> at one day, two days or five days.
>
> Celia?
>
> DR. MAXWELL: This is really brief. I just wanted to comment that as
> John was here talking, this is an indication in adults because he was
> reminding me that, in children, you can get transient primary
> bacteremias with Staph that clear by themselves. So I am mostly
> confining my comments to adults.
>
> DR. LEGGETT: Alan?
>
> DR. CROSS: I will be brief by combining responses to 1 and 2. I
> totally agree with the difficulty of having a separate incident for
> primary bacteremia in part because, as has been said, if you look hard
> enough, you are more likely to find a focus.
>
> That brings me to a second point, having done similar types of
> studies, or at least in part of them, as Dr. Tally pointed out, it is
> very, very difficult even with something as relatively common as Staph
> aureus to, one, get consent within a very short period of time and,
> two, there is always the consideration that, by the time you get there
> with your new drug, that the patient has already been on some other
> empiric therapy.
>
> While, in the case of Staph aureus, perhaps you still have, perhaps,
> more time because of the difficulty in clearing Staph aureus
> bacteremia and all the things that Barth pointed out, still, I think,
> in terms of cleanness of study, it is good to have your experimental
> drug started as early as possible.
>
> So, in thinking about this, I would just like to, perhaps, ask Dr.
> Fleming to comment either now or later about a type of approach that
> we have had at least in the cancer and infectious-disease field where
> you often will have preemptive or even prophylactic antibiotics. So,
> clearly, if a patient comes to an emergency room and there is a high
> suspicion of Staph aureus bacteremia, the physicians will start
> antimicrobials even before the patient hits the floor.
>
> So I am just wondering about a type of design in which a patient is
> randomized at that point and then you actually embed into your study a
> subsequent workup which may include as much imaging as Dr. Powers
> pointed out or your echo and at least have that already built into
> your study so you have already prospectively defined these more
> complicated cases and how you analyze them.
>
> But, in the meantime, what that does is it allows you to get your drug
> on board much more quickly and also to allow the 48 hours, at least to
> obtain informed consent which is really a formidable problem.
>
> DR. LEGGETT: Tom, do you want to make a statement?
>
> DR. FLEMING: I actually would want to get to that. I am going to
> defer. There are two or three other critical questions that I would
> like to have some time to talk about and that point comes up in one of
> those later questions. So, just to be brief on this one, I am very
> persuaded that, with the diagnosis of Staph aureus bacteremia, it is
> very important to do everything possible that is practical to achieve
> knowledge about the site.
>
> The site clearly has a lot of influence on our projected efficacy and
> outcome. The challenge, as I understand it, is in maybe 20 percent, we
> are not going to succeed in that, at least within the time frame that
> we have available to us. So where are you left with those 20 percent?
> I understand that this primary bacteremia category is basically those
> for whom we haven\'t been able to identify a primary site except maybe
> catheter-related.
>
> So what do we do with this 20 percent? I am endorsing all the comments
> that we would certainly want to understand site if we can and that
> would then be how we would characterize those people. But what do you
> do in the 20 percent if you don\'t consider them a separate
> indication?
>
> DR. LEGGETT: Jan?
>
> DR. PATTERSON: I was just going to explain my yes, as requested. I
> guess it is my hospital epidemiology hat since I have been doing that
> for 15 years. I am very comfortable calling a catheter-related
> bacteremia a primary bacteremia. I think it is a distinct clinical
> entity and it has different implications than other catheter-related
> bacteremias which we treated differently.
>
> I agree that the reasonable amount of workup needs to be done, which
> we usually do for Staph aureus catheter-related bacteremia to make
> sure that it is nothing else.
>
> DR. LEGGETT: Nate?
>
> DR. THEILMAN: So this is a difficult issue. I worry that, if we split
> things up too much, we are not going to be left with anything to
> study. So, to some extent, some lumping may be required. Of course,
> attendant with that is the risk of heterogeneity in the population
> that we seek to study and invalid results.
>
> Dr. Powers, in his third slide, has given a definition for primary
> bacteremia, evidence of systemic signs and symptoms with positive
> blood cultures for Staph aureus and no identified source of infection
> at time of enrollment.
>
> I think, if we prospectively figure out how we are going to try to
> identify sources of infection at that time, and that could range from
> including a transesophageal echocardiogram to tagged white blood-cell
> scanning as was done in one of the studies present. This might be
> doable. I would not advocate, by the way, for tagged white blood-cell
> scans in everyone but I think I would for a TEE.
>
> DR. LEGGETT: Don?
>
> DR. PORETZ: Maybe I disagree but I really think there is an entity of
> primary Staphylococcus aureus bacteremia. I have seen a number of
> individuals. I have looked and looked for a focus. I can\'t find a
> focus. They had the mucous-membrane break or a skin break and that is
> how the organism got into the blood culture.
>
> If you can\'t define that as primary bacteremia, I mean that is what
> it is. I am not sure those people need to be treated\--they do need to
> be treated, but I am not sure\--in 24 hours, many of those people are
> better on therapy. I am not sure all those people who are better in 24
> hours need to have, because of the potential to have a valve infection
> or a metastatic focus of infection\--need to have a very, very
> prolonged course of therapy.
>
> DR. LEGGETT: John?
>
> DR. BRADLEY: You bring up an excellent point. If you find Staph aureus
> in the bloodstream, you go after what might be the primary site you
> and investigate them. As was brought up earlier and in John\'s
> definition, now obvious secondary site at the time of enrollment. We
> all know that chest X-rays, echos, can all become positive after your
> first evaluation.
>
> So building into a protocol the points at which a repeat evaluation
> would need to be made and how detailed that repeat evaluation would
> need to be are important to decide because you are right; many of them
> get better but there could be just a mild infiltrate that clears with
> oral therapy in a subset.
>
> DR. LEGGETT: Chris?
>
> DR. OHL: I was just going to, I think, clarify some of what we have
> all been saying also. What is different is would a clinician find such
> an indication useful. I would say to that, yes, they would find that
> useful. But, unfortunately, it is such a complex issue in trying to
> show what primary bacteremia is. At this point in time, with our
> current technology, may not be well definable enough to answer the
> question that the clinician wants to know.
>
> The other thing that struck me and I know Barth and others have been
> thinking about this for a lot longer than I have in these types of
> settings, but clinicians, I think, are much easier to take information
> that is shown that the difficult situation, the more difficult
> diagnosis, the more difficult infection, if there is efficacy there,
> they are much more willing to extrapolate it back to more simple
> situations.
>
> So realizing that the numbers that we are going to need to get
> clinical trials to study the more complicated bacteremias, and the
> most common complicated, I guess, would be endocarditis, we would need
> much time, not only to get the trial done but also to have enough
> clinical acumen and experience with what is it there for lesser
> indications in order to go for that.
>
> So I think that is my understanding of the complexity of the issue. So
> the question you initially asked is that, if our technology was there,
> in order to completely define what that is, the answer would be yes.
> But I am not sure that our technology is there right now for us to be
> able to define that to make that trial doable.
>
> DR. LEGGETT: If I understand you right, what you are saying is that
> you would want to feel comfortable in the most complex situations. In
> other words, you would first like to see the drug work in endocarditis
> and other complicated bacteremias before you went down to Don\'s
> simple one which is the exact opposite of what they were talking, if I
> understood correctly today, the stepwise approach which was going from
> the simple to the complex.
>
> Barth.
>
> DR. RELLER: From a clinical standpoint, actually, I am in complete
> agreement with Don. The question is how to safely separate those. So
> one possibility, and I could envision this as doable\--one possibility
> would be to have a category of uncomplicated primary bacteremia and
> then a complicated bacteremia that would encompass endocarditis that
> has other set of considerations.
>
> But that an indication not be given for complicated, necessarily; in
> other words, that it wouldn\'t be either/or because you have to sort
> out the endocarditis and there may be an endocarditis indication.
> There may be an endocarditis indication and a primarily uncomplicated
> indication. Then you could say, well, what about the others.
>
> Well, I think the others, the outcome, is actually also very much
> dependent on what you do about that complication. So getting to that
> uncomplicated primary that would include a catheter that was removed
> would be something that you come to by exclusion of complications.
>
> One of the things that I think is a real plus on the studies that Dr.
> Tally presented, or the study in progress, was this concept of you
> can\'t just say it is uncomplicated and start something and ignore
> them. But you are watching them like a hawk. You are making sure that
> you don\'t miss something. And you are following them for a long
> enough time to see what came back to bite you that you missed, this
> \"seek and ye shall find,\" usually\--not always, depending on how
> hard you go.
>
> So I think that it is not that it is impossible, but it is the care
> with which it is done because I think, from a clinical standpoint, the
> uncomplicated bacteremia with Staph aureus is a reality that would not
> necessarily mandate for everyone for six weeks of therapy.
>
> DR. LEGGETT: Let\'s jump to the last slide because it is now\--by the
> time we finish, it will be quarter after 12:00. Tom, do you want to
> address those issues?
>
> DR. FLEMING: All right. Actually, what I would like to focus on, just
> to drill down, is on two issues, the last issue on Slide 22 on our
> handout and the last issue on Slide 23.
>
> The last issue on Slide 22 is should patients who develop a site of
> infection after randomization be handled. There were several questions
> during John\'s presentation that led up to this summary question. To
> address this, I am going to, in fact, propose what I would think would
> be the kind of information I would want to look at as outcome because
> it sets up my answer.
>
> In this setting, what we are looking for\--certainly, one component of
> this would be negative blood cultures. But we know that is not enough.
> That certainly isn\'t sufficiently predictive of what is happening at
> primary sites. We would also want to look at complete resolution of
> entry signs and symptoms.
>
> But, from my perspective, in particular, the elements that I would
> really hope for as being affected with an effective antimicrobial here
> would be to reduce some of the more particularly serious sequelae, to
> reduce the risk of mortality, to reduce the risk of metastatic
> infection or infective endocarditis.
>
> So, if someone, post-randomization, develops a metastatic infection,
> that is an outcome. That is not a subgroup-defining characteristic.
> So, if we were to pull those people out of the analysis and do
> subgroups, then we are missing the fact that the occurrence of these
> post-randomization events could be part of the signal of the
> effectiveness of the antimicrobial intervention in preventing or
> reducing the risk of these events which comes back to the principle
> that intention-to-treat analyses are really critical if we believe in
> the importance of randomization.
>
> Randomization gets rid of systematically occurring imbalances but only
> if we, in fact, include all randomized people in the analysis.
>
> Now, in the need to randomization and initiate therapy before all
> baseline insights are in hand, one could envision that certain samples
> could be obtained that would be analyzed in the next 48 hours. One
> could state that if those samples were taken at randomization, then
> the intervention didn\'t influence the outcome and analyses could be
> done that did and didn\'t include those patients.
>
> But those are different from the cases where post-baseline information
> is used to exclude patients because of events that occur
> post-baseline.
>
> So, in essence, I would argue that, to preserve the integrity of
> randomization, if there are infections that occur post-randomization,
> those are outcomes and those people should be left in the analysis as
> outcomes. It does mean, though, as a result, it is very important for
> us to do the very best diagnostic assessments as practical at baseline
> so that preexisting conditions can be identified and not need to be
> included as outcomes because those that aren\'t found are, then,
> obviously going to dilute the assessment of efficacy.
>
> Nevertheless, unless you can tell me that you know for a fact that
> what is found after randomization was present at randomization, then
> we could missing part of the signal of treatment effect by excluding
> those people and not counting those events as outcomes.
>
> Moving to the last question which was one relating to in a setting
> where you have very effective active comparator interventions on
> endpoints such as mortality. Now you are assessing a new
> antimicrobial. What is an acceptable margin? Dr. Powers was giving us
> slides that were referring to the setting where you had maybe a
> 30 percent mortality rate.
>
> The question is, now you are going head-to-head against that
> comparator and intervention. Clearly, we know, in this setting, that
> this intervention has a profound effect on that endpoint. In the
> absence of the comparator, mortality rates would be very much higher
> than 30 percent.
>
> But the driving issue here in ensuring that you don\'t have too large
> a margin comes down to what is clinically acceptable for how much
> higher mortality risk would you allow. He gave what might be viewed to
> be some compelling arguments for allowing a big margin.
>
> If you allow a 15 percent margin, if you say, I just need to rule out
> the mortality at 30 percent is not increased to more than 45 percent,
> you might be talking about sample sizes of 150 per arm while, if you
> were talking about ruling out a 5 percent increase, you might be
> talking about sample sizes that are tenfold that large.
>
> The difficulty, though, is how much are we willing to allow in truth
> clinically, in terms of lesser efficacy. If we are lenient in allowing
> considerable flexibility here to accept small sample sizes, then, when
> we get a second generation intervention that maybe, in fact, truly
> does have a 40 percent mortality and we now use this as our active
> comparator, how many iterations of noninferiority trials are we going
> to go through before we have the risk that we are now accepting
> interventions that have truly a substantially higher mortality rate.
>
> So when I think if what is the margin that we would allow, I just turn
> the tables around and say, suppose, in fact, 45 percent mortality was
> the standard and you could come through with an intervention that
> would reduce that to 30. Would that be an important advance? You bet
> it would. You bet it would. So why would you allow that big a loss of
> efficacy?
>
> If you had 40 percent mortality and you could reduce it to 30 percent
> with an experimental antimicrobial, would that be an important
> advance? I would suspect strongly that it would. So, to allow for
> remarkably large margins, based on artificial motivation that is
> statistical to get small sample sizes, can compromise the best
> interest of public health in patients.
>
> In reality, I argue that the sample-size picture that Dr. Powers put
> up, while accurate, might not, in fact, be that burdensome in the
> following sense. If those calculations were all based on the
> assumption that the experimental is no better than the standard, if
> the experimental is slightly better than the standard, then you can
> rule out that you are modestly worse with much smaller sample sizes
> than were shown here.
>
> So what it means if, if I am not improving public health, yes, it does
> take a big sample size to rule out that I am taking a step back. But
> if I am actually providing a very modest improvement, not enough of an
> improvement that I could show is statistically significantly superior,
> but a modest improvement so I could rule out I am modestly worse, that
> is an important advance and that can be assessed with a much more
> modest sample size.
>
> Final point and that is historical controls. Can you use historical
> controls? If we do an uncontrolled trial, it truly is controlled. It
> is controlled by our best sense of how these patients would have done
> in the absence of our intervention. It is an historical control.
>
> When can you use those? You can use historical controls when you have
> a very clear idea of what the result would be in this population in
> the absence of your intervention and where you are looking for really
> big effects. Well if, in fact, we said the margin that we, in fact,
> would accept here would be 5 to 10 percent on mortality, meaning that
> the comparator is going to have about a 30 percent mortality, we want
> to know that we don\'t have more than a 35 to 40 percent mortality.
>
> But I don\'t want to do a controlled trial, randomizing half these
> patients to the control arm. I want to use historical controls. It is
> treacherous. To be able to distinguish an observed mortality rate of
> 35 to 40 percent and to be able to conclude that that, in fact, truly
> reflects benefit, that this would have, in fact, been 30 percent,
> means you have to have a highly homogenous, highly predictable
> setting.
>
> Everything that I have heard today says, no way. There are an awful
> lot of factors out here that can influence outcome. It is exactly the
> circumstance where I cannot use an historical control, where I have a
> lot of heterogeneity and I am trying to discern modest differences on
> critically important endpoints. I have to have a proper randomized
> comparator.
>
> DR. LEGGETT: Thank you. I think we will adjourn for lunch. We have to
> be back here promptly at 1:00 for the Open Public Hearing.
>
> (Whereupon, at 12:20 p.m., the proceedings were recessed to be resumed
> at 1:00 p.m.)
>
> [A F T E R N O O N P R O C E E D I N G S]{.underline}
>
> (1:15 p.m.)
>
> DR. LEGGETT: We are going to open the afternoon session with the Open
> Public Hearing for which we have two known speakers and we will see if
> anyone else wishes to speak.
>
> **Open Public Hearing**
>
> DR. LEGGETT: First of all, I need to make this statement. Both the
> Food and Drug Administration and the public believe in a transparent
> process for information gathering and decision making. To ensure such
> a transparency at the Open Public Hearing session of the advisory
> committee meeting, the FDA believes that it is important to understand
> the context of an individual\'s presentation.
>
> For this reason, FDA encourages you, the Open Public Hearing speaker,
> at the beginning of your written or oral statement, to advise the
> committee of any financial relationship that you may have with any
> company or any group that is likely to be impacted by the topic of
> this meeting.
>
> For example, the financial information may include a company\'s or a
> group\'s payment of your travel, lodging or other expenses in
> connection with your attendance at the meeting. Likewise, the FDA
> encourages you at the beginning of your statement to advise the
> committee if you do not have any such financial relationships.
>
> If you choose not to address this issue of financial relationships at
> the beginning of your statement, it will not preclude you from
> speaking.
>
> The first speaker at this session is going to be Dr. Tim Henkel.
>
> DR. HENKEL: Thank you, Dr. Leggett, and thank you to the agency for
> the opportunity to address the committee today.
>
> (Slide.)
>
> What I would like to do, since I have the much sought-after
> after-lunch spot here, I will keep my remarks brief, is describe our
> experience with a catheter-related bloodstream-infection study
> conducted according to the current guidance.
>
> What I won\'t do, since it has been done by others and that
> conversation will be continued this afternoon, is talk about medical
> need, talk about epidemiology of disease, talk about statistical
> considerations because I think those have been well covered.
>
> I am going to focus on study design and conduct of the study. Even
> though this study is completed, I also won\'t talk about results here
> today. It has been presented in part at the European Congress of
> Clinical Microbiology and Infectious diseases and will be published in
> full in an upcoming issue of Clinical Infectious Diseases. So I would
> like to focus on the design issues.
>
> (Slide.)
>
> This is a Phase II study, a randomized, controlled, open-label study
> of dalbovancin, a new lipo-glycopeptide antibiotic under development
> administered once weekly compared to vancomycin administered twice
> daily.
>
> The study used clinical and microbiological entry criteria, which I
> will describe further, consistent with the draft guidance for CRBSI.
> The primary endpoint of the study was the global response; that is,
> the combined clinical and microbiological outcome at the time of a
> follow up visit some two weeks after the end of therapy.
>
> The sample size planned here was about 60 patients per group. This is
> a Phase II study with descriptive statistics only, 95 percent
> confidence intervals planned around the point estimates of success.
>
> (Slide.)
>
> The inclusion criteria utilized documented Gram-positive bacteremia at
> baseline which is how most patients were entered into the study. We
> did allow for empiric enrollment of patients with signs and symptoms
> of bacteremia, basically signs and symptoms of the systemic
> inflammatory-response syndrome, fever, hypothermia, leukocytosis,
> leukopenia, or a left shift in the white count, tachycardia, tachypnea
> or transient hypotension.
>
> (Slide.)
>
> We excluded patients, consistent with guidance, who had received more
> than 24 hours of antibiotics for that episode of Gram-positive
> infection. We excluded patients who had a documented alternate focus
> of infection identified at the time of randomization.
>
> We also excluded patients who had recent Staph aureus bacteremia with
> a documented source other than a central venous catheter out of
> concern that it was actually a recurrence of that alternate source
> rather than a new bacteremia.
>
> We included patients only for whom a two-week course of antibiotics or
> less was deemed to be appropriate. Creatinine clearance of less than
> 50 or neutropenia, these largely were the results of the phase of
> development we were in with the compound at the time and, as Dr. Tally
> mentioned, not knowing what the appropriate adjustments for renal
> insufficiency were at the time.
>
> We also excluded patients on chronic immunosuppressive drugs or with
> organisms with documented resistance to either of the study drugs.
>
> (Slide.)
>
> In terms of microbiological methods, I think Dr. Murray outlined a few
> of these already this morning. We did catheter cultures where
> catheters were available for culture, either roll-plate or sonication
> techniques. We looked at time-to-positivity of catheter cultures
> versus peripheral cultures when that data was available at a given
> site.
>
> We also looked at quantitative cultures again where sites could
> conduct that analysis, cultures of exudates at insertion sites and
> then, for organisms other than Staph aureus, looked at antibiograms
> and, to confirm identify of paired isolates, pulsed field gel
> electrophoresis.
>
> (Slide.)
>
> In terms of the outcome definitions, clinical outcomes were defined as
> improvement in signs and symptoms such that no additional therapy was
> required. So, in this case, a metastatic focus of infection would have
> been identified after two weeks of therapy. The patient would have
> required more therapy and would have been classified as a failure.
>
> We looked at microbiological success or failure simply as clearance of
> blood cultures as success, persistence as a failure.
>
> (Slide.)
>
> We developed several classes of catheter-related bloodstream
> infections for purposes of analysis. A definite catheter-related
> bloodstream infection, per guidance, was defined as one of the
> following; at least one positive peripheral blood culture plus either
> a positive semi-quantitative catheter-tip culture; a quantitative
> catheter culture or a positive hub or tunnel exudate culture.
>
> It could also have been more than a five-fold increase in the
> colony-forming units per ml of an identical pathogen from a central
> versus a peripheral culture or where sites could conduct the analysis
> again, a more than two-hour time lag in the time-to-positivity for the
> peripheral culture relative to the central culture.
>
> (Slide.)
>
> There was an additional category of probable catheter-related
> infection. So, for Staph aureus, at least one positive peripheral
> blood culture in the absence of other sources of infection in addition
> to a physical examination, chest X-rays, urine cultures, and then any
> imaging directed by the physical examination of other signs and
> symptoms.
>
> Patients also had an echocardiogram. A transesophageal echo was
> strongly recommended although we would accept a transthoracic
> echocardiogram. Those could actually be done after the randomization
> decision. So it was possible with the design that a patient with
> endocarditis could have been randomized and would later have been
> classified as a failure. That, in fact, did not happen.
>
> For other organisms such as coag-negative Staph, we required two
> positive blood cultures as I have described already, at least one of
> those peripherally.
>
> (Slide.)
>
> We opened 34 centers in North America and enrolled the study over a
> period of 17 months. Just over 2,600 patients were screened, and I
> will give you the reasons for the screen failures in just a moment, to
> enroll 75 patients. So we fell short of the 60 patients per arm that
> we had hoped to enroll but chose to close enrollment at this point.
>
> (Slide.)
>
> In terms of reasons for screening failure, the most common was
> inadequate culture data. In large measure, this reflected the
> difficulties with getting the culture data for coagulase-negative
> Staph. So some of these are certainly the patients we have talked
> about this morning with a single positive culture who probably don\'t
> have disease.
>
> The second most common reason was prior antibiotic usage. This
> excluded patients with both coag-negative Staph as well as Staph
> aureus but, in fact, is more problematic for the Staph aureus
> patients. I might also add that these reasons are not necessarily
> mutually exclusive. This is the reason listed first for screening
> failure.
>
> I talked about renal insufficiency already. 13 percent of the patients
> screened had an alternate focus of infection identified prior to
> randomization. Patients were also excluded if they had mixed
> Gram-negative and Gram-positive infections or if they were
> neutropenic.
>
> (Slide.)
>
> So, just to conclude, the difficulties in conducting the study and the
> reasons that patients couldn\'t get in. Identifying patients with
> Gram-positive bacteremia, as you all well know, is easy. There are
> lots of them. Some of them clearly don\'t have infection, in the case
> of coag-negative Staph. The population was quite heterogenous. I think
> the inclusion and exclusion criteria applied per guidance\--this is
> slightly more liberal than the guidance, not more strict\--I think
> result in a population randomized that may not be representative of
> the disease spectrum. So the generalizability of the data, I think we
> have to question.
>
> The microbiological methods that are dictated by the guidance are
> really not standard in many hospitals, the time-to-positivity of
> cultures or the semi-quantitative cultures. Catheter-tip cultures are
> actively discouraged in many places today.
>
> So our conclusion was that a Phase 3 study with the current design
> really was not feasible. I think we badly need alternate approaches to
> bacteremia indications, different study designs. My personal
> perspective is that I would rather not see us lump coag-negative Staph
> with Staph aureus. I understand the rationale for the guidance in
> terms of insuring that a coag-negative Staph is really a pathogen. I
> think that is appropriate. But I think it eliminates patients with
> Staph aureus that truly do have infections.
>
> One of the things that already has been mentioned today in terms of
> exclusions that would help enroll patients with Staph aureus
> bacteremia in trials, and that is simply relaxing the time frame that
> one allows prior therapy before the randomization decision.
>
> It does a couple of things. It allows you to get culture data back
> from laboratories and confirm that it is really Staph aureus, number
> one. It allows you to do a little more of an evaluation for other foci
> of infection. You can get the echocardiogram done and, in fact, doing
> echos or even transesophageal echos, in the United States in a short
> time frame really was not terrible difficult. It allows you to get a
> CT scan if you need one, for that matter.
>
> So, from my point of view, I would urge the committee not to continue
> with the current guidance that looks at both coag-negative Staph and
> Staph aureus in the same kind of indication but to entertain an
> alternate design that found a way to look for Staph aureus bacteremia.
>
> Thank you.
>
> DR. LEGGETT: Thank you very much.
>
> Are there any questions?
>
> Don?
>
> DR. PORETZ: I understand. It is obvious the difficult in doing these
> studies and the low number of patients that are enrolled, but I have a
> separate question. Of the 70-some-odd patients that you enrolled in
> the study, how many had Staph aureus in the blood?
>
> DR. HENKEL: About half of the patients with the baseline pathogen had
> Staph aureus in the blood.
>
> DR. PORETZ: So if 35 or so had Staph aureus in the blood and you
> eliminated those with metastatic foci of infection and those with
> endocarditis because you had a two-week\--you only gave two doses.
>
> DR. HENKEL: Correct.
>
> DR. PORETZ: One dose a week for two weeks.
>
> DR. HENKEL: That\'s correct.
>
> DR. PORETZ: Of those patients that were enrolled, those 30-some-odd
> patients who had Staph aureus in the blood, as they were followed
> after the study ended, because I am sure you had follow-up study. They
> were followed for X period of time. Vis-a-vis our conversation this
> morning when we talked about 35, 50 percent incidence perhaps of
> metastatic focus, what percent of those 35 patients had, after two
> weeks of therapy, a metastatic focus of infection that you could prove
> three or four weeks after the drug was stopped?
>
> DR. HENKEL: With this small sample size, none of the patients had a
> demonstrated metastatic focus during the follow up.
>
> DR. PORETZ: How does that go with what we discussed earlier this
> morning?
>
> DR. HENKEL: Well, I think the screening procedures used, the
> echocardiograms, the physical exams, chest X-rays, urine cultures, did
> exclude some of those at baseline, because the other way to ask it is
> a little less objective. But the investigator, at baseline, needs to
> believe that two weeks of therapy is going to be adequate for that
> patient.
>
> So there is a little bit of clinical judgement in there. If the
> patient has back pain that is new and on palpation of the disc, that
> patient didn\'t get into the study.
>
> DR. LEGGETT: Any other questions?
>
> Thank you so much.
>
> Our next speaker will be Dr. Charles Knirsch.
>
> DR. KNIRSCH: I am Charles Knirsch and I am employee of Pfizer\'s.
> Thank you.
>
> (Slide.)
>
> I would also like to thank you, Dr. Leggett, and members of the
> advisory committee for the chance to talk a little bit about some of
> the issues we have had in conducting a catheter-related infection
> study.
>
> (Slide.)
>
> A very common site in ICUs in this country and elsewhere, but I think
> it is clear that we all, and this committee has been working on trying
> to find ways to find evidence of antimicrobial efficacy and safety in
> this patient population.
>
> (Slide.)
>
> This was reviewed earlier. The size of the problem is large. There is
> significant morbidity and mortality. I think because of the difficulty
> and how sick these patients are, there should be a way to get
> antimicrobial efficacy studies done in this patient population.
>
> (Slide.)
>
> We have an ongoing trial so I do not have results but I would like to
> talk a little about some of the issues. I will try to focus on
> thoughts related to the incident because this trial is a Phase III
> trial very similar to the Phase II trial that Dr. Henkel described,
> very much consistent with the CRBSI Guidance from 1999.
>
> We do have pooled microbiology because a central lab is being used.
> So, in the 600 patients enrolled to date, nearly 100 patients have
> Staph aureus both from the catheter site and from peripheral blood. So
> that is the easy territory, I think.
>
> Slightly less than that have Staph aureus from one of the different
> catheter components, either from a blood draw, a cath-tip culture. And
> then, moving into coag-negative Staph, you can see that the numbers
> are actually smaller which actually we are quite happy about but
> still, with about 38 patients that have coag-negative from both the
> catheter and peripheral blood.
>
> (Slide.)
>
> This study wouldn\'t have been conducted had we not had some
> preliminary data in the organisms that would be involved, so data from
> methicillin-resistant Staph aureus, from VRE and, actually, a
> pediatric study that had a number of patients that were enrolled that
> actually turned out to have catheter-related infections.
>
> I think particularly important was a complicated skin study of good
> power that was in the original Phase III database. This gave us the
> basis for moving right into Phase III in a catheter-related study.
>
> (Slide.)
>
> So, looking at what potentially is the primary endpoint for which the
> power calculations would be based on is the issue of concordance, so
> the paired specimen from the catheter and the blood. Using the
> assumptions, actually, in one of the scenarios that Dr. Powers showed,
> note the delta of 15 which some people think is a little bit large,
> especially, maybe, for the coag-negative Staph, maybe not for the
> Staph aureus, an equivalence trial would need 147 evaluable patients
> per arm.
>
> To get to those evaluable patients with the microbiology rates I
> showed you, with about 30 percent of patients being evaluable, you are
> actually getting close to 1,000 patients. The current guidance asks
> for two studies to be done.
>
> (Slide.)
>
> We have also had slow enrollment in the study, at times less than 20
> patients per month. So we did a bit of an audit on the U.S. sites to
> see what were the problems with the screening failures. Now, remember,
> we have not analyzed the study. This is just that the patients did not
> make it into the study.
>
> Our rate of entry into the study was about 7.6 percent. The top five
> reasons were driven, actually, by the first two at about 20 percent
> each was previous antibiotic treatment for greater than 24 hours,
> infection that turned out not to be catheter-related when assessed by
> the study team. Then other causes, leading causes, were bacteremia
> that did not turn out to be a Gram-positive pathogen, a catheter
> actually being removed before the study team came to evaluate the
> patient or, in fact, no signs of catheter infection.
>
> (Slide.)
>
> So, as it turns out, with our current rate of entry, we would need to
> screen just over 25,000 patients to enroll both of these studies. That
> is a lot of patients. I think everybody knows that and it is at a rate
> of entry that is unlike any other trial that we do in anti-infectives.
>
> (Slide.)
>
> I think some of the ways to make these studies more feasible would be
> to allow greater than 24 hours on any staphylococcal therapy. So I
> think I heard some glimmers of hope along that line in the discussion
> this morning, at least for Staph aureus. I don\'t think 48 hours of
> Staph aureus therapy is going to prevent metastatic complications. Do
> we have data that shows that? Yes; actually, we do have data that
> shows that actually sometimes 10 to 14 days of therapy is not enough.
> I don\'t know whether 48 hours is different than 24 hours, but we
> would liberalize that. That has been confirmed, actually, by some of
> the physicians on our steering committee for the study. They think,
> actually, the enrollment would double just by changing that criteria
> alone to 48 hours.
>
> We could talk a long time about the different criteria for Staph
> aureus. The only point here to make would be that I think that if we
> are drawing Staph aureus out through the peripheral catheter in a
> patient that is sick and you rule out other causes that, potentially,
> you would consider that patient evaluable.
>
> Then there is the argument about whether to separate the coag-negative
> Staph. If you do that, though, and you are just looking at Staph
> aureus, the numbers are rather large. I mentioned originally to do a
> Phase III study in this indication, we had data that were
> organism-specific but also a large study in complicated skin.
>
> So I would argue that one adequately powered study when you have
> supportive data in a relevant indication, and there are other relevant
> indications, but I will point out at least complicated skin, that that
> should be considered by the committee.
>
> (Slide.)
>
> So just backing up a little bit on definitions. If you look at the
> IDSA guidelines and start working with a definition for CRI, one could
> say, or work with this, that it is an infection that involves a
> catheter at any point including the intravascular subcutaneous or the
> exit-site portions.
>
> Then a catheter-related infection actually may or may not be
> accompanied by bacteremia for a variety of reasons. There may have
> never been bacteremia. There may be bacteremia that is not picked up
> by the techniques that are involved either by the team that was
> drawing the cultures, the laboratory processing, delays in processing,
> et cetera.
>
> (Slide.)
>
> So the catheter, itself. There are multiple ways that this can be made
> manifest; a frank septic phlebitis, an exit-site infection, a tunnel
> infection, a pocket infection or a catheter-tip infection which would
> not be a soft-tissue infection, actually. Any of these phenomena can
> lead to a blood-stream infection.
>
> (Slide.)
>
> This is modified from the advisory committee meeting in October of
> \'98. We took certain liberties with it which was to place the CRI
> definition I gave within complicated skin and soft-tissue infection.
> So I added the C because most of these CRI patients will have systemic
> signs, or clinical signs of systemic infection. So that is why I do
> think it is complicated. Whether it is complicated or uncomplicated, I
> am not too worried about. So we do see it as a subset of skin and
> soft-tissue infections.
>
> (Slide.)
>
> I can see this pretty well on my screen. Hopefully, you can see it on
> the board. But this is clearly somebody that has a catheter-related
> infection. I think most of us would pull this line and start
> antibiotic therapy right away. We won\'t find out for 24 to 48 hours
> whether or not this patient is bacteremic.
>
> I think this is a patient worth studying in antimicrobial trials and
> looking, also, at the bacteremia but not, necessarily, looking at the
> bacteremia as the primary endpoint.
>
> (Slide.)
>
> So, in summary, as I mentioned, I think that a well-powered CRI study
> complementary to an existing relevant indication addresses the medical
> need for a drug approval for CRI. We are always caught between the
> guidelines that come out and actually operationalizing the guidelines
> and implementing them. I think that remodeling the process, at least
> having a chance to be part of the dialogue, is a good thing and I see
> that the guidelines\--it looks like there is an effort to evolve
> these. To make the indication more practical is a good thing and,
> hopefully, will allow for future innovation and anti-infectives in
> these areas.
>
> Thank you.
>
> DR. LEGGETT: Thank you.
>
> Are there any questions? Dr. Knirsch, obviously we would all agree
> with the photo that you showed that there was an infection there.
> Short of that, how do you have a hard endpoint and at what point do we
> go down the tricky slope of getting Staph aureus through a culture of
> a catheter and then not really knowing if the person is sick or not,
> or even if they are infected or not.
>
> DR. KNIRSCH: I think, ultimately, what it comes down to is whether you
> need the paired specimens in bacteremia to be the primary endpoint
> that you power the study off of. If you want definitive proof with
> deltas of 5, that is obviously the best evidence. But if we are basing
> treatment decisions to add gentamicin to nafcillin based on 11
> patients or what not, you have to weigh the relative amount of data
> you have.
>
> We also have catheter treatment guidelines based on almost zero data,
> as mentioned in the briefing document. So I think what is needed is
> incentive to have people do these studies with a wide variety of
> antimicrobials.
>
> That being said, I don\'t think anybody would leave that patient, even
> if you know, a priori, that they were not going to be bacteremic, with
> antimicrobial therapy. So treat it as a complicated skin infection,
> decide what amount of bacteremia data you need but not as the primary
> endpoint that would be meaningful\--be evaluated by practicing
> physicians.
>
> DR. LEGGETT: I see that, whether or not there is bacteremia, that is
> one end of the spectrum. What I am worried about is the other end not
> really being real.
>
> DR. KNIRSCH: I think you have to depend on the quality of
> investigators at academic centers somewhat. When you need 180
> investigators to get these types of studies done, then the quality may
> dip off. But there are 180 good sites that can do these studies. I
> think most of these investigators know, or at least with a pretty good
> amount of specificity, when somebody has catheter infection.
>
> Are they wrong sometimes? Absolutely.
>
> DR. LEGGETT: John?
>
> DR. BRADLEY: I have a question about the natural history of
> catheter-related infections in adults. Certainly in pediatrics, we are
> more conservative and tend to treat even after the catheters are
> pulled. In conferences where you and other adult ID colleagues are
> present, I understand that it is much more often that, once you pull
> the catheter, you basically don\'t continue antibiotics, particularly
> for coagulase-negative Staph.
>
> I get nervous just looking at the picture that you showed. We would
> certainly pull that catheter. My question is, in the adult world, if
> you have Staph aureus that is causing that subcutaneous infection,
> whether there is bacteremia or not, if you pulled that catheter, would
> you continue to treat that patient or would you think, since the
> catheter has been pulled, that the patient is likely to spontaneously
> resolve their local inflammation and, as a parenthetical remark, to
> differentiate between Staph aureus and Staph epidermidis or the
> coagulase-negative Staph.
>
> The systemic systems, the degree of fever, degree of white count, in
> our experience with kids, is vastly different. The amount of local
> inflammation is vastly different.
>
> Thank you.
>
> DR. LEGGETT: I would think there is a variety of opinion. But there is
> at least a large minority opinion that, if it is coag-negative Staph,
> you just pull the line and let them go. With Staph aureus, you have
> got about 50/50 chance with Gram-negatives and Candida that you have
> got a 0 percent chance of cure without pulling the line.
>
> Oh; that guy gets his line yanked. That person gets their line taken
> out.
>
> DR. BRADLEY: And antibiotics.
>
> DR. LEGGETT: And antibiotics.
>
> DR. BRADLEY: Okay; that was my question.
>
> DR. LEGGETT: But not for four weeks.
>
> DR. BRADLEY: Okay.
>
> DR. LEGGETT: Chris?
>
> DR. OHL: Just a point of clarification. In putting the indication for
> catheter-related infections complementary to, say, skin and
> soft-tissue which was the example, would that, then, just be those
> components of catheter-related infections that had a skin and
> soft-tissue inflammatory component and, within that subgroup, would
> you include exit-site infections also or just tunnel infections?
>
> DR. KNIRSCH: That is a good question because I think that
> coagulase-negative Staph is often a colonizer and then causes
> infection on the catheter tip. So I think it is a different problem. I
> think that there is a fair amount of suggestion in the literature
> that, even when you don\'t know and you are desperately short of
> additional sites to put the line in, because changing a line over a
> guidewire is not a particularly good idea, either, that some people
> will risk treating to the line waiting for evidence of the cultures.
>
> But Staph aureus, people will pull the line at that point. If it is
> coag-negative, there are efforts to treat the line. That is a whole
> other line of study that could be propose, actually. So I think that,
> scientifically, it would nice to separate Staph aureus and
> coag-negative Staph. Absolutely. I agree with that. And the studies
> would be very different.
>
> Practically, to get a study done, I am recommending treating the
> syndrome of CRI.
>
> DR. LEGGETT: John?
>
> DR. POWERS: Could I ask Chuck a take-off question from that. On your
> Slide 11, you listed a number of these catheter-related infections.
> The last one is catheter-tip infection. Could you define more clearly
> for us what that actually is?
>
> DR. KNIRSCH: I think, in most cases, that is coag-negative Staph. So I
> think it is somewhat different. If you were going to split these
> apart, I would recommend that that would be more of a coag-negative
> Staph type of study, maybe treat through the line with combination
> therapy.
>
> DR. POWERS: So that is just colonization of the tip of the catheter
> without any other signs and symptoms?
>
> DR. KNIRSCH: No, no, no. First of all, all of these patients, if they
> don\'t have obvious sign of catheter infection have some signs and
> symptoms, high white count, tachypnea, those types of things. So they
> need to be sick with some suspicion.
>
> I think, in practice, what is going to happen, if you expand out to 48
> hours, good clinical-trial groups will be monitoring the microlab
> looking for Gram-positive cocci in clusters and then enrolling those
> patients in studies. I think that is a good way, actually, to get
> these studies done.
>
> DR. LEGGETT: Any further questions? Thank you, Dr. Knirsh.
>
> DR. FLEMING: Maybe just one?
>
> DR. LEGGETT: Oh; sorry, Tom.
>
> DR. FLEMING: Your primary endpoint focused on the microbiological
> element. Certainly there is some uncertainty about whether that is
> adequate consistent with what the actual clinical effects will be. Did
> you believe that the sample sizes would be a lot larger to be looking
> at a more global endpoint, an endpoint that included clinical
> elements?
>
> DR. KNIRSCH: Well, first, let me comment about, if you were suggesting
> this morning that we should get a one-tailed test and do
> noninferiority studies, I think that that may be a potential option
> here. I mean, we tend to do two-tailed tests of equivalence always. So
> that may be one way, and I think that is what you were saying this
> morning.
>
> I think, with bacteremia, you need to prove that the bacteria is gone.
> I supposed that plus a clinical response is also important and that is
> what you will get. In the MITT population, that is what you will get.
> And then the microbiologic evaluable populations.
>
> DR. LEGGETT: Barth?
>
> DR. RELLER: I would like to come back to the clinical picture with the
> tunnel infection. The way for clinical trials as well as clinical
> care, I would assess that if the blood culture were obtained to the
> catheter and was positive for a staphylococcus and there was
> no\--excuse me\--staphylococcus demonstrated there were no positive
> blood cultures, it would qualify as a skin and skin-structure
> infection but I don\'t see how you could ever categorize it as a
> CRBSI.
>
> If it were Staph aureus and there was a positive blood culture through
> the catheter and one peripheral, I would not think it is necessary
> with the same, and an antibiogram with Staph aureus, given the
> relative pretest probability that it is going to be real, that one
> would need pulse field gel electrophoresis. But you would still need,
> through the catheter and peripheral, at a minimum, or two peripherals.
>
> In contrast, if this were a Staph epidermidis, which it could be, one
> would need, at a minimum of through the catheter and a peripheral and
> that they would be the same by pulse field for clinical-trial purposes
> given the much lower pretest probability that\--in other words,
> through the catheter only with the Staph epi, I don\'t think that is
> enough. If you don\'t have a positive blood culture, I don\'t see how
> you could ever enroll a patient for a CRBSI clinical study.
>
> DR. LEGGETT: Alan?
>
> DR. CROSS: I would agree with that Barth. A real problem is with,
> again, as was pointed out here, your cancer patients who have a large
> portion of the chronic indwelling catheters, who do get a lot of the
> coag-negative Staph infections, oftentimes their low platelet counts,
> actually, unfortunately, preclude a peripheral culture.
>
> So when you see these patients, especially in things like triple
> lumens, you get all sorts of I guess we heard the word this morning
> urban legend, about whether one, two or three portions of a triple
> lumen are positive in the absence of a peripheral culture, whether or
> not that is significant or not.
>
> So I agree with what you say but then what that would mean is that a
> significant population that, I would imagine, we would be interested
> in would be left out of the studies.
>
> DR. LEGGETT: Janice?
>
> DR. SORETH: I think what we are getting at here is the idea, perhaps,
> Dr. Reller, that you might think in terms of a patient population and
> an indication that would read something like catheter-related
> infections with or without bacteremia.
>
> Clearly, patients who were not bacteremic would not fall under a
> CRBSI. But I think there may be the potential to look at this patient
> population with the semantics that I just said, don\'t know entirely
> but it has merit and is one of the issues on the table.
>
> DR. RELLER: The reason why I mentioned it is obvious is there is a
> body of literature, particularly from Europe, that is emphasizing
> CRBSI with negative blood cultures. I think, for clinical trials, that
> is not possible to objectively study.
>
> DR. SORETH: Correct. And that is not the path we are going down. At
> least, I don\'t think it is.
>
> DR. RELLER: But others have gone that way.
>
> DR. SORETH: That is Europe.
>
> DR. LEGGETT: Are there any other speakers here who would like to say
> something during the Open Public Hearing? Yes, sir.
>
> DR. SHLAES: I am David Shlaes. I am from Idenix Pharmaceuticals. We
> actually currently don\'t have any antibacterials in the clinic or
> preclinic, but I will try and make a few comments anyway.
>
> First of all, just to put things in a little bit of perspective, 80
> percent, based on a number of studies, of antimicrobial usage in
> hospitals is for empiric therapy. Empiric therapy, right now, is
> not\--there is no indication for empiric therapy. Our regulatory
> agencies have no direct input in educating physicians about empiric
> therapy.
>
> The way the industry approaches this is to try and get many
> indications that are regulated to make physicians feel comfortable
> that those patients who have an unknown source of infection can be
> safely treated.
>
> But one of the most common causes of infection in the hospital for
> which empiric therapy is given is the one that you are considering
> which is primary bacteremia. So I think it is an important issue in
> terms of actually being able to speak to physicians about how they use
> the antibiotics in the hospital.
>
> So I just wanted to emphasize what I think is the importance of the
> topic that you are considering to clinicians and patients.
>
> The other thing I would point out is that, and maybe Jan Patterson can
> actually correct me if I am wrong here, but there are a number of
> epidemiological studies mainly from the CDC which have indicated that
> approximately 80 percent of what we call primary bacteremia is
> probably catheter-related bacteremia which has not otherwise been
> documented. Although the data that support that are kind of indirect
> based, again, on epidemiologic deductive reasoning, I think it is a
> reasonable deduction and it does come from the CDC.
>
> In terms of the issues around metastatic infections that you have been
> thinking about, and I think John Powers made this point, and the
> timing of metastatic infection, I think a lot of these patients who
> develop medication infections during the course of therapy probably
> had it at baseline or close to baseline.
>
> I don\'t know how many of you have gotten CAT scans on patients with
> left-sided endocarditis, but I have. You find a lot of things in there
> that you didn\'t suspect clinically and I am sure that a lot of that
> exists. The question, then, is can the therapy that you give over a
> period of time resolve those preexisting, probably, metastatic
> infections. I think that is one of the things that you get at in a
> trial like this.
>
> Finally, I will point out that I don\'t know how long it has been
> since a sponsor has submitted for an indication for endocarditis, but
> I think it has been a long time. This pathway would be a way to
> encourage sponsors to get back into the business of endocarditis. I
> think, without something like this, it is going to be hard for that to
> happen. So I think that is another reason to seriously consider this
> sort of indication.
>
> So I will stop. Thanks.
>
> DR. LEGGETT: Any questions for Dr. Shlaes? Jan, did you have any
> comment about the CDC?
>
> DR. PATTERSON: I would agree.
>
> DR. LEGGETT: Thank you.
>
> I would like to thank all the speakers who spoke during this session
> which will now be closed. We will continue with discussion of issues
> in studying catheter-related bacteremia. Dr. Janice Pohlman.
>
> Sorry; John?
>
> DR. BRADLEY: Not to complicate things more but, as we talk about
> organisms causing bacteremia, I certainly agree with separating Staph
> aureus from Staph epi and focusing on catheter-related and infective
> endocarditis. However, in pediatrics, there are at least two other
> entities that involve the catheter. One has to do with a neutropenic
> child who has got horrible mucositis and gets fevers and presumably a
> transient bacteremia from rectal ulcerations, occasionally oral
> ulcerations, so the organisms in the bloodstream reflect both gut and
> oral flora.
>
> Secondly, as the neonatologists get better at saving the smaller and
> smaller babies, there is a whole cohort of children with short-gut
> syndrome. As those children have their oral feedings increased, we see
> a fair amount of translocation of gut flora. These kids all have
> catheters in for parenteral nutrition and, when they get fevers, you
> draw the blood cultures and it has got flora. Subsequently the
> catheters remain infected because they have been in for a while and,
> presumably, the organisms that they are bacteremia with stick to the
> catheter.
>
> Then you have to deal with an infected catheter. Although the source
> is probably the gut, there is no identifiable source, no erosion that
> you can point out. So, as we simplify things, I also want to
> complicate things.
>
> Thank you.
>
> DR. LEGGETT: Thank you. Dr. Pohlman.
>
> **Issues in Studying Catheter-Related Bacteremia**
>
> DR. POHLMAN: I learned that there is a problem being the last speaker
> of the day and that, aside from sort of the post-prandial siesta,
> people have already stolen your thunder and your talk, so I will try
> not to be too repetitive. But I don\'t want to get too far off track.
>
> (Slide.)
>
> The focus of my presentation this afternoon is to revisit the existing
> catheter-related bloodstream guidance document.
>
> (Slide.)
>
> I am going to start off\--I won\'t go through this whole slide but
> sort of why we got there. As we mentioned, the numbers are subject to
> all our estimating, our surveillance data estimations. Prospective
> studies have identified attributable mortality rates as high as 12 to
> 25 percent depending a little bit, primarily, on the pathogens that
> have been isolated in those studies.
>
> Again, the main epidemiology that we are looking at are the
> Gram-positive organisms, coagulase-negative Staph and Staph aureus
> with the other organisms falling somewhere down the list dependent on
> the patient populations you are looking for.
>
> There is, obviously, a paucity of randomized clinical-trial data in
> the study of CRBSI. I guess I would add when this guidance document
> was developed, it was in the face of increasing antibiotic resistance
> and the institution of vancomycin utilization control strategies.
>
> (Slide.)
>
> In terms of going back to where we were in 1999 and sort of the
> discussion, the issues, obviously, are still there. As mentioned, we
> did\--in the guidance document, there were clinical criteria that were
> established to sort of help guide us to prospectively identify a
> patient that might be at risk from a catheter-related bloodstream
> infection.
>
> However, we recognized that there was lack of pathognomonic signs and
> symptoms of catheter-related blood-stream infections. The clinical
> criteria fever is nonspecific. There was one study that said that up
> to 80 to 90 percent of new fever in the ICU is not related to
> catheter-related blood-stream infection.
>
> Catheter exit-site inflammation is not very sensitive. Perhaps 85, 90
> percent of catheter-related infections in prospective studies are not
> associated with any inflammation at the exit site.
>
> I think it was recognized that this was a very complex undertaking,
> tremendous heterogeneity in terms of the patient population, whether
> patients were acutely or chronically ill. The catheter types; was it a
> tunneled catheter or a non-tunneled catheter. Were these catheters in
> place for short-term or long-term duration? Certainly, we recognize
> that there is a difference in virulence of causative pathogens.
>
> (Slide.)
>
> I think the bulk of discussion at the previous advisory committee
> revolved around these two issues. One was how do we go about
> establishing the diagnosis of a catheter-related blood-stream
> infection. In terms of employing microbiologic criteria to determine
> that the catheter is involved with the infection as opposed to a
> clinical diagnosis of exclusion, bacteremia in a patient with a
> catheter and no other focus of infection presuming a reasonable
> strategy depending on the clinical presentation of the patient to rule
> out another focus.
>
> Then another big topic of conversation was the use of microbiologic
> criteria to identify the catheters as the source of the blood-stream
> infection. I think there were a number of issues in terms of
> discussion, a little bit of thresholds for what these criteria ought
> to be. The literature, if you look at the literature, you can find a
> variety of thresholds that are used.
>
> The problem is if you set your threshold for sensitivity too low, you
> are going to lose some specificity in the overall diagnosis.
>
> (Slide.)
>
> Some additional issues that didn\'t garner as much conversation but
> were recognized as potential pitfalls in the study were the inability
> to estimate the magnitude of the antimicrobial treatment effect versus
> just catheter removal for organisms of low virulence that colonize the
> skin.
>
> We talked a little bit before about the ramifications of adjunctive
> catheter removal post-randomization and initiation of therapy where,
> if an investigator should decide the catheter is not needed anymore
> and pull it, what we would look at in a clinical trial as a clinical
> failure because the catheter is coming out even though there might not
> have been an indication of failure.
>
> The last topic was whether we use clinical or microbiologic endpoints
> to define treatment efficacy. By that, I mean test-of-cure blood
> cultures.
>
> (Slide.)
>
> We heard a little bit before, and I really was trying to be discrete
> in terms of identification although this information was presented
> publicly at a workshop in an April, 2004 joint FDA-IDSA-ISAP workshop
> on catheter-related blood-stream infections. We have seen this data
> earlier that, out of 200,630 patients that were screened for potential
> admission to this catheter-related blood-stream infection, 75, or 2.8
> percent of the population, were ultimately enrolled in the trial.
>
> The primary reasons that were outlined were that 30 percent of the
> patients did not meet the microbiologic criteria for diagnosis. It
> isn\'t clear to me whether or not it was the fact that\--I gather that
> it was that the cultures were not obtained versus the culture results
> were not definitive by the microbiologic criteria laid out, although
> that wasn\'t totally understood. And 20 percent, with some overlap,
> with the other exclusion criteria were excluded on the basis of prior
> antimicrobial therapy.
>
> (Slide.)
>
> So I am just trying to garner\--at the point when we were putting this
> together, we had that information that had been presented publicly. So
> I was trying to establish how easy or how difficult is it to enroll
> patients in the trial figuring that the number of patients that meet
> the microbiologic criteria for the definition of CRBSI might relate to
> the method of screening.
>
> There was a published report of a Phase II trial for the treatment of
> CRBSI using an approved drug where 23 out of 39 patients, or 59
> percent, enrolled had evidence of Gram-positive bacteremia or
> infection.
>
> Then, along with additional pharmaceutical-industry experience where
> 25 percent of patients identified by clinical criteria and/or local
> inflammation met minimal microbiologic criteria for the diagnosis of
> CRBSI. That would include a peripheral blood culture plus a catheter
> exudate or exit-site culture.
>
> I probably stand a little corrected because I don\'t have specific
> screening data on the total population screened. So I apologize
> because those numbers may overrepresent the number of patients that
> were actually studied. But when I was going back and looking at
> diagnostic methods, when you look at prospective studies of patients
> with clinically suspected CRBSI\--and this was primarily in the trials
> that were looking at differential time-to-positivity\--they yielded
> approximately 10 to 15 percent of subjects with microbiologic evidence
> of catheter-related blood-stream infection.
>
> The 10 to 15 percent rate, however, the patient populations that were
> primarily studied in these were cancer patients with long-term
> catheters. Actually, the largest study, I think it was only 4 percent
> of their population had microbiologic criteria that fit
> catheter-related blood-stream infection.
>
> (Slide.)
>
> So what has happened since the advisory committee in 1999? We have had
> the guidelines for the management of intravascular catheter-related
> infections released, a joint effort by IDSA, American College of
> Critical Care Medicine and SHAE. However, they are evidence-based
> recommendations. The data to support the recommendations is based on
> small clinical trials and not randomized controlled clinical trials.
>
> The problem with using these to somehow develop our guidance, the
> guidelines, the management guidelines, assume that you already have
> effective therapy. They are useful for clinical practice but they are
> not designed to assess the efficacy of new antimicrobial therapies.
>
> (Slide.)
>
> Now, turning to the CRBSI microbiologic diagnostics, there are two
> pathways to go down. One is where the catheter is maintained and one
> is where the catheter is removed. Obviously, there are reasons to
> prefer the maintenance of the catheter, especially in patients in whom
> access is difficult.
>
> Historically, quantitative blood cultures have been the study
> methodology that people used. However, this is very\--there are not
> very many hospitals in the United States or, I would believe,
> worldwide that do this. It is very labor-intensive. I think the number
> at the last advisory committee was perhaps 5 percent of hospitals are
> doing quantitative blood cultures.
>
> The buzzword at the last meeting was this differential
> time-to-positivity which relied on automated blood-culture systems
> that\--basically, blood that was collected through the catheter became
> positive two hours or more prior to the peripheral blood culture.
>
> Some other additional investigational techniques, looking through the
> literature, an acridine orange leukocyte cytospin which, actually,
> takes a little sample of blood from the catheter, you spin it down and
> you stain it looking for bacteremia DNA. This method actually was
> used, I believe, to stain catheters in the past, whole catheters.
>
> There is also an endoluminal brush technique where you kind of go down
> the lumen of the catheter and then you culture the brush that you have
> used. However, I would say that those are pretty investigational.
> Stick to differential time-to-positivity.
>
> (Slide.)
>
> At the last advisory, there were two published studies that had
> indicated utility primarily in immunocompromised patients with
> long-term or tunneled catheters. A recently published study in the
> Annals of Internal Medicine in 2004 indicated utility in patients with
> both short and long-term catheters.
>
> However, when you look at the definition of short-term catheters,
> these were defined as catheters in place for less than 30 days. In
> terms of looking at the pathogenesis of catheter-related infections,
> we know that somewhere around up to ten days, the primary sites of
> colonization are the skin followed a little bit by the lumen in terms
> of direct contamination of the line. Long-term lines greater than 30
> days, you have primarily intraluminal colonization so that somewhere
> in that window of 10 to 30 days, you have a switchover from the
> primary site of colonization.
>
> One of the things that, when you look at these studies, and there were
> about six in the literature that I reviewed, the diagnosis of
> catheter-related bloodstream infection relies on some other previously
> studied methodology. There is not a gold standard. There is no
> quantitative gold standard. It looks at either in relation to
> semi-quantitative catheter tip or quantitative blood cultures.
>
> In terms of sort of what the results from this 2004 study, the
> sensitivity was lower in short-term catheters. Specificity was lower
> in long-term catheters. One of my problems when I read the literature
> related to this is that when you have concordant\--obviously, you need
> concordant blood cultures, the catheter and the peripheral. But what
> happens is that, when people don\'t fit the mold, when they have
> discordant cultures, oftentimes, there isn\'t enough information
> published about the patients that don\'t have concordance.
>
> I think sometimes there are some conclusions that are being reached
> that are a little bit of a stretch. But differential
> time-to-positivity, I think you need automated blood culture systems.
> You need some basic assumption on the process that those blood culture
> bottles are being inoculated evenly, that the processing time getting
> to the lab is the same.
>
> I guess, additionally, in terms of is there somebody there that can
> actually look at the bottle when the sensor goes off, is that really
> positive at that point in time or is that merely the sensor and the
> blood culture subsequently would not be positive at that point in
> time.
>
> So I think there are some things to keep in mind.
>
> (Slide.)
>
> Problems associated with catheter-maintained diagnostics. If you
> can\'t aspirate blood back, you can\'t have a catheter culture. Which
> lumen of the catheter should be cultured? The sensitivity of cultures
> may vary, again, as I mentioned, establishing the appropriate
> threshold for positive results.
>
> I think even in our current rendition of the guidance document, there
> is a catheter to peripheral ratio of 3:1 to 5:1. Which do we use?
> Problems associated in particular with quantitative blood cultures not
> available in many institutions. You can tell I didn\'t train or
> practice at an institution that had them because I think the
> turnaround time is even longer than the 48 to 72 hours. It may be as
> much as 72 to 96 hours.
>
> (Slide.)
>
> So if you want to take the other tactic and you are going to remove
> the catheter, the primary methods are quantitative or
> semi-quantitative catheter-tip or catheter-segment cultures. The
> problems associated with these; oftentimes, the catheters are removed
> needlessly when there is really not a CRBSI. As with blood cultures,
> they take time so both of these are retrospective. You don\'t have the
> answer when you are initially screening patients when potentially you
> could randomize and treat.
>
> Again, the establishment of appropriate threshold is the cutoff.
> Fifteen colonies is the appropriate cutoff, greater than 10^3^. It
> depends on methodology. Some of them are organism-dependent. There has
> also been a study that demonstrated potential inhibitory effect of
> antimicrobial-impregnated catheters on subsequent catheter cultures.
> That is totally an in vitro phenomenon but presumably if you had
> reasonably fresh antimicrobial-impregnated catheters and you don\'t
> include inhibitors in your media, you could actually inhibit
> catheter-culture growth.
>
> (Slide.)
>
> Then, in terms of the overall, do we really need this catheter-culture
> data? I think the general consensus of the 1999 advisory committee was
> yes, particularly when you are talking about an infection where the
> predominant pathogen is also the most frequent blood culture
> contaminant. If you are going to go down to using pulse-field gel
> electrophoresis to establish concordance, then probably yes, we should
> be looking at catheter data.
>
> You could also take the contrary viewpoint that, if you have a patient
> with a catheter, you isolate coagulase-negative Staph from the blood,
> you have two independent blood cultures that have that result, no
> other obvious focus of infection, that is a catheter-related
> infection. So you could take that tactic.
>
> We have seen alternative definitions proposed by the pharmaceutical
> industry. You see it in published studies, these categories of
> definite or probable or suspected catheter-related blood-stream
> infections in which patients with a catheter have a positive
> peripheral blood culture, hopefully, a second positive independent
> blood culture for organisms associated with skin contamination, there
> is no other secondary source of infection identified and the catheter
> cultures have either not been done\--the catheter was pulled and you
> don\'t have that as a source\--or there is no differential that is
> demonstrated.
>
> (Slide.)
>
> Then what I thought I would do before we try to consider where we are
> going to go from here is just kind of run through what the current
> guidance document says. The microbiologic criteria for diagnosis and,
> while I say these are criteria for diagnosis, they are actually
> included in the guidance document as inclusion criteria. We know we
> are not going to have these results at the time that the patient
> is\--or it is not likely that we are going to have these results at
> the time that the patient is randomized and therapy is initiated.
>
> But the requirement is for concordant growth of the same organism from
> peripheral blood in one of the following; quantitative catheter blood
> culture, catheter peripheral ratio of 3:1 to 5:1, quantitative
> catheter segment greater than or equal to 10^3^ colony-forming units
> or semiquantitative catheter segment greater than 5 colony-forming
> units regardless of pathogen, culture of the inner catheter hub
> greater than or equal to 10^3^ colony-forming units for skin
> colonizers, any growth for other pathogens, culture of catheter
> entry-site exudate regardless of pathogen, and culture of infusate
> regardless of pathogen.
>
> (Slide.)
>
> Concordance requires that you have growth of the same species with the
> same antibiogram and, as I mentioned, pulse-field gel electrophoresis
> is strongly recommended for skin colonizers. When one considers
> populations for analysis, the modified intent-to-treat population is
> defined by all randomized to meet the clinical and microbiologic
> inclusion criteria. That serves as the co-primary population for
> noninferiority efficacy analysis.
>
> Outcome of cure is defined as resolution of entry signs and symptoms
> and negative blood cultures at test-of-cure visit.
>
> (Slide.)
>
> Now what I would like to do\--this is a little bit separate from the
> questions but it is probably considerations based on the discussion we
> had this morning in terms of willingness to proceed or to go down the
> path of a primary bacteremia due to Staph aureus.
>
> I think the options that we have at hand, one is to maintain the
> current guidance. The pros for this: there is a systematic approach to
> study of treatment efficacy; it maintains a current level of
> diagnostic specificity; it is not organism-specific and may provide
> data on catheter-related blood-stream infections due to a variety of
> organisms.
>
> I think the cons\--we have already heard what the cons are in terms of
> difficult enrollment. It is hard to find the patients to actually fit
> these criteria to enroll in the studies; adjunctive catheter removal
> after randomization and initiation of therapy is problematic;
> antimicrobial treatment effect and infections due to low virulence
> pathogens is not known; and a single positive peripheral blood culture
> with a catheter-site culture raises issue regarding specificity of
> diagnosis, particularly for low-virulence organisms that colonize the
> skin.
>
> (Slide.)
>
> I guess if we maintain the current guidance, I would kind of like to
> get some feeling on whether the committee has any advice or
> suggestions for facilitation of clinical trials, what types of
> investigators, what types of centers, do you have a colleague that you
> want to volunteer or volunteer to be a principal investigator for some
> of these studies.
>
> (Slide.)
>
> The second option would be a modification of the guidance. In putting
> the word \"major\" here, it is perhaps a value judgment that I didn\'t
> want to put out there, but this would be sort of changing a
> definition. Eliminating the need for microbiologic criteria for the
> catheter-related infection would allow us to increase the number of
> patients eligible for inclusion and evaluability. However, it might
> decrease the specificity of diagnosis thereby decreasing the
> scientific rigor of the study.
>
> (Slide.)
>
> Perhaps third, and we touched on it briefly this morning, in terms of
> considering a catheter-related blood culture infection within the
> context of a primary bacteremia due to Staph aureus indication. I
> think the pros, in terms of this, would be that we are studying a
> virulent pathogen where antimicrobial treatment effect is better
> defined. Catheters are more likely to be removed.
>
> In terms of this last pro that is listed, you can actually look at the
> flip side of that and see a con in it, but it may increase the
> available population for study, although I think we have kind of
> talked ourselves out of doing the primary bacteremia Staph aureus
> indication. It would limit the patients that had catheters but it
> would have opened it up to patients with Staph aureus.
>
> In terms of the cons of doing this, it limits the variety of organisms
> we study. There are certainly catheter-related blood-stream infections
> that are secondary to coag-negative Staph.
>
> I think that, perhaps, there is still a lack of consensus on duration
> of treatment for uncomplicated cases. Does everybody treat for two
> weeks or do people choose to treat for four for uncomplicated cases?
> And then the problem of differentiating uncomplicated cases that
> become complicated on the basis of persistent fever or persistently
> positive blood cultures from early treatment failure in a
> drug-efficacy trial and need for additional diagnostic tests such as
> echo which certainly add cost to the study.
>
> I think, at that point, that concludes my formal remarks. If anyone
> has any particular questions?
>
> **Questions from Committee**
>
> DR. LEGGETT: Don?
>
> DR. PORETZ: I just have a basic question. You say catheter, catheters.
> Are all catheters made of the same material? I mean, we are talking
> about it as if it is one thing.
>
> DR. POHLMAN: No.
>
> DR. PORETZ: Does that need to be broken down as to the type of
> catheters, the material it is made of, whether it is coated or not
> coated with antimicrobics?
>
> DR. POHLMAN: You know, that is a good question. The studies that have
> been done have examined\--there are different catheter types. There
> is, perhaps, greater association of infections or biofilm formation
> associated with certain types of catheters. Oftentimes, I don\'t think
> practitioners know whether or not antimicrobial catheters are being
> used\--you know, maybe whatever your supplier purchases.
>
> So, in terms of for studies, for companies that are going out, if you
> are not in control of that, a variety of things could be happening.
>
> DR. PORETZ: The data on the antimicrobic coated catheters seems to be
> pretty good. I mean, how popular are they at the present time? Are
> they selling? Are they being used commonly?
>
> DR. POHLMAN: I don\'t think I can answer that.
>
> DR. LEGGETT: John?
>
> DR. POWERS: Last summer there was a meeting of the Medical Device
> Related Infections Group which is a group of investigators that wants
> to study this. I think one of their major complaints\--this was in San
> Antonio last August. One of their major complaints was that these
> things were not being used as widely as they should be.
>
> We analyzed some of that data and their effectiveness is highly
> dependent upon how you defined a blood-stream infection. The way that
> blood-stream infections were defined in those was a positive blood
> culture plus a positive catheter tip associated with it. When you look
> at all blood-culture positivity, there is not much difference.
>
> Then a couple of people wrote back letters to the editor with these
> trials saying, well, wait a minute. If you culture the cath tip and
> there are antibiotics on the cath tip, that is going to make the cath
> tip look negative. So the question is should you be looking, defining
> blood-stream infections as positive blood culture plus a cath tip
> because that is going to falsely look low in the people that have
> coated catheters.
>
> DR. LEGGETT: Jan?
>
> DR. PATTERSON: I just wanted to comment that in the infection-control
> community, they are not widely used primarily due to expense reasons.
> The antiseptic coated catheters, the chlorhexadine-coated catheters
> which are intermediate between non-coated and the antibiotic coated in
> terms of lowering risk for blood-stream infection are more commonly
> used.
>
> DR. LEGGETT: I think it also depends on where you start. It might make
> sense if your catheter infection rates were very high. Ours at our
> hospital are so low that they couldn\'t possibly be any better.
>
> Thank you, Dr. Pohlman.
>
> **Questions to the Committee and Discussion**
>
> DR. POHLMAN: Did you want me to run through the questions here again?
>
> DR. LEGGETT: Yes; shall we attack the questions there and then come
> back\--okay.
>
> DR. POHLMAN: In terms of ending my talk, I think I have presented the
> options as sort of maintain, modify the guidance or study within the
> context of a primary bacteremia due to Staph aureus.
>
> In the interest of sort of continuing on from the morning discussion,
> what I am going to do is run through all the questions. I believe, two
> of the questions on this sheet dealt with catheter-related issues. But
> just to sort of remind us and refresh our memories where we were, I
> have been told to proceed on through the questions.
>
> No. 1 we did talk about extensively this morning, about the primary
> bacteremia due to Staph aureus as an indication, itself. What patient
> populations with Staph aureus bacteremia should be included in a
> clinical development program? Should bacterial endocarditis due to
> Staph aureus be a separate indication? If so, what additional
> information from clinical trials in serious Staph aureus infections
> should be available to support such a claim?
>
> In terms of the catheter-related blood-stream-infection questions;
> should catheter-related blood-stream infections have its own
> indication or should this indication be subsumed into a more general
> primary bacteremia due to Staph aureus indication?
>
> If it is a separate indication, what additional information on the
> treatment of serious Staph aureus infection should be available to
> support it? Can data on catheter-related infections with or without
> bacteremia be included as a subset of the complicated skin-infection
> indication? What specificity of diagnosis would be recommended
> especially regarding common skin organisms?
>
> And then the final two questions. Given that blood-stream infections
> due to Staph aureus have the potential to cause serious morbidity and
> mortality, what types of preclinical and early clinical information
> should be available prior to initiating large clinical trials? How
> many positive blood cultures are required prior to study entry in
> clinical trials of primary bacteremia due to Staph aureus?
>
> Question 8; I don\'t know. Should I read through this, John? Okay. For
> the interest of completion; screening patients for admission into
> clinical trials is complicated due to factors such as the potential
> for an occult primary source of infection. What advice can you provide
> regarding a general approach to screening patients? Should patients
> with an identified focus be entered or remain in trials? Is
> endocarditis a special case in this regard?
>
> DR. LEGGETT: Should we address them in order to discuss? Is that what
> you guys would like? Okay.
>
> Could we have somebody put the first question up on the screen so we
> could\--the question is, should primary bacteremia due to Staph aureus
> be an indication? If so, what results from our other clinical trials
> would, in general, be expected prior to proceeding with clinical
> trials?
>
> This morning, I don\'t think we completely wrapped ourselves around
> that. And with the comments of the Open Public Hearing speaker, Dr.
> Shlaes, I would like to have another little go at that and then, also,
> talk about what other clinical trials might take on the use of
> bacteremia for empiric therapy goes back to the point you don\'t know
> that that drug that stays very well in the bloodstream is going to go
> out of the bloodstream anyplace else.
>
> So, without other trials showing efficacy in other tissues, I don\'t
> know that that helps me very much to make that decision about using
> empiric therapy. I am sure I am going to get some debate about that.
>
> Yes, sir?
>
> DR. MALDONADO: Just a quick question. How do you define primary
> bacteremia because, in the morning, I sensed that there was not a very
> good working definition of what primary bacteremia\--I mean, the words
> \"primary bacteremia,\" people might think that is a blood culture
> that is positive. But I think that, in one of your slides, John, you
> attempted to actually define it with some other clinical caveats and
> that might actually help us to find out what the answer might be.
>
> DR. POWERS: We had some internal discussion about what we should call
> this. One of the issues that came up was based on that the committee,
> in the past, had told us that bacteremia is not a disease. The
> question was do you call it sepsis? What do you call it?
>
> We are open to any suggestions you folks might have but the reason we
> were hesitant to call it bacteremia is that, technically, that just
> means a positive blood culture and we had to link it to some clinical
> signs and symptoms in the patient. That is why, when I put up that
> definition, that was in there of clinical signs and symptoms that go
> along with it.
>
> But you are right. It implies just the positive blood culture.
>
> DR. LEGGETT: Don?
>
> DR. PORETZ: But, surely, you have seen enough patients in an emergency
> room to look at and say, this patient is sick. This patient may be
> bacteremic. They are having shaking chills. They are febrile. They
> have a high white count and your best medical opinion is you need to
> get them on an antimicrobic.
>
> So you go over them and you examine them and their lungs are clear and
> their chest X-ray is negative and there is no pneumonia. And you get a
> urinalysis and the urine doesn\'t show any white cells or no evidence
> of infection. And their belly exam is completely normal. So it is
> probably not an intra-abdominal process but yet you are really worried
> about them.
>
> They have no skin infection. You are worried about them saying they
> are really sick, and I need to put this person on an antibiotic. The
> white count is 20,000. That is a clinical decision you make. I am not
> sure it is that hard, really. So there are people who will come in and
> you say the patient is sick and the patient looks like they could be
> bacteremic. We find no other cause. We are going to put them on an
> antimicrobic anyway. You are going to draw blood cultures anyway;
> right?
>
> Yes, it may turn out that the following day they will blossom into a
> pulmonary infiltrate or something else will happen but, nevertheless,
> I think that is a valid clinical decision at that time.
>
> DR. POWERS: I think there is an issue of what Sam was bringing up.
> There is the other end of that spectrum, similar to what Jim said.
> Bacteremia, if you just look at the word, could also mean the guy that
> had one blood culture for Staph epi that pops us six days into the
> time he is sitting there and you walk into the room and he is reading
> the newspaper and he looks fine.
>
> That is what we don\'t want in bacteremia drugs.
>
> DR. PORETZ: But that is not the person we just described who you are
> examining?
>
> DR. POWERS: Right; exactly.
>
> DR. PORETZ: So you don\'t include that in your definition.
>
> DR. POWERS: Right. Sam\'s issue was bacteremia as a definition.
>
> Let me bring up another, though, and that is that the FDA doesn\'t
> really have empirical therapy indications except in one spot and that
> is febrile neutropenic patients because what we want to know in
> clinical trials is exactly what Jim just said. We want to know that
> the drug works in a defined disease.
>
> The fact that you choose it to use it for empiric therapy is because
> you know it is going to work in that particular setting if the
> patient, in fact, turns out to have the disease you think they might
> have. But, in terms of studying it, one of the biggest issues, when I
> showed those two big circles on the graph, was actually picking out,
> first and foremost, in a clinical trial who has the illness you are
> trying to study.
>
> So we probably don\'t want to go down the path of designing an
> empirical therapy kind of study in this indication.
>
> DR. LEGGETT: Janice?
>
> DR. SORETH: I am trying to remember what I was going to say. Oh; I
> know. I think, to come back to Dr. Poretz\' point, as well as Sam\'s,
> I think that we probably all readily agree on what patients look like
> and what they are labs look like and their studies look like when they
> endocarditis and they have Staph aureus in their blood, and that
> labeling drugs for that patient population makes sense.
>
> We have done it in the past and we really would like to do it again.
> So we are happy that there is some ongoing inquiry in this arena in
> endocarditis.
>
> That said, to come back to the patient you described, again, like
> pornography, God, I know it when I see it. We are just trying to
> agree, if we can, in the setting of a clinical trial, what the
> appropriate inclusion/exclusion criteria would be for those patients
> and that, if we can agree on that, it would seem to me, then, to make
> sense to so label a drug study that had an appropriate risk/benefit
> ratio for you and all the other physicians who are faced with that
> person in the E.R., on the ward at 3:00 a.m., in the boondocks, et
> cetera, because it would seem, perhaps, that that would merit
> labeling, perhaps in a package insert. If not, then that is why we are
> here today to talk about why not.
>
> DR. LEGGETT: Jan?
>
> DR. PATTERSON: Well, I would agree with the definition of primary
> bacteremia that is on Slides 3 and 4 of Dr. Powers and that is the
> signs and symptoms of infection with positive blood culture for Staph
> aureus, no identified source at the time of enrollment and then, on
> Slide 4, saying bacteremia related to an intravascular catheter, often
> a diagnosis of exclusion so it may be logical to include in this
> category.
>
> With diagnosis of exclusion, I think that a physical exam, an
> echocardiogram, preferably a TEE, a chest X-ray and probably a C.T.
> abdomen preferably with contrast would be the screens I would use to
> exclude other sources.
>
> But I would feel very comfortable including catheter-related
> bacteremia in that definition of primary bacteremia of Staph aureus. I
> think that it is logical to differentiate it from coag-negative Staph
> because it is very different than that. It is much more of an acute
> and invasive disease and it is more important disease. It is becoming
> more and more common and I think that leading to a possible indication
> of endocarditis is important because we are seeing more endocarditis.
>
> We don\'t know that we have an ideal treatment right now and there are
> more drugs to treat it so what should be use. I think that is really
> an unanswered question.
>
> DR. LEGGETT: My two bits and then give it to Alan about primary
> bacteremia. One of my colleagues, not to say my boss, is a stickler
> for using erysipelas when you are talking about a Group A
> streptococcal infection and everybody else in the world calls it
> cellulitis. The problem with the primary bacteremia is that we all
> know what we are talking about. It is the pornography issue.
>
> So I don\'t know that I would be so hung up about using something that
> all clinicians understand. But you have got other issues. I understand
> about that.
>
> Alan?
>
> DR. CROSS: I just wanted to reemphasize the obvious. Although this
> first question is talking about primary bacteremia due to Staph
> aureus, sometimes our discussions here were lapsing into Staph epi or
> coag-negative. They are quite distinct entities. I think we have to
> really bear this in mind.
>
> But, John, in your excellent review, did you happen to find out\--how
> often does Staph aureus bacteremia occur in the absence of fever,
> white count or any other clinical symptoms? I am sure it occurs but do
> we have any handle on that?
>
> DR. POWERS: All we know is looking at endocarditis studies in the
> past, the number that gets quoted in those is 5 percent. So it is not
> impossible for it to occur, but it doesn\'t\--but then, again, I think
> it is what Dr. Poretz brought up, you don\'t go looking for it unless
> the patient has those signs and symptoms to start with. So it becomes
> very circular reasoning.
>
> DR. CROSS: But the point is we are not going to have a person sitting
> in bed reading a newspaper with a Staph aureus bacteremia unless
> they\--
>
> DR. POWERS: And I think that gets back to what Dr. Patterson said
> about that, but that can happen with Staph epidermidis. The question
> is separating those out.
>
> DR. LEGGETT: Nate?
>
> DR. THEILMAN: I was wondering if we could ask Barth Reller to comment
> on that because he did a very large study of blood cultures in the
> 1990s, I believe, and characterized all bacteremias with regard to
> their significance. Correct, Barth?
>
> DR. RELLER: To comment and, in part, address that and follow up on
> Don\'s comments. One of the difficulties I think we have in grappling
> with these terms that have been used is yes, for an experienced
> clinician, it is straightforward of what to do. But that is different
> from what the requirements are for infection-control practitioners in
> categorization for nationwide survival for NIS which, I believe, and
> Jan, correct me, if that is not where the concept of primary and
> secondary bacteremia are embedded in the literature and practice.
>
> So it was done for NIS to capture those persons who have an
> identifiable focus and the bacteremia is perceived to be a consequence
> of that versus primary bacteremia. The reality is, with the primary
> bacteremias in that definition, with coagulase-negative
> staphylococcus, we know that there is a lot of noise because, when
> Jerry Tocars looked that, maybe 30 percent, maybe more, of the ones in
> that definition, a single positive blood culture for coag-negative
> Staph and intent-to-treat which no one here would accept for entry
> into a clinical trial.
>
> Now, the point of this is that for epidemiological purposes, at least
> 80, maybe 90, percent, maybe 95 percent, of primary bacteremias with
> coagulase-negative staphylococci are, in fact, catheter-associated.
>
> With the other bacteremias that the committee, in past deliberations,
> have shied away from, this idea of spontaneous\--everything has a
> source. I think the field has evolved so that one has pneumonia where
> bacteremia may be present and adds great specificity so you have
> pneumococcal pneumonia or lower-respiratory-tract infections,
> pneumococcal pneumonia accompanied by bacteremia or you have
> complicated urinary-tract infection accompanied by E. coli bacteremia.
>
> So the labeling may be including bacteremias. So it is approved for
> complicated urinary-tract. It is approved for lower-respiratory-tract
> infections, community-associated pneumonia, including those that have
> bacteremia with pneumococcus.
>
> The problem with Staph aureus bacteremia is, in Don\'s patient, if he
> identified a focus, it would be a priori a secondary bacteremia. Easy.
> But the reality is, I think, that most, or a very good share, and an
> increasing share, of staphylococcal bacteremias, especially those that
> are healthcare associated, whether coming into the hospital from
> chronic dialysis, et cetera, there is not a necessarily confirmed
> source so that one has a disproportionate number of what would be, for
> epidemiological purposes, classified as primary bacteremia and many of
> those are associated, either chicken or egg, with catheters.
>
> The studies more recently increasingly show that, especially
> healthcare-associated and especially those with diabetes and long-term
> catheters and tunneled catheters, that, although it may have started
> with the catheter, a break in the skin and get in through the
> catheter, that there are a lot more complications associated with that
> including that most staphylococcal endocarditis now is not Nolan and
> Beaty 1976 community-associated but most staphylococcal endocarditises
> are hospital-acquired and they are associated with the catheters and
> the need to separate out that.
>
> So I think that one of the difficulties on this coming to agreement
> that there really is agreement of the uncomplicated staphylococcal
> bacteremias is the constraints of the past of the definitions for NIS
> and the concepts of bacteremia as a complication of a primary source
> of infection, and the two in a very complex way, intersect here. The
> ones that are straightforward, that get the shorter course of therapy
> and are readily recognized and the ones that, boy, depending on how
> you search, the horse may already be out of the barn and they will
> come back to bite you if you don\'t recognize those and if you give
> short-course therapy you are going to be sorry.
>
> To me, I know it is a long comment, but I think that is part of the
> reason that it is difficult, even though there is agreement, to get a
> handle on what is the definition for the purpose of enrollment in a
> clinical trial that is doable.
>
> DR. LEGGETT: Any ideas?
>
> Don?
>
> DR. PORETZ: Just a matter of semantics. We are looking for sources of
> the infection. Consider the use of the term \"entry site.\" Maybe it
> was just a break in the integrity of the integument of the skin or a
> mucous membrane. That could have been the entry site.
>
> I don\'t think it has to be a source of infection. It doesn\'t have to
> be an abscess or a cellulitis. So maybe consider the term \"entry
> site.\"
>
> DR. LEGGETT: Or what we always say, \"portal of entry.\"
>
> Barth.
>
> DR. RELLER: I think others should speak first. But I won\'t forget.
>
> DR. LEGGETT: Okay.
>
> Sam?
>
> DR. MALDONADO: John, I know that empiric therapy has actually worked
> well apparently regulatoryally for patients with fever and neutropenia
> and also clinically. The reason I said that, I mean, when you, as a
> clinician, see a patient, you don\'t treat, really, a bacteremic
> patient with Staph aureus. You treat a patient, period.
>
> You treat a clinical presentation. That doesn\'t mean that you will
> disregard, when you are looking at your endpoints, the microbiology.
> But if that clinical presentation is well defined, even regulatoryally
> defined, what kind of patient you are trying to capture. For example,
> a patient who has a systemic inflammatory response syndrome and you
> can define it, whatever, if you think that some of those definitions
> are not independent. There are ways to lump them, for example; for
> example, hypothermic tachycardia/tachypnea, either of those, and
> leukopenia or leukocytosis.
>
> So that is a clinical presentation that actually, as Dr. Poretz said,
> that is what you see when you get a patient and that is what makes
> you, as a clinician, treat the patient.
>
> Why wouldn\'t it work, if it has worked regulatoryally and clinically
> with immunosuppressed patients, in patients who are not
> immunosuppressed.
>
> DR. POWERS: I think it is way too broad to say that there haven\'t
> been regulatory issues with empirical-therapy trials in the febrile
> neutropenic population first and foremost of which if you even take
> something like antifungal therapy, we have no idea what the benefit of
> amphotericin B over placebo is.
>
> We made a decision in 1995 that we were going to set that margin at 10
> percent but we had a meeting at the Bacterial Mycosis Study Group last
> year about all these issues regarding empirical therapy. It has not
> been easy, including a five-component composite endpoint that we have
> heard all sorts of comments about.
>
> So, to just sort of say that that is easily regulatoryally done, I
> don\'t think that that is actually the case.
>
> The other issue is what Dr. Reller was bringing up earlier about the
> reason we divide these indications into specific body sites is because
> each of those has a different natural history and a different
> progression and things that happen. We know that when a person shows
> up in the emergency room, I mean, it is not just that clinical
> presentation. What you are doing is doing a good history and physical
> trying to find out where the portal of entry might be or at least try
> to come up with that best guess.
>
> So what we are trying to say is to differentiate between management of
> patients and determining the efficacy of a new drug. It is fine that
> you decide to manage your patient by empirically giving the drug but
> you do that because you know that drug is already effective for
> treating those various diseases that you are worried about. That is a
> different setting than actually trying to determine whether a drug is
> effective or not in an experimental setting.
>
> DR. LEGGETT: Jan?
>
> DR. PATTERSON: I think one of the things we were asked to address is
> what would make it easier to do these studies and still have good
> scientific data.
>
> I think one of the things we have been talking about, and I agree
> with, is that we could extend the time on antibiotics to 48 hours for
> Staph aureus. I think there is not going to be a difference in outcome
> between 24 and 48 hours of therapy. So that is one thing we could do.
>
> Then I was intrigued with Dr. Powers\' comment about not using the
> positive blood cultures in the lab to screen but starting it
> empirically. I think the problem with that is then\--for instance, one
> of these studies, 30 percent of the people that were excluded it was
> because they lacked microbiologic data.
>
> So you wait for the positive blood culture and allow a little more
> time on antibiotics or you have more people that you screen that
> don\'t get to stay in the study. So it is kind of a balance. But I
> think if we did allow more time on antibiotics, particularly 48 hours,
> that that would help some.
>
> DR. LEGGETT: There is no free lunch. You either enrich your population
> or you dilute it and there is a problem either way.
>
> Don?
>
> DR. PORETZ: But I have been at the other end trying to get patients on
> protocols. It is very, very frustrating and very difficult. You can\'t
> get the patient on a protocol because it is too late or the
> culture\--all those things that have been mentioned. I think, for
> pharmaceutical companies who want to do these studies, it makes sense.
>
> You may end up putting more people on at the time the patient is
> originally seen, and many of those people may not be evaluable. But
> accept that as a fact. I think you will get more results than you will
> at the other end by restricting the number of people you can put on a
> protocol.
>
> DR. LEGGETT: Alan?
>
> DR. CROSS: I would like to emphasize that. I mean, actually a point
> they made this morning is to just start people right at the outset
> and, at that point, enroll them in the trial and prospectively define
> how you will handle endocarditis and perhaps other complications.
>
> I think that probably, Tom, it is worthwhile mentioning a discussion
> was had after that. Tom brought up the very valid point of what
> happens, for example, with certain biologics for sepsis when lots of
> people were enrolled on the agent and then prospectively analyzed only
> those Gram-positive bacteremia.
>
> Tom made the important point that, when you do that kind of
> study\--that is, enroll lots of people but prospectively define a
> subpopulation\--that you still have to follow all those you enrolled
> who didn\'t qualify with your Staph aureus bacteremia. You still have
> to follow them in terms of outcome and safety.
>
> But I think that is doable. I would rather capture patients up front
> seeing how difficult\--and I have had the exact same experience that
> Don has had.
>
> Lastly, I still wonder about just the operational point which I think
> still has some validity about Staph aureus bacteremia due to \"a
> removable and non-removable focus.\" That is something that most
> people understand and there already is at least some paradigm about
> how you might treat those two patient populations differently.
>
> DR. LEGGETT: Joan?
>
> DR. HILTON: I would like to come back to some study-design issues and
> to return to your statement earlier about the purpose of performing
> clinical investigations is to distinguish the effects of a drug from
> other influences such as spontaneous change in the course of the
> disease.
>
> What I picked up on there was change in the course of the disease. I
> think, when we use a cross-sectional study design, we assume that all
> the patients are similar at the starting point. I think that is not
> what we have got here.
>
> To address that, I have a couple of different proposals. One is to use
> a longitudinal outcome. One possibility is time-to-treatment-failure
> but I think something that would be a lot more sensitive would be some
> type of a continuous response. Maybe the one that Janice suggested,
> differential-time-to-positivity, or some others, could be put on the
> table. But anything that captures the patient\'s status at baseline
> would be a lot more sensitive to use.
>
> To address the heterogeneity in the pool of patients and this issue
> about baseline, the duration of the baseline period during which you
> collect data and characterize those patients, we want to know who the
> responders are. We need a lot of baseline data in order to
> characterize who responds and who doesn\'t.
>
> Ideally, that is all collected prior to randomization. But if it is
> collected on a very strict per-protocol basis, it could still be
> collected for some window of time post-randomization and still be used
> as a covariate in the analysis. So a couple of possible variables I
> was thinking of.
>
> Another one is whether or not the device is removed during the study
> follow-up period. There is an example, not of a baseline sort of
> covariate but as a time-dependent covariate. So, again, if you have
> got a longitudinal outcome variable, you can analyze a time-dependent
> covariate. So I think there are a lot of reasons to be a little more
> flexible with the study design and use some of these.
>
> DR. LEGGETT: John?
>
> DR. POWERS: I think we have thought about some of the issues of
> looking at longitudinal outcomes and actually adjusting for some of
> those things that occur post-randomization. We have talked a little
> about that internally. It depends what outcome you are going to look
> at longitudinally or if we are going to use\--you are suggesting,
> like, time-to-analysis?
>
> DR. HILTON: I think that is one possibility but I prefer, myself, some
> sort of a continuous repeated-measures variable.
>
> DR. POWERS: Because we looked at\--if you take something like this
> that has a high mortality, whether you die on Tuesday or die on
> Thursday doesn\'t seem very clinically relevant. So, depending upon
> which outcome you are following over time, it may be either useful or
> not useful. Time-to-death probably doesn\'t make any sense. Time-to
> analyses have been used in HIV trials;
> time-to-loss-of-virologic-response, but that is a chronic ongoing
> illness. Time-to-death here probably doesn\'t make a whole lot of
> sense.
>
> DR. LEGGETT: Did you want to add something, Janice?
>
> DR. SORETH: I was just chuckling at John\'s pronouncement that it
> didn\'t matter whether you died on Tuesday and Thursday. It probably
> did to the patient who died, but that is neither here nor there.
>
> DR. LEGGETT: John and then Chris.
>
> DR. BRADLEY: The whole concept of primary bacteremia is something that
> we are trying to both acknowledge that there is a clinical definition
> and define for a study. From old data, it is clear that we all
> actually have intermittent bacteremia all the time, so a primary
> bacteremia with no focus is not unusual.
>
> For the patients that end up, whether they are children or adults that
> end up coming to medical care, they probably have other factors that
> are involved in a persisting continuing bacteremia even if there is no
> particular focus. In many of the kids that we see with osteomyelitis,
> you may find a skin lesion, a portal of entry, which isn\'t an
> abscess, doesn\'t look like something that you would even give a
> second thought to ordinarily, but when you examine a child who has got
> osteomyelitis for their entry site, more often than not, you can find
> it.
>
> So, whether we define primary bacteremia as bacteremia with no focus
> and whether you are including the skin as the focus or not, I think,
> is just semantics. If you exclude skin, if you say, sure, you can have
> an entry site but it is not considered a focus of infection, I would
> be happy to consider that primary bacteremia.
>
> Likewise, if there is a gut focus from these kids with short-gut
> syndrome, I would agree to define that as primary bacteremia even
> though you can probably define where the organisms are coming from. It
> is how we define it for the study.
>
> In terms of enriching for those patients who look like they are septic
> and are more likely to have bacteremia, I think the sicker you are on
> the spectrum, the more likely you are to have actual bacterial
> infection. With pneumococcus, this was beautifully demonstrated in
> children. So, in designing a study, we can either go with making them
> febrile, have systemic inflammatory response with shock and have very
> few enrolled but, of those enrolled, many will actually be bacteremic
> versus saying, well, anyone with fever and an elevated white count can
> go in, in which case, you will be enrolling many who don\'t have
> bacteremia. It will be a more sensitive test but the specificity and
> how easy it is to actually evaluate their outcomes would be much more
> difficult.
>
> I would favor enrolling the more severe patients. The one that you
> described would be the one that I am particularly interested in
> capturing and seeing if a drug works.
>
> DR. LEGGETT: Chris?
>
> DR. OHL: Since I put my hand up, I think a lot of the comments have
> been addressed. One word of caution. I think we need to be careful and
> I am probably stating this for the record more than anything, but
> going down a slope of going towards empiric treatment of sick people
> with antibiotics, we have got to be careful. I don\'t think that is
> really the intention of this. But I just want to make sure that is on
> the record.
>
> We are going to need to continue to have to have definable infectious
> disease states at some point or another. Then I am very happy to hear
> Alan\'s comments straight after that, and I am not going to repeat
> them all, but I think that there may be some meat in there that might
> be helpful as long as the clinical trials can be designed to fruition
> so that we don\'t end up repeating the same thing with catheter
> infections where we have to enroll an inordinate number of people.
> There may be some ways to do that and maybe now is not the time to
> discuss all those.
>
> I think, within this purview, including catheters in that discussion
> is genuine and can be done because it is the clinical reality that is
> a good amount of them. I think Jan\'s ideas of a reasonable number of
> studies up front to rule out those primary infections that we would
> reasonably look for as clinicians in the first few hours of infection
> is also reasonable.
>
> DR. LEGGETT: Tom and then we can decide whether we want to take a
> break or keep pressing forward.
>
> DR. FLEMING: I would like to revisit a couple of the issues that we
> have talked about here. One relates to how can we allow for easier
> enrollment into these trials so that they are more achievable. If we
> need, for example, 300 patients to evaluate treatment effects or 300
> per arm, whichever it turns out to be, if we are modifying the
> enrollment criteria in ways that increase the number of people who we
> have in our analysis, then that is, in fact, a step ahead.
>
> So if we are saying, for example, that we are going to allow 48 hours
> of anti-Staph treatment rather than 24, such that we are substantially
> increasing the number who are eligible and will be retained in the
> analysis, if we believe that we haven\'t diluted the focus of our
> assessment, we will, in fact, have gained substantial efficiency. I
> think that is very rational.
>
> On the other hand, if we allow for easier enrollment of people who we
> are expecting, in all likelihood, to, in large fraction, be excluded
> based on subsequent assessments that are made, then we are not coming
> up with any net increase in efficiency and I think we are actually
> complicated the analysis for reasons that Alan was referring to, that
> if you, in fact, end up enrolling 600 people but only analyze 300
> because, retrospectively, only 300 are really, in fact, meeting the
> eligibility criteria that you are interested in, you are technically
> now not coming out ahead.
>
> You still only have 300 but you have complicated the analysis because
> you now have 600 people that you have treated and you have to, in
> fact, assess the safety profile on all 600 which was, in fact, part of
> what led to problems in severe sepsis with agents that were targeting
> Gram-negative sepsis when they, in fact, were enrolling large numbers
> of people who ultimately were not eligible.
>
> So I would suggest that what we focus on here is ways of increasing
> the numbers of people who would actually be included in the final
> analysis. That will be, in fact, allowing us to make these studies
> more achievable.
>
> And then the other point; I would like to support a couple of issues
> that I think I heard from Dr. Hilton. One is that it certainly is to
> our advantage for us to be able, within what is practically
> achievable, to get as much baseline information as we can that will
> allow us to have a more efficient analysis based on our ability to
> define what are the characteristics of people at baseline that, in
> fact, might be predictive of outcome or effect modifiers.
>
> I also agree that, for the outcome measure, it would be important to
> try to capture what is really globally important here. So, rather than
> just focus on the blood cultures, certainly focus on signs and
> symptoms but also, I believe, the really critical elements of what
> happens post-randomization for metastatic infections and time-to-death
> and I.E.
>
> I do endorse what Dr. Powers was saying, though, about when you do use
> that global information, how do you do it? Do you use it as
> time-to-event or do you use it in some analysis method that takes into
> account all of the information but for death, for example, if it
> occurs, does it matter if it occurred at Week 1 versus at Week 2. So
> if, in the end, that Week 2 mortality is 30 percent but we have
> improved mortality by 5 percent at Week 1, but there is no improvement
> in mortality at Week 2, this is an acute setting and so time-to-event
> isn\'t in fact, particularly relevant there.
>
> Where time-to-event is relevant is in a chronic setting. It is not
> just whether the event occurred but how soon it occurred mattered. So,
> if we are talking about a 30-day outcome here, I wouldn\'t consider
> time-to-event as being additively informative but I would consider the
> multiplicity of different components of the endpoint to be very
> important.
>
> So if we just said success/failure, where failure is the occurrence of
> any one of the above, we might be losing information\--than if we were
> taking into account, in a more global multivariate fashion, did the
> patient die, did the patient have metastatic infection, did the
> patient have I.E., did the patient have clearance of signs of
> symptoms, did the patient have microbial clearance.
>
> So there are ways that we can increase the efficiency by taking into
> account all of the relevant aspects although I think the time-to-event
> aspect isn\'t additively informative.
>
> DR. LEGGETT: Barth. And then let\'s take a break. Go ahead and talk
> and then we will take a break.
>
> DR. RELLER: I would like to float a potential way out of the box for
> consideration. First, I think we might make more progress in building
> on a complicated/uncomplicated paradigm because there is a good
> history in the trials and regulatory arena with those definitions and
> leave aside, for the moment, primary/secondary NIS because,
> particularly in the primary related to catheters, I think there is
> some reconsiderations going there on what constitutes a good database
> for those. First point.
>
> The second is I think it would be easier to work with if we think of
> coag-negative and Staph aureus with two different approaches. I think
> what has been done for catheter-related bloodstream infections already
> related to coagulase-negative are pretty close to the mark, maybe some
> tweaking but pretty close.
>
> The reason for that is that almost all real coag-negative
> staphylococcal bacteremias, which is the minority of all of them, are
> device-related and, among the device-related, the most common, far and
> away, are catheter. I am aware of the lugdenensis, native-valve
> endocarditis or the lugdenensis like or\--et cetera. But I think that
> would be easier to deal with.
>
> Then, for the staphylococcal bacteremias, the way I am trying to put
> together everything that we heard today and from the past and the
> literature is I would conceptualize as complicated or uncomplicated.
> Okay; how do you define that?
>
> Well, complicated to me is\--or lets do uncomplicated first.
> Uncomplicated is with a specified search, the elements to be put in
> place, a doable, practical, financially feasible search that there is
> no source that is pathophysiologically recognized to be associated
> with bacteremia. There is no osteomyelitis, et cetera.
>
> Most of those are going to be associated with catheters so that what
> one would do there is to separate out those catheter-associated, or
> maybe catheter-initiated, that already have resulted in problems that
> are recognizable so that if you can\'t find any source and you have
> got a catheter, there is an uncomplicated.
>
> Then the complicated ones would be ones where you do already have a
> complication, the pyogenic arthritis, the osteomyelitis, the
> splenisepsis and including those with endocarditis. So a key point in
> the complicated ones is endocarditis yes/no because one could have
> osteomyelitis and endocarditis or septic joint and endocarditis and
> then the endocarditis yes/no has to do with the duration of therapy
> and the utility of TEE for management because in the endocarditis with
> Staph aureus, you have got the surgery/no-surgery aspect of it.
>
> So I think that may be a framework in which to get specifics around it
> that is congruous with the past and clearly those patients who have
> complicated denoting a source, most of those are going to fall, if not
> all of them, into the secondary if you were looking at from an
> infection-control practitioner\'s perspective.
>
> But I am thinking more in terms of clinical care, clinical-trials,
> perspective. So I think the epidemiological surveillance needs and the
> clinical-trial needs and the clinical-practice needs overlap like the
> Venn diagrams but they have their distinctive peculiarities that must
> be kept in mind in order to not get it into\--we all agree that we
> can\'t define dilemma.
>
> DR. LEGGETT: Let me see if I understand because if I do, everybody
> does. Uncomplicated would be whether or not you have a catheter but
> you can\'t already find a complication. Complicated would be, at the
> time of enrollment, you already have a complication.
>
> DR. RELLER: Basically, that\'s it, and including endocarditis at the
> get-go.
>
> DR. LEGGETT: John?
>
> DR. POWERS: We can ask this question after the break if you want.
>
> DR. LEGGETT: Go ahead.
>
> DR. POWERS: The question is that the issue that we came up against was
> those complications may occur within a short period of time. So, in
> other words, you get enrolled in the trial and\--you get enrolled on a
> Friday afternoon, heaven forbid. Your echo isn\'t getting done. We all
> know that. And it gets done on Monday so you are three days into the
> trial and your echo is positive.
>
> Now you have a complicated infection but you got enrolled in the
> uncomplicated trial. And then there is another one. Then the second
> thing is those complications are not all the same. How would we lump
> together osteomyelitis, septic pulmonary emboli, endocarditis all into
> that complicated?
>
> DR. RELLER: I am trying to remember the numbers that Frank Tally and
> others presented. Do I think infective endocarditis and osteomyelitis
> are different, and there are some different therapeutic and
> intervention considerations? Yes. But, I mean, if we divide them into
> all of that, then we are back to staphylococcal osteomyelitis with or
> without accompanying bacteremia.
>
> So this was not the solution but a proposed approach to the solution.
> I mean, there has to be a degree of lumping even of things that are
> not exactly similar if you are ever going to have enough numbers to
> put them into a logical category.
>
> One of the things that was driving my consideration on this is you
> either have the approach of, if it is staphylococcal bacteremia and it
> is real, everybody gets four to six weeks of therapy or that\--whether
> it is endocarditis or osteomyelitis, it may mean four weeks of
> parenteral therapy or six weeks of parenteral therapy. But if it is
> none of those, et cetera\--so it is\--and I think the 48 hours is a
> good point.
>
> The 48 hours, you know, may be too lenient for the uncomplicated but,
> for the complicated, I don\'t think what is given in the first 48
> hours if the patient is still alive is really going to determine what
> the ultimate outcome is in those patients. It is going to be the
> drainages and the\--you know, et cetera.
>
> So it as an attempt\--because, in the uncomplicated, many of them in
> adults especially are going to be associated with catheters, some in
> pediatrics. But that uncomplicated bacteremia with Staph aureus where
> no metastatic complications are delineated at the outset would
> encompass the kids with staphylococcal bacteremia with breaks in skin,
> the pimples, and the \"I can\'t find with a reasonable effort.\"
>
> DR. LEGGETT: Why don\'t we take a break and return to this. It is
> 3:15; 3:29. That way, by the time we sit you down, it will be 3:30.
>
> (Break.)
>
> DR. LEGGETT: We agree to disagree about No. 1 and move on to No. 2. We
> have got to get to No. 8 by 4:30.
>
> DR. FLEMING: 30 seconds, real quickly on two points. Having argued
> against time-to-event analysis for the death endpoint in this setting
> because the major signal is is there a difference in whether you do
> die or not die. It doesn\'t matter in a relative sense so much
> whether, if you are going to die, if you die at Day 3 or Day 6.
>
> In contrast, as this committee had discussed in the past year in acute
> bacterial sinusitis, the same thing would be true in acute otitis
> media. In those settings where resolution is going to occur with
> almost 100 percent, the signal is in how soon resolution occurs,
> resolution of signs and symptoms.
>
> So I wanted to make sure that the message wasn\'t being conveyed that
> time-to-event isn\'t ever useful. In those settings, it would be the
> right thing to do.
>
> The other point that I had wanted to add to is, while I very much
> endorse the concept that it is important to get as much baseline
> information as possible to allow us to address some of this
> heterogeneity and improve some of the precision in our estimate, my
> own sense is, if we are going to use information post-randomization,
> information such as catheter use post-randomization, we have got to be
> very confident that the intervention, itself, is not influencing that
> outcome because, if it is influencing that outcome, now are
> estimating\--if we use time-dependent covariates, now we are factoring
> out part of the actual signal or treatment effect.
>
> DR. LEGGETT: Question No. 2; what patient populations with Staph
> aureus bacteremia should be included in a clinical-development
> program. I mean, we have been talking about that the whole time we
> have been talking about No. 1. I think the last thing to say about
> that is we already, this morning, talked about, I think, our general
> feeling that we would like to see concurrent or previous clinical
> trials so that we know that the drug is going to be effective where
> the metastatic foci from bacteremia are going to end up.
>
> Anybody else want to say anything about No. 2? Chris?
>
> DR. OHL: I think that all our previous discussion encompasses this
> enough that I don\'t think any more discussion is warranted.
>
> DR. LEGGETT: Janice?
>
> DR. SORETH: Those specific other serious infections would be serious
> pneumonias\--
>
> DR. LEGGETT: Yes; pneumonia, even though that is going to be hard to
> do because there are not that many Staph aureus pneumonias that I know
> for sure are\--osteo\--
>
> DR. SORETH: You are getting to the point where you have some, I think,
> ideally, prior knowledge of the penetration of that drug and how
> patients fare when they are on it with serious and life-threatening
> infections in general.
>
> DR. LEGGETT: Right.
>
> DR. SORETH: Which may include some experience, however limited, with
> Staph aureus.
>
> DR. LEGGETT: And I think skin and soft-tissue is important and maybe
> osteo/arthritis but certainly osteo would be nice.
>
> DR. SORETH: Right. Tend not to get that one, but that is okay.
>
> DR. LEGGETT: Yes; I know.
>
> DR. SORETH: We will keep trying.
>
> DR. LEGGETT: Jan and then Nate.
>
> DR. PATTERSON: I just wanted to say that, in terms of patient
> populations, I would hope that the pediatric population would be
> studied because of this increasing problem of MRSA and also that we do
> see a fair amount of Staph pneumonia in terms of nosocomial pneumonia.
> Then, last year with the flu season, there were a number of cases of
> community MRSA pneumonia in children as well that were associated with
> bacteremias and very invasive type pneumonias.
>
> DR. LEGGETT: Does that mean you are wishing to avian flu?
>
> Nate?
>
> DR. THEILMAN: Just to the issue of what patient populations we could
> liberalize our entry criteria for and addressing the issue
> specifically of 48 hours of prior treatment being acceptable, well, I
> should just throw this out. What is the evidence for 48 hours or prior
> treatment with, say, vancomycin would be acceptable?
>
> For instance, if 50 percent of the drug\'s success is achieved in the
> first 48 hours of treatment, and we study Drug X beginning at 48 hours
> and find it to be effective, we could be encountering some misleading
> data.
>
> So I just wonder if additional studies might be needed at that point
> to look at initial clearing or other evidence for what really happens
> in those first 48 hours of therapy.
>
> DR. LEGGETT: One point that hopefully we will bring up again in the
> animal models, I can tell you that you don\'t get any killing with
> vancomycin at all in a mouse thigh model. So I am not really too
> confident that that is going to happen in people.
>
> Janice?
>
> DR. SORETH: Also, if the vast majority of patients in a trial have
> multiple antibiotics for 48 hours, or whatever the period of time is,
> we usually include that information in product labeling. It is not to
> say that someone isn\'t free to use it however they please off-label
> or approximately according to the label, but at least we try to
> incorporate that information into the product insert so that
> physicians can see how close they are or how far off base they are in
> choosing to use it this way or that way.
>
> DR. LEGGETT: Alan?
>
> DR. CROSS: I think, just to reemphasize a point that Barth made before
> the break is that, if we are talking about complicated or
> non-removable infections, it would be unlikely that 48 hours of an
> antimicrobial would cure that.
>
> DR. THEILMAN: In uncomplicated, it could be.
>
> DR. PATTERSON: I think with Staph aureus, it doesn\'t.
>
> DR. LEGGETT: Agreed. No. 3; should bacterial endocarditis due to Staph
> aureus be a separate indication? If so, what additional information
> from clinical trials in a serious Staph aureus infection should be
> available to support such a claim.
>
> Again, we go back over stuff we have been talking about but maybe we
> could make it a little more specific.
>
> DR. MALDONADO: I am sure this question was prompted by something. Why
> is that definition of an indication so specific? Why the need to be so
> specific for Staph aureus?
>
> DR. POWERS: I think what we were really getting at here is can we
> enroll patients who have Staph aureus bacteremia, get the
> echocardiogram and, if they have endocarditis, leave them on the drug
> and get some experience with endocarditis within these trials as
> opposed to making folks go out and do separate entire studies for
> endocarditis.
>
> DR. LEGGETT: Since we know that we can\'t really predict who is going
> to get endocarditis and a major portion of folks who get Staph aureus
> bacteremia are at risk, I would not want to exclude the very people
> that I am most worried about.
>
> Additional trials in serious Staph aureus infections should be
> available?
>
> Oh; sorry. Chris?
>
> DR. OHL: Sorry; I was just going to make a comment and I forgot to
> raise my hand. This gets back to the comments I was making this
> morning. I think that, since such a large number of these patients, as
> we saw this morning from the early results of a trial, are going to
> have endocarditis. I think that information would be useful to have
> and I would say yes to that question.
>
> DR. LEGGETT: In terms of what other clinical-trial data, I think the
> similar sorts of things as what we have been saying before.
>
> No. 4; should catheter\--oh; sorry Barth.
>
> DR. RELLER: On No. 3, just so it is captured in the record, although
> alluded to earlier, I think, before a trial would be allowed to retain
> patients who have endocarditis, as opposed to being dropped out, that
> there must be sufficient evidence of efficacy of drug against Staph
> aureus in other sites. It may be skin and skin-structure infections. I
> don\'t want to get into the specifics, but I mean there should be a
> sufficient body of an data, other site infections, to say that this is
> an ethical thing to do, to keep the patient on a drug.
>
> I am in total agreement that if it seems reasonable and there is a
> reasonable basis that it would be good to include because that is
> really the acid test for complicated\--I mean, if it works for
> endocarditis, it will work for\--assuming there is penetration, unless
> there is something special about getting into bone, but for most
> things, if it works for endocarditis, it will work for other
> complicated staphylococcal infections with the appropriate drainages
> and other things.
>
> DR. LEGGETT: John?
>
> DR. BRADLEY: I think the issue can be more complicated than that given
> the fact that many of the drugs that should be active in endocarditis
> would not be active against metastatic infections like in the CNS or,
> perhaps, in bone or with dapto in the lung.
>
> So the supporting evidence for each drug may be different based on its
> specific characteristics and, as is in the package label for
> daptomycin right now, there is a specific notation regarding pulmonary
> infection.
>
> So my comment is only to qualify the degree of supporting information
> that we would need for these drugs.
>
> DR. LEGGETT: Thanks for the qualification. We know that we have
> clindamycin and vancomycin already approved and they don\'t get into
> the CNS. So I think the thing can be said about a lot of drugs.
>
> No. 4; Should CRBSI have its own indication or should this indication
> be subsumed into a more general PBSA indication? If it is a separate
> indication, what additional information in the treatment of serious
> Staph aureus infection should be available to support it?
>
> When we were talking about the complicated versus uncomplicated
> before, and Barth was saying, well, let\'s put\--whether they have got
> a catheter or not, they go into the uncomplicated, I think that, you
> know, one way to sort of work on this catheter-related bloodstream
> infection might, in fact, be to study it first in Staph aureus and
> then attack coag-negative Staph or other sorts of things afterwards,
> after people got some experience with\--because I think the way you
> are going to treat the catheter with Staph aureus in a coag-negative
> Staph can be different.
>
> Chris?
>
> DR. OHL: Agreed.
>
> DR. LEGGETT: Now, that was succinct.
>
> John?
>
> DR. BRADLEY: I will the loyal opposition here. I am certainly
> flexible. I think catheters represent a persisting site of infection
> and, in some of the patients that I treat, they have had multiple
> catheters and we just don\'t have another site to put the catheter in.
> So there is some interest in trying to treat through a catheter
> infection.
>
> I would really like a drug that could do that. In addressing Chuck\'s
> picture with that catheter infection where we would all automatically
> pull that, if there is a drug that comes along that gets into biofilm
> well, that may not be our subsequent direction in catheter-related
> infections so that you might not need to pull the catheter.
>
> If we set things up so that the catheters are automatically pulled,
> then\--
>
> DR. LEGGETT: I don\'t know that we need to do that. I think that is
> something that the FDA would work out with the drug company when they
> designed what they were going to do in terms of laying out the thing
> rather than sort of in a broad mode.
>
> Alan?
>
> DR. CROSS: I would just like to emphasize again, which is all the more
> reason to separate out Staph aureus from Staph epi. Again, I treat
> patients who are so compromised that they haven\'t seen a neutrophil
> in months, that they have coagulase-negative bacteremia and we treat
> through it all the time, and it resolves very, very quickly as opposed
> to Staph aureus.
>
> So I think, in all this discussion, we should really be focusing on
> Staph aureus and Staph epi should be separate.
>
> DR. LEGGETT: I propose that we rename the Question No. 4 into CRBPSA
> indication.
>
> Chris?
>
> DR. OHL: As far as, and I am not sure this is an answer, but moving it
> into its own indication within what we have been calling the primary
> bloodstream for Staph aureus, is that\--what this is going to end up
> doing probably is when you are moving things into the overtreatment
> end of things rather than\--so that is going to have to be in the
> consideration because, if you are looking for an entity where a
> removable focus such as this can be done, with a quick shorter course
> of therapy, this is probably going to be about it.
>
> If you merge it into the primary bloodstream-infection aspect, isn\'t
> that going to make that harder to do? That would be my only comment.
>
> DR. LEGGETT: The quandary, I think, is pointed out by the fact that
> many of the people who have a Staph aureus catheter-related infection
> go on to have complications whereas, some people, you pull it in and
> there is no problem. But we don\'t know that a priori. If we allow an
> indication for catheter-related Staph aureus infection, and somebody
> shows that and they luck out or the people are chosen so that they
> find out a way to make that easy group, then we are going to be stuck
> with complicated problems later on that we don\'t want.
>
> DR. OHL: Just to clarify. That would then say that it would be
> mergable.
>
> DR. LEGGETT: It would be merged.
>
> John, Janice, do you guys need anything more on 4 or do you want
> anything more on 4?
>
> DR. SORETH: We have the practical issue of having guidance for
> catheter-related bloodstream infections on the web, although all
> guidances are drafts, but\--
>
> DR. LEGGETT: So, in other words, somebody probably is already studying
> it and we are pulling the rug out from under their feet.
>
> DR. SORETH: If it is on a respirator at this point, do we revive it
> somehow or do we pull the plug\--the guidance, that is, not the
> patient.
>
> DR. LEGGETT: Right now, I am not going to the catheter-related
> bloodstream infection. Is there another question down the road that we
> can then address that?
>
> DR. SORETH: Okay.
>
> DR. LEGGETT: And just stick this with the Staph aureus.
>
> DR. SORETH: Okay.
>
> DR. LEGGETT: So that was 4(a) and we will come back to 4(b).
>
> No. 5; can data on catheter-related infections\--okay, now we have
> headed into the Staph aureus\--do you want to stay with Staph aureus
> and do preclinical stuff and then switch over\--okay.
>
> No. 6; given that bloodstream infections due to Staph aureus have the
> potential to cause serious morbidity and mortality, what types of
> preclinical and early clinical information should be available prior
> to initiating large clinical trials?
>
> Alan?
>
> DR. CROSS: Well, I think it was already alluded to, but I would hope
> that there would be some data on clinical efficacy in less serious
> infections; that is to say, I don\'t think that the first clinical
> trial with a new agent that we don\'t have much information about
> ought to be in complicated Staph aureus bacteremia.
>
> In the case of Staph aureus, it is particularly important because,
> although we can accumulate lots of in vitro data, one thing we really
> didn\'t talk about is that animal models for Staph aureus are really
> problematic. People have been trying for years and years and there
> still is no good animal model.
>
> Even with all the caveats for the applicability of animal models for
> disease in general, it holds particularly in the case of Staph aureus.
> So I think that, before going to complicated infection, we should, at
> least, have some clinical efficacy in less severe infections.
>
> DR. LEGGETT: Regarding the preclinical stuff, I think that the Staph
> aureus mouse thigh model has been around since the 40s. And there is
> still some question with some drugs whether you are looking at mice
> that can\'t walk to get water and eat and that is why they die,
> because their thighs swell up to everything, or the drug doesn\'t
> work. So it is going to have to more than just one model.
>
> The other problem is that the models often have very limited time
> frames. There is the example I gave of the vancomycin. No matter what
> drug levels you get, you get static CFUs until 18 hours and then,
> boom, it falls off the curve. So, it depends. If you had looked at it
> 12 to 18 hours, you would say the drug doesn\'t work. If you carry
> your therapy on to 36 or 48, it works.
>
> So I think that you are going to want to have a variety of stuff. The
> trouble with the rabbit\--the trouble with any osteomyelitis is how
> far out you go and whether you have got good dosing regimens. Remember
> that the only way you are going to get that is you take a pair of
> pliers and break their leg and then you squirt bugs in their blood.
> That is the way you get the osteomyelitis model.
>
> I think in terms of endocarditis models, the rat is what I would sort
> of refer to as a right-sided model. The rabbit would be a left-sided
> model. They need to be done well and so that you don\'t just get a
> drop from 8 logs to 5 logs and that is clinically significant.
>
> So I think that the model data is going to have to improve but there
> are a variety of existing models that certainly should be looked at
> knowing their intrinsic problems before we go into this.
>
> Any other thoughts of folks? Any other thoughts about early clinical
> information? I would agree with Alan that what we want to see first is
> simple stuff, uncomplicated skin and soft-tissue, UTIs if it is
> renally excreted and that sort of stuff.
>
> DR. POWERS: Jim, could you ask folks to comment on the bacteriostatic
> versus bactericidal issue and is that distinction even useful?
>
> DR. LEGGETT: Any ideas? My take on it is that it has never been quite
> as clear as we have made it. It we give more and more TNP sulfa and
> more and more clinda and, for some bugs as opposed to other bugs, they
> are cidal instead of static and that sort of thing. I think it is
> often a question of we have got white cells and we lived a long time
> before antibiotics even if we are not chewing on chinchona in the
> Amazon.
>
> But I think it is a question of how much drug gets to the site and is
> it enough that it will\--even if it holds down bacteria, the white
> cells will take over, or does not enough get there. I don\'t know that
> a simple, oh, this is cidal but we only gave it two times in the MIC
> and it didn\'t work versus, it is static but we gave it 12 times in
> the MIC and it worked.
>
> Alan? Tom, did you want to say something, too?
>
> DR. CROSS: I mean, we already have the example of the timeless
> classic, Keflin. It is not efficacious in the treatment of Staph
> aureus endocarditis.
>
> DR. LEGGETT: Barth?
>
> DR. RELLER: I would just emphasize that it is not that a drug is cidal
> or static. It is how the testing is done and which organism you are
> talking about. So what is static for one may be cidal for another.
>
> I think it is important, though, not to disregard to conceptual
> importance of having bactericidal activity for certain kinds of
> infections, namely, meningitis and endocarditis where one is
> really\--I mean, you are dependent upon the drug and, in the case of
> endocarditis, the adjunctive complementary surgical therapy.
>
> So you don\'t have to get rid of the concepts if one recognizes that
> drugs\--I mean, chloramphenicol is bactericidal for the pneumococcus
> unless it is penicillin-resistant. I mean, it doesn\'t necessary
> follow logic but it is true if you look at the complexity of the
> issues and the interactions and the methodology for doing it.
>
> Another example is Staph aureus. Nafcillin is cidal for Staph aureus
> but it can be very hard to show that depending on whether you do it in
> plastic or whether you do it in glass, et cetera. So there are
> methodologic issues and one just has to beware of rubbish.
>
> DR. LEGGETT: And playing tonic versus adhered bacteria. No. 7; how
> many positive blood cultures are required prior to study entry in
> clinical trials of bacteremia Staph aureus?
>
> Sorry, John. You have got to raise your hand louder.
>
> DR. BRADLEY: I will work on that one; the next guidance document. In
> addition to meningitis and endocarditis, I though John had brought up
> neutropenic hosts. I think, again, traditionally, we wouldn\'t want to
> go there. A neutropenic host still has macrophages and opsonizing
> antibodies so it is not an all-or-none phenomenon.
>
> But I think before I would study a drug in neutropenia, I would, for
> sure, like to make sure it works in someone with white cells. The idea
> of bacteriostatic and bactericidal, certainly I agree with Barth, it
> is a spectrum. Based on the mechanism of action, some drugs are
> certainly more rapidly cidal no matter what system you put them in.
> The more severe the infection, the more life-threatening, the more
> bactericidal I would like the drug to be when I am treating a patient.
>
> But the ultimate outcome, the endpoints that we measure, are the best
> way to find out whether the drugs are equivalent or not.
>
> DR. LEGGETT: My point was taking it to the statement that I wouldn\'t
> say, no, you can\'t study it because your drug is \"static.\"
>
> So how many positive blood cultures do we want before clinical trials?
> Don is giving the victory sign.
>
> DR. PORETZ: Two.
>
> DR. POWERS: Could we qualify where those two are coming from, as
> central line versus peripheral?
>
> DR. PORETZ: If someone is clinically ill and septic and you draw it
> from the central line, or even the peripheral, why would you assume it
> is not significant?
>
> DR. POWERS: Barth, I think you actually did this with Mel Weinstein. I
> think there was an article that you wrote about trying to correlate
> catheters and peripheral stuff, if you want to comment on that.
>
> DR. RELLER: That one was with Richard Everts, one of our fellows. It
> just looked at simultaneously obtained blood cultures from peripheral
> venous puncture and then different categories of catheters including
> arterial to look at the likelihood of contamination. The least is with
> the peripherally drawn.
>
> I mean, I agree that two are necessary. The guidance document related
> to the coag-negative permitted one through if there were a validator
> peripherally. When a catheter is not removed, you could have one
> through the catheter and one peripherally. I think one could even go
> so far as, in those patients with lifelines, to have one through the
> catheter that could not have a peripheral if one had confirmation that
> was concrete; for example, C.T.-guided aspirate of an abscess or from
> the bone.
>
> Usually, one would be able to have a peripheral. But I am just trying
> to think of what situations would you not be able to have that second
> blood culture.
>
> DR. PORETZ: You have no access to drawing blood. I guess you could do
> a femoral-artery stick, but sometimes there is no venous blood that
> you can draw in a lot of these people. You just don\'t have access to
> it. So I guess you could get an arterial line, but if someone was
> clinically septic and you had Staph aureus grow out of the central
> line, that should be fairly valid as to the cause of why they are
> looking septic.
>
> DR. LEGGETT: Repeatedly, I buy that for Staph aureus.
>
> DR. PORETZ: Well, I am talking about\--the question says PBSA.
>
> DR. POWERS: So then, when we talk about two blood cultures drawn
> through a central line, we would assume that that means\--you know how
> this happens in practice. You send the medical student in, he draws a
> big vat of 60 ccs out and fills out ten blood-culture bottles and
> sends them off to the lab. True; right?
>
> So the question would be that would be two blood cultures separated in
> time by some amount so that we are actually getting two distinct
> measurements?
>
> DR. LEGGETT: Jan?
>
> DR. PATTERSON: Well, my comment is that I think you want at least one
> peripheral blood culture positive. The problem with, like you said, in
> getting it from the catheter only\--I mean, it may well be the source
> of infection but it may not be, particularly in somebody who might
> have something\--diverticulitis or something else going on in their
> bowel.
>
> I don\'t think, with Staph aureus bacteremia, it is not like Strep
> viridans in that we are going to draw a culture and then wait six
> hours and then get another culture. So a lot of times, you end up
> getting two sets at the same time, and is that meaningful?
>
> Like two sets, like you are talking about from the same catheter site
> at the same time, are not really meaningful. Yet you don\'t want to
> wait another hour or two on that patient to start antibiotics.
>
> I think the ideal thing is that you would want one from the catheter
> and one peripheral. If you had those two positive, even if it was at a
> single point in time, that would be okay. I just don\'t think that it
> is realistic to say we are going to wait two or three hours to start
> antibiotics to get another culture.
>
> DR. LEGGETT: Let\'s not just talk about catheters. Let\'s also talk
> about just plain old primary\--you know, the Staph aureus. So we
> don\'t have a catheter, or we have got a burned-out I.V. drug user and
> we have no access, those kind of hemodiabetic, peripheral vascular
> disease, dialysis person who has used up all his vein grafts.
>
> DR. PATTERSON: I think if you can\'t get a peripheral blood culture in
> a patient without a catheter, you can\'t put them on the study.
>
> DR. LEGGETT: Barth.
>
> DR. RELLER: I would like to emphasize that there is a difference,
> obviously, between what would be acceptable, though, to initiate
> therapy in a sick patient. But I think it is something different for
> the specificity required to rigorously assess a patient in a clinical
> trial that would stand the test of time.
>
> I think that, if you can\'t get the blood cultures and have two
> independent acquisitions of blood, not this two through the same
> catheter or one blue lumen, red lumen. I agree completely with Jan
> that that is just not somebody that is going to be able to be enrolled
> in the trial.
>
> DR. PORETZ: Can I say one thing?
>
> DR. LEGGETT: Yes.
>
> DR. PORETZ: You can\--why not, if it is not available on the venous
> site, do an arterial site. Why should that exclude a patient from a
> study if you can get an arterial puncture, culture.
>
> DR. RELLER: I am just arguing for two independent collections of
> blood.
>
> DR. PORETZ: Fair enough.
>
> DR. PATTERSON: Yes; I didn\'t say peripheral venous. I said just
> peripheral.
>
> DR. LEGGETT: Chris?
>
> DR. OHL: Just to clarify. Would that be, then, either single site, two
> points in time or one site, two cultures or\--I am not saying that
> right\--same site, two points in time or two different sites at one
> point in time.
>
> DR. LEGGETT: Either one.
>
> DR. RELLER: If one had the same vein and you went into twice with
> independent preparations, it would be an unusual situation where you
> would have to do that, but that would be acceptable. It is the
> independence that is critical. This is, of course, much more an issue
> with coag-negative Staph than Staph aureus because there are few Staph
> aureus that are contaminants. But it is not zero. So, consequently,
> for clinical trials, I think one needs to adhere to two independently
> obtained blood cultures.
>
> DR. POWERS: I don\'t think this is going to be an insignificant issue
> because I know, when I am on service at NIH, one of the biggest
> problems that I have in seeing patients is the fact that blood
> cultures are routinely drawn through central lines only as a matter of
> convenience.
>
> Having done my residency at a place that had no blood drawing, I know
> you can get blood out of a stone. So, if their heart is pumping, you
> can get some blood out of them somewhere. But that is not what happens
> out there. We know that a lot of this is done out of convenience, that
> people will draw multiple blood cultures out of the line.
>
> So I just want to bring this up that that may become as big an issue
> as getting data from a catheter when all we are going to have in these
> patients is data from blood cultures drawn through a catheter without
> any peripheral data to go along with it.
>
> DR. LEGGETT: Enough. Uncle. Let\'s turn our attention to the
> catheter-related bloodstream infections not due to Staph aureus.
> Should it have its own indication or should this indication be
> subsumed into a more general indication? If there is a separate
> indication, what additional information should be available? Can we
> phrase it that way? Is that going to help you?
>
> In terms of thinking about this in a catheter-related blood-stream
> infection, to try to help companies get adequate people in, I think we
> have to remember that we have got to be able to try to fashion a trial
> for some sick people without taking away folks who have entered into a
> trial of a drug that they aren\'t sure is going to work, and then we
> take that away from them so they have got nothing.
>
> So I would have a hard time pulling back and saying, no; we can\'t do
> that. I think we have got ourselves into it and we have got to figure
> out a way to do it. The two sides of the pros and cons, I think, sort
> of wrap that up but I think we need to find a way of tightening up the
> ship if we can in the next half an hour.
>
> DR. CROSS: Again, I will just expand on the comments I made earlier
> about how very different catheter-related Staph aureus infections are
> from coag-negative. Again, I deal with patients who have central
> catheters in and the oncologists work in a setting where any fever,
> like 99.8, is taken as an indication of occult sepsis even if the
> patient is reading a newspaper. They will start therapy based on that
> alone with, it turns out, a not unreasonable expectation that they
> will have coag-negative Staph.
>
> On the other hand, once we are called in, they ask whether or not they
> can treat through the probably catheter-related sepsis. It turns out
> we have done this and it is not only that we have done this, but
> usually, once we start, most often, vancomycin, the fever resolves. We
> get a blood culture 24 hours later and 48 hours later and it has
> cleared so there is both the clinical and microbiologic clearing and,
> within five days, it has been our practice that if everyone responds
> to simply stop therapy and observe them based on the observation that,
> if they relapse, so be it. We will know and we can always restart.
>
> It is really an extrapolation of what we do at the other end which is
> that, for empiric therapy, we don\'t start vancomycin on Day 1 because
> the teaching is that you always have time to wait for your blood
> cultures in the case of Staph epi so you don\'t need empiric therapy.
>
> So we have just reversed that with the idea that, if it is not urgent,
> to start at the outset when we have time that maybe we have time to
> wait for a relapse. As I said, the duration of therapy in that
> situation for Staph epi has been very, very different from Staph
> aureus which is why I think we do need to study them separately and,
> perhaps, not extrapolate from how we practice with Staph aureus to how
> we practice with Staph epi.
>
> Furthermore, if you just look in Bergey\'s Manual at the various
> virulence factors associated with Staph aureus versus what you see
> with Staph epi, it is a full page versus a few lines.
>
> DR. LEGGETT: Do we then fashion this trials bug-by-bug or if somebody
> has a drug that works against Gram-positives and Gram-negatives, do we
> let them take all comers even though there are not going to be very
> many Enterobacters? Any thoughts Jan?
>
> DR. PATTERSON: Well, my comment was going to be that I think the
> modification of the guidance should be for Staph aureus and really
> just Staph aureus, for one thing to differentiate it from the other
> Gram-positive bacteremias like coag-negative Staph and to allow this
> category of primary bacteremia, including catheter-related
> bacteremias, and with the definition of primarily being no source of
> infection after echo, chest X-ray, perhaps C.T. abdomen with contrast
> and to allow the 48 hours of antibiotics.
>
> My read on it is that the modification should just be for Staph aureus
> primary bacteremia.
>
> DR. LEGGETT: Do we allow trials currently going on to then open up to
> bacteremias after they are fashioned or\--what do we do with these
> people that have already given of their time?
>
> DR. PATTERSON: That may be more of a question for Tom and Joan.
>
> DR. HILTON: The only comment I would like to add to that is if there
> is highly different prognosis for different bugs, then I would keep
> them separate.
>
> DR. LEGGETT: Does anybody have any more comments about coag-negative
> Staph catheter-related?
>
> Chris?
>
> DR. OHL: I assume this is in the purview of Question 5.
>
> DR. LEGGETT: Yes; 4(b) and 5.
>
> DR. OHL: As far as including catheter-related infections as a subset
> of complicated skin infections, for the issues of the two different
> organisms, there is one big difficulty that I have problems with. The
> other issue is that a lot of catheter-related infections have nothing
> to do with the pathophysiology of skin and soft-tissue infections.
>
> If you are including just tunnel infections, possibly, but I am not so
> sure that was the implication of this question. So I would say no.
> But, having said that, we do need to find something for the ongoing
> trials that are being done.
>
> DR. LEGGETT: Although, if we are talking about coag-negative Staph, I
> mean, there is only one place it came from. So you could have the
> drug\--it is going to warrant a study if it is Gram-positive. It is
> going to warrant a study in skin and soft-tissue infections, anyway,
> and the label could then say complicated skin and soft-tissue
> infections including catheter-related bacteremia, or
> something\--catheter-related bloodstream, or catheter-related
> infections, even though the pathophysiology may\--it is sort of more
> of a portal of entry focus then. It is the same thing, cause, in
> cellulitis.
>
> Jan?
>
> DR. PATTERSON: I think you can have a catheter-related infection
> without bacteremia and a tunnel infection being an example. I my mind,
> that would fit with a complicated skin infection. I don\'t think you
> see it that often, but, I mean, it is possible.
>
> DR. LEGGETT: John?
>
> DR. POWERS: Could I ask folks to make that distinction, though? Chris
> brings up a good issue about the picture that we were shown is
> essentially a tunnel infection where you are seeing the erythema march
> along the area where the catheter is underneath the skin. Probably
> much more common, though, are exit-site infections where you just see
> some erythema around the outside or even what gets more confusing is
> the patient had some tape around there, and they took the tape off and
> now there is a little redness there and it grows coag-negative
> staphylococci.
>
> I am trying to get further and further away from the most clear case
> we saw on that slide. Then there is the issue of what I would like you
> guys to address about this thing called catheter-tip infections in
> terms of do catheters get infected or is it the infection in the
> person that we are worried about and does colonization of a catheter
> with no bacteremia and nothing else, how would we analyze that data?
>
> DR. LEGGETT: Barth?
>
> DR. RELLER: If I recall correctly, Dennis Mackey\'s original article
> in the New England Journal was to accurately categorize colonized
> catheters from non-colonized catheters. It had nothing to do with
> catheter infection.
>
> In our laboratory, we do not culture inanimate pieces of plastic
> devices, et cetera. We want tissue attached thereto like pocket
> infections with pacemakers, et cetera. I think the patients are
> infected. The devices may be the source of infection but of their
> introduction to the patient or colonization and I would not put\--I
> would just turn it around about 180 degrees and follow up to Jan\'s
> comment in addressing this question specifically, and that is
> cellulitis as a complicated of the catheter, or associated with the
> catheter, as opposed to catheter-associated cell\--you see what I
> mean?
>
> It is just a way of thinking about it so that if one had a pacemaker
> pocket infection, if it is tracking down leads and it is associated
> with bacteremia, we and others have published on that. That means one
> thing in terms of removal.
>
> But if it is confined and not egressed into the bloodstream and things
> are changed and it is debrided and drained, I mean, it could be a
> cellulitis or a subcutaneous abscess that is related to the device. So
> I think that those are all variations on skin and soft-tissue
> infections that, in truth, are related to the catheter.
>
> But I think that we need\--or I would advise that, as Alan has
> emphasized, that bacteremias associated with catheters, with Staph
> aureus, are different from coag-negative Staph and the rigorous
> definition for catheter-related blood-stream infections with
> coag-negative Staph is very important to maintain the integrity of the
> entity and, where there is not bacteremia, that they be cellulitis,
> subcutaneous abscess, soft-tissue, et cetera and, if you want to throw
> in \"related to the catheter,\" that is okay.
>
> DR. LEGGETT: Alan?
>
> DR. CROSS: I just want to emphasize that, in the Mackey article, the
> question he was asking is how do we know if you have a positive
> peripheral culture whether or not the catheter could be implicated.
>
> So, in doing that, you had to have both a peripheral blood culture
> submitted that was positive and have a catheter tip which, on
> semi-quantitative culture, were positive. Now, unfortunately, when I
> make rounds and see the house staff, they are always culturing the tip
> and never get the peripheral culture.
>
> Then we are asked, what do we do with a positive catheter tip based on
> a misinterpretation of that Mackey article? The answer is, you throw
> it away. So the catheter-tip culture is only a tool to help you make
> some decision on what you have in your peripheral blood culture.
>
> DR. LEGGETT: The other thing is go back and look at the graph. It was
> an arbitrary post hoc drawing the line at 15 because, down to 15, he
> had positive blood cultures. Below 15, he did not. If you look at that
> diagram, almost all the positive blood cultures are in the \"too
> numerous to count.\" So maybe we should\--the cutoff should be too
> numerous to count and not 15.
>
> John?
>
> DR. BRADLEY: In a practical sense, a lot of these catheters, when they
> are pulled out, will be pulled out through goopy exit sites and the
> catheter, itself, may not be infected. But, once you pull it through
> it through the site and culture it, unless you do it under the
> strictest of conditions, you get a false-positive catheter-tip
> infection.
>
> DR. LEGGETT: Jan?
>
> DR. PATTERSON: I think, in answer to John\'s specific question, I
> don\'t think a catheter tip gets infected. I think it gets colonized
> and the infection\--you are using it to define whether it is a
> catheter infection.
>
> DR. LEGGETT: Or a catheter as the portal of entry for an infection.
>
> Chris?
>
> DR. OHL: So it is more we are discussing skin and soft-tissue
> infections secondary to or associated with the catheter rather than
> the reverse.
>
> DR. LEGGETT: Rather than the other way around.
>
> Any other questions regarding that specific thing? No 5; how many data
> on catheter-related infections\--if we are going to put it with the
> skin and soft-tissue, it obviously has got to be a peripheral and one
> through the catheter. I don\'t think there is any way around that.
>
> No. 8; screening patients for admission in clinical trials is
> complicated due to factors such as the potential for an occult primary
> source of infection, to not be noticed, I assume the end of the
> sentence should read. What advice can you provide regarding a general
> approach to screening patients?
>
> In other words, what you are asking\--this is back to that \"primary
> bacteremia,\" or whatever we are going to call it; right? I mean, I
> think the obvious things that we always do when we sort of work up a
> fever; you have got to evaluate the lungs, evaluate the urine, look
> over the skin. I don\'t know that you have got to see if their back
> hurts and go there.
>
> I don\'t know that you have to sort of make a standard for everybody,
> but I am not so sure that, for a clinical trial, that you might not
> have to have a minimum of stuff and then you could have things on top
> of that that would be indicated by what you thought might be going on.
>
> So I don\'t think we would proscribe somebody getting a C.T. of the
> belly or an M.R. of spine or X-rays of the ankle or something, but I
> don\'t know that we necessarily would have to do all that.
>
> I guess the question is what are we going to do about the
> echocardiogram stuff?
>
> Yes?
>
> DR. THEILMAN: I actually think that a very intentional strategy should
> be outlined. Clinicians can get sloppy at times and rely on
> technology. I think everybody should have a careful joint exam.
> Everyone should look for splinter hemorrhages, palatal and
> conjunctival petechiae. Given the ramifications and the context of a
> clinical trial, I think everyone with Staph aureus bacteremia should
> have a TEE.
>
> DR. LEGGETT: John?
>
> DR. POWERS: Could I ask a question about\--one of the things we
> discussed internally was what is the added benefit of a
> transesophageal echo above a transthoracic because we thought that,
> when it comes to just the ease of doing these trials, I don\'t
> know\--do all centers have the ability to do transesophageal at this
> point?
>
> DR. LEGGETT: We all support our local cardiologists.
>
> DR. POWERS: Then there is the issue of if you get a transthoracic and
> it is positive, obviously, you don\'t need the transesophageal. So
> could folks address that difference and what incremental benefit would
> there be in taking people who get negative transthoracics in making
> them get a transesophageal.
>
> DR. LEGGETT: With the risk of complications.
>
> Barth, do you want to expound a little bit?
>
> Personally, if I have Staph aureus bacteremia and he looks like Don\'s
> patient, I don\'t even get an echocardiogram because I am not going to
> change my therapy. But I keep watching them, make sure their P.R.
> interval doesn\'t start doing things. Then, if I am starting to get
> worried, if they are looking bad, then, at that point, if it is going
> to give you some added information, like going to the O.R., whether
> that is transthoracic or transesophageal, that is where it helps me.
>
> But I, personally, don\'t even get them with Staph aureus bacteremia.
>
> DR. POWERS: I think, though, that that is the issue that we are going
> to have to deal with here. Even if you have a very sick-looking
> patient, we are going to need some specificity of that diagnosis to
> call that person endocarditis or not. So, even if you have a high
> clinical suspicion, we would still need some kind of data to be able
> to call that person endocarditis and would, in that case, a
> transthoracic be okay.
>
> DR. LEGGETT: And then, if the trial comes out, you are going to be
> driving clinical practice into that area again. But, I think, for the
> purposes of a clinical trial, it is a little bit different than
> clinical practice.
>
> Barth.
>
> DR. RELLER: To me, there are three components; the clinical trial,
> clinical practice and the severity of how the patient presents.
> Coupling Don\'s earlier comments and Nate\'s now, I think all patients
> entered into such a trial would have to have the two independent Staph
> aureus blood cultures. If a thorough physical examination and history,
> in the setting, not a chronic dialysis patient, et cetera\--in other
> words, from the literature, a low-risk patient for complications, I do
> not think that every one of those needs a TEE.
>
> If one has a transthoracic that is positive, obviously, in good hands,
> it is superfluous to get the TEE. But, I think, clearly, the
> literature and everyone here would agree that to have the full
> sensitivity, one needs a TEE. So a sick patient who has got rumblings,
> when there is noise, when there is smoke, I think you need a TEE.
>
> So it is a matter of categorizing the patients, that if there are no
> leads of any kind, I think it would be going too far to say two
> positive blood cultures, catheter in place that is removed, looks
> uncomplicated. Some clinicians would give two weeks if the patient\'s
> temperature comes down immediately, their white count is okay, their
> physical exam and you follow them and you see them each day and
> everything is okay, to say everyone of those needs a TEE? I think that
> would be going too far.
>
> DR. POWERS: Should they get some echo, though, or none at all?
>
> DR. RELLER: I can\'t quote the numbers. Maybe Don, others, Al, could
> help. I think there are some figures in terms of the economic\--is it
> better to do the less expensive transthoracic and then follow up only
> the negatives with the TEE or is it better to separate the patients
> who should have a TEE or not have a TEE and just go for the one that
> is the most sensitive and skip the intermediate step?
>
> I can\'t remember the data on that, but I think that has been looked
> at, maybe not as thoroughly and carefully as it should. My preference
> is to either get it or not get it and not get it halfway. That is my
> opinion.
>
> DR. LEGGETT: Chris?
>
> DR. OHL: It showed, I think, though, that in that setting of that
> patient that you described with the catheter removable focus and such
> where one might go for shorter-course therapy that, in that setting, a
> TEE should be done in order to rule out cult endocarditis before
> committing to that shorter course.
>
> So, in that particular setting, I would say that echocardiograms for
> the purposes of study, which may be different than clinical practice,
> I agree\--but echocardiograms for purposes of study should be done.
> TTE is okay if positive. If not, TEE.
>
> DR. LEGGETT: To follow up on the point. Even the physical exam on the
> form to fill out can have a sign that says, splinter, check yes or no.
> I mean, we are going to tell them what they have got to do. It is not
> going to leave it up to whatever they feel like doing.
>
> DR. POWERS: Even in that person, isn\'t there some literature that
> says that size of the vegetation may have some impact on outcome. So,
> in those people, it might be useful information to get the echo. I
> guess I want to go back to what I tried to bring up this morning that,
> if we leave the decision about what kind of workup to get, echo or no
> echo, up to investigator discretion, what we are going to be measuring
> is just that, investigator discretion and we will have very distinct
> populations of people.
>
> The people that Dr. Poretz described has, perhaps, Staph aureus in his
> blood. Whether he has endocarditis or not is a completely different
> question to answer. But we know that there are clinicians who will
> behave as if, oh, the patient looked really sick; therefore, I am
> going to treat for four weeks, whereas the same exact\--different
> clinician, same E.R., would treat that guy for two weeks.
>
> DR. LEGGETT: Okay. Agreed.
>
> Jan, we have got five minutes left.
>
> DR. PATTERSON: I was just going to some of us talked about the
> importance of an endocarditis indication and, if we really mean that,
> then I think we are unrealistic if we are only going to use the
> criteria for definite endocarditis with echo. So I think we have to
> include patients that have probable endocarditis in that as well.
>
> DR. LEGGETT: Agreed.
>
> We have talked about this a little bit before. Should patients with an
> identified focus be entered/remain in trials? We sort of talked around
> this before. Does anybody have anything more to say? And is
> endocarditis a special case? We talked about keeping the endocarditis
> in the bacteremia trial.
>
> In the brief time that remains, unless anybody has any other
> questions, or you guys have any questions of us\--
>
> DR. FLEMING: On this point?
>
> DR. LEGGETT: Or on any. Speak now or forever hold your peace.
>
> DR. FLEMING: In PBSA, if you knew the primary site, then, technically,
> this person is not in your eligibility criteria, I assume. So, if you
> knew it advance, I am assuming you wouldn\'t enter the patient unless
> you were wanting to look at an issue broader than PBSA.
>
> The issue, though, is what if you don\'t know it at baseline and you
> find out subsequently it is skin or something, is that the other part
> of your question? I mean, I certainly would hope that, unless there is
> available information indicating lack of efficacy in such a patient, I
> would certainly presume that it would be most logical to continue
> treatment and to analyze the results in those patients.
>
> You may want to do subsequent analyses that would include or exclude
> that patient but I would encourage, if you found out post-baseline the
> source that you hadn\'t know before that you continue to follow that
> person through.
>
> DR. LEGGETT: Quick.
>
> DR. CROSS: I just want to make one fast obvious point. I was impressed
> with all the presentations this morning that, despite 40 or 50 years
> of study, how little prospective controlled studies we have. And then,
> after having seen the difficulty of enrolling this patient population,
> I would just like to make plea that rather than wait until we have the
> perfect clinical design that at least we have some feasible design
> which allows rigorous analysis but allows us to enroll patients at
> least as a first step so we could get some experience and know how to
> refine that rather than to be stymied for that perfect trial.
>
> DR. LEGGETT: Janice?
>
> DR. SORETH: I think, as always, better can be the enemy of good or
> fair.
>
> As we wrap up, I just wanted to make note of the fact that this is our
> last advisory committee meeting that Dr. Jim Leggett is chairing as he
> is rotating off in November, and also Dr. Cross, your tenure with us
> also comes to an close and in recognition of two colleagues who are
> not here at the table, Dr. Steve Ebert and Dr. Julio Ramirez.
>
> We thank you very much.
>
> DR. LEGGETT: Thank you.
>
> **Summary**
>
> DR. LEGGETT: In summary, first of all, I would like to thank the
> speakers for their presentations and the committee members for their
> efforts and their tolerance of my idiosyncracies and my bad puns.
>
> Today, we have discussed many complex issues related to trial design
> and analysis in studying Staph aureus bacteremia and catheter-related
> blood-stream infections. We heard the regulatory history of bacteremia
> indications. We were updated on the epidemiology of Staph aureus
> bacteremia and we learned of new microbiological diagnostic techniques
> in the diagnosis of Staph aureus bacteremia.
>
> We debated clinical-trial issues with Staph aureus bacteremia without
> reaching a final consensus but, certainly, we were cognizant of why a
> great trial studying Staph aureus bacteremia has yet to be done.
>
> In the Open Public Hearings, we saw the difficulty of enrolling
> patients in a bacteremia trial and heard of design issues in
> catheter-related infection studies. We heard of issues relating to
> studying catheter-related blood-stream infections this afternoon and,
> again, tackled with the reiteration of the current CRBSI, or at least
> an attempt to, guidance document.
>
> I would like to thank you all for your patience and the meeting is now
> adjourned.
>
> (Whereupon, at 4:30 p.m., the meeting was adjourned.)

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