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
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 (Continued)
David Shlaes M.D., Ph.D., Idenix
Issues in Studying Catheter-Related Bacteremia:
Janice Pohlman, M.D. 247
Questions from Committee 269
Questions to Committee and Discussion 272
Summary 366
P R O C E E D
I N G S
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
(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 103. 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 103 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 103 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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