ATDEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ANTI-INFECTIVE DRUGS
ADVISORY COMMITTEE MEETING
OPEN SESSION
Holiday Inn
The
Ballrooms
PARTICIPANTS
James E. Leggett, Jr.,
M.D., Chairman
Tara P. Turner, Pharm.D., Executive Secretary
MEMBERS:
John S.
Bradley, M.D.
Alan S.
Cross, M.D.
Celia J. Maxwell,
M.D.
Jan E.
Patterson, M.D.
Donald M.
Poretz, M.D.
Ciro V.
Sumaya, M.D.
Ellen R.
Wald., M.D.
CONSULTANTS (Voting):
Janet D.
Elashoff, Ph.D.
Joan F.
Hilton, Sc.D., M.P.H. (Consultant-CBER)
L. Barth
Reller, M.D.
Keith A. Rodvold,
Pharm.D. (Acting Consumer Rep)
ACTING INDUSTRY REP (Non-Voting):
Kenneth R. Brown, M.D.
CONSULTANTS (Non-Voting):
David G.
Armstrong, DPM, M.Sc.
Allan R. Tunkel, M.D., Ph.D.
FDA:
Mark Goldberger, M.D., MPH
Edward Cox, M.D., MPH
John Powers,
M.D.
Janice
Soreth, M.D.
David Ross,
M.D., Ph.D.
Regina Alivisatos, M.D.
Alfred Sorbello, D.O.
Guest Speakers (Non-Voting)
Carl Norden,
M.D.
Dr. Tony Berendt, BM, BCh,
FRCP
C O N T E N T S
Call to Order and Introduction of the Committee, 4
James E.
Leggett, Jr., M.D., Chairman
Conflict of Interest Statement,
Tara P.
Turner, Pharm.D., Executive Secretary 6
Guidance for Diabetic Foot Infections,
Janice
Soreth, M.D., Director,
Division of
Anti-Infective Drug Products, FDA 8
Diabetic Foot Infections: Overview,
Dr. Tony
Berendt, BM. BCh. FRCP, Bone Infection
Unit,
Nuffield Orthopaedic Centre, Oxford, U.K. 11
Clinical
Trials Consideration in DM Foot
Infections,
Carl Norden, M.D.,
Medical
Director, Pfizer Inc. 34
Lessons
Learned from Previous Review
of Drugs for
Diabetic Foot Infections,
Alfred
Sorbello, D.O., Medical Officer, Division
of
Anti-Infective Drug Products, FDA 60
Microbiologic
Diagnosis of Diabetic Foot
Infections,
Albert Sheldon, Ph.D., Microbiology
Team Leader, Division of Anti-Infective Drug
Products, FDA 77
Ruling
Out Osteomyelitis in Trials of Diabetic Foot
Infections, Regina Alivisatos, M.D., Medical
Officer
Division of Special Pathogen and
Immunologic
Drug Products, FDA 88
Implications
for Clinical Trials for Diabetic
Foot
Infections, David Ross, M.D., Ph.D.,
Medical Team
Leader, Division of Anti-Infective
Drug
Products, FDA 106
Open Public Hearing 115
Charge to the Committee, Edward Cox, M.D.,
Office of
Drug Evaluation IV, FDA 115
Committee Discussion 117
P R O C
E E D I N G S
Call to Order
DR. LEGGETT: Good
afternoon. I hope we can get started on
the topic of clinical trial design in diabetic foot infections. Members of the committee, you can sort of
relax. There is no yes or no vote this
afternoon, so we can all pontificate and there is nothing afterwards. Why don't we get started with introductions? Mark, do you want to start?
Introductions
DR. GOLDBERGER: Mark
Goldberger, Director of the Office of Drug Evaluation IV.
DR. COX: Ed Cox,
Deputy Director, Office of Drug Evaluation IV.
DR. POWERS: John
Powers, Lead Medical Officer, Antimicrobial Drug Development and Resistance.
DR. SORETH: Good
afternoon. I am Janice Soreth, the
Director of the Anti-Infectives Division.
DR. ROSS: David
Ross, Medical Team Leader, Anti-Infectives.
DR. ALIVISATOS:
Regina Alivisatos, Medical Officer, Special Pathogens.
DR. SORBELLO: Fred
Sorbello, Medical Officer, Division of Anti-Infective Drug Products.
DR. ELASHOFF: Janet
Elashoff, Biostatistics, Cedars-Sinai and UCL.
DR. HILTON: Joan
Hilton, Biostatistician, University of California San Francisco.
DR. RODVOLD: Keith
Rodvold, Colleges of Pharmacy and Medicine, University of Illinois Chicago.
DR. RELLER: Barth
Reller, Infectious Diseases and Clinical Microbiology, Duke University.
DR. TURNER: Tara
Turner, Executive Secretary for the Committee.
DR. LEGGETT: Jim
Leggett, Infectious Diseases, Oregon Health Sciences University.
DR. WALD: Ellen
Wald, Pediatric Infectious Diseases, University of Pittsburgh.
DR. CROSS: Alan
Cross, Infectious Diseases, University of Maryland.
DR. PATTERSON: Jan
Patterson, Infectious Diseases, University of Texas Health Science Center San
Antonio.
DR. SUMAYA: Ciro
Sumaya, School of Rural Public Health, Texas A&M University.
DR. PORETZ: Donald
Poretz, Infectious Diseases, Fairfax, Virginia.
DR. MAXWELL: Celia
Maxwell, Infectious Diseases, Howard University.
DR. ARMSTRONG: David
Armstrong, Podiatry, with the Diabetes Lower Extremity Research Group at the VA
in Tucson.
DR. TUNKEL: Allan
Tunkel, Infectious Diseases, Drexel University College of Medicine.
DR. BROWN: Ken
Brown, retired from industry and University of Pennsylvania.
DR. LEGGETT: Thank
you. Tara, could you please read us the
conflict of interest statement?
Conflict of Interest
Statement
DR. TURNER: Thank
you. The following announcement
addresses the issue of conflict of interest with respect to this meeting, and
is made a part of the record to preclude even the appearance of such at this
meeting.
The Food and Drug Administration has granted waivers to the
following special government employees which permits them to participate in
today's discussions, Drs. Jan Patterson, John Bradley, Keith Rodvold and David
Armstrong.
A copy of the waiver statements may be obtained by
submitting a written request to the agency's Freedom of Information Office,
Room 12A-30 of the Parklawn Building.
The topics of today's meeting are issues of broad
applicability. Unlike issues before a
committee in which a particular product is discussed, issues of broader
applicability involve many industrial sponsors and academic institutions. The committee participants have been screened
for their financial interests as they may apply to the general topic at
hand. Because general topics impact so
many institutions, it is not prudent to recite all potential conflicts of
interest as they apply to each participant.
We would also like to note for the record that Dr. Kenneth
Brown is participating in this meeting as an acting industry representative,
acting on behalf of regulated industry.
FDA acknowledges that there may be potential conflicts of
interest but, because of the general nature of the discussion before the
committee, these potential conflicts are mitigated. In the event that the discussions involve any
other products or firms not already on the agenda for which FDA participants
have a financial interest, the participant's involvement and their exclusion
will be noted for the record.
With respect to all other participants, we ask in the
interest of fairness that they address any current or previous financial
involvement with any firm whose products they may wish to comment upon. Thank you.
DR. LEGGETT: Thank
you. There has been a slight change in
the agenda, and Janice Soreth will give us some opening remarks on the guidance
for diabetic foot infections.
Guidance for Diabetic Foot
Infections
DR. SORETH: I have
only one slide, so don't look for any copies in your folder.
We begin now the open portion of our two-day advisory
meeting on anti-infective guidance development, specifically this afternoon
diabetic foot. You might ask why more
guidance. Well, very simply, despite our
agency effort in the last decade to tackle anti-infective guidance development
infection by infection, we have not yet for some infections put pen to paper or
finger to keystroke.
I would like today publicly to renew our commitment to
tackle some of the guidances that we have left to the end, I think necessarily
some of the more difficult ones. To name
a few, I think we have left as yet unwritten anti-infective guidance
development particular to sepsis products, topical anti-infectives, bone and
joint infection and our topic for this afternoon, diabetic foot
infections. While we have written
guidance on complicated skin and skin structure infections, of which a part is
diabetic foot, we have discussed everything but the diabetic foot aspects of
that guidance, and not for some time.
As we look across applications that we have received from
sponsors looking to get a claim for diabetic foot infections, we see pretty
variable case definitions, a collection of data in a given drug development
program that is sometimes inconsistent between investigators and certainly
inconsistent between drug development programs and, lastly, endpoint assessment
that is quite variable.
So, the main reason we are here today is to address
definitions and point assessment, and to try to bring, I think, consistency,
reproducibility, if not accuracy, to the trials that we design and then
conduct. Why? So that we will know what treatments work
best.
The stats that you will hear this afternoon in greater
detail I think are staggering. Since the
year 2000, in the U.S. we make a diagnosis of diabetes mellitus in over one
million patients per year. There are
over 100,000 hospital admissions for diabetic foot infections yearly and almost
a similar number of lower extremity amputations.
[Slide]
For me, the personal statistics are equally staggering and
my only slide is a family portrait of my grandfather who, unfortunately, became
a type II diabetic as an adult and died, to me, at the very young age of 60 of
complications of diabetic foot infection.
He had twin daughters, my mother and her twin sister, my aunt. My aunt developed diabetes mellitus as an
adult as well and she also succumbed to complications of diabetic foot
infections. While my mother is not a
diabetic, she has given birth to children who, unfortunately, are becoming
diagnosed with type II diabetes.
My hope today is that our discussions will outline
definitively and clearly how best to design trials to study diabetic foot
infections, modalities to treat them, including the use of antimicrobial
agents, so that we might have a better outcome for my generation and for my
children's generation. Thank you.
DR. LEGGETT: Thank
you, Dr. Soreth. The next two speakers
will have lots of areas of overlap so we are going to take questions after Dr.
Norden's presentation. Our first
presenter will be Dr. Tony Berendt, and he will talk about diabetic infections,
an overview. I would like to ask all the
speakers to try to stay on time and stop at that red light.
Diabetic Foot Infections:
Overview
DR. BERENDT: Thank
you very much. I am very conscious of
the honor that has been done to me by inviting me to come and address the
committee today, as a Brit speaking to something run by the federal government
of America.
[Slide]
I think my only real claim to be here is my involvement in
both the IDSA Clinical Practice Guidelines Committee on Diabetic Foot
Infections and also a subgroup of the International Consensus on the Diabetic
Foot which, this year, produced a supplement to the International Consensus,
specifically looking at the management of infection in the diabetic foot. I will talk more about that later.
[Slide]
The main messages that I would like to get across to the
committee today are that despite considerable advance in these areas, there is
still a great deal we don't know about diabetic foot infection and that,
despite some progress in the production of expert consensus guidances, that
really doesn't compensate for the dearth of optimally conducted studies which
do leave us with many unanswered questions.
So, I will be talking to you really with more questions than answers
today but at least you will get some perspective of where we are. There certainly is a definite and I think
urgent need for standardized definitions of infection in the diabetic foot both
to allow the kind of multicenter studies that your draft guidance recommends
and, indeed, to permit comparison between different studies conducted
independently but, therefore, capable of more rigorous analysis and
meta-analysis.
[Slide]
So, in the rest of my time I am going to try and get
through the following points really, the epidemiology and importance of
infection; the clinical spectrum and whether that leads us onto a working
definition of diabetic foot infection for the purposes of this group; how one
goes about diagnosing a diabetic foot infection--slightly different to defining
it perhaps; and then where expert opinion has got to in this area. This is necessarily brief and will miss some
areas but they will be covered in more detail by others later today I think.
[Slide]
To put the numbers back onto that very personal view of
diabetic foot infection that we have just heard, the worldwide projections are
for there to be some 250 million diabetics by 2025, of whom all the evidence
would suggest some two to five percent will develop foot ulceration annually,
with a point prevalence of ulceration estimated at between four and ten percent
depending on the study one looks at.
Some 40-60 percent of all non-traumatic lower extremity amputations are
in diabetics and the overwhelming majority are preceded by foot ulceration.
[Slide]
When we look at the socioeconomic importance of that, we
see that foot problems account for the largest number of bed days used by
diabetic persons; that their average length of stay is some 30-40 days, which
is considerably longer than diabetic patients who do not have foot ulceration;
and that over three-quarters of the over 75 year olds in the U.S.A. who have
amputation for the foot ulceration do not return to independent living. Quite apart from the unpleasantness of that
from a personal point of view, the costs to themselves or society are enormous.
[Slide]
It is not, therefore, surprising that a number of studies
have suggested that it may well be cheaper to save a limb than to amputate
it. Although it is at some distance, you
can see the broad figures there--but they are on the handout--and the figures
highlighted in yellow are from the U.S.
Those are U.S. specific studies.
But the general theme of this is the same around the world, some 7,000
to 10,000 U.S. dollars to heal an ulcer, and considerably more to deal with the
consequences of removing the limb the ulcers are formed on. That long-term cost analysis, carried out
in Sweden by Apelqvist, shows you that
the primary healing at a three-year endpoint is between $16,000 and $26,700 in
patients, the difference depending upon the level of ischemia, whereas healing
with amputation is between $43,000 and $63,000, the differences depending upon
minor versus major amputation.
[Slide]
So, infection has a key role in this area. It is known to be a major event on the road,
as it were, to amputation. It does that
because it contributes to soft tissue loss, to delayed wound healing. It is a threat to foot biomechanics. If it compromises the issues and the bones
enough, it is a cause of acute or chronic systemic effects. Any of those may ultimately end up being a
good reason to remove a limb rather than to keep it on.
[Slide]
The clinical spectrum is broad and confusing. I have chosen to split it into those
conditions with intact soft tissues and include a small number of primary
muscular or skeletal infections and those that really complicate an obvious breach
in the integument, either a paronychia at the site of a nail or, more usually,
an infected ulcer, cellulitis and then the formation of more complex forms of
soft tissue infection and, of course, ultimately bone infection.
So, there are may different manifestations but I am going
to suggest that perhaps the ones that we are really the most interested in
that, if you like, constitute the diabetic foot syndrome and the infectious end
of that, are those that complicate ulceration.
[Slide]
So, we then move to this difficult area of how we define a
diabetic foot infection, and there are a number of possibilities here. In fact, I spoke with Ben Lipsky who, as many
of you will know, has worked extensively on this subject in Seattle but who
couldn't be here today.
Here are a couple of possible definitions that one can
debate. The first would be the broadest
possible view, which is that a diabetic foot infection is a foot infection in a
diabetic. In other words, any infection
as defined by the International Consensus or some other consensus process that
involves the foot--and I think we have to call that the structure below the
malleoli--in a person with diabetes, for which there are formal definitions.
But there is a more specific version of that, if you like,
where we would include the necessity for the infection to have originated in
some injury to the skin that might be chronic or acute and that might be
complicated by neuropathy or ischemia, or both.
[Slide]
That I think is an area that is clearly open to
debate. One can justify that. It starts there by saying that neuropathy is
undoubtedly the dominant cause of skin breaches in the feet of people with
diabetes; that the clinical features of the majority of infections that we deal
with in this context support a contiguous focus model. So, the ulcer is evidently the portal of
entry of the infection and the infected structures are contiguous to the
ulceration.
The presence of ischemia is known to have a major bearing
on the outcome of infection, and it is absolutely clear that effective foot
care services have a major impact on reducing amputation rates, at least in the
initial stages where one is able to catch large numbers of people who can be
managed for their neuropathy correctly to prevent episodes of further
ulceration, and who can be spared precipitate amputation when more conservative
treatments can be effective. It does
have to be conceded that there is no evidence comparing outcomes one way or
another in the so-called non-neuropathic, non-ischemic patients but perhaps we
might actually more accurately call pre-neuropathic and pre-ischemic diabetic
persons compared to those without diabetes.
What am I saying there?
The question really is if you don't have neuropathy and you don't have
ischemia and you get a foot infection, are your outcomes worse than for someone
who doesn't have a diagnosis of diabetes?
And, I am not sure we know the answer to that.
[Slide]
This picture is really put up just to illustrate some of
those problems in definition. Does this
person have a diabetic foot infection?
They have an area of ulceration above the malleoli and clearly have
numerous soft tissue changes related to their diabetes. Although you can't see it very well here,
they do in fact have an ulcer that looks uninfected on the end of the hallux. But I think I would suggest that is not a
diabetic foot infection in terms of what one would be wanting to study even if
we thought the cellulitis there is originating from that ulcer.
[Slide]
So, how do we diagnose diabetic foot infection? This is a big problem. Just a quick reminder for those not thinking
constantly about this, infection describes the multiplication and invasion of
tissues, usually associated with a host response, and this is distinct from the
inevitable colonization of either normal skin or an ulcer with bacteria that
may not be causing harm in a discernible way.
That is also distinct from contamination, which is more of a problem for
those trying to make a diagnosis from a sample that should normally have no
organisms present.
[Slide]
So, the diagnosis of infection really has remained a
clinical one. I realize this is a
problem potentially for the committee needing very specific definitions of
infection. It has generally been made on
the basis of systemic signs or symptoms of infection, local signs and symptoms
of infection and, clearly, there are some things that would alert one to that
possibility such as gangrene or necrosis or very fetid odor.
Laboratory diagnosis of infection is, by definition,
nonspecific unless it is a positive blood culture. The sensitivity in diabetic persons has been
shown to be low in a number of studies.
The role of imaging I think is more in identifying the
anatomic nature of infection rather than the presence or absence of it. So, it is more about identifying where there
are structures that probably need surgery, rather than saying this is an
infection.
[Slide]
We are left with a number of controversies if we are using
clinical diagnosis, particularly how to diagnose infection in the context of
some of these confounders that diabetic patients also frequently develop--acute
Charcot changes, gout, other common co-morbidities producing inflammation of
the skin.
We are left also uncertain when ischemia can significantly
confound the inflammatory response so that individuals might have infection but
with false-negative signs of it. That, I
think, again is a debatable matter but one that people certainly worry about at
times.
We are left with the question as to whether clinical
criteria really allow us to reliably distinguish an infected from an uninfected
ulcer.
[Slide]
At the microbiological level, I have already explained that
because of colonization of ulcers there is a real issue about how one makes a
microbiological diagnosis of infection.
It is really on that basis that I think many of us in the field would
say we are not able to diagnose these infections by their microbiology. There are, of course, some exceptions to that
statement. The culture of pus taken from
an obvious abscess or a positive culture from what should be a sterile site
taken in a reliable way, preferably through a non-infected field, is clearly
going to be diagnostic. So, a bone
biopsy that yields a Staph. aureus that has been taken through uninfected skin
is going to be a truly diagnostic microbiology result.
But a much more common scenario is what we do with cultures
taken from ulcers or from necrotic tissue that is at the base of an ulcer but
may have been ultimately contiguous with the outside world. Then, this intermediate difficult area is
probably what we face most of the time with relatively expert practice. That is to say, someone has done a
debridement of an open lesion and then taken some cultures of the material, the
base of it, and that is what we would consider the most reliable but that still
is potentially confounded by the flora of the more superficial parts of the
ulcer.
[Slide]
The recommendations that have emerged through the
International Consensus process and the IDSA Clinical Practice Committee take
account of previous studies that have shown a poor relationship between
superficial swabs and deep microbiology.
This is from cases particularly with osteomyelitis but also other deep
infection. Therefore, the
recommendations are that the ulcer should be debrided in order to expose
essentially viable but infected tissue at the base of the ulcer. If pus is present, it can be aspirated and
preferably some form of tissue sample is taken from that ulcer with a curette
or scraped with a scalpel blade and that tissue is processed rather than using
swabs.
Swab cultures are generally discouraged in the guidance,
although that has been an area of some controversy and there are certainly some
who would argue that swabs taken from the base of the debrided ulcer may be as
close and as accurate as tissue samples that have been taken from slightly
deeper.
There is a question that emerges from a number of the
clinical trials and antibiotics already done as to whether all the
microorganisms that have been isolated from these more reliable samples
actually need to be treated. There is
certainly a school of thought that suggests that maybe some of what we would
definitely see as being important and pathogenic might actually be in some way
fellow travelers with more virulent organisms like Staph. aureus. This doesn't get away from the fact that
there are some cases where enterococci or coagulase negative staphylococci are
the sole pathogen isolated, particularly from cases of osteomyelitis.
There is a question that is left also as to whether
quantitative microbiological approaches can do any better than clinical
judgment in diagnosing actual or incipient infection.
[Slide]
To understand the basis of this, I think it is worth a
quick diversion into laboratory science and what we now understand about the
pathogenesis of staphylococcal infections, given that Staph. aureus is one of
the dominant pathogens in this condition.
If we look at the course of an infection over time from
initial inoculum, we can see that organisms move out of lag phase and start to
proliferate in logarithmic phase before they run out of nutrients and flatten
off into this post-exponential phase. We
know that Staph. aureus is an organism formidably armed with adhesive
structures on the surface of its cell wall and with a number of toxins, and we
know that initially organisms tend not to be expressing toxins but to be
expressing adhesins. As they move into
logarithmic growth, the phenomenon of quorum sensing kicks in, and this is a
process by which organisms are releasing certain substances that are able to
act as density-dependent triggers to gene expression. In the case of Staph. aureus, it is clear
that this is a cyclic octapeptide and as the amounts of this material build up
the action of a gene NSHGR is triggered, and this results in the global
expression of a number of different toxin genes.
[Slide]
So, the organism moves from being in a sense non-toxigenic
to one that is producing large numbers of toxins. We might see this as a mechanism for breaking
down tissue and moving out into other areas where nutrients are no longer
limiting. This phenomenon probably also
operates in terms of the maturation of some of the adhesive forms of growth
that are seen in the form of biofilms.
That may be of more importance in osteomyelitis than in other contexts.
[Slide]
That has led a number to suggest that in the context of the
infected or uninfected ulcer the density of organisms present might be critical
in triggering the moment when infection is about to happen or can be defined as
just beginning. There is some evidence
in acute wounds and burns that density of organisms greater than 105/g
is a crucial transition point between infection and colonization. The evidence for that in chronic wounds in
the diabetic foot I think is less clear, and there is certainly alternative
evidence one can cite, for example, clear evidence of inhibition between other
species of staphylococci and Staph. aureus that this quorum sensing can be in
some way down-modulated, that is to say one species of bacteria can affect the
signals that another one is using to trigger its own behavior. That might mean that high loads of pathogens
could, in fact, be tolerated in a mixed wound flora because some of the other
bacteria are trying to effectively hold the staph. in check.
[Slide]
So, there is a lot we don't know. Where has expert opinion got to in this area?
[Slide]
I am going to refer very briefly to clinical
guidelines. I have already mentioned
that there is now an International Consensus on diagnosing and treating the
infected diabetic foot. This is in the
public domain via CD ROM which is purchasable from a website but I think will
shortly be published as well. There are
also clinical practice guidelines coming out by the IDSA, which are probably
being finalized this year and I guess will be published either late this year
or, more likely, early next year.
These have been both interdisciplinary and international
expert panels, with clinical representation both from academia and government
health services. They worked on a
consensus basis, and what has been striking is that the recommendations are
really not graded for their level of evidence because of problems in the
overall quality of the studies and in the definitions that have been used. So, if you like, this is a group of experts
but nobody pretends that the last word is here in terms of the quality of the
evidence.
[Slide]
The approach to infection that these panels have adopted is
that in view of the varied clinical spectrum simplicity is what is required,
and this needs to begin with assessments of the patient, the limb for ischemia,
the foot for biomechanics and then the ulcer for its depth, its size and the
presence of infection. Infection is
assessed in relation to its severity, mainly in terms of impact on the host and
the limb, and really put into three very broad categories, mild infections,
moderate infections that can be summarized as limb threatening, and severe
infections that are immediately life threatening.
[Slide]
You can see here the kinds of thinking that has gone into
this. Mild infections are characterized
by a small amount of erythema but clinical evidence of infection in an
ulcer. They are usually monomicrobial,
mainly with aerobic gram-positive cocci.
Moderate infections have more spreading erythema or
evidence of involvement of deeper tissues including bone and joint. Moderate can be mono or polymicrobial.
Severe infections are really defined specifically by the
presence of systemic symptoms. These are
known to be relatively muted in diabetic patients and, therefore, the presence
of them is considered to be evidence of potentially life-threatening conditions
such as septicemia or fasciitis. The
ulceration is often deeper and these are often polymicrobial infections.
[Slide]
In terms of duration, there really is not good data on this
but there have been a number of clinical studies using those kinds of
classifications already that suggest pretty clearly that you can treat mild infections
for one to two weeks of oral therapy.
You can probably treat them with topical therapies as well. I know that may not be an area of where the
committee wants to go today.
Moderate infections can be treated for up to four weeks
unless there is osteomyelitis present where it is generally considered wise to
treat for longer.
Severe infections are usually going to require surgery, in
fact, which is probably part of the reason it is still not necessary to treat
them for more than about four weeks. It
is just that they need more doing.
For osteomyelitis, the expert consensus view is that a lot
depends on what you do. If you are
taking all the bone away that is involved in the infection and you are doing
that through normal soft tissue, then really there is nothing left to treat and
a long duration of antibiotic treatment is not necessary.
[Slide]
Bony ablation with no residual infected soft tissue can be
treated from the basis of a soft tissue infection. Whereas once you are leaving behind parts of
the bone involved in infection, it is really necessary to decide where there is
dead and infected bone left and that really helps set the duration of therapy
needed.
[Slide]
What about classifications--in my last remaining
minute? The consensus process came up
with a classification scheme called PEDIS, the Latin word for foot. This is intended to be a specific rather than
sensitive scheme. It should allow what
we want, that is to say, multicenter studies and categorization of case mix.
[Slide]
To quickly take you through it, perfusion is given three
grades, in line with the Trans-Atlantic Inter-Society Consensus. This is people who study peripheral vascular
disease. Grade I is apparently
normal. There is no nought because you
can't be sure something is absent. Grade
II is noon-critical ischemia; III is critical.
These are rigorously defined in the guidance. E is extent of the ulcer in square
centimeters, and suggested studies could report ulcer size in quartiles to get
an idea of the spread there. D is the
depth which follows very closely the University of Texas system of making a
transition between bone and joint and other subcutaneous tissues. Fir infection I will show you the grades very
quickly in a minute. Sensation is either
the presence or absence of protective sensation.
In fact, if the depth was given four grades so that grade I
was no ulceration, one would have a catch-all for classifying all diabetic
feet, but this was a research classification scheme for ulcers so it has to
begin with ulceration.
[Slide]
What are they very quickly, and you will see some of the
problems? There is a clinically
uninfected ulcer but obviously one can see from looking at that the kinds of
problems frequently arising. Infection
involving the skin and subcutaneous tissue would be a grade II infection. This has, as before, the 0.5-2 cm cutoff for
its erythema, at least two of these other features of infection, and no more
probably cause of the inflammatory response.
[Slide]
Just to show you the kinds of problems on has with using
this is that this would be a moderate infection. Sorry, I got myself in a muddle because I am
rushing. That is the mild infection with
a 2 cm radius of erythema.
[Slide]
The difficult one I think is the grade III because it
encompasses such a wide range of infections, deep sort tissue, or bone, or
joint, but is specified as having no systemic inflammatory response.
[Slide]
So, this case with a probe going into a joint and obvious
infection of the whole of that toe would be moderate. So would the case on the left with
penetration into the joint, but also the case on the right with very
substantial Charcot infection in the mid-foot.
Even in that case, with a lot of gangrene and obvious gross infection,
if the patient remains systemically well, would be categorized as moderate with
these scheme.
[Slide]
Finally a grade IV infection would be one that we would
otherwise call severe, with a systemic inflammatory response, rigorously
defined here. So, what makes that a grade
IV infection is not the appearance of the foot but the appearance of the whole
patient.
[Slide]
Where are we left?
We really do need to finalize and agree on how to use these more robust
definitions and classification schemes.
Almost any scheme that everyone uses will probably be better than having
no scheme. The role of antimicrobials in
uninfected ulcers and in wound healing after infection needs to be sorted
out. Duration of treatment and the role
of surgery in osteomyelitis and the cost effectiveness of limb salvage in these
very much more complex cases that many of us are now seeing. So, really a lot does need to be done.
[Slide]
In conclusion, while I think there has been some progress
in general understanding and the existence of these consensuses is I think
major progress. There are some
difficulties that we have to solve.
I think that that PEDIS classification might actually help
us considerably and, certainly, further consensus definitions, for example of
osteomyelitis, would be helpful.
It is worth noting that some of these changes in practice,
assuming that not all osteomyelitis needs many, many weeks of antibiotics,
might be useful for allowing some cases, depending on their surgical
management, to be included in cSSSI trials.
[Slide]
I would like to conclude by acknowledging Ben Lipsky from
Seattle, Carl Norden whom you all know, and the drivers of the International
Consensus process who have done a tremendous job, and my own clinical
colleagues in Oxford. Thank you.
DR. LEGGETT: Thank
you for that whirlwind tour. The next
speaker is Dr. Norden.
Clinical Trials
Consideration in DM Foot Infections
DR. NORDEN: Thanks
very much, Jim. It is a pleasure to be
here. It is an honor to have been
invited by Dr. Soreth, and it is nice to be back at a committee where I spent
four of the most challenging and I think stimulating years in terms of my
academic career.
What I am going to try and do today is to talk about
potential guidelines for clinical trials of diabetic foot infection. I think Tony has given a very nice overview
and background. My talk is going to be
based primarily on my own experience, as well as a large clinical trial that we
recently conducted with the help of Ben Lipsky from Seattle, whose name you
have heard a couple of times already.
I am going to present ideas which are designed to elicit
discussion and, obviously, not final ideas in any sense of the word, and to
take some positions for the sake of argument so that the committee can debate
them and shoot at them. The guidelines I
will talk about are for systemic antimicrobial agents, not for topical
antimicrobial agents. Then there will be
a few talks from the FDA to follow which will go into more detail.
I think the two major areas that I would like to raise as
issues as I go through the talk for you to consider are, one, the use of
adjunctive therapy and how do you evaluate the success of antimicrobial agents
and, two, osteomyelitis--do we include, exclude or simply treat these patients
as a separate group?
[Slide]
We have guidelines for complicated skin and soft tissue
infection. Why do we need separate
guidelines for diabetic foot infection, or do we need them? I think we do, and I think that patients that
we enroll in trials of diabetic foot infection differ from the other patients
in several ways, first of all, the risk factors which are vascular, neuropathic
and diabetes itself and, secondly, the use of adjunctive therapy which, in the
management of a diabetic patient with a foot infection, is major and part of
standard care, and that is debridement and surgery, wound care itself or wound
dressings and off-loading which is a term, by the way, I knew nothing about
until I got involved with Ben Lipsky and Tony Berendt.
[Slide]
What are the desirable features of a study? Well, I think you want to optimize
enrollment. The most recent trial we did
enrolled 370 patients, which is a large number.
I think it should include most types of diabetic foot infections. It should allow inpatient or outpatient therapy. It should allow intravenous or oral therapy
if the agents are capable of doing this.
And, it should allow additional antibiotic agents for organisms which
are resistant to the study drug or comparator that are being tested.
[Slide]
Inclusion criteria--I am going to go through this and pause
when we come to those things I think are real issues. Some of these are obvious and standard, over
age 18; informed consent. The patients
should obviously have diabetes mellitus by ADA criteria; and they should have
an infected lesion of the lower extremity.
You can see from the list that I have put here that these are much the
same as Tony had, except that I have left osteomyelitis off and that is for
purposes of discussion.
Clearly, we need to define an infected lesion and Tony has
gone through that. The PEDIS
classification I think is very helpful.
I would only say that I second what he said, I think it is a clinical
diagnosis, not a microbiologic diagnosis.
Microbiology is important but I don't think you make the diagnosis of
diabetic foot infection on the basis of the culture.
[Slide]
The infected lesion can require extensive debridement or
surgery, but for purposes of a study it should not require complete resection
or amputation. If that takes place, then
clearly you can't evaluate the effect of the antimicrobial agent.
It can be open or closed.
It can be anywhere on the foot.
You can have multiple lesions but you ought to select on as the study
lesion, if you will. I believe it can
have been treated with potentially effective antibiotics before the study, but
only for 72 hours or less. Now, there is
no magic about that. It could be 48; it
could probably be 24; and it might be longer.
I don't think we have any data as to how quickly antimicrobial treatment
renders an infectious lesion no longer infectious or how long it takes to
eradicate the organisms but, at least in my experience, you can go for at least
three days without clearing a diabetic foot infection of bacteria.
[Slide]
The exclusion criteria--certain local conditions of the
lower extremity; critical ischemia which we will come back to in a moment; the
expectation that the entire infection will be resected or amputated; more than
72 hours of an agent active against the pathogen; an infected device that can
or will not be removed; a patient who required additional non-study antibiotics
for any reason other than an organism resistant to the study drug; and I think
the presence of extensive either dry or wet gangrene.
[Slide]
For ischemia, I think we can define this reasonably
well. Critical ischemia would be defined
as absence of palpable posterior tibial or dorsalis pedis pulses; absent or
abnormal Doppler wave forms plus a toe blood pressure less than 4 mm Hg.
Can you enroll patients who have critical ischemia? Well, we know it affects healing. We know it affects outcome of infection. I think if you have a vascular surgeon who
feels you can include this patient in the trial, you could but I think it is
simpler if you use these criteria and say no.
[Slide]
Now, what about osteomyelitis? Tony touched upon this and Dr. Alivisatos is
going to talk about it a bit more. But
it occurs in more than about a quarter of diabetic foot infections. It can be difficult to diagnose. It is difficult to define. It can certainly be more difficult to
eradicate once osteo is present. It
requires more prolonged antimicrobial therapy, and there really is no good
clinical data on the required duration.
Tony has suggested some good guidelines I think, but trying to get a
group of clinicians or researchers to agree that you have resected bone back to
blood bone or live bone, analysis and so on, is very difficult. So, to say that depending on the extent of surgery
your optimal duration is such-and-such I think might work well with a small
group of research scientists but won't work well in a clinical trial. The last point is obvious, that osteo
requires surgical debridement or resection.
[Slide]
So, how do you diagnose osteo in clinical trials? Some of it easy, or at least we think it is
easy. If there is an open wound and the
bone is visible I think most people would agree that osteo is present. If there is an open wound and the probe to
bone test is done and is positive, most people agree that that is osteo,
although we will come back to that and others will talk about how that is based
on one clinical study, done by Grayson and Kartchmer, in a group that had a
high prior probability of osteo.
Although the test is very good, it has not really been validated in
other studies.
More commonly, if you don't have an open wound and you
can't see the bone or you probe it, we rely on either baseline x-ray or MRI
which are read as active on osteomyelitis.
I think you need to define the criteria for osteomyelitis very
critically, and it should be standardized in the protocol. This is hard to do, and one of the things no
one has looked at is inter-observer variability. If you gave the same x-ray or MRI to two or
three radiologists, would they read it similarly? I have some experience with this as a fellow
with urinary track infections and giving x-rays for pyelonephritis to a group
of radiologists and the discrepancies where somewhat surprising to me at the
time. They are no longer surprising I
think. Nuclear scan is not sufficient to
exclude osteo.
[Slide]
So, in order to set up criteria I thought, this being
Washington, I would take one moment and just give you all a quote that I think
most of you remember from the Supreme Court:
I shall not today attempt to define the kinds of material--and Justice
Stewart was talking about pornography--but I know it when I see it. I think too often most of us are convinced we
know osteo when we see it. For a
clinical trial that doesn't work and you have to have accurate definitions.
[Slide]
So, what kind of studies would one do in a clinical
trial? Plain x-ray; probe to bone for
open lesions; culture and sensitivity testing; wound description and I think
photography, if you could get it as a standardized thing would be very helpful;
a wound score by a standard protocol; and a vascular evaluation. I am just going to talk about a few of these
briefly.
[Slide]
Wound cultures--Tony talked about that already a little
bit. We get them from all patients. They should be set up for aerobic and
anaerobic culture. I think it is
simplest to say that swab specimens are not acceptable. However, they are the norm in clinical
practice and it is true that there was one small study where patients who had
ulcers that were debrided and then had swabs versus tissue biopsy taken and
there was great comparability in these two.
However, in most patients the swabs are taken directly from the basement
ulcer and they are not taken from a debrided lesion, and I think it is simpler
if you are establishing a protocol to say you can't do swabs.
Having said that, I think you then have to deal with the
people who are doing the study. We would
prefer to see curettage of the wound base or tissue specimens obtained at the
bedside or the OR, or aspiration for secretions or cellulitis.
[Slide]
Wound scoring systems--Dr. Lipsky has put out one designed
to give an objective wound score. It
basically includes quantifying the wound parameters, peripheral pulses, wound
measurements and the wound infection score itself.
[Slide]
Probe to bone--I am just going to say a few words about
this. In one study, an excellent study I
should add, by Grayson, et al., published in 1995, 76 patients at, again, a
high prior probability of osteo; 66 percent sensitivity; 85 percent
specificity; a very high positive predictive value and a mediocre negative
predictive value. So, they concluded
that if the test was positive the patient had osteo. They compared this to bone biopsy as the gold
standard, which I think was appropriate.
The technique of doing this is very important. You have to use a metal probe. You have to follow the technique that was
described in the article. Too many
people, for example, use the reverse end of a Q-tip or swab and put it into the
lesion and try to feel for bone, and you can't get the same sensation which is
what you want to feel, a gritty, metal feel as the probe hits the bone. So, you have to do it the way it is
described. I think it is a good test,
however.
[Slide]
What would we write for guidelines for treatment? For drug versus comparator, the comparator
should be the gold standard. There are
only three drugs right now that are approved for diabetic foot infection,
piperacillin tazobactam, which does not have an oral form; trovafloxacin, which
is no longer available or not widely used; and linezolid, which was just
approved.
In the treatment you can add other agents for activity
against organisms not covered by the study drug. So, if your drug has spectrum,
for example, only against gram-positives you want to cover for
gram-negatives. Seven to 21 days of
antibiotics I think would be allowed, and 14 days is the usual duration in most
clinical trials.
[Slide]
Adjunctive therapy includes debridement and surgery; dressing
changes; off-loading, and not allowed would be topical antibiotics, antiseptics
or other antimicrobial agents such as Betadine.
I think the issue that comes up here, which is the second
issue I wanted to bring up, is one that the FDA has raised, and I think raised
appropriately. If you have all of these
top three adjunctive measures going on, how do you know what the antimicrobial
agent is doing? Might the patient do
just as well if they only got the adjunctive therapies?
So, one of the suggestions has been could you do a clinical
trial of adjunctive therapy plus placebo versus adjunctive therapy plus the
antimicrobial agent in question? I would
say I don't think you can. I think it
would be very difficult to get any group of infectious disease people who would
be willing--or diabetologists--who would be willing to treat infected lesions
without using antimicrobial agents unless they were absolutely the mildest of
infections. So, I don't think you can do
that, and I think you just have to assume in a clinical trial for diabetic foot
infection that the adjunctive therapies are part of the standard of care. After all, in a sense we do this with
intra-abdominal infections in clinical trials, everybody gets surgery as well
as antimicrobial agents and we don't ask the question what is the role of
surgery versus the role of the antimicrobial agents.
[Slide]
I am going to skip through most of these. Wound dressing--there are lots of types. None has been proven best. I think the bottom line is that the more you
can standardize these adjunctive measures of therapy, the better but it is
difficult to do in practical terms in clinical settings where institution A
believes in one type of wound dressing and institution B in another, and there
is no data to prove that one is better than the other.
[Slide]
The same holds for off-loading, which I have learned is
invaluable in terms of curing infection.
Many devices are used. None has
been proven best. Again, although we
would like to standardize it in clinical trials, it can be very difficult to
do.
[Slide]
I am almost at the end.
In terms of efficacy evaluations, I believe that we should have a
follow-up for test of cure at 14-21 days after the end of therapy. I think end of therapy evaluations add very little.
The clinical response to therapy is defined as resolution
of pre-therapy clinical signs and symptoms of infection. In my belief, it does not include wound
healing or lesion healing. Although they
obviously move in parallel and obviously a wound that remains infected is
unlikely to close, but the criterion should be the resolution of clinical sings
and symptoms of infection. Final
categories are cured, failed or indeterminate.
[Slide]
Surgical debridement is allowed during the trial and is
considered part of standard care.
Complete resection of the infected area would remove the patient from
the trial.
[Slide]
The last slide, and I am very happy that we have at least
two statisticians sitting at the table, how do you pick a sample size? I think most people would agree that 80
percent success rate for the comparator is reasonable. That obviously depends on what kind of
patients you have in the trial and the severity of infection. A difference in cure rate of less than 10
percent would be considered equivalent.
If we are trying to do trials of superiority, I think you need to decide
what criterion you would use, and I don't really have a recommendation for
that. I think you would like to be at
least 10 percent better than the comparator but I think that is up to people
designing the trial and the FDA.
I am going to stop at this point. Jim, I made it with two minutes to go,
actually.
DR. LEGGETT: That
will give us time for questions. Dr.
Berendt, would you like to come up? Does
anyone have a question for either of these two speakers?
DR. PATTERSON:
Hyperbaric oxygen is being used as adjunctive therapy a lot these
days. Would that be accepted as well?
DR. NORDEN: Well, I
will answer that first. I mean, it is
being used. There is absolutely no data
still to support it. It just complicates
things immensely in terms of managing the patient and I would think I would not
want to have it in a clinical trial.
DR. BERENDT: I know
there are great enthusiasts about hyperbaric, and other people who don't have
it available who are the unenthusiastic or don't know. All the views that I am aware of have still
concluded that there is no real evidence for the role of hyperbaric and,
therefore, I don't think we would know how to use it. The people who advocate its use would
probably say it is about equivalent to an antibiotic in terms of what it adds
so it probably should be considered in the same way as someone who elects to
add another antibiotic to the trial and, therefore, that might not be allowed
for those reasons.
DR. CROSS: Assuming
that the vascular insufficiency doesn't impair the ability of the myeloid or
white cells to enter the wound, what do we know now about the ability of
diabetic white cells to produce pro-inflammatory cytokines which may affect the
clinical appearance of the lesion?
DR. BERENDT: Carl
very sensibly asked me to do that. I am
not sure I can give you a good answer to that question actually. There have been some studies done a long time
ago on some of the more gross aspects of white cell behavior like chemotaxis,
and so on, but I don't know whether there have been any systematic studies more
recently so I would have to admit ignorance of that. Somebody in the room might know but I don't.
DR. LEGGETT: Dr.
Berendt, would you have a single cut-off for when ischemia is enough? I think it was Carl who had an arbitrary 45
mL. I mean, I don't think it is an
on/off phenomenon.
DR. BERENDT: No, it
is not. That is difficult. The PEDIS scheme does set out absolutely specific
criteria for ischemia. I can't quite
quote them off the top of my head, but they are clearly laid down. I think I would agree with Carl that if
critical ischemia persists during the trial, then you probably can't include
the patient. You would have to make a
decision about what to do if someone presents with critical ischemia and is
successfully revascularized as to whether they can be enrolled or stay
enrolled, as it were.
DR. LEGGETT: Don?
DR. PORETZ: One of
the problems as I see it is that in the diabetic foot you have a whole
potpourri of physicians who are taking care of patients. You have general practitioners; you have
general internists; you have infectious disease doctors; you have podiatrists;
you have orthopedic surgeons; you have vascular surgeons and general surgeons,
and plastic surgeons. So, you have at
least seven or eight different disciplines.
Any criteria I think is going to have to be agreed upon by all of these
disciplines, which is really hard to do, but it seems to me if you don't do
that you are not going to be able to have a reasonable system.
DR. NORDEN: I would
agree with that, Don; I don't have any problem with that, and it is very hard
to do it.
DR. PORETZ: The
International Consensus was only diabetologists?
DR. NORDEN: No, it
had others.
DR. BERENDT: The
International Consensus does have representation from vascular surgeons,
orthopedic surgeons, infectious disease specialists, surgical podiatrists as
per in the States, as well as endocrinologists.
So, that probably has a fairly broad grouping but whether each of those
people is then able to say there is an international consensus from their own
specialty group that would feed into this particular version of the
International Consensus is another matter. I mean, I think the consensus is there in a
sense to be challenged and validated, and I agree with you, there is a huge
number of people. That is probably why
there are already so many guidances that deal with the general diabetic
foot. So, you know, lot of different
expert societies have their own guidance on diabetic foot in general.
DR. LEGGETT: If it
is a follow-up, Don. Otherwise, if it is
a new question, we have other people.
DR. PORETZ: Just
quickly, it is just like the pneumonia guidelines. There are half a dozen pneumonia guidelines
from various authorities, but maybe if it could be published in specialty
journals and everyone agrees, that would be the best way to do it.
DR. LEGGETT: Dr.
Armstrong?
DR. ARMSTRONG: As a
follow-up on that, Dr. Berendt, you mentioned two definitions that you sort of
proposed of diabetic foot infection. One
was sort of general where it had a couple of co-morbid factors associated with
it. Of those, you were sort of
non-committal. Which one would you
prefer?
DR. BERENDT: Well, I
think a lot of it comes down to this issue of sensitivity versus specificity
really. The pre-meeting discussions I
had with the FDA folk have helped me to understand that there is a special
interest in having a very specific definition.
If that is what you want, then I would go for the more specific version
where, in fact, for example in your study which looked at the contributions of
ischemia, depth and infection to amputation rates, I think if I have done the
numbers right, over 90 percent of the cases in that study had ulceration with
ischemia or neuropathy as part of it.
So, I think if you exclude the people with intact skin you probably
don't exclude all that many actually from the group you are interested in. But I think that is an area that people would
want to debate because, you know, it all depends on whether you are taking a
clinical view that a clinician seeing a patient with diabetes who comes into
their room and has a foot infection would like to feel that the licensing of a
drug and the guidance that has come through covers that patient, and that is
where the argument goes that from the clinical end you want a sensitive
definition, whereas from the regulatory end, the research end, you want a
specific definition.
DR. LEGGETT: Dr.
Powers?
DR. POWERS: Dr.
Berendt, I think that is exactly the point that we are worried about, the
specificity of people getting enrolled into a trial. Because one of the things that Dr. Norden
pointed out is--and this came up in the advisory committee back in 1999
regarding a topical drug called pexiganin, where the committee actually had
this issue of did the people enrolled in this trial really have infections or
not. In the pictures you showed, it
seems that all these people have some degree of redness up around the lesion,
some of which is chronic venostasis changes as well.
So, what I wanted to ask was could you and Dr. Norden give
us an idea--many of these scales that you showed us say infection with
whatever, and you gave us a pathophysiologic definition of what an infection
is, and I think this gets back to Justice Potter's quote of we all know
infection when we see it, but in terms of a protocol we would need to put in
specific definitions of what that means.
Are these definitions specific enough in diabetic foot or even sensitive
enough? Two-thirds of people aren't
febrile. Leukocytosis may be
absent. Are there some things, other
than a diabetic with a break in the foot, such as new erythema that hasn't
occurred in the last 48 hours; new drainage; some other things that would help
us increase the specificity of diagnosis in these trials?
DR. BERENDT: I mean,
you are right. It is definitely a
problem. You could certainly add things
like that I guess. I think that that
PEDIS scheme at least makes it clear, you know, if a trial is reported
according to the categories within it, then at least you are a bit clearer
about what is going on. You could say,
yes, as an improvement of that you want new things. And, there is some work done with other kinds
of chronic wounds to suggest that there are some secondary characteristics that
might be more useful than the classical definitions of infection which relate,
as you have said, to sort of changes in drainage, or changes in smell, or
changes in granulation tissue.
But I wonder if I put those things up as my criteria you
would be equally critical of that because that would imply someone who has
already seen the foot and who was reporting the change. And, you know, is that any more reliable? So, I am not sure whether that would take us
further forward, but I am sure that what we need are studies that use some of
these sorts of frameworks that try and validate it. I am also sure that one of the things you
can't use as validation is the natural history because nobody is going to say,
well, I'm not sure; I think that is infected but I'll wait a few days for it to
get a whole lot worse and then I'll know that it was. So, I think some of your concerns are,
unfortunately, unanswerable actually and we will be stuck with clinical
definitions unless it turns out that using quantitative micro or some other
thing is better.
DR. POWERS: Could I
ask a follow-up question, and that is the idea of looking at the PEDIS scale
where you have grades I through IV for infection. I guess it gets us into a conundrum there
with you saying we need to validate those going forward. However, what we would need in a clinical
trial is an already validated scale.
This comes up in many infectious diseases, the idea of how does one
actually qualify severity. Again, it
goes back to what is severity? What we
have looked at is trying to define severity for these guidances as something
that tells us that those clinical characteristics portend a worse outcome
regardless of treatment. So, that
doesn't need a placebo arm. I would
refer to the patient outcome research treatment studies for community-acquired
pneumonia where people get treated but certain factors portend a worse outcome,
anywhere from 0.1 to 30 percent mortality.
Have any of these scales been validated in that way? I know Dr. Armstrong's has been for wounds,
but how about for the infectious component of that?
DR. BERENDT: I think
the answer is no. I mean, it is the
deficiency of the process really. It
comes back to whether an agreement to all use the same thing, even if it is
flawed, is better than an agreement for everyone to keep thinking up their own
better version that is sort of personalized and impossible to compare.
DR. LEGGETT: Dr.
Maxwell?
DR. MAXWELL: I just
wanted to ask Drs. Berendt and Norden, in the inclusion of this definition of a
diabetic foot that you have, whether it was threatening the limb or not
threatening the limb, where would that fit in?
Because that is somewhat the definition that I see bandied around in
Mandell and other sources.
DR. NORDEN: That is
a good question, Dr. Maxwell, but again, like most of the others, there really
is no good definition. It is used in
Mandell and in most infectious disease textbooks. I think, well, we know a limb-threatening
infection when we see one. You know, the
patient looks more toxic. The deeper the
infection, the more undermining there is.
The greater the extent of the infection is more limb threatening than
not limb threatening. A small ulcer is
probably not limb threatening by definition.
We tried to look at that in one clinical trial and really
didn't find it very helpful. Maybe we
didn't have precise enough measurements but that would be my impression, that
it doesn't help a lot.
DR. LEGGETT: Dr.
Wald?
DR. WALD: I have a
question about the exclusion criteria for osteo. The statement was nuclear scan alone is not
sufficient to exclude osteo. That means
normal is not sufficient? I guess the
question I would ask is, is abnormal enough to include a patient because it
seems to me that a lot of these patients might have some contiguous
inflammation which really didn't necessarily represent bone infection.
DR. NORDEN: Yes,
Ellen, I think the slide isn't very clear and the way I wrote it isn't very
good. Actually, a negative scan is so
rare that it probably makes osteo very unlikely, but it is so rare to see a
negative scan. No, I think a positive
scan of any kind, whether it is technetium or indium, does not establish a diagnosis
of osteo.
DR. LEGGETT: One
final question--I assume you two will be around later this afternoon during our
discussion session? Okay.
DR. CROSS: I was
wondering whether in any of the previous studies a return to function has been
used as a measure of efficacy, given what we heard about how many people who
have these infections may be incapacitated for prolonged periods of time?
DR. NORDEN: I can
only speak to the linezolid trial and the answer is no. It is a good measure but there wasn't enough
follow-up available and sometimes people didn't have--I will leave it at that,
no.
DR. LEGGETT: Thank
you. The next speaker will be Dr.
Sorbello to give us a talk about lessons learned from previous review of drugs
for diabetic foot infection.
Lessons Learned from
Previous Review of Drugs for
Diabetic Foot Infection
DR. SORBELLO: Good
afternoon.
[Slide]
The focus of my presentation today will be on issues that
were identified from previous submissions to FDA related to drug development
for diabetic foot infections.
[Slide]
The way I am going to structure my approach to my
presentation is really to make it more of a conceptual discussion of some
important issues, which we have already heard a fair amount about but still are
very critical issues in trying to evaluate clinical trials and clinical study
results in relation to not only drug development but looking forward to trying
to develop a guidance document for drug development for diabetic foot
infections.
[Slide]
We have already heard some discussions about developing a
definition of a diabetic foot infection so some of this will be repetitive, but
there are just a couple of points that I do want to again bring to your
attention.
First, looking at the issue of developing a definition of
diabetic foot infection, as of yet there is still no generally accepted
definition, and both a definition as well as a classification system for
diabetic foot infections remain an area of controversy and discussion and an
area of a considerable amount of work.
It is important to remember that foot infections in
diabetics can be either ulcer or non-ulcer related and that statistically about
15 percent of diabetics are at risk to develop a chronic non-healing ulcer in
their lifetime. But even amongst those
who develop chronic non-healing ulcers not all are infected. It gets back to one of the prior discussion
issues of how do you define and determine whether a chronic foot ulcer is
actually actively infected.
Regarding clinical trials that have been submitted to the
agency, many of them are submitted under the complicated skin and skin
structure infection guidance, and these are broad, large studies with a broad
mix of different types of complicated skin infections, of which diabetic foot
infections are one subgroup. These are
usually supplemented with studies limited to diabetics with lower extremity
infections to provide more specific data.
The eligibility criteria for many of these studies relate
to either specific disease entities, such as cellulitis, paronychia, deep soft
tissue infection; discrete clinical findings such as drainage, redness, warmth,
swelling of the infected limb; and sometimes the presence or absence of a foot
ulcer. Again, there is not any uniformly
applied or clearly described definition of what a diabetic foot infection is or
even what constitutes the different specific disease entities that are being
studied.
[Slide]
There has been obviously discussion about making a clinical
diagnosis of diabetic foot infections, and I just wanted to reiterate the point
that diabetics do tend to have other problems that can affect their lower
extremities which can produce signs and symptoms that may appear similar to
some of the changes that you may see in a lower extremity infection or may
actually predispose to lower extremity infections. Certainly, diabetics can have significant
developmental foot abnormalities, hammer toes, valgus deformities that,
combined with sensory peripheral neuropathy and inability to appreciate and
feel pain in their feet, they could develop into lower extremity ulcers and not
be aware of them for considerable periods of time, that get colonized with
bacteria and chronically and slowly smolder and become infected and become a
more complicated infection.
Patients develop significant soft tissue changes from
chronic lower extremity edema, stasis dermatitis, dependent redness, and they
certainly are at risk for neuropathic joints, Charcot joints with advanced
peripheral neuropathy. Certainly their
vascular status is important because the significance of peripheral vascular
disease in diabetics and the potential effect on wound healing becomes an
important complicating factor in ability to get some of these infections to
heal successfully.
[Slide]
With this slide I wanted to just show you some data from a
study which looked at diabetics with osteomyelitis of the foot. A long list of different features were
evaluated to try to see if any of them, or any combination, would be good prognostic
factors for those who had a good outcome versus those with a poor outcome, and
poor outcome usually portended amputation.
As you can see from the list of features and the comparator
percentages there, the only two findings that were statistically significant as
far as prognosticating factors were the presence of swelling and the absence of
necrosis in patients who had a good outcome.
As was alluded to earlier, findings such as temperature
occurred in very few patients. I think
overall about 17 percent of the population that were studied had fever and most
of the others did not. Other findings,
such as redness, drainage, warmth and presence of a foot ulcer were comparable
in both studies and really were not good distinguishing characteristics. Again, it tends to underline that physical findings
can certainly be of clinical value but they are of some limited value,
especially with respect to not only looking at prognosticators for
responsiveness to infection but possibly also to even evaluating the severity
of an infection.
[Slide]
I wanted to kind of use those concepts to look at a
framework for defining a diabetic foot infection. We have obviously heard definitions for
diabetic foot infections. What I thought
I would do is basically just propose certain concepts to at least think about
in developing a definition. There is
obviously some overlap between defining and diagnosing diabetic foot infections
but I think there is a need to do that.
I think first deciding about whether the presence or
absence of some type of lead point, an open wound, a foot ulcer, or any type of
break in the skin, is that really a necessary or should that be a necessary
part of defining a diabetic foot infection in a clinical trial? Clinical findings themselves--I suspect
probably a constellation of findings would probably be of more benefit than
looking specifically at evidence of erythema or swelling or foot ulcer
individually.
The anatomic location or site of infection probably would
be important, not only defining it, as was mentioned earlier, to sites in the
foot distal to the malleoli line but also possibly the location within the foot
as there are certain areas, such as the areas beneath the metatarsal heads,
which are more prone to being sites of ulcer development.
I think depth of infection is a very key aspect here
because, in many ways, diabetic foot infections are contiguous infections, that
is, a high risk of spread and extent of infection from skin to soft tissue to
the deeper structures and especially the distinguishing of skin soft tissue versus
bone and joint infections is a critical one because bone and joint infections
probably should be considered in separate studies because the pathophysiology
is different; the ability of drugs to penetrate into bone is different. They involve different endpoints, different
durations of treatment, etc.
I would also consider in the definition the issue of
isolating pathogenic bacteria. This
obviously would be more specific to a person who has an open wound or foot
ulcer but, again, distinguishing not only that the bacteria are there but that
you actually have pathogens as opposed to colonizers, and obtaining these
cultures from what would be considered an appropriately obtained specimen.
[Slide]
Classification systems is a second and, again, important
consideration in developing a guidance document for diabetic foot
infections. We have certainly heard
important information about ways to classify diabetic foot infections but, in
general, there have been two approaches.
One has been to look at the severity of infection and the other have
been approaches centered more on the status of the foot ulcer and the
progression of the foot ulcer with disease.
To date, there is not a generally accepted classification
system. They do differ in the criteria
that is utilized, the complexity of the parameters that they are being assessed
and, certainly, they would require some type of validation to be applied
full-scale in a clinical trial.
[Slide]
To talk a little bit about the classification systems, the
two main types of classification systems have been mentioned based on severity
or either limb threatening or non-limb threatening which basically, again is
looking at extent of disease. Localized
disease is not limb threatening, which does not have clinical signs and
symptoms of sepsis, without evidence of any osteomyelitis, with no or very
minimal vascular compromise, as opposed to limb-threatening infections which
are more extensive, high risk of osteo, usually associated with ischemia or
gangrene, usually aggressive deep infections.
Mild, moderate and severe basically can be thought of as graded
progression from superficial to deep infections, from minimal to no ischemia to
progressive ischemia, from no osteomyelitis to evidence of osteomyelitis and,
obviously, from no systemic symptoms to persons who appear clinically septic.
[Slide]
I just wanted to list some of the classification systems
that are in the literature. These
include the Wagner system, which is one of the earliest; University of Texas
system; the S(AD) SAD, which stands for size, area depth, sepsis arteriopathy
and denervation and simple staging; and we have heard today about the PEDIS
system.
Again, if anything, it is just to point out that there
remains controversy, debate about how to think about classifying these
infections; what would be the appropriate parameters to include in a
classification; and how to use these then in the context of a clinical study
and clinical trial.
[Slide]
Again, kind of as we did we definition, just to consider
some concepts as a framework to try to classify diabetic foot infections, I
think as we have already heard discussions today earlier, standardized
definitions are needed so that investigators in the studies are really looking
and evaluating these infections with some uniformity. The clinical disease entities that would be
studied should be delineated. There
should be some kind of a uniform consideration of how to approach evaluating
these patients for ischemia and neuropathy and what would be considered significant
or profound ischemia versus lesser grades, and the same with neuropathy.
Classification systems that might correlate with the extent
and natural history and the prognosis of the infection would be important
because certainly, especially in infections that are treated for longer periods
of time, you might be able to correlate the status of the infection from
baseline to points later on and end of therapy and follow-up where patients had
a course of therapy, and it would be another way to objectify what has been
happening in response to treatment.
Again, distinguishing skin and soft tissue from bone and
joint infections is an important consideration, as I already mentioned, and I
think in many ways bone and joint infections probably should be examined in a
separate trial because of all the fundamental differences from skin and soft
tissue.
Lastly, as has been described, a classification system
probably would need validation before being adopted.
[Slide]
Moving on to some other concepts within the development of
a guidance, another one would be characterization of the study population. This is a very critical consideration because
there are a number of demographic and co-morbid factors that need to be
assessed on patients who are enrolled.
Baseline assessments need to be performed and clinical diagnoses need to
be developed for the patient depending on the extent of their disease.
[Slide]
I have listed here some demographic parameters that should
be assessed in enrolled subjects, and these would include age, gender, race,
weight, country of origin for an international study or the study center or
site, and co-morbid factors, whether they have insulin dependent or non-insulin
dependent diabetes, evidence of peripheral neuropathy, peripheral vascular
disease or renal insufficiency which may be complications from the underlying
diabetes, any history of osteomyelitis affecting the limb or any history of
lower extremity surgery, be it podiatric, orthopedic or vascular which, again,
may involve treatment of prior osteomyelitis or revascularization procedure to
improve blood flow.
[Slide]
Baseline assessments should include both laboratory as well
as various other types of imaging procedures.
Labs should include routine hematology and chemistry and hemoglobin A1C
to give some idea of recent glycemic control and, obviously, appropriate
cultures, either wound, tissue and/or blood.
Radiologic imaging would be important in evaluation for concomitant
osteomyelitis, and this will be discussed later on this afternoon. Neurovascular evaluation, as was already
mentioned, and, lastly, assessment of the wound or the ulcer size or dimensions
either through measurements or wound score or as appropriate.
[Slide]
Clinical diagnoses in diabetes really reflect on the heterogeneity
of the disease. This slide illustrates
for you just a little bit about the complexity of a diabetic population with
foot infections. The small box on the
left-hand side which says "CRF tabulation" is basically seven
diagnoses utilized in one study to categorize patients with diabetic foot
infections. These were basically
extracted from the case report form.
On the right-hand side is just the kind of breadth of types
and complexity of infection from the FDA analysis, really to show you that patients
with diabetic foot infections tend to have multiple concomitant processes
going. They have an infected ulcer. They have cellulitis. They have an associated septic arthritis
and/or osteomyelitis. So, their
infections tend to be complex. There is
a greater risk of depth and extent of infection which tends to be
complicated. Trying to identify those
with bone or joint infection becomes important, again, because they may well
need to be assessed in a separate trial, in a separate study with parameters,
etc., that are more appropriate for those types of infections.
[Slide]
I wanted to spend a little bit of time on adjunctive
treatments and this was mentioned previously.
Adjunctive treatments are, in many ways, the standard of care in the
treatment of patients with diabetic foot infections. These can involve a multitude of different
types of interventions, from off-loading to reduce edema, from dressing
changes, other types of local wound care, medical therapy including
antibiotics, putting patients on insulin coverage, etc. to get blood sugars
under control, and various surgical interventions which can range from
debridement to revascularization of the lower extremity to improve blood flow.
So, there are a number of different interventions that are
being done and it is important within the protocol to try to specify what
treatment should or should not be permitted because, most importantly, they do
augment wound healing and resolution of infection which is a very important
response in all this. But there are some
other effects of these adjunctive treatments that need to be considered in
analyzing efficacy data. In particular,
whether or not they are used equally in all the subjects in both arms of a
comparator trial for example, and whether adjunctive treatments may have a
beneficial effect as far as clinical success and outcome, possibly making
dissimilar drugs appear more similar or more indistinguishable.
[Slide]
This is data which is basically an FDA analysis of a
submission of a drug for a diabetic foot infection indication where the
assessment was to look at surgical debridement as adjunctive treatment, and if
there was any relation of that to the clinical outcomes observed.
The debridements were broken down by those which had no
debridement; those which had one to two; and those which had three or
more. As you can see, it was broken out
by the number of patients who received study drug or comparator and their
outcome as far as cure at end of therapy.
The main point here is that although the numbers are small,
as the number of debridements increased the overall trend was a trend of
improvement in the cure rate. Increasing
number of debridements tend to be associated with an improvement in the cure rate
and the cure percentage. These percentages
were not statistically significant but certainly it is an important observation
which may underscore that adjunctive treatments may be having a contributory
effect to the clinical success that is seen, and they probably should be
considered in efficacy analysis.
[Slide]
I want to finish up with just a couple of concepts on
microbiologic considerations. This will
be discussed later on this afternoon but, again, there are some important
points. One is the need to identify
pathogens amongst polymicrobial infections and distinguish them from
colonizers; two, the need to standardize methodology as far as what are
acceptable and appropriate specimens, in particular the issue about swabs; and
microbiologic outcomes.
This really underscores the point that many times diabetic
foot infections are clinically driven and that patients who have pre-therapy
wounds which then heal during the course of therapy, obviously, don't have an
accessible site for reculture at end of therapy and their outcomes are presumed
or extracted based upon the clinical response.
[Slide]
In summary, issues to consider for guidance development for
diabetic foot infections: Number one,
definitions and classifications of diabetic foot infections and diabetic foot
ulcers; appropriate characterization of the study population; recognition that
the primary focus tends to be on clinical outcome; the need for standardized
microbiologic methodology; to consider the effect of adjunctive treatments on
clinical outcome; and drug development for bone and joint infections probably
should be addressed with a separate clinical trial, possibly with a separate
guidance due to their differences in pathophysiology and treatment. Thank you.
DR. LEGGETT: Thank
you. Unless there are any really specific
questions we will move on. The next
speaker will be Dr. Albert Sheldon, who is going to talk to us about
microbiologic diagnosis of diabetic foot infections.
Microbiologic Diagnosis of
Diabetic Foot Infections
DR. SHELDON: Good
afternoon, ladies and gentlemen. I am
absolutely delighted to be here to talk to you about the microbiology of
diagnosis of diabetic foot infections. I
can tell you that as a microbiologist, this is one of the more difficult
indications that we have to address.
[Slide]
During this discussion I will focus on the controversies
that exist in the acquisition and interpretation of microbiological samples
obtained from decubitus ulcers and, hopefully, you will find that this
presentation will complement those that have come before me to help you answer
the questions that you are going to have to address this afternoon.
[Slide]
Before I proceed, I think what I would like to do is to
give you some insight into our thinking regarding the guidance that has been
created within the agency to develop drugs for the treatment of foot infections
in diabetic patients. These include that
all patients should have pre-therapy cultures.
We would like to see gram stains and cultures obtained from acceptable
sources using acceptable methods. These
methods will include leading edge needle aspiration, soft tissue and joint
aspirations, bone biopsy and/or surgical debridement. The microorganisms isolated should be
assessed as true pathogens, colonizers or contaminants. Finally, only microorganisms designated as
true pathogens should be considered in determining microbiological evaluability
of enrolled subjects.
[Slide]
In order to understand the microbiology of decubitus
ulcers, I think we need to understand the factors that influence the risk of
infection. These were actually
articulated by Altemeire in 1965, where he stated that the risk of wound
infection varies according to the following equation, that is, the dose of the
bacterial contamination involved, the virulence of those organisms and the
resistance of the host to that infection.
[Slide]
The host factors that influence infection rates include
diversity and abundance of microorganisms present in the wound, and include the
wound type, depth, location and quality.
They include the presence of nonviable exogenous contamination;
peripheral blood insufficiency and the immune competence of the host, as
already stated.
[Slide]
In doing the microbiology of decubitus ulcers, the
"Manual of Clinical Microbiology," published by the American Society
of Microbiology, in obtaining the use of specimens says, "the use of
specimens for bacteriological analysis requires that specific clinical material
be collected, stabilized, and transported according to exacting specifications
to insure valid results."
[Slide]
Implicit in this definition are two issues that are of
interest to the discussion of decubitus infections. The first is the methods used to collect the
clinical sample and the other is the validity of the results to assess the
involvement of an organism in the etiology of that disease.
[Slide]
Now I will address the first, which is methods used in
collection of microbiological wound samples.
These can be basically divided into two types of techniques. The first is deep tissue techniques, and they
include biopsy and surgical debridement; leading edge needle aspiration; joint
fluid or synovial fluid; bone specimen and blood. The surface sampling techniques include the
swab; curettage; dermabrasion; velvet pad surface imprints. There are actually others but these are the
most prevalent.
Also, the methods that are most frequently used in
published literature are the biopsy, leading edge, swab and curettage. The methods recommended in our guidance
document are all deep tissue techniques.
[Slide]
What I would like to do now is to give you an example of
studies that have been performed to compare the sampling methods that are used
in decubitus ulcers. Here we have an
example of a study that was done by Sapico where he compared the ability of ulcer
swabs, curettage, needle aspiration and deep tissue to be able to determine the
types of organisms that could be isolated by each of these methods in decubitus
ulcers.
You can see that using deep tissue or the biopsy method as
the gold standard, we see that they were able to isolate approximately three
aerobic species and two anaerobic species using this technique. Compared to the ulcer swab method, we see
that the values are actually much larger, that is, the number of species that
can be sampled using the swab sample method are greater than with the deep
tissue method.
[Slide]
Then what they did was to try to determine quantitative
concordance between these two methods.
Again you can see that using the biopsy method as the gold standard,
needle aspiration was considered to have the highest concordance, followed by
curettage and then the ulcer swab technique.
One of the things that they concluded from this study specifically was
that the ulcer swab method was not a method that should be used in these kinds
of studies.
[Slide]
A study was also performed by Thomson to determine the
relationship between a swab culture method and a tissue biopsy method. Their conclusion was that there was
concordance or there was a correlation between the two methods. If you look at the biopsy numbers of two and
three, that is, 102 and 103, they had a swab culture
relationship of plus 1. If you look at
organisms that had 107 organisms or 106, a plus 4 was
considered to be concordant with that quantitative number.
I think that one of the things that we need to remember
here in looking at establishment of concordance between methods is that one of
the critical aspects is that we also need to establish concordance with the
clinical outcomes. In other words, we
need to correlate what these methods are telling us clinically and what that
clinical outcome actually is.
[Slide]
This is actually what Breidenbach and Trager tried to do in
their particular study. Here they tried
to determine the relationship between the quantity of bacteria and infection in
complex extremity wounds. They compared
the predictive value for wound infection of qualitative cultures versus other
factors considered to have predictive value for wound infections. I am only going to focus on the last purpose.
[Slide]
They evaluated 50 patients with complex wounds. These were defined as soft tissue defects
that required flap for closure. They did
quantitative culture biopsies. These
were compared to clinical parameters.
These were factors that had predictive value in wound infection and
included wound position, mechanism of injury and fracture, fracture type.
They also did a comparison to laboratory tests, primarily
the swab culture method. Twenty-eight
patients had quantitative cultures obtained after debridement and high pressure
wash prior to flap closure. Sixteen
patients had swab cultures, and two to five samples were obtained per wound,
depending on the wound size.
[Slide]
These are some of the results that they got. Here, what they did was to determine what
kind of criteria, using the positive test criteria and the negative test
criteria, correlated with clinical outcome.
Looking at the first line, the quantitative, we see that
positive test criteria were considered 104 organisms per gram of
tissue. In eight of nine situations they
were found to have a high prevalence of infection, for a prevalence of 89
percent. The negative test criteria were
considered less than 104 colony forming units per gram of
tissue. In only one case did they have
infection out of 19 cases, for a prevalence of five percent. So, there was reasonably good concordance
using this method in the analysis.
[Slide]
Now let's look at the swab method. Again, the same kind of study. In this particular instance they defined the
positive test criteria as having positive organisms in the swab. In this particular instance, in only 5 of 13
cases did they have infection, for a prevalence rate of 38 percent.
The negative test criteria were the presence of no
organisms, and here they had an infection rate of one in three, for a
prevalence of 33 percent. This is a very
small number so I don't know how much we can really extrapolate from that
particular negative test criteria.
[Slide]
What was different in this study from others is that they
then did predictive values, sensitivities and specificities of the previous
study. What they found was that the
positive predictive value for a quantitative culture was 89 percent, with the confidence
intervals presented in brackets. The
negative predictive value was 95 percent, and the sensitivity and specificity
were 89 percent and 95 percent respectively.
[Slide]
Using the swab culture method in comparison, the positive
predictive value here was 38 percent; the negative predictive value was 67
percent; and the sensitivity and specificity were 83 percent and 20 percent
respectively.
[Slide]
The one point that I want to make about the previous slide
is that we must have good positive predictive value and we must have good specificity
in a method that is used in a clinical trial.
[Slide]
Now I would like to talk a little bit about the
interpretation of microbiological diabetic foot infection samples. This is qualitative microbiology. I only have one slide. I think that this has already been discussed
by previous speakers. Most diabetic foot
ulcers are polymicrobic in nature. In
the study that was done by Sapico 25 of the 30 samples were polymicrobic in
nature. The predominant organism is
Staph. aureus, followed by Staph. epidermidis, streptococci, P. aeruginosa,
Enterococcus and coliform bacteria. The
predominant anaerobic species are Bacteroides and Prevotella.
[Slide]
Now I would like to discuss some of the schools of thought
that I encountered in my reading of the published literature. Although microorganisms are responsible for
wound infections, there is controversy regarding their role. The published literature is rather
inconclusive, and I think that has been brought out by some of the other
speakers. Some believe that the density
of microorganisms is the critical factor in determining whether a wound is
likely to heal. Other published
literature suggests that the presence of specific pathogens is of primary
importance in delayed healing. Further
others believe that microorganisms are of minimal importance in delayed
healing, and there is debate as to whether a wound should be sampled, the value
of the results and the methods that should be used.
[Slide]
In conclusion, there is widespread controversy regarding the
exact mechanisms by which microorganisms cause wound infections; regarding the
significance of microorganisms in non-healed wounds that did not exhibit signs
of clinical infection; regarding the best microbiological techniques to monitor
the microbiology of wounds; and the ASM Manual of Clinical Microbiology states,
"a swab is not the specimen of choice...since a swab specimen of a
decubitus ulcer provides no clinical infection."
[Slide]
A regulatory agency must require microbiological methods
that provide us with confidence and data necessary to assess the response of
antimicrobials for their indented uses.
We describe, in our guidance document, what we consider to be relevant
methods, and these are the deep tissue techniques that were discussed in a
previous slide.
[Slide]
I leave you with one final thought that was articulated
over a hundred years ago, "the germ is nothing. It is the terrain in which it is found that
is everything." That concludes my
presentation.
DR. LEGGETT: Thank
you. Any specific questions?
[No response]
We will move on then to the next speaker, who will be Dr.
Alivisatos on ruling out osteomyelitis in trials of diabetic foot infections.
Ruling out Osteomyelitis in
Trials of
Diabetic Foot Infections
DR. ALIVISATOS: Good
afternoon.
[Slide]
I was asked to address the issue of the imaging assessment
of diabetic foot infections with you
this afternoon.
[Slide]
The initial question is why? Why are we discussing imaging techniques
within the context of complicated skin and soft tissue infection in clinical
trials that have as a goal to obtain not only the complicated skin and soft
tissue infection indication, but a specific mention of diabetic foot infections
in the label?
As you all know, subjects with osteomyelitis, an infectious
process that requires a more prolonged course of antimicrobial treatment and
often surgical intervention, should be identified in order to ensure not only
that they receive the most appropriate course of treatment but, within the
clinical trials context, to ensure a relatively homogenous efficacy
population. Subjects with osteomyelitis
are usually excluded from the protocol populations of complicated skin and soft
tissue infection trials, and often the preclinical development programs do not
support the labeling for the long-term administration necessary to treat
osteomyelitis.
I would also like to point out that despite the attempt at
exclusion of such subjects from these trials, between 7-14 percent of enrolled
subjects have osteomyelitis and are subsequently excluded from the protocol
populations. Additionally, as per the
protocol, these subjects are usually classified as failures in the ITT
analysis.
[Slide]
So, does it matter if there are subjects with osteomyelitis
within the study population of complicated skin and soft tissue infections or
within the subset of subjects with diabetic foot infections? The inadvertent inclusion of such subjects
may not be an issue in double-blind, randomized trials as the distribution of
these subjects should be equal between the treatment arms. However, this is not always the case.
And, what happens if that distribution is not equal? As we know, clinical success is defined as
total resolution of all signs and symptoms of the infection or improvement of
the signs and symptoms to such an extent that no further antimicrobial
treatment is necessary. So, subjects
with osteomyelitis who receive further antimicrobial treatment could be, and
usually are, classified as clinical failures, leading to an inaccurate
assessment of the true efficacy for one or both of the treatment arms.
In trials where there are small numbers of subjects with
diabetic foot infections, the exclusion of subjects with osteomyelitis from the
per protocol population leads to a decrease in the size of the efficacy
database. As cure rates potentially
decrease, confidence intervals widen and difficulties develop in drawing
conclusions about efficacy.
So, the questions of which imaging procedure or procedures
should be recommended, if any, and is this enough of an issue to justify the
cost associated with the more sensitive and specific procedures are raised.
[Slide]
I would like to review what we have seen at the agency to
date in studies of complicated skin and soft tissue infections, and these are
seven applications. In all of these,
subjects with osteomyelitis were excluded in the protocols. In the two oldest, which are A and B on the
slide and which were from the late '80s and early '90s, the method of
assessment of such subjects was not specified.
In later applications, C and D, x-ray of the infected area
was performed at the investigator's discretion if the skin and soft tissue
infection was proximal to bone and how the determination of proximity to bone
was determined was not specified.
In one application all subjects had to have baseline
radiologic evaluation, and that is F, whereas in another, more recent protocol,
all subjects also had to undergo probe to bone.
If the probe was positive, a confirmatory x-ray was performed.
In another application, and that is G, if osteomyelitis was
suspected clinically, and the clinical suspicion was not described, at least
one of the following studies could be performed, and those included x-ray, bone
scan, indium scan, MRI or bone biopsy. So, no procedure was uniformly recommended or
applied and this makes comparisons across trials difficult.
[Slide]
What complicates the interpretation of study results in
patients with diabetic foot infections or determination of infection of
diabetic foot is complicated because of superimposed neuropathic
osteoarthropathy and peripheral vascular disease. These complicate the images that can be
obtained not only with x-ray but with the other techniques. Neuropathic disease can lead to fracture,
deformity, bone production and hyperemia which can mimic infection on an MRI
and bone scanning and increase the number of false positives. Peripheral vascular disease can prevent
contrast material or tracer from reaching the site of concern and lead to an
increased number of false negatives. So,
the simple and cheaper tests are often not sensitive or specific enough to
correctly identify these subjects.
[Slide]
Before reviewing the currently available techniques, I
would like to reiterate that the goal in obtaining an accurate diagnosis is not
only to ensure that the clinical trial population is appropriate but, more
importantly, to ensure that each individual patient receives the most
appropriate course of treatment.
As a reminder, the presence of osteomyelitis impacts on the
failure rate of soft tissue infection where failure is defined as the need for
additional antimicrobial treatment within the follow-up period. With regards to diagnostic methods, the
diagnostic gold standard is bone histology and culture through non-infected
tissue.
The procedures I am going to go over include plain films,
radionuclide scans including the triple phase bone scan, gallium scan,
indium-labeled leukocyte scan, also MRIs and probe to bone.
[Slide]
First I am going to talk about plain film radiographic
examinations. This procedure remains the
initial tool because these films are easily obtained, relatively inexpensive
and, even if non-diagnostic, they provide anatomical information that may be
useful in the interpretation of other tests that may be performed. Demineralization, periosteal reaction and
bony destruction are the classic triad of findings and usually appear after
30-50 percent of bone is destroyed.
These changes can take as long as two weeks to appear, and they can be
found in other conditions such as fracture or deformity. Sensitivity of plain films is usually around
54 percent, whereas specificity is approximately 80 percent.
Just quickly regarding CAT scans, CAT scans were used in
the past to diagnose osteomyelitis but today have mostly been replaced by
MRIs. They do give good images of the
cortex and can be used to aid in the determination of cortical extent of
infection.
[Slide]
After plain films, the question is whether to proceed to
one of the available radionuclide imaging techniques or to an MRI, and I am
going to quickly go over the available to most clinicians, in clinical
settings, radionuclide techniques.
[Slide]
First, triple phase bone scans which may be positive as
early as 24 hours after the onset of osteomyelitis, so it is a much more
sensitive indicator of early changes. A
dynamic scan over the region of the suspected osteomyelitis is obtained during
the first minute following administration of the technetium-99 phosphate
compound, followed by an immediate blood pool image and then delayed images at
two to four hours. Both osteomyelitis
and cellulitis demonstrate increased activity in the early images due to
increased vascularity, whereas only osteomyelitis tends to have increased
activity in the delayed images.
This pattern though also can be seen in fractures,
neuropathic joints and in some cases of cellulitis. So, the specificity of the test is
decreased. The addition of a 24-hour image
can increase the specificity because diphosphonate accumulation ceases in
normal bone after four hours, while it presumably continues to increase for
several more hours in abnormal bone.
Generally though in situations where bone remodeling is increased, a
second imaging test that can help localize the site of infection, such as a
gallium or an indium scan are recommended in order to increase specificity.
[Slide]
As an example of the high sensitivity and low specificity
of the triple phase bone scan, in a retrospective review of 20 reports of 1,166
patients, by Schauwecker in 1991, the sensitivity and specificity of the triple
phase bone scans in subjects who did not have prior bone abnormalities--and
here they had normal plain films--were 94 percent and 85 percent respectively,
whereas in subjects with complicating conditions that increased bone remodeling
the sensitivity was again high, at 95 percent, but the specificity decreased to
33 percent. In this, as well as some
other slides, the methods of confirmation of the osteomyelitis diagnoses are
not referred to so we don't know if they had biopsy or not.
[Slide]
Gallium uptake in infected foci is due to many factors,
including direct bacterial uptake; direct leukocyte uptake; and binding to
local proteins released from leukocytes.
Osteomyelitis is distinguished from cellulitis by focal localization to
bone with or without a soft tissue component.
Images are obtained at 24-72 hours following tracer administration and,
in general, osteomyelitis is diagnosed when the gallium uptake exceeds the
technetium-99 phosphate uptake at a specific site. In other words, the results of the two scans
are discordant. Often however, the
opposite occurs and the technetium-99 uptake is greater than or equal to that
of the gallium.
In a compilation of results of 15 studies, the sensitivity
with the gallium scan was approximately 81 percent and the specificity was 69
percent. So, a major drawback of this
type of scan is the added cost of the gallium and the triple phase bone scan together
that may exceed the cost of a single more sensitive and specific test, such as
indium-labeled leukocyte scan or an MRI.
[Slide]
Of the scans available, indium-labeled leukocyte scans
provide the highest sensitivity and specificity in patients with and without
prior bone abnormalities. The patient's
leukocytes are labeled with a radionuclide tracer, such as indium-111 oxine and
after readministration to patients, images are obtained at 4 and at 24
hours. The laborious process of labeling
the patient's leukocytes in conjunction with the later image may be less
practical within the context of outpatient clinical trials.
Localization to the site of infection by direct leukocyte
migration and a diagnosis of osteomyelitis is made when labeled leukocyte
uptake is moderately or markedly greater than that in a comparable adjacent or
contralateral bone. Indium does not
accumulate at sites that are not infected, and a compilation of sensitivity and
specificity for 142 diabetic subjects from 5 studies revealed a sensitivity of
88.6 percent and a specificity of 84 percent.
[Slide]
Now to discuss MRIs, MRI with gadolinium contrast
enhancement is recommended as often as indium scanning or combined triple phase
bone scanning and indium scanning in subjects with preexisting bone
abnormalities. Decreased signal
intensity of marrow and T1 weighted images and increased signal intensity on Y2
weighted images with marrow enhancement after injection of gadolinium contrast
are strongly suggestive of osteomyelitis.
Associated findings such as soft tissue mass, cortical
destruction, sequestrum formation and sinus tracts with ulceration increase the
diagnostic certainty. An additional
benefit is the very good anatomical detail provided with this method. Sensitivity and specificity are comparable to
those with the indium scan.
In a review of 129 diabetics with foot infections, cited in
the American College of Radiology's appropriateness criteria for the imaging
diagnosis of osteomyelitis in patients with diabetes, the sensitivity and
specificity of MRI were 86 percent and 84 percent respectively. Again, the method of confirmation of the
osteomyelitis diagnoses in these reports was not specified.
[Slide]
In a publication entitled, "Osteomyelitis in the Feet
of Diabetics," published by Morrison in Radiology in 1995, the
authors described the prospective evaluation of 62 feet from 59 subjects, 27 of
which were diabetic. Confirmation of the
presence of osteomyelitis was obtained, primarily by histologic evaluation and
biopsy specimens. In the 27 diabetic
feet, 17 feet had osteomyelitis and the sensitivity and specificity of MRI were
82 percent and 80 percent respectively.
Overall accuracy did increase with contrast-enhanced studies as opposed
to non-contrast studies.
[Slide]
In this table of reports of sensitivity and specificity,
taken from the Morrison publication and modified slightly by the addition of
the MRI data at the bottom, when triple phase bone scan was combined with
indium scanning in a number of studies, the overall results were comparable to
those of MR imaging.
The authors concluded that the use of the triple phase bone
scan is an excellent way to rule out osteomyelitis in uncomplicated situations
because of the low false-negative rate.
But both triple phase bone scanning and gallium scanning have low
specificity in the diagnosis of osteomyelitis in diabetic feet because of the
uptake of radiotracer by neuropathic joints.
Triple phase bone scanning with indium scanning has a higher specificity
in this setting and would be the optimal scintigraphic method.
The authors concluded that with MRI there is an initial
cost savings because the MRI can be more rapidly obtained and, in general, they
are competitively priced as compared with the combination of the triple phase
bone scan with an indium or with a gallium scan.
[Slide]
I would like to briefly presentation some information about
another technique that has been used to identify subjects with underlying
osteomyelitis, that Dr. Norden also mentioned earlier, and this technique is
probing to bone in infected ulcers, which was described by Grayson in JAMA, in
1995.
This was a single-center study. There were 75 subjects with 76 ulcers. They were prospectively assessed. A diagnosis was confirmed histologically if
possible. There were no cultures
performed. If bone was not available for
histology, then radiographic evidence of bony destruction in association with a
purulent ulcer or identification of friable, nonviable bone by the surgeon
during debridement were also acceptable.
Osteomyelitis was diagnosed in 50 of the 76 ulcers, or 66 percent. In 46 of those there was histologic
confirmation. It was excluded in 26
ulcers, or 34 percent.
Among the 50 ulcers with continuous osteomyelitis, bone was
probed in 33 or, again, 66 percent, and bone was visible in only 3 of the
33. In the 26 ulcers without
osteomyelitis bone was probed in 4. So,
as an indication of underlying osteomyelitis, the sensitivity of the positive
probe was 66 percent and the specificity was 85 percent. Palpable bone on probing had a positive
predictive value for underlying osteomyelitis of 89 percent, while the
predictive value of a negative probe for the absence of underlying
osteomyelitis was 56 percent.
The authors concluded that palpation of bone is strongly
correlated with the presence of osteomyelitis, and that probing should be
included in the initial assessment of diabetics with infected ulcers. I would like to reiterate though that this
was a single-center study and, until I saw Dr. Berendt's slides a few days ago,
we were at least unaware that these findings had ever been reproduced, and the
data is not published from the second study and so hasn't been reviewed.
[Slide]
I would like to touch on the issue of cost briefly. As you can see, we don't have recent data but
plain films are the most inexpensive test, whereas indium-labeled leukocyte
scans and MRIs are both relatively and similarly expensive. Issues such as the sensitivity and
specificity of a test, availability, as well as cost aid in the determination
of which test a clinician would order, as well as which test should be broadly
recommended within the clinical trial setting.
[Slide]
To conclude, I would like to show you this table of
sensitivities and specificities of the various imaging procedures discussed,
and stress that the methods with which these data were obtained are not
necessarily comparable and are highly dependent on the use of the bone biopsy
as the gold standard to diagnose the disease.
Again, I would like to remind you that the goal is to recommend a
procedure that has as high a sensitivity and specificity as possible not only
to ensure that the clinical trial population has the disease under study, but
to ensure that the patient receives the most appropriate course of treatment.
In a clinical trial setting, if we wanted to study
osteomyelitis one would opt for studies with high specificity, whereas if one
is studying complicated skin and soft tissue infections and excluding subjects
with osteomyelitis, high sensitivity is paramount.
A number of sources continue to suggest that conventional
plain film should be utilized as the initial screening procedure in all
patients. This test is the most readily
available and reasonably priced, but the question of are the results good
enough to ensure that osteomyelitis is ruled out remains. If positive, yes; if negative, then the
diagnosis cannot be excluded.
At this juncture, and given that most diabetics have
underlying bony abnormalities, most sources recommend either an indium scan or
an MRI, both of which have high sensitivity and specificity. The costs of both are similar given the
rapidity with which the MRI can be obtained compared to the indium scan where
the patient has to go through the initial labeling of the white cells followed
by a 24-hour scan.
In subjects without underlying bone lesions on plain films,
a triple phase bone scan is highly sensitive and specific. Finally, probing to bone in conjunction with
plain films is also an option in the initial approach of the diabetic subject. If the probe or the film is positive, then
the patient can be excluded. However, if
bone cannot be probed and the plain films are negative, then the diagnosis of
osteomyelitis cannot be excluded. Thank
you.
DR. LEGGETT: Thank
you. Yes, Don?
DR. PORETZ: I am not
sure of something, getting a bone biopsy is obviously the gold standard if it
shows histologically osteomyelitis. What
percent of the bones that show osteomyelitis on histology grow an organism?
DR. ALIVISATOS: I
don't know that, Don. Maybe some of the
experts know.
DR. PORETZ: Does
anyone know?
DR. LEGGETT: It is
not 100 percent.
DR. PORETZ: Because
I have seen numerous biopsies that show osteomyelitis under the microscope, yet
half of them grow. What is the
experience?
DR. ALIVISATOS: Dr.
Norden seems to know about that issue.
DR. NORDEN: I can
make an educated guess--
DR. LEGGETT: You
need a microphone.
DR. NORDEN: You are
absolutely right that a certain number of patients don't grow an organism with
positive histology. I would say it is
anywhere from 30-40 percent. Whether
that is a sampling error--you know, the organisms are obviously not
homogeneously distributed throughout the bone.
But I think most of us would accept either histology or a culture, a
positive culture as a positive bone biopsy.
So, it is the best that we have at this point.
DR. LEGGETT: Yes,
Janet?
DR. ELASHOFF: I
would just like to comment that in both this talk and the preceding one the
sample sizes that estimates of sensitivity and specificity were based on were,
generally speaking, too small and many times far too small to have any real
idea of the comparative sensitivity and specificity of these techniques.
DR. LEGGETT: Thank
you. Why don't we go on to the next
speaker? David Ross will give us the
implications for clinical trials.
Implications for Clinical
Trials
for Diabetic Foot
Infections
DR. ROSS: Good
afternoon. I know everyone is waiting
for a break so I will try and talk quickly.
[Slide]
We have been talking a lot about the distinction between
clinical trials and clinical practice, and I think that is extremely important
to keep in mind. Having said that, I
would like to move to a clinical case because I think that is ultimately what
is driving the trials, the need for more knowledge for how to treat diabetic
foot infections.
[Slide]
This is a gentleman whom I saw about three weeks ago. He is a 74-year old veteran in a nursing
home. I was called because of a stage IV
pressure ulcer which was thought to be infected. As you can see, this patient had a
complicated medical history, type I diabetes, peripheral vascular disease and
chronic renal insufficiency. On exam he
was afebrile. He actually was not
complaining of a whole lot of pain.
He had a large ulcer distal to the left malleolus with
clearly exposed bone. There was a
smaller ulcer on the dorsum of the left foot with an eschar and surrounding
erythema. He had a white count of over
18,000. Interestingly, a plain x-ray did
not show any bony changes suggestive of osteo.
He had been started on piperacillin tazobactam, actually for nosocomial
pneumonia but also with the thought that this would cover a diabetic foot
infection. He did not show improvement
of the erythema on this, and vancomycin was added because of worsening
cellulitis. He was transferred to the
vascular surgery service. He continued
not only to show no clinical improvement but actually deteriorated and is
currently in the SICU for hypoxemia.
Just before this afternoon's session I spoke to the second
most reliable source of information about patients. The first most reliable, of course, is the
primary care nurse. In this case she
wasn't available so I spoke to the fourth year medical student. The patient's hypoxemia has improved but his
foot has deteriorated and they are talking about an AKA.
[Slide]
I won't belabor the public health impact of this sort of
patient multiplied many fold. Dr.
Berendt did an excellent job of outlining that.
But I will just mention that, as Dr. Soreth mentioned, we have over a
million cases of diabetes mellitus a year that are newly diagnosed, and this
has increased from the '90s when it was more in the neighborhood of 700,000 to
800,000. There are roughly about 140,000
hospital admissions for diabetic foot infection every year in this country, a
quarter of all admissions for diabetes; over 80,000 lower extremity amputations
due to diabetes; and over a billion dollars a year in direct costs for LEA
associated care. That does not include
costs for things like rehabilitation, prostheses and so on.
The patient I just described, if he undergoes the AKA, his
odds of being alive in three years are around 50 percent. In five years, his odds of being alive are
less than a third. Five-year mortality
after LEA is 68 percent.
[Slide]
Did those antibiotics that he was receiving actually help
him? It is hard to say. In looking through the literature to see what
I could find about randomized, controlled trials for diabetic foot infections
that were specific to that entity and not part of complicated skin and skin
structure infections, I was not able to find a whole lot, probably about 350
patients in these sort of trials. I am
sure there are some that I missed, but the point that I would like to make is
that there are relatively few trials.
They have varying populations, varying regimens and it is very hard to
put them together to say anything meaningful.
For example, the study by Grayson looked at
limb-threatening infections, whereas the study by Chantelau, in 1996, looked at
much more superficial infections and in this study placebo actually beat
amoxicillin clavulanic acid.
[Slide]
So, why don't we pose the question what antibiotics really
work in diabetic foot infections? To
address that we need to think about some issues. What should the clinical definition of
diabetic foot infections for a clinical trial be? How should we identify true pathogens in
diabetic foot infections in such trials?
How should such trials handle osteomyelitis? Finally, how do we take into account
adjunctive therapies and other confounders?
[Slide]
Let me start with the question of what the clinical
definition of diabetic foot infection should be. My first sub-bullet there, thanks to the
wonders of Power Point, should be clinical trials do not equal clinical
practice. We want high sensitivity in
practice. We don't want to miss a
patient whom we want to treat. But in
order to adequately define a patient population we need high specificity. Obviously, you have to have an appropriate
balance if you want to have generalizability from clinical trials.
Nonspecific definitions run the risk of allowing enrollment
of patients without disease, potentially obscuring differences between
drugs. One possible definition, and
there are many others and I am just drawing this out is a defect in epidermal
integrity with new erythema and/or swelling and/or fever and/or leukocytosis
and/or loss of glycemic control.
[Slide]
How should true pathogens be identified in diabetic foot
infections? Dr. Sheldon spoke about some
of the data underlying different methods and the sensitivity, specificity and
predictive values of those methods. It
is clear that we need accurate microbiologic data to assess the strengths and
limitations of clinical efficacy data.
In order to be confident that a drug really works in diabetic foot
infections clinically, it should be active in vitro against the
organisms that are the true pathogens.
We have had applications in which claims have been sought for organisms
for which there was no in vitro activity.
It is also important to remember that a particular drug, in
order to guide practitioners, is labeled for an infection due to specific
organisms. In order to get maximum
possible specificity and most reliable information, we would suggest curettage
or biopsy with semi-quantitative culture.
[Slide]
How should we handle clinical trials as far as
osteomyelitis? Rather, how should
clinical trials handle osteomyelitis? As
Dr. Alivisatos pointed out, this is not just a clinical trial issue. We know that inadequate treatment of acute
osteo or even chronic osteo runs the risk of converting one infection into a
more chronic form with a poor outcome.
It is important to remember that imbalances in osteomyelitis patients
across arms, which is certainly possible in a relatively small study, confound
assessments of differences in drug efficacy.
We would suggest excluding osteomyelitis patients, potentially by
MRI. If the study drug is topical or has
no bone penetration they could be rolled over to a separate trial if the drug
does have bone penetration.
[Slide]
Finally, how do we take into account adjunctive therapies
and other confounders? I will just
mention that the most recent issue of The Annals of Internal Medicine
has a study by Landy and coworkers reporting on the use of nerve growth factor
in treatment of neuropathic ulcers. This
excluded diabetic patients but we will certainly see this sort of technology
applied. I will also note that in
looking for controlled trials in diabetic foot infections I found more studies
dealing with adjunctive therapies than I did with antibiotics.
Confounders may contribute to differences in apparent
efficacy, either adjunctive therapies or other confounders. For this reason, we need to define patient
characteristics potentially affecting outcome, and some of these have been
mentioned, such things as transcutaneous PO2, demographics, co-morbidities and
so on. Wound classifications are
potentially useful but they need to be validated for trials and they don't, by
themselves, define infection.
[Slide]
I just want to give this quote, and I want to thank Dr.
Powers for pointing me to this:
"Thus, it is easy to prove that the wearing of tall hats and the
carrying of umbrellas enlarges the chest, prolongs life, and confers
comparative immunity from disease; for the statistics shew that the classes
which use these articles are bigger, healthier, and live longer than the class
which never dreams of possessing such things." G.B. Shaw had some things to tell us, I
think, about what to think about as far as clinical trials.
[Slide]
So, I am going to leave you with some questions. Actually, since writing this we realize there
are even more questions so those will be on the agenda and I won't go over these
in detail. But we look forward to your
discussion of these issues and for your advice and recommendations. Thank you.
DR. LEGGETT: Thank
you, David. Any specific questions?
[No response]
Then I suggest we take a 15-minute break and be back here at
3:45.
[Brief recess]
DR. LEGGETT: The
next item on the agenda is the open public hearing. We did not have anyone contact the FDA about
wishing to speak during this open public hearing. Is there anyone in the room who would like to
use this time to read us a statement?
Seeing no one wishing to give a statement, we will pass on to the next
item on the agenda which is the charge for the committee that will be delivered
by Ed Cox.
Charge for the Committee
DR. COX: Thank you,
and I will keep my comments brief. I
just wanted to start out by thanking all the presenters. We have had a series of excellent and very
insightful presentations on some of the issues in diabetic foot infections,
including issues regarding the microbiologic evaluation, diagnosis of diabetic
foot infections, evaluations for osteomyelitis.
There is no question that managing diabetic foot infections
is challenging clinically and many of these challenges from the clinical arena
carry on over to the clinical studies of antimicrobial drugs that are being
evaluated for their safety and efficacy in the treatment of diabetic foot
infections, the issues of other chronic conditions underlying skin disease and
vascular disease that may also impact upon the outcomes in patients with
diabetic foot infections. Fortunately,
the presentations do mesh very well with the questions that we have for the
committee today.
Without further ado, I will just move on to the five
questions at this point in time. The
questions are being asked in terms of clinical trial design and clinical study
design, so that is just one point to keep in mind as we move through them.
What I will do is give the Reader's Digest version
of the questions because I am sure we will come back to them as we progress
through them. But essentially the first
question deals with the definition of diabetic foot infection and asks also how
we should handle the issue of breaks in the skin in the setting of diabetic
foot infections.
The second question deals with how we should handle infected
ulcers and whether the ulcers are infected or not infected, and how to handle
the diagnosis of infection in the setting of ulcer.
The next question deals with the microbiologic methods that
should be used for the diagnosis of diabetic foot infections.
Question four moves on and looks at evaluations for
osteomyelitis and the methods that should be used there. We will be able to use a lot of the
information that was presented here today in the earlier presentations.
Then the final question, question number five, deals with
how we should define clinical success or failure in the setting of diabetic
foot infection clinical trials.
So, we look forward to the committee discussion on these
questions and, once again, I would like to thank all the presenters for really
excellent presentations on the topic of diabetic foot infections. With that, I will turn it back over to Dr.
Leggett.
Committee Discussion
DR. LEGGETT: Thank
you. I had cut people off who had
questions of Dr. Berendt and Dr. Norden before, but I think if there are
questions we can, hopefully, ask them in the context of trying to answer these
questions.
So, number one, how does one define a diabetic foot
infection? Who wants to start? Don?
DR. PORETZ: Well,
you can be very simplistic I guess or you can be very erudite, but the way I
think about it is a person who has diabetes who has an infection in their foot
is not equal to a person who does not have diabetes and has an infection in
their foot, i.e., I always take a diabetic patient with an infection more
seriously, no matter where the infection is.
So, to be simplistic, I guess, diabetes mellitus and cellulitis in the
foot or ulcer in the foot or closed wound in the foot, I would consider that a
diabetic foot infection. I don't know if
you have to go more advanced than that or not, but I am always more aggressive
in treating those patients than non-diabetics.
DR. LEGGETT: David,
what would you care to add to that?
DR. ARMSTRONG: Well,
I must say that when I came in here I was favoring that view. I think it was very simplistic and that is
really the way that I would think about it.
I would say maybe using the ADA criteria for diabetes, then we define
foot as that which is below the malleoli and then an infection based on the
criteria that you heard Dr. Berendt and Dr. Norden describe. But after hearing some of the concerns in
clinical trial design, I am wondering whether we should consider going for more
specificity and adding in something like the presence of neuropathy, or an open
wound, or something else. I have not
really come to any conclusion. I am
still looking at that first as the thing I am favoring but I would open it for
discussion amongst those who have so much more experience in clinical trial
design than us clinicians and clinical investigators.
DR. LEGGETT: I can
just think of the most recent patient I saw with diabetes who had bad
tenosynovitis from Staph. aureus and no lesion.
He lost part of his foot. So, I
think you can have a severe infection without necessarily requiring there to be
an ulcer.
DR. ARMSTRONG:
Absolutely.
DR. WALD: In
children with diabetes we don't see these infections. So, I think that it is not enough to be a
diabetic. I think that probably there
has to be some component of either neuropathy or ischemia or both.
DR. LEGGETT: Don?
DR. PORETZ: Yes, I
think that is a problem. I think the
difference between a diabetic and a non-diabetic are those exact things, and
all things being equal, diabetics don't do as well as non-diabetics drug for
drug, treatment for treatment, infection for infection. Because of the neuropathic changes and the
vascular changes, which I think you have to presume are present in a diabetic
who has one of these infections, that is why I think they need to be treated
more aggressively and that is what I would call a diabetic foot infection.
DR. LEGGETT: Go
ahead, Ellen.
DR. WALD: I guess I
would just ask are there adult diabetics for whom your statement is not true,
that they really do the same as other comparable patients without diabetes
because, in fact, they don't have neuropathy and they don't have ischemia so
they are healthy diabetics in their 20s, 30s or their 40s who don't have any
component of ischemia or neuropathy and they do just fine.
DR. PORETZ: I think
a lot of them do have small vessel disease and, maybe that is the case, but in
general I think if you are a diabetic and you have an infection in your foot
you don't do as well as a non-diabetic, period.
DR. LEGGETT: John?
DR. POWERS: Maybe I
can try and clarify what it is that we are looking for here, and it is
something Dr. Wald just pointed out. If
you took a 30-year old, well-controlled type I diabetic who has no problems and
no foot issues other than this, and comes in with cellulitis on their foot the
size of a quarter, that is not the same kind of person in the pictures that Dr.
Berendt was showing earlier today. So,
if you go for that broader definition, both kinds of patients get enrolled in
the same clinical trial and that is a problem for us, if they are unequal
across the arms of the trial, in determining the efficacy of the drug.
The first kind of patient, you don't know how much the drug
contributes because those kind of people might get better spontaneously. What we are trying to get to is a more
specific definition, and again, because of the things that the speakers have
raised about adjunctive therapies, etc., who is the kind of patient we would be
pretty sure where that adjunctive therapy isn't going to cut it? In other words, you know, we all know the
patient that comes in with redness from the tip of their toe up to their knee
that wasn't there two days ago--that is the kind of definition we are trying to
go for, something that allows us a little more specificity in picking those
people.
DR. LEGGETT: Jan?
DR. PATTERSON: Well,
the PEDIS classification I thought was very useful in the sense that it
quantifies the severity of perfusion, extent and size of the ulcer, the depth,
tissue loss and so forth. So, if that
was used in terms of the definition of infection, you could quantify the
severity and, thereby, in terms of the clinical response, you could quantify
how much it gets better if it goes from grade IV to grade II.
In terms of cellulitis, I don't see that it really fits
into the PEDIS classification. Correct
me if it does. But I would see a
diabetic foot infection cellulitis as a cellulitis in a diabetic that is in the
foot.
DR. LEGGETT: Dr.
Maxwell?
DR. MAXWELL: I kind
of like the classification that I saw in Mandell where it seems to me, and I
could be wrong, that they are really calling a diabetic foot infection an
infection that actually has an ulcer that you can ascertain is penetrating
beyond the subcutaneous tissue; that it has not just cellulitis but extensive
cellulitis; has a lymphangitis; and then ischemia and polymicrobial or not type
of bacterial growth. So, I think it is
more than just a cellulitis. It has to
actually penetrate behind the borders.
So, that would be my feeling for the definition.
DR. LEGGETT: David?
DR. ARMSTRONG: Maybe
then to sort of steer the discussion toward that, just as Dr. Powers said, we
are not looking for all of these patients with cellulitis or maybe an infected
ingrown toenail. I think maybe something
that will confer some specificity might be just what Dr. Maxwell said, which is
perhaps an infected break in the skin and an infected break in the integument,
that being a diabetic foot ulcer. Maybe
that is your touchstone that you use for your definition for clinical
trials. Will it exclude a number of what
we might still consider as diabetic foot infections clinically? Absolutely.
But perhaps then something like a wound would make it a little bit
easier to standardize these things across strata, using something like you saw
Dr. Berendt show in terms of the International Consensus classification on
infection as well.
DR. LEGGETT: That
would certainly make the population more homogeneous. Allan Tunkel?
DR. TUNKEL: I was
thinking why wouldn't we include those people?
I mean, this is how it begins.
This is really where they first get their first infection that winds up
progressing and you start chopping away little bits of their feet until you
wind up doing that below or above the knee amputation.
So, part of my definition of diabetic foot is if I am going
to treat the patient with antibiotics, I think they have a diabetic foot
infection and maybe that isn't a great definition--
DR. LEGGETT: You
mean somebody with an ulcer?
DR. TUNKEL: Well, I
guess whether it is that quarter size area of cellulitis with a tiny break in
the skin. If I am giving them
antimicrobial therapy to resolve it, they have a diabetic foot infection.
DR. LEGGETT: That
leaves things open to having a predominance of folks in your trial if you want
your new drug to work. Alan Cross?
DR. CROSS: I think
part of the problem is we have been saying if a patient has an infection, but,
yet, we really are begging the plan. I
think one of the problems we see is these patients do have chronic stasis
changes. They do have erythema and I
think what John suggested earlier is that there has to be perhaps a new
finding; perhaps a new erythema or tenderness or swelling that hadn't been
there in a defined period of time.
Otherwise, you are always going to be stuck with how to deal with these
chronic stasis changes.
DR. LEGGETT: Ken?
DR. BROWN: I think
what the FDA is asking is an impossible question because what they really want
the group to do is to tell them how to define when a patient has microvascular
disease. If they just have a neuropathy
the patients do very well, as in leprosy, and in leprosy patients with a
terrible ulcer on the planter surface--you wash it once, wrap them up for six
weeks and immobilize them, and at the end of the six weeks they are fine.
So, I think what we need is a way to define these people,
at least the young versus the not so young, in terms of their vascular ability
to deliver the goods to the site.
DR. LEGGETT: Good
point. I don't think you would get any
disagreement from anyone about that. Dr.
Elashoff?
DR. ELASHOFF: It
seems to me that part of what is happening here is not so much a definition of
what is a foot infection or not, but a definition of a person who has a
situation that is serious enough to make sense to have an indication for
it. So, we are kind of mixing
definitions of this and with a definition of poor prognosis or severity, or
something, and I think it might help if we kind of separated those two issues a
little bit more clearly.
DR. LEGGETT: Barth?
DR. RELLER: To
extend what Dr. Brown said, this is inherently a dynamic process that is
heterogeneous and we will never come to a definition that is comprehensive
enough if we want one definition. It
seems to me what Dr. Poretz pointed out is sort of the bare necessity ofwhat
Dr. Norden put in, over 18; and then there is no substitute for categorization
of the patients in terms of extent, severity, neuropathy, vascular status. Rather than trying to reinvent all of those
items, since in the end the people doing the trials are going to be those
clinicians who are actively involved in this area and to get collaboration to
apply drugs that would be approved, involves many different disciplines.
So, the way I would go about it is to take what Dr. Berendt
presented in terms of the stratification, take the base definition that we
could agree on, and then one has to stratify the patients between comparator
and study drug. They have to be
distributed comparably according to severity, etc., according to vascular
compromise, etc. Then we could get into
the details of what kind of microbiology we want; what is valid, etc.; what
kind of imaging we want, etc. But I
think there is no substitute for differentiation of patients so that they are
comparable in the groups, but it is impossible to put all diabetic foot
infections in one definition.
DR. LEGGETT: It
seemed that Dr. Elashoff had a good point.
If we are going to give a specific indication, it really should sort of
be weighted towards the more severe folks at risk. There would be an easy way to do that if you
want to say that we have a drug that is very effective; it is given
parenterally; that can be transitioned to oral; and we are going to have a
trial that enrolls patients who are of grade II/III or grade III or IV
severity. Or, it is effective in those
with this degree of severity and assume that if it is effective in that it
would be effective in those that are less severe. I think in the end the patients have to be
comparable and there have to be objective definitions of the degree of the
severity because I think we all agree on the principles--no blood supply; it is
not going to heal. You know, if it is
dead, it has to be taken out or taken off, etc.
Keith?
DR. RODVOLD: I agree
a little bit with what Barth was saying.
Looking at grading of II, III and IV is that one of the things where, at
least from an agency point of view, you are going to have to have a comparator? You only have two comparators that are
legitimately used on the market that have this labeling at this point. For example, linezolid being the last one
that was approved, how many of the linezolid patients that were in that trial
fit into that grade III/IV versus II?
You know, if most of them are III and IV, is that a lead to you to find
out that maybe everything that you need in this indication is III and IV?
When I look at grade II in this definition--and I may be
wrong; I am not a physician, I am a pharmacist--I look at grade II and I kind
of read a little bit of complicated skin and skin structure infection for the
recently approved daptomycin because 30 percent of their patients were
diabetic. They try to remind you of that
in their advertisement a lot to get you enticed to use the drug. But they weren't really what I think most of
us would think of as diabetic foot and they don't have that labeling
specifically. So, I kind of see grade II
here bordering on just the typical definition of complicated skin and skin
structure infections and III and IV lead you up to diabetic foot that I think
everyone in this room would be comfortable with. If you could treat III and IV with a new
agent, then you should be able to slip down to a little bit more tricky case of
II. But from a regulatory point of view,
III and IV would fit the bill of having spelled out criteria that this is the
target you have to hit to get the data.
But I think at the same time that you are thinking that,
you have to back up and look at what comparators--will they be a legitimate
comparator to the new guy coming up.
DR. LEGGETT: Ciro?
DR. SUMAYA: I am
thinking similarly with the last two comments, being more comfortable with the
PEDIS classification to try to categorize people to some level of
severity. I like that one in particular
because it does touch on the neuropathy, and it does touch very well on the
ischemia aspects. So, I think we could
hit the cellulitis for mild disease and then go into more severe levels.
Just one other modification perhaps, it could be as in
rheumatoid fever where one has minor and major components, and perhaps out of
those five there may be two we want to consider more major criteria and the
other three would be more minor. But
they could be manipulated I think to categorize into different levels of
severity to do the clinical trials.
DR. LEGGETT: Don?
DR. PORETZ: Would it
be reasonable for any prospective study to consider the concept of digital
photography where prospectively you could have an independent review of a
reading person? You know, they do this in
ophthalmology where there are independent reviewers, that have nothing to do
with the patient per se, who read the fundoscopic pictures. They do it in neuropathy with nerve
conduction times where independent neurologists, having nothing to do with the
case, read the nerve conduction times.
Maybe there could be a standardized digital photographic way of doing
things where independent readers look at it and then you can prospectively go
forward and get some idea of what is going on.
DR. LEGGETT: In our hospital,
in the last ten years I have never seen a podiatrist see a patient without
having plenty of pictures.
DR. PATTERSON: Well,
I think a digital picture would be very helpful as supplemental information,
but it wouldn't tell you, for instance, about the depth of the ulcer and some
of these other things that are in the PEDIS classification, the ischemia and so
forth. So, I think it would be helpful
supplemental information but I think you would still have to have some other,
more objective criteria.
DR. LEGGETT: John?
DR. BRADLEY: I too
am interested in trying to stratify these patient groups based on all the
different factors because you are getting a 3 X 3 matrix of vascular disease,
peripheral neuropathy, and something that people haven't brought up and I don't
know if it has not been studied or is difficult to quantitate, but the control
of the diabetes because, certainly, that may impact the wound healing.
The other thing that Don and I were talking about is burn
patients. After you clean a wound, you
biopsy the wound and you can get an idea of histology and quantitative cultures
which leads you to believe that it is truly infection as opposed to just
colonization. To me, that will enhance
the quality of the data. So, if you have
nice histologic data you need fewer patients to actually show benefit. Then, of course, Don said a lot of people
would be reluctant to do biopsies because these wounds may not heal. So, it is putting the patient at additional
risk.
DR. LEGGETT: Any
further discussion about this? Can we
take up that second phrase in number one and, ignoring the people without
breaks, what do we do with the preexisting breaks in the skin? Ellen?
DR. WALD: I think in
clinical practice we do this all the time.
We look at something and we say it is clean and dry; it doesn't look
infected. When we think it is infected
it is because there is new onset of erythema and oftentimes there is
accompanying discharge, and it may be warm to the touch. And, if the patient has sensation, it may be
painful. So, I think those classic
findings of inflammation, accompanied by discharge, are what persuade us
clinically.
DR. LEGGETT: David?
DR. ARMSTRONG: Maybe
just to clear some of those initial diagnosis issues, and we have been mulling
over this issue for sometime now; maybe for too much time, some might say, but
Dr. Berendt has some knowledge of that committee and what is coming out of
there, and maybe you could share some of that about the specific diagnosis of
infection and what is being used. Is it
greater than two cardinal signs of inflammation? Is it presence of purulence, advancing
erythema? Is there any way you could
share some of that perhaps to clear some of this up?
DR. BERENDT: I think
the thing to say is that generally speaking the IDSA guidance was worked out
very similar to the International Consensus guidance. So, yes, from my memory, it is two or more of
the clinical signs of infection that you have really been describing. I mean that, of course, is a clinical
classification and is slightly different to the research type classifications
you have been describing.
DR. LEGGETT: Did you
want to say something? Any other
thoughts? Yes, John?
DR. POWERS: Dr.
Elashoff asked me a question at the break that I kind of wanted to address
because it has come up now several times around the table. That is, stratifying people according to
severity. Dr. Elashoff asked me what did
the FDA mean by validating the severity scores.
I think one of the issues we get into is the idea of do
these severity scores really predict severity?
By severity, what we have interpreted that to mean is that patients with
these given characteristics do worse than patients with those given
characteristics regardless of what therapy they get. So, this does not require a
placebo-controlled trial.
Speaking with Dr. Norden too at the break, we were saying
we don't have the answers to this. That
doesn't mean we can't go forward, but these could be incorporated in future
trials. But the question I ask myself is
does somebody that has 1.9 cm of erythema really differ from somebody who has
2.6 cm of erythema round their ulcer?
And, that is the way this reads.
The difficulty we get into in the setting of a non-inferiority trial is
that drugs may come out looking the same and a drug sponsor may say to us, oh,
but look, I have more patients with grade II.
So, we want in our label that we are better than this guy, over
here." If those severity scales haven't been validated it is very
difficult for us to know what to do with that information going down the line.
DR. LEGGETT: The
only easy one is going to be I versus IV.
Joan?
DR. HILTON: I wonder
if there isn't a registry that exists in which you could choose some outcome,
whether it is time to death or some other very severe endpoint, and figure out
the relative weight of these different prognostic factors, like the PEDIS
classifications. I don't know if you can
resolve this with opinions. It seems the
data have to speak.
DR. POWERS: I think
one of the reasons why we are bringing this forward to the committee is also to
raise the question that there are pieces of data that are missing about very
commonly treated diseases that we need folks to do research on outside of the
clinical trials of the FDA, but we need help on answering these questions.
DR. LEGGETT: Carl,
do you know if there is any such registry or any ongoing trials to try to
validate the PEDIS system or any of the others?
DR. NORDEN: The
simple answer is no, I don't know of any trials that are ongoing. But I think it is critical but I don't think
it should stop us from doing clinical trials.
I mean, you can within clinical trials try to validate things and get answers
to prognostic questions and you can look, for example, at other diagnostic
tests. You can do a lot of things within
trials if the drug company is willing to do it and if they sense that this is
an appropriate thing to do. But, no, I
don't know that there is any data at all.
DR. LEGGETT: What
about the University of Texas system which has been around far longer?
DR. ARMSTRONG: Well,
the answer to that is that I think we may be comparing apples and oranges when
we talk about stratifying based on severity of infection versus looking at the
wound as a whole. I mean, a large number
of wounds we shouldn't even be talking about because they are not
infected. They may be treated just with
good debridement, off-loading and coming back frequently for care. But something like the UT system is probably
a good system for assessing wounds as a whole but when it came to the issue of
infection, I can tell you that we had a very difficult time, just as we are
having a very difficult time here, and we just decided to dichotomize it,
saying it is infected or it is not. That
was how we sort of skirted the whole issue of infection. We did include things like depth so certainly
probe to bone might confer a higher risk for osteomyelitis. Some of the data supported that if you had a
deeper wound, then one was at higher risk for developing osteomyelitis in that
360 patient study. But, again, I think
to use a system like that would be inappropriate for looking at infection.
DR. LEGGETT: Alan
Cross?
DR. CROSS: I was
impressed by the presentation of Dr. Ross when he actually showed the slide of
the published DFI randomized clinical trials.
Of the five he found, there was only one that had more than 100
patients, and that was 108. So, here we
are having some discussion about stratification, and we are having all these
other discussions about how do we handle all these confounding variables that
we will not be able to control for.
I think at least one approach to this is to have a large
enough trial, such that it allows these confounding variables, hopefully, to be
handled through a large trial. The
implication of that is that we have to come up with perhaps some definitions
and treatment endpoints that would allow one to do a large enough trial in
order to have an assessment of all the concerns that have been voiced here.
DR. LEGGETT: Janet?
DR. ELASHOFF: Also,
the issue of whether certain severity classification is predictive of prognosis
brings up the issue of what we are talking about with respect to
prognosis? Are we talking about cured,
not cured in eight weeks? Or, are we
talking about a year from now how the patient is doing? If we are talking about longer-term
prognosis, then we would have to be talking about an entirely different kind of
trial in order to validate these things than if we are talking about a
shorter-term yes/no cure.
DR. LEGGETT: Could
we leave that until we get to question five, which I think addresses that? Jan?
DR. PATTERSON: Well,
I was just going to say that the PEDIS classification--I mean, whether or not
grade IV or grade III is actually more severe than grade II, maybe we don't
really know the answer to that in terms of the prognosis. But it does give us an objective way to
assess the infection at baseline and to give us objective criteria for
improvement. You know, if it goes to a
lesser grade, that is improved.
In terms of the criteria, I mean, it is just like with any
other study. If you have a criterion
that, you know, you have to have a fever greater than or equal to 100.4 to be
in the study, if you have 100.3 you may clinically fit but you can't get into
the study. So, it is just like anything
else; you have to have a cut-off somewhere.
DR. LEGGETT: And it
certainly looks like clinically people who do this can tell the difference
between grade II and III, looking at whether it involves other structures and
other sorts of things. So, it is not
just one factor involved. It is not just
1.9 cm versus 2.1 cm. David, you look
like you want to say something.
DR. ROSS: The
thought that came to mind, and this is really a question for Dr. Armstrong, I
was thinking about the process by which Fine and coworkers defined prognostic
categories for community-acquired pneumonia.
Obviously, we have to start somewhere in terms of defining grades of
severity, but the question is to what extent is there a difference between 1.9
cm and 2.0 cm, square centimeters. I
guess one way to define that, not putting everything on hold while we do this,
is to prospectively follow patients and collect data. I was just wondering if I could ask Dr.
Armstrong, since there is such a huge concern for the VA health system, if that
is anything that is even a twinkle in the VA central office's eye.
DR. ARMSTRONG:
Certainly not speaking for Secretary Principe, by any means, but I think
that it certainly should be a twinkle in the Department of Veteran Affairs'
eye. It is certainly common enough. I think that the trouble with doing a VA-wide
study is while I think care is excellent at a lot of VAs, if you have seen one
VA, you have seen one VA and there may be differences in approaches to
care. Even though there is a nationwide
pact program that has been excellent, I think standardizing things is still a
little bit difficult. But I think that
would be certainly of interest to the VA health services research and
development and other grant-making agencies to look at. I think it could be done.
DR. LEGGETT:
Basically, Dr. Berendt and Dr. Norden, this PEDIS thing is still just a
bunch of old fogies getting in a room in Hawaii, right?
[Laughter]
DR. BERENDT: In
fact, the PEDIS thing is considerably more than that actually. That is to say, it is a bunch of old and
young fogies getting together in a number of rooms over a very long period of
time, actually. The International
Consensus process that Carol Backer initiated, has been on the go for about 12
years. They have had four quadrennial
meetings during that time. The Consensus
guidelines on sort of management and prevention of diabetic foot in general
were issued four years ago through a process of international consensus, with a
working group of about I think 30 or 40 people from, literally, all over the
world and from multiple disciplines.
The infection subgroup was a smaller subgroup, once again
specifically required to be international in its composition. It has sort of authoring members and
corresponding members. Ben Lipsky was on
the chair of that group and I was involved in that, but widespread, people sort
of across Europe and the world. Then
that was signed up to by this much larger group who met at the Holland meeting
earlier this year. In fact, David
Armstrong was one of the people whose signature is on that piece of paper.
So, I am not saying that it has total legitimacy at all,
but I think it does have a reasonable degree of face validity. The criterion validity remains to be
established, and that is accepted, and for that reason in the outdated version
of the consensus it is listed as a report on progress rather than as a final
version of a classification.
From your point of view today, it is perhaps a shame that
it is a classification system for research on foot ulcers because that meant
that people without ulceration were eliminated from consideration. So, unfortunately, the cellulitis in the
diabetic is sort of unclassifiable by PEDIS.
I think that is a pity. Whether
one could get that changed over time is an interesting issue. I think it is worth saying that, based on
your deliberations here, even if PEDIS could classify those sort of cases, the
sort of cellulitis cases, they would, as long as your stratifying the reporting
of the trial be an obvious difference between the cellulitis case, who would be
a sort of P1 which would be, you know, normal perfusion; P0 for no area;
D--let's say--0 if it existed; I3; S1 for protective sensation present. So, that is kind of our uncomplicated
diabetic person with infection. That is
dramatically different from the kind of P2E 25 cm, or whatever it is, you know,
D2/I3/S2. You can see how different they
would actually come out, and that might help you duck the issue of having to
make the definition, if you want to duck it.
The other question in my mind, having heard you debate
this, is whether those individuals who don't yet have complications of diabetes
and don't have a wound are covered anyway by the cSSSI or SSSI definition. I am assuming diabetes is not an exclusion to
be licensed under those. So someone has
already thought about them; you have.
So, those are the main things to say. Trying to come back to the legitimacy of
PEDIS, which is, yes, designed mainly for research, the authors, or some of the
authors involved in the UT system, the S(AD) SAD system and the clinical
staging system are also signatories to that.
So, in that sense, some people have accepted that their own personal
systems that they have already advocated in the literature would be superseded
by the development of this system. I
mean, that is just sort of a sales job on that.
But I think everyone accepts that it needs to be validated. Clearly, if the agency requires that before
they adopt it, or ask other people to do it, then you can't sort of turn up to
it now but we hope you might later.
DR. LEGGETT: Janice?
DR. SORETH: I just
wanted to say that Dr. Berendt raised a good point, which was that most drug
manufacturers don't seek diabetic foot indication in a vacuum. They do it in the setting of having usually
two large, multicenter--at least one, sometimes two large, multicenter trials
of complicated skin and skin structure infections fairly well defined in a
broad spectrum of patients, some of whom may be diabetic and have a cellulitis,
let's say, on the thigh. To augment that
experience, they then go to another trial, which we like to see as a
comparative trial, in which they enroll the various spectrum of patients that
we discussed today, diabetic foot infections with what we expect are the
complicating factors of not normal vasculature, not normal neuropathic
system. So, we feel that in the intact
patient the drug is studied within the organ of skin in a complicated setting.
DR. LEGGETT: Barth?
DR. RELLER: Dr.
Berendt, what do you mean by validation?
This word has been used multiple times but what exactly are we seeking
here?
DR. BERENDT: My
understanding of any classification system that is being used for clinical work
is that it should have what is called face validity and it should have what is
called criterion validity. Face validity
I understand to mean that there is a common sense basis to the classification
and that a clinician looking at it would say, yes, that makes sense to me; I
can see where you got to that and I can see how I can use it.
Criterion validity would be about the fact that
classifications inevitably also attract people into wanting to assume that
there is a prognostic significance to that difference. That specifically addresses the issue of 1.9
versus 2.5 and is that, in fact, a prognostic factor or not.
So, the kind of validation that I think one would like to
see the PEDIS system go through, as any other, would be, one, would anybody use
it. If no one will, it has clearly
lacked face validity and it is gone immediately.
Secondly, when people did use it, was there some kind of
obvious difference in outcomes when one looked at the different groups within
it. Clearly, the goal of expert treatment
would be that there aren't any differences in outcome because your treatment
would be tailored to your classification.
That is a common difficulty with all classification systems, that the
worse the scoring, the more intensive the treatment and, therefore, sometimes
the better the outcome.
DR. RELLER: Well,
the reason I ask--and I like the PEDIS concept.
I mean, it sounds plausible.
These are the things we know affect outcome. So, I should think that there is a high
probability of pretty widespread--given the tremendous amount of work. I mean, this is an enormous effort that has
already been undertaken. So, the face
validity may be pretty close.
Now, the validity as regards prognosis, outcome, etc., how
can one possibly get at that in the pure sense unless you treated some people
and didn't treat others, or you just watched the natural history of these
things without doing anything? Or, if
this face validity has an element of does it make sense, maybe the validation
in terms of prognosis and outcome has to have a common sense element of how can
we do that unless we get an adequate number of patients and get them into
trials, categorize them and see. I think
it is pretty likely that if drug A is better than drug B, the people in
comparable categories--that everybody is going to do better if they are down
the PEDIS ranking and they are going to do worse if they are up the PEDIS
ranking, and there may be differences between two drugs. Now, you can argue about how big the
difference is, etc., but it is hard for me to imagine that somebody with a
lousy PEDIS score is not going to do worse on balance than good if you have
enough patients to be able to show a difference.
So, I don't know how one could, without using it, establish
pre-use validation unless--I mean, it becomes so artificial. I mean, what one needs to have is something
that people can buy into so they would be willing to enroll sufficient numbers
of patients and accurately categorize them, including digital image but not
limited to that because it is not sufficient, but in this categorization there
is, you know, depth.
The thing that is really appealing to me about the PEDIS
approach is that it doesn't have so many categories that you have so many
little subsets that, as Dr. Elashoff talked about, you end up not having enough
people in the cells. I mean, it is
pretty straightforward. I particularly
like the sensation. I mean, it is grade
I or grade II; you can feel or you can't feel.
I am sure they have in there how you assess the feeling. Similarly with the perfusion.
So, no matter what we do or what the FDA does, I should
say, in the end it is going to have to have buy-in. To take something and tweak it that already
has considerable buy-in, it seems to me that it would get us there a lot sooner
to get to the point that we really need, and that is a lot of patients who are
properly assessed that we could actually see for clinical trial purposes
whether one agent contributes more than another agent does for comparable
patients.
DR. LEGGETT: Janet?
DR. ELASHOFF: Yes, I
would agree with a great deal of what you said.
I just wanted to add two things that haven't been mentioned about using
a severity classification. Before I
start, I want to say that generally speaking some classification is better than
none and a small number of categories is generally good. But the important thing is whether people are
going to actually use it. So, if it is
easy to use will people who are doing the clinical trial, or perhaps even
people who are looking at a patient and deciding whether to use a particular
antibiotic use it?
Also, the issue of inter-observer variability ought to be
low. If you have two different people
look at patients, will they agree a fairly high proportion of the time as to which
category the patients are in. So, those
are some other things to think about in choosing and evaluating a system.
DR. LEGGETT: Ellen?
DR. WALD: I just
wanted to ask a question. It seems to me
that maybe you could do both things at once.
We clearly need a score because we need to make sure that patients are
stratified so that one therapy isn't overloaded with more severe patients than
the other. The validation though is
really another thing. You like to
validate something according to something relatively objective, except clinical
outcomes are not so objective. But we
could look at things like requirement for amputation, or certainly mortality
although it may be that some patients who adverse event grade IV will die as
opposed to patients who are grade I or, again, either amputation or long-term
outcome in terms of not eradication of infection maybe but time to overall
healing, and we could define healing however we wanted to that. Would that be the way to validate the score?
DR. ELASHOFF: Well,
it is basically what people agree on as being important aspects of
prognosis. I don't think the objectivity
or lack of it is as important as long as things are randomized and
double-blind. The essential issue is--I
mean, if you think the quality of life down the line is the important thing,
even though it is kind of subjective, that is what we should be looking at to
see this correlation with. It is what is
the really important outcome that you want to find out about that we should be
looking for, and not so much objective, non-objective, although it ought to be
somewhat correlated with pretty much any measure that you use of outcome. If it is not correlated at all with some and
really correlated strongly with others, then that it suggests some issue that
we haven't looked at hard enough.
DR. LEGGETT: Celia?
DR. MAXWELL: I just
have a question and I don't know the answer.
But shouldn't the degree of disease--let's say a diabetic that has
always been well controlled versus someone that is not well
controlled--wouldn't the degree of disease that you find in the limb be
different depending on the control or the lack thereof, and should not that be
part of the criteria? Because it seemed
like it would make a difference. Someone
spoke earlier about the young diabetic versus someone that was more mature.
DR. LEGGETT: David?
DR. ARMSTRONG: I am
sure that that makes a difference, certainly the degree of glucose control,
whatever metric you use. But I think we
are charged with defining a diabetic foot infection right now, and I think you
can look at that continuous variable as regards a certain outcome when more
people are enrolled in a trial. I am not
sure that validating this system is of primary importance right now. What it strikes me as is that it is a
framework for discussion and for definition of potential severity. At least it is talking points, if you will.
I think it maybe gets back to how do we define a diabetic
foot infection. I think the question is
are we going to have a broad definition, as Dr. Poretz mentioned, an infection
below the malleoli in a person with diabetes?
Or, is it going to be someone with an open wound? I think that is the fundamental question. Personally, I think there is more buy-in for
this PEDIS classification, speaking again as someone who took part in
this. There is buy-in worldwide amongst
people who will be doing these trials.
So, I think it might be worthwhile using this as just a framework
because if I look at this, this looks to me like a lot of our inclusion or
exclusion criteria for the bulk of projects, at least the local inclusion and
exclusion criteria, personally.
DR. LEGGETT: One
last comment because I don't think we are ever going to get an answer today and
we still have five or six more things to do.
Joan?
DR. HILTON: I was
also thinking about the validation that I mentioned as being driven by the need
to define the eligibility criteria. So,
some of these PEDIS categories, say three categories, some are continuous like
size and such. So, the objective that I
had in mind is to try to find where to draw cut points for each of these five
and possibly for a few additional factors like cellulitis and control of
infection.
Then in the analysis of the clinical trial each of these
could be analyzed as individual prognostic factors. But what I was thinking that you needed to
get to right now was how to define a homogeneous subgroup of subjects, with
sort of a homogeneous risk of quality of life, or amputation, or whatever some
important outcome is rather than including all patients with diabetic foot
disease.
DR. LEGGETT: Thank
you. Why don't we move on to question
two, which we have sort of addressed already, in patients with preexisting skin
ulcer, how does one define infected versus non-infected ulcers? Jan, I think you made the comment before of
two or more criteria.
DR. PATTERSON: Well,
I think the PEDIS classification, in terms of criteria for grade II, grade III
infection, I would think that would be a pretty objective way to do that. Grade IV has systemic inflammatory response,
signs and symptoms as well.
DR. LEGGETT: Any
other comments, other than what we already mentioned?
[No response]
Number three, what is the most accurate way to obtain
microbiologic information in patients with diabetic foot infections? Alan?
DR. CROSS: I guess a
question I have is that looking at the data, the most impressive data was from
a supplement. That is, the Trager study
looking at quantitative bacteriology looked like it really was able to separate
out what was probably infection from non-infection and avoid problems of swab
and other things. I am just
puzzled. That was done a while ago and
there certainly is a lot of precedent for doing quantitative cultures certainly
in burn patients. I am just curious why
that hasn't been followed up by other studies in peer reviewed journals.
DR. LEGGETT: David,
could you address that again? Do you
think the people who would be doing these trials would all be adapt at and
willing to enter somebody in a trial with a quantitative culture?
DR. ARMSTRONG: I am
not sure that it is even as important as who is taking the culture because I
think that could be standardized. I
think that is not very well standardized right now, but I think that could be
standardized. I think while I would love
to see quantitative cultures taken everywhere, I think there might be a mutiny
in a lot of microbiology labs if a lot of these were taken. We try to get them--I am just speaking from
our center, and I think trying to get them and trying to get those standardized
is somewhat problematic.
That said, it would be wonderful if that were done. But I would personally just want to try to
work to standardize things on the front end, that being that we take good
quality biopsy from the actual wound. I
am not talking about a giant biopsy where you take a big divot out of the
wound. I am talking about a biopsy from
the actual wound which is relatively easy, or taking wound base curettage which
is also easy to teach and do. I think that
is just not done enough. I think in most
of these studies you sometimes have a technician that is just swabbing the
wound and then it will sit on the desk for three or four hours. Then, when it gets down to the microlab, as
Ben Lipsky often says, it is a Rodney Dangerfield--you know, it doesn't get any
respect. So, I don't think we get a true
estimation of what we are growing out of these wounds.
DR. LEGGETT: Barth,
would you like to address this from a microlab's point of view or any other way
you want to address it?
DR. RELLER: I am
hesitant to do this but while these were being presented I jotted down ten
aphorisms about microbiology.
[Laughter]
First, many are colonized; fewer are infected. Two, unlike people, all microorganisms are
not created equal. Three, the less
secure the meaning of the microorganism, the more rigorous the need for quality
of the specimen. Four, quantitation may
be important but it can't replace the quality of the specimen. Five, transport is important but a dog in the
first class seat is still a dog.
[Laughter]
Six, infection yes/no is a clinical enterprise. It can be supplemented by imaging. For example, physical exam is important but
chest x-ray is also important for diagnosis of pneumonia. So, it is a clinical enterprise. Seven, not all clinicians are Osler. Eight, histology is historic but it is still
relevant. This is for the osteomyelitis. Nine, microbiology can help with the
etiology. Indeed, it is crucial for
therapy susceptibility testing but it doesn't make a diagnosis of
infection. Ten, just thrown in for
clinical trials, specificity is more important than sensitivity.
So, what does all that mean? Our laboratory accepts swabs but it only
looks for Staph. aureus and group A streptococcus. You don't have one of those two, that is all
you are going to get from an aerobic culture of a swab. There is a greater intensity of effort
depending on the quality of the specimen.
You know, we get to the other end and get a bone biopsy and you have a
pristine--you know, the ultimate in specimen and whether you request it or not
you will get aerobic and anaerobic culture.
We know that there can be a mixture of organisms in some of these
infections but we still think Staph. aureus and group A streptococcus in the
early stages--and these things, as we know, may evolve. What starts out as one thing, with treatment
and you don't take care of the vascularity, etc., may down the line get into
something worse, sort of the elevation in the grades in the PEDIS scheme.
So, if you are going to ascribe significance, and there are
published reports of this, for osteomyelitis you had better have a very good
specimen and swab won't hack it. So, I
think although these are not ironclad, I think that they can be translated. You know, swabs are not acceptable unless you
isolate the Staph. aureus or group A streptococcus. So, those are some of my thoughts.
DR. LEGGETT: What
about swab of a purulent drainage? In
other words, there is frank pus. Put
your swab into that area.
DR. RELLER:
Colonizing organisms love pus.
DR. LEGGETT: Is that
number eleven? John?
DR. BRADLEY: It was
nice to hear David say that the biopsy wouldn't be the problem but the
microbiology lab would be. Having done
investigations in appendicitis, if you want to see a microbiology lab go crazy
just have them isolate all the organisms from drainage from a ruptured
appendix. I think the best way to define
whether there is an infection present--and I have looked at biopsies from burn
wounds--is a quantitative culture and histology on a biopsy. If you think that the biopsies can be done,
then that is defined evidence. You can
have a pathologist look at all of the histologic samples. You can look for evidence of invasion as
opposed to the organisms sitting on top of the skin. You get some idea of whether the skin is
viable or not. So, you can find out
whether it is invasion of viable tissue, which would meet your definition of
infection as opposed to just a soup that is necrotic tissue in which organisms
are growing. So, if a biopsy can be
done, I think that is clearly the most quantitative, non-subjective way to
document infection.
DR. LEGGETT: Just as
an aside, we are headed towards an awfully expensive clinical trial if now we
have the pathologists and our indium scans and our MRIs and da-da-da-da.
DR. PORETZ: I agree
that Staph. aureus and group A strep. if isolated is significant even from
superficial draining changes. But if you
saw osteomyelitis, what was read as osteomyelitis on an MRI or a bone scan and
you grew Staph. aureus from the pus, would you make the pronouncement that the
osteomyelitis was due to Staph. aureus?
DR. RELLER: You are
aware of the literature as well as I. I
think that it is possible that you have the right organism but it has more to
do with the pre-test probability of what would be causing it in a patient with
diabetes in the first place. In other
words, I am not so sure that from a poor specimen growing the organisms is what
makes it more likely than simply that Staph. aureus is an important player in
osteomyelitis in these patients. If one
has a contiguous osteomyelitis with a longer-standing ulcer, we know those
things are often mixed, and my empirical therapy is often, for example,
piperacillin tazobactam or something comparable to that.
So, I think Staph. aureus from the draining pus from
something--if you have an osteomyelitis and there is persistent drainage, I
mean, you think it is osteo there. If
you have Staph. aureus growing out of that with a little bit of epi. and other
things and it is relatively acute, I think the credence of the aureus also has
to do with how fresh this thing is. So,
if they have just broken through and you are draining pus and you have a few
other things there and you get a Staph. aureus that is on a gram stain
smear--that is the other thing, whether it is there on the gram stain
smear--and they haven't seen a lot of antibiotics, I think it is pretty likely,
along with the pre-test probability. If
you have had somebody that has been around a long time, they have a chronic
ulcer; the thing stinks; and just because they are in the hospital and they
have MRSA growing out of the soup, along with other things, I am not so
sure. That is the patient I would like
to image and biopsy. What do you think
about that?
DR. PORETZ: I think
you are right.
DR. LEGGETT: Jan?
DR. PATTERSON: I
don't remember what number it was but I agree with Dr. Reller that quality is
more important than quantity. I think
that the most accurate and practical way, in terms of what can actually happen
in microbiology labs, to get the information would be deep tissue curettage or
biopsy or an OR debridement sample. I
think quantitative cultures are not really going to be a practical way to do
it. If you have some center that is
interested in it and you want to do a little side study out of interest, that
is one thing but I don't think across the board that would be a practical thing
to do.
DR. RELLER: In the
specimen that Jan is talking about I don't think one can overemphasize the
importance of the gram stain smear, correlate of that. So if you have poly and you have lots of
organisms and you grow something, even if there are a few other things around,
I think you have infection.
DR. LEGGETT: It is
not like there is not consensus to go for what I think was called the deep
culture techniques in the presentation.
The next number, and we have already sort of been
approaching this but let's take a direct investigation of it, what are the
considerations for clinical trials for ruling out osteomyelitis in patients in
trials of diabetic foot infections?
DR. POWERS: Jim, can
I ask you a question to start off with that?
DR. LEGGETT: Yes.
DR. POWERS: One of
the things that Dr. Alivisatos showed in her slide was that what we see in
clinical trials is all over the place.
One of the other things that she said was that except for one trial, it
left it up to the clinician's discretion as to whether or not to even examine the
patient for osteomyelitis. When we reviewed
this lit it appeared that there is a fair number of people that end up having
osteomyelitis that the clinician never suspected they had in the first
place. So, one of our initial questions
would be should everybody in these trials get some kind of imaging study and,
if so, which one?
DR. LEGGETT: Just to
put up the whole range of stuff before we start talking, if we were to just
dictate a plan x-ray, realizing its sensitivity and specificity, are there
statistical methods that would allow you to determine an N big enough, if we
had some way of differentiating preexisting osteo or failure of a drug and
developing of osteo in a clinical trial, would you, as a statistician, be able
to tell us that we need 15,000 or 1,000 people?
Can you overcome that noise that the x-ray is going to tell you? On the other end of the spectrum, if we get
MRIs on everybody they are almost too sensitive and, you know, the same thing
could apply. Is that possible?
DR. ELASHOFF: Well,
certainly if you can lay out some scenario of assumptions, then it is
straightforward enough to do sample size calculations. What I was thinking about myself with respect
with this is to use some relatively easy definition of osteomyelitis and simply
stratify patients on that basis. If the
proportion of people having it is not too large, it won't dilute your trial too
badly even if you are not really careful about having done it. But as long as you have some system that you
have agreed on for classifying them, then you can learn a little something by
the end.
DR. LEGGETT: Ellen?
DR. WALD: It seemed
to me that anybody in PEDIS classification III or IV would need to have a study
because certainly duration of therapy is very dependent upon whether or not you
have an osteo. So, we wouldn't want to
fault a drug because we hadn't used it long enough because we hadn't made the
right diagnosis. From what we heard
today, it sounded to me like either indium or MRI.
DR. LEGGETT: Just as
an aside, at our hospital if you use indium you need a separate explanation and
a separate thing. I mean, that is going
to be hard. So, you have to get not only
consent for the trial but you are going to need to get a separate consent to do
the indium study. Jan?
DR. PATTERSON: I
think everybody ought to have a plain film and then for grades III and IV, if
you can probe to bone I think you should assume they have it, or they have a
plain that is positive, then have it.
But if both of those are negative they should have MRI.
DR. LEGGETT: I don't
know about your radiologists but our radiologists can't tell diabetic
osteolysis from osteomyelitis. Allan?
DR. TUNKEL: I agree
with Jan because I think it is a step-wise approach so we should do whatever we
can first to prove that the patient does have osteomyelitis. So, you see the bone, or probe, or do a
simple radiographic study. Even if maybe
there is controversy, that at least excludes a group of patients from the study
that you don't have to consider. Then
either the MRI or perhaps the technetium bone scan or indium, whatever is
better, or maybe the investigator could have a choice on one of those studies
if we think the sensitivity or negative predictive value is relatively good for
all of them.
DR. LEGGETT: David?
DR. ARMSTRONG: I
don't know if I am speaking for other people but I am very worried about this
aspect of trial design, not from an academic perspective but from a
practicality perspective. I am really
concerned about the cost of a huge number of MRIs, the lack of dedicated
musculoskeletal radiologists in various centers with the expertise and interest
in looking at these, and the difficulties perhaps in getting nuclear scans in
some of these centers, just by the vagaries of protocols.
I think maybe for a large number of these infections sometimes,
just for simplicity sake, serial radiography seems to have some benefit. But, again, I think as we look at those data,
I don't think there are good data to guide us in that area, seeing as they are
very insensitive. But for someone where
there is not a high suspicion of osteomyelitis, why not have everyone get a
serial radiograph? Obviously, you will
be probing to bone as that is part of a local physical examination. If, indeed, the patient can probe to bone one
may proceed with another investigation, perhaps an MRI, at that point and then,
perhaps at the end of the study or at some point at the end of the study, get
another radiograph, giving them point A and point B to compare. That would seem to reduce the cost of this
versus getting blanket exams on all these patients. I don't think that is perfect by any
stretch. In fact, I think it is not so
good but I think this is going to be very difficult in thousands and thousands
of patients.
DR. LEGGETT: Alan?
DR. CROSS: While it
is true that having an MRI would add to the cost, I don't know if, as Ellen
suggested that you restricted at least as part of the protocol to grade III and
IV, how much extra it would be over what would be good clinical practice. I would certainly agree with Jim that just
doing plain films in the case of just diabetic osteolysis has provided more
misinformation than information, and I think that would be a big mistake. So, I would simply echo that in the more
serious cases it really is imperative that we rule out osteomyelitis and
requiring some type of thing like MRI would not add that much over what would
be required by good clinical practice.
DR. LEGGETT: Celia?
DR. MAXWELL: Just to
echo the concern about cost, certainly in a population like what I see most people
have no insurance. So, even getting an
MRI might be difficult. It is my
understanding that if you can probe to bone, isn't that one of the definitions
of osteomyelitis, if you can actually touch the bone? So, it seems to me that if you can probe to bone
there is a strong possibility that there is osteo and it is only when you can't
really do that that you should look to some of these more definitive and
definitely expensive tests. I mean, not
to mention the cost of the antibiotics.
So, I think that that has to factor in when trials are done because what
happens is that once a trial is done guidelines are put forth and then you are
held to these standards and oftentimes it might end up costing patients access
to care because you just can't provide it.
So, I think that that should be considered.
DR. LEGGETT: David?
DR. ARMSTRONG: Well,
just to make this more complicated, the probing to bone may not be all it is
cracked up to be. You heard I think some
excellent concern by Janet, and I think there may be data over the next year or
two from some of the larger trials to suggest that maybe it is the pre-test
probability of having osteomyelitis in your given center that confers the
positive predictive value on this probe.
Maybe if you have a much lower prevalence of osteo than, say, 66 percent
which was in the Grayson study, then the positive predictive value may be no
better than flipping a coin. I don't
mean to badmouth the probe because I really believe that it is a very useful
tool, with that in the back of your mind, but I think that you have to maybe
combine common sense and some of these instruments. As was said by Jan and others, that might be
the way to go and maybe stratifying patients, as was said earlier, might be the
way to go. I just don't think there is a
good answer to this though.
DR. LEGGETT: John
and then Ellen.
DR. POWERS: I think
what our issue is here too is what you are going to do with patients who
eventually you think have osteomyelitis.
If you have a drug and the sponsor decides they don't want to study
osteomyelitis, or they have a drug that, say, is a topical agent, or one that
from preclinical testing has absolutely no penetration into bone, then your
goal there is to exclude patients with osteomyelitis.
What we want there is almost the opposite of what we have
been saying all day. We want high
sensitivity because we don't want them in the trial. We are not saying don't treat them, don't do
whatever you do in clinical practice but we don't want them in the trial. If, on the other hand, you are going to roll
them over into a separate trial, now we want both. Now we want high sensitivity and we want to
be sure that the people actually have osteomyelitis when they get into the osteomyelitis
trial.
There are all the issues you said about probe to bone. I think about our earlier discussions about
surrogate markers. It may be that is
just a coincidence, that they had probe to bone and that you are really just
picking the population that has it. So,
the other issue is probe to bone may be okay in the sense that if you can probe
to bone, fine; they are out of the trial from the complicated skin aspect. But if you then want to roll those people
into an osteo trial, is that good enough by itself to get you in?
DR. LEGGETT:
Question, does that level of discussion need to be in a guidance or can
that be on a drug case-by-case basis when you work it out with the company?
DR. POWERS: I think
what we are trying to do is to formulate a guidance that would address--as Dr.
Norden said today, he addressed his to just systemic drugs. What we were trying to do is say how would
you stratify this into, say, topical drugs versus a drug that doesn't have bone
activity versus one that does. Because
you would hate to see those patients just get excluded and not get studied for
osteomyelitis when, in fact, the drug may have activity there. You could examine those patients and the
drug's efficacy.
DR. LEGGETT: Allan
Tunkel?
DR. TUNKEL: David, I
just have a question for you. If this is
a person who needs to go to the OR for debridement, if a podiatrist goes in,
can they make a determination in the OR and say the bone is definitively not
infected?
DR. ARMSTRONG: Well,
we would like to think we can. You know,
podiatrists tend to think that if they cut something and it bleeds, then it
looks intact. But, in fact, I think our
eyes are not petri dishes or microscopes.
But I think that also raises another issue. In some of those higher grade infections
perhaps those patients will have a higher incidence of intraoperative
debridement. Therefore, we will have a
more definitive diagnosis of those patients as well. So, maybe an MRI in those patients may not be
needed because we will have already taken that patient to the operating room
and taken a good bone biopsy. I think
that is probably what you were alluding to.
DR. LEGGETT: David?
DR. ROSS: Two
points. One, certainly we are very
mindful of the cost. I will just mention
the patient whom I described in my presentation. The day that we saw him we recommended an
MRI. Three weeks later he still has not
gotten it.
The other thing I wanted to say though is that if one is
studying osteo, especially chronic osteomyelitis because we do not think that
is a disease, obviously, with a high placebo response rate, that might be a
setting where a small number of patients who are rigorously characterized could
yield very important information on drug treatment effects and give rise to a
label claim in terms of focused development.
DR. LEGGETT: I want
to bring the discussion around to something called clinical cure or clinical
failure. If we are doing diabetic foot
trials and we are only looking at the soft tissue part of it, why does the
osteo, and how can we tell the development of an osteo on therapy versus
preexisting osteo, and can't you make a case, to play either devil's or angel's
advocate depending on what side you are on, that improvement in that soft
tissue, whether or not anything happens in the bone, is what we are after? So, I would like some discussion if people
have some ideas about how we address that issue. This is assuming that we are not going to be
a perfect situation and, no matter what route we go, we are going to have at
least one person in a clinical trial who has an unrecognized osteo when we sign
him up for the soft tissue diabetic foot infection protocol.
DR. ARMSTRONG: All
right, I will give this a try.
DR. LEGGETT: Good.
DR. ARMSTRONG: I
think that when it comes to diabetic osteomyelitis and the diabetic foot we
often have a little time to react. It
may be sacrilegious to say that but I think sometimes we have time. In the acute limb-threatening diabetic foot
infection we don't. We have to go after
those patients very aggressively with antimicrobials and I think with
adjunctive means like intraoperative debridement. I am certain that there are patients that
will have a smidgeon of osteo after some of these acute infections are
resolved. But I am not sure how critical
that is from the initial endpoints that we are looking at, and I am not certain
how much of--
DR. LEGGETT: I don't
know we know the endpoints yet. That is
the next question.
DR. ARMSTRONG: But
if we are looking at resolution, say, of cardinal signs of inflammation or
recession of erythema, those will happen very frequently even if someone has,
say, an osteitis or a superficial osteomyelitis, or something along those
lines.
DR. LEGGETT: What if
we don't realize that the drug doesn't penetrate into bone, and then we say
that the soft tissue improved and, therefore, we can use this in all diabetic
foot infections? Ellen?
DR. WALD: I think we
will get to know because the patient will become symptomatic again. I mean, isn't that what happens? You stop therapy and two weeks later they
have pain, or redness, or swelling, or drainage just starts again. So, I think, you know, you have healed the
superficial part that you are looking at with your eyes but something is going
on underneath and that is how you find out.
I don't know of any laboratory parameters that are particularly helpful.
DR. LEGGETT: But I
don't know how long we are going to be following these people to find
that. In diabetic osteo it can show up
three months later.
DR. WALD: Yes, when
we talk about when we should look at outcome, you know, I think this is one of
those infections where you don't want to only look at the end of therapy but
you do want to select some arbitrary time--one month, two months, three months,
I don't know what that would be. But,
certainly, we wouldn't be content with end of therapy as the complete
evaluation.
DR. LEGGETT: John?
DR. POWERS: Dr.
Wald, you said something earlier about we wouldn't want to discard a good drug
or say that one drug is inferior to another, and that gets to the case of if
you didn't know that there was an imbalance at baseline between the arms. So, that goes back to Dr. Leggett's question,
is development of osteomyelitis in somebody where we are studying a drug for
soft tissue infection, would we consider that a failure? So, we are looking three weeks, four weeks
down the line and their soft tissue infection doesn't come back but now the
person develops a draining sinus that has osteomyelitis. Is that a failure? Would you consider that a failure for the
initial soft tissue infection? And,
should we consider that a failure in those trials?
DR. WALD: No, I
would consider it probably a failure of diagnosis. So, what you would want to know is if the two
groups were comparable, if you are comparing two drugs, we expect a miss in a
certain number of cases in both groups but if you had many more misses on one
side than the other, then it would suggest that it was in effectiveness of
treatment rather than misdiagnosis.
5:15
p.m. DR. LEGGETT: Janet or Joan, what sort of proportion of
missed diagnoses--obviously it is based on the number of the N that you have,
but what is the range of mistakes that can sort of be taken care of? You made the comment before, Janet, that it
often wasn't that important if it was small.
DR. ELASHOFF: Of
course, that is under the assumption that you have a fairly sizeable
trial. I guess it is also to some extent
under the assumption that you are looking at a superiority trial because if you
are looking at these kind of equivalence things where you are thinking that
maybe a ten percent difference is important, then if you are talking about
misdiagnosis rates of three percent or four percent, that is a pretty big piece
of the outcome. I don't know what to do
there but that, of course, is another reason for finding it problematic to do a
non-inferiority trial.
DR. LEGGETT:
Wouldn't clinical cure or clinical failure also be depending on what the
company was trying to look for? If a
company wanted to include osteo in that category, then the drug would have to
be considered clinical failure. If the
company was only going after a soft tissue portion, could that in another
situation be looked at as a clinical cure?
Or, is that not possible with guidance and with those kind of
considerations?
DR. POWERS: I think
that is the question that we are actually trying to get at. When we look at other diseases, so if you
have a child with otitis media who then develops meningitis two days into
therapy, is that because that child had meningitis when they came in the door
and it was, as Dr. Wald said, a failure of diagnosis? Or, does that mean the drug wasn't working in
those people? It is a question in almost
all trials, this one more so than others because the diagnosis of osteomyelitis
is so delayed into the person's treatment that by the time you find out the
person is on day 10 or 12 of their treatment and it is hard to figure out.
DR. LEGGETT: And
that is the lag phasing with MRIs, by the way.
DR. PATTERSON: Well,
I think we agree that with grades III and IV we would do some type of
definitive test for osteo. I guess I
would just like to ask Drs. Armstrong and Norden, in your experience, people
who have grade II infection, how many of those people end up having osteo?
DR. ARMSTRONG: As
you are ambling up, Dr. Norden, I think a rather low percentage in people that
have a superficial wound that does not initially involve bone; that may not
have a long chronicity, although chronicity is notoriously difficult in these
patients as well; who have a negative radiograph. The prevalence of osteo in that population,
say in a grade II if you are using this PEDIS system, is quite low and the rate
of misdiagnosis, at least in our experience, has been quite low. When you get higher up into these categories
I think you have a greater risk for misdiagnosis, depending upon your style of
treatment.
DR. LEGGETT: Dr.
Norden?
DR. NORDEN: I just
have a couple of comments. I agree with
David's answer to that. I think it is
very low. I just want to comment on bone
penetration because people keep talking about it. I have studied osteo for a long time and I
have never seen a drug that doesn't penetrate the bone in all of the studies
that we did. So, I don't think that is
really an issue. They penetrate in
varying amounts and percentages, but unless the MIC of the bug you are looking
at is very high, that is not going to be an issue.
I think in terms of the question both John and David
raised, if you can argue that somehow you have to say this patient has osteo, you
have to make up your mind, and if you use probe to bone is positive as one of
the best tests we have now and say, okay, those patients who were positive have
osteo and we are going to take them out of the trial and put them in another
trial, if you are going to do a definitive trial with those patients for osteo
I think they should have bone biopsy.
That is the definitive test. It
is still the best test. You may get an
organism out and then you at least know what you are treating.
I wouldn't like to mandate MRIs for everybody. I think it is prohibitively expensive and the
yield--you know, although the sensitivity and specificity may be very high, as
we say, sometimes they are over-read and, as David pointed out, you need a
radiologist who understands musculoskeletal radiology. We had one person in our institution that we
took all bone MRIs to because he was the only one who could read them well.
DR. LEGGETT: Dr.
Berendt?
DR. BERENDT: Yes, my
answer would be concordant with the others, very low for the grade II type
infections.
DR. LEGGETT: What
kind of numbers would we be talking about in terms of what you would envisage
in a trial in grades III and IV? What
kind of numbers of people would we be sending to the orthopedic surgeon or the
podiatrist or somebody to get an intraoperative bone biopsy or a biopsy through
intact skin? Any idea of that at all?
DR. ARMSTRONG: Well,
I would weigh in that clinically most of the patients that fall under those
definitions by any community standard of care ought to be either taken to the
operating room or at least into an area where they can be washed out and have
it investigated. So, I think I would say
a large number of those patients should go for a biopsy or some form of
definitive kind of investigation.
Whether that happens or not, I don't know. There are a lot of times where patients will
go to the operating room for a washout, say, by someone who may be tangentially
associated with the study. Let's just
use an example. That person would just
forget to get a biopsy, and that happens a large percentage of time. This would have to be very well coordinated,
but I think that that is what should be happening.
DR. LEGGETT: So, for
the FDA, it sounds as if the people that are going to have osteo are going to
get biopsied anyway. Then, no matter
which way we do the trials, if you develop osteo that we missed it should
probably called a failure.
DR. POWERS: Let me
read to you an example of why we are worried about this. This was a trial that was published in JAMA
in 1991 by Newman. So, this predates the
PEDIS trial. How these patients apply in
PEDIS, I have no idea. When you look at
the patient inclusion criteria, it is 54 patients that had diabetic foot
ulcers. We can't tell what kind of
grading they would fit into. These are
people who had osteomyelitis determined by bone biopsy and culture, a very
small number of people. But
osteomyelitis was found to underlie 28/41, 68 percent of diabetic foot
ulcers. Only 9 of those 28, or 32
percent, were diagnosed clinically by the referring physician, and 19 of those
28, or 68 percent, occurred in people that did not have ulcers exposing
bone. When we read things like that we
say, wow, gee, well, if there is nothing to stick a probe into and it is not
near the probe, how is this going to help us?
The other thing is when we talk about ruling out
osteomyelitis, it seems like if you stick a probe in there and you hit bone,
okay, it is pretty good. If you stick a
probe in and you don't hit bone, there are an awful lot of those people,
according to the Grayson trial, that still have osteomyelitis.
DR. LEGGETT: Ellen?
DR. WALD: Those
sound like they are patients who are grade III or more. Right?
So, I think this grading system is going to be very helpful. If we say those are patients who probably do
require debridement, then I think it is very logical to say that they will go
to the OR and we will get some tissue, and we will get a good culture and we
will get histology.
DR. LEGGETT: Barth?
DR. RELLER: It is
hard for me to imagine, at least at our place and I would be interested in
Don's and others' comments, of someone going to the OR for a biopsy for
osteomyelitis in this situation without imaging. I mean, it just doesn't happen at our place.
DR. LEGGETT: Why do
they get the MRI? They get it because
they want to know where to get the biopsy so as not to miss it and have a false
negative. Ergo, I am all for Jan's
approach, that people need to have an MRI and if they have osteo, then they
need a biopsy to give us the histology for the histologic diagnosis and then we
get a good sample so that we can get an etiologic diagnosis, which is different
from a histologic diagnosis. Dr.
Berendt?
DR. BERENDT: Thanks
for allowing me to comment. I just wanted
to say that in relation to that study by Newman that was quoted, quite a lot of
people in the field also find that study worrying and, as with any other study
where there is only a single study showing such a surprising result, are
anxious to understand how that fits in to what they actually see, and I don't
think there is a resolution on that matter.
So, I just wanted to say that, you know, that is an N of one and it
ought to be ranked alongside other kinds of N of ones, recognizing that it does
raise a concern.
DR. LEGGETT: Don?
DR. PORETZ: Should
we eliminate the bone scan completely?
DR. LEGGETT: I vote
yes.
DR. PORETZ: I do
too. I just find it more irritating than
anything else. We end up doing a bone
scan and then we do an MRI. It seems to
me that bone scan, which has been promulgated for years and years, should be
abandoned for osteo as long as we have access to an MRI.
DR. LEGGETT: Ellen?
DR. WALD: I would
just be cautious to say that for this kind of contiguous osteo I would absolutely
agree with you.
DR. PORETZ: No, we
are talking about--
DR. LEGGETT:
Diabetic foot, yes. Go ahead.
DR. ARMSTRONG: Just
to respond, while I am certain that there are many centers that will get an MRI
on patients that are going to the operating room for an acute diabetic foot
infection, I would say that that is probably not the majority of centers
throughout the country. We will do that
on many occasions but not on every occasion.
Why? There are a whole host of
reasons why. Most of the time it is
time. The other reason for common sense
because most of these infections--I mean, you are often looking at the bone
preoperatively and we can see where that contiguous source of presumed osteo is
so we have a good idea about where we are going to go when we take that
biopsy. So, I wouldn't just say that we
mandate MRI in all these patients. I
would vote for an approach that says maybe an and/or kind of concept, quite
frankly.
DR. LEGGETT: Jan?
DR. PATTERSON: Well,
I was just going to reiterate that I think it varies very much by center. As David knows since he used to be there in
San Antonio, we are very fortunate to have aggressive podiatrists who will go
in and biopsy without an MRI when it is appropriate. You know, we talked about having an MRI for
grades III and IV anyway, so I would think that you would want either an MRI or
a bone biopsy in grades III and IV.
DR. LEGGETT: And I
don't think that we are going to come to a consensus about whether we call them
cures or failures. That ought to be
another day I think to end that one.
That is part of number four, I am talking about.
In number five, how does one define clinical success or
failure in a clinical trial of diabetic foot infections? This will probably only take 30 seconds.
[Laughter]
Don?
DR. PORETZ: Well,
for the soft tissue infections you can know failure quickly. For the bone infections you are right, it may
take two, three or four months because some of those things do exacerbate later
on. So, soft tissue infections, you will
know fairly soon.
DR. LEGGETT: When we
talk about clinical success or failure, what do we mean by clinical? It is only going to be those two or more
symptoms of inflammation. Or, is it
going to be return of the function? Is
it going to be appearance goes back to where it was? Is it going to be some wound healing? That is sort of what I was trying to get
at. David?
DR. ARMSTRONG: Yes,
I would vote rather strenuously against those other, softer criteria, strictly
because I think that the thing that is going to confer success in the long term
in terms of wound healing, in terms of quality of life, other whatever
instrument you want to apply to that, has nothing to do with the
antibiotic. It has everything to do with
the adjunctive care, as you heard very eloquently from all the lecturers about
off-loading, debridement, activity modulation, things of that nature.
DR. LEGGETT: Do we
require adjunctive therapy of everyone and then do we make it the same for
everyone? What kind of leeway do we
give?
DR. ARMSTRONG: I
think we have more leeway here than we would, say, in a wound healing study
where I think the criteria have to be much more stringent. But I think there should be guidance on
regular debridement of necrotic tissue on some regular basis. We saw some data to suggest that the more we
debride the better these patients do. I
think that is very true, and I think there are other data to suggest that too,
and I think there are center effects there too.
In terms of off-loading, that is also very important. I don't think we should mandate that these
patients be placed into total contact casts.
Although those are rapidly becoming what many would call a gold standard
based on randomized, controlled trials, I think that most patients with infections
are not going to go into total contact casts.
That is a relative contraindication.
But I think attention to off-loading, meaning being in a brace or
something other than their shoe that caused the ulcer, that caused the
infection in the first place is very important and that should be stipulated
for all of these trials.
DR. LEGGETT: And do
we let everybody use normal saline or do we let people use whatever the heck
their wound care nurses want to use?
DR. ARMSTRONG: I
will try this one. I think that as we
move on over these next several years we are going to find actually fewer and
fewer centers using just normal saline wet to moist dressings. Whether or not we believe there are any data
to support this, while important, I think is beside the point from a pragmatic
standpoint. I think maybe what we should
stipulate is that there not be any active agents in the dressing that may be
antimicrobial or antiseptic in nature, or anything in there that may be bioengineered
like, say, a cytokine or bioengineered tissue which are becoming more and more
popular, depending on where you go, but something that is a passive dressing
rather than a so-called active dressing, and there are good definitions of that
now.
DR. LEGGETT: Alan
Cross?
DR. CROSS: I would
like to ask Dr. Berendt, among patients who have grade III or IV PEDIS
classifications, what percentage of them may be expected to have loss of
function? For example, unable to
ambulate?
DR. BERENDT: I think
that is a difficult question to answer because you would need to know the other
elements of the prognostic features. So,
the answer is that it doesn't depend just on the infection. Again, the data from the University of Texas
showed quite well that ischemia is a massive confounder in terms of the
likelihood of amputation, so that when you get into severe ischemia
complicating infection, amputation rates become very high. I mean, so it wouldn't be just about
infection or not. So, I am going to sort
of duck it in terms of giving you percentages.
It becomes kind of multi-dimensional really but the more adverse
prognostic factors you notch up, quicker you end up with very high percentages
of that group requiring amputation at some point.
DR. CROSS: The point
I am getting at is that it may be possible, on the one hand, to have a cure of
the cellulitis but have a clinical failure in the sense of what was defined at
the outset about the number of people who actually are going to
amputation. On the other hand, it seems
like we will have a very difficult time trying to have an agreed upon
adjunctive therapy since those criteria for success and failure are even looser
or more difficult to achieve. So, I
think at least one thing is to try and come up with a clinically relevant,
perhaps composite endpoint over and above simply a response to the cellulitis.
DR. BERENDT: I
sympathize with what I think you are driving at because how can you have an
endpoint that is so easy that you could have mega-trials on this kind of
stuff? I can see where you are coming
from. Whether that is something that is
going to work for this committee in terms of new drugs which, by definition,
are not going to be put through mega-trials to register them, I don't know. I like the ambition, but I am not sure how it
works for here.
DR. LEGGETT: Thank
you. Ellen?
DR. WALD: It
probably goes without saying, but I am going to say it anyway, that the
adjunctive therapy, of course, has to be standard across all the studies that
are done. Whatever it is you decide you
want to have done, it really must be meticulously standardized across groups
within a study and across all people who are embarking on studies.
DR. POWERS: I think
the question we would ask is are there adjunctive therapies which would even
affect the outcome of just the cellulitis, like raising your foot up? We have all seen people where that makes the
swelling go down tremendously regardless of the antibiotic. So, those kinds of things, it would seem,
would need to be standardized across the arms.
DR. LEGGETT: Agreed. Ciro?
DR. SUMAYA: A
question from a pediatric mind set, but as you are looking for the clinical
outcomes, I realize the adjunctive type of modalities that are used are
important and a uniform assessment of that, and the type of drugs you are assessing,
and realizing that this is a long-standing problem with ischemia and neuropathy
in the more severe patients, where does the glycemic control fit into the
assessment of that? I am assuming that
if they are wildly out of control they are not going to be doing as well. Is that assumption not correct?
DR. POWERS: The
problem is it is very circular. Having a
bad infection makes your glycemia get out of control. Having your glycemia out of control is a risk
factor for getting an infection. How one
sorts that out, using that as an endpoint in a trial, is very tricky.
DR. SUMAYA: But does
it need to be assessed at least?
DR. SORETH: Yes, it
needs to be assessed, and we are at such a basic level of data capture that we
cannot even say across different drug development programs that have this as an
indication what the underlying glycemic control was in any given program
because, if it was captured, it wasn't put on the case report form so you can't
even tell, treatment versus control group, what that information was.
DR. LEGGETT: A
couple of points I would like to bring up that sort of tie in with this
clinical success or failure, what do we do in the person that we want to enter
into the trial--this is the osteo/not osteo--who has had some bone debrided? So, now the podiatrist or the orthopedic
surgeon tells me he has bleeding bone and there is no osteo, what do we do
about that, David? So he had a biopsy
and the biopsy is negative?
DR. ARMSTRONG: And
that raises another issue. Often this
can be a quasi-excisional biopsy because we are talking about small bones. Often those small bones are the same thing
that caused the ulcer in the first place.
So, the clinician, when he or she is in the operating room, may say,
well, I want to do something that may help cure this area of pressure as well
as help cure this infection. I think if
you remove all of the bone and you have a margin, I think it is fairly standard
to take a biopsy of the residuum of, say, a metatarsus, for instance. Then, that person cannot be considered to
have osteomyelitis.
DR. LEGGETT: Going
back to Dr. Norden's hypothetical thing, you made the point--if I understood
this right--that there may be multiple lesions but you should select one study
lesion. I don't know how that fits in
with what the FDA or other people are saying because I can envisage a couple of
different ulcers, one of which improves and the other doesn't. So, do you count them all, and how does that
get factored in, in terms of success or failure? Joan?
DR. HILTON: It is
actually possible to study more than one within a patient as long as you use
longitudinal models that account for that.
DR. POWERS: I think
what we are worried about here is getting back to something Dr. Armstrong said
earlier, the difference between healing an open wound versus healing the signs
and symptoms of the active infection. In
that case, it probably doesn't matter how many holes you have in your
foot. It is the surrounding erythema,
swelling and those other things that we want to see go away, not the healing of
which hole.
DR. LEGGETT: But
that is what I am saying. Under your
foot metatarsal the erythema gets better but on the dorsum, your unrecognized
tendinitis, that doesn't get better.
DR. POWERS: I think
though since we are talking about systemically administered drugs, one would
have to consider that failure because the drug is going to all of those sites.
DR. LEGGETT: So, the
drug company is going to have to give us data about each particular
lesion. Did I interpret what you were
saying, Carl?
DR. NORDEN: Fine.
DR. PORETZ: Can I
just ask one question? I was very
surprised to find out that there are only three drugs that are approved for
diabetic foot infections, of which one drug is not even on the market anymore. Those drugs are approved for diabetic foot
infections including contiguous osteomyelitis?
DR. POWERS: No.
DR. PORETZ: So,
tissue diabetic infections?
DR. POWERS:
Yes. There is a caveat to that
though. Well, let me make one
correction. Trovafloxacin is still on
the market.
DR. PORETZ: It is
not being used.
DR. POWERS: I know
it is not being used but it is still on the market. But one of the issues is there are a number
of drugs that have been studied for complicated skin and soft tissue infections. The question is how many have actually looked
at the specific subset of people with diabetes and foot infections? That is what David showed, that there is a
much smaller subset looking at that group of people.
One of the things that we are trying to get at too is could
we actually, in terms of what we talked about for streamline drug development,
look at an overall complicated skin and soft tissue infection trial and then
examine a subset of people that have diabetic foot infections within that trial
so we wouldn't require separate trials across the board for this as well?
DR. LEGGETT: Any
other comments about this? I don't think
we are going to get much further today.
DR. COX: I just want
to thank everyone on the committee. I
think we got a lot of very helpful discussion and a lot of very helpful advice
today, helping us navigate through some of the challenges here in clinical
trial design for diabetic foot infections.
So, my thanks to everyone for the discussions and advice today.
DR. LEGGETT:
Great. So, 8:30 tomorrow.
[Whereupon, at 5:40 p.m., the proceedings were recessed, to
resume on Wednesday, October 29, 2003 at 8:30 a.m.]
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