1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

JOINT SESSION WITH THE

NONPRESCRIPTION AND DERMATOLOGIC DRUGS

ADVISORY COMMITTEE

VOLUME I

Wednesday, March 23, 2004

8:00 a.m.

Hilton Washington DC North

620 Perry Parkway

Gaithersburg, Maryland

P A R T I C I P A N T S

Alastair Wood, M.D., Chair

Shalini Jain, PA-C, Executive Secretary

Committee Members:

Michael C. Alfano, DMD, Ph.D., Industry

Representative

Terrence F. Blaschke, M.D.

Ernest B. Clyburn, M.D.

Frank F. Davidoff, M.D.

Jack E. Fincham, Ph.D.

Sonia Patten, Ph.D.., Consumer Representative

Wayne R. Snodgrass, M.D., Ph.D.

Robert E. Taylor, M.D., Ph.D., F.A.C.P., F.C.P

Mary E. Tinetti, M.D.

Special Government Employee (Voting):

Michele L. Pearson, M.D.

Government Employee Consultants (Voting):

John S. Bradley, M.D.

John M. Boyce, M.D.

Ralph B. D'Agostino, Ph.D.

Thomas R. Fleming, Ph.D.

Elaine L. Larson, R.N., Ph.D.

James E. Leggett, Jr., M.D.

Jan E. Patterson, M.D.

FDA Participants:

Tia Frazier, R.N., M.S.

Charles Ganley, M.D.

Michelle Jackson, Ph.D.

Susan Johnson, Pharm.D., Ph.D.

John Powers, M.D.

Curtis Rosebraugh, M.D.

Debbie Lumpkins, Team Leader

C O N T E N T S

Call to Order and Introductions

Alastair Wood, M.D., Chair 4

Conflict of Interest Statement, Shalini Jain, PA-C

Acting Executive Secretary 8

Issue Overview, Susan Johnson, Pharm.D., Ph.D. 10

Regulatory History of Healthcare Antiseptic Drug

Products, Tia Frazier, R.N., M.S. 21

Testing of Healthcare Antiseptic Drug Products,

Michelle Jackson, Ph.D. 31

Microbiological Surrogate Endpoints in Clinical

Trials of Infectious Diseases, John Powers, M.D. 54

Antiseptic and Infection Control Practice,

John Boyce, M.D., Yale School of Medicine 106

Prevention of Surgical Site Infections,

Michelle Pearson, M.D., CDC 127

Question and Answer Period 163

Open Public Hearing:

Steven C. Felton, Ph.D. 204

J. Khalid Ijaz, DVM, Ph.D. 211

The Quset for Clinicaql Benefit

Steven Osborne, M.D. 214

OTC-TFM Monograph Statistical Issues of Study

Design and Analysis, Thamban Valappil, Ph.D. 224

Industry Presentation:

The Value of Surrogate Endpoint Testing for

Topical Antimicrobial Products,

George Fischler 250

Statistical Issues in Study Design,

James P. Bowman 276

Committee Discussion 299

P R O C E E D I N G S

Call to Order and Introductions

DR. WOOD: Let's get started. Welcome to

the Over-the-Counter Advisory Committee. Let's

begin by going around the table and everybody

introducing themselves, and we will start on this

side, Charlie.

DR. GANLEY: Charley Ganley, Director of

OTC.

DR. POWERS: John Powers, Lead Medical

Officer for Antimicrobial Drug Development and

Resistance Initiatives in the Office of Drug

Evaluation IV.

DR. ROSEBRAUGH: Curt Rosebraugh, Deputy

Director, OTC.

DR. JOHNSON: Sue Johnson, Associate

Director, OTC.

DR. LUMPKINS: Debbie Lumpkins. I am a

Team Leader in OTC.

DR. DAVIDOFF: I am Frank Davidoff. I am

an internist and editor emeritus of Annals of

Internal Medicine and a member of the OTC

committee.

DR. FLEMING: Thomas Fleming, Chair,

Department of Biostatistics, University of

Washington.

DR. FINCHAM: Jack Fincham, professor at

the University of Georgia, College of Pharmacy, and

I am a member of the committee.

DR. CLYBURN: I am Ben Clyburn. I am an

internist at Medical University of South Carolina

and a member of the committee.

DR. BRADLEY: I am John Bradley, a

pediatric infectious disease doctor from Children's

Hospital, San Diego, and I am a member of the

Anti-Infective Drugs Advisory Committee.

DR. PATTERSON: Jan Patterson, Infectious

Diseases and Infection Control, University of Texas

Health Science Center, San Antonio and South Texas

Veterans Healthcare System.

MS. JAIN: Shalini Jain, Acting Executive

Secretary for today's meeting.

DR. PATTEN: Sonia Patten. I am the

consumer representative on the panel, and I am an

anthropologist on faculty at Macalester College in

St. Paul, Minnesota.

DR. SNODGRASS: Wayne Snodgrass,

pediatrician and clinical pharmacologist at the

University of Texas Medical Branch.

DR. LARSON: Elaine Larson, from the

School of Nursing and School of Public Health at

Columbia University, in New York.

DR. TAYLOR: Robert Taylor, Chairman,

Department of Pharmacology, Howard University, in

Washington, internist and clinical pharmacologist.

DR. BLASCHKE: Terry Blaschke, internist,

clinical pharmacologist, Stanford, member of the

committee.

DR. TINETTI: Mary Tinetti, internist,

Yale University and member of the committee.

DR. D'AGOSTINO: Ralph, D'Agostino,

biostatistician from Boston University, consultant

to the committee.

DR. LEGGETT: Jim Leggett, infectious

diseases at Portland Medical Center and Oregon

Health Sciences University, and I am a member of

the Anti-Infective Drugs Advisory Committee.

DR. ALFANO: I am Mike Alfano, New York

University College of Dentistry, industry liaison

to NDAC.

DR. WOOD: And I am Alastair Wood and I am

the Chairman of the NDAC and Associate Dean at

Vanderbilt.

So, let's get started. Shalini, do you

want to read the conflict of interest statement?

While she is digging that up, the weather has

caught us and the first speaker from CDC is stuck

in Atlanta--the story of people's life in the

Southeast. So, what she is going to do, she is on

her way back to her office and she is going to

e-mail us slides and then we will try and project

the slides later in the morning, with her talking

to us over the telephone. So, that will be a

nightmare I suspect.

[Laughter]

That means we will time shift everything

up and then probably, depending on how she gets on,

we may have the question and answer period for the

first ones a little bit earlier and take an earlier

break and then come back to hear her, depending on

how the technology is behaving. Shalini, go ahead.

Conflict of Interest Statement

MS. JAIN: The Food and Drug

Administration has prepared general matters waivers

for the following special government employees who

are attending today's meeting of the

Nonprescription Drugs Advisory Committee on the

microbiologic surrogate endpoints used to

demonstrate the effectiveness of antiseptic

products used in healthcare settings. The

committee will also discuss related public health

issues, trial design and statistical issues.

This meeting is held by the Center for

Drugs Evaluation and Research. The following

meeting participants have waivers: Dr. Jan

Patterson, Dr. Sonia Patten, Dr. Thomas Fleming,

Dr. John Boyce, Dr. Ralph D'Agostino and Dr. John

Bradley.

Unlike issues before a committee in which

a particular product is discussed, issues of

broader applicability such as the topic of today's

meeting will involve many industrial sponsors and

academic institutions. The committee members 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 practical to recite all potential conflicts of

interest as they apply to each member. FDA

acknowledges that there may be potential conflicts

of interest but, because of the general nature of

the discussions before the committee, these

potential conflicts are mitigated.

With respect to FDA's invited industry

representative, we would like to disclose that Dr.

Michael Alfano is participating in this meeting as

a non-voting industry representative, acting on

behalf of regulated industry. Dr. Alfano's role on

this committee is to represent industry's interests

in general and not any one particular company. Dr.

Alfano is Dean, College of Dentistry, New York

University.

In the event that discussions involve any

other products or firms not already on the agenda

for which FDA participants have a financial

interest, the participants' involvement and their

exclusion will be noted for the record.

With respect to all other participants, we

ask in the interest of fairness that they address

any current or previous financial involvement with

any firm whose product they may wish to comment

upon. Thank you.

DR. WOOD: Thanks a lot. Let's go

straight on to the first presentation from Susan

Johnson. Susan?

Issue Overview

DR. JOHNSON: Good morning.

[Slide]

My name is Susan Johnson and I am the

Associate Director of the Division of OTC Drug

Products. On behalf of the division, I would like

to welcome the members of the Nonprescription

Advisory Committee and the Anti-Infective Advisory

Committee and our other guests. As I am sure the

committee members would agree, the bulk of the

background package as a metric of the challenge

that we face today is certainly significant, and we

certainly appreciate everyone making as much

headway as they could with that background package.

We very much appreciate all of your

assistance today. There is a wide variety of

issues to discuss and so you will see the

representation of the committee being broadened

from NDAC to include the Anti-Infective committee

members, and we appreciate everyone's attendance,

as well as our consultants.

I will just be providing a brief

introduction to the regulatory issues associated

with the efficacy of OTC healthcare antiseptics.

[Slide]

The OTC healthcare antiseptics include

three categories of drug products, the healthcare

personnel handwashes; surgical hand scrubs; and

patient preoperative skin preparations that are

used to scrub the skin prior to surgery.

[Slide]

FDA's current approach to the evaluation

of healthcare antiseptic efficacy assumes that

healthcare antiseptics play a critical role in

infection control, and Dr. Michelle Pearson and Dr.

John Boyce will discuss this role in additional

detail. However, the efficacy of individual

products must be demonstrated to meet regulatory

requirements. FDA's current regulatory standards

are based on actual product performance and have

been supported in previous public discussions such

as this one. Ms. Tia Frazier will explain more

about the regulatory history of these products.

FDA currently determines the efficacy of

healthcare antiseptics using a surrogate endpoint,

and that is used as the reduction in a log

10 count

of bacteria from the site of the test product

application. Dr. Michelle Jackson, from the

Division of OTC, will discuss how the standard is

used in the test methodology.

[Slide]

This meeting has been convened because we

have received citizen petition requests to change

the threshold criteria for bacterial reduction. We

wish to present our review for your consideration

of the efficacy data in the literature for these

products. We are asking that the advisory

committee provide input about the standards that

FDA needs to have in place to make regulatory

decisions.

[Slide]

What are some of the factors that can

influence efficacy of the healthcare antiseptics?

This is by no means an exhaustive list but is

intended to give you an idea of why product testing

is required to demonstrate efficacy.

The first group of factors I am going to

discuss are associated with the actual product.

The active ingredient obviously affects efficacy.

The spectrum of activity for each individual active

ingredient is tested in associated testing criteria

in vitro. The potency or dose response of the

active ingredient shall also be taken into

consideration, although in some cases it is not

well known.

The formulation of the product can impact

its efficacy and influence that to increase or

decrease efficacy so the concentration and dose

delivered to the site and vehicle and other

inactives in the products can affect efficacy. One

thing that influences efficacy quite a bit is how

the product is actually used, and that is led in

large part by the way the product is labeled.

[Slide]

Other factors that influence efficacy of

healthcare antiseptics include actual use

parameters, adherence to the labeling and other

practice standards and actual implementation of

both labeling and practice standards.

There are many patient parameters that can

affect the efficacy of these products, including

things like health status which influences the risk

for infection, as well as the type of procedure

that is being conducted.

Resident and transient bacteria, resident

bacteria being normal flora and transient bacteria

being those sorts that are introduced during

healthcare processes, can affect efficacy as well.

The amount of bacteria that is delivered and that

resides on the skin, either prior to or that is

left residually after product use, is an important

determinant of overall efficacy. Virulence of the

bacteria that exists on the skin affects efficacy

as well. A small amount of bacteria can be present

and provide a great risk of infection.

[Slide]

FDA in general assesses efficacy using

randomized, controlled trials for the most part.

These provide analytical strength and can be

designed to control for multiple confounders.

Critical to the design of controlled trials is the

selection of active and vehicle control, and we

will be discussing that later today.

[Slide]

The endpoints that are normally used in

randomized, controlled trials are clinical or

surrogate endpoints. Randomized, controlled trials

typically use clinical endpoints because the

relevance is more evident. In some situations the

difficulty and expense of conducting clinical

trials is very important to industry. An

alternative to clinical endpoints is surrogate

endpoints, and Dr. John Powers will later discuss

the scientific and regulatory precedent for using

surrogates. Just as a reminder, and I am sure you

have gleaned this from your reading already, but

the current standards for OTC healthcare antiseptic

efficacy are surrogate endpoints.

[Slide]

The factors that should be considered when

using a surrogate to assess healthcare antiseptic

efficacy include validity. We acknowledge from the

outset of this discussion that there is limited

information about the links between clinical

outcomes and efficacy and use of the surrogates to

determine efficacy. Dr. Steve Osborne will discuss

the literature surrounding this question a little

bit later.

The existing trials in the literature are

not designed to validate our practice standards.

Instead, our practice standards and use of

surrogate are based on the use of antiseptics in

practice and our experience with marketed drug

products.

Test methodology is also an important

factor to consider when using surrogates. Test

methodology should evaluate the conditions of use,

largely directed by the labeling or the intended

labeling. The test methodology to evaluate

healthcare antiseptics with surrogates needs to

characterize the tolerability of drug products.

While we are talking primarily about efficacy

today, the tolerability of these drug products is a

major safety concern and does come up as part of

the testing methodology. Test methods do need to

be standardized with regard to all inherent

procedures.

[Slide]

Other factors that should be considered

when using surrogate endpoints are the decision

thresholds and, as I have said, the current

criteria are based on the NDA performance of

existing approved products. We suggest that any

changes to these criteria on decision thresholds

should be data driven.

Analysis of test data is critical, and

later today Dr. Thamban Valappil will be discussing

the analysis of these data. His talk is predicated

on the previous discussions that we will be having

about validity methods and thresholds, and he will

talk about the need to evaluate the response of

test products in the context of variability in both

test methods and in patient response.

[Slide]

Epidemiologic studies do provide

information for healthcare antiseptics. They

provide actual use information on large populations

and can often be used to suggest practice

standards. They are often used to generate

hypotheses to be later studied in randomized,

controlled trials. But they are relatively

insensitive to treatment differences and changes in

things like threshold criteria. So, using them to

extrapolate for regulatory decision-making is of

limited value.

[Slide]

What specifically are we asking the

advisory committee to address? First, can we

continue to rely on surrogate markers to assess

healthcare antiseptic efficacy? I would like to

remind the committee, as we will several times

today I am certain, that we have the need for

ongoing assessment and decision-making of these

products so we do need to have standards in place

now and in the near future, as well as into the

distant future.

If surrogates can be applied, at least in

the short term, is there compelling evidence to

change our surrogate efficacy criteria now? What

is the best way to analyze the efficacy data? And,

what labeling information would be helpful for

clinicians to understand product efficacy and

potentially to compare among different products?

With that, I will turn it over to Tia

Frazier, who is a regulatory project manager in the

Division of OTC Drug Products, and she will be

discussing regulatory history.

DR. WOOD: Just before you take that slide

off, there is sort of an underlying assumption

there, which I think is right but I just wanted to

articulate that there is a sort of regulatory

inertia which is that in the absence of evidence we

shouldn't change criteria. Is that fair? I am not

disagreeing with that, I am just trying to put

number two in that context.

DR. JOHNSON: Yes, I think that is very

essential to this discussion. What we have tried

to make clear, and will make clear in other

presentations, is that the surrogates are based on

as much information as we have had prior to the

mid-'70's, when this regulatory mechanism was

invoked, until now. There still is not a body of

evidence, while we are asking you to assess that

body of evidence and whether you think that compels

us to change. So, there are standards in place and

we think that those standards are based on the

information that has been available to this point.

At this point we are reconsidering the standards

and we do think, and we are suggesting to the

committee that any change in the standards should

be data driven.

DR. WOOD: Just to summarize, so what you

are saying is that you don't want the committee

particularly to consider the quality of the data

supporting the standards; you want the committee to

consider the quality of the data supporting a

change in the standards.

DR. JOHNSON: Well, I think it is both but

our concentration is really on the latter part of

that.

DR. WOOD: All right, thanks. The next

speaker will be Tia Frazier.

Regulation History of Healthcare

Antiseptic Drug Products

MS. FRAZIER: Good morning.

[Slide]

I am Tia Frazier, and I am a project

manager in the OTC Division, and I will briefly

review the regulatory history of the monograph for

OTC healthcare antiseptic drug products.

[Slide]

The monograph includes both consumer and

professional use products. Today we are addressing

issues related to the professional use products

included in the monograph, which we call the

healthcare antiseptics. I will start first by

defining the healthcare antiseptics. There are

three recognized uses, that Susan has already told

you about, included in the tentative final

monograph. These are patient preoperative skin

preparations used to cleanse patient skin prior to

surgery; surgical scrubs which are used by

operating room personnel prior to performing

surgery; and healthcare personnel handwashes which

are the soaps and leave-on products that are used

by all personnel in healthcare settings prior to

contact with patients.

[Slide]

We have two different mechanisms for

regulating OTC healthcare antiseptics. Companies

can submit new drug applications, which we call

NDAs, for specific drug products to the FDA. Data

provided in NDAs remains confidential. The second

mechanism that we have for regulating these

products is the OTC drug monograph review process.

Products submitted to the monograph review are

judged on the safety and efficacy of their

individual active ingredients. The data review for

monograph drug products is public.

[Slide]

Just to add to this brief description, I

will also tell you that the OTC drug monograph

review began in 1972. At that time, and for some

years later, the agency made determinations about

the safety and efficacy of over 200,000 OTC

products that were on the market at that time. We

have reviewed 700 active ingredients in 26

therapeutic categories with the help of expert

panels.

[Slide]

The advisory review panel reviewed and

made recommendations on ingredients and products to

further the development of a drug monograph. FDA

then categorizes ingredients considered in the

monograph review according to their safety and

effectiveness for a particular use described in the

review. I won't say much more about how we

categorize and evaluate ingredients since the focus

of today's meeting is on the effectiveness criteria

that we use to evaluate this particular group of

professional use products. The OTC review panel's

recommendations are then published in an advance

notice of proposed rule-making, or ANPR.

[Slide]

After the ANPR is published we consider

public comments as we develop a tentative final

monograph, or TFM. A TFM is FDA's proposed

monograph.

[Slide]

FDA usually receives more data and public

comments on any TFM that we publish. Typically, we

publish a final monograph after a tentative final

monograph. In this case, we published a second

tentative final monograph in 1994 after the first,

which was published in 1978.

[Slide]

We, at FDA, have the current view that

antiseptics do play a pivotal role in the practice

of infection control today. We operate from the

presumption that antiseptics can decrease the

number of organisms on the surface of the skin and

this probably reduces the spread and development of

nosocomial infections.

Based on this presumption, we adopted

surrogate endpoints, measurements of log reductions

on the skin surface that are intended to indirectly

measure the effectiveness of antiseptics that we

regulate. This is the reason that FDA and the

European regulatory bodies selected this particular

surrogate endpoint, the reduction of the organisms

on the skin surface, to evaluate the effectiveness

of these products.

[Slide]

The advisory review panel recommended in

1974 that we use surrogate endpoints to measure

antiseptic effectiveness. To date, unfortunately,

we still have not figured out how to design a

clinical study that can measure the contribution of

an antiseptic in reducing the likelihood of

contracting or spreading nosocomial infection.

With any luck, today Dr. Pearson will explain later

why designing studies like this is so difficult.

[Slide]

So, now I am going to go into the history

of the monograph as it relates to the surrogate

endpoints. The first defined surrogate endpoint

for patient preoperative skin preparations appears

in our 1974 ANPR. It was also incorporated in the

first tentative final monograph which, I said, was

published in 1978. Then the panel recommended a

3-log reduction in organisms on the surface of the

skin as the requirement for patient preoperative

skin preparation. At that time, NDA products were

often approved for patient preoperative skin

preparation indications based on their ability to

meet a 3-log reduction and the monograph simply

adopted this commonly used NDA standard.

It is important to realize that the

effectiveness criteria used today to evaluate

products marketed under the monograph are really

based on the effectiveness criteria often applied

to NDA products. NDAs, of course, can be approved

with alternate clinical endpoints and are not

necessarily bound by the monograph standards.

[Slide]

Moving on to the surgical hand scrub

criteria, the history on this is that Hibiclens is

an NDA product that was approved in 1975 based on a

new surrogate model developed to evaluate surgical

scrubs. FDA incorporated the effectiveness

criteria applied to Hibiclens surgical scrub into

the developing antiseptic monograph. These

criteria were published in our second tentative

final monograph, on June 17, 1994.

Hibiclens is often included as a positive

or active control in testing designs for antiseptic

products. Because these are laboratory tests,

companies are required to include a positive

control arm using an approved product like

Hibiclens to ensure that the tests are conducted

correctly.

[Slide]

The current 3-log reduction criteria

proposed for healthcare personnel handwashes in the

second tentative final monograph was based on FDA's

evolving understanding of what the NDA products

under review at that time could achieve.

[Slide]

As I have said before, this monograph is

unusual because there are two tentative final

monographs associated with it. In 1994 we elected

to publish a second tentative final monograph

rather than a final monograph to allow for public

comment on the new testing requirements. The

current proposed testing requires in vitro studies

of the product spectrum and kinetics of

antimicrobial activity and of the potential for the

development of resistance. We also require in vivo

studies of effectiveness under conditions that we

think simulate how the product is actually used in

that healthcare setting.

Another unusual aspect of this monograph

is that it requires in vitro and in vivo testing

not only for the approval of new products but also

for the approval of new formulations. We require

this testing to be done because changes in the

inactive ingredients or dosage forms can affect the

product's effectiveness.

[Slide]

Products are required to meet key

attributes important to their performance in

healthcare settings. We state that a healthcare

personnel handwash should be persistent if

possible. We would like it to be non-irritating,

fast acting and be able to kill a broad spectrum of

organisms as well.

Persistence, or the ability to have a

residual effect for some time after the product is

used, is also an attribute that we would want a

surgical scrub or a patient preoperative skin

preparation to have as well.

[Slide]

We have had two prior public discussions

about these effectiveness criteria. We discussed

performance testing at an advisory committee

meeting in 1998. This was a general discussion

only and we did not present questions for the

committee to vote on. Then in 1999 we held a

public feedback meeting to hear the industry

coalition present an alternative model or framework

for evaluating antiseptics. Dr. Jackson will cover

the effectiveness criteria proposed by this

industry coalition in her presentation that follows

mine.

[Slide]

I think everyone here today would agree

that it is critical that FDA ensures it uses the

right criteria to evaluate antiseptic products.

There are many dangers we can imagine might occur

if we allow ineffective products to be sold and

used in hospitals. We need these products to work.

The OTC and anti-infective divisions admit that the

effectiveness criteria we currently use are not

based on data from clinical studies. We recognize

this as a limitation of our current standards.

The divisions recently reviewed available

scientific data on topical antiseptic products used

in healthcare settings. We searched for data that

could be used to support effectiveness standards

for this class of products. Our review of more

than 1,000 studies submitted by industry and picked

up through our own literature search is included in

the committee background packages. Dr. Steven

Osborne will present the results of his review and

evaluation of a section of those references that

address clinical benefit later on this morning.

[Slide]

The monograph for OTC healthcare

antiseptic drug products is in the tentative final

monograph or proposed rule stage. We are in the

process of writing a final rule, and we need your

recommendations on what the effectiveness criteria

should be in order to finalize this monograph.

Now I would like to introduce my

colleague, Dr. Michelle Jackson, who is a

microbiology reviewer in the Division of

Over-the-Counter Drug Products. She will review

the testing methodologies used to evaluate these

products.

Testing of Healthcare Antiseptic Drug Products

[Slide]

DR. JACKSON: My talk will focus on the

testing criteria for healthcare antimicrobial drug

products, and currently the development and

standardization of protocols regarding the testing

criteria for healthcare antiseptic drug products

are based on earlier NDA review process.

[Slide]

My presentation will discuss where we are

with the proposed monograph requirements in regards

to clinical simulation testing procedures for

healthcare personnel handwash, surgical hand scrub

and patient preoperative skin preparation, and the

use of surrogate endpoints, also referred to as log

reductions, with the three healthcare professional

products. Then I will go over the industry

coalition's position of wanting to use alternative

criteria. [Slide]

During the early stages of the antiseptic

NDA review process standardized protocols did not

exist. However, the agency requires standardized

and reproducible methods, therefore, as the NDA

review process evolved clinical protocols used

throughout the NDA review process also evolved into

protocols now recommended in the tentative final

monograph.

So, what makes a good clinical simulation

test method? It should simulate as close as

possible the actual use conditions. Ideally,

clinical simulations should include design

characteristics such as test product, also referred

to as final formulation; the test product contains

the active antimicrobial agent; a vehicle control

arm is the test product without the active

antimicrobial agent and vehicle, and negative

control that shows how much contribution of

reduction is due to just the mechanical action of

washing the hands.

A current trial design in TFM does not

recommend inclusion of a vehicle for healthcare

personnel handwash and patient preoperative

testing. The active control arm is also referred

to as the positive or internal control. The active

control is used to assess the reproducibility of

the clinical simulation studies and also used to

validate the study. This standard is usually a

chlorhexidine gluconate containing product.

Clinical simulations should also measure the

desired product performance. This simulation

testing generates the surrogate endpoints and it

should also be reproducible.

I will briefly go over the three testing

criteria for healthcare personnel handwash,

surgical hand scrub and patient preoperative skin

testing.

[Slide]

For healthcare personnel handwash, the

label indicated use is handwash to help reduce

bacteria that potentially can cause disease. The

products are used by healthcare professionals on a

daily basis up for to 50 handwashes per day. The

testing process predicts the reduction of organisms

that may be achieved by washing the hands after

handling contaminated objects or caring for

patients. Here we are focused on the removal of

transient organisms. The testing process is

designed for frequent use and it measures the

reduction of transient organisms after a single use

or multiple uses to initial baseline level.

The studies are designed to demonstrate a

cumulative effect of an antiseptic, meaning that

the product gets better and better in reducing the

bacterial load on the hands. Thus, the products

are considered broad spectrum, fast acting and, if

possible, persistent. The TFM surrogate endpoints

propose a 2-log reduction for the first wash and a

3-log reduction for the 10th wash.

[Slide]

For the inclusion criteria subjects

participating in the studies must be between the

ages of 18-69, generally in good health, and have

no clinical evidence of dermatosis, open wounds,

hangnails or other skin disorders.

The subjects are excluded if they have

been diagnosed with having medical conditions such

as diabetes, hepatitis, or having an immune

compromised system, subjects having any sensitivity

to antimicrobial products, pregnant or nursing

women also would be excluded from participating in

a study.

For the healthcare personnel handwash

there is a one-week washout period where subjects

are instructed to use a non-antimicrobial product,

such as soaps, deodorant and shampoos, and avoid

bathing in chlorinated pools and hot tubs.

[Slide]

The outline of the test procedure includes

a test practice wash using bland soap. This

basically removes any oils and dirt from the hands,

and the bacteria counts are compared to the

baseline counts. The hands are contaminated with

Serratia marcescens and immediately sampled, and

the baseline is determining the number of organisms

on the surface of the skin prior to using an

aseptic product.

The handwashing schedule involves ten

washes performed on one day. At the first wash the

hands are contaminated and washed with the test

product. The hands are then sampled for microbial

counts. Eight additional washes are performed, and

at the tenth wash the hands are sampled for

microbial counts and the product must achieve a

specific log reduction after the first and tenth

washes. The repetitive hand washing aspect of the

study design is intended to mimic the repeated use

of a product in hospitals. The repetitive washing

is also used to measure the cumulative effect, and

cumulative effect is a progressive decrease in the

number of microorganisms recovered following the

repeated application of the test product.

[Slide]

Once the hand washing procedure is

completed, the subject's hands are decontaminated

by sanitizing the hands with 70 percent alcohol.

The purpose of this is to destroy any residual

Serratia marcescens left on the skin. Typical

handwashing procedures involve contaminating the

hands with a microorganism, Serratia marcescens.

The hands are rubbed together for 45 seconds, and

the hands are held away from the body and allowed

to dry for a few minutes.

[Slide]

Once the hands are dry, a specific amount

of test product is dispensed into the cupped hands

and the next step is to lather and wash all over

the surface of the hands and above the wrists.

After the completion of the wash, the hands and

forearms are rinsed under regulated tap water with

a temperature of 40 degrees Celsius for 30 seconds.

[Slide]

The hands are then placed in plastic bags

and sampling fluid is added to the bag containing

neutralizers. Neutralizers are reagents that stop

the antimicrobial reaction. Sampling should occur

within five minutes after each wash. The bags are

tightly secured above the wrist with a strap. The

hands are massaged for one minute, paying

particular attention to the fingers and underneath

the nails.

[Slide]

An aliquot of the sampling fluid is

aseptically withdrawn from the bag and transferred

immediately to dilution tubes. The microbial count

determination is performed by surface plating and

this is done within 30 minutes of sampling. The

plates are incubated for two days at 30 degrees

Celsius.

[Slide]

This diagram depicts the colony forming

units, CFUs, from two dilution plates. CFUs are

then converted into log counts. Serratia

marcescens produces a red pigment color for easy

identification, and it distinguishes itself from

the normal flora of the hands that appear white or

yellowish on agar plates. Here, I want to

emphasize that we are just counting bacteria.

[Slide]

Here the industry coalition suggest a 1.5

log reduction for the first wash, and suggest

eliminating the tenth wash. We require the test

product to show a cumulative effect, that is an

evaluable attribute, that shows a progressive

decrease in the number of organisms recovered

following repeated application of a test product.

[Slide]

For surgical hand scrub the indication use

is to significantly reduce the number of organisms

on the skin prior to surgery. These products are

used to reduce the resident and eliminate the

transient flora of the hands of surgeons and

surgical personnel, thus reducing the incidence of

post-surgical site infection.

The testing process is designed to measure

the immediate and persistent reduction of resident

organisms after a single or repetitive treatment.

Here there is no artificial contamination of the

hands, and the testing of the surgical hand scrub

involves multiple test product use and repeated

measurements of the bacterial reduction. These

antiseptics are considered broad spectrum, fast

acting and persistent. The TFM surrogate endpoints

propose a 1-log on day 1 for the first wash; 2-log

on day 2 at the second wash; and 3-log on day 5 at

the 11th wash.

[Slide]

The subjects are selected through the

inclusion/exclusion criteria for surgical hand

scrub testing. A 14-day or 2-week washout period

is required. Soon after the washout period the

baseline counts are determined, and they are

sampled two times, first on day one and the second

estimate includes one of the three options. On day

3 and 5, 5 and 7, or 3 and 7.

Subjects with a baseline greater than or

equal to 5 logs after the first and second baseline

estimates will qualify for the study testing

period. So, no sooner than 12 hours and no longer

than 4 days after completion of the baseline

determination subjects perform the initial scrub

with the test product. The surgical hand scrub

testing requires a total of 11 scrub washes over a

5-day period. The sampling occurs on day 1, day 2

and day 5.

The reason we test 5 days is that the

procedure mimics typical usage and permits the

determination of both immediate and long-term

bacterial reduction. Each day the antimicrobial

soap is used it produces a greater effect due to

the persistence of minute residues left from the

previous scrub. This effect is called cumulative

effect, and that is the reason why we test for 5

days.

[Slide]

An amount of the test product is dispensed

according to the manufacturer's labeling

instructions. The soap is distributed all over the

hands and two-thirds of the forearms.

[Slide]

The hands are then scrubbed according to

the manufacturer's directions, and if no directions

are provided the TFM requires two five-minute scrub

procedures. A scrub brush is used to scrub the

hands including the nails, the fingers, and

interdigital spaces of the hands.

[Slide]

A lab technician will don sampling gloves

on the subjects. One-third of the hands in a

treatment group is sampled immediately. The gloves

remain on the test subjects' hands for either three

hours or six hours prior to sampling. Enumeration

of bacterial flora three hours after the scrub is

conducted in order to demonstrate continued

effectiveness of the product during the time

required for a surgical setting. The enumeration

of bacterial flora six hours after the scrub is

conducted to demonstrate the suppression of

bacterial counts over a period of time chosen as

representing the maximum duration of most surgical

procedures, that is, on average most surgeries will

not last greater than six hours and, if so,

surgeons usually rescrub.

[Slide]

A specified amount of sampling fluid then

is added to the glove pan, and the gloves are

fastened securely above the wrist and strapped, and

the hands are then massaged for one minute, paying

particular attention underneath the nails.

[Slide]

An aliquot of the sampling fluid is

aseptically withdrawn from the glove and

transferred immediately to dilution tubes

containing neutralizers. A microbial count

determination is performed by surface plating, and

this is done within 30 minutes of sampling. The

plates are incubated for two days at 30 degrees

Celsius.

[Slide]

Here the industry coalition agrees with

the 1-log reduction for the first wash. They

suggest eliminating the second and 11th wash. They

suggest that persistence of antimicrobial activity

should not be a requirement for surgical hand

scrub. We require an assessment of persistent

activity in case there is a tear in the surgeon's

glove, and it is assumed that the persistent effect

will prevent the multiplication of resident flora

on the gloved hand, thus preventing contamination

of the surgical field.

[Slide]

For the patient preoperative skin

preparation or surgical prep labeled for the

indicated use helps reduce bacteria that

potentially can cause skin infection. These

antiseptic products must be fast acting, broad

spectrum and persistent and, statistically reduce

the number of organisms on intact skin. They are

designed for use by healthcare professionals to

prep the patient's skin prior to invasive surgery

or prior to injection. These indications, however,

do not cover more specific indications such as

catheter insertions and open wounds.

The testing process measures the immediate

and persistent reduction of resident bacteria after

a single treatment. The TFM surrogate endpoint

proposed a 1-log reduction for pre-injection; 2-log

for the abdomen or dry site; and 3-log for the

groin or moist site area.

[Slide]

The subjects are selected through the

inclusion/exclusion criteria for patient preop

testing. A 14-day washout period is required, and

no bathing 24 hours prior to the baseline

screening. We want to try to obtain a high

bacterial count for the baseline. The TFM

recommends the baseline screening counts for

pre-injection to be greater than or equal to 3

logs. The TFM recommends that baseline screening

counts for the common surgical sites for both dry

and moist site areas, and the sites are to present

bacterial populations large enough to allow the

demonstration of bacterial reduction for up to 2

logs centimeters squared for the abdomen sites and

up to 3 logs centimeters squared on the groin

sites.

[Slide]

For the abdominal site testing a 5 X 5

treatment site area is marked on the skin using a

permanent marker. The template is divided into

four quadrants for baseline, 10 minutes, 30 minutes

and 6 hours sampling.

[Slide]

The baseline sampling is performed using

the cylinder sampling technique. A sterile

scrubbing cup is held firmly against the skin over

the site to be sampled. The scrub solution

containing neutralizers is placed into the cup and

scrubbed with moderate pressure for one minute

using a sterile rubber-tipped spatula. This

procedure is also used for sampling for the

treatment site.

[Slide]

The application of the prep formulation is

applied to the testing area. For 30-minute and

6-hour sampling sites a sterile gauze is placed

over the prep area to help prevent microbial

contamination. The gauze pad is held in place by

the sterile teeth dressing.

[Slide]

The treatment samples are taken from the

site areas using the cylinder sampling technique.

A similar procedure is also used for testing the

groin site area.

[Slide]

Here the industry coalition agrees with

the 1-log reduction at the pre-injection site, and

they suggested that only a 1-log reduction should

be required for the abdomen site and a 6-hour

persistent is not needed. For the groin site a

2-log reduction should be required and a 6-hour

persistent is not needed.

[Slide]

FDA has received objections to the TFM

proposed effectiveness criteria through comments in

a citizen's petition. Industry contended that the

current performance criteria for healthcare

antiseptics are overly stringent. They claim that

two category ingredients, alcohol and iodine, and

one NDA approved ingredient, CHD, cannot pass the

current testing requirements. They claim that all

antiseptic products only need to be effective after

a single use, and they also do not want to meet the

persistence requirement.

[Slide]

This table summarizes the bacterial log

reduction in industry's proposal for the healthcare

antiseptic compared to FDA current standards for

final formulation for healthcare personal handwash,

surgical hand scrub and patient preoperative skin

preparation I just reviewed. Over the years the

industry coalition has made several proposals for

the revised effectiveness criteria.

For the healthcare personal handwash, it

should be effective following a single use. A

cumulative effect should not be a requirement. For

surgical hand scrub, it should be effective

following a single use and also a cumulative effect

should not be a requirement. And for patient

preop, the pre-injection and abdomen dry site a

1-log reduction is suggested, and for a worst-case

scenario such as the groin site area, it should

need a 2-log reduction.

[Slide]

We are aware the surrogate endpoints lack

the clinical validation of a test method and

performance criteria. They do not measure the

level of residual bacteria on the skin and

virulence of the residual bacterial is not factored

into the log reduction determination. We realize

that we are just measuring the mean log reduction.

The criteria is based largely on earlier

NDA performance and we have approved over 20 NDAs

based on using surrogate endpoints. These criteria

are consistently applied to monograph products and

many NDAs. Industry has deviated from following

the TFM in regards to variability in testing

procedures such as scrub techniques and lab

analysis, and it is not compared to vehicle or

active control. We will later hear from Dr.

Valappil regarding improving statistical analysis

that could be applied to the existing criteria.

[Slide]

Overall, it is impossible to compare the

data across studies due to the vast differences and

methodologies that were used, and other limitations

such as the following: The majority of the studies

were designed as product comparisons; studies were

not designed to assess the product's ability to

meet the TFM effectiveness criteria. There were

significant variations in how the studies were

conducted; different testing procedures were used;

and neutralizer validation data were not generally

provided. More than half the data submitted did

not include neutralizers in the testing procedures,

which can result in artificially high log

reductions. Generally, sample sizes were small in

the studies and there was a limited number of

subjects included in the testing procedure. And,

alcohol alone did not meet the 10th wash 3-log

reduction. However, most were able to meet the

3-log reduction of the first wash. We are

currently evaluating the alcohol leave-ons and

alcohol gel products.

[Slide]

This slide was included to show that other

countries also use surrogate endpoints. The

European performance criteria for handwash require

that the test product mean log reduction factor

should be greater than soap that has an average

reduction log of 2.8. The performance criteria for

hand rub require that the test product mean log

reduction factor should be equal to or greater than

60 percent isopropyl alcohol that has an average

reduction log of 4.6.

[Slide]

In summary, we measure bacterial log

reduction and testing methodology for healthcare

personnel handwash, surgical hand scrub and patient

preop. These log reductions are used as surrogate

endpoints to evaluate effectiveness. How should we

analyze this data?

Later this morning we will hear from Dr.

Valappil a presentation on statistical analysis for

healthcare and aseptic drug products. You will

also hear from Dr. Steve Osborne who will discuss

the relationship of these outcomes and

corresponding reduction in the incidence of

nosocomial infections in healthcare settings where

the product use remains undefined.

[Slide]

We are aware of the limitations of these

test methods, and we assume that the incidence of

infections as related to current use of existing

products and lowering these standards may increase

the infection rates. We need research to validate

these surrogates, and we need to have products on

the market now and in the use of actionable

criteria in the meantime. That concludes my

presentation.

DR. WOOD: Mike, you approached me earlier

about some confusion about the data. Do you want

to comment on that at this stage?

DR. ALFANO: Yes, I have been advised that

industry is not recommending removal of the 6-hour

persistence requirement but, rather, the cumulative

effect requirements. Apparently, that came about

because of some confusion over a table that the

industry submitted.

DR. WOOD: Can you put slide 12 back up?

Is that the one that we are talking about here, on

page 6? Is that where the confusion is?

DR. ALFANO: Actually, it was brought to

my attention versus the questions that we are to

answer today, which is on the last page of the

agenda.

DR. WOOD: I was just trying to clarify

these slides. So, there is no confusion about what

industry's position is on the slides? Is that

right?

DR. ALFANO: That is correct.

DR. WOOD: Well, I think there is

actually. Somebody seems to want to comment.

DR. FISCHLER: George Fischler, manager of

microbiology for the Dowell Corporation,

representing the STA-CTFA coalition. Yes, there is

some confusion. On this slide, yes, where it says

surgical hand scrub, there is an asterisk and

patient preoperative skin preparation, an asterisk.

Industry has not recommended the removal of the

6-hour persistence criteria. The only criteria

that we recommended approval for is the cumulative

effect.

DR. WOOD: Okay. Well, let's come back to

discussing that later. I am even more confused now

but let's go on to the next speaker.

DR. JACKSON: The next speaker is John

Powers. He is the lead medical officer in the

Antimicrobial Drug Development and Resistance

Division, and he will discuss the biological

surrogate endpoints in the clinical trials of

infectious disease.

Microbiological Surrogate Endpoints in Clinical

Trials of Infectious Diseases

DR. POWERS: Thanks, Michelle.

[Slide]

Today I am going to discuss issues related

to microbiological surrogate endpoints in clinical

trials of infectious diseases. Some of the members

of the Anti-Infective Drugs Advisory Committee

won't be surprised by any of this since this is an

issue that has come up in infectious disease trials

over and over again. So, I am going to try to

discuss just some of the general points that have

to do with selecting surrogate endpoints in these

types of trials.

[Slide]

The first thing I am going to talk about

is differentiating what we do in clinical practice

and how one develops clinical practice guidelines

with what one actually does in a clinical trial,

and how those are very different situations. Then

what I would like to do is define our terms and

talk about what is an endpoint; define what a

clinical endpoint and surrogate endpoints are and

differentiate those from biomarkers. One of the

things you will hear often, and probably we will

make the mistake today, is using the term surrogate

markers rather than surrogate endpoints, which is

rather non-specific and causes some confusion.

Then we will talk about the utility of

surrogates in clinical trials and differentiating

surrogate endpoints from surrogates as risk

factors, which is an entirely different

consideration. I will talk about some of the

strengths and limitations of surrogate endpoints

and then, finally, relate all of that information

to the use of surrogates in the setting of topical

antiseptics.

[Slide]

What we do in clinical practice is we are

using drug products that are already proven to be

safe and effective and, hopefully, we are not

experimenting on our patients; we are using the

products in a way where they are already shown to

work.

In clinical practice we impose several

interventions on patients and hope they get better.

We are not really concerned with why they get

better when we do all that stuff to them, only the

fact that they get out of the bed and they leave

the hospital cured. We develop treatment

guidelines to help us describe the use of the

products based on whatever the best available

evidence is, and a lot of current treatment

guidelines actually put grades on the evidence

where you will see A-1 all the way down to D that

talk about whether it is from randomized,

controlled trials versus observational evidence as

well, but optimally these treatment guidelines are

based on randomized, controlled trials. When that

data is not available we oftentimes have to put

things into these guidelines based on the best

available evidence that we have.

The unfortunate thing is that sometimes

these guidelines then become the reason for not

getting the data from randomized, controlled trials

because people will come to us and say the

guidelines say this, therefore, you can't do a

trial to evaluate it. And, that is probably not

what the people who alter these guidelines actually

are intending.

This differs from clinical trials which

are experiments in human beings to determine if

drug products are safe and effective. Clinical

trials differ from clinical practice in that we are

using the scientific method. We are trying to hold

as much as possible constant, except for the

interventions, so that we can apply the outcomes to

causality related to the interventions themselves,

which is very, very different from clinical

practice. So, how we do this is often to use

concurrent controls which is something that we do

not do in clinical practice. In clinical practice

we look at what the patient is at baseline and

compare what happens at the end. That is not what

we do in clinical trials where we are comparing

what happens at the end in patients who receive the

test product versus a control.

These clinical trials are, hopefully, to

provide the evidence for formulation of practice

guidelines and, as I said, hopefully, it is not

vice versa where the guidelines determine that we

can or cannot do a clinical trial. But the big

issue in clinical trials is that we need to

determine some yardstick to determine if products

are safe and effective. How are we going to

measure those products to make that kind of

assessment? That is really what we are asking

today.

And, the reason for this slide is to sort

of outline the real question today. We are not

questioning whether handwashing is important or

whether handwashing should be done in clinical

practice. What we are asking today is how do we

develop a yardstick to determine which products are

safe and effective to use in handwashing.

[Slide]

So, let's define some of the terms that we

are going to use today. An endpoint is a measure

of the effect of an intervention on an outcome,

outcome being defined, for instance, as success or

failure in a clinical trial in the treatment or

prevention of a disease. Again, it is important to

realize that what we are talking about here is a

disease. We are not preventing someone getting an

organism on their skin. What we are really trying

to look at is does that prevention of getting an

organism on the skin, in turn, result in prevention

of disease.

But whenever we are picking an endpoint we

have several questions that we have to address.

The first one is what are we going to measure?

Obviously, this should be clinically relevant to

the disease in question. We are not going to ask

if your left earlobe hurts when we are trying to

evaluate something that has to do with foot pain.

The next question is how to measure it?

And, we should be able to measure differences

between therapies, should they exist, and that gets

to this issue of the yardstick and that we need to

be able to differentiate effective from ineffective

products.

The next issue is when do we actually

measure it? If we apply a product and come back in

two years and then try to determine if there are

differences between the patients we are probably

not going to see a whole lot in a non-lethal

illness.

The next question is how much to measure,

what magnitude of difference actually makes a

difference to patients? A lot of this has to do

with sample size. We could take a product that is

99 percent effective and show that it is

statistically different than a product that is 90

percent effective if we studied thousands and

thousands of patients. So, it gets to the issue of

clinical significance versus statistical

significance.

Then, one of the big issues I am going to

ask you to talk about today is when we get some

results, how do we analyze those results so that we

can logically draw conclusions from them?

[Slide]

This is a cartoon from the New Yorker,

which sort of outlines the issue in choosing

endpoints that are relevant to patients. Here

there is a doctor who has just done an endoscopy on

a miserable patient, and the doctor says

congratulations, the endoscopy was negative;

everything is perfectly all right. So, according

to the surrogate endpoint of what the doctor saw on

the endoscopy, the patient feels great but the

patient is saying my symptoms bother me. I am

worried and concerned. I can't exercise; I can't

eat. My whole life is affected. So, that gets to

the difference between measuring a surrogate and

measuring what the patient actually feels.

[Slide]

This seems sort of redundant but it is

probably important to define what a disease

actually is. In these terms we are talking about a

constellation of signs and symptoms experienced by

the patient. Although infectious diseases are

caused by pathogenic organisms, those result in a

host response and it is actually the host response

that causes a lot of the symptoms that we see.

When we are talking about surrogates we

often hear about Koch's postulates. Well, these

fulfill Koch's postulates so the surrogate must

work in the setting of an endpoint of a clinical

trial. But Koch's postulates relate to proving the

cause of a disease, that a pathogen actually causes

that particular illness, and Koch's postulates were

never designed to measure the effect of an

intervention. It is very important in our

discussion today to separate out cause from effect

which are two different considerations.

One of the issues we always talk about is

that patients seek the care of clinicians because

they have symptoms when they have a disease, not

because of the presence of an organism. So, a

patient may come and say, doctor, I have this

terrible cough I can't get rid of it. They don't

come in and say, doctor, I have mycoplasma in my

respiratory tract. Although that may be the cause

of it, the reason patients come to see us is for

relief of symptoms.

In prevention trials, on the other hand,

we are actually seeking to prevent those symptoms

from ever occurring, but still here we are talking

about the relevant endpoints being those actual

symptoms that patients may encounter.

[Slide]

So, what is the difference between

clinical endpoints and surrogate endpoints? We are

so used to using surrogates that sometimes we call

things clinical endpoints that are, in fact,

surrogates. The definition of a clinical endpoint

is actually fairly simple. It is measures of how

the patient feels, functions or survives, and a

simple way to think of it is anything that measures

something other than that is a surrogate endpoint.

For instance, clinical endpoints would be measures

of mortality or resolution or prevention of

symptoms of a disease.

On the other hand, surrogate endpoints are

laboratory measurements or physical signs used as a

substitute for a clinical endpoint. Fever is a

surrogate endpoint. Fever does not necessarily

measure how the patient feels. Although fever may

make the person feel terrible, what we really want

to measure is the person feeling terrible not what

the level of the temperature is but we are so used

to using this in infectious disease trials. But

other things like culture results, which we are

going to talk a lot about today, chest x-rays,

histology or even data like pharmacokinetic

information are all surrogate endpoints and need to

be correlated with what is actually clinically

happening to the patient.

The important part here, as discussed at

NIH Biomarkers Definition Working Group, published

in 2001, is that surrogate endpoints by themselves

do not confer direct clinical benefit to the

patient and we need to make that link. This is

also reiterated in the International Conference on

Harmonization, ICH E9 document. The International

Conference on Harmonization is a group consisting

of U.S., Japanese, European regulators and members

of the pharmaceutical industry.

[Slide]

So, how do we differentiate biomarkers

from surrogate endpoints? Biomarkers are any set

of analytical tools that are used to assess

biological parameters so it is a big, broad

category. Biomarkers are useful for many other

purposes other than surrogate endpoints in trials.

This is why the term surrogate marker isn't really

very helpful to us because we can use these

biomarkers for any number of things. One may be as

a diagnostic tool. We can use the test as

inclusion criteria to define the disease based on

the presence of organisms. Differentiating

diagnosis from endpoint is a very, very important

process. As members of our Anti-Infective Drugs

Advisory Committee that are here will tell you, we

have had several advisory committees for instance

addressing acute otitis media in children and acute

bacterial sinusitis in children and adults where we

have tried to make the distinction between needing

microbiologic data to diagnose that the person

actually has the disease, but how useful it is as

an endpoint is an entirely different consideration.

We can also use biomarkers to describe the

mechanism of action of the drug and the effect on

the organisms of an antibacterial or antiviral

product is really the mechanism by which it

achieves its effect, not necessarily the goal of

therapy alone. We have certainly been told by a

number of sponsors--the direct quote, all

antibiotics do is affect organisms. Well, that is

true but that is the mechanism by which they do

what they do, not the goal of why we give them to

patients in the first place.

The third thing is that biomarkers can be

a risk factor for acquiring the disease. For

instance, we know that colonization with a

particular organism is a risk factor for getting an

infection. That doesn't mean that risk factors end

up being the same thing as an endpoint. Also, some

of these things can be risk factors for outcome.

They can indicate disease prognosis and how poorly

or well the patient is going to do. For instance,

HIV viral load and CD4 counts in HIV--we can look

at those to actually predict how a patient is going

to do down the line. Then, finally, biomarkers can

be used as surrogate endpoints, which are different

from the previous four things we talked about.

[Slide]

The word surrogate comes from the Latin

root surrogatus, which means to choose in place of

another, or to substitute or put in place of

another. So, what we are doing with a surrogate

endpoint is actually substituting microbiologic

outcomes in patients for clinical outcomes. One of

the problems in looking at this is that

investigators have looked at people only who have

failed and then tried to relate clinical and

microbiological outcomes in only the failures. But

we need to look at these correlations both in

people who succeed and people who fail, which is

pivotal in these clinical trials to prove drug

efficacy.

[Slide]

Surrogate endpoints are very useful. They

can be used in early drug development as proof of

principle that the drug has some biological

activity, and they can be used in selecting

candidates to go on and study in future phase 3

trials. They are also useful in phase 3 trials

when the surrogate endpoint can be measured sooner

in time than the clinical endpoint. The obvious

example of this is HIV trials, which I will go into

in a little more detail.

When the clinical endpoint events are more

rare it allows us to complete a trial with a

smaller sample size. In other words, if the effect

on the surrogate endpoint is quite large and the

effect on the clinical endpoint is small, we can do

a trial with a smaller amount of patients in a

shorter amount of time. Of course, this is all

predicated on knowing that the surrogate actually

predicts clinical outcomes.

Some examples of where the agency has

allowed surrogates and they have been used

successfully are things like lowering cholesterol

which, in turn, has been shown to prevent

cardiovascular disease; lowering blood pressure to

prevent cardiovascular disease; and perhaps the

best example is suppression of HIV viral load as a

surrogate endpoint in the prevention of either

AIDS-defining events or death in the treatment of

HIV and AIDS.

[Slide]

In this example what we see is a

three-dimensional graph. On the right-hand side

there are CD4 counts which actually are predictors

of the host's immune response. On the other axis

is the viral load, or HIV RNA concentration. On

the upward axis there is the three-year probability

of patients progressing to AIDS. You can see from

this that as the person's CD4 count declines and as

the HIV viral load goes up, the risk of developing

AIDS-defining events and death also goes up. So,

both HIV viral load and CD4 counts are predictors

of what is going to happen to the patient

independently.

The interesting thing about this is that

this is measuring the organism but CD4 count is

also measuring the host's immune response. HIV is

very unique in that the virus itself blunts the

host's immune response so one of the things that

complicates the measurement of surrogates is that

measuring the surrogate itself often doesn't

measure what is happening to the person. So, viral

load is very unique in that the virus itself knocks

out the immune response and takes that piece out of

the equation.

[Slide]

So, HIV viral load and CD4 counts are also

a good example of the difference between risk

factors and endpoints. Both HIV viral load and CD4

counts are risk factors for disease progression to

HIV and AIDS, as I showed you on the previous

slide, however, only HIV viral load functions well

as a surrogate endpoint, much better than CD4 count

does in clinical trials.

Seven of eight trials with a positive

effect on CD4 count also showed a positive effect

on progression to AIDS or death. But the effect in

6/8 trials that had a positive effect on CD4 count

also showed a negative effect on AIDS progression

or death. This again gets back to the issue that

you cannot cherry-pick which studies you like. You

need to look at both success and failure of the

surrogate to be able to get an overall assessment

of what is going on here. If we only looked at

these studies we would think that CD4 count was

great as a surrogate endpoint.

This also gets to the issue that how you

use the surrogate is very important. It may be

that CD4 count would function as a decent surrogate

endpoint if we followed patients for longer periods

of time than we follow the viral load because it

just may be that the CD4 count may not change fast

enough over the time that we measure it in a

clinical trial to be very useful. But if we

measured it for longer, that may be a different

story.

[Slide]

What are some of the strengths and

limitations then of evaluating surrogates? Part of

this is the logic string we go through as related

here to topical antiseptic products. We know

colonization with organisms precedes infection and,

therefore, the surrogate may be useful as a risk

factor for disease. We know that these organisms

can cause infection and result in a host response.

So, the logic is that since the organisms cause

infection, eliminating or decreasing the organisms

should result in positive clinical outcomes for

patients. This seems very logical. It seems very

objective and reproducible. But the question is,

is it correct?

This article by DiGruttola, and Dr.

Fleming is a co-author on this, talks about are we

being misled in terms of looking at these

surrogates? What we just did up here was an

example of the old Arthur Conan Doyle Sherlock

Holmes deductive reasoning. We worked backwards

from the end and said, well, it must be caused by

this. However, what we do in clinical trials is

inductive reasoning. We start off with a

hypothesis and we test the hypothesis. So, we need

to test this logic to see if it is actually true.

One of the seminal articles on surrogates was

written by Prentice where he actually says that in

a given clinical trial we need to test does the

intervention have an effect on the clinical outcome

and, in the same trial, does that intervention also

have an effect on the surrogate so that we can link

the two together?

[Slide]

Well, why may it be that an intervention

having an effect on a surrogate which, in turn, has

an effect on the clinical does not predict what

actually happens to the patient? And there are

five potential reasons why this may happen.

The first is that there may be unmeasured

harms caused by the intervention which actually are

not picked up by just measuring the surrogate.

The second is that there may be unmeasured

benefits, that the intervention actually does

something good that is not measured by the

surrogate and actually has a better clinical

outcome than predicted by the surrogate.

The next issue is that there may be other

pathways of disease that result in a clinical

endpoint that have nothing to do with the

intervention that you applied.

Finally, there are issues with how we

measure the surrogate and how we measure the

clinical endpoint. Let's go through each one of

those one at a time.

[Slide]

As I said, surrogates may not take into

account unmeasured harm and benefits. This gets to

the issue of we cannot just look at whether a

surrogate correlates with a clinical endpoint

because, even if there are these unmeasured harms

and unmeasured benefits, there will still be an

association between the surrogate endpoint and the

clinical endpoint. It will be, however, that that

association is not predicting the net clinical

outcome in patients because it is not taking into

account these other unmeasured benefits and harms.

It is not too hard to understand why this

occurs because the body actually has a finite

number of processes to accomplish the things it

wants to accomplish. So, giving a drug product is

still giving a foreign antigen to the body which

may affect processes other than the ones that we

actually intended to affect in the first place. We

know that, for instance, in antimicrobial products

what we are really trying to affect is the organism

which, in turn, has a positive effect on the host.

The reason why we get adverse events is that all of

these products have some effect on the host that is

unintended in terms of adverse events.

[Slide]

What are some examples of unmeasured

benefits? Well, there may be effects of the drug

other than eradication of the organism. Actually,

this is a misnomer. We constantly use this term

"eradication" but what we really mean is that we

have suppressed the organism to below a level of

detection. If we think that we are actually

sterilizing somebody's body, we really are fooling

ourselves. There may be sub-inhibitory effects of

antimicrobials on the organisms. Even though those

organisms are present, they can't do what they

normally do in terms of invading. It may be that

we don't need to kill the organisms to actually

have some effect on the ultimate outcome and,

again, that may be because we are having other

effects, other than killing, that do something to

the organism. Then, again, there may be direct

effects of the antimicrobials on the host immune

system. These articles that I have shown up here

are actually things that talk about the effect of

antimicrobial products on white cell phagocytosis

and other processes on the human immune system.

There also may be unmeasured harms in

terms of deleterious effects on the host that may

promote infection. For instance in topical

products, if a product actually would cause

micro-breaks in the skin that would not be visible

to either the infection or the patient that may

allow more invasion of organisms to cause wound

infections. We also may have replacement of one

organism with another. We get rid of the one

organism we are worried about and, nature abhors a

vacuum, and something else comes in its place that

is actually worse than what we got rid of. There

may be other sources of infection, other than those

affected by the drug.

[Slide]

Are there some examples of where we have

seen this happen in the past? The answer is yes.

This is why we have such pause when evaluating

surrogates. For instance, last year the FDA

approved rifaximin as a treatment for travelers

diarrhea. If one evaluates the rate of negative

cultures from the stool in rifaximin compared to

placebo, there was no statistical difference

between the number of organisms at the end of

treatment in the stool in patients who received the

drug versus those who did not.

Regardless of that, there was still

decreased time to resolution of diarrhea with

rifaximin compared to placebo. You could say,

well, that means rifaximin isn't acting as an

antibacterial agent; it is doing something else, it

is decreasing GI motility. Well, if that is the

case, then why did rifaximin have an effect on some

organisms like E. coli, but not on diarrhea caused

by other organisms like Campylobacter? If it was

just acting as a motility agent it should have

equal effects on everything. So, perhaps this drug

is doing something to the organisms other than

killing them.

Other examples of unmeasured harms--well,

a classical example of this is the dose escalation

trial of clarithromycin that was studied at 500,000

and 2,000 mg for disease due to Mycobacterium

avium-intracellulare in patients with AIDS. When

we looked at that dose response, the higher doses

had higher rates of negative blood cultures for

MAI. However, those higher doses also had higher

mortality in terms of the clinical outcomes. So, a

better microbiologic outcome actually resulted in a

worse clinical outcome in this trial.

[Slide]

Are there also other pathways of disease

that may be unaffected by the intervention? Do we

have an example of that?

[Slide]

Well, several trials showed decreased

rates of colonization in the nose with Staph.

aureus with intranasal mupirocin. However, three

trials now done in the last several years show that

prevention of infections with mupirocin, the

clinical outcome, was not lower in patients than

placebo even though there was a dramatic effect in

terms of negative cultures done from the nose with

this particular product. One hypothesis for why

this may not be effective is that Staph. aureus is

on numerous sites on the body other than just your

nose and we may not be affecting that just by

putting a product on one site in the body.

[Slide]

The next issue is with accuracy of how the

surrogate is measured. One of the things that we

constantly hear about surrogates is that they are

reproducible. Well, reproducibility talks about

precision, but the example you can think about here

is how to differentiate precision from accuracy.

If I take a bow and arrow and I shoot it at a

target I can hit the same spot on the target all

the time, but it may be way far away from where the

bulls eye actually is. So, even though we are

getting reproducibility, are we getting accuracy?

Are we getting the correct inference? This has to

do with what, when, how and the magnitude of what

is measured for that particular surrogate.

[Slide]

The culture techniques that we use for

bacteria are based on methodology actually from the

late 1800's. We know that there is inherent error.

For instance, if we take the exact same colony of

organisms and measure it two separate times we can

get minimum inhibitory concentrations for a

particular drug that are actually off by one or two

tube dilutions jut by testing it a second time.

So, we know that there is some inherent error here.

There are a lot of issues with

microbiological outcomes. For instance, what is

the patient population that we sample? What is the

sampling technique that was used? What was the

methodology used to get the culture? Actually, I

see Al Sheldon sitting in the back. When he used

to work for us he gave a great talk last year on

diabetic foot infections where we talked about how

superficial cultures from the foot may not tell us

anything related to deeper cultures from the foot

in diabetic infections, and that methodology is

very important.

When is the culture performed? On therapy

cultures may be very misleading because when we

take a sample we are actually taking the antibiotic

with it and putting it onto the culture plate as

well, which may give false-negative cultures.

How often do we sample, and what is a win?

What is the criteria for classifying that this

organism is there or not? Do we have an all or

nothing approach that says bug present/bug not

present? Or, do we so something like HIV viral

load where we have a quantitative assessment of how

much organism is present?

[Slide]

The quantitative assessment may be very

important, as I show on this graph. On the bottom

axis we have time where we can make a baseline

measurement and on therapy measurement and what

happens when a drug is gone after the study is

over, compared to microbial load. If one patient

starts out at a higher level than the other

patient, they both may decrease simultaneously at

exactly the same rate, but if we make an on therapy

assessment this patient may still have a positive

culture and this one does not just because we have

gone below some level of detection of how many

organisms we can actually detect. Does that mean

that these two patients are really different? We

don't know. It may just be a factor of how many

organisms we were actually able to detect. If we

only looked at an on therapy assessment, that may

not tell us what happens after the drug is removed

from the body. In one patient the bugs may come

roaring back because all we did was suppress them.

In the other patient it may continue to decline and

we get rid of the organism altogether.

[Slide]

One of the issues that I am sure we will

talk about today is this issue of practicality, and

practicality is in the eye of the beholder when it

comes to clinical trials. People have said because

it is difficult to measure the clinical endpoint we

should just rely on surrogates, which is very

difficult logic in terms of perhaps needing to do a

better job of actually measuring clinical

endpoints. An inaccurate measurement of clinical

endpoints does not justify the use of unvalidated

surrogates.

[Slide]

For example, there is a recent article,

and there has been an ongoing debate in the

Clinical Infectious Disease journal about the

utility of catheter tip decolonization which, in

this study, are claimed to be validated as a

surrogate endpoint for clinical trials in

prevention of catheter-related bloodstream

infections based on the correlation of the two

endpoints. What they did, however, in these trials

is they defined a bloodstream infection in some of

these trials as a positive blood culture and a

positive culture of a catheter tip. So, this

correlation is highly dependent upon the definition

of the clinical endpoint.

Dr. David Patterson, from the University

of Pittsburgh, wrote in about one of these studies

and said, residual antimicrobial activity in the

removed catheter sufficient to prevent growth from

the cultured catheter segments would substantially

reduce the apparent rate of catheter-related

bloodstream infections--and I put the emphasis on

there--could it be that use of these coated

catheters impregnated with antibiotics prevents

growth from catheters in the microbiology

laboratory but does not eliminate the clinical

syndrome of catheter-related bloodstream infection?

So, a more rational use of an endpoint

here would be all people that have positive blood

cultures and symptoms of a clinical infection, not

just those who have to have a positive catheter tip

because that is circular reasoning.

One of the issues we always get into at

the FDA is what gets published is all the

successes, and people will look at those and say,

look, there is this great correlation. What is

missing, and there has also been a lot in The New

York Times recently, is about negative trials.

What is missing is the data the FDA sits on showing

where those surrogates did not work. We have had

several examples now, both in catheter tip

decolonization and in products that are actually

put on topically around the catheter site, where

they had a dramatic effect on decolonizing the

catheter and no effect at all relative to placebo

in preventing bloodstream infections. I cannot

enlighten you anymore than that because this is

proprietary information and we can't share it, but

the interesting thing sitting at the FDA is you

always wish that you could talk about the negative

examples but, unfortunately, we can't share those.

[Slide]

One of the other issues with correlating a

surrogate is how well does it actually predict

outcomes? A perfect correlation would be a slope

of 1 in terms of evaluating the surrogate related

to clinical success so an 80 percent success rate

with a surrogate would result in an 80 percent

success rate in the clinical outcomes. But we

don't expect that to happen, especially in

prevention trials where we know that a good number

of people on these trials will achieve no benefit

from the product. So, what we want to look at is

what is the actual correlation between the

surrogate and the clinical outcome.

[Slide]

The other thing that is very important is

that the correlation may differ from drug class to

drug class or from drug product to drug product,

and this may actually be highly misleading in terms

of what we actually measure. For instance, let's

take drug A and drug B that have two different

correlations in terms of the clinical and the

surrogate. If we did then a measure of drug A and

drug B in terms of the surrogate, it appears here

that drug B is better than drug A in terms of the

outcome with the surrogate. But if these two

slopes of the correlation are different what

actually is misleading is that in reality drug A is

actually better than drug B in terms of clinical

success so the surrogate actually flip-flops these

and misleads us in terms of telling us why would

these slopes be different.

That gets back to the five things we

actually talked about. Unmeasured harms,

unmeasured benefits and those other things may be

why these products have different correlations. We

actually did this with otitis media and showed that

the spread of lines here actually goes from 0.4 all

the way down to 0.1 for various different drug

products. So, saying that this won't occur--we

have actually seen places where this correlation is

actually all over the map for various drug

products.

[Slide]

Finally, there are regulatory issues with

surrogate endpoints. Traditional approval is based

on surrogate endpoints only in cases where the

endpoint is already validated to predict clinical

benefit. However, there is an accelerated approval

clause in the Code of Federal Regulations based on

surrogate endpoints for serious and

life-threatening diseases, otherwise known as

Subpart H. This is where a surrogate endpoint is

reasonably likely to predict clinical outcome.

However, this part of the Code of Federal

Regulations requires confirmatory post-approval

trials based on the clinical endpoint to prove that

what we saw with the surrogate is actually true.

The important thing to note today is that

this clause actually came out in the mid-1990's and

what we are talking about today is a monograph that

started out in the early 1970's. So, if you ask

the question, well, why doesn't the monograph jive

with what we are saying up here, it is because we

are talking about something that happened 20-30

years before this regulation.

[Slide]

Let's relate all of the stuff we just

talked about with surrogates to the issues related

to topical antiseptics. Are there some potentials

for unmeasured harms with topical antiseptics?

Well, we may have unintended effects on microscopic

breakage in the skin which may actually result in a

greater clinical infection rate. We know this can

happen, for instance, in trials that examine

peri-operative shaving. This trial by Seropian,

done in the American Journal of Surgery in 1971,

actually showed a 5.6 percent rate of postop

infection with shaving compared to a 0.6 percent

rate without shaving. So, we know that there can

be unintended effects.

If you go back and look at the hypothesis

of that trial, it was exactly what we are trying to

say today, clipping hair off may decrease the

amount of bacteria near the wound and, therefore,

should result in a decrease in infections. It

didn't; it did the exact opposite because of

unintended harms that they didn't think about until

after the trial was done. It is always fascinating

to see how someone's hypothesis changes after the

actual results come out.

Also, the effects on common pathogens may

be less than that on the marker organisms on the

skin. Michelle Jackson showed you that what we are

measuring here is resident microbial flora in two

of the three indications and we are contaminating

people with Serratia marcescens in another.

Serratia marcescens is not a common cause of skin

infection so the question is does predicting an

effect on Serratia tell us anything about staph.,

strep., E. coli, enterococci and the other common

causes of infection?

Also, there is this issue of are we

selecting resistance to systemic antimicrobials by

using these topical antibiotic products? This

really is something that deserves its own whole

discussion, but there is some evidence at least in

the test tube that there may be afflux pumps which

confer resistance to both topical products and to

the systemic antimicrobials simultaneously, at

least in E. coli and Pseudomonas. People have

questioned what is the clinical relevance of that

but that really is the question, isn't it? Once

again, it is how does that surrogate predict what

is going to happen clinically? I always think it

is fascinating when you don't want to use a

surrogate, all of a sudden it is not relevant.

When you do want to use a surrogate, we will accept

everything we want to believe about it.

So, can there be unintended benefits?

Well, it may be that some of these products have

positive effects other than those on the organisms.

It does something to the host immune system that

actually results in a decreased infection rate,

more than we would predict by what it does to the

bug. Also, could the effects on common pathogens,

like staph. or strep. be greater than on something

like Serratia? So, it may be a better benefit than

what we think.

[Slide]

Are there other mechanisms not affected by

the intervention? Well, at least in terms of

patient preop, for that indication we can look at a

study that was done by Brown et al. in 1989 at the

University of Virginia. The data that we are

obtaining from this surrogate is really from the

most superficial layers of the stratum corneum of

the epidermis.

[Slide]

Here is an anatomical picture of the skin.

What you see here is that the top 30 layers of the

skin are this dead, keratinized layer called the

stratum corneum of the epidermis. What is down

here is the stratum germinativum where these cells

come from. The cells die off. They become highly

keratinized at the stratum granulosum layer which

forms a barrier between this and the stratum

corneum. What we are measuring in these trials is

what is way up here.

[Slide]

So, what is way up there is right here on

this graph. This is actually from the CDC

guidelines on prevention of surgical infections.

What we are worried about is infections here, here,

here and here. So, the real question is does doing

something up here do something down here in terms

of affecting the organisms?

[Slide]

This group in Virginia actually did a very

elegant experiment with a methodology that was

developed by Pincus in 1952. What they did was

they took regular old cellophane tape and they

showed that by putting cellophane tape and

stripping it off the skin you can take one layer of

that stratum corneum off at a time. They evaluated

this in 12 different sites on the body, and they

showed that these 12 different sites in the body

had highly variable colony counts of organisms

depending upon whether you are looking at the arm,

the back or other sites.

They also showed that the number of

colonies decreased over the top five layers of the

stratum corneum but then stabilized in the

remaining 20 layers of the stratum corneum. So,

there were more organisms up at the top than there

were in the lower layers of the stratum corneum.

But then they did something very

interesting. They took alcohol and decolonized the

area that they had stripped, put a gauze pad over

it and came back 18 hours later. They then did

plasmid profiles on the coagulase-negative

staphylococci that were there at the beginning of

the experiment and there 18 hours later and saw

identical plasmid profiles for those staphylococci.

So, they hypothesized that this indicates

a reservoir for these organisms that may be below

the stratum corneum, in the hair follicles and

sebaceous glands of the dermis so where infection

may come from is actually from the organisms that

are lower down. This is one of the reasons why we

give systemic antimicrobials as perioperative

prophylaxis, trying to affect those organisms that

may be down deeper in the dermis.

We also know that studies in perioperative

systemic antimicrobials show that if the antibiotic

isn't around at this layer at the time you get

operated on they will not be effective. For

instance, you cannot give the antibiotic two

seconds before you make the surgical cut because

they will not affect the subsequent infection rate.

[Slide]

Then there are all the issues with

measurement of the surrogate, which we are going to

talk about today. Are we actually measuring the

surrogate in a population that we are going to use

it in? No, we are not. We are measuring healthy

volunteers, not healthcare workers or patients.

As we already discussed, the organisms

measured are not necessarily those that cause

infection. Is the timing of these measurements

relative to the disease process we are actually

trying to prevent? That gets at this issue of do

we need to get persistent effect or not; how long

do we have to look for that; and how long should we

look for it? For instance, we know that some

patients may undergo prolonged surgery. Surgeries

may last hours and hours so an immediate effect is

not the only thing we want to look at.

Are the conditions of testing the same as

those that would be encountered in real-life

situations? And, what happens with variations in

the methodology? One of the things that is

interesting at the FDA is that you will see people

submit things that say I am using the such-and-such

method approved by the CDC or the NIH. But it is a

modified method. I always joke I am a modified

millionaire movie star; I am just not a movie star

and I don't have a million dollars. So, modifying

the method--it is no longer the method. So, we

need to take into account that changing the method,

even if we have a valid surrogate, may actually

change the correlations between the surrogate and

the clinical outcomes.

The next question is what log reduction is

clinically significant? And, how do we analyze

those numbers obtained on log reductions? Dr.

Thamban Valappil is going to go through a great

talk that actually walks through some of these

issues with how do we analyze the numbers.

[Slide]

What is the data showing correlation of

reduction of bacteria with a decrease in infection

rates? Steve Osborne is going to go through our,

believe me, exhaustive, over 1,000-paper literature

search. You should have helped us out with this;

that was a thrill!

What does the dose-response curve look

like for infection rates and numbers of bacteria?

Is it a threshold effect, or is it a continuous

variable, and is it the same for all types of

products?

[Slide]

What do I mean by dose response? Down on

the bottom it should read numbers of bacteria on

the skin, not change in numbers of bacteria. On

the Y axis we have rates of infection. What we

want to know is does the dose-response curve look

like this? Sorry, this doesn't show up very well

but it is a straight line. Or, does the

dose-response curve look like this? The first

straight line is a continuous variable. The more

organisms there are, the more infections patients

get. The curved line is really a threshold effect

that we talk about. At some certain level of

bacteria people are more likely to get infected and

below that level they are less likely to get

infected.

Why is this important for us? Well, if we

look at a linear correlation between numbers of

bacteria and rates of infection, what we will see

is that the decrease of the numbers of bacteria by

this much will actually result in a corresponding

decrease in the number of infections by some

amount.

[Slide]

On the other hand, if it is a sigmoidal

threshold type effect, what we will see is that

that same, exact change in the number of bacteria

if it is on the flat part of the curve results in

very little change in infection. So, this gets to

what does a 3-log reduction actually mean? If this

is 10 7 and this is 104 that is a

3-log reduction but

we are on the flat part of the curve so there is

very little effect on what happens to the patient.

If we go from 10

4 to 101 that is a 3-log reduction

too but if we are on the steep part of the curve

that may be telling us something very, very

different. So, where you start may be as important

as what the delta change is, and we don't have any

information to tell us what this dose response

actually looks like.

[Slide]

What I would like to leave you with then

is sort of the thought process we have had to go

through for the last several months in terms of

trying to look at this. The first question you

have to ask is what kind of endpoint are you going

to pick to evaluate these products? Are we going

to pick a clinical endpoint or a surrogate

endpoint? Ideally, there would be the data right

here that links the clinical and the surrogate

endpoint together, and Steve Osborne is going to

talk about our attempts to actually make that kind

of a link.

The second question is what are we

actually going to measure? Let me get back to this

issue of practicality. As I said earlier,

100

practicality ends up being in the eye of the

beholder. One of the things you will hear about is

that it takes more patients to do these clinical

trials than it does to the surrogate endpoint

trials.

Well, size is actually an issue but size

really relates more to the time that it takes to do

a trial which, let's be honest, relates to cost to

do the trial. One of the questions you have to ask

when you are getting into this debate is how much

does it cost to do it wrong? How much does it cost

the patients if we don't get this information and

we don't actually know whether these products are

effective? That side of the equation needs to be

factored in as well.

The other issue that comes up is ethics.

Ethics are only if you are denying somebody a

proven effective treatment. What we are trying to

evaluate here is are these things proven effective

101

or not, so we need to keep that in mind when we are

discussing the ethics issue. When we talk about

clinical trials the endpoint is very simple, it is

infection in patients. On the other hand, with the

surrogate we are looking at numbers of bacteria.

Then we need to talk about how do we

design these studies and how do we define success.

Well, the definition of success, again, with the

clinical endpoint is much simpler actually. It is

just the percent of patients that don't get an

infection. However, when we talk about selecting

an endpoint for a surrogate we have several

decisions to make that Thamban is going to go

through. Do we look at mean log reductions, median

log reductions, the percent of subjects who meet

some log reduction? And, where do you get this

information from? Well, actually optimally it

would be from a clinical trial that evaluated both

of these things simultaneously.

Finally, how do we analyze the results

that we get? Again, it is much simpler in a

clinical trial. We just compare it with a

102

concurrent control. This is one of the issues when

people point to the studies, and Steve is going to

go through this in some detail, they say we already

know these things work. There is no concurrent

control. What these things are is quasi

experimental studies where they took what we were

doing last year and they applied something new in

the hospital and said, look, my infection rate went

down.

What that ignores is natural changes in

baseline infection rates that may occur. Even

though the trials say, well, we didn't do any other

interventions on these patients, you know in the

real world and, hopefully our AIDAC members can

enlighten us on this, when you have an outbreak of

some particular organism you do not do one

intervention. You cohort patients together; you

start using gowns and gloves on those people; you

do a lot of other interventions that really call

into question what was the cause of why the

infection rate went down. Was it just related to

the product that you used?

So, here we would make this comparison and

either design these as superiority or

non-inferiority trials, otherwise called

103

equivalence trials, that show that the product is

no worse than something that is already out there.

On the other hand, there are a lot more

complex decisions with a surrogate endpoint. Do we

say that these things meet some threshold that we

set? If so, where does that threshold come from?

Where does the data come from to say? And, do we

still need some comparison with a control given the

variability in the method? Michelle Jackson showed

you on one of her slides that at least that article

in The Journal of Hospital Infection, based on the

European methodology which is slightly different

from that that is in the TFM, shows at least a 2 to

2.5 log drop with soap and water all by itself.

So, do we need to look at how these things compare

to some vehicle or another product? And, again, we

have the choice of superiority or non-inferiority.

[Slide]

To conclude then, surrogate endpoints must

104

not only correlate with clinical outcomes but they

must also take into account unmeasured harms and

benefits; the methodology and uncertainties in

measuring the surrogate; and the appropriate

measurement of the clinical endpoint.

The clinical endpoint for efficacy of

topical antiseptic products would be prevention of

infections but actually the clinical design of

these trials would vary depending upon whether we

are talking about patient preop surgical hand

scrubs or healthcare personnel handwash.

One of the things that I am sure we will

hear about is what Semmelweis did in 1847 was he

showed that medical students who went and examined

corpses with their bare hands and then went and

delivered babies--there was actually a higher rate

of death in the mothers who had their babies

delivered by these medical students than the

midwives who were spared the odious task of doing

the autopsies.

That is not what we are doing today. We

are not digging our hands into gram-negatives of

105

dead people and then going and operating on

someone. So, the conditions of Semmelweis were

huge bacterial load, probably with gram-negative

organisms. So, what Semmelweis showed was that

washing your hands is a good thing. Semmelweis did

not do a randomized trial of one product compared

to handwashing alone or handwashing compared to

nothing. We are not debating that Semmelweis was

correct and that you need handwashing. What we are

debating is handwashing with what, and how do we

determine that that "what" is effective compared to

just maybe plain soap and water? So, we are going

to discuss further today what is known about

surrogates in the setting of topical antiseptics,

and Steve Osborne is going to go over this clinical

correlation and tell us some more about it.

[Slide]

I would like to leave you with this quote

by the statistician John Tukey which I think really

relates to surrogates: Far better an approximate

answer to the right question, which is often vague,

than an exact answer to the wrong question, which

106

can always be made precise. I will stop there.

Thank you very much.

DR. WOOD: Thanks very much. It appears

that we still don't have the slides from Michelle

Pearson. Is John Boyce here? Yes? Good, so at

least our next speaker is here. I suggest that we

take a quick break right now and be back at ten

o'clock and we will start again. We are hoping to

get Michelle Pearson in before we do the questions.

We will get back at ten o'clock.

[Brief recess]

DR. WOOD: Let's go to Dr. Boyce and then

we will come back to Dr. Pearson, whose talk we do

now have somewhere in the building, as they say,

but we have been unable to play it yet. So, Dr.

Boyce?

Antiseptic and Infection Control Practice

DR. BOYCE: Good morning. I am having

some Power Point problems today because of a switch

in versions so I hope this is going to work.

[Slide]

First I want to talk a little bit about

107

the importance of hand hygiene in preventing

transmission of healthcare-associated infections.

Most of you know that transmission of

healthcare-associated pathogens often occurs via

transiently contaminated hands of healthcare

workers. For that reason, handwashing has been

considered one of the most important infection

control measures for preventing

healthcare-associated infections. Despite this,

the availability of published handwashing

guidelines has not helped, and compliance with

healthcare workers with recommended handwashing

practices has remained low for decades.

[Slide]

This slide shows the percent compliance on

the Y axis in 37 published observational studies of

healthcare worker handwashing compliance. The main

point here is that compliance rates varied from

about 5 percent to 80 percent. The second point is

that there is no trend towards improvement over

this more than 20-year period. So, getting people

to wash their hands as frequently as possible has

108

been a very difficult chore.

[Slide]

In 2002 the CDC published the guideline

for hand hygiene in healthcare settings. I am

going to briefly mention a few indications for hand

hygiene that are listed. One is that it is

recommended that we wash our hands with a

non-antimicrobial soap or an antimicrobial soap if

our hands are visibly contaminated with blood, body

fluids or other proteinaceous materials. If the

hands are not visibly soiled, then the guideline

recommended the routine use of an alcohol-based

hand rub for decontaminating hands in most other

clinical situations. Alternatively, hands can be

washed with an antimicrobial soap and water in

other clinical situations.

The guideline recommends that healthcare

workers decontaminate their hands before having

direct contact with patients, donning sterile

gloves to insert a central intravascular catheter,

before inserting indwelling urinary catheters or

peripheral IV catheters, and before eating.

[Slide]

It is recommended that we decontaminate

our hands after having direct contact with a

109

patient's intact skin, like taking a blood

pressure; contact with body fluids or wound

dressings if our hands are not visibly soiled;

after moving from a contaminated body site to a

clean body site during an episode of patient care;

after contact with inanimate objects in the

immediate vicinity of the patient; and after

removing gloves. So, there are a lot of

indications for cleaning your hands.

[Slide]

In fact, the number of hand hygiene

opportunities that healthcare workers have can vary

considerably. In a large study, done by Dr.

Pittet, they found that the average number of hand

hygiene opportunities per hour of care was 24 in

pediatric units, and the average was 43 per hour in

intensive care units. In fact, the lack of

sufficient time to actually perform this large

number of handwashing episodes is a major factor

110

influencing poor handwashing compliance.

[Slide]

This slide shows the results of a number

of observational studies where healthcare workers

were observed to see how many times they actually

cleaned their hands. You can see on your right

that the average number of times per 8-hour shift

was anywhere from 13 times to 26 times in an 8-hour

shift. So, we are talking about frequent use of

these products.

That sounds pretty frequent but let me

present it another way, in a recent prospective

trial that we conducted that involved 57 volunteer

nurses working in intensive care units, a

hematology-oncology ward and general medical ward,

each nurse carried a portable counting device and

prospectively clicked the counter every time they

cleaned their hands. On the right you see a graph

that, along the X axis, shows the number of hand

hygiene episodes that these nurses recorded during

a 3- to 3.5-week trial period. You can see that

most nurses cleaned their hands anywhere from 100

111

to 450 times in a 3- to 3.5-week period.

[Slide]

So, one thing that is very clear is that,

because of the high frequency of use of these

products, providing healthcare workers with

products that are well tolerated is very important.

Poorly tolerated products result in poor compliance

often because of irritant contact dermatitis, as

shown in the picture, where this physician has

bleeding knuckles after using soap and water

handwashing 57 times over a period of a couple of

weeks. Products that have a high degree of

antimicrobial activity, that is, a high log

reduction, but are poorly tolerated may actually be

counterproductive.

[Slide]

Now, another important issue for which we

have very little information is what level of log

reduction of bacterial counts on the hands is

actually necessary to prevent transmission of

pathogens. As you know, the efficacy of these

agents is often expressed as a number of log

112

reductions of bacterial counts on the hands of

volunteers, 1, 2 or 3 log reductions for example.

Although the review of the literature that

I did apparently is not as big as what FDA has

actually done, I reviewed over about 700 articles

and couldn't find any evidence regarding the number

of log reductions that are necessary to prevent

transmission of healthcare-associated pathogens.

So, we just don't know how many log reductions we

need.

[Slide]

Another thing for which I think there is

little, if any, data relates to whether or not we

need products that have a cumulative effect. As

you know, the tentative final monograph requires

that healthcare personnel handwash agents produce a

2-log reduction after the first wash and a 3-log

reduction after the 10th wash, therefore showing a

cumulative effect.

In the review of the literature that I did

I failed to identify any data supporting the need

for a cumulative effect. As a clinician with 25

113

years of experience working in hospitals, I am not

aware of any evidence that patients who are cared

for in the middle or at the end of a work shift are

at higher risk of infection than those that are

cared for at the beginning of a shift. I am also

not aware of any evidence that patient care

activities that are performed in the middle or near

the end of a work shift result in greater hand

contamination than those that are performed at the

beginning of a shift. So, frankly, from the

standpoint of a clinician or of infection control,

I fail to see the logic in requiring a cumulative

activity of this type of product given the way they

are used and the types of patients that we take

care of.

[Slide]

Another thing that actually has changed

since the TFM was originally developed is the

frequency of glove use. Since the late 1980's

nurses, physicians and other healthcare workers use

gloves far more frequently than they ever did in

the past. A recent observational survey done of

114

nurses working on a general medical ward found that

these nurses visited patients an average of about

54 times during an 8-hour shift, and they found

that the use of gloves varied depending on the type

of patient care activity. When the nurses were

going to have contact with body fluids they wore

gloves 86 percent of the time. If they were going

to have skin contact only, then it was more like a

little over 30 percent of the time that they wore

gloves; even less frequently for equipment contact.

So, in fact, glove use does vary among healthcare

workers but it is certainly far more common than in

the past.

[Slide]

A number of studies, shown here, have

documented that gloves can and do reduce the level

of hand contamination when they are worn.

McFarland looked at hand contamination with C.

difficile and found that 46 percent of healthcare

workers who did not wear gloves contaminated their

hands with C. dif.. No healthcare workers who wore

gloves had C. dif. on their hands. Olsen and

115

colleagues found that gloves prevented hand

contamination in 77 percent of instances. Dr.

Pittet found that when no gloves were used and they

measured hand contamination rates, they found out

that the hands were contaminated with 16

CFUs/minute of patient care when no gloves were

used, but only 3 CFUs/minute when gloves were used,

showing the protective effect of gloves. Finally,

Tenorio et al. found that gloves reduced the risk

of hand contamination by vancomycin-resistant

enterococci by 71 percent. So, in fact, to the

extent that people do wear gloves during patient

care nowadays, their hands are probably less

heavily contaminated than they were back in the

'60's, '70's and early '80's.

[Slide]

One thing that I thought that I was

supposed to try to address was whether or not there

is any evidence that the products that are

currently on the market have any kind of clinical

benefit in a healthcare setting. I wanted to

mention this model by Ehrenkranz. It was a field

116

study that was supposed to reproduce clinical hand

contamination. Nurses touched the skin of patients

who were heavily contaminated with gram-negative

bacteria. They then cleaned their hands. They

either used plain soap and water handwashing or

they used the 63 percent isopropyl alcohol hand

rinse. After cleaning their hands, the nurses

touched catheter material, like a Foley catheter

type material, and then that catheter material was

cultured on agar plats.

What they found is that bacteria were

transferred from the hands of the nurses onto this

catheter material in 11/12 experiments when plain

soap was used to clean their hands but only 2/12

experiments when the alcohol hand rinse was used.

[Slide]

Now, in terms of clinical trials, which I

think is a major issue as was discussed in part by

the last speaker, this slide shows one sequential

trial of three hand hygiene regimens. It was done

in the surgical intensive care unit by a very

experienced infection control physician. They

117

looked at non-medicated soap, 10 percent

povidone-iodine or 4 percent chlorhexidine

gluconate. Each product was used exclusively in

the ICU for 6 weeks. Surveillance for nosocomial

infections was performed. What they found was that

the incidence of healthcare-associated infections

was 50 percent lower during times when the two

antiseptic-containing handwash agents were used,

suggesting that these hand hygiene products that

were available at that time reduced infections

better than plain soap and water handwashing in

this short trial which was only done in one ICU.

[Slide]

This slide discusses a prospective trial

done to compare two hand hygiene regimens. It was

a prospective trial with a multiple crossover

design. It was done in three intensive care units

in a university hospital that just happened to have

one of the largest and most highly respected

infection control programs in the country at that

time. So, they had lots of resources relatively

speaking. They followed over 1,800 adult patients

118

for nearly 8,000 patient-days at risk. The two

regimens compared were 4 percent chlorhexidine

gluconate versus a combination regimen of isopropyl

alcohol and a non-medicated soap. Healthcare

workers were told that when the alcohol and

non-medicated soap were available they were

supposed to use the alcohol routinely for cleaning

their hands.

[Slide]

What they found was that the number of

patients who developed a healthcare-associated

infection was 96 in the chlorhexidine time period

and 116 when the alcohol and plain soap were

available. So, the incidence density was lower

with the 4 percent chlorhexidine. The number of

healthcare-associated infections was 152 during

periods when the 4 percent chlorhexidine was used

compared to 202 when the combination regimen was

available--again, a lower rate with the 4 percent

chlorhexidine. Infection rates were significantly

lower in 2/3 ICUs when the chlorhexidine was used.

[Slide]

Despite this being planned by a very

experienced and highly respected individual, with a

large team working with him, this clinical trial

119

ran into some problems. First of all, the overall

compliance of healthcare workers, as shown on the

left, was not the same during the two trials. It

was about 42 percent compliance when the

chlorhexidine was available versus 38 percent when

the other regimen was available in the units. The

difference was actually statistically significant.

Another important problem that emerged,

despite this trial being well planned and designed,

was that the volume of the products used varied

significantly. The amount of soap and isopropyl

alcohol used when available was significantly lower

than the volume of chlorhexidine used when that

product was available. Even though healthcare

workers were told they should use the isopropyl

alcohol routinely when available, for reasons that

are not either understood or discussed by the

authors, the healthcare workers hardly ever used

the alcohol. So, this trial was really more a

120

comparison of 4 percent chlorhexidine against plain

soap and water for the most part.

So, one problem with this trial is that it

is very difficult to control the activities of all

these healthcare workers in all these ICUs over an

8-month period, and to get them all to do exactly

the same thing and to do it with exactly the same

frequency.

[Slide]

From the eyes of a beholder here who works

in a hospital, that is one of the problems with

clinical trials. When you use a nosocomial

infection rate as the outcome measure for efficacy

of hand hygiene agents, there are many, many

confounding variables including host factors; the

rate of importation of organisms from nursing homes

or other sites into the hospital and onto the

wards; the level of compliance of healthcare

workers with recommended hand hygiene, with

recommended barrier precautions, how frequently

they follow guidelines for central line placement

and for ventilator-associated pneumonia prevention.

121

If you are talking about surgical site infections

you have to worry about the skill of the surgeon;

whether or not prophylactic antibiotics were used

and timed appropriately; and whether or not any

active surveillance cultures are being done on the

wards where the studies are being conducted.

So, from my viewpoint, there are so many

confounding variables that that, in and of itself,

makes the clinical trials extremely difficult to do

and extremely costly. To me, it seems like the use

of surrogate endpoints to assess efficacy of hand

hygiene products still has merit.

[Slide]

I want to mention a little bit more about

clinical benefit. None of the things I am going to

mention are carefully controlled, prospective

trials partly for all the reasons I have just

mentioned. This one publication involved a surgeon

whose hands, but not other body parts, were

colonized with a virulent strain of Staphylococcus

epidermidis that caused an outbreak of surgical

site infections related to cardiac surgery. This

122

surgeon was using a noon-antimicrobial soap for a

preoperative scrub because of previous problems

with hand dermatitis so he followed the

recommendation of his dermatologist.

An epidemiologic investigation that

included case control studies and molecular typing

clearly implicated the surgeon as the source of

this outbreak, and we told him he had to stop doing

cardiac surgery and to start using a 4 percent

chlorhexidine gluconate surgical scrub. After he

did so the outbreak terminated and we did not see

that strain any further in cardiac surgery

infections, demonstrating that the antimicrobial

soap that was available didn't appear to have

benefit.

[Slide]

An outbreak of vascular surgery-related

surgical site infections occurred when an operating

room was not provided standard povidone-iodine.

The surgeons were used to using preoperative

surgical hand scrubs. The vascular surgeons in the

hospital decided to use plain soap for hand

123

scrubbing before surgery, while other surgeons used

a 2 percent iodine with 70 percent alcohol for

preoperative hand scrubbing. Hand scrubbing with

plain soap was significantly associated with the

occurrence of this outbreak of surgical site

infections and reinstitution of povidone-iodine

hand scrubbing terminated the outbreak, again

suggesting that this povidone-iodine product had

value in reducing surgical site infections.

[Slide]

Of course, the CDC guideline for hand

hygiene was published in 2002 and the guideline

recommends routine use of alcohol-based hand

sanitizers for cleaning hands before and after

patient contact as long as the hands are not

visibly contaminated.

[Slide]

Not long after the guideline was

published, actually in January of 2003, the Joint

Commission on Accreditation of Healthcare

Organizations sent out a sentinel event alert to

hospitals and recommended that hospitals comply

124

with the CDC's new hand hygiene guideline. So, I

think both the Joint Commission and CDC are

standing behind the guideline.

[Slide]

This study was done where a 70 percent

ethanol hand gel was introduced hospital-wide into

the hospital. A multidisciplinary program to

improve hand hygiene was carried out. During the

following 12 months the alcohol hand product was

used an estimated 440,000 times by healthcare

workers and they found a consistent reduction in

the proportion of all methicillin-resistant Staph.

aureus that was hospital-acquired during the

12-month period.

[Slide]

This slide shows the impact of one of

these alcohol hand sanitizers on the hand hygiene

compliance in our hospital. Compliance rate is

shown on the Y axis. Observational surveys

conducted by the same infection control

practitioners each time revealed that, by having

this new alcohol hand gel available and promoting

125

its use and educating people about it, the overall

hygiene compliance improved from 38 percent to 63

percent, and the proportion of all hand hygiene

episodes which were performed using the alcohol

hand gel, which is shown in the red part of the

bars, increased significantly.

Not shown on this slide is the fact that

the proportion of all methicillin-resistant Staph.

aureus--let me put that another way, the proportion

of all Staph. aureus isolates that are due to

methicillin resistance in our hospital levelled off

about the time that survey 2 was done, and actually

decreased by 5 percent over the following year and

a half. This decrease in MRSA in our hospital

occurred during the same time frame when MRSA

continued to increase in prevalence in the

hospitals that participate in CDC's National

Nosocomial Infection Surveillance program, or NNIS.

Although it is rather crude data, we think that the

hand hygiene program probably has helped reduced

MRSA in our hospital as well.

[Slide]

In conclusion, conducting clinical trials

to assess the efficacy of healthcare personnel

handwash products is, in fact, extremely difficult,

126

expensive and, as far as I am concerned, largely

not practical. If they are to be done, they are

going to be very expensive.

Widespread experience with currently

available products, combined with some of the

epidemiologic studies that I mentioned, provide

some evidence of their clinical benefit in

healthcare settings. Multiple studies have shown

that promoting the routine use of alcohol-based

hand santizers, when combined with educational and

motivational material, can improve hand hygiene

practices among healthcare workers.

[Slide]

There are no published data that I am

aware of demonstrating that cumulative activity of

healthcare personnel handwash agents or surgical

scrub products results in lower rates of

healthcare-associated infections. Removal from the

market of hand hygiene products that are currently

127

in widespread use in healthcare facilities would,

in fact, disrupt national efforts to improve hand

hygiene practices among healthcare workers. So, I

personally would hope that there is no regulatory

action that ends up removing a lot of the current

products from the market because I am convinced,

again on a personal level, that they do have value.

Thank you.

DR. WOOD: We have received Dr. Pearson's

slides from the wilds of Atlanta and we think we

can show them. Is that right?

MS. JAIN: Yes.

DR. WOOD: Unfortunately, sort of like CNN

breaking news, because the slides are just in we

don't have a handout. We are going to have her on

the phone. Dr. Pearson, can you hear us?

DR. PEARSON: I can.

DR. WOOD: As you go through the slides,

Dr. Pearson, if you tell us when you want to change

to the next slide, we will be able to do that.

Let's go.

Prevention of Surgical Site Infections

DR. PEARSON: Good morning and thanks to

the meeting organizers for tolerating my

inconvenience and thank you for the opportunity to

128

present on the topic.

[Slide]

What I hope to do in the next few minutes

is really to talk about some of the epidemiologic

complexities of looking at the effectiveness of any

preventive measure, whether it be cutaneous

antiseptic or other preventive measures, using

surgical site infections as the context for that

discussion. Next slide.

What I am going to do is first provide an

overview of what we know about the epidemiology of

surgical site infections, including the incidence

and risk factors for infection. I will talk next

about some of the preventive strategies that have

been shown to decrease that risk; highlight some of

the current surveillance systems for monitoring the

incidence of surgical site infections; and conclude

with talking about how we, here at the CDC, go

about developing our policies and recommendations

129

for prevention of healthcare-associated infections,

such as SSIs. Next slide.

Just to give you a little bit of an idea

of why this is an important topic and to frame it

with some numbers, it is estimated that somewhere

in the neighborhood of 20 million inpatient

surgical procedures are done each year in the

United States, and 2-5 percent of these procedures

are complicated by a surgical site infection.

Based on our surveillance system, surgical

site infection is the second most common

healthcare-associated infection, comprising about a

quarter of all of the infections reported to CDC.

These infections come not only at a cost to the

patient but also a cost to the healthcare delivery

system. These infections result in anywhere from

an additional week of hospital stay and they cost

anywhere from $400 to $2,600 per infection, and

these total well in excess, and approaching in some

instances, close to a billion dollars a year in

terms of healthcare dollars. Next slide.

In terms of the way we define or look at

surgical site infections at CDC, we classify them

either as incisional surgical site infections, and

130

those include superficial infections which involve

the skin and the underlying subcutaneous tissue, or

deep incisional surgical site infections which

involve the underlying soft tissue as well.

Obviously, the most severe and costly infections

are those that involve the underlying organ or

organ space surgical site infections and those

involve really any part of the anatomy other than

the incision that might have been opened or

manipulated during the procedure. Next slide.

This is a cross-sectional schematic to

illustrate just a little bit more clearly an

abdominal wall that shows the various

classifications. As you can see, a superficial

incisional SSI would involve the skin and the

subcutaneous tissue. A deep incisional SSI would

extend down into the fascia and the muscle. The

organ space surgical site infection, obviously,

would include the organs in that surrounding

131

tissue. Next slide.

Now, when we look at the organ or the

potential sources for the pathogens that result in

a surgical site infection, overwhelmingly these

arise from the patient's own endogenous flora.

There are also secondary sources for the pathogens

that result in a surgical site infection. Those

can result from pathogens that are available in the

operating room theater environment. They may

result from operating room personnel that are in

and around the surgical field or, not uncommonly,

at the head of the table of the anesthesiologist.

Less commonly, these infections may result from

seeding of the operative site from a distant site

of infection. Next slide.

If we look at the microbiology of the

surgical site infections--and this slide is

somewhat dated but suffice it to say that the

distribution of these pathogens is still

predominantly--the primary organism are

staphylococcal infections, not surprisingly because

these arise primarily from the patient's own

132

endogenous flora. The predominance of these

pathogens is Staph. aureus, and then with certain

procedures like cardiac surgery, and more recently

we have been looking at some data from prosthetic

joint infections, and it appears that staphylococci

now account for in the neighborhood of around 50

percent of the infections causing surgical site

infections. We have also seen an increase in the

proportion of those staph. infections that are due

to resistant organisms, such as

methicillin-resistant Staph. aureus. Next slide.

Less commonly, SSIs may be due to some

unusual pathogens, such as the ones shown on this

slide that are typically due to either contaminated

products or solutions that are used in and around

the surgical site, or to colonized healthcare

workers, again, that might be part of the surgical

team. When you see clusters of infections that are

due to these unusual pathogens you should think of

a common source, such as the contaminated vehicle

or potentially the colonized healthcare worker who

is disseminating the organism. Next slide.

Regardless of where the organism arises,

the pathogenesis of a surgical site infection can

kind of be distilled into this numerical formula

133

and relationship shown here. That relationship

really is a combination of the dose or the amount

of bacterial contamination at the surgical site

infection, the virulence of the colonizing or

contaminating organism, and then the underlying

sort of resistance of the host. Those three

factors are really give rise to the risk of

surgical site infection. Next slide.

If we look at some of the epidemiologic

factors that have been associated with influencing

the risk of acquiring a surgical site infection,

they can be broadly categorized into those that are

host- or patient-related factors, such as age, body

mass index, obesity, the presence of diabetes and,

as we will see later it may not just be a patient

who is labeled with diabetes but having

hyperglycemia at the time of surgery, the

nutritional status of the patient, whether the

patient has a prolonged preoperative stay, again,

134

whether there is infection at a remote site at the

time of surgery, and whether the patient is on

immunosuppressive medication such as steroids, or

whether the patient is a smoker or uses nicotine.

Some of the procedural factors that have

been associated with influencing the risk of

surgical site infection are things like hair

removal or shaving, the duration of the procedure,

surgical technique, the presence of foreign bodies

such as drains, and things like the appropriateness

or inappropriateness of antimicrobial prophylaxis.

Next slide.

What I am going to do now with the next

series of slides is talk a little bit about some of

these modifiable factors in terms of things that we

recommend, or things that are recommended, to be

done to minimize or moderate the risk of a patient

acquiring a surgical site infection. Next slide.

There are a number of randomized,

controlled trials showing the benefit of

perioperative prophylaxis and I won't belabor you

with those data. The feeling is that this is

135

probably one of the most important things that we

can do in terms of modifying risk of infection.

When we talk about antimicrobial prophylaxis we are

really referring to a brief course, most commonly a

single dose, of an antimicrobial agent that is

given just before the operation begins.

Antimicrobial prophylaxis is not intended as

therapy. It really is a preventive strategy ,and

it really should be used as an adjunctive

preventive measure and not really used to supplant

basic things like aseptic technique and some of the

other basic principles of preventing surgical

infection.

Now, antimicrobial prophylaxis, as I said,

has been studied in a number of procedures, a

number of well done randomized, controlled trials

and it is shown that its use, if done

appropriately, can decrease the risk of surgical

site infection at least 5-fold. Next slide.

But surgical prophylaxis--again, to show

you how complex this whole issue is, is not a

matter of just giving an agent and giving the right

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agent, but also giving it at an appropriate time.

Now, this slide summarizes a study done by Classen,

and I think it is one of the more classic studies

looking at the importance of timing of

antimicrobial prophylaxis in terms of its efficacy

in preventing surgical site infection.

What Classen did was actually study nearly

3,000 elective clean and contaminated surgery. He

looked at the timing of the antibiotic and its

influence or relationship to the risk of infection.

If you look at what he called early antimicrobial

prophylaxis, that is antibiotics given 2-24 hours

before incision, the rate of infection in that

cohort was 3.8 percent. If he looked at

antibiotics that were given postoperatively, that

is 3-24 hours after incision, the rate of infection

was 3.3 percent. If he looked at antibiotics that

were given within 3 hours after the incision, the

rate of infection was 1.4 percent. Lastly, the

rate of infection was lower for antimicrobial

prophylaxis that was given within 2 hours of the

incision, 0.6 percent. So, again, it is not just a

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matter of giving prophylaxis and giving the right

agent, but this issue of timing is critically

important. Next slide.

This next series of slides talks not only

about this notion of giving antibiotics at a

critical point before incision, but talks about the

impact of prolonged surgical prophylaxis. This is

a study that was a prospective study that looked at

a cohort of CABG patients. They looked at those

patients who received antibiotic prophylaxis within

48 hours of the procedure and those for whom the

prophylaxis was continued for greater than 48 hours

after the procedure. Next slide.

They looked at two outcomes, not only the

incidence of surgical site infection but also the

likelihood of acquiring a resistant organism if a

surgical site infection did occur. Interestingly,

what they found is that nearly half of the patients

received antimicrobial prophylaxis greater than 48

hours after the procedure. Again, antimicrobial

prophylaxis is intended to be given around the time

of incision to get the maximal sterilization, if

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you will, of the surgical site. But here we see

that at least in half the cases patients are

getting prophylaxis beyond two days after the

surgery.

What they found is that the incidence of

infection in this cohort of patients really was no

different if antibiotic prophylaxis was

discontinued within 48 hours or if it was continued

for greater than 48 hours. But, interestingly, the

rate of acquiring a resistant pathogen was 60

percent higher in those patients who received

prolonged antimicrobial prophylaxis. So, again,

antimicrobial prophylaxis and its influence on SSI

is not only getting the right agent but getting it

within the right interval and discontinuing it as

soon as possible following the surgical procedure.

Next slide.

Another area that I think is particularly

intriguing as to the complexity of things that

would have to be considered or controlled for in

looking at SSI risk is this whole issue of glucose

control and perioperative management of

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hyperglycemia. This slide actually summarizes a

prospective study that was done in a group of

diabetic patients who were undergoing cardiac

surgery, over nearly a decade at one hospital.

They had two groups of patients. Again,

this is a prospective intervention trial with a

pre- and post-design. The control patients were

those who had received sort of the traditional

therapy with their glucose being measured and

monitored intermittently, and being given

subcutaneous insulin. What they called the treated

group were patients who were placed on a continuous

IV insulin drip for the immediate operative period

and for up to 48 hours postoperatively. Next

slide.

The outcomes were that they looked at the

levels of blood glucose that were below 200 mg/dL,

and that was sort of the target level, within the

first two days postoperatively. The other outcome

obviously was the incidence of surgical site

infection, and they focused on deep SSIs. What

they found is that in the group who got traditional

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management using subcutaneous insulin on a PRN

basis the rate of surgical site infection was 2

percent as compared with the 0.8 percent in those

patients who were managed with a continuing IV

drip. This difference was highly statistically

significant.

Now, there have been some subsequent

studies that have looked at sort of the prevalence

of patients who are hyperglycemic who don't carry

the diagnosis or label of diabetes. Again, this

notion of perioperative glucose management probably

has broader implications beyond just the diabetic

patient population. Next slide.

Another sort of titillating article that

is summarized here and I think alludes to some of

the complexity of this issue is this notion of

perioperative oxygenation, the theory being that

better oxygenated tissues are less likely to be at

risk or be prone to developing an infection.

This was a study that was published in the

New England Journal in 2000. It was a randomized,

controlled, double-blind trial that looked at a

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relatively small group, 500 patients who were

undergoing colorectal surgery. Again, I want to

emphasize that this was colorectal surgery. The

intervention was that patients were randomized to

receive either 30 percent or 80 percent inspired

oxygen during and for up to 2 hours following the

surgical procedure.

Now, what they found is that the incidence

of surgical site infection was 5.2 percent in those

who received higher 32 percent versus 11 percent in

those who received 30 percent oxygen. That

difference was statistical significant.

There has been a more recent study that

came out in JAMA, and I did not summarize that

here, looking at a more heterogeneous population of

patients undergoing intra-abdominal procedures,

again, randomizing them to receive 70 percent

oxygen versus 30 percent inspired oxygen. That

study concluded that there was not only no

beneficial effect to a higher level of inspired

oxygen but, in fact, there might be some

detrimental consequences. In fact, they found a

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higher rate of surgical site infections in those

people who got more oxygen.

I say this to say again that this

difference might be in part attributable to the

population that was studied in terms of procedures.

So, a lot of these things have to be factored in,

in terms of trying to extrapolate findings from one

cohort to another--not only what the intervention

was but the population and the procedure that was

studied. Next slide.

What about the issue of antisepsis and

antiseptics? Probably, as you have heard from Dr.

Boyce, a lot of the studies around the efficacy and

the benefits of antiseptics really use bacterial

count on scans and the amount of cutaneous flora

remaining after their use as the primary outcome

measure. When we look at hard outcomes or harder

outcomes in terms of patient outcomes, data becomes

much thinner.

These are just summarizing some data, and

these are admittedly older studies and, you know,

these studies to be done today are much more

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difficult for a variety of reasons, but these three

studies summarize data looking at surgical site

infection rate with patients receiving preoperative

showers versus those not getting showers. The

earliest study was in the '70's where the rate

among those who did not get showers was 2.3 percent

versus 1.3 percent. In the subsequent two studies,

in the 1980's, the actually the difference was

quite closer.

Again, I think some of these studies,

although they did not show a statistically

significant difference, may be confounded by

failure or inability to control for a lot of the

factors that we mentioned up to this point. But,

also, I am not convinced that these studies were