**[Primary Bacteremia due to *Staphylococcus aureus* (PBSA) and
Catheter-Related Blood Stream Infections (CRBSI)]{.underline}.**

**FDA Briefing Document for**

**Anti-Infective Drugs Advisory Committee Meeting**

**October 14, 2004**

# I. Introduction

The FDA's approach to prescription drug labeling for claims related to
bacteremia has varied over time based on changes in the science and
advice from the Anti-Infective Drugs Advisory Committee (AIDAC). The
Agency established the precedent of granting indications in drug
labeling based on a particular disease syndrome or site of infection,
given the known differences between the natural history and
pathophysiology of infectious diseases at various body sites. Experience
has validated this approach in that FDA has reviewed drugs that were
effective in one body site yet were not proven effective in infections
at other body sites. Approvals based on bacteremia alone may not account
for potential differences in drug efficacy based on the primary site of
infection. Therefore, FDA has taken the position to include data on
outcomes in bacteremic patients within the context of a primary site of
infection.

In 1999, AIDAC members suggested that catheter-related blood stream
infections (CRBSI) should be a potential source of study, and FDA issued
draft guidance on drug development for this indication. At the time, the
committee members outlined the potential pitfalls in performing
scientifically rigorous studies in this area. Drug sponsors engaged in
studying CRBSI have encountered many of these issues. In addition, other
drug sponsors have approached FDA with studies seeking to evaluate the
efficacy and safety of drugs in primary bacteremia due to
*Staphylococcus aureus* (PBSA). Many *S aureus* bacteremias without an
obvious source may have a portal of entry related to an intravascular
catheter. In this advisory meeting, we will discuss the scientific,
regulatory and practical issues of a potential indication in primary
bacteremia due to *S. aureus* as well as revisit the guidance on
catheter related bloodstream infections.

This briefing document outlines the regulatory history of indications
related to bacteremia, as well as CRBSI. It includes a discussion of
issues that have been encountered in attempting to study CRBSI and how
such data might be reflected in product labeling. Additionally, we
summarize the epidemiology and natural history of *S. aureus*
bacteremia, and relate this to scientific issues in clinical trial
design to support such a claim.

The Agency seeks the Committee's advice on resolution of the problems
encountered by sponsors in following the current guidance on CRBSI; the
merits of a PBSA indication; and the optimal approach to the design,
conduct and analysis of CRBSI and PBSA clinical trials.

# II. Regulatory History

Prior to 1992, the labeling of anti-infective drugs included the terms
*bacteremia* and *septicemia*. Bacteremia was defined as an infection
accompanied by one positive blood culture, whereas septicemia was
defined by two positive blood cultures. Analyses of clinical data used
in granting those indications involved pooling data from patients with
infections associated with *concurrent* bacteremia, often from diverse
unrelated infections (e.g., UTI, pneumonia). In addition, the clinical
context was variable, as transient bacteremia, bacteremia secondary to a
known source, and bacteremia of unknown origin were considered together,
despite their differing pathophysiology.

In 1992, the FDA published the "Guidance to Industry on Clinical
Development and Labeling of Anti-Infective Drug Products" (also called
the "Points to Consider" document) to assist sponsors in formulating
development plans for anti-infective drug products^1^. The Points to
Consider document contained information related to the Agency's
perspective on specific indications, recognizing the differences in
pathophysiology between diverse diseases. The term "indication" referred
to "the treatment of infections at a specific body site(s) due to a
specified susceptible microorganism(s)"^2^. At that time, FDA raised
questions about the appropriateness of "bacteremia" indications as they
related to infections at specific body sites.

These questions resulted in a meeting of the AIDAC in 1993. Committee
members discussed the issues related to "bacteremic sepsis" as a
potential new anti-infective drug product indication. ^3^ At the time,
"bacteremic sepsis" represented new terminology that was proposed to add
specificity and clarity to the previously used terms "bacteremia" and
"septicemia".

The then-proposed new indication incorporated definitions of sepsis and
bacteremia, as provided in a consensus document of the American College
of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM)
published in 1992. ^4^ The ACCP/SCCM Consensus document defined a
hierarchy of syndromes from infection to severe sepsis. The document
defined *infection* as "a microbial phenomenon characterized by an
inflammatory response to the presence of microorganisms or the invasion
of normally sterile host tissue by those organisms". The document
defined *bacteremia* as the laboratory recovery of viable bacteria in
the blood. The systemic inflammatory response to severe clinical insults
was termed *systemic inflammatory response syndrome* (SIRS), manifested
by two or more of the listed criteria: temperature \>38 ºC or \<36 ºC,
heart rate \>90 beats per minute, respiratory rate \>20 breaths per
minute or PaCO2 \<32 torr, and WBC count of \>12,000 cells/mm^3^, \<4000
cells/mm^3^, or \>10% bands (immature forms). SIRS could be of
infectious or non-infectious etiologies. *Sepsis* was defined as
patients with signs and symptoms of SIRS due to an infectious etiology.
The document defined *severe sepsis* as sepsis associated with
hypotension, hypoperfusion, and organ dysfunction. Drug sponsors defined
the potential new indication of \"bacteremic sepsis\" as SIRS due to
infection with associated positive blood cultures, but without the
hypotension, hypoperfusion, and organ dysfunction that characterize
severe sepsis.

While these definitions are useful in clinical practice, Committee
members at the 1993 AIDAC identified several issues related to clinical
trial design and prescription drug product labeling that served as focal
points for discussion. These issues included 1) whether bacteremic
sepsis was a clinically meaningful disease entity; 2) the heterogeneity
of the patient population under study; 3) the clinical significance of a
positive blood culture, in terms of adding specificity to the
identification of the underlying infecting microorganism; and 4) whether
drug efficacy in treating an organism in the blood can be extrapolated
to efficacy in infections at particular body sites, the putative source
of the bacteremia.

In their comments about the use of the terms "bacteremia" and
"septicemia" in product labeling, the AIDAC expressed concerns about the
overall lack of specificity of the definitions, the heterogeneity of the
patient population, the pooling of data involving bacteremias with
varied sites of origin and differing underlying pathophysiology, and the
inability to distinguish patients with SIRS who had concurrent
bacteremia from those without bacteremia on a clinical basis.

Following extensive discussion, the 1993 AIDAC members recommended
elimination of "bacteremic sepsis" as an indication, continuing to use
the site of infection in defining an indication for an anti-infective
drug, and including bacteremia in product labeling in the context of
site-specific infection (e.g., "community-acquired pneumonia with
concurrent bacteremia").

During the five years following the 1993 AIDAC meeting until the AIDAC
meeting in 1998, there were no anti-infective drugs approved for the
indication of bacteremia. However, the issue of bacteremia as an
indication was again considered by the 1998 AIDAC.^5^ The discussion
arose in light of the rising incidence of bacteremia due to
antimicrobial resistant (predominantly Gram-positive) microorganisms,
the increased incidence of bacteremias without an identifiable source,
and the use of data involving patients with positive blood cultures to
enhance the specificity of diagnosis in clinical trials.

Following extensive discussion, the 1998 AIDAC members concluded that
product labeling regarding "bacteremia", secondary to an identified site
of infection, should *not* be considered as a separate indication.
Rather, the Committee advised the Agency that it should be retained
within the context of the site-specific indications. In addition, the
1998 AIDAC identified primary bacteremia (including catheter-related
bloodstream infections) as a potential area for study. Catheter-related
bloodstream infections (CRBSI) were considered a potential focus for
future investigation. Committee members considered this indication a
potential source of useful information, due to the increased incidence
of CRBSI in hospitals, growing antimicrobial drug resistance among
bacteria with limited treatment options for such infections, and the
lack of controlled clinical trials for antimicrobial drugs for the
treatment and prevention of CRBSI.

Following the 1998 Advisory meeting, the FDA formed a CRBSI Working
Group to develop a Guidance Document for Industry on Drug Development
for CRBSI (see Appendix A). The preliminary guidance was presented at an
AIDAC meeting in 1999. ^6^ Committee members identified several issues
related to drug development for the treatment of CRBSI:

(1) The patient population in CRBSI studies could be very heterogeneous
    with varying host factors and underlying illnesses, different types
    of intravascular catheters, and diverse causative microorganisms
    that differ in virulence and natural history of disease. Varying
    host factors could include different clinical presentations of
    illness in adults compared to pediatric patients, differing
    approaches to patients with prosthetic devices, and differences in
    individual patient requirements for long-term intravenous access.

(2) Difficulties might be encountered in establishing the catheter as
    the source of bacteremia. The issue reflects potential problems in
    acquiring culture data from catheters, which may then necessitate
    screening a large number of patients to enroll sufficient cases with
    a diagnosis of bacteremia related to a catheter. The large sample
    size might require substantial time for patient accrual.

(3) The committee discussed issues related to the microbiological
    criteria for establishing proof of CRBSI. Certain microbiological
    tests used to diagnose CRBSI, such as quantitative blood cultures,
    might not be available in some institutions. The committee concluded
    that additional data were necessary on other methods of diagnosis,
    such as the differential time to positive blood culture and various
    types of catheter cultures. Obtaining these data is complicated by
    the lack of a gold standard against which to compare these tests.

(4) The lack of a known (or proven) magnitude of the benefit of
    antimicrobial treatment for certain etiologic microorganisms, such
    as *Staphylococcus epidermidis*, which are often the most common
    organisms in CRBSIs.

(5) The lack of standardized procedures for the management of an
    intravascular catheter in CRBSI. Such differences in management may
    affect outcomes independent of the effect of the antimicrobial
    administered. There was discussion about whether factors such as the
    type of catheter (tunneled vs non-tunneled) and suspected pathogen
    (such as *S. epidermidis* vs. *S. aureus*) should be considered in
    decisions related to catheter removal.

(6) Issues related to establishing the specificity of the diagnosis of
    CRBSI due to some common skin pathogens. The committee discussed
    appropriate laboratory testing to establish the concordance of
    catheter and blood culture isolates, such as pulse-field gel
    electrophoresis for *S. epidermidis.*

Many of these scientific and practical issues remain, and sponsors have
a dilemma in trying to complete their studies of CRBSI.

# III. Drug Sponsors Experiences with CRBSI Trials

# 

Since the introduction in 1999 of the CRBSI guidance, several sponsors
have attempted studies in this indication. The Agency has received
feedback from some of those sponsors on problems they have encountered
in the study of CRBSI. In April 2004, FDA co-sponsored a public workshop
on antimicrobial drug development in which some data on experiences with
CRBSI trials were presented. Dr. Timothy Henkel (Vicuron
Pharmaceuticals) outlined the practical and scientific issues in CRBSI
trials from his company's perspective. In Dr. Henkel's experience,
investigators were identifying the majority of potential patients for
study by screening for positive blood cultures, rather than identifying
patients by clinical inclusion criteria. Using blood cultures as the
screening method, 75 of 2639 (2.8%) patients screened were subsequently
enrolled in the study over a period of 17 months. Just as the AIDAC
Committee discussed previously, the most difficult piece of data to
obtain was culture data from catheters. Thirty percent (30%) of screened
patients could not be enrolled due to inadequate culture data, with the
microbiologic evidence from catheter cultures the most common missing
piece of information. Another twenty percent (20%) were excluded on the
basis of prior antibiotic usage. Additional challenges noted by Dr.
Henkel included other points previously discussed: heterogeneity of the
patient population, issues with inclusion/exclusion criteria,
microbiologic methods not the standard of care at many institutions, and
lack of an approved comparator.

Other sponsors have met with the Agency to discuss their experience with
similar clinical trials aimed at garnering a claim for CRBSI. Their
experience confirms the difficulty in obtaining sufficient numbers of
patients, along with confirmatory microbiology, in CRBSI trials.
Sponsors have indicated that, despite enrollment of patients based on
clinical criteria consistent with catheter-related infection, along with
removal and culturing of the catheter, only about a quarter of patients
enrolled meet the most liberal of the microbiologic definitions for
CRBSI (concordant growth of an organism from peripheral blood and
catheter site exudate).

Since the AIDAC in October 1999, the Infectious Diseases Society of
America, the American College of Critical Care Medicine, and the Society
for Healthcare Epidemiology of America have published guidelines for the
diagnosis and management of CRBSI. ^7^ These guidelines represent a
compilation of the available evidence from the literature and the
strength of that evidence to assist clinicians in clinical practice.
However, while the clinician is provided with an algorithmic approach to
diagnosis, catheter management, and antimicrobial treatment strategy
based on the type of catheter and pathogen responsible, none of these
recommendations is based on evidence from randomized, controlled
clinical trials. The recommendations serve the practitioner at the
bedside, but do not necessarily provide sufficient information on the
optimal design and analytic plan for a formal clinical trial in CRBSI.

The issue of lack of a gold standard for diagnosis of CRBSI, discussed
thoroughly at the AIDAC meeting in 1999, still remains. Since 1999,
authors have published several studies on alternative methods of
diagnosis of CRBSI. It is difficult to compare sensitivity and
specificity of these methods in the absence of a benchmark. Different
studies apply different, sometimes widely variant, definitions for
CRBSI. In addition, some of the methods (such as quantitative peripheral
and catheter blood cultures, differential incubation time and thus
positive culture result for catheter and peripheral blood cultures,
catheter tip cultures processed by the roll-plate, Brun-Buisson, or
sonication methods) may vary in sensitivity and specificity of
diagnosis, depending on the patient population or catheter type studied.
There have been additional studies in the published literature on the
utility of differential time to positive culture result for catheter
versus peripheral blood cultures. The studies demonstrating the utility
of this method in diagnosis have been performed primarily in
immunocompromised patients with the majority of patients having tunneled
catheters.^8,9,10,11^ The results of differential time to
positive-culture studies have not been validated in a medical-surgical
ICU population with short-term catheters.^12^ Additionally, the
assessment of sensitivity and specificity of this method has been made
on the basis of quantitative blood cultures and semi-quantitative or
quantitative catheter tip cultures, with no single method serving as a
validated standard.

At the April 2004 FDA Workshop, academic investigators and drug sponsors
suggested the possibility and discussed the merits of studying the
indication of treatment of primary bacteremia due to *Staphylococcus
aureus* (PBSA). In this context, FDA would like to review the existing
CRBSI guidance document and how it may relate to a potential indication
of PBSA. Given the difficulties experienced by sponsors in the design
and conduct of CRBSI trials, the Agency seeks guidance from AIDAC
members on how to move forward to address the CRBSI indication, as well
as the merits of a claim for treating primary bacteremia due to *S.
aureus*.

In this document, we have included discussion points for both primary
bacteremia due to *S. aureus* and catheter related bloodstream
infections. At the Advisory meeting, you will be provided with an
integrated set of questions so that both topics can be discussed at the
same time.

# Issues for Discussion -- Catheter-Related Blood Stream Infections

1.  Should FDA maintain the CRBSI Guidance Document in its present form?

2.  Are there modifications to the CRBSI Guidance that Committee members
    would suggest that would allow more efficient enrollment of patients
    while still maintaining adequate specificity of diagnosis and
    gaining useful information for clinicians?

3.  Can sponsors include data on patients who may have bacteremia due to
    *S. aureus,* secondary to a presumed portal of entry of an
    intravascular catheter, as part of a PBSA indication? Could patients
    with CRBSI and patients with PBSA be handled within a unified
    guidance document?

4.  Can sponsors garner an indication of "catheter site infections\",
    with or without bacteremia, as part of another indication (i.e.,
    complicated skin and skin structure infections)? How would one
    ensure the specificity of diagnosis in patients with minimal signs
    and symptoms of skin infection and where the organism cultured from
    blood and/or skin is normal skin flora?

# IV. Potential Indication of Primary *S. aureus* Bacteremia

At the April 2004 FDA co-sponsored public workshop, investigators and
sponsors addressed the topic of a potential indication for PBSA. The
participants discussed the potential advantages of this indication
relative to an indication for CRBSI. A PBSA indication would concentrate
on only one organism, which causes serious disease and for which there
may be data on the magnitude of the treatment effect of antimicrobials.
In general, the magnitude of the treatment effect for some organisms,
like *S. epidermidis*, *Corynebacteria* and some *Bacillus* species, is
not known. In addition, it may be more difficult to differentiate true
infection from false-positive blood cultures for these common skin
organisms. A primary bacteremia claim would also eliminate the most
common difficulty in CRBSI trials, namely the link of the disease to a
catheter as the source. As discussed below, many cases of PBSA may be
linked to a portal of entry from an intravascular device, but this is
often a diagnosis of exclusion, and diagnosis in clinical practice is
often "presumed". In addition, as discussed previously, there is no
validated gold standard for diagnosing CRBSI. Finally, there may be the
potential to acquire data on the efficacy of antimicrobials in patients
with infective endocarditis (IE) from such trials.

However, many of the challenges present in trials of CRBSI, such as a
heterogeneous patient population, may still be present in clinical
trials of PBSA. We will discuss these issues in light of the
epidemiology and natural history of bacteremia due to *S. aureus*.

# Epidemiology and Natural History of *Staphylococcus aureus* Bacteremia (SAB)

# *Epidemiology*

From 1980-1989, the rates of SAB from all sites of infection reported to
the National Nosocomial Infection Surveillance (NNIS) system increased
in teaching hospitals.^13^ *Staphylococcus aureus* has become the second
most common bloodstream isolate, contributing to 16% of all
hospital-acquired bacteremias.^14^ The rate of both community and
hospital acquired bacteremia due to *S.aureus* has increased over the
last few years.^15^ []{.mark} Rates of IE due to *S.aureus* have also
increased.^16,17,18^ The majority of IE are still community-acquired,
however there is an increasing incidence of hospital-acquired IE due to
*S.aureus*. ^19^

## "Primary" S. aureus Bacteremia without a known source

The source of *S. aureus* bacteremia is an important consideration when
attempting to design clinical trials to examine the efficacy of an
antimicrobial. Recent examples have shown that an antimicrobial may be
effective in disease caused by a given pathogen at one body site and yet
not be proven effective in disease caused by that same pathogen at a
different body site. It is hypothesized and certainly logical that all
patients with PBSA must have some occult portal of entry of the organism
into the blood stream. However, in clinical trials of PBSA, it will be
important to rule out a known primary source of infection in a standard
way in the protocol. Patients with a known primary source of infection,
such as skin infections and pneumonia, can be studied in clinical trials
of that particular body site.

Data show that most patients with bacteremia due to *S. aureus* have a
known site of infection. This may limit the available patient population
for clinical trials of PBSA. In one study of 37 patients with *S.aureus*
bacteremia, a primary source was identified in 24 patients (62%). ^20^
Mylotte et al. reported that a primary focus was identified in 91/114
(80%) episodes of SAB. ^21^ In a study of 79 non-drug addict patients, a
primary focus was identified in 59 (75%) patients. ^22^

The following graph shows the distribution of primary foci in patients
with SAB from a compilation of studies over five decades. Presently,
about 20% of patients with SAB have no identified primary focus of
infection.^23^

![](media/image1.png){width="3.125in" height="1.71875in"}

![](media/image2.png){width="2.95in" height="0.15in"}

## S. aureus Bacteremia and Catheters

Much of the disease attributed to "primary" SAB is related to
intravascular devices. Intravascular device-associated SAB accounts for
a large fraction of the documented increase in hospital-acquired SAB. In
a study by Steinberg et al., an increase in the number of intravascular
device-associated bacteremias accounted for 70% of the increase in the
number of nosocomial *S.aureus* bloodstream infections. ^15^ Jensen et
al. found an intravenous catheter as the source in 45% of patients with
hospital-acquired SAB. ^23^ In a study by Fowler et al. of 103 patients
with SAB, 69 (67%) had an intravascular catheter as the source. ^24^An
intravascular catheter was considered the source if 1) there was
evidence of inflammation at the catheter insertion site, or 2) a
catheter-tip culture was positive for *S.aureus*, or both, and 3) there
was no evidence of an alternative source. Community-acquired disease is
increasingly associated with the use of intravascular devices.^19,25^
This may be a reflection of changes in medical care with increasing
number of patients receiving medical care in outpatient settings.^32^ In
a study from the Netherlands, 25/75 (33%) patients had a central venous
catheter in place at the time of diagnosis, and in 12 of these, the
catheter was used in a community setting. ^26^

## Heterogeneity of Patient Populations with S. aureus Bacteremia

There appear to be differences in host factors and clinical
presentations within the group of patients with PBSA. This has important
clinical implications, as different clinical presentations may result in
different lengths of therapy. Patient heterogeneity also has important
implications for the designs and analysis of clinical trials, as
different patient populations may have different success rates even with
appropriate therapy. Clinical trials attempt to measure drug effects
independent of the natural history of the disease, host factors and
other confounding factors. Failure to account for important differences
in patient populations may result in measured differences between
therapies in a clinical trial that may not be related to drug effects
but to other confounding factors. While randomization gives an equal
*probability* of distribution of these factors between arms of the
trial, randomization is not foolproof. One study that evaluated the
importance of randomization and blinding showed that at least one
prognostic factor was not distributed equally between arms of the trial
in 14.0% of trials that were blinded and randomized. ^27^ Unequal
distribution of factors between the arms of a trial may have an impact
on the interpretation of the results. The importance of unequal
distribution of various factors not only depends on the statistical
significance of the difference in the distribution of the factor between
the study arms but on the strength of the association of the outcome
with that factor. In other words, one should consider small differences
in the distribution of factors between study arms as clinically
significant if the factor has a known large impact on outcomes, even
though the differences are not statistically significant. ^28^ Small
differences between arms of a PBSA trial in the presence of important
factors like infective endocarditis have the potential to affect the
interpretation of the results, even if the differences between study
arms are not statistically different. Therefore, one should attempt to
account for these important factors prior to enrollment in a clinical
trial. We outline some of the potentially important factors in PBSA
trials below.

### Community versus nosocomial acquisition

The proportions of the location of acquisition of SAB vary between
studies partly due to differences in the definitions of community versus
hospital acquired disease (positive culture within 48 hours or 72 hours
of hospitalization). Additionally, some authors differentiate
community-acquired disease into those with any health care contact in
the preceding few months, while in other reports these patients are not
clearly separated.

Investigators studied the prevalence of community-acquired SAB in a
one-year period in Connecticut. A total of 48% of SAB were
community-acquired and the incidence was 17/100,000. Sixty-two percent
(120/192) of patients with community-acquired SAB had contact with the
healthcare system in the preceding 12 months. ^29^ This is similar to
results of the study by Jensen et al. where 131/278 (47%) SAB were
community acquired. ^23^ Mylotte et al. reported slightly higher rates
(58%) using 72 hours as the cut off to differentiate community acquired
from hospital acquired disease. ^30^

The difference between community-acquired and hospital-acquired disease
may be important in clinical trials, as patients with community-acquired
SAB have a higher likelihood of developing metastatic disease and IE.
There appear to be differences in clinical success rates between
patients with and without metastatic disease and those with and without
IE. The higher rate of metastatic disease may be related to the
prolonged duration of bacteremia prior to detection. ^31^ In their
series of 278 patients, Jensen et al. found that intravenous catheters
and post operative wound infections were most often the primary foci of
SAB infection in hospital-acquired cases, while skin lesions were more
common in community-acquired cases. Patients with community-acquired
disease were more likely to have an unknown portal of entry, a higher
frequency of secondary infection, and a slightly higher mortality. ^23^

Complicated versus uncomplicated bacteremia due to *[S.
aureus]{.underline}*

There appear to be differences in clinical success rates between
patients with what has been termed "complicated" compared to
"uncomplicated" bacteremia due to *S. aureus*. Again, this may be an
important factor to account for in clinical trials. Investigators
prospectively evaluated risk factors for developing complicated SAB in
724 adults hospitalized with SAB from 1994-1999. They defined
complicated SAB as attributable mortality, complicated infection,
embolic stroke, or recurrent *S.aureus* infection during the 12-week
follow up period. Patients with complicated infection had a site of
infection remote from the primary focus caused by hematogenous seeding
or extension of infection beyond the primary focus. Of the 722 patients
with follow up data, 310 had complicated SAB and 412 had uncomplicated
SAB. Risk factors for complicated SAB were positive blood culture at
48-96 hours, community acquisition, skin examination with findings
suggesting acute systemic infection (defined as presence of petechiae,
vasculitis, infarcts, ecchymoses, or pustules), and persistent fever at
72 hours. ^32^

While the criteria described above for distinguishing complicated from
uncomplicated infection may be useful in clinical practice, their
application may be more problematic in the setting of a clinical trial.
Some of the criteria, such as presence of persistent fever, and
persistently positive blood cultures, are not measurable at the time of
enrollment in the trial. In addition, some of these factors may differ
between an effective and an ineffective drug. Using such criteria would
confuse the natural history of the disease with the ability of the drug
to affect the course of the illness.

### SAB with and without endocarditis

Given the differences in clinical success rates between patients with
and without IE, it will be important to make an accurate diagnosis of
the presence or absence of IE in PBSA trials. The information necessary
to make an accurate diagnosis of IE, such as echocardiographic data,
often will not be available at the time of randomization. Clinical
differentiation of SAB from endocarditis can be difficult in the absence
of typical clinical features of IE, such as a new murmur, embolic
lesions etc. Nolan and Beaty suggested three useful bedside criteria for
predicting presence of IE in patients with SAB; community-acquisition,
no apparent primary focus, and metastatic foci.

IE may be difficult to diagnose on clinical grounds alone and
echocardiography may be necessary to make the diagnosis. In a study by
Røder et al. from Denmark, IE was not diagnosed clinically in over half
of the 152 pathologically confirmed cases due to *S.aureus*. In a
prospective study by Fowler et al., 103 patients with SAB were evaluated
by transesophageal echocardiography (TEE) and transthoracic
echocardiography (TTE). Clinical evidence of IE was seen in only 7 (7%)
of patients. ^24^

The numbers of patients with PBSA who have IE may be substantial. The
prevalence of IE in patients with community-acquired SAB varies from
6-64%.^33^ Among 104 patients with SAB, 33 (32%) had
echocardiographically confirmed endocarditis; 23 were community acquired
and 10 were nosocomially acquired. ^34,19^ Increasing numbers of cases
of IE are now nosocomially acquired. ^15^ In a study by Fowler et al.,
the authors noted clinical differences between patients with community
acquired versus hospital acquired IE. Patients with community acquired
disease were more likely to have vascular phenomena and no evident
source for bacteremia while those with hospital acquired IE were more
likely to have IE due to MRSA. Out of 59 cases of IE due to *S.aureus*
identified over a 3-year period, 27 (45.8%) patients had
hospital-acquired infection. In over half of the patients an
intravascular device was the presumed source of infection. ^19^

The most common foci of *S. aureus* infection in patients with a known
site of infection are usually from skin, soft tissue, or bone but IE can
occur in patients who have no detectable primary focus.^22^ In the study
by Fowler et al. in the 26 cases with IE, 3 had no focus of infection, 7
had deep tissue infection, and 16 had a catheter focus. ^24^ In a study
by Chang et al., of the 505 cases with SAB 64 (13%) had IE, seven of
whom had new endocarditis as a complication of SAB. ^35^ Risk factors
for development of IE identified were: native valve disease \[OR 4.5,
2.0-9.9\], presence of prosthetic valve \[OR 10.5, 2.5-43.7\],
persistent bacteremia \[OR 10.5, 3.3-16.6\], IVDU \[OR 3.2, 1.2-8.6\],
unidentifiable portal of entry \[OR 3.3, 1.3-6.6\], history of prior
endocarditis \[OR 10.0, 2.0-50.0\], and community acquisition \[OR 2.9,
1.4-4.9\].

### Metastatic Disease

Metastatic infection may complicate SAB. This is an important
consideration given the implications for treatment and considerations as
to whether metastatic foci developing on therapy are indicative of
clinical failure. The efficacy of various drugs may differ at distant
metastatic sites. For example, a drug which does not have penetration
into the central nervous system (CNS) may not have efficacy in treating
metastatic CNS disease. Metastatic complications may be evident at first
presentation or may become evident weeks later. Ringberg et al. found
metastatic complications in 53% of patients.^36^ In a study of 39
patients with SAB, suppurative sequelae were reported in 9 (23%)
patients, all of whom were diagnosed after the first week of bacteremia.
^20^ Jensen et al. found that secondary foci developed in approximately
30% of patients with community-acquired disease and only 5% of those
with hospital-acquired disease. ^23^ In a retrospective study of 281
patients with SAB, common sites of metastatic disease were joints (36%),
kidneys (29%), CNS (28%), skin (16%), intervertebral disc (15%). More
than one metastatic site of infection was present in half the cases.
^37^

Prospective studies have examined risk factors for metastatic infection
in patients with SAB. ^21,\ 23,\ 38,\ 39^ These risk factors may be
important exclusions for clinical trials in PBSA. Underlying cardiac
disease is an important risk factor for development of IE in patients
with SAB. ^40^ Besides rheumatic heart disease, other structural
anomalies like mitral valve prolapse, bicuspid aortic valve,
senile/degenerative aortic valve stenosis or sclerosis, prosthetic
valves, and previous IE are common predisposing conditions. ^41^ In a
study of 44 patients with prosthetic cardiac valves who developed SAB,
15 (34%) developed IE. ^42^

Presence of an implanted prosthetic device is a risk factor for the
development of metastatic complications. Among 33 prospectively
identified patients with a permanent pacemaker or implantable
cardioverter defibrillator who developed SAB, the rate of confirmed
device infection was 45.4%.^43^ Non cardiac prosthetic devices such as
orthopedic devices are also at risk of seeding during an episode of SAB.
^44^ The presence of an indwelling foreign body is also an important
risk factor for subsequent relapse. ^45^

Patients with community-acquired SAB have a higher likelihood of
developing metastatic disease. In a prospective study of patients with
SAB, the prevalence of endocarditis in patients with community-acquired
SAB was 21% (43/206), 12% (11/95) in hemodialysis patients, and 5%
(10/204) in patients with hospital-acquired SAB. ^46^

A prospective study of 104 patients examined the role of persistent
bacteremia in predicting secondary metastatic infections. Fifty-three
patients had negative blood cultures between 24-48 hours after effective
therapy and 51 had sustained bacteremia. Metastatic infections developed
in 59% of patients with sustained bacteremia versus 17% in those without
sustained bacteremia. ^46^ This data indicates that the occurrence of
metastatic disease after some initial period on therapy may be an
indicator of a less effective therapy.

### Length of Therapy

Decisions regarding the length of therapy usually depend on the extent
of disease and on host risk factors. Patients with complicated
infections such as IE, deep tissue abscesses, and infected prosthetic
devices usually receive a minimum of 4-6 weeks of intravenous therapy
and surgical intervention as clinically indicated. ^41^ Appropriate
length of therapy for patients with uncomplicated SAB, especially those
associated with intravascular catheters is still unclear. Some
investigators have proposed that a 14-day course of therapy will
suffice. ^47^ Other investigators have proposed longer length of therapy
based upon the finding of increased complication rates in patients
treated with short-course therapy. ^48^ The Infectious Diseases Society
of America (IDSA), the American College of Critical Care Medicine (for
the Society of Critical Care Medicine), and the Society for Healthcare
Epidemiology of America have issued recommendations for the management
and diagnosis of catheter-related infections. ^7^

For the purposes of clinical trials, it would be important to
standardize the length of treatment for various clinical presentations.
In this way, one can compare patients with similar clinical
presentations across arms of the trial. If length of therapy is not
standardized, more patients in one arm of the trial may receive longer
duration of therapy than the other arm for the same clinical
presentation. Any differences in outcome in this setting may be related
to differences in length of therapy rather than inherent differences
between the drugs.

### Outcomes

About one third of patients with SAB develop one or more metastatic
complications. ^37,\ 38^ Acute systemic complications such as septic
shock, acute respiratory distress syndrome (ARDS), and disseminated
intravascular coagulation (DIC) occur most commonly within 48 hours of
an initial positive blood culture. Higher complication rates have been
reported by others; 90% of 113 South African patients with
community-acquired SAB and no history of injection drug use had one or
more complications. ^31^

In the study by Verhagen et al., 35% of patients with SAB developed
complications. Twelve percent of patients had a relapse within 3 months
of follow up. ^26^ Similar relapse rates have been reported by others.
^23,\ 38^ Eradication of the focus of infection is associated with lower
recurrence rates. ^23^ Failure to remove an intravascular device was the
most important risk factor for treatment failure in one study. ^38^ Some
studies have reported that relapse rates are higher in patients with
persistent bacteremia ≥3 days, failure to remove the source, and
vancomycin therapy. ^49^ However, other studies with vancomycin show
similar success rates to patients treated with anti-staphylococcal
penicillins.

Reported mortality rates in studies have ranged from 16%-43%. ^50^
Studies have differed in the patient populations included, definitions
of mortality and sample sizes. Mortality is highest in the first 30 days
after onset of bacteremia; 83-90% of patients died within 28-30 after
onset of bacteremia. ^30,\ 51^ Factors associated with increased
mortality include acute severity of illness at onset of SAB, unknown
source of infection, and older age. ^30,31,52,53^ The mortality rate for
patients with eradicable foci is lower than if the focus is
non-eradicable. ^23^ Kim et al. showed that mortality in patients with
non-eradicated foci was higher than in those with eradicated foci \[OR
4.17 (1.09-3.62)\]. ^51^

# V. Issues in Describing an Indication and Designing/Analyzing Clinical Trials in PBSA

There are several issues prompting the Agency to seek the advice of
Committee members in determining whether PBSA should be designated as a
separate indication. The first of these is the importance of studying
this indication in providing information to prescribing physicians and
their patients. Based on comments at the April 2004 Workshop,
academicians and drug sponsors indicated that data from clinical trials
in PBSA may provide information on efficacy and safety of an
antimicrobial in a more serious yet relatively common disease and
address some of the challenges in studying CRBSI. Data from PBSA trials
may provide information on CRBSI due to *S. aureus* as well as provide
information on treatment of IE.

Secondly, FDA will ask the committee to discuss what kinds of in vitro,
animal model data, and prior clinical trials in other serious infections
(e.g., pneumonia, complicated skin) would be recommended prior to, or in
some circumstances concurrent with, trials in PBSA. Ideally, a more
comprehensive clinical development program would include evidence from
treatment of patients with serious Staph aureus infections in other
indications (e.g., pneumonia, complicated skin, etc.) including some
bacteremic patients.

Finally, FDA would like the Committee to discuss is the ideal, yet
practical, clinical trial design for PBSA. How best would investigators
exclude patients with a known primary focus of infection due to *S.
aureus?* When would investigators perform evaluations of patients with
echocardiography to determine which patients may have endocarditis? FDA
will ask the Committee to discuss appropriate comparator regimens, as
well as clinical and microbiologic endpoints.

In this document, we have included discussion points for both primary
bacteremia due to *S. aureus* and catheter related bloodstream
infections. At the Advisory meeting, you will be provided with an
integrated set of questions so that both topics can be discussed at the
same time.

# Issues for discussion- PBSA

1.  Would data from clinical trials in patients with primary bacteremia
    due to *S. aureus* provide useful information for clinicians? Should
    PBSA be designated as a separate indication?

2.  Are there additional preclinical studies (e.g., animal models of
    endocarditis) that would be recommended prior to initiation of
    clinical trials in patients with PBSA?

3.  What results from other clinical trials (e.g., pneumonia,
    complicated skin infections) would, in general, be expected prior to
    proceeding with clinical trials in PBSA?

4\. How would one define PBSA in terms of both clinical findings at
enrollment as well as positive blood cultures to ensure the specificity
of the diagnosis? What kind of standard evaluation should patients
receive prior to enrollment to rule out a known source of infection?
What kind of evaluation should patients receive to rule out
endocarditis?

5\. How would one differentiate occult sites of infection in the
bacteremic patient that may be present at time of enrollment from
bacteremic patients who develop site specific lesions (e.g., heart
valve, bone) while on therapy?

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